The frequency of celiac disease in patients with juvenil idiopathic arthritis
Abstract:
Objectives: We aimed to assess the frequency of celiac disease (CD) in patients with juvenil idiopathic arthritis (JIA).
Methods: This prospective study was carried out from October 2015 to August 2016 and included 96 patients with JIA. We used 85 age- and sex-matched healthy subjects as a control group. Patients were evaluated in terms of clinical and laboratory findings of CD. Levels of total IgA and tissue transglutaminase (tTG) IgA antibody were measured in both patients and control groups. Those with increased level of tTG IgA were tested for anti-endomysium IgA antibodies (EMA). Gastroduodenoscopy and intestinal biopsy were planned for a definite diagnosis of CD in patients with positive EMA.
Results: Of the 96 patients in this study, 56 (58.3%) were female, and 40 (41.7%) were male. The mean age and weight was 11.58±4.59 years and 38.69±15.53 kg, respectively. 34 of our patients (35.4%) had oligoarticular form of JIA, 29 (30.2%) had polyarticular form, 12 (12.5%) had enthesitis-related arthritis (ERA) form, 11 (11.5%) had systemic form, and 10 (10.4%) psoriatic form. 16 of our patients (16.6%) were not using any drugs during the study. No patients were positive for tTG IgA, so EMA IgA antibodies were not analysed in any of patients, and also gastro-duodenoscopy was not performed. In the control group: 50 subjects (58.8%) were female and 35 (41.2%) were male. Only one subject from the control group was positive for tTG IgA but EMA positivity was not detected.
Conclusion: We did not find CD in children with JIA. According to our results, we think that there is no relationship between celiac disease and JIA disease in children. Larger studies are needed to provide healthier interpretation.
Key words: juvenil idiopathic arthritis, celiac disease, children
Introduction
Juvenile idiopathic arthritis (JIA) is exclusion diagnosis applied to any arthritis of unknown etiology that begin before the age of 16 and persist for more than 6 weeks (1).
The subgroups of JIA include oligoarthritis (40%), entesit-related arthritis (ERA) (15%), systemic arthritis (14%), polyarthritis (14%), psoriatic arthritis (14%), and other types of arthritis (16%). All subgroups have different phenotype, clinical symptoms, and prognosis (2). Approximately one in every 1000 children in the world suffer from JIA (3). Juvenile idiopathic arthritis is a chronic rheumatic disease in childhood, and is a prominent cause of short- and long-term disability (4).
Celiac disease (CD), is an immune-mediated systemic disease triggered by gluten intake in genetically susceptible individuals (5). The prevalence of CD is estimated to be 0.5-1% in different parts of the world. However, the developing risk of celiac disease is higher in diabetes, autoimmune disorders, and relatives of celiac patients because they share the same HLA types (6).
Celiac patients may present with gastrointestinal symptoms, extraintestinal symptoms or also without symptoms. Approximately 50% of celiac patients present extraintestinal or atypical symptoms such as anemia, osteoporosis, dermatitis herpetiformis, arthritis, and dental enamel hypoplasia (7). It has been reported that prevalence of arthritis was found to be 26% in Italian celiac patients (8).
Juvenile idiopathic arthritis is characterized by chronic arthritis, and autoimmune etiology. A gene locus 4q27 related with rheumatoid arthritis, psoriatic arthritis, and celiac disease is associated with susceptibility to JIA (9).
Patients with JIA may present with significant gastrointestinal symptoms, and growth failure. Medications or the disease itself may cause many of these complications, further other possibility including primary gastrointestinal diseases should also be considered. It has been reported that there is an association between celiac disease and different rheumatic diseases (10-12).
It has been reported that several patients with JIA had been diagnosed with celiac disease (13-15). However, the number of prospective study investigating the prevalence of celiac disease is limited in children with JIA (16-20).
To our knowledge, there is no study investigating the incidence of CD in patients with JIA in our country. We aimed to evaluate the frequency of CD in children with JIA.
Material-methods
Patients selection:
This prospective study was carried out between October 2015 to August 2016. 96 patients with JIA were included randomly. All patients were diagnosed according to International League of Associations for Rheumatology (ILAR) diagnostic criteria for JIA (21). Patients with coincidental disease, and refused to participate the study were excluded from the study. All included patients were followed-up for at least 6 months at our clinic.
