Image description

Published yearly: 

4 Issues


ISSN: 2320-964X (Online) 

ISSN: 2320-7817  (Print)



Dr. Santosh Pawar 




Int. Journal of Life Sciences, 2017; 5(2): 141- 150    |    Available online, June 27, 2017

Deciphering the association of celiac disease and other comorbidities in patients with rheumatoid arthritis using systems and clinical medicine approaches

Sami Bahlas MD1#, Ibtisam M Jali1, Laila Abdullah Damiati M. Sc2#, Nadia Dandachi MBBS1,

Hesham Sait MBBS1 and Peter Natesan Pushparaj PhD3



1Department of Internal Medicine, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia   |    2University of Jeddah, Jeddah, Kingdom of Saudi Arabia   3Center of Excellence in Genomic Medicine Research, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia

*Corresponding Author(s)

Dr. Peter Natesan Pushparaj PhD, Center of Excellence in Genomic Medicine Research (P.O.Box: 80216), Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah-21589 , Kingdom of Saudi Arabia

Email: or  | Mobile: +966557869423

Prof. Sami Bahlas MD, Department of Internal Medicine, Faculty of Medicine, King Abdulaziz University Hospital, Jeddah , Kingdom of Saudi Arabia | Email:    | Mobile:+966505625857

#Authors contributed equally in this work

Received: 31.03.2017    |     Accepted: 23.06.2017    |      Published :27.06.2017

In this study, we decipher the association of celiac disease (CD) and other comorbidities in patients with rheumatoid arthritis (RA) using key clinical risk factors and systems medicine approaches for the differential diagnosis and personalized treatment.

In the systems medicine approach, we have used the Ingenuity Pathway Analysis knowledgebase (IPA, Qiagen, USA) to decipher the upstream regulators of the disease, canonical pathways, molecular networks and disease specific pathways commonly shared in RA and CD. Besides, eighty-two RA patients who have satisfied “American College of Rheumatology (ACR)” classification criteria for RA and 20 healthy volunteers were participated. RA patients with CD were identified based on serum levels of immunoglobulin A (IgA) autoantibodies to tissue transglutaminase (tTG-IgA). Besides, clinical parameters such as fasting blood sugar (FBS) and glycosylated hemoglobin A1C (HbA1C) were measured to assess the diabetic state. Clinical parameters such as erythrocyte sedimentation rate (ESR), rheumatoid factor (RF), C-reactive protein (CRP), mean cell volume (MCV), mutated citrullinated vimentin antibodies (anti-MCV), white blood count (WBC), albumin, calcium (Ca2+) and vitamin D3 (VitD3) were analyzed in healthy volunteers, RA, and RA with CD cohorts respectively.

Systems medicine analyses showed that both RA and CD strongly associated with diabetes mellitus. Furthermore, clinical analyses indicate that FBS, HbA1C, Anti-MCV, RF, CRP and tTG-IgA concentrations were significantly increased in both RA and RA with CD cohorts than healthy controls. tTG-IgA levels were significantly elevated in RA with CD cohorts compared with RA. On the other hand, anti-MCV levels were significantly increased in RA compared to RA with CD group. Besides, both RA and RA with CD cohorts have significantly reduced levels of VitD3 and Albumin in the serum compared with healthy controls.

In conclusion, the RA and RA with CD cohorts have poor glycemic rheostat compared to healthy controls. Higher serum tTG-IgA levels in these cohorts indicate the susceptibility of RA patients to develop CD. The reduction in serum VitD3 levels in both RA and RA with CD cohorts further worsens disease prognosis. The systems medicine and clinical analyses, therefore, showed the potential association of diabetes mellitus (DM) and CD in RA patients.  


Key words: Rheumatoid Arthritis, Diabetes Mellitus, Celiac Disease, Immunoglobulin A, Tissue Transglutaminase, Fasting Blood Sugar, Vitamin D3, Personalized Treatment.


Editor: Dr. Arvind Chavhan


Cite this article as:

Sami Bahlas, Laila Abdullah Damiati, Nadia Dandachi, Hesham Sait, Peter Natesan Pushparaj (2017) Deciphering the association of celiac disease and other comorbidities in patients with rheumatoid arthritis using systems and clinical medicine approaches, International J. of Life Sciences, 5  (2): 141-150.



Prof.Sami Bahlas is currently supported by DSR small grants. Dr.Peter Natesan Pushparaj is funded by the King Abdulaziz City of Science and Technology (KACST) Strategic Grants (KACST 12-BIO2719-03 & 12-BIO2267-03). We thank all the patients and healthy volunteers for their participation in this study.


Conflicts of interest: The authors stated that no conflicts of interest.



Copyright: © 2017 | Author(s), This is an open access article under the terms of the Creative Commons Attribution-Non-Commercial - No Derivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.


