Personalized medicine. Closing the gap between knowledge and clinical practice.

Personalized medicine encompasses a broad and evolving field informed by a patient distinctive information and biomarker profile. Although terminology is evolving and some semantic interpretations exist (e.g., personalized, individualized, precision), in a broad sense personalized medicine can be coined as: "To practice medicine as it once used to be in the past using the current biotechnological tools." A humanized approach to personalized medicine would offer the possibility of exploiting systems biology and its concept of P5 medicine, where predictive factors for developing a disease should be examined within populations in order to establish preventive measures on at-risk individuals, for whom healthcare should be personalized and participatory. Herein, the process of personalized medicine is presented together with the options that can be offered in health care systems with limited resources for diseases like rheumatoid arthritis and type 1 diabetes.

[1]  A. Silman,et al.  Comparison of the response to infliximab or etanercept monotherapy with the response to cotherapy with methotrexate or another disease-modifying antirheumatic drug in patients with rheumatoid arthritis: results from the British Society for Rheumatology Biologics Register. , 2006, Arthritis and rheumatism.

[2]  J. Hawk,et al.  Editorial: Photoprotection: does it work? , 2008, Lupus.

[3]  J. Bijlsma,et al.  Personalized biological treatment for rheumatoid arthritis: a systematic review with a focus on clinical applicability. , 2016, Rheumatology.

[4]  D. van Schaardenburg,et al.  How does established rheumatoid arthritis develop, and are there possibilities for prevention? , 2015, Best practice & research. Clinical rheumatology.

[5]  Michael J Goodman,et al.  Priorities among effective clinical preventive services: results of a systematic review and analysis. , 2006, American journal of preventive medicine.

[6]  P. Airó,et al.  Decreased Circulating CD28-negative T Cells in Patients with Rheumatoid Arthritis Treated with Abatacept Are Correlated with Clinical Response , 2010, The Journal of Rheumatology.

[7]  M. Ward,et al.  Validity of clinical associations of biomarkers in translational research studies: the case of systemic autoimmune diseases , 2010, Arthritis research & therapy.

[8]  P. Laurberg,et al.  Prevention of autoimmune hypothyroidism by modifying iodine intake and the use of tobacco and alcohol is manoeuvring between Scylla and Charybdis , 2013, Hormones.

[9]  J. Anaya,et al.  The Autoimmune Ecology , 2016, Front. Immunol..

[10]  G. Speer.  [Impact of vitamin D in neurological diseases and neurorehabilitation: from dementia to multiple sclerosis. Part I: the role of vitamin D in the prevention and treatment of multiple sclerosis]. , 2013, Ideggyogyaszati szemle.

[11]  E. Yow,et al.  Vitamin D status is a determinant of atorvastatin effect on carotid intima medial thickening progression rate in children with lupus: an Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) substudy , 2014, Lupus Science & Medicine.

[12]  Rostyslav V Bubnov,et al.  Assessing value of innovative molecular diagnostic tests in the concept of predictive, preventive, and personalized medicine , 2015, EPMA Journal.

[13]  P. Gregersen,et al.  Prevention of autoimmune rheumatic disease: state of the art and future perspectives , 2010, Annals of the rheumatic diseases.

[14]  M. Knip,et al.  Strategies for the prevention of autoimmune Type 1 diabetes , 2011, Diabetic medicine : a journal of the British Diabetic Association.

[15]  M. Pender,et al.  Prevention of autoimmune attack and disease progression in multiple sclerosis: current therapies and future prospects , 2002, Internal medicine journal.

[16]  P. Emery,et al.  Defining populations at risk of rheumatoid arthritis: the first steps to prevention , 2014, Nature Reviews Rheumatology.

[17]  D. Symmons,et al.  Effectiveness of Rituximab in Patients with Rheumatoid Arthritis: Observational Study from the British Society for Rheumatology Biologics Register , 2012, The Journal of Rheumatology.

[18]  S. Patten,et al.  The case for vitamin D supplementation in multiple sclerosis. , 2013, Multiple sclerosis and related disorders.

[19]  B. Dijkmans,et al.  The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept , 2010, Annals of the rheumatic diseases.

