Genes encoding functional components of the immune system are enriched within loci associated with the development and natural history of rheumatoid arthritis; protein products pathogenetically implicated include cytokines themselves [IL-2, IL-21, G-CSF and granulocyte macrophage-colony stimulating factor (GM-CSF)], their receptor components [for IL-6, IL-20, interferon (IFN)-γ and IL-2] and elements of their downstream signalling machinery (e.g. TYK2, STAT4 and TNFAIP3). The range of epigenetic and other mechanisms via which such variants might disrupt cytokine homeostasis to confer disease risk is only beginning to be understood, together with an appreciation that they will best be dissected at a cellular level in relevant disease contexts [11,12]. This becomes pertinent when considering measurable alterations in a number of circulating cytokines that have, with some consistency, been observed prior to symptom onset amongst those who subsequently develop rheumatoid arthritis compared with healthy individuals. These include increased pro-inflammatory examples (TNF, IL-6, IL-1β and/or IL-1RA, GM-CSF) as well as IL-4, IL-12, IL-17 and the eosinophil chemotactic chemokine, eotaxin (Table 1). Against a facultative genetic background, such mediators may variously arise from the paucicellular joint itself, bone marrow or elsewhere in the periphery, but their presence reinforces the likely contribution of cytokines to systemic and general immune dysregulation prior to overt synovitis. In a recent study interrogating serum analyte profiles of ACPA seropositive patients with joint pain (arthralgia), the discriminatory value of the Th2-specific cytokine IL-5 for rheumatoid arthritis progression was highlighted [13▪]. Together with the elevated circulating IL-4 and eotaxin mentioned above, these data recall much earlier observations of transient Th2 cytokine profiles in synovial fluid of early seropositive synovitis patients who progressed to rheumatoid arthritis . Th2 effector responses protect against inflammatory arthritis in certain contexts , and the extent to which such observations reflect ‘failed regulation’ or merely emphasize the role of humoral responses during preclinical rheumatoid arthritis remains to be clarified (Table 1).
Type I interferons including the prototype IFNα, produced mainly by plasmacytoid dendritic cells, may provide a further example of cytokine-mediated autoantibody modulation. These factors are known to promote a number of functions linked to autoimmune pathology including B-cell differentiation and IgG class-switching. Up-regulation of their target gene expression in whole blood (interferon gene signature, IGS), used as a surrogate of circulating cytokine levels, has been shown to predict IgG development in at-risk, ACPA+ individuals, as reflected predominately by its presence in polymorphonuclear granulocytes [21▪▪], and IGS elements were recently shown to correlate with ACPA titres in a Mexican population .
Aside from the largely pro-inflammatory moieties discussed above, recent investigations into a number of ‘regulatory’ cytokines that shed light on means by which immune homeostasis might be restored during rheumatoid arthritis development are also considered. For example, the observation that spontaneous resolution of synovitis in a mouse model is dependent on IL-9 raised the intriguing possibility that this cytokine could also regulate human RA persistence: an enrichment of IL-9-producing type 2 innate lymphoid cells (ILC-2s) was indeed present in the circulation and synovium of patients with active rheumatoid arthritis compared with those on effective treatment and controls [32▪▪]. Tertiary lymphoid organs (TLOs) that closely resemble lymphoid follicles (with segregated T- and B-cell zones, follicular dendritic cell networks and a supporting stroma) are observed in approximately 40% of patient with rheumatoid arthritis synovium, where they support local autoantibody responses and may be a marker of adverse prognosis. It was recently shown that IL-27 inhibits TLO development via the inhibition of podoplanin-expressing Th17 cells . Any therapeutic gains in the light of these insights remain some way off, but they offer a rich field for future research.
Papers of particular interest, published within the annual period of review, have been highlighted as:
1. Malmstrom V, Catrina AI, Klareskog L. The immunopathogenesis of seropositive rheumatoid arthritis
: from triggering to targeting. Nat Rev Immunol 2016; 17:60–75.
2. Pratt AG, Isaacs JD. Seronegative rheumatoid arthritis
: pathogenetic and therapeutic aspects. Baillieres Best Pract Res Clin Rheumatol 2014; 28:651–659.
3. Hensvold AH, Magnusson PK, Joshua V, 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 2015; 74:375–380.
4. Kharlamova N, Jiang X, Sherina N, et al. Antibodies to porphyromonas gingivalis indicate interaction between oral infection, smoking, and risk genes in rheumatoid arthritis
etiology. Arthritis Rheumatol 2016; 68:604–613.
5. Reynisdottir G, Olsen H, Joshua V, et al. Signs of immune activation and local inflammation are present in the bronchial tissue of patients with untreated early rheumatoid arthritis
. Ann Rheum Dis 2016; 75:1722–1727.
6. Kampstra AS, Toes RE. HLA class II and rheumatoid arthritis
: the bumpy road of revelation. Immunogenetics 2017; 69:597–603.
7. Frisell T, Hellgren K, Alfredsson L, et al. Familial aggregation of arthritis-related diseases in seropositive and seronegative rheumatoid arthritis
: a register-based case-control study in Sweden. Ann Rheum Dis 2016; 75:183–189.
