Abstract
Rheumatoid arthritis (RA) is a common immune-mediated inflammatory disease. Research
on RA is increasingly focused on the earliest stages of the disease, and has provided
strong evidence that clinical signs and symptoms may be preceded by a preclinical
phase during which evidence of systemic autoimmunity may be present. To facilitate
research in this area, a number of international initiatives have proposed definitions
of the phases of disease leading up to RA. The first of these initiatives was the
European League Against Rheumatism's (EULAR) set of recommendations on terminology
in persons at risk for RA, which suggested that the "at-risk phases" be described
in terms of patients variably having: (A) genetic risk factors for RA; (B) environmental
risk factors for RA; (C) systemic autoimmunity associated with RA; (D) symptoms without
clinical arthritis; and (E) unclassified arthritis. The phrase clinically suspect arthralgia (CSA) is now widely used and can be regarded as describing a subgroup of patients
in phase D. A definition of CSA was recently proposed by a EULAR taskforce, and primary
research has begun to explore the full range of symptoms, as well as their sensitivity
and specificity alone and in combination with other factors, that characterize this
phase. Similarly, immune abnormalities at mucosal and others sites that precede and/or
are associated with the onset of musculoskeletal symptoms are being increasingly studied
and understood. Whether some of these at-risk phases, in particular CSA, represent
entities meriting their own classification criteria is an essential area for consensus
and will be discussed.
Key words
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 accessOne-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 TherapeuticsAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- When does rheumatoid disease start?.Arthritis Rheum. 1985; 28: 485-489
- Increased levels of C-reactive protein in serum from blood donors before the onset of rheumatoid arthritis.Arthritis Rheum. 2004; 50: 2423-2427
- Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors.Arthritis Rheum. 2004; 50: 380-386
- Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis.Arthritis Rheum. 2010; 62: 383-391
- 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
- Familial associations of rheumatoid arthritis with autoimmune diseases and related conditions.Arthritis Rheum. 2009; 60: 661-668
- Smoking and overweight determine the likelihood of developing rheumatoid arthritis.Ann Rheum Dis. 2013; 72: 1654-1658
- Autonomic dysfunction precedes development of rheumatoid arthritis: a prospective cohort study.EBioMedicine. 2016; 6: 231-237
- Association between a history of periodontitis and the risk of rheumatoid arthritis: a nationwide, population-based, case-control study.Ann Rheum Dis. 2013; 72: 1206-1211
- Periodontitis in RA—the citrullinated enolase connection.Nat Rev Rheumatol. 2010; 6: 727-730
- Dietary fish and fish oil and the risk of rheumatoid arthritis.Epidemiology. 2009; 20: 896-901
- Towards prevention of autoantibody-positive rheumatoid arthritis: from lifestyle modification to preventive treatment.Rheumatology (Oxford). 2016; 55: 607-614
- Genetic and environmental risk factors for rheumatoid arthritis.Best Pract Res Clin Rheumatol. 2017; 31: 3-18
- Effects of B-cell directed therapy on the preclinical stage of rheumatoid arthritis: the PRAIRI study.Ann Rheum Dis. 2019; 78: 179-185
- Predicting and preventing the development of rheumatoid arthritis.Rheumatology (Oxford). 2016; 55: 1-3
- Immunotherapy for type 1 diabetes: why do current protocols not halt the underlying disease process?.Cell Metab. 2017; 25: 233-241
- 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
- Preclinical inflammatory rheumatic diseases: an overview and relevant nomenclature.Rheum Dis Clin North Am. 2014; 40: 569-580
- EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis.Ann Rheum Dis. 2017; 76: 491-496
- A prediction rule for the development of arthritis in seropositive arthralgia patients.Ann Rheum Dis. 2013; 72: 1920-1926
- 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
- Antibody responses to citrullinated and noncitrullinated antigens in the sputum of subjects with rheumatoid arthritis and subjects at risk for development of rheumatoid arthritis.Arthritis Rheumatol. 2018; 70: 516-527
- 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
- A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22.JCI Insight. 2016; 1e90045
- Different stages of rheumatoid arthritis: features of the synovium in the preclinical phase.Ann Rheum Dis. 2011; 70: 772-777
- Features of the synovium of individuals at risk of developing rheumatoid arthritis: implications for understanding preclinical rheumatoid arthritis.Arthritis Rheumatol. 2014; 66: 513-522
- Effect of dexamethasone on autoantibody levels and arthritis development in patients with arthralgia: a randomised trial.Ann Rheum Dis. 2010; 69: 571-574
- Validation of the EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis.Rheumatology (Oxford). 2017; 56: 2123-2128
- Pre-symptomatic autoimmunity in rheumatoid arthritis: when does the disease start?.Semin Immunopathol. 2017; 39: 423-435
- Symptom complexes at the earliest phases of rheumatoid arthritis: a synthesis of the qualitative literature.Arthritis Care Res (Hoboken). 2013; 65: 1916-1926
- 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
- Impact of symptoms on daily life in people at risk of rheumatoid arthritis.Musculoskeletal Care. 2016; 14: 169-173
- Initial validation and results of the symptoms in persons at risk of rheumatoid arthritis (SPARRA) questionnaire: a EULAR project.RMD Open. 2018; 4e000641
- Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction.Nat Rev Rheumatol. 2018; 14: 542-557
- Elevated IgA plasmablast levels in subjects at risk of developing rheumatoid arthritis.Arthritis Rheumatol. 2016; 68: 2372-2383
- Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis.PLoS One. 2012; 7e35296
- Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis.Arthritis Rheum. 2013; 65: 899-910
- Anti-citrullinated protein antibodies are associated with neutrophil extracellular traps in the sputum in relatives of rheumatoid arthritis patients.Arthritis Rheumatol. 2017; 69: 1165-1175
- Environmental and gene-environment interactions and risk of rheumatoid arthritis.Rheum Dis Clin North Am. 2012; 38: 405-426
- Association of fish intake and smoking with risk of rheumatoid arthritis and age of onset: a prospective cohort study.BMC Musculoskelet Disord. 2019; 20: 2
- Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis.Nat Rev Rheumatol. 2014; 10: 645-653
- Lower omega-3 fatty acids are associated with the presence of anti-cyclic citrullinated peptide autoantibodies in a population at risk for future rheumatoid arthritis: a nested case-control study.Rheumatology (Oxford). 2016; 55: 367-376
- The association between omega-3 fatty acid biomarkers and inflammatory arthritis in an anti-citrullinated protein antibody positive population.Rheumatology (Oxford). 2017; 56: 2229-2236
- Pro-resolving lipid mediators are leads for resolution physiology.Nature. 2014; 510: 92-101
Article info
Publication history
Published online: June 09, 2019
Accepted:
April 10,
2019
Received in revised form:
March 27,
2019
Received:
February 20,
2019
Identification
Copyright
© 2019 Published by Elsevier Inc.