[20]  Manolis Tsiknakis,et al.  Development of interactive empowerment services in support of personalised medicine , 2014, Ecancermedicalscience.

[21]  C. Lewis,et al.  EULAR recommendations for terminology and research in individuals at risk of rheumatoid arthritis: report from the Study Group for Risk Factors for Rheumatoid Arthritis , 2012, Annals of the rheumatic diseases.

[22]  P. Emery,et al.  Is localized autoimmunity the trigger for rheumatoid arthritis? Unravelling new targets for prevention. , 2015, Discovery medicine.

[23]  M. Dougados,et al.  Fcγ receptor type IIIA polymorphism influences treatment outcomes in patients with rheumatoid arthritis treated with rituximab , 2012, Annals of the rheumatic diseases.

[24]  J. Morales-Rull,et al.  β blockers in patients with heart failure and atrial fibrillation , 2015, The Lancet.

[25]  J. C. Salazar,et al.  Familial disease, the HLA-DRB1 shared epitope and anti-CCP antibodies influence time at appearance of substantial joint damage in rheumatoid arthritis. , 2009, Journal of autoimmunity.

[26]  R. Furie,et al.  Abetimus sodium: a medication for the prevention of lupus nephritis flares , 2009, Expert opinion on pharmacotherapy.

[27]  N. Rose.  Prediction and Prevention of Autoimmune Disease in the 21st Century: A Review and Preview. , 2016, American journal of epidemiology.

[28]  N. Bizzaro,et al.  Can supplementation with vitamin D reduce the risk or modify the course of autoimmune diseases? A systematic review of the literature. , 2012, Autoimmunity reviews.

[29]  P. Airó,et al.  Baseline Numbers of Circulating CD28-negative T Cells May Predict Clinical Response to Abatacept in Patients with Rheumatoid Arthritis , 2011, The Journal of Rheumatology.

[30]  A. Valdés,et al.  Genetics of the HLA Region in the Prediction of Type 1 Diabetes , 2011, Current diabetes reports.

[31]  M. Bertero.  Primary prevention in antiphospholipid antibody carriers , 2012, Lupus.

[32]  J. Anaya,et al.  The Autoimmune Tautology: From Polyautoimmunity and Familial Autoimmunity to the Autoimmune Genes , 2012, Autoimmune diseases.

[33]  Georges Dionne,et al.  Handbook of insurance , 2000 .

[34]  F. Ponchel,et al.  Genetic data: The new challenge of personalized medicine, insights for rheumatoid arthritis patients. , 2016, Gene.

[35]  D. Schatz,et al.  Autoimmune markers in diabetes. , 2011, Clinical chemistry.

[36]  S. Yehuda,et al.  Prediction and prevention of autoimmune skin disorders , 2008, Archives of Dermatological Research.

[37]  E. Bonifacio,et al.  Advances in the prediction and natural history of type 1 diabetes. , 2010, Endocrinology and metabolism clinics of North America.

[38]  D. Lavallee,et al.  Incorporating Patient-Reported Outcomes Into Health Care To Engage Patients And Enhance Care. , 2016, Health affairs.

[39]  Muin J Khoury,et al.  A population approach to precision medicine. , 2012, American journal of preventive medicine.

[40]  J. Lafata,et al.  Understanding patient perceptions of shared decision making. , 2014, Patient education and counseling.

[41]  P. Lichstein.  Returning to the Bedside , 2015, North Carolina Medical Journal.

[42]  A. Michels,et al.  Type 1 diabetes: A predictable disease. , 2015, World journal of diabetes.

[43]  K. Liao,et al.  Association of Environmental and Genetic Factors and Gene–Environment Interactions With Risk of Developing Rheumatoid Arthritis , 2013, Arthritis care & research.

[44]  P. Gregersen,et al.  Rheumatoid arthritis risk allele PTPRC is also associated with response to anti-tumor necrosis factor alpha therapy. , 2010, Arthritis and rheumatism.

[45]  L. Vilá,et al.  Association of sunlight exposure and photoprotection measures with clinical outcome in systemic lupus erythematosus. , 1999, Puerto Rico health sciences journal.

[46]  B. Dijkmans,et al.  The clinical response to infliximab in rheumatoid arthritis is in part dependent on pretreatment tumour necrosis factor α expression in the synovium , 2007, Annals of the rheumatic diseases.

