Patients with rheumatoid arthritis can be divided into two major subsets characterized by the presence versus absence of antibodies to citrullinated protein antigens (ACPAs) and of rheumatoid factor (RF). The antibody-positive subset of disease, also known as seropositive rheumatoid arthritis, constitutes approximately two-thirds of all cases of rheumatoid arthritis and generally has a more severe disease course. ACPAs and RF are often present in the blood long before any signs of joint inflammation, which suggests that the triggering of autoimmunity may occur at sites other than the joints (for example, in the lung). This Review summarizes recent progress in our understanding of this gradual disease development in seropositive patients. We also emphasize the implications of this new understanding for the development of preventive and therapeutic strategies. Similar temporal and spatial separation of immune triggering and clinical manifestations, with novel opportunities for early intervention, may also occur in other immune-mediated diseases.
At a glance
- The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 31, 315–324 (1988). et al.
- 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann. Rheum. Dis. 69, 1580–1588 (2010). 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. Ann. Rheum. Dis. 70, 1575–1580 (2011). et al.
- Rheumatoid factor and anti-citrullinated protein antibody positivity are associated with a better effectiveness of abatacept: results from the Pan-European registry analysis. Arthritis Rheumatol. 68, 1346–1352 (2016). 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).
Provides the first description of a gene–environment interaction that implicates a role for the lungs in the triggering of anti-citrulline immunity.
- Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann. Rheum. Dis. 65, 366–371 (2006). et al.
- On the occurrence of a factor in human serum activating the specific agglutination of sheep blood corpuscles. APMIS 115, 422–438 (1939).
- Immune complexes can trigger specific, T cell-dependent, autoanti-IgG antibody production in mice. J. Exp. Med. 161, 242–256 (1985).
- Efficient and selective presentation of antigen–antibody complexes by rheumatoid factor B cells. J. Exp. Med. 173, 487–489 (1991). &
- New serum factor in patients with rheumatoid arthritis; the antiperinuclear factor. Ann. Rheum. Dis. 23, 302–305 (1964). &
- Anti-keratin antibodies in rheumatoid arthritis. BMJ 2, 97–99 (1979). , , , &
- The antiperinuclear factor and the so-called antikeratin antibodies are the same rheumatoid arthritis-specific autoantibodies. J. Clin. Invest. 95, 2672–2679 (1995). et al.
- Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. J. Clin. Invest. 101, 273–281 (1998).
The first article to describe citrullinated peptides and proteins as targets of RA-associated autoantibodies.
, , , &
- The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro)filaggrin by deimination of arginine residues. J. Immunol. 162, 585–594 (1999). et al.
- The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum. 43, 155–163 (2000). et al.
- Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage. Proc. Natl Acad. Sci. USA 108, 17372–17377 (2011). et al.
- Identification of novel antiacetylated vimentin antibodies in patients with early inflammatory arthritis. Ann. Rheum. Dis. 75, 1099–1107 (2016). et al.
- Anti-CarP antibodies in two large cohorts of patients with rheumatoid arthritis and their relationship to genetic risk factors, cigarette smoking and other autoantibodies. Ann. Rheum. Dis. 73, 1761–1768 (2014). et al.
- Antibodies to carbamylated α-enolase epitopes in rheumatoid arthritis also bind citrullinated epitopes and are largely indistinct from anti-citrullinated protein antibodies. Arthritis Res. Ther. 18, 96 (2016). et al.
- Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen. Arthritis Rheum. 52, 3424–3432 (2005). et al.
- Humoral immune response to citrullinated collagen type II determinants in early rheumatoid arthritis. Eur. J. Immunol. 35, 1643–1652 (2005). et al.
- Identification of citrullinated α-enolase as a candidate autoantigen in rheumatoid arthritis. Arthritis Res. Ther. 7, R1421–R1429 (2005). et al.
- Antibodies from patients with rheumatoid arthritis target citrullinated histone 4 contained in neutrophils extracellular traps. Ann. Rheum. Dis. 73, 1414–1422 (2014). et al.
- Identification of an immunodominant peptide from citrullinated tenascin-C as a major target for autoantibodies in rheumatoid arthritis. Ann. Rheum. Dis. 75, 1876–1883 (2015). et al.
- Rheumatoid factors antedating clinical rheumatoid arthritis. J. Rheumatol. 18, 1282–1284 (1991). , , , &
- Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum. 48, 2741–2749 (2003). et al.
- Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 50, 380–386 (2004).
References 26 and 27 demonstrate that ACPAs are present in blood long before the development of RA.
- 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). et al.
- Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLoS ONE 7, e35296 (2012). et al.
- Multiplex analyses of antibodies against citrullinated peptides in individuals prior to development of rheumatoid arthritis. Arthritis Rheum. 65, 899–910 (2013). et al.
- Anti-carbamylated protein (anti-CarP) antibodies precede the onset of rheumatoid arthritis. Ann. Rheum. Dis. 73, 780–783 (2014). et al.
- Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression. Ann. Rheum. Dis. 64, 1744–1749 (2005). 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). et al.
- Structural changes and antibody enrichment in the lungs are early features of anti-citrullinated protein antibody-positive rheumatoid arthritis. Arthritis Rheumatol. 66, 31–39 (2014).
Demonstrates that both structural changes and immune activation occur in the lungs of patients with early untreated ACPA-positive RA.
- Signs of immune activation and local inflammation are present in the bronchial tissue of patients with untreated early rheumatoid arthritis. Ann. Rheum. Dis. 75, 1722–1727 (2015). 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). et al.
- Inducible bronchus-associated lymphoid tissue (iBALT) in patients with pulmonary complications of rheumatoid arthritis. J. Clin. Invest. 116, 3183–3194 (2006). 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). et al.
- IgA plasmablasts are elevated in subjects at risk for future rheumatoid arthritis. Arthritis Rheumatol. 68, 2372–2383 (2016). et al.
- Anti-cyclic citrullinated peptide antibodies, IgM and IgA rheumatoid factors in the diagnosis and prognosis of rheumatoid arthritis. Rheumatology 42, 677–680 (2003). , , &
- Associations with smoking and shared epitope differ between IgA- and IgG-class antibodies to cyclic citrullinated peptides in early rheumatoid arthritis. Arthritis Rheumatol. 67, 2032–2037 (2015). et al.
- A gene–environment interaction between smoking and shared epitope genes in HLA-DR provides a high risk of seropositive rheumatoid arthritis. Arthritis Rheum. 50, 3085–3092 (2004). , , , &
- 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). et al.
- Occupational exposure to textile dust increases the risk of rheumatoid arthritis: results from a Malaysian population-based case–control study. Ann. Rheum. Dis. 75, 997–1002 (2015). 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). et al.
- COPA mutations impair ER–Golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis. Nat. Genet. 47, 654–660 (2015). et al.
- Antibodies to citrullinated α-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis Rheum. 58, 3009–3019 (2008). et al.
- Antibody responses to Porphyromonas gingivalis (P. gingivalis) in subjects with rheumatoid arthritis and periodontitis. Int. Immunopharmacol. 9, 38–42 (2009). et al.
- Purification, characterization, and sequence analysis of a potential virulence factor from Porphyromonas gingivalis, peptidylarginine deiminase. Infect. Immun. 67, 3248–3256 (1999). , , &
- Autoimmunity to specific citrullinated proteins gives the first clues to the etiology of rheumatoid arthritis. Immunol. Rev. 233, 34–54 (2010). et al.
- Prevalence of periodontitis in patients with established rheumatoid arthritis: a Swedish population based case–control study. PLoS ONE 11, e0155956 (2016). et al.
- Antibodies to Porphyromonas gingivalis indicate interaction between oral infection, smoking, and risk genes in rheumatoid arthritis etiology. Arthritis Rheumatol. 68, 604–613 (2016). et al.
- The intestine and rheumatism. Acta Rheumatol. Scand. 16, 177–183 (1970).
- The origin of rheumatoid arthritis. Rheumatology 6, 322–328 (1975).
- Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2, e01202 (2013). et al.
- Loss of sex and age driven differences in the gut microbiome characterize arthritis-susceptible 0401 mice but not arthritis-resistant 0402 mice. PLoS ONE 7, e36095 (2012). et al.
- Stimulation of TLR2 and TLR4 differentially skews the balance of T cells in a mouse model of arthritis. J. Clin. Invest. 118, 205–216 (2008). et al.
- Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 32, 815–827 (2010). et al.
- The metabolic role of the gut microbiota in health and rheumatic disease: mechanisms and interventions. Nat. Rev. Rheumatol. 12, 446–455 (2016). , &
- Effects of smoking and shared epitope on the production of anti-citrullinated peptide antibody in a Japanese adult population. Arthritis Care Res. 66, 1818–1827 (2014). 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. 74, 375–380 (2015). et al.
- Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum. 62, 383–391 (2010). et al.
- Anti-citrullinated protein antibodies acquire a pro-inflammatory Fc glycosylation phenotype prior to the onset of rheumatoid arthritis. Ann. Rheum. Dis. 74, 234–241 (2015).
Demonstrates that ACPAs from patients with RA have unusual glycosylation of the antigen-binding portion.
- The shared epitope hypothesis: an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum. 30, 1205–1213 (1987). , &
- Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012).
Provides a genetic dissection of the amino acid requirements of the association between HLA alleles and ACPA-positive RA.
- A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis. J. Exp. Med. 210, 2569–2582 (2013).
Presents the first crystal structure of citrullinated peptides presented by HLA-DR.
- Celiac disease: autoimmunity in response to food antigen. Semin. Immunol. 27, 343–352 (2015). &
- Identification and functional characterization of T cells reactive to citrullinated vimentin in HLA-DRB1*0401-positive humanized mice and rheumatoid arthritis patients. Arthritis Rheum. 63, 2873–2883 (2011). et al.
- Citrulline-specific Th1 cells are increased in rheumatoid arthritis and their frequency is influenced by disease duration and therapy. Arthritis Rheumatol. 66, 1712–1722 (2014).
Uses ex vivo phenotyping of several different citrulline-specific CD4+ T cells in patients with RA and in HLA-matched healthy controls to demonstrate both increased numbers and higher frequencies of effector/memory CD4+ T cells in patients with RA.
- The tyrosine phosphatase PTPN22 discriminates weak self peptides from strong agonist TCR signals. Nat. Immunol. 15, 875–883 (2014). , , &
- The PTPN22 allele encoding an R620W variant interferes with the removal of developing autoreactive B cells in humans. J. Clin. Invest. 121, 3635–3644 (2011). et al.
- Gene–gene and gene–environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am. J. Hum. Genet. 80, 867–875 (2007). et al.
- Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci. Transl. Med. 8, 331ra38 (2016). et al.
- The immunopathology of joint inflammation in rheumatoid arthritis. Adv. Immunol. 16, 265–336 (1973).
- Barcode-enabled sequencing of plasmablast antibody repertoires in rheumatoid arthritis. Arthritis Rheumatol. 66, 2706–2715 (2014). et al.
- Autoantibodies from single circulating plasmablasts react with citrullinated antigens and Porphyromonas gingivalis in rheumatoid arthritis. Arthritis Rheumatol. 68, 614–626 (2016). et al.
- Monoclonal IgG antibodies generated from joint-derived B cells of RA patients have a strong bias toward citrullinated autoantigen recognition. J. Exp. Med. 210, 445–455 (2013). et al.
- Single cell cloning and recombinant monoclonal antibodies generation from RA synovial B cells reveal frequent targeting of citrullinated histones of NETs. Ann. Rheum. Dis. 75, 1866–1875 (2015). et al.
- Citrullinated self antigen-specific blood B cells carry cross reactive immunoglobulins with effector potential. Ann. Rheum. Dis. 75, A2.33 (2016). et al.
- Molecular mechanisms of congenital heart block. Exp. Cell Res. 325, 2–9 (2014). , &
- Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J. Clin. Invest. 122, 1791–1802 (2012).
Provides the first demonstration that ACPAs can promote osteoclast differentiation.
- Identification of a novel chemokine-dependent molecular mechanism underlying rheumatoid arthritis-associated autoantibody-mediated bone loss. Ann. Rheum. Dis. 75, 721–729 (2016). et al.
- Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat. Commun. 6, 6651 (2015). et al.
- Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. Ann. Rheum. Dis. 75, 730–738 (2016). et al.
- Human osteoclasts and osteoclast- like cells synthesize and release high basal and inflammatory stimulated levels of the potent chemokine interleukin-8. Endocrinology 139, 4353–4363 (1998). et al.
- A prediction rule for the development of arthritis in seropositive arthralgia patients. Ann. Rheum. Dis. 72, 1920–1926 (2013). , , &
- Chemokine contribution to neuropathic pain: respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons. Pain 154, 2185–2197 (2013). , , , &
- Antibodies against citrullinated proteins enhance tissue injury in experimental autoimmune arthritis. J. Clin. Invest. 116, 961–973 (2006). et al.
