Skip to main content
Top

17-06-2014 | Rheumatoid arthritis | Review | Article

Defining populations at risk of rheumatoid arthritis: the first steps to prevention

Journal: Nature Reviews Rheumatology

Authors: Laura Hunt, Paul Emery

Authors: Laura Hunt, Paul Emery

Publisher: Nature Publishing Group UK

Abstract

Preventing disease is a public health priority. In recent years, this focus has evolved to include noncommunicable chronic diseases such as cardiovascular disease and diabetes mellitus but is novel in rheumatic diseases such as rheumatoid arthritis (RA). In order to prevent RA, the 'at-risk' populations need to be defined. To date, a number of studies have attempted to clarify our understanding of these cohorts and how they could be identified. Suggested terminology has now been published to define individuals who might go on to develop RA. This Review considers categories of these 'at-risk' individuals, with a focus on those with systemic autoimmunity. Trials in very early RA demonstrate that disease outcomes can be reduced with early intervention. These principles are widely accepted in other diseases such as type 1 diabetes mellitus, in which steps have been taken to prevent disease in genetically predisposed individuals. Large population-based studies provide insights into potential interventions for RA prevention. By quantifying risk in different populations, the prospect of preventing this disease is feasible.

Nat Rev Rheumatol 2014;10:521–530. doi:10.1038/nrrheum.2014.82

Literature
1.
Lard, L. R. et al. Early versus delayed treatment in patients with recent-onset rheumatoid arthritis: comparison of two cohorts who received different treatment strategies. Am. J. Med. 111, 446–451 (2001).PubMedCrossRef
2.
Quinn, M. A. & Emery, P. Window of opportunity in early rheumatoid arthritis: possibility of altering the disease process with early intervention. Clin. Exp. Rheumatol. 21, S154–S157 (2003).PubMed
3.
Nell, V. P. et al. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology (Oxford) 43, 906–914 (2004).CrossRef
4.
van der Linden, M. P. et al. Long-term impact of delay in assessment of patients with early arthritis. Arthritis Rheum. 62, 3537–3546 (2010).PubMedCrossRef
5.
JBS3 Board. Joint British Societies' consensus recommendations for the prevention of cardiovascular disease (JBS3). Heart 100, ii1–ii67 (2014).
6.
Gerlag, D. M. 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. Ann. Rheum. Dis. 71, 638–641 (2012).PubMedCrossRef
7.
del Puente, A., Knowler, W. C., Pettitt, D. J. & Bennett, P. H. The incidence of rheumatoid arthritis is predicted by rheumatoid factor titer in a longitudinal population study. Arthritis Rheum. 31, 1239–1244 (1988).PubMed
8.
van Steenbergen, H. W., Huizinga, T. W. & van der Helm-van Mil, A. H. The preclinical phase of rheumatoid arthritis: what is acknowledged and what needs to be assessed? Arthritis Rheum. 65, 2219–2232 (2013).CrossRefPubMed
9.
Jonsson, T. et al. Population study of the importance of rheumatoid factor isotypes in adults. Ann. Rheum. Dis. 51, 863–868 (1992).PubMedPubMedCentralCrossRef
10.
Aho, K., von Essen, R., Kurki, P., Palosuo, T. & Heliovaara, M. Antikeratin antibody and antiperinuclear factor as markers for subclinical rheumatoid disease process. J. Rheumatol. 20, 1278–1281 (1993).PubMed
11.
Aho, K. et al. Antifilaggrin antibodies within 'normal' range predict rheumatoid arthritis in a linear fashion. J. Rheumatol. 27, 2743–2746 (2000).PubMed
12.
Majka, D. S. et al. Duration of preclinical rheumatoid arthritis-related autoantibody positivity increases in subjects with older age at time of disease diagnosis. Ann. Rheum. Dis. 67, 801–807 (2008).PubMedCrossRef
13.
Chibnik, L. B., Mandl, L. A., Costenbader, K. H., Schur, P. H. & Karlson, E. W. Comparison of threshold cutpoints and continuous measures of anti-cyclic citrullinated peptide antibodies in predicting future rheumatoid arthritis. J. Rheumatol. 36, 706–711 (2009).PubMedPubMedCentralCrossRef
14.
Kokkonen, H. et al. Antibodies of IgG, IgA and IgM isotypes against cyclic citrullinated peptide precede the development of rheumatoid arthritis. Arthritis Res. Ther. 13, R13 (2011).PubMedPubMedCentralCrossRef
15.