Study Design:
A total of 96 children with JIA, followed-up at Department of Pediatric Rheumatology at Cerrahpasa Medical School (Istanbul University), were randomized for the study. We used 85 age- and sex-matched healthy kids as a control group. The study protocol was approved by the Institutional Review Board at the Istanbul University, Cerrahpasa Medical School (313624 / 06 October 2015). An informed written consent has been obtained from healthy children, patients and their parents prior to the study. Patients were evaluated in terms of clinical and laboratory findings of CD. Venous blood samples were collected from the patients and controls. Each sample was divided into aliquots and samples were stored at -80°C until analysis.
Immunoturbidimetric method (Roche Diagnostics GmbH, Mannheim, Germany) was used for determination of total IgA and ELISA was performed in order to assess the tTG IgA (Catalog No. 3503, Aesku Diagnostics Gmbh, Wendelsheim, Germany).
The cut-off value for tTG IgA was 12 U/ml. Patients with positive tTG IgA results were planned to be analysed for EMA IgA which is performed by IFA technique (Inova Diagnostics, Inc. Lübeck, Germany) at the “Duzen Laboratory Group” in Istanbul, Turkey. Gastroduodenoscopy and small intestinal biopsy were planned to perform on patients with positive EMA antibodies for a definitive diagnosis of the celiac disease.
Statistical analysis: Statistical analysis was performed using SPSS software version 13.0 (SPAA Inc, Chicago IL, USA). Frequency, percentage, and mean ± standard deviation (SD) were used as descriptive statistics. The relationships between categorical variables were analyzed by chi-square test. P value was considered statistically significant as a <0.05.
Results:
Of the 96 patients in our study, 34 (35.4%) had oligoarticular form of JIA, 29 (30.2%) had polyarticular form, 12 (12.5%) had ERA form, 11 (11.5%) had systemic form, and 10 (10.4%) had psoriatic form. 15 (15.6%) of our patients were being treated with etanercept, 14 (14.6%) were receiving methotrexate, while other patients were receiving NSAIDs, corticosteroids and/or immunosuppressive therapy, and 16 (16.6%) were receiving no therapy at the time of the study.
56 (58.3%) of our patients were female, and 40 (41.7%) were male. The mean age, height and, weight of patients were 11.58±4.59 years, 143.18±22.60 cm, and 38.69±15.53 kg, respectively (Table I). No IgA deficiency was detected in patients group. No patients were positive for tTG IgA, so EMA IgA antibodies were not analysed, and also gastro-duodenoscopy was not performed.
In the control group, 50 subjects (58.8%) were female and 35 (41.2%) were male. The mean age, and weight were 11.31±4.54 years, and 38.42±15.53 kg, respectively (Table I). tTG IgA positivity was detected in only one patient, but EMA IgA positivity was not detected.
Discussion
Due to the use of serologic tests, the prevalence of CD has increased dramatically in the last 20 years. Symptomatic patients represent only 10% of celiac patients. Even if the screening for CD is recommended at high risk groups, usually a majority of asymptomatic patients remains undiagnosed (22).
It can be difficult to diagnose CD in systemic rheumatic diseases because they are often associated with a number of gastrointestinal symptoms and diseases (23). Lymphocyte cytotoxicity may be abnormally increased in the intestinal mucosa of patients with JIA, and this can cause similar clinical symptoms in CD (24).
Antibodies associated with JIA are common in celiac patients and their first-degree relatives, this also indicates a common genetic predisposition (25).
Highly specific and sensitive tests have modified the approach to diagnosis of CD. It has been shown that both EMA IgA and tTG IgA are highly specific and sensitive in the diagnosis of CD (26). European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) suggests tTG IgA and IgA tests for initial screening of CD. If tTG IgA positivity is detected, EMA IgA test should be analysed. The small intestinal biopsy is suggested in patients with EMA positivity (5). In patients with IgA deficiency, tTG IgG and EMA IgG are helpful to make a decision for small intestinal biopsy (27). When EMA and tTG are used in combination, they have a sensitivity and specificity of 95% (28).
The prevalence of CD was found to be 0-6.6% in patients with JIA in retrospective and prospective studies (16-20,29-31).
In Francis et al. (29) study, CD was diagnosed in one of 160 patients (0.63%), and this prevalence is similar to that of general population.
