Key Points
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Rheumatoid arthritis (RA) is associated with severe ocular surface complications such as scleritis
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RA is the most common autoimmune disease associated with dry eye syndrome
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The immunological landscape of the eye has much in common with that of the joint in RA; the eye is accessible to noninvasive techniques for monitoring the changes in the immune system in RA
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Innate and adaptive defences of the eye and the joint are disturbed in RA, which can result in different clinical manifestations of ocular surface inflammation
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Systemic treatment of RA counteracts ocular complications; topical, targeted treatment of ocular surface inflammation with less toxicity could be possible for RA
Abstract
Rheumatoid arthritis (RA), the most common autoimmune disorder associated with dry eye syndrome, is also associated with sight-threatening ocular diseases such as peripheral ulcerative keratitis, scleritis and corneal melts. Tissue damage on the ocular surface of patients with RA is autoimmune-mediated. Findings from patients with dry eye have implicated defects in innate immunity (Toll-like receptors, S100A and resident antigen-presenting cells), cytokines, chemokines and T helper (TH)-cell subsets (including TH1 and TH17) in disease pathogenesis. Some of these features are probably important in dry eye related to RA, which can occur at a different time from articular disease and is more clinically severe than idiopathic dry eye. Ocular surface immune factors can be influenced by the systemic immune landscape. Depending on the severity of ocular inflammation in RA, treatment can include ciclosporin, topical corticosteroids, tacrolimus, autologous serum and systemic immunosuppression. Tissue damage is treated by inhibiting matrix metalloproteinases. Potential therapeutic strategies benefit from an improved understanding of ocular surface immunology, and include targeting of T-cell subsets, B-cell signalling or cytokines.
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Change history
25 June 2014
In the version of this article initially published online, the name of author York Kiat Tan was misspelled. The error has been corrected for the HTML, PDF and print versions of the article.
References
Firestein, G. S. Evolving concepts of rheumatoid arthritis. Nature 423, 356–361 (2003).
Widdifield, J. et al. The epidemiology of rheumatoid arthritis (RA) in Ontario, Canada. Arthritis Rheum. 66, 786–793 (2014).
Albani, S., Koffeman, E. C. & Prakken, B. Induction of immune tolerance in the treatment of rheumatoid arthritis. Nat. Rev. Rheumatol. 7, 272–281 (2011).
Sibilia, J., Sordet, C., Mrabet, D. & Wachsmann, D. Understanding rheumatoid arthritis [German]. Rev. Prat. 55, 2134–2142 (2005).
Smith, J. B. & Haynes, M. K. Rheumatoid arthritis—a molecular understanding. Ann. Intern. Med. 136, 908–922 (2002).
Barabino, S. et al. Immune response in the conjunctival epithelium of patients with dry eye. Exp. Eye Res. 91, 524–529 (2010).
Knop, N. & Knop, E. Regulation of the inflammatory component in chronic dry eye disease by the eye-associated lymphoid tissue (EALT). Dev. Ophthalmol. 45, 23–39 (2010).
Stern, M. E., Schaumburg, C. S. & Pflugfelder, S. C. Dry eye as a mucosal autoimmune disease. Int. Rev. Immunol. 32, 19–41 (2013).
Kloppenburg, M. & Kwok, W. Y. Hand osteoarthritis—a heterogeneous disorder. Nat. Rev. Rheumatol. 8, 22–31 (2012).
Teoh, S. C. & Dick, A. D. Diagnostic techniques for inflammatory eye disease: past, present and future: a review. BMC Ophthalmol. 13, 41 (2013).
Ambati, B. K. et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature 443, 993–997 (2006).
Azar, D. T. Corneal angiogenic privilege: angiogenic and antiangiogenic factors in corneal avascularity, vasculogenesis, and wound healing (an American Ophthalmological Society thesis). Trans. Am. Ophthalmol. Soc. 104, 264–302 (2006).
Cursiefen, C. et al. Nonvascular VEGF receptor 3 expression by corneal epithelium maintains avascularity and vision. Proc. Natl Acad. Sci. USA 103, 11405–11410 (2006).
Li, J. et al. S100A expression in normal corneal-limbal epithelial cells and ocular surface squamous cell carcinoma tissue. Mol. Vis. 17, 2263–2271 (2011).
Zhou, L. et al. Identification of tear fluid biomarkers in dry eye syndrome using iTRAQ quantitative proteomics. J. Proteome Res. 8, 4889–4905 (2009).
Marsovszky, L. et al. In vivo confocal microscopic evaluation of corneal Langerhans cell density, and distribution and evaluation of dry eye in rheumatoid arthritis. Innate Immun. 19, 348–354 (2012).
Lee, S. Y., Petznick, A. & Tong, L. Associations of systemic diseases, smoking and contact lens wear with severity of dry eye. Ophthalmic Physiol. Opt. 32, 518–526 (2012).
Nataneli, N. & Chai, J. S. Images in clinical medicine: Bilateral corneal perforation. N. Engl. J. Med. 370, 650 (2014).
Artifoni, M., Rothschild, P. R., Brezin, A., Guillevin, L. & Puechal, X. Ocular inflammatory diseases associated with rheumatoid arthritis. Nat. Rev. Rheumatol. 10, 108–116 (2014).