Rantapaa-Dahlqvist, S. et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 48, 2741–2749 (2003).PubMedCrossRef
16.
Nielen, M. M. et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004).PubMedCrossRef
17.
van der Woude, D. et al. Epitope spreading of the anti-citrullinated protein antibody response occurs before disease onset and is associated with the disease course of early arthritis. Ann. Rheum. Dis. 69, 1554–1561 (2010).PubMedCrossRef
18.
van de Stadt, L. A. et al. The extent of the anti-citrullinated protein antibody repertoire is associated with arthritis development in patients with seropositive arthralgia. Ann. Rheum. Dis. 70, 128–133 (2011).PubMedCrossRef
19.
Sokolove, J. et al. Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS ONE 7, e35296 (2012).PubMedPubMedCentralCrossRef
20.
Brink, M. et al. Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis. Arthritis Rheum. 65, 899–910 (2013).CrossRefPubMed
21.
Arkema, E. V. et al. Anti-citrullinated peptide autoantibodies, human leukocyte antigen shared epitope and risk of future rheumatoid arthritis: a nested case–control study. Arthritis Res. Ther. 15, R159 (2013).PubMedPubMedCentralCrossRef
22.
Ioan-Facsinay, A. et al. Anti-cyclic citrullinated peptide antibodies are a collection of anti-citrullinated protein antibodies and contain overlapping and non-overlapping reactivities. Ann. Rheum. Dis. 70, 188–193 (2011).PubMedCrossRef
23.
Ioan-Facsinay, A. et al. Marked differences in fine specificity and isotype usage of the anti-citrullinated protein antibody in health and disease. Arthritis Rheum. 58, 3000–3008 (2008).PubMedCrossRef
24.
Aho, K. et al. Serum immunoglobulins and the risk of rheumatoid arthritis. Ann. Rheum. Dis. 56, 351–356 (1997).PubMedPubMedCentralCrossRef
25.
Aho, K. et al. Serum C-reactive protein does not predict rheumatoid arthritis. J. Rheumatol. 27, 1136–1138 (2000).PubMed
26.
Nielen, M. M. J. et al. Increased levels of C-reactive protein in serum from blood donors before the onset of rheumatoid arthritis. Arthritis Rheum. 50, 2423–2427 (2004).PubMedCrossRef
27.
Nielen, M. M. J. et al. Simultaneous development of acute phase response and autoantibodies in preclinical rheumatoid arthritis. Ann. Rheum. Dis. 65, 535–537 (2006).PubMedCrossRef
28.
Rantapaa-Dahlqvist, S., Boman, K., Tarkowski, A. & Hallmans, G. Up regulation of monocyte chemoattractant protein-1 expression in anti-citrulline antibody and immunoglobulin M rheumatoid factor positive subjects precedes onset of inflammatory response and development of overt rheumatoid arthritis. Ann. Rheum. Dis. 66, 121–123 (2007).PubMedCrossRef
29.
Jorgensen, K. T. et al. Cytokines, autoantibodies and viral antibodies in premorbid and postdiagnostic sera from patients with rheumatoid arthritis: case–control study nested in a cohort of Norwegian blood donors. Ann. Rheum. Dis. 67, 860–866 (2008).PubMedCrossRef
30.
Karlson, E. W. et al. Biomarkers of inflammation and development of rheumatoid arthritis in women from two prospective cohort studies. Arthritis Rheum. 60, 641–652 (2009).PubMedPubMedCentralCrossRef
31.
Deane, K. D. et al. The number of elevated cytokines and chemokines in preclinical seropositive rheumatoid arthritis predicts time to diagnosis in an age-dependent manner. Arthritis Rheum. 62, 3161–3172 (2010).PubMedPubMedCentralCrossRef
32.
Kokkonen, H. et al. Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum. 62, 383–391 (2010).PubMed
33.
Stahl, E. A. et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat. Genet. 42, 508–514 (2010).PubMedPubMedCentralCrossRef
34.
Eyre, S. et al. High-density genetic mapping identifies new susceptibility loci for rheumatoid arthritis. Nat. Genet. 44, 1336–1340 (2012).PubMedPubMedCentralCrossRef
35.
Okada, Y. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).PubMedCrossRef
36.