[47]  S. le Cessie,et al.  Improved treatment strategies reduce the increased mortality risk in early RA patients. , 2010, Rheumatology.

[48]  J. Anaya,et al.  Meta-analysis of HLA-DRB1 polymorphism in Latin American patients with rheumatoid arthritis. , 2007, Autoimmunity reviews.

[49]  S. Ojeda,et al.  Results of a specific smoking cessation program for patients with arthritis in a rheumatology clinic , 2013, Rheumatology International.

[50]  R. Shields.  Common Disease: Are Causative Alleles Common or Rare? , 2011, PLoS biology.

[51]  C. Deighton,et al.  Anti-TNF-&agr; Agents Are Less Effective for the Treatment of Rheumatoid Arthritis in Current Smokers , 2010, Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases.

[52]  S. Bombardieri,et al.  The 158VV Fcgamma receptor 3A genotype is associated with response to rituximab in rheumatoid arthritis: results of an Italian multicentre study , 2013, Annals of the rheumatic diseases.

[53]  B. Zinman,et al.  Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. , 2014, Circulation.

[54]  D. van Schaardenburg,et al.  Smoking and overweight determine the likelihood of developing rheumatoid arthritis , 2012, Annals of the rheumatic diseases.

[55]  G. Collins,et al.  Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD Statement , 2015, BMC Medicine.

[56]  P. Roche,et al.  Macropinocytosis in phagocytes: regulation of MHC class-II-restricted antigen presentation in dendritic cells , 2015, Front. Physiol..

[57]  Ö. Özdemir.  Any role for probiotics in the therapy or prevention of autoimmune diseases? Up-to-date review , 2013, Journal of complementary & integrative medicine.

[58]  C. Allaart,et al.  Five-year outcomes of probable rheumatoid arthritis treated with methotrexate or placebo during the first year (the PROMPT study) , 2013, Annals of the rheumatic diseases.

[59]  Robert J. Smith,et al.  Personalized medicine in diabetes. , 2011, Clinical chemistry.

[60]  J. Anaya,et al.  Familial clustering of autoimmune diseases in patients with type 1 diabetes mellitus. , 2006, Journal of autoimmunity.

[61]  Maša Umićević Mirkov,et al.  Pharmacogenetics of disease-modifying antirheumatic drugs in rheumatoid arthritis: towards personalized medicine. , 2013, Pharmacogenomics.

[62]  E. Steyerberg,et al.  Prognosis Research Strategy (PROGRESS) 3: Prognostic Model Research , 2013, PLoS medicine.

[63]  W. Robinson,et al.  Impact of baseline anti-cyclic citrullinated peptide-2 antibody concentration on efficacy outcomes following treatment with subcutaneous abatacept or adalimumab: 2-year results from the AMPLE trial , 2015, Annals of the rheumatic diseases.

[64]  Heejung Bang,et al.  How to Establish Clinical Prediction Models , 2016, Endocrinology and metabolism.

[65]  D. Bogdanos,et al.  Vitamin D in autoimmune liver disease. , 2013, Clinics and research in hepatology and gastroenterology.

[66]  A. Michels,et al.  Lessons from type 1 diabetes for understanding natural history and prevention of autoimmune disease. , 2014, Rheumatic diseases clinics of North America.

[67]  S. Wedrén,et al.  Patients with early rheumatoid arthritis who smoke are less likely to respond to treatment with methotrexate and tumor necrosis factor inhibitors: observations from the Epidemiological Investigation of Rheumatoid Arthritis and the Swedish Rheumatology Register cohorts. , 2011, Arthritis and rheumatism.

[68]  M. Holick.  Vitamin D: Important for Prevention of Osteoporosis, Cardiovascular Heart Disease, Type 1 Diabetes, Autoimmune Diseases, and Some Cancers , 2005, Southern medical journal.

[69]  W. Duan,et al.  Rectification and phase locking of graphite , 2015 .

[70]  C. Wijbrandts,et al.  Body mass index and clinical response to infliximab in rheumatoid arthritis. , 2011, Arthritis and rheumatism.