- Cytokines induced neutrophil extracellular traps formation: implication for the inflammatory disease condition. PLoS ONE 7, e48111 (2012). et al.
- Citrullination enhances the pro-inflammatory response to fibrin in rheumatoid arthritis synovial fibroblasts. Ann. Rheum. Dis. 72, 1400–1406 (2013). et al.
- Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcγ receptor. Arthritis Rheum. 63, 53–62 (2011).
Provides the first demonstration that immune complexes with citrullinated antigens have proinflammatory potential.
, , &
- Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med. 15, 1414–1420 (2009). et al.
- Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes. Nat. Commun. 7, 11849 (2016). et al.
- Stromal transcriptional profiles reveal hierarchies of anatomical site, serum response and disease and identify disease specific pathways. PLoS ONE 10, e0120917 (2015). et al.
- Smoking induces transcription of the heat shock protein system in the joints. Ann. Rheum. Dis. 73, 1423–1426 (2014). et al.
- High anti-collagen type-II antibody levels and induction of proinflammatory cytokines by anti-collagen antibody-containing immune complexes in vitro characterise a distinct rheumatoid arthritis phenotype associated with acute inflammation at the time of disease onset. Ann. Rheum. Dis. 66, 537–541 (2007). , , &
- Identification of new citrulline-specific autoantibodies, which bind to human arthritic cartilage, by mass spectrometric analysis of citrullinated type II collagen. Arthritis Rheumatol. 66, 1440–1449 (2014). et al.
- How antibodies to a ubiquitous cytoplasmic enzyme may provoke joint-specific autoimmune disease. Nat. Immunol. 3, 360–365 (2002). et al.
- Low prevalence of antibodies to glucose-6-phosphate isomerase in patients with rheumatoid arthritis and a spectrum of other chronic autoimmune disorders. Arthritis Rheum. 48, 944–954 (2003). et al.
- Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. EMBO J. 10, 4025–4031 (1991). et al.
- Role of cytokines in rheumatoid arthritis: an education in pathophysiology and therapeutics. Immunol. Rev. 223, 7–19 (2008). &
- How cytokine networks fuel inflammation: toward a cytokine-based disease taxonomy. Nat. Med. 19, 822–824 (2013). , , , &
- Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges. Nat. Rev. Rheumatol. 11, 276–289 (2015). &
- OP0182. Prevention of rheumatoid arthritis by B cell directed therapy in the earliest phase of the disease: the PRAIRI study. Ann. Rheum. Dis. 75 (Suppl. 2), 125–126 (2016). et al.
- Citrullinated peptide dendritic cell immunotherapy in HLA risk genotype-positive rheumatoid arthritis patients. Sci. Transl. Med. 7, 290ra87 (2015). et al.
- Autologous tolerogenic dendritic cells for rheumatoid and inflammatory arthritis. Ann. Rheum. Dis. http://dx.doi.org/10.1136/annrheumdis-2015-208456 (2016). et al.
- Expanding antigen-specific regulatory networks to treat autoimmunity. Nature 530, 434–440 (2016). et al.
- Therapeutic vaccination of active arthritis with a glycosylated collagen type II peptide in complex with MHC class II molecules. J. Immunol. 176, 1525–1533 (2006). et al.
- Preclinical development and first-in-human study of ATX-MS-1467 for immunotherapy of MS. Neurol. Neuroimmunol. Neuroinflamm. 2, e93 (2015). , , , &
- Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum. 52, 3433–3438 (2005). et al.
- Genetic markers of rheumatoid arthritis susceptibility in anti-citrullinated peptide antibody negative patients. Ann. Rheum. Dis. 71, 1984–1990 (2012). et al.
- Identification of anticitrullinated protein antibody reactivities in a subset of anti-CCP-negative rheumatoid arthritis: association with cigarette smoking and HLA-DRB1 'shared epitope' alleles. Ann. Rheum. Dis. 74, 579–586 (2015). et al.
- Fine mapping seronegative and seropositive rheumatoid arthritis to shared and distinct HLA alleles by adjusting for the effects of heterogeneity. Am. J. Hum. Genet. 94, 522–532 (2014). et al.
- Anti-citrullinated peptide antibodies and their value for predicting responses to biologic agents: a review. Rheumatol. Int. 36, 1043–1063 (2016). 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. Ann. Rheum. Dis. 75, 709–714 (2016). et al.