Gregersen, P. K., Silver, J. & Winchester, R. J. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213 (1987).CrossRefPubMed
37.
Lin, J. P. et al. Familial clustering of rheumatoid arthritis with other autoimmune diseases. Hum. Genet. 103, 475–482 (1998).PubMedCrossRef
38.
MacGregor, A. J. et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 43, 30–37 (2000).CrossRefPubMed
39.
Hemminki, K., Li, X., Sundquist, J. & Sundquist, K. Familial associations of rheumatoid arthritis with autoimmune diseases and related conditions. Arthritis Rheum. 60, 661–668 (2009).PubMedCrossRef
40.
Frisell, T. et al. Familial risks and heritability of rheumatoid arthritis: role of rheumatoid factor/anti-citrullinated protein antibody status, number and type of affected relatives, sex, and age. Arthritis Rheum. 65, 2773–2782 (2013).PubMedCrossRef
41.
Silman, A. J., Hennessy, E. & Ollier, B. Incidence of rheumatoid arthritis in a genetically predisposed population. Br. J. Rheumatol. 31, 365–368 (1992).PubMedCrossRef
42.
El-Gabalawy, H. S. et al. Immunogenetic risks of anti-cyclical citrullinated peptide antibodies in a North American Native population with rheumatoid arthritis and their first-degree relatives. J. Rheumatol. 36, 1130–1135 (2009).PubMedCrossRef
43.
Kolfenbach, J. R. et al. A prospective approach to investigating the natural history of preclinical rheumatoid arthritis (RA) using first-degree relatives of probands with RA. Arthritis Care Res. 61, 1735–1742 (2009).CrossRef
44.
Arlestig, L. et al. Antibodies against cyclic citrullinated peptides of IgG, IgA and IgM isotype and rheumatoid factor of IgM and IgA isotype are increased in unaffected members of multicase rheumatoid arthritis families from northern Sweden. Ann. Rheum. Dis. 71, 825–829 (2012).PubMedCrossRef
45.
Barra, L. et al. Anti-citrullinated protein antibodies in unaffected first-degree relatives of rheumatoid arthritis patients. Arthritis Rheum. 65, 1439–1447 (2013).PubMedCrossRef
46.
Demoruelle, M. K. et al. Performance of anti-cyclic citrullinated peptide assays differs in subjects at increased risk of rheumatoid arthritis and subjects with established disease. Arthritis Rheum. 65, 2243–2252 (2013).PubMedPubMedCentralCrossRef
47.
Young, K. A. et al. Relatives without rheumatoid arthritis show reactivity to anti-citrullinated protein/peptide antibodies that are associated with arthritis-related traits: studies of the etiology of rheumatoid arthritis. Arthritis Rheum. 65, 1995–2004 (2013).PubMedPubMedCentralCrossRef
48.
Gale, E. A., Bingley, P. J., Emmett, C. L. & Collier, T. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomised controlled trial of intervention before the onset of type 1 diabetes. Lancet 363, 925–931 (2004).CrossRefPubMed
49.
Schmid, S., Buuck, D., Knopff, A., Bonifacio, E. & Ziegler, A. G. BABYDIET, a feasibility study to prevent the appearance of islet autoantibodies in relatives of patients with type 1 diabetes by delaying exposure to gluten. Diabetologia 47, 1130–1131 (2004).PubMedCrossRef
50.
Knip, M. et al. Dietary intervention in infancy and later signs of β-cell autoimmunity. N. Engl. J. Med. 363, 1900–1908 (2010).PubMedPubMedCentralCrossRef
51.
El-Gabalawy, H. S. et al. Familial clustering of the serum cytokine profile in the relatives of rheumatoid arthritis patients. Arthritis Rheum. 64, 1720–1729 (2012).PubMedCrossRef
52.
Miller, F. W. et al. Epidemiology of environmental exposures and human autoimmune diseases: findings from a National Institute of Environmental Health Sciences Expert Panel Workshop. J. Autoimmun. 39, 259–271 (2012).PubMedPubMedCentralCrossRef
53.
Lahiri, M., Morgan, C., Symmons, D. P. & Bruce, I. N. Modifiable risk factors for RA: prevention, better than cure? Rheumatology (Oxford) 51, 499–512 (2012).CrossRef
54.