Ahlstrom S, Gedda PO, Hedberg H (1956) Disappearance of radioactive serum albumin from joints in rheumatoid arthritis. Acta Rheumatol Scand.;2(3):129-36.

Arnett FC, Edworthy SM, Bloch DA, et al. (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum,;31(3):315-24.

Bang H, Egerer K, Gauliard A, et al. (2007) Mutation and citrullination modifies vimentin to a novel autoantigen for rheumatoid arthritis. Arthritis Rheum.;56(8):2503-11.

Barrot A, Dupuy AM, Badiou S, Bargnoux AS, Cristol JP (2012) Evaluation of three turbidimetric assays for automated determination of hemoglobin A1c. Clin Lab. 2012;58(11-12):1171-7.

Billett HH. Hemoglobin and Hematocrit. In: Walker HK, Hall WD, Hurst JW, eds. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd ed. Boston1990.

Biswas S, Manikandan J, Pushparaj PN (2011) Decoding the differential biomarkers of Rheumatoid arthritis and Osteoarthritis: A functional genomics paradigm to design disease specific therapeutics. Bioinformation; 6(4):153-7.

Chapoteau E, Czech BP, Zazulak W, Kumar A (1993) New reagent for colorimetric assay of calcium in serum. Clin Chem.;39(9):1820-4.

Chen J, Liu W, Lin Q, Chen L, Yin J, Huang H (2014) Vitamin D deficiency and low bone mineral density in native Chinese rheumatoid arthritis patients. Int J Rheum Dis.;17(1):66-70.

Choudhry AA, S GR, Gururaja A, Prabhu K (2014) Correlation of Plasma Lipid Profile with Salivary Oxidative Stress Markers in Type II Diabetes Mellitus Patients. J Clin Diagn Res.;8(6):CC08-10.

De Maddi F, Pellegrini F, Raffaele CG, Tarantino G, Rigante D (2013) Celiac disease and juvenile idiopathic arthritis: a still enigmatic crossover. Scand J Gastroenterol.; 48(4):511-2.

Decavele AS, Fiers T, Penders J, Delanghe JR (2012) A sensitive quantitative test strip based point-of-care albuminuria screening assay. Clin Chem Lab Med.;50(4):673-8.

Dehghan A, Rahimpour S, Soleymani-Salehabadi H, Owlia MB (2014) Role of vitamin D in flare ups of rheumatoid arthritis. Z Rheumatol.;73(5):461-4.

Duerksen DR, Ali M, Leslie WD (2012) Dramatic effect of vitamin D supplementation and a gluten-free diet on bone mineral density in a patient with celiac disease. J Clin Densitom.;15(1):120-3.

Dzhambazov B, Lindh I, Engstrom A, Holmdahl R (2009) Tissue transglutaminase enhances collagen type II-induced arthritis and modifies the immunodominant T-cell epitope CII260-270. Eur J Immunol. Sep;39(9):2412-2423.

Evron E, Abarbanel JM, Branski D, Sthoeger ZM (1996) Polymyositis, arthritis, and proteinuria in a patient with adult celiac disease. J Rheumatol.;23(4):782-3.

Ferraz-Amaro I, Garcia-Dopico JA, Medina-Vega L, Gonzalez-Gay MA, Diaz-Gonzalez F (2013) Impaired beta cell function is present in nondiabetic rheumatoid arthritis patients. Arthritis Res Ther.;15(1):R17.

Ferraz-Amaro I, Gonzalez-Juanatey C, Lopez-Mejias R, Riancho-Zarrabeitia L, Gonzalez-Gay MA (2013) Metabolic syndrome in rheumatoid arthritis. Mediators Inflamm.; 710928.

Furuya T (2011) [Bone and calcium metabolism in patients with rheumatoid arthritis]. Clin Calcium.;21(9):1369-75.

Gonzalez-Lopez L, Rocha-Munoz AD, Ponce-Guarneros M, et al. (2014) Anti-cyclic citrullinated peptide (anti-CCP) and anti-mutated citrullinated vimentin (anti-MCV) relation with extra-articular manifestations in rheumatoid arthritis. J Immunol Res.;2014:536050.

Green PH, Cellier C (2007) Celiac disease. N Engl J Med.; 357(17):1731-43.

Grey V, Perlas M, Aebi C (1996) Immunoturbidimetric method for determination hemoglobin A1c. Clin Chem.;42(12):2046-7.

Gutierrez-Achury J, Coutinho de Almeida R, Wijmenga C (2011) Shared genetics in coeliac disease and other immune-mediated diseases. J Intern Med.;269(6):591-603.

Hallert C, Grant C, Grehn S, et al. (2002) Evidence of poor vitamin status in coeliac patients on a gluten-free diet for 10 years. Aliment Pharmacol Ther.;16(7):1333-9.