[71]  J. Anaya,et al.  How do autoimmune diseases cluster in families? A systematic review and meta-analysis , 2013, BMC Medicine.

[72]  J. Hirshleifer.  The Private and Social Value of Information and the Reward to Inventive Activity , 1971 .

[73]  G. Ginsburg,et al.  The integration of molecular diagnostics with therapeutics. Implications for drug development and pathology practice. , 2003, American journal of clinical pathology.

[74]  M. Gershwin,et al.  The Implication of Vitamin D and Autoimmunity: a Comprehensive Review , 2013, Clinical Reviews in Allergy & Immunology.

[75]  J. Anaya,et al.  HLA-Class II in Latin American patients with type 1 diabetes. , 2010, Autoimmunity reviews.

[76]  Genetic Testing with Primary Prevention and Moral Hazard , 2012, Journal of health economics.

[77]  F. Marincola,et al.  A road map to Translational Medicine in Qatar and a model for the world , 2012, Journal of Translational Medicine.

[78]  Juan-Manuel Anaya,et al.  Evaluation of 19 Autoimmune Disease-associated Loci with Rheumatoid Arthritis in a Colombian Population: Evidence for Replication and Gene-Gene Interaction , 2011, The Journal of Rheumatology.

[79]  Samuel Barbosa,et al.  La nueva reforma a la salud en Colombia: el derecho, el aseguramiento y el sistema de salud , 2015 .

[80]  D. Henriet,et al.  Genetic Information: Comparing Alternative Regulatory Approaches When Prevention Matters , 2011 .

[81]  J. Norris,et al.  Towards prevention of autoantibody-positive rheumatoid arthritis: from lifestyle modification to preventive treatment , 2015, Rheumatology.

[82]  H. Leffers,et al.  Efficacy of abatacept and tocilizumab in patients with rheumatoid arthritis treated in clinical practice: results from the nationwide Danish DANBIO registry , 2011, Annals of the rheumatic diseases.

[83]  M. Pirmohamed.  Acceptance of Biomarker‐Based Tests for Application in Clinical Practice: Criteria and Obstacles , 2010, Clinical pharmacology and therapeutics.

[84]  P. Emery,et al.  Management of nonresponse to rituximab in rheumatoid arthritis: predictors and outcome of re-treatment. , 2010, Arthritis and rheumatism.

[85]  S. Wassenberg,et al.  Impact of patient and disease characteristics on therapeutic success during adalimumab treatment of patients with rheumatoid arthritis: data from a German noninterventional observational study , 2011, Rheumatology International.

[86]  L. Dimeglio,et al.  Established and emerging biomarkers for the prediction of type 1 diabetes: a systematic review. , 2014, Translational research : the journal of laboratory and clinical medicine.

[87]  Reinhard Guthke,et al.  Rheumatoid arthritis, a complex multifactorial disease: On the way toward individualized medicine , 2006, Medicinal research reviews.

[88]  V. Bykerk.  Strategies to prevent rheumatoid arthritis in high-risk patients , 2011, Current opinion in rheumatology.

[89]  J. Souberbielle,et al.  Role of vitamin D in acquired immune and autoimmune diseases , 2014, Critical reviews in clinical laboratory sciences.

[90]  P. Geborek,et al.  Predictors of response to anti-TNF therapy according to ACR and EULAR criteria in patients with established RA: results from the South Swedish Arthritis Treatment Group Register. , 2007, Rheumatology.

[91]  G. Finazzi.  Primary antithrombotic prevention in carriers of antiphospholipid antibodies without systemic autoimmune disorders , 2012, Lupus.

[92]  G. Herrero-Beaumont,et al.  Disease remission and sustained halting of radiographic progression with combination etanercept and methotrexate in patients with rheumatoid arthritis. , 2007, Arthritis and rheumatism.

[93]  J. Morel,et al.  Predictive Factors of Response to Biological Disease Modifying Antirheumatic Drugs: Towards Personalized Medicine , 2014, Mediators of inflammation.

[94]  I. Olivieri,et al.  Obesity and reduction of the response rate to anti–tumor necrosis factor α in rheumatoid arthritis: An approach to a personalized medicine , 2013, Arthritis care & research.

