Advertisement

Predicting Rheumatoid Arthritis in At-risk Individuals

      Abstract

      The typical evolution of rheumatoid arthritis (RA) is that a person with genetic risk factors develops autoantibodies and subclinical inflammation under relevant environmental influences, culminating in symptoms and finally clinically detectable arthritis. Because several of these characteristics can be present before the outbreak of clinical arthritis, it is possible to study the at-risk phase (the presence of ≥1 risk factors for RA in an individual) with the aim of quantifying the risk for that individual. As a person progresses through the different phases of disease development, different markers can be used for prediction. In the early asymptomatic phase, genetics, environmental factors, and autoantibodies are relevant, whereas in later phases additional markers, such as symptoms and imaging, come into play, conveying the risk of not only RA but sometimes even of imminent RA. Prediction is of limited use when not coupled with the possibility to intervene and lower the risk of RA. There is a clear need for effective preventive strategies that take the phase of disease development into account. On the other hand, selecting the right persons for preventive treatment according to their stage of disease development requires the improvement of current prediction models and strategies. This commentary presents an overview of risk factors and their combination into prediction models for use in different stages of RA development. Although clear progress has been made and assuming a future with effective options to intervene, there are still several gaps in our knowledge that need to be filled before it is clear who should be tested and when.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Deane K.
        • Holers V.M.
        The natural history of rheumatoid arthritis.
        Clin Ther. 2019; 41: 1256-1269
        • Raza K.
        • Gerlag D.M.
        Preclinical inflammatory rheumatic diseases: an overview and relevant nomenclature.
        Rheum Dis Clin North Am. 2014; 40: 569-580
        • Nielen M.M.
        • van Schaardenburg D.
        • Reesink H.W.
        • et al.
        Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors.
        Arthritis Rheum. 2004; 50: 380-386
        • van de Stadt L.A.
        • de Koning M.H.
        • van de Stadt R.J.
        • et al.
        Development of the anti-citrullinated protein antibody repertoire prior to the onset of rheumatoid arthritis.
        Arthritis Rheum. 2011; 63: 3226-3233
        • Rombouts Y.
        • Ewing E.
        • van de Stadt L.A.
        • et al.
        Anti-citrullinated protein antibodies acquire a pro-inflammatory Fc glycosylation phenotype prior to the onset of rheumatoid arthritis.
        Ann Rheum Dis. 2015; 74: 234-241
        • Nielen M.M.
        • van Schaardenburg D.
        • Reesink H.W.
        • et al.
        Increased levels of C-reactive protein in serum from blood donors before the onset of rheumatoid arthritis.
        Arthritis Rheum. 2004; 50: 2423-2427
        • Gent Y.Y.
        • Voskuyl A.E.
        • Kloet R.W.
        • et al.
        Macrophage positron emission tomography imaging as a biomarker for preclinical rheumatoid arthritis: findings of a prospective pilot study.
        Arthritis Rheum. 2012; 64: 62-66
        • Boers M.
        • Verhoeven A.C.
        • Markusse H.M.
        • et al.
        Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis.
        Lancet. 1997; 350: 309-318
        • Goekoop-Ruiterman Y.P.
        • de Vries-Bouwstra J.K.
        • Allaart C.F.
        • et al.
        Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial.
        Arthritis Rheum. 2005; 52: 3381-3390
        • Linos A.
        • Worthington J.W.
        • O'Fallon W.M.
        • Kurland L.T.
        The epidemiology of rheumatoid arthritis in Rochester, Minnesota: a study of incidence, prevalence, and mortality.
        Am J Epidemiol. 1980; 111: 87-98
        • Frisell T.
        • Saevarsdottir S.
        • Askling J.
        Family history of rheumatoid arthritis: an old concept with new developments.
        Nat Rev Rheumatol. 2016; 12: 335-343
        • Ferucci E.D.
        • Templin D.W.
        • Lanier A.P.
        Rheumatoid arthritis in American Indians and Alaska Natives: a review of the literature.
        Semin Arthritis Rheum. 2005; 34: 662-667
        • Deane K.D.
        • Demoruelle M.K.
        • Kelmenson L.B.
        • Kuhn K.A.
        • Norris J.M.
        • Holers V.M.
        Genetic and environmental risk factors for rheumatoid arthritis.
        Best Pract Res Clin Rheumatol. 2017; 31: 3-18
        • Stanford S.M.
        • Bottini N.