Hansen KE, Bartels CM, Gangnon RE, Jones AN, Gogineni J (2014) An evaluation of high-dose vitamin D for rheumatoid arthritis. J Clin Rheumatol.;20(2):112-4.

Hochberg MC, Chang RW, Dwosh I, Lindsey S, Pincus T, Wolfe F (1992) The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum.;35 (5) :498-502.

Hoffmanova I and Andel M (2014) Osteoporosis and bone alterations in celiac disease in adults]. Vnitr Lek.;60(7-8):601-6.

Hogg-Kollars S, Al Dulaimi D, Tait K, Rostami K (2014) Type 1 diabetes mellitus and gluten induced disorders. Gastroenterol Hepatol Bed Bench. Fall;7(4):189-97.

Kang HP, Scott MG, Joe BN, Narra V, Heiken J, Parvin CA (2004) Model for predicting the impact of gadolinium on plasma calcium measured by the o-cresolphthalein method. Clin Chem.;50(4):741-6.

Kemppainen T, Kroger H, Janatuinen E, et al. (1999) Osteoporosis in adult patients with celiac disease. Bone.;24(3):249-55.

Keshgegian AA, Straub CW, Loos EF, Grenoble BK. (1994)  Rheumatoid factor measured with the QM300 nephelometer: clinical sensitivity and specificity. Clin Chem.;40(6):943.

Larizza D, Calcaterra V, Klersy C, et al. (2012) Common immunogenetic profile in children with multiple autoimmune diseases: the signature of HLA-DQ pleiotropic genes. Autoimmunity.;45(6):470-5.

Lauret E, Rodrigo L (2013) Celiac disease and autoimmune-associated conditions. Biomed Res Int., 127589.

Lawrence RC, Helmick CG, Arnett FC, et al. (1998) Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis & Rheumatism.;41(5):778-99.

Lorentz K (1982) Improved determination of serum calcium with 2-cresolphthalein complexone. Clin Chim Acta.;126(3):327-34.

McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med.;365(23):2205-19.

Mendler MH, Corbinais S, Sapey T, et al. (1999) In patients with cirrhosis, serum albumin determination should be carried out by immunonephelometry rather than by protein electrophoresis. Eur J Gastroenterol Hepatol.;11(12):1405-11.

Meyer O (2004) Is the celiac disease model relevant to rheumatoid arthritis? Joint Bone Spine.;71(1):4-6.

Michelin CM, Aikawa NE, Diniz JC, Jesus AA, Koda YK, Silva CA (2011) Association of systemic-onset juvenile idiopathic arthritis and celiac disease - a case report. Acta Reumatol Port.;36(4):404-7.

Molteni N, Bardella MT, Vezzoli G, Pozzoli E, Bianchi P (1995) Intestinal calcium absorption as shown by stable strontium test in celiac disease before and after gluten-free diet. Am J Gastroenterol.;90(11):2025-8.

Mota Vargas R, Nevado L, Pijierro Amador A, Bureo Dacal JC (1996) Rheumatoid arthritis and celiac disease: a chance association?. An Med Interna.;13(5):252-3.

Nast A, Malysheva O, Krause A, Wahle M, Baerwald CG (2009) Intracellular calcium responses to cholinergic stimulation of lymphocytes from healthy donors and patients with rheumatoid arthritis. Rheumatol Int.;29(5):497-502.

Neuhausen SL, Steele L, Ryan S, et al. (2008) Co-occurrence of celiac disease and other autoimmune diseases in celiacs and their first-degree relatives. J Autoimmun. ;31(2):160-5.

Neve A, Corrado A, Cantatore FP (2014) Immunomodulatory effects of vitamin D in peripheral blood monocyte-derived macrophages from patients with rheumatoid arthritis. Clin Exp Med.;14(3):275-83.

Ojeda-Rivera J, Rosado Carrion B, Antommattei Frontera O, Bredy-Dominguez R (2012) Osteoporosis in celiac disease: a Hispanic pilot study. Bol Asoc Med P R.; 104(2):25-9.

Okada Y, Wu D, Trynka G, et al. (2014) Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature.;506(7488):376-81.

Orge E, Cefle A, Yazici A, Gurel-Polat N, Hulagu S (2010) The positivity of rheumatoid factor and anti-cyclic citrullinated peptide antibody in nonarthritic patients with chronic hepatitis C infection. Rheumatol Int.;30(4):485-8.

Paccou J, Boudot C, Renard C, et al. (2014) Total calcium-sensing receptor expression in circulating monocytes is increased in rheumatoid arthritis patients with severe coronary artery calcification. Arthritis Res Ther.;16(5):412.

Rashtak S, Murray JA (2007) Tailored testing for celiac disease. Ann Intern Med.;147(5):339-41.