[95]  R. Upmanyu,et al.  IL-6 pathway-driven investigation of response to IL-6 receptor inhibition in rheumatoid arthritis , 2013, BMJ Open.

[96]  P. Emery,et al.  Review: Preclinical Rheumatoid Arthritis: Progress Toward Prevention , 2016, Arthritis & rheumatology.

[97]  A. Barton,et al.  Genome-Wide Association Study of Genetic Predictors of Anti–Tumor Necrosis Factor Treatment Efficacy in Rheumatoid Arthritis Identifies Associations with Polymorphisms at Seven Loci , 2011, Arthritis and rheumatism.

[98]  S. Sedimbi,et al.  Prevention of beta-cell destruction in autoimmune diabetes: current approaches and future prospects. , 2010, Advances in experimental medicine and biology.

[99]  A. Barton,et al.  Replication of Association of the PTPRC Gene With Response to Anti–Tumor Necrosis Factor Therapy in a Large UK Cohort , 2012, Arthritis and rheumatism.

[100]  A. Kaneko,et al.  Concomitant methotrexate and tacrolimus augment the clinical response to abatacept in patients with rheumatoid arthritis with a prior history of biological DMARD use , 2015, Rheumatology International.

[101]  M. Nikpour,et al.  Hydroxychloroquine in lupus: emerging evidence supporting multiple beneficial effects , 2012, Internal medicine journal.

[102]  D. Villalta,et al.  Is vitamin D a player or not in the pathophysiology of autoimmune thyroid diseases? , 2015, Autoimmunity reviews.

[103]  A. Czaja.  Review article: the prevention and reversal of hepatic fibrosis in autoimmune hepatitis , 2014, Alimentary pharmacology & therapeutics.

[104]  L. Szablewski.  Role of immune system in type 1 diabetes mellitus pathogenesis. , 2014, International immunopharmacology.

[105]  G. Wu,et al.  Greater remission rates in patients with early versus long-standing disease in biologic-naive rheumatoid arthritis patients treated with abatacept: a post hoc analysis of randomized clinical trial data. , 2011, Clinical and experimental rheumatology.

[106]  Michael J Joyner,et al.  Chasing Mendel: five questions for personalized medicine , 2014, The Journal of physiology.

[107]  J. C. Salazar,et al.  Anti-CCP antibodies are associated with early age at onset in patients with rheumatoid arthritis. , 2011, Joint, bone, spine : revue du rhumatisme.

[108]  M. Jaberi-Douraki,et al.  Autoimmune responses in T1DM: quantitative methods to understand onset, progression, and prevention of disease , 2014, Pediatric diabetes.

[109]  S. Rappaport.  Implications of the exposome for exposure science , 2011, Journal of Exposure Science and Environmental Epidemiology.

[110]  A. Rowe,et al.  Gene expression analysis in RA: towards personalized medicine , 2014, The Pharmacogenomics Journal.

[111]  L. Hood,et al.  A personal journey of discovery: developing technology and changing biology. , 2008, Annual review of analytical chemistry.

[112]  E. Karlson,et al.  Comparative effectiveness and predictors of response to tumour necrosis factor inhibitor therapies in rheumatoid arthritis. , 2012, Rheumatology.

[113]  I. Bruce,et al.  Modifiable risk factors for RA: prevention, better than cure? , 2011, Rheumatology.

[114]  G. Plewig,et al.  Use of sunscreens to protect against ultraviolet-induced lupus erythematosus. , 2004, Arthritis and rheumatism.

[115]  M. Joyner,et al.  Is precision medicine the route to a healthy world? , 2015, The Lancet.

[116]  Charles Auffray,et al.  Predictive, preventive, personalized and participatory medicine: back to the future , 2010, Genome Medicine.

[117]  G. Burmester,et al.  Clinical remission and/or minimal disease activity in patients receiving adalimumab treatment in a multinational, open-label, twelve-week study. , 2008, Arthritis and rheumatism.

[118]  Denis Horgan,et al.  Is precision medicine the route to a healthy world? , 2015, The Lancet.

[119]  J. Gómez-Reino,et al.  Rheumatoid factor as predictor of response to abatacept, rituximab and tocilizumab in rheumatoid arthritis: Systematic review and meta-analysis. , 2013, Seminars in arthritis and rheumatism.