        PTPN22: the archetypal non-HLA autoimmunity gene.
        Nat Rev Rheumatol. 2014; 10: 602-611
        • Messemaker T.C.
        • Huizinga T.W.
        • Kurreeman F.
        Immunogenetics of rheumatoid arthritis: understanding functional implications.
        J Autoimmun. 2015; 64: 74-81
        • Kurreeman F.
        • Liao K.
        • Chibnik L.
        • et al.
        Genetic basis of autoantibody positive and negative rheumatoid arthritis risk in a multi-ethnic cohort derived from electronic health records.
        Am J Hum Genet. 2011; 88: 57-69
        • Sparks J.A.
        • Costenbader K.H.
        Genetics, environment, and gene-environment interactions in the development of systemic rheumatic diseases.
        Rheum Dis Clin North Am. 2014; 40: 637-657
        • Sugiyama D.
        • Nishimura K.
        • Tamaki K.
        • et al.
        Impact of smoking as a risk factor for developing rheumatoid arthritis: a meta-analysis of observational studies.
        Ann Rheum Dis. 2010; 69: 70-81
        • Kim K.
        • Jiang X.
        • Cui J.
        • et al.
        Interactions between amino acid-defined major histocompatibility complex class II variants and smoking in seropositive rheumatoid arthritis.
        Arthritis Rheumatol. 2015; 67: 2611-2623
        • Karlson E.W.
        • van Schaardenburg D.
        • van der Helm-van Mil A.H.
        Strategies to predict rheumatoid arthritis development in at-risk populations.
        Rheumatology (Oxford). 2016; 55: 6-15
        • van Beers-Tas M.H.
        • Turk S.A.
        • van Schaardenburg D.
        How does established rheumatoid arthritis develop, and are there possibilities for prevention?.
        Best Pract Res Clin Rheumatol. 2015; 29: 527-542
        • Alpizar-Rodriguez D.
        • Finckh A.
        Environmental factors and hormones in the development of rheumatoid arthritis.
        Semin Immunopathol. 2017; 39: 461-468
        • Feng J.
        • Chen Q.
        • Yu F.
        • et al.
        Body mass index and risk of rheumatoid arthritis: a meta-analysis of observational studies.
        Medicine (Baltimore). 2016; 95: e2859
        • Qin B.
        • Yang M.
        • Fu H.
        • et al.
        Body mass index and the risk of rheumatoid arthritis: a systematic review and dose-response meta-analysis.
        Arthritis Res Ther. 2015; 17: 86
        • Lahiri M.
        • Morgan C.
        • Symmons D.P.
        • Bruce I.N.
        Modifiable risk factors for RA: prevention, better than cure?.
        Rheumatology (Oxford). 2012; 51: 499-512
        • Alpizar-Rodriguez D.
        • Pluchino N.
        • Canny G.
        • Gabay C.
        • Finckh A.
        The role of female hormonal factors in the development of rheumatoid arthritis.
        Rheumatology (Oxford). 2017; 56: 1254-1263
        • Hu Y.
        • Costenbader K.H.
        • Gao X.
        • et al.
        Sugar-sweetened soda consumption and risk of developing rheumatoid arthritis in women.
        Am J Clin Nutr. 2014; 100: 959-967
        • Di Giuseppe D.
        • Crippa A.
        • Orsini N.
        • Wolk A.
        Fish consumption and risk of rheumatoid arthritis: a dose-response meta-analysis.
        Arthritis Res Ther. 2014; 16: 446
        • Chen H.
        • Wang J.
        • Zhou W.
        • Yin H.
        • Wang M.
        Breastfeeding and risk of rheumatoid arthritis: a systematic review and metaanalysis.
        J Rheumatol. 2015; 42: 1563-1569
        • Ren L.
        • Guo P.
        • Sun Q.M.
        • et al.
        Number of parity and the risk of rheumatoid arthritis in women: a dose-response meta-analysis of observational studies.
        J Obstet Gynaecol Res. 2017; 43: 1428-1440
        • Chen Q.
        • Jin Z.
        • Xiang C.
        • Cai Q.
        • Shi W.
        • He J.
        Absence of protective effect of oral contraceptive use on the development of rheumatoid arthritis: a meta-analysis of observational studies.
        Int J Rheum Dis. 2014; 17: 725-737
        • Qi S.
        • Xin R.
        • Guo W.
        • Liu Y.
        Meta-analysis of oral contraceptives and rheumatoid arthritis risk in women.