Lahiri, M. et al. Using lifestyle factors to identify individuals at higher risk of inflammatory polyarthritis (results from the European Prospective Investigation of Cancer-Norfolk and the Norfolk Arthritis Register—the EPIC-2-NOAR Study. Ann. Rheum. Dis. 73, 219–226 (2014).PubMedCrossRef
55.
Sugiyama, D. et al. Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies. Ann. Rheum. Dis. 69, 70–81 (2010).CrossRefPubMed
56.
Klareskog, L. et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum. 54, 38–46 (2006).PubMedCrossRef
57.
Makrygiannakis, D. et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann. Rheum. Dis. 67, 1488–1492 (2008).PubMedCrossRef
58.
Karlson, E. W. et al. Cumulative association of 22 genetic variants with seropositive rheumatoid arthritis risk. Ann. Rheum. Dis. 69, 1077–1085 (2010).PubMedCrossRef
59.
Karlson, E. W. & Deane, K. Environmental and gene-environment interactions and risk of rheumatoid arthritis. Rheum. Dis. Clin. North Am. 38, 405–426 (2012).PubMedPubMedCentralCrossRef
60.
Karlson, E. W. et al. Association of environmental and genetic factors and gene-environment interactions with risk of developing rheumatoid arthritis. Arthritis Care Res. (Hoboken) 65, 1147–1156 (2013).CrossRef
61.
de Hair, M. J. H. et al. Smoking and overweight determine the likelihood of developing rheumatoid arthritis. Ann. Rheum. Dis. 72, 1654–1658 (2013).PubMedCrossRef
62.
Haj Hensvold, A. et al. Environmental and genetic factors in the development of anticitrullinated protein antibodies (ACPAs) and ACPA-positive rheumatoid arthritis: an epidemiological investigation in twins. Ann. Rheum. Dis. http://​dx.​doi.​org/​10.​1136/​annrheumdis-2013-203947.
63.
Demoruelle, M. K. et al. Brief report: airways abnormalities and rheumatoid arthritis-related autoantibodies in subjects without arthritis: early injury or initiating site of autoimmunity? Arthritis Rheum. 64, 1756–1761 (2012).PubMedCrossRef
64.
Willis, V. C. et al. Sputum autoantibodies in patients with established rheumatoid arthritis and subjects at risk of future clinically apparent disease. Arthritis Rheum. 65, 2545–2554 (2013).PubMedPubMedCentral
65.
Rangel-Moreno, J. et al. The development of inducible bronchus-associated lymphoid tissue depends on IL-17. Nat. Immunol. 12, 639–646 (2011).PubMedPubMedCentralCrossRef
66.
Wegner, N. et al. Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis. Arthritis Rheum. 62, 2662–2672 (2010).PubMedPubMedCentralCrossRef
67.
de Pablo, P., Dietrich, T. & McAlindon, T. E. Association of periodontal disease and tooth loss with rheumatoid arthritis in the US population. J. Rheumatol. 35, 70–76 (2008).PubMed
68.
Arkema, E. V., Karlson, E. W. & Costenbader, K. H. A prospective study of periodontal disease and risk of rheumatoid arthritis. J. Rheumatol. 37, 1800–1804 (2010).PubMedPubMedCentralCrossRef
69.
Demmer, R. T., Molitor, J. A., Jacobs, D. R. Jr & Michalowicz, B. S. Periodontal disease, tooth loss and incident rheumatoid arthritis: results from the First National Health and Nutrition Examination Survey and its epidemiological follow-up study. J. Clin. Periodontol. 38, 998–1006 (2011).PubMedPubMedCentralCrossRef
70.
Chen, H. H. et al. Association between a history of periodontitis and the risk of rheumatoid arthritis: a nationwide, population-based, case–control study. Ann. Rheum. Dis. 72, 1206–1211 (2013).PubMedCrossRef
71.
Hitchon, C. A. et al. Antibodies to Porphyromonas gingivalis are associated with anticitrullinated protein antibodies in patients with rheumatoid arthritis and their relatives. J. Rheumatol. 37, 1105–1112 (2010).PubMedCrossRef
72.
de Smit, M. J. et al. Antibodies against Porphyromonas gingivalis correlate with rheumatoid arthritis-specific auto-immunity in arthralgia patients [abstract #1202]. Arthritis Rheum. 64 (Suppl. 10), S514 (2012).
73.
Mikuls, T. R. et al. Porphyromonas gingivalis and disease-related autoantibodies in individuals at increased risk of rheumatoid arthritis. Arthritis Rheum. 64, 3522–3530 (2012).PubMedCrossRef
74.