[120]  Chi-Chen Lin,et al.  Increasing levels of circulating Th17 cells and interleukin-17 in rheumatoid arthritis patients with an inadequate response to anti-TNF-α therapy , 2011, Arthritis research & therapy.

[121]  R. Vasan,et al.  Assessing the clinical utility of biomarkers in medicine. , 2007, Biomarkers in medicine.

[122]  P. Hudelson,et al.  Primary prevention of rheumatoid arthritis: a qualitative study in a high-risk population. , 2013, Joint, bone, spine : revue du rhumatisme.

[123]  H. Willard,et al.  Genomic and personalized medicine: foundations and applications. , 2009, Translational research : the journal of laboratory and clinical medicine.

[124]  J. Anaya,et al.  What is next after the genes for autoimmunity? , 2013, BMC Medicine.

[125]  G. Burmester,et al.  Prognostic factors for abatacept retention in patients who received at least one prior biologic agent: an interim analysis from the observational, prospective ACTION study , 2015, BMC Musculoskeletal Disorders.

[126]  D. Gravano,et al.  Promotion and prevention of autoimmune disease by CD8+ T cells. , 2013, Journal of autoimmunity.

[127]  Jacques-Olivier Pers,et al.  Are autoimmune diseases predictable? , 2012, Autoimmunity reviews.

[128]  A. Barton,et al.  Association of rheumatoid factor and anti-cyclic citrullinated peptide positivity, but not carriage of shared epitope or PTPN22 susceptibility variants, with anti-tumour necrosis factor response in rheumatoid arthritis , 2008 .

[129]  T. Huizinga.  Personalized medicine in rheumatoid arthritis: is the glass half full or half empty? , 2015, Journal of internal medicine.

[130]  M. Dougados,et al.  Positivity for anti-cyclic citrullinated peptide is associated with a better response to abatacept: data from the ‘Orencia and Rheumatoid Arthritis’ registry , 2012, Annals of the rheumatic diseases.

[131]  Y. Shoenfeld,et al.  Primary biliary cirrhosis , 1998, Immunologic research.

[132]  T. Jørgensen,et al.  Graves′ hyperthyroidism and moderate alcohol consumption: evidence for disease prevention , 2013, Clinical endocrinology.

[133]  Joshua T. Cohen,et al.  Does preventive care save money? Health economics and the presidential candidates. , 2008, The New England journal of medicine.

[134]  Liang Zhu,et al.  Long-Term Effects of Mid-Dose Ursodeoxycholic Acid in Primary Biliary Cirrhosis: A Meta-analysis of Randomized Controlled Trials , 2006, The American Journal of Gastroenterology.

[135]  C. Allaart,et al.  Personalized medicine: predicting responses to therapy in patients with RA. , 2013, Current opinion in pharmacology.

[136]  M. Holick.  Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. , 2004, The American journal of clinical nutrition.

[137]  P. V. van Riel,et al.  Highest clinical effectiveness of rituximab in autoantibody-positive patients with rheumatoid arthritis and in those for whom no more than one previous TNF antagonist has failed: pooled data from 10 European registries , 2011, Annals of the rheumatic diseases.

[138]  K. Crocker,et al.  The theory of risk classification , 2013 .

[139]  I. Raftakis,et al.  Vitamin D and rheumatoid arthritis , 2012, Therapeutic advances in endocrinology and metabolism.

[140]  A. Groen,et al.  Forward Individualized Medicine from Personal Genomes to Interactomes , 2015, Front. Physiol..

[141]  J. Anaya,et al.  STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and systemic lupus erythematosus in Colombians , 2008, Genes and Immunity.

[142]  M. Dougados,et al.  B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: a six-month, national, multicenter, open-label study. , 2011, Arthritis and rheumatism.

[143]  H. Yamanaka,et al.  Efficacy and tolerability of tocilizumab in rheumatoid arthritis patients seen in daily clinical practice in Japan: results from a retrospective study (REACTION study) , 2010, Modern rheumatology.

[144]  R. Francavilla,et al.  Impact of the birth’s season on the development of celiac disease in Italy , 2015, European Journal of Pediatrics.