Renger F, Bang H, Feist E, et al. (2010) Immediate determination of ACPA and rheumatoid factor--a novel point of care test for detection of anti-MCV antibodies and rheumatoid factor using a lateral-flow immunoassay. Arthritis Res Ther.;12(3):R120.

Riente L, Chimenti D, Pratesi F, et al. (2004) Antibodies to tissue transglutaminase and Saccharomyces cerevisiae in ankylosing spondylitis and psoriatic arthritis. J Rheumatol.;31(5):920-4.

Sangha O (2000) Epidemiology of rheumatic diseases. Rheumatology.;39(suppl 2):3-12.

Shakiba M, Iranmanesh MR (2013) Vitamin D requirement in pregnancy to prevent deficiency in neonates: a randomised trial. Singapore Med J.;54(5):285-8.

Shen PU, Blair JL (2006) Cholesterol crystals causing falsely elevated automated cell count. Am J Clin Pathol.; 125(3):358-63.

Shetlar MR, Payne RW, Stidworthy G, Mock D (1956) Absence of serum albumin associated with rheumatoid arthritis. Ann Intern Med.;51:1379-84.

Siemons L, Ten Klooster PM, Vonkeman HE, van Riel PL, Glas CA, van de Laar MA (2014) How age and sex affect the erythrocyte sedimentation rate and C-reactive protein in early rheumatoid arthritis. BMC Musculoskelet Disord.;15(1):368.

Smith JB, Haynes MK (2002) Rheumatoid arthritis: a molecular understanding. Annals of internal medicine.;136(12):908-22.

Swaminathan A, Lunt H, Chang WS, Logan FJ, Frampton CM, Florkowski CM (2013a) Impact of prandial status on the comparison of capillary glucose meter and venous plasma glucose measurements in healthy volunteers. Ann Clin Biochem.;50(Pt 1):6-12.

Swaminathan A, Lunt H, Frampton CM, Florkowski CM (2013b) What is the lower limit for postprandial venous plasma glucose in healthy young adults? Ann Clin Biochem.;50(Pt 6):614-7.

Tavakkoli A, DiGiacomo D, Green PH, Lebwohl B (2013) Vitamin D status and concomitant autoimmunity in celiac disease. J Clin Gastroenterol.;47(6):515-9.

Teichmann J, Voglau MJ, Lange U  (2010) Antibodies to human tissue transglutaminase and alterations of vitamin D metabolism in ankylosing spondylitis and psoriatic arthritis. Rheumatol Int.;30(12):1559-63.

Tillett WS, Francis T (1930) Serological Reactions in Pneumonia with a Non-Protein Somatic Fraction of Pneumococcus. J Exp Med.;52(4):561-71.

van der Windt DA, Jellema P, Mulder CJ, Kneepkens CM, van der Horst HE (2010) Diagnostic testing for celiac disease among patients with abdominal symptoms: a systematic review. JAMA.;303(17):1738-46.

Viljamaa M, Kaukinen K, Huhtala H, Kyronpalo S, Rasmussen M, Collin P (2005) Coeliac disease, autoimmune diseases and gluten exposure. Scand J Gastroenterol.;40(4):437-43.

Villanueva J, Maranda L, Nwosu BU (2012) Is vitamin D deficiency a feature of pediatric celiac disease? J Pediatr Endocrinol Metab.;25(5-6):607-10.

Vreugdenhil G, Wognum AW, van Eijk HG, Swaak AJ (1990) Anaemia in rheumatoid arthritis: the role of iron, vitamin B12, and folic acid deficiency, and erythropoietin responsiveness. Ann Rheum Dis.;49(2):93-8.

Westergren A (1957) Diagnostic tests: the erythrocyte sedimentation rate range and limitations of the technique. Triangle.;3(1):20-5.

Xun P, Liu K, Cao W, Sidney S, Williams OD, He K (2012) Fasting insulin level is positively associated with incidence of hypertension among American young adults: a 20-year follow-up study. Diabetes Care.;35(7):1532-7.

Zeman MN, Scott PJ (2012) Current imaging strategies in rheumatoid arthritis. Am J Nucl Med Mol Imaging.; 2(2):174-220.

Zhernakova A, Stahl EA, Trynka G, et al. (2011) Meta-analysis of genome-wide association studies in celiac disease and rheumatoid arthritis identifies fourteen non-HLA shared loci. PLoS Genet.;7(2):e1002004.

Zhernakova A, Withoff S, Wijmenga C (2013) Clinical implications of shared genetics and pathogenesis in autoimmune diseases. Nat Rev Endocrinol.;9(11):646-59.






    Origin & Evolution

    Print ISSN : 2320-7817 

    Online ISSN:2320-964X


    46, Guruwandan, Jawahar Nagar, 

    VMV Road, Amravati- 444604

    Maharashtra, India.

    Tel  + 91- 9970559438  |   9420775527  

    Email: |