Bos, W. H. et al. Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: a prospective cohort study. Ann. Rheum. Dis. 69, 490–494 (2010).PubMedCrossRef
75.
Arnett, F. C. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988).PubMedCrossRef
76.
van de Stadt, L. A., van Sijl, A. M., van Schaardenburg, D. & Nurmohamed, M. T. Dyslipidaemia in patients with seropositive arthralgia predicts the development of arthritis. Ann. Rheum. Dis. 71, 1915–1916 (2012).PubMedCrossRef
77.
Rakieh, C. et al. Predicting the development of clinical arthritis in anti-CCP positive individuals with non-specific musculoskeletal symptoms: a prospective observational cohort study. Ann. Rheum. Dis. http://​dx.​doi.​org/​10.​1136/​annrheumdis-2014-205227.
78.
Bos, W. H., Dijkmans, B. A., Boers, M., van de Stadt, R. J. & van Schaardenburg, D. Effect of dexamethasone on autoantibody levels and arthritis development in patients with arthralgia: a randomised trial. Ann. Rheum. Dis. 69, 571–574 (2010).PubMedCrossRef
79.
Visser, H., le Cessie, S., Vos, K., Breedveld, F. C. & Hazes, J. M. W. How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive) arthritis. Arthritis Rheum. 46, 357–365 (2002).PubMedCrossRef
80.
van der Helm-van Mil, A. H. M. et al. A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: How to guide individual treatment decisions. Arthritis Rheum. 56, 433–440 (2007).PubMedCrossRef
81.
van de Stadt, L. A., Witte, B. I., Bos, W. H. & van Schaardenburg, D. A prediction rule for the development of arthritis in seropositive arthralgia patients. Ann. Rheum. Dis. 72, 1920–1926 (2013).PubMedCrossRef
82.
Skyler, J. S. Primary and secondary prevention of type 1 diabetes. Diabet. Med. 30, 161–169 (2013).PubMedPubMedCentralCrossRef
83.
Lampeter, E. F. et al. The Deutsche Nicotinamide Intervention Study: an attempt to prevent type 1 diabetes. DENIS Group. Diabetes 47, 980–984 (1998).PubMedCrossRef
84.
Diabetes Prevention Trial—Type I Diabetes Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus. N. Engl. J. Med. 346, 1685–1691 (2002).
85.
Skyler, J. S. et al. Effects of oral insulin in relatives of patients with type 1 diabetes: The Diabetes Prevention Trial—Type 1. Diabetes Care 28, 1068–1076 (2005).CrossRefPubMed
86.
US National Library of Medicine. ClinicalTrials.gov [online], (2011).
87.
US National Library of Medicine. ClinicalTrials.gov [online], (2014).
88.
US National Library of Medicine. ClinicalTrials.gov [online], (2014).
89.
Âkerblom, H. K. & The TRIGR Study Group. The Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study: recruitment, intervention and follow-up. Diabetologia 54, 627–633 (2011).PubMedCrossRef
90.
Vaarala, O. et al. Removal of bovine insulin from cow's milk formula and early initiation of β-cell autoimmunity in the FINDIA pilot study. Arch. Pediatr. Adolesc. Med. 166, 608–614 (2012).PubMedCrossRef
91.
US National Library of Medicine. ClinicalTrials.gov [online], (2014).
92.
van Dongen, H. et al. Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: a double-blind, randomized, placebo-controlled trial. Arthritis Rheum 56, 1424–1432 (2007).PubMedCrossRef
93.
Emery, P. et al. Impact of T-cell costimulation modulation in patients with undifferentiated inflammatory arthritis or very early rheumatoid arthritis: a clinical and imaging study of abatacept (the ADJUST trial). Ann. Rheum. Dis. 69, 510–516 (2010).PubMedCrossRef
94.
Machold, K. P. et al. The Stop Arthritis Very Early (SAVE) trial, an international multicentre, randomised, double-blind, placebo-controlled trial on glucocorticoids in very early arthritis. Ann. Rheum. Dis. 69, 495–502 (2010).PubMedCrossRef
95.
Verstappen, S. M. et al. Beneficial effects of a 3-week course of intramuscular glucocorticoid injections in patients with very early inflammatory polyarthritis: results of the STIVEA trial. Ann. Rheum. Dis. 69, 503–509 (2010).PubMedCrossRef
96.