        Ther Clin Risk Manag. 2014; 10: 915-923
        • Song G.G.
        • Bae S.C.
        • Lee Y.H.
        Association between vitamin D intake and the risk of rheumatoid arthritis: a meta-analysis.
        Clin Rheumatol. 2012; 31: 1733-1739
        • Cerhan J.R.
        • Saag K.G.
        • Merlino L.A.
        • Mikuls T.R.
        • Criswell L.A.
        Antioxidant micronutrients and risk of rheumatoid arthritis in a cohort of older women.
        Am J Epidemiol. 2003; 157: 345-354
        • Costenbader K.H.
        • Kang J.H.
        • Karlson E.W.
        Antioxidant intake and risks of rheumatoid arthritis and systemic lupus erythematosus in women.
        Am J Epidemiol. 2010; 172: 205-216
        • Hu Y.
        • Sparks J.A.
        • Malspeis S.
        • et al.
        Long-term dietary quality and risk of developing rheumatoid arthritis in women.
        Ann Rheum Dis. 2017; 76: 1357-1364
        • Sparks J.A.
        • Barbhaiya M.
        • Tedeschi S.K.
        • et al.
        Inflammatory dietary pattern and risk of developing rheumatoid arthritis in women.
        Clin Rheumatol. 2019; 38: 243-250
        • de Hair M.J.
        • Landewe R.B.
        • van de Sande M.G.
        • et al.
        Smoking and overweight determine the likelihood of developing rheumatoid arthritis.
        Ann Rheum Dis. 2013; 72: 1654-1658
        • Lahiri M.
        • Luben R.N.
        • Morgan C.
        • 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. 2014; 73: 219-226
        • Hashimoto M.
        • Yamazaki T.
        • Hamaguchi M.
        • et al.
        Periodontitis and Porphyromonas gingivalis in preclinical stage of arthritis patients.
        PLoS One. 2015; 10e0122121
        • Arkema E.V.
        • Karlson E.W.
        • Costenbader K.H.
        A prospective study of periodontal disease and risk of rheumatoid arthritis.
        J Rheumatol. 2010; 37: 1800-–
        • de Smit M.
        • van de Stadt L.A.
        • Janssen K.M.
        • et al.
        Antibodies against Porphyromonas gingivalis in seropositive arthralgia patients do not predict development of rheumatoid arthritis.
        Ann Rheum Dis. 2014; 73: 1277-1279
        • Chibnik L.B.
        • Keenan B.T.
        • Cui J.
        • et al.
        Genetic risk score predicting risk of rheumatoid arthritis phenotypes and age of symptom onset.
        PLoS One. 2011; 6e24380
        • van Beers-Tas M.H.
        • Blanken A.B.
        • Nielen M.J.
        • et al.
        The value of joint ultrasonography in predicting arthritis in seropositive arthralgia patients: a prospective cohort study.
        Arthritis Res Ther. 2018 Dec 19; 20: 279
        • Karlson E.W.
        • Chibnik L.B.
        • Kraft P.
        • et al.
        Cumulative association of 22 genetic variants with seropositive rheumatoid arthritis risk.
        Ann Rheum Dis. 2010; 69: 1077-1085
        • Karlson E.W.
        • Ding B.
        • Keenan B.T.
        • et al.
        Association of environmental and genetic factors and gene-environment interactions with risk of developing rheumatoid arthritis.
        Arthritis Care Res (Hoboken). 2013; 65: 1147-1156
        • Scott I.C.
        • Seegobin S.D.
        • Steer S.
        • et al.
        Predicting the risk of rheumatoid arthritis and its age of onset through modelling genetic risk variants with smoking.
        Plos Genet. 2013; 9e1003808
        • Sparks J.A.
        • Chen C.Y.
        • Jiang X.
        • et al.
        Improved performance of epidemiologic and genetic risk models for rheumatoid arthritis serologic phenotypes using family history.
        Ann Rheum Dis. 2015; 74: 1522-1529
        • Rantapaa-Dahlqvist S.
        • de Jong B.A.
        • Berglin E.
        • et al.
        Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis.
        Arthritis Rheum. 2003; 48: 2741-2749
        • Kokkonen H.
        • Mullazehi M.
        • Berglin E.
        • et al.
        Antibodies of IgG, IgA and IgM isotypes against cyclic citrullinated peptide precede the development of rheumatoid arthritis.
        Arthritis Res Ther. 2011; 13: R13
        • Arkema E.V.