- Rheumatoid arthritis. Lancet 388, 2023–2038 (2016). , &
- The influence of ACPA status and characteristics on the course of RA. Nat. Rev. Rheumatol. 8, 144–152 (2012). , , &
- Rheumatoid factor and antibodies to cyclic citrullinated peptides are associated with severe extra-articular manifestations in rheumatoid arthritis. Ann. Rheum. Dis. 66, 59–64 (2007). et al.
- Anti-cyclic citrullinated peptide (CCP) antibodies in patients with long-standing rheumatoid arthritis and their relationship with extra-articular manifestations. Clin. Biochem. 39, 961–965 (2006). , , &
- A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Ann. Rheum. Dis. 70, 259–265 (2011). et al.
- Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 506, 376–381 (2014).
A comprehensive analysis of the genetics of RA and its implications for therapeutic approaches.
- Familial aggregation of arthritis-related diseases in seropositive and seronegative rheumatoid arthritis: a register-based case–control study in Sweden. Ann. Rheum. Dis. 75, 183–189 (2016). et al.
- Nationwide prevalence of rheumatoid arthritis and penetration of disease-modifying drugs in Sweden. Ann. Rheum. Dis. 70, 624–629 (2011). , , & ARTIS Study Group.
- Alcohol consumption is associated with decreased risk of rheumatoid arthritis: results from two Scandinavian case–control studies. Ann. Rheum. Dis. 68, 222–227 (2009). et al.
- Integrating autoimmune risk loci with gene-expression data identifies specific pathogenic immune cell subsets. Am. J. Hum. Genet. 89, 496–506 (2011). et al.
- Chromatin marks identify critical cell types for fine mapping complex trait variants. Nat. Genet. 45, 124–130 (2013). et al.
- Autoimmune diseases — connecting risk alleles with molecular traits of the immune system. Nat. Rev. Genet. 17, 160–174 (2016). , &
- Additive effect of anti-citrullinated protein antibodies and rheumatoid factor on bone erosions in patients with RA. Ann. Rheum. Dis. 74, 2151–2156 (2015). et al.
- Symptom complexes in patients with seropositive arthralgia and in patients newly diagnosed with rheumatoid arthritis: a qualitative exploration of symptom development. Rheumatology 53, 1646–1653 (2014). et al.
- A novel HLA-DRB1*10:01 restricted T cell epitope from citrullinated type II collagen relevant for rheumatoid arthritis. Arthritis Rheumatol. 68, 1124–1135 (2016). et al.
- Immune complexes regulate bone metabolism through FcRγ signalling. Nat. Commun. 6, 6637 (2015). et al.
- A cascade of cytokines mediates mechanical inflammatory hypernociception in mice. Proc. Natl Acad. Sci. USA 102, 1755–1760 (2005). et al.
- Toll-like receptor 2/MyD88 signaling mediates zymosan-induced joint hypernociception in mice: participation of TNF-α, IL-1β and CXCL1/KC. Eur. J. Pharmacol. 674, 51–57 (2012). et al.
- CCL2 and CXCL1 trigger calcitonin gene-related peptide release by exciting primary nociceptive neurons. J. Neurosci. Res. 82, 51–62 (2005). , &
- The chemokine CXCL1/growth related oncogene increases sodium currents and neuronal excitability in small diameter sensory neurons. Mol. Pain 4, 38 (2008). et al.
- Affinity purified anti-citrullinated protein/peptide antibodies target antigens expressed in the rheumatoid joint. Arthritis Res. Ther. 16, R167 (2014). et al.
- Evidence in support of a self-perpetuating HLA-DR-dependent delayed-type cell reaction in rheumatoid arthritis. Proc. Natl Acad. Sci. USA 79, 3632–3636 (1982). , , , &
- Secretion of anti-citrulline-containing peptide antibody by B lymphocytes in rheumatoid arthritis. Arthritis Rheum. 44, 41–47 (2001). et al.
- Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case–control study, using incident cases. Ann. Rheum. Dis. 62, 835–841 (2003). et al.
- Smoking and overweight determine the likelihood of developing rheumatoid arthritis. Ann. Rheum. Dis. 72, 1654–1658 (2013). et al.
- Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted α-Enolase T Cell Epitope in Rheumatoid Arthritis. Front. Immunol. http://dx.doi.org/10.3389/fimmu.2016.00494 (2016). et al.