8. Blanco FJ, Moricke R, Dokoupilova E, et al. Secukinumab in active rheumatoid arthritis
: a phase III randomized, double-blind, active comparator- and placebo-controlled study. Arthritis Rheumatol 2017; 69:1144–1153.
9. Scott IC, Ibrahim F, Simpson G, et al. A randomised trial evaluating anakinra in early active rheumatoid arthritis
. Clin Exp Rheumatol 2016; 34:88–93.
10. Smolen JS, Agarwal SK, Ilivanova E, et al. A randomised phase II study evaluating the efficacy and safety of subcutaneously administered ustekinumab and guselkumab in patients with active rheumatoid arthritis
despite treatment with methotrexate. Ann Rheum Dis 2017; 76:831–839.
11. McGovern A, Schoenfelder S, Martin P, et al. Capture Hi-C identifies a novel causal gene, IL20RA, in the pan-autoimmune genetic susceptibility region 6q23. Genome Biol 2016; 17:212.
12. Noss EH, Nguyen HN, Chang SK, et al. Genetic polymorphism directs IL-6 expression in fibroblasts but not selected other cell types. Proc Natl Acad Sci 2015; 112:14948–14953.
13▪. Chalan P, Bijzet J, van den Berg A, et al. Analysis of serum immune markers in seropositive and seronegative rheumatoid arthritis
and in high-risk seropositive arthralgia patients. Sci Rep 2016; 6:26021.
This study measured a range of analytes in the sera of prospectively followed ACPA+ arthralgia patients and identified the Th2 cytokine IL-5 as having a potential discriminator for progression to rheumatoid arthritis.
14. Raza K, Falciani F, Curnow SJ, et al. Early rheumatoid arthritis
is characterized by a distinct and transient synovial fluid cytokine profile of T cell and stromal cell origin. Arthritis Res Ther 2005; 7:R784–R795.
15. Chen Z, Andreev D, Oeser K, et al. Th2 and eosinophil responses supress inflammatory arthritis. Nat Commun 2016; 7:11596.
16. Hughes-Austin JM, Deane KD, Derber LA, et al. Multiple cytokines
and chemokines are associated with rheumatoid arthritis
-related autoimmunity in first-degree relatives without rheumatoid arthritis
: Studies of the Aetiology of Rheumatoid Arthritis
(SERA). Ann Rheum Dis 2013; 72:901–907.
17▪▪. Pfeifle R, Rothe T, Ipseiz N, et al. Regulation of autoantibody activity by the IL-23-TH17 axis determines the onset of autoimmune disease. Nat Immunol 2017; 18:104–113.
Building on the observation that IL-23−/− mice fail to develop collagen-induced arthritis despite developing collagen-specific autoantibodies, this work dissected a mechanism via which IL-23 is required to ‘unlock’ the potential of autoantibodies to cause arthritis, via IgG glycosylation and as a result of Th17-plasmablast cross-talk. Analogous altered Fc glycoslyation is seen in human RA prior to disease onset, implicating a prominent role for the IL-23/Th17 ‘axis’ during this specific phase of seropositive disease.
18. Harre U, Lang SC, Pfeifle R, et al. Glycosylation of immunoglobulin G determines osteoclast differentiation and bone loss. Nat Commun 2016; 6:6651.
19▪▪. Krishnamurthy A, Joshua V, Haj Hensvold A, et al. Identification of a novel chemokine
-dependent molecular mechanism underlying rheumatoid arthritis
-associated autoantibody-mediated bone loss. Ann Rheum Dis 2016; 75:721–729.
These experiments provide an attractive model of how IL-8 may be pivotal in the propensity of autoantibodies to mediate osteoclast activation and, potentially, arthritis onset and bony erosion.
20▪. Wigerblad G, Bas DB, Fernades-Cerqueira C, et al. Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine
-dependent mechanism. Annals Rheum Dis 2016; 75:730–738.
Further experiments by the same group implicated the same mechanism in the development of pain in mice – suggesting a biological mechanism for arthralgia seen in seropositive humans before the clinical onset of arthritis in rheumatoid arthritis.
21▪▪. de Jong TD, Lubbers J, Turk S, et al. The type I interferon signature in leukocyte subsets from peripheral blood of patients with early arthritis: a major contribution by granulocytes. Arthritis Res Ther 2016; 18:165.
This group have described the potential value of type I IFNs to predict rheumatoid arthritis progression amongst ACPA+ arthralgia patients, suggesting a role for these cytokines in at least a subgroup of these individuals.
22. Castaneda-Delgado JE, Bastian-Hernandez Y, Macias-Segura N, et al. Type I interferon gene response is increased in early and established rheumatoid arthritis
and correlates with autoantibody production. Front 2017; 8:285.
23▪. Burgers LE, van Steenbergen HW, Ten Brinck RM, et al. Differences in the symptomatic phase preceding ACPA-positive and ACPA-negative RA: a longitudinal study in arthralgia during progression to clinical arthritis. Ann Rheum Dis 2017; 76:1751–1754.