Aletaha, D. et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 62, 2569–2581 (2010).PubMedCrossRef
97.
Villeneuve, E. et al. Preliminary results of a multicentre randomised control trials of etanercept and methotrexate to induce remission in patients with newly diagnosed inflammatory arthritis [abstract]. Arthritis Rheum. 63 (Suppl. 10), 2465 (2011).
98.
Emery, P. et al. Induction of remission in patients with up to 12 months of moderate-to-severe rheumatoid arthritis symptoms treated with etanercept plus methotrexate over 52 weeks [abstract]. Arthritis Rheum. 64 (Suppl. 10), 2549 (2012).
99.
Karlson, E. W., Shadick, N. A., Cook, N. R., Buring, J. E. & Lee, I. M. Vitamin E in the primary prevention of rheumatoid arthritis: The Women's Health Study. Arthritis Care Res. 59, 1589–1595 (2008).CrossRef
100.
Walitt, B. et al. Effects of postmenopausal hormone therapy on rheumatoid arthritis: The Women's Health Initiative randomized controlled trials. Arthritis Rheum. 59, 302–310 (2008).PubMedPubMedCentralCrossRef
101.
Jick, S. S., Choi, H., Li, L., McLnnes, I. B. & Sattar, N. Hyperlipidaemia, statin use and the risk of developing rheumatoid arthritis. Ann. Rheum. Dis. 68, 546–551 (2009).PubMedCrossRef
102.
Shadick, N. A. et al. Low-dose aspirin in the primary prevention of rheumatoid arthritis: The Women's Health Study. Arthritis Care Res. 62, 545–550 (2010).CrossRef
103.
Shi, J. et al. Anti-carbamylated protein antibodies are present in arthralgia patients and predict the development of rheumatoid arthritis. Arthritis Rheum. 65, 911–915 (2013).PubMedCrossRef
104.
van Baarsen, L. G. M. et al. Gene expression profiling in autoantibody-positive patients with arthralgia predicts development of arthritis. Arthritis Rheum. 62, 694–704 (2010).PubMedCrossRef
105.
Limper, M. et al. The acute-phase response is not predictive for the development of arthritis in seropositive arthralgia—a prospective cohort study. J. Rheumatol. 39, 1914–1917 (2012).PubMedCrossRef
106.
van de Sande, M. G. H. et al. Different stages of rheumatoid arthritis: features of the synovium in the preclinical phase. Ann. Rheum. Dis. 70, 772–777 (2011).PubMedCrossRef
107.
Krabben, A. et al. MRI of hand and foot joints of patients with anticitrullinated peptide antibody positive arthralgia without clinical arthritis. Ann. Rheum. Dis. 72, 1540–1544 (2013).PubMedCrossRef
108.
van de Stadt, L. A. et al. The value of ultrasonography in predicting arthritis in auto-antibody positive arthralgia patients: a prospective cohort study. Arthritis Res. Ther. 12, R98 (2010).PubMedPubMedCentralCrossRef
109.
Gent, Y. Y. J. et al. Macrophage positron emission tomography imaging as a biomarker for preclinical rheumatoid arthritis: Findings of a prospective pilot study. Arthritis Rheum. 64, 62–66 (2012).PubMedCrossRef
110.
Ropes, M. W., Bennett, G. A., Cobb, S., Jacox, R. & Jessar, R. A. 1958 Revision of diagnostic criteria for rheumatoid arthritis. Bull. Rheum. Dis. 9, 175–176 (1958).PubMed
111.
Heliovaara, M. et al. Coffee consumption, rheumatoid factor, and the risk of rheumatoid arthritis. Ann. Rheum. Dis. 59, 631–635 (2000).PubMedPubMedCentralCrossRef
112.
Jacobsson, L. T. H., Jacobsson, M. E., Askling, J. & Knowler, W. C. Perinatal characteristics and risk of rheumatoid arthritis. BMJ 326, 1068–1069 (2003).PubMedPubMedCentralCrossRef
113.
Karlson, E. W., Mandl, L. A., Aweh, G. N. & Grodstein, F. Coffee consumption and risk of rheumatoid arthritis. Arthritis Rheum. 48, 3055–3060 (2003).PubMedCrossRef
114.