Mohsenin, A. & Huang, J. J. Ocular manifestations of systemic inflammatory diseases. Conn. Med. 76, 533–544 (2012).
Akpek, E. K., Thorne, J. E., Qazi, F. A., Do, D. V. & Jabs, D. A. Evaluation of patients with scleritis for systemic disease. Ophthalmology 111, 501–506 (2004).
Ollier, W. E., Harrison, B. & Symmons, D. What is the natural history of rheumatoid arthritis? Best Pract. Res. Clin. Rheumatol. 15, 27–48 (2001).
Pincus, T. & Callahan, L. F. What is the natural history of rheumatoid arthritis? Rheum. Dis. Clin. North Am. 19, 123–151 (1993).
Humphreys, J. H. & Symmons, D. P. Postpublication validation of the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis: where do we stand? Curr. Opin. Rheumatol. 25, 157–163 (2013).
Fujita, M. et al. Correlation between dry eye and rheumatoid arthritis activity. Am. J. Ophthalmol. 140, 808–813 (2005).
The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul. Surf. 5, 75–92 (2007).
Stevenson, W., Chauhan, S. K. & Dana, R. Dry eye disease: an immune-mediated ocular surface disorder. Arch. Ophthalmol. 130, 90–100 (2012).
Bouysset, M., Noel, E. & Tebib, J. G. Rheumatoid arthritis: a general disease and local diseases [French]. Rev. Prat. 55, 2121–2133 (2005).
Lemp, M. A. Dry eye (Keratoconjunctivitis Sicca), rheumatoid arthritis, and Sjogren's syndrome. Am. J. Ophthalmol. 140, 898–899 (2005).
Markovitz, E., Perry, Z. H., Tsumi, E. & Abu-Shakra, M. Ocular involvement and its' manifestations in rheumatoid arthritis patients [Hebrew]. Harefuah 150, 713–718 (2011).
Angayarkanni, N. et al. Tear specific potential protein biomarker identification by 2D-DIGE based proteomics in dry eye syndrome associated with rheumatoid arthritis [abstract 4308]. Presented at Association of Research in Vision and Ophthalmology 2013.
Danjo, Y., Lee, M., Horimoto, K. & Hamano, T. Ocular surface damage and tear lactoferrin in dry eye syndrome. Acta Ophthalmol. (Copenh.) 72, 433–437 (1994).
Yolton, D. P., Mende, S., Harper, A. & Softing, A. Association of dry eye signs and symptoms with tear lactoferrin concentration. J. Am. Optom. Assoc. 62, 217–223 (1991).
Saal, J. G. et al. Keratomalacia in rheumatoid arthritis: immunohistologic and enzyme histochemical studies [German]. Z. Rheumatol. 50, 151–159 (1991).
Villani, E., Galimberti, D., Papa, N. D., Nucci, P. & Ratiglia, R. Inflammation in dry eye associated with rheumatoid arthritis: Cytokine and in vivo confocal microscopy study. Innate Immun. 19, 420–427 (2013).
Sommerfelt, R. M., Feuerherm, A. J., Jones, K. & Johansen, B. Cytosolic phospholipase A2 regulates TNF-induced production of joint destructive effectors in synoviocytes. PLoS ONE 8, e83555 (2013).
Hata, M. et al. Atypical continuous keratitis in a case of rheumatoid arthritis accompanying severe scleritis. Cornea 31, 1493–1496 (2012).
Karampetsou, M. P., Liossis, S. N. & Sfikakis, P. P. TNF-α antagonists beyond approved indications: stories of success and prospects for the future. QJM 103, 917–928 (2010).
Kang, M. H. et al. Interleukin-17 in various ocular surface inflammatory diseases. J. Korean Med. Sci. 26, 938–944 (2011).
Oh, J. Y. et al. Investigating the relationship between serum interleukin-17 levels and systemic immune-mediated disease in patients with dry eye syndrome. Korean J. Ophthalmol. 25, 73–76 (2011).
Okada, M. et al. Retinal venular calibre is increased in patients with autoimmune rheumatic disease: a case-control study. Curr. Eye Res. 38, 685–690 (2013).
Van Doornum, S. et al. Retinal vascular calibre is altered in patients with rheumatoid arthritis: a biomarker of disease activity and cardiovascular risk? Rheumatology (Oxford) 50, 939–943 (2011).
Klein, R., Klein, B. E., Knudtson, M. D., Wong, T. Y. & Tsai, M. Y. Are inflammatory factors related to retinal vessel caliber? The Beaver Dam Eye Study. Arch. Ophthalmol. 124, 87–94 (2006).
Wooley, P. H., Luthra, H. S., Stuart, J. M. & David, C. S. Type II collagen-induced arthritis in mice. I. Major histocompatibility complex (I region) linkage and antibody correlates. J. Exp. Med. 154, 688–700 (1981).
Komatsu, N. & Takayanagi, H. Autoimmune arthritis: the interface between the immune system and joints. Adv. Immunol. 115, 45–71 (2012).