Stagi et al. (30) investigated the incidence of celiac disease in 151 patients with JIA. Of the 151 patients, 92 had oligoarticular form of JIA, 49 had polyarticular form, and 10 had systemic form. AGA, tTG, and EMA tests were analysed in all patients. Gastroduodenoscopy was performed to patients with any test positivity. Ten (6.6%) patients were diagnosed with CD, seven of them had oligoarticular form of JIA, and three of them had polyarticular form. In this retrospective study, the frequency of CD was found seven times more than control group, and it was shown that patients with JIA had higher prevalence of celiac disease.
In an another study, 119 patients with JIA (87 female) who had a mean age of 11.5 years were included (17). All patients were treated in one of two pediatric rheumatology centers. Of 119 patients, 65 had pauciarticular form of JIA, 43 had polyarticular form, and 11 had systemic form. 62 patients of them were receiving NSAIDs, 29 were receiving steroids and/or immunosuppressants, and 28 were receiving no therapy during the study. EMA positivity was detected in four of the patients, intestinal biopsy was performed on them, and three (2.5%) of them were diagnosed with CD. One of them had polyarticular form of JIA, one of them had pauciarticular form, and one of them had systemic form. No IgA deficiency was detected. After gluten-free diet, first patient had rapid remission, anti-inflammatory drugs were gradually tapered off, and the dose of immunosuppressive drug was reduced. The second patient benefited little, and no benefit was seen in the third patient. The prevalence of CD was found 7-fold in patients with JIA, according to these results systemic screening of CD has been recommended in all patients with JIA (17).
In an another study, the prevalence of CD was investigated in autoimmune rheumatic diseases, AGA, EMA and tTG tests were analysed in all patients, and no positivity was detected in 32 patients with JIA (16).
In Stoll et al. (18) study, total IgA and tTG IgA tests were analysed in 42 patients with JIA. It has been shown that there was no correlation in terms of tTG IgA levels between patients taking NSAIDs or any other medication. IgA deficiency was detected in only one patient. Two patients were referred to gastroenterology clinic, but one of them had admitted. Gastroduodenoscopy was performed on this patient, and the pathology was determined normal.
In a retrospective study including 417 patients with JIA, three patients (0.7%) were diagnosed with CD (31). Three patients had also polyarticular form of JIA, and one of them had been diagnosed with CD before the diagnosis of JIA. All patients diagnosed with CD were receiving methotrexate and intra-articular glucocorticoid injections occasionally. It has been shown that gluten-free diet had no effect on arthritis in patients diagnosed with CD.
A 13-year follow-up study including 108 children with JIA was carried out between 1992 and 2004 (19). At the diagnosis of JIA and thereafter every year, patients were evaluated for CD by tTG and EMA tests since 1998. As EMA and/or tTG was found positive, after 4 months one more test was also analysed, intestinal biopsy was performed on patients with two consecutive positive tests for the definitive diagnosis of CD. One patient had been diagnosed with CD before the diagnosis of JIA. The mean age at JIA diagnosis in other 107 JIA patients was 5.7 years. 70 of them had oligoarticular form of JIA, 24 had polyarticular form, and 13 systemic form. The mean follow-up period of patients was 5.5 years (50 days to 12.3 years). When JIA was diagnosed, EMA tests were negative in all of the patients but tTG was found positive in only one patient. The next test of this patient was found to be negative. However, consecutive tests were detected positive in two cases 3.5 and 4.6 years after the diagnosis of JIA, respectively. The small intestinal biopsy was performed, and so CD was diagnosed. Both of the patients had no clinical symptoms of CD. After a gluten free diet, improvement of JIA symptoms has been shown. In this study, the prevalence of CD at the diagnosis of JIA was found to be 0.9%, and 2.8% at the end of study. The limitation of this study was a lack of control group. The systematic screening of CD might help in early CD diagnosis in patients with JIA. However, extensive screening programs may have higher costs, in other words screening might be done in patients with HLA-DQ2/DQ8 positivity.