        • Goldstein B.L.
        • Robinson W.
        • 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. 2013; 15: R159
        • Brink M.
        • Hansson M.
        • Mathsson L.
        • et al.
        Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis.
        Arthritis Rheum. 2013; 65: 899-910
        • Sokolove J.
        • Bromberg R.
        • Deane K.D.
        • et al.
        Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis.
        PLoS One. 2012; 7e35296
        • WJJ Falkenburg
        • van Schaardenburg D.
        Evolution of autoantibody responses in individuals at risk of rheumatoid arthritis.
        Best Pract Res Clin Rheumatol. 2017; 31: 42-52
        • Rakieh C.
        • Nam J.L.
        • Hunt L.
        • 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. 2015; 74: 1659-1666
        • Bos W.H.
        • Wolbink G.J.
        • Boers M.
        • et al.
        Arthritis development in patients with arthralgia is strongly associated with anti-citrullinated protein antibody status: a prospective cohort study.
        Ann Rheum Dis. 2010; 69: 490-494
        • Gerlag D.M.
        • Safy M.
        • Maijer K.I.
        • et al.
        Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study.
        Ann Rheum Dis. 2019; 78: 179-185
        • Ramos-Remus C.
        • Castillo-Ortiz J.D.
        • Aguilar-Lozano L.
        • et al.
        Autoantibodies in prediction of the development of rheumatoid arthritis among healthy relatives of patients with the disease.
        Arthritis Rheumatol. 2015; 67: 2837-2844
        • Kolfenbach J.R.
        • Deane K.D.
        • Derber L.A.
        • et al.
        Autoimmunity to peptidyl arginine deiminase type 4 precedes clinical onset of rheumatoid arthritis.
        Arthritis Rheum. 2010; 62: 2633-2639
        • Shi J.
        • van de Stadt L.A.
        • Levarht E.W.
        • et al.
        Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis.
        Ann Rheum Dis. 2014; 73: 780-783
        • van de Stadt L.A.
        • de Vrieze H.
        • Derksen N.I.
        • et al.
        Antibodies to IgG4 hinge can be found in rheumatoid arthritis patients during all stages of disease and may exacerbate chronic antibody-mediated inflammation.
        Arthritis Rheumatol. 2014; 66: 1133-1140
        • Shi J.
        • van de Stadt L.A.
        • Levarht E.W.
        • et al.
        Anti-carbamylated protein antibodies are present in arthralgia patients and predict the development of rheumatoid arthritis.
        Arthritis Rheum. 2013; 65: 911-915
        • Verheul M.K.
        • Bohringer S.
        • van Delft M.A.M.
        • et al.
        Triple positivity for anti-citrullinated protein autoantibodies, rheumatoid factor, and anti-carbamylated protein antibodies conferring high specificity for rheumatoid arthritis: implications for very early identification of at-risk individuals.
        Arthritis Rheumatol. 2018; 70: 1721-1731
        • Wiitavaara B.
        • Fahlstrom M.
        • Djupsjobacka M.
        Prevalence, diagnostics and management of musculoskeletal disorders in primary health care in Sweden - an investigation of 2000 randomly selected patient records.
        J Eval Clin Pract. 2017; 23: 325-332
        • Young K.A.
        • Deane K.D.
        • Derber L.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. 2013; 65: 1995-2004
        • Tak P.P.
        • Doorenspleet M.E.
        • de Hair M.J.H.
        • et al.
        Dominant B cell receptor clones in peripheral blood predict onset of arthritis in individuals at risk for rheumatoid arthritis.
        Ann Rheum Dis. 2017; 76: 1924-1930
        • Musters A.
        • van Beers-Tas M.
        • Doorenspleet M.
        • et al.
        OP0204 Dominant B cell receptor clones in peripheral blood predict onset of arthritis in individuals at risk for rheumatoid arthritis: a validation cohort.
        Ann Rheum Dis. 2018; 77: 151
        • 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. 2013; 72: 1920-1926
        • Stack R.J.
        • van Tuyl L.H.
        • Sloots M.
        • et al.
        Symptom complexes in patients with seropositive arthralgia and in patients newly diagnosed with rheumatoid arthritis: a qualitative exploration of symptom development.
        Rheumatology (Oxford). 2014; 53: 1646-1653
        • van Nies J.A.
        • Alves C.
        • Radix-Bloemen A.L.
        • et al.