Doran, M. F., Crowson, C. S., O'Fallon, W. M. & Gabriel, S. E. The effect of oral contraceptives and estrogen replacement therapy on the risk of rheumatoid arthritis: a population based study. J. Rheumatol. 31, 207–213 (2004).PubMed
115.
Karlson, E. W., Mandl, L. A., Hankinson, S. E. & Grodstein, F. Do breast-feeding and other reproductive factors influence future risk of rheumatoid arthritis? Results from the Nurses' Health Study. Arthritis Rheum. 50, 3458–3467 (2004).CrossRefPubMed
116.
Pattison, D. J., Harrison, R. A. & Symmons, D. P. M. The role of diet in susceptibility to rheumatoid arthritis: a systematic review. J. Rheumatol. 31, 1310–1319 (2004).PubMed
117.
Bengtsson, C., Nordmark, B., Klareskog, L., Lundberg, I. & Alfredsson, L. Socioeconomic status and the risk of developing rheumatoid arthritis: results from the Swedish EIRA study. Ann. Rheum. Dis. 64, 1588–1594 (2005).PubMedPubMedCentralCrossRef
118.
Stolt, P. et al. Silica exposure is associated with increased risk of developing rheumatoid arthritis: results from the Swedish EIRA study. Ann. Rheum. Dis. 64, 582–586 (2005).PubMedCrossRef
119.
Benito-Garcia, E., Feskanich, D., Hu, F. B., Mandl, L. A. & Karlson, E. W. Protein, iron, and meat consumption and risk for rheumatoid arthritis: a prospective cohort study. Arthritis Res. Ther. 9, R16 (2007).PubMedPubMedCentralCrossRef
120.
Costenbader, K. H., Feskanich, D., Holmes, M., Karlson, E. W. & Benito-Garcia, E. Vitamin D intake and risks of systemic lupus erythematosus and rheumatoid arthritis in women. Ann. Rheum. Dis. 67, 530–535 (2008).PubMedCrossRef
121.
Bengtsson, C., Theorell, T., Klareskog, L. & Alfredsson, L. Psychosocial stress at work and the risk of developing rheumatoid arthritis: results from the Swedish EIRA study. Psychother. Psychosom. 78, 193–194 (2009).PubMedCrossRef
122.
Mandl, L. A., Costenbader, K. H., Simard, J. F. & Karlson, E. W. Is birthweight associated with risk of rheumatoid arthritis? Data from a large cohort Study. Ann. Rheum. Dis. 68, 514–518 (2009).PubMedCrossRef
123.
Pikwer, M. et al. Breast feeding, but not use of oral contraceptives, is associated with a reduced risk of rheumatoid arthritis. Ann. Rheum. Dis. 68, 526–530 (2009).PubMedCrossRef
124.
Rosell, M., Wesley, A. M., Rydin, K., Klareskog, L. & Alfredsson, L. Dietary fish and fish oil and the risk of rheumatoid arthritis. Epidemiology 20, 896–901 (2009).PubMedCrossRef
125.
Stolt, P. et al. Silica exposure among male current smokers is associated with a high risk of developing ACPA-positive rheumatoid arthritis. Ann. Rheum. Dis. 69, 1072–1076 (2010).PubMedCrossRef
126.
Lahiri, M. et al. Higher fruit and fructose consumption is associated with a reduced risk of inflammatory polyarthritis and rheumatoid arthritis in men. Results from the European Prospective Investigation of Cancer (Norfolk) and the Norfolk Arthritis Register [abstract #1895]. Arthritis Rheum. 63 (Suppl.), S739 (2011).
127.
Arkema, E. V. et al. Exposure to ultraviolet-B and risk of developing rheumatoid arthritis among women in the Nurses' Health Study. Ann. Rheum. Dis. 72, 506–511 (2013).PubMedCrossRef
128.
Crowson, C. S., Matteson, E. L., Davis, I. J. M. & Gabriel, S. E. Contribution of obesity to the rise in incidence of rheumatoid arthritis. Arthritis Care Res. 65, 71–77 (2013).CrossRef
129.
Parks, C. G. et al. Childhood socioeconomic factors and perinatal characteristics influence development of rheumatoid arthritis in adulthood. Ann. Rheum. Dis. 72, 350–356 (2013).PubMedCrossRef
130.
Scott, I. C. et al. The protective effect of alcohol on developing rheumatoid arthritis: a systematic review and meta-analysis. Rheumatology (Oxford) 52, 856–867 (2013).CrossRef