In an another study including 42 patients with JIA (24 female), it was observed that 36 of them had either gastrointestinal symptoms or growth failure (20). AGA, EMA, and reticulin tests were evaluated in all patients, small intestinal biopsy was performed on patients with any positive tests. Serologic tests were positive in 18 patients, 10 of them had systemic form of JIA, five had polyarticular form, and three had pauciarticular form. Intestinal biopsy was performed on 16 patients, and only one (2.38%) patient with EMA positivity was diagnosed with CD. Two patients had EMA positivity with gastrointestinal symptoms and/or growth failure. Also, these patients had mild focal intestinal villous atrophy. Authors suggest that after a follow-up period, re-biopsy may confirm the diagnosis of CD, and the prevalence of CD may be increased up to 7% (20). In this study, it is suggested that screening for silent CD may be useful in children with JIA.
The limitations of most of the studies are inadequate number of patients, the lack of healthy control group, use of the different criteria for the diagnosis of CD, and being retrospective.
Our study was carried out according to ESPGHAN criteria in 2012. No tTG IgA positivity was found in any patients in our study including 96 patients, therefore EMA IgA antibody was not analysed, and gastroduodenoscopy was not performed. As compatible with previous study, there was also no difference in terms of tTG levels between the patients using NSAIDs or other drugs in our study (18). In the control group, tTG positivity was found in only one patient, but EMA positivity was not found, so CD was not detected. As consistent with previous studies we found no CD in children with JIA, but the number of our patients is approximately three times higher than that of studies (16,18).
To conclude, according to our results we believe that there is no relation between CD and JIA, but larger studies are needed to provide healthier interpretation.
References
1. Prakken B, Albani S, Martini A. Juvenile idiopathic arthritis. Lancet 2011; 377: 2138-49.
2. Minden K, Niewerth M, Listing J, Biedermann T, Schöntube M, Zink A. Burden and cost of illness in patients with juvenile idiopathic arthritis. Ann Rheum Dis 2004; 63: 836-42.
3. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I Arthritis Rheum 2008; 58: 15-25.
4. Weis JE, Ilowite NT. Juvenile idiopathic arthritis. Rheum Dis Clin North Am 2007; 33: 441-70.
5. Husby S, Koletzko S, Korponay-Szabo IR, et al. ESPGHAN guidelines for the diagnosis celiac disease in children and adolescents: an evidence-based approach. J Pediatr Gastroenterol Nutr 2012; 54: 136-60.
6. Gujral, N, Freeman HJ, Thomson ABR. Celiac disease: Prevalence, diaggnosis, pathogenesis and treatment. World J Gastroenterol 2012; 18: 6036-59.
7. Rampertab SD, Pooran N, Brar P, Singh P, Green PH. Trends in the presentation of celiac disease. Am J Med 2006; 119: 355.e9-14.
8. Lubrano E, Ciacci C, Ames PR, Mazzacca G, Oriente P, Scarpa R. The arthritis of coeliac disease: prevalence and pattern in 200 adult patients. Br J Rheumatol 1996; 35: 1314-8.
9. Albers HM, Kurreeman FA, Stoeken-Rijsbergen G, et al. Association of the autoimmunity locus 4q27 with juvenile idiopathic arthritis. Arthritis Rheum 2009; 60: 901-4.
10. Collin P, Maki M. Associated disorders in celiac disease: clinical aspects. Scan Gastroenterol 1994; 29: 769-75.
11. Buderus S, Wagner N, Lentze M. Concurrence of celiac disease and juvenile dermatomyositis; result of a spesific immunogenetic susceptibility? J Pediatr Gastroenterol Nutr 1997; 25: 101-3.
12. Collin P, Korpela M, Hallstrom O, Viander M, Keyrilainen O, Maki M. Rheumatic complaints as presenting symptom in patients with coeliac disease. Scand J Rheumatol 1992; 21: 20-3.
13. Maki M, Hallstrom O, Verronen P, et al. Reticulin antibody, arthritis, and coeliac disease in children. Lancet 1988; 1: 479-80.
14. Pinals RS. Arthritis associated with gluten-sensitive enteropathy. J Rheumatol 1986; 13: 201-4.
15. Michelin CM, Aikawa NE, Diniz JC, Jesus AA, Koda YK, Silva CA. Association of systemic-onset juvenile idiopathic arthritis and celiac disease – a case report. Acta Reumatol Port 2011; 36: 404-7.
16. Koehne Vde B, Bahia M, Lanna CC, Pinto MR, Bambirra EA, Cunha AS. Prevalence of serological markers for celiac disease (IgA and IgG class antigliadin antibodies and IgA class antiendomysium antibodies) in patients with autoimmune rheumatologic diseases in Belo Horizonte, MG, Brazil. Arq Gastroenterol 2010; 47: 250-6.