        Reappraisal of the diagnostic and prognostic value of morning stiffness in arthralgia and early arthritis: results from the Groningen EARC, Leiden EARC, ESPOIR, Leiden EAC and REACH.
        Arthritis Res Ther. 2015; 17: 108
        • van Steenbergen H.W.
        • van der Helm-van Mil A.H.
        Clinical expertise and its accuracy in differentiating arthralgia patients at risk for rheumatoid arthritis from other patients presenting with joint symptoms.
        Rheumatology (Oxford). 2016; 55: 1140-1141
        • van Steenbergen H.W.
        • Aletaha D.
        • Beaart-van de Voorde L.J.
        • et al.
        EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis.
        Ann Rheum Dis. 2017; 76: 491-496
        • van Beers-Tas M.H.
        • Ter Wee M.M.
        • van Tuyl L.H.
        • et al.
        Initial validation and results of the symptoms in persons at risk of rheumatoid arthritis (SPARRA) questionnaire: a EULAR project.
        RMD Open. 2018; 4e000641
        • Gent Y.Y.
        • Ter Wee M.M.
        • Ahmadi N.
        • et al.
        Three-year clinical outcome following baseline magnetic resonance imaging in anti-citrullinated protein antibody-positive arthralgia patients: an exploratory study.
        Arthritis Rheumatol. 2014; 66: 2909-2910
        • Krabben A.
        • Stomp W.
        • van der Heijde D.M.
        • et al.
        MRI of hand and foot joints of patients with anticitrullinated peptide antibody positive arthralgia without clinical arthritis.
        Ann Rheum Dis. 2013; 72: 1540-1544
        • van Steenbergen H.W.
        • van Nies J.A.
        • Huizinga T.W.
        • Reijnierse M.
        • van der Helm-van Mil A.H.
        Subclinical inflammation on MRI of hand and foot of anticitrullinated peptide antibody-negative arthralgia patients at risk for rheumatoid arthritis.
        Arthritis Res Ther. 2014; 16: R92
        • Mangnus L.
        • van Steenbergen H.W.
        • Reijnierse M.
        • van der Helm-van Mil A.H.
        Magnetic resonance imaging-detected features of inflammation and erosions in symptom-free persons from the general population.
        Arthritis Rheumatol. 2016; 68: 2593-2602
        • van Steenbergen H.W.
        • Mangnus L.
        • Reijnierse M.
        • Huizinga T.W.
        • van der Helm-van Mil A.H.
        Clinical factors, anticitrullinated peptide antibodies and MRI-detected subclinical inflammation in relation to progression from clinically suspect arthralgia to arthritis.
        Ann Rheum Dis. 2016; 75: 1824-1830
        • Nieuwenhuis W.P.
        • van Steenbergen H.W.
        • Mangnus L.
        • et al.
        Evaluation of the diagnostic accuracy of hand and foot MRI for early rheumatoid arthritis.
        Rheumatology (Oxford). 2017; 56: 1367-1377
        • Nam J.L.
        • Hensor E.M.
        • Hunt L.
        • Conaghan P.G.
        • Wakefield R.J.
        • Emery P.
        Ultrasound findings predict progression to inflammatory arthritis in anti-CCP antibody-positive patients without clinical synovitis.
        Ann Rheum Dis. 2016; 75: 2060-2067
        • van de Stadt L.A.
        • Bos W.H.
        • Meursinge Reynders M.
        • et al.
        The value of ultrasonography in predicting arthritis in auto-antibody positive arthralgia patients: a prospective cohort study.
        Arthritis Res Ther. 2010; 12: R98
        • Yarwood A.
        • Han B.
        • Raychaudhuri S.
        • et al.
        A weighted genetic risk score using all known susceptibility variants to estimate rheumatoid arthritis risk.
        Ann Rheum Dis. 2015; 74: 170-176
        • van Zanten A.
        • Arends S.
        • Roozendaal C.
        • et al.
        Presence of anticitrullinated protein antibodies in a large population-based cohort from The Netherlands.
        Ann Rheum Dis. 2017; 76: 1184-1190
        • Gerlag D.M.
        • Raza K.
        • van Baarsen L.G.
        • 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. 2012; 71: 638-641
        • Sparks J.A.
        • Iversen M.D.
        • Yu Z.
        • et al.
        Disclosure of personalized rheumatoid arthritis risk using genetics, biomarkers, and lifestyle factors to motivate health behavior improvements: a randomized controlled trial.
        Arthritis Care Res (Hoboken). 2018; 70: 823-833