Studies of this kind lay very important groundwork for necessary (but currently very challenging) work seeking to identify pathophysiologically relevant predictors rheumatoid arthritis specifically in seronegative individuals with arthralgia.
24. Anderson AE, Pratt AG, Sedhom MA, et al. IL-6-driven STAT signalling in circulating CD4+ lymphocytes is a marker for early anticitrullinated peptide antibody-negative rheumatoid arthritis
. Annals of the Rheumatic Diseases 2016; 75:466–473.
25. Pratt AG, Lendrem D, Hargreaves B, et al. Components of treatment delay in rheumatoid arthritis
differ according to autoantibody status: validation of a single-centre observation using national audit data. Rheumatology (Oxford) 2016; 55:1843–1848.
26. Nakagawa I, Kamimura D, Atsumi T, et al. Role of inflammation amplifier-induced growth factor expression in the development of inflammatory diseases. Crit Rev Immunol 2015; 35:365–378.
27▪. Firestein GS, McInnes IB. Immunopathogenesis of rheumatoid arthritis
. Immunity 2017; 46:183–196.
This excellent review contains a helpful summary of mechanisms via which proinflammatory cytokines mediate systemic manifestations of rheumatoid arthritis.
28▪. Bommarito D, Hall C, Taams LS, Corrigall VM. Inflammatory cytokines
compromise programmed cell death-1 (PD-1)-mediated T cell suppression in inflammatory arthritis through up-regulation of soluble PD-1. Clin Exp Immunol 2017; 188:455–466.
An intriguing new mechanism via which inflammatory cytokines mediate CD4+ T-cell dysregulation is proposed on the basis of these experiments.
29. Crowley T, O’Neil JD, Adams H, et al. Priming in response to pro-inflammatory cytokines
is a feature of adult synovial but not dermal fibroblasts. Arthritis Res Ther 2017; 19:35.
30▪▪. Filer A, Ward LS, Kemble S, et al. Identification of a transitional fibroblast function in very early rheumatoid arthritis
. Annals of the Rheumatic Diseases 2017; 76:2105–2112.
Work from this group has established the synovial fibroblast as an active player in RA pathogenesis. These experiments demonstrate these cells develop a unique and transient phenotype in very early synovitis, exemplified by an altered response to IL-6 exposure.
31▪. Kragstrup TW, Greisen SR, Nielsen MA, et al. The interleukin
-20 receptor axis in early rheumatoid arthritis
: novel links between disease-associated autoantibodies and radiographic progression. Arthritis Res Ther 2016; 18:61.
This study suggests that the activity of IL-20 and related cytokines have a predictive role restricted to early rheumatoid arthritis with respect to disease severity, consistent with a temporal window in which they are pathogenetically more influential.
32▪▪. Rauber S, Luber M, Weber S, et al. Resolution of inflammation by interleukin
-9-producing type 2 innate lymphoid cells. Nat Med 2017; 23:938–944.
Having identified that autoimmune inflammatory arthritis (AIA) in IL-9−/− mice failed to resolve, this work dissected a role for IL-9 in facilitating resolution of autoimmune inflammation that was dependent upon type 2 ILCs. Some evidence for a relationship between IL-9 levels and rheumatoid arthritis activity is also presented, consistent with the possibility that the same mechanisms are important in human autoimmunity.
33. Jones GW, Bombardieri M, Greenhill CJ, et al. Interleukin
-27 inhibits ectopic lymphoid-like structure development in early inflammatory arthritis. J Exp Med 2015; 212:1793–1802.
34. Burmester GR, Rigby WF, van Vollenhoven RF, et al. Tocilizumab combination therapy or monotherapy or methotrexate monotherapy in methotrexate-naive patients with early rheumatoid arthritis
: 2-year clinical and radiographic results from the randomised, placebo-controlled FUNCTION trial. Ann Rheum Dis 2017; 76:1279–1284.
35. Emery P, Bingham CO3rd, Burmester GR, et al. Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naive patients with early, active rheumatoid arthritis
with poor prognostic factors: 1-year results from C-EARLY, a randomised, double-blind, placebo-controlled phase III study. Ann Rheum Dis 2017; 76:96–104.
36. Burmester GR, McInnes IB, Kremer J, et al. A randomised phase IIb study of mavrilimumab, a novel GM-CSF receptor alpha monoclonal antibody, in the treatment of rheumatoid arthritis
. Ann Rheum Dis 2017; 76:1020–1030.
37. Cooles FA, Anderson AE, Lendrem D, et al. The interferon gene signature is increased in early rheumatoid arthritis
and predicts a poorer response to initial therapy. J Allergy Clin Immunol 2017; doi: 10.1016/j.jaci.2017.08.026. [Epub ahead of print].
38▪. Orr C, Sousa E, Boyle DL, et al. Synovial tissue research: a state-of-the-art review. Nat Rev Rheumatol 2017; 13:463–475.
This review contains a helpful summary of means by which synovial tissue may have value in predicting therapeutic responsiveness in future, and the direction of research in this developing field.