17. Lepore L, Martelossi S, Pennesi M, et al. Prevalence of celiac disease in patients with juvenile chronic arthritis. J Pediatr 1996; 129: 311-3.
18. Stoll ML, Patel AS, Christadoss ML, Punaro M, Olsen NJ. IgA transglutaminase levels in children with Juvenile Idiopathic Arthritis. Ann Paediatr Rheumatol 2012; 1: 31-5.
19. Alpigiani MG, Haupt R, Parodi S, Calcagno A, Poggi E, Lorini R. Coeliac disease in 108 patients with juvenile idiopathic arthritis: a 13-year follow-up study. Clin Exp Rheumatol 2008; 26: 162.
20. Al-Mayouf SM, Al-Mehaidib AI, Alkaff MA. The significance of elevated serologic markers of celiac disease in children with juvenile rheumatoid arthritis. Saudi J Gastroenterol 2003; 9: 75-8.
21. Petty RE, Southwood TR, Baum J, et al. Revision of the proposed classification for juvenile idiopathic arthritis: Durban 1997. J Rheumatol 1998; 25: 1991-4
22. Garnier-Lengline H, Cerf-Bensussan N, Ruemmele FM. Celiac disease in children. Clin Res Hepatol Gastroenterol 2015; 39: 544-51.
23. Luft LM, Barr SG, Martin LO, Chan EK, Fritzler MJ. Autoantibodies to tissue transglutaminase in Sjögren’s syndrome and related rheumatic diseases. J Rheumatol 2003; 30: 2613-9.
24. Arvonen M, Ikni L, Augustin M, Karttunen TJ, Vähäsalo P. Increase of duodenal and ileal mucosal cytotoxic lymphocytes in juvenile idiopathic arthritis. Clin Exp Rheumatol 2010; 28: 128-34.
25. Neuhausen SL, Steele L, Ryan S, et al. Co-occurrence of celiac disease and other autoimmune diseases in celiacs and their first-degree relatives. J Autoimmun 2008; 31: 160-5.
26. Giersiepen K, Lelgemann M, Stuhldreher N, et al.; ESPGHAN Working Group on Coeliac Disease Diagnosis. Accuracy of diagnostic antibody tests for coeliac disease in children: summary of an evidence report. J Pediatr Gastroenterol Nutr 2012; 54: 229-41.
27. Murch S, Jenkins H, Auth M, et al.; BSPGHAN. Joint BSPGHAN and Coeliac UK guidelines for the diagnosis and management of coeliac disease in children. Arch Dis Child 2013; 98: 806-11.
28. Hill ID. What are the sensitivity and specificity of serologic tests for celiac disease? Do sensitivity and specificity vary in different populations? Gastroenterology 2005; 128: S25-32.
29. Francis J, Carty JE, Scott BB. The prevalence of celiac disease in rheumatoid arthritis. Eur J Gastroenterol Hepatol 2002; 14: 1355-6.
30. Stagi S, Giani T, Simonini G, Falcini F. Thyroid function, autoimmune thyroiditis and coeliac disease in juvenile idiopathic arthritis. Rheumatology 2005; 44: 517-20.
31. Pohjankoski H, Kautiainen H, Kotaniemi K, Korppi M, Savolainen A. Autoimmune diseases in children with juvenile idiopathic arthritis. Scand J Rheumatol 2010; 39: 435-6.
Table
Table I. Demographic and laboratory characteristics of patients and healthy controls
Patients Healthy controls p
(n=96) (n=85)
Mean±SD Mean±SD
Age (yrs) 11,58±4,59 11,31±4,51 0.694
Height (cm) 143,18±22,60 141,86±22,69 0.696
Weight (kg) 38,69±15,53 38,42±15,53 0.907
Hemoglobine (mg/dL) 12,44±1,33 12,80±1,47 0.095
MCV 81,61±5,10 80,26±4,36 0.055
Plt (/mm3) 307,41±91,63 285,33±75,33 0.074
tTG IgA (U/ml) 1,04±1.42 1,55±2.44 0.097
Total IgA (mg/dl) 153,95±77,24 134,96±59,76 0.065
Age at diagnosis (yrs) 6,44±4,17 – –
Plt=thrombocytes, MCV= mean corpuscular volume, tTG=tissue transglutaminase