Stuart, J. M. & Dixon, F. J. Serum transfer of collagen-induced arthritis in mice. J. Exp. Med. 158, 378–392 (1983).
Stuart, J. M., Tomoda, K., Yoo, T. J., Townes, A. S. & Kang, A. H. Serum transfer of collagen-induced arthritis. II. Identification and localization of autoantibody to type II collagen in donor and recipient rats. Arthritis Rheum. 26, 1237–1244 (1983).
Taniguchi, H., Wang, M. C., Nakajima, A. & Hori, J. ocular immune pathological analysis in a murine model of anterior scleritis [abstract 6246]. Presented at Association of Research in Vision and Ophthalmology 2012.
Niederkorn, J. Y. et al. Desiccating stress induces T cell-mediated Sjogren's syndrome-like lacrimal keratoconjunctivitis. J. Immunol. 176, 3950–3957 (2006).
Zhang, X. et al. Desiccating stress induces CD4+ T-cell-mediated Sjogren's syndrome-like corneal epithelial apoptosis via activation of the extrinsic apoptotic pathway by interferon-γ. Am. J. Pathol. 179, 1807–1814 (2011).
Zheng, X., de Paiva, C. S., Li, D. Q., Farley, W. J. & Pflugfelder, S. C. Desiccating stress promotion of Th17 differentiation by ocular surface tissues through a dendritic cell-mediated pathway. Invest. Ophthalmol. Vis. Sci. 51, 3083–3091 (2010).
Zhang, X. et al. NK cells promote Th-17 mediated corneal barrier disruption in dry eye. PLoS ONE 7, e36822 (2012).
Yoon, K. C. et al. Expression of Th-1 chemokines and chemokine receptors on the ocular surface of C57BL/6 mice: effects of desiccating stress. Invest. Ophthalmol. Vis. Sci. 48, 2561–2569 (2007).
El Annan, J. et al. Regulation of T-cell chemotaxis by programmed death-ligand 1 (PD-L1) in dry eye-associated corneal inflammation. Invest. Ophthalmol. Vis. Sci. 51, 3418–3423 (2010).
Li, S., Nikulina, K., Vijmasi, T. & McNamara, N. in Association of Research in Vision and Ophthalmology 5332 (Fort Lauderdale, USA, 2008).
DeVoss, J. et al. Cellular control of autoimmunity in the Aire-deficient mouse model of Sjögren's syndrome [abstract 190]. Presented at Association of Research in Vision and Ophthalmology 2008.
McNamara, N. A. et al. Essential role of CD4+ T cell-dependent macrophage infiltration in the pathogenesis of Sjögren's syndrome-associated dry eye [abstract 1282]. Presented at the Association of Research in Vision and Ophthalmology 2012.
Okuma, A. et al. Enhanced apoptosis by disruption of the STAT3-IκB-ζ signaling pathway in epithelial cells induces Sjogren's syndrome-like autoimmune disease. Immunity 38, 450–460 (2013).
Chen, J. et al. Comprehensive evaluation of different T-helper cell subsets differentiation and function in rheumatoid arthritis. J. Biomed. Biotechnol. 2012, 535361 (2012).
Brejchova, K., Liskova, P., Cejkova, J. & Jirsova, K. Role of matrix metalloproteinases in recurrent corneal melting. Exp. Eye Res. 90, 583–590 (2010).
Choi, H. M., Lee, Y. A., Yang, H. I., Yoo, M. C. & Kim, K. S. Increased levels of thymosin beta4 in synovial fluid of patients with rheumatoid arthritis: association of thymosin β4 with other factors that are involved in inflammation and bone erosion in joints. Int. J. Rheum. Dis. 14, 320–324 (2011).
Johnson, A. C. et al. Activation of toll-like receptor (TLR)2, TLR4, and TLR9 in the mammalian cornea induces MyD88-dependent corneal inflammation. Invest. Ophthalmol. Vis. Sci. 46, 589–595 (2005).
Rodriguez-Martinez, S., Cancino-Diaz, M. E. & Cancino-Diaz, J. C. Expression of CRAMP via PGN-TLR-2 and of alpha-defensin-3 via CpG-ODN-TLR-9 in corneal fibroblasts. Br. J. Ophthalmol. 90, 378–382 (2006).
Zhang, L. et al. TLR-mediated induction of proinflammatory cytokine IL-32 in corneal epithelium. Curr. Eye Res. 38, 630–638 (2013).
Zhang, L., Lu, R., Zhao, G., Pflugfelder, S. C. & Li, D. Q. TLR-mediated induction of pro-allergic cytokine IL-33 in ocular mucosal epithelium. Int. J. Biochem. Cell Biol. 43, 1383–1391 (2011).
Cawthorne, C. et al. Biodistribution, pharmacokinetics and metabolism of interleukin-1 receptor antagonist (IL-1RA) using [18F]-IL1RA and PET imaging in rats. Br. J. Pharmacol. 162, 659–672 (2011).
O'Neill, L. A. TAMpering with Toll-like receptor signaling. Cell 131, 1039–1041 (2007).
Choi, W. et al. Expression of CCR5 and its ligands CCL3, -4, and -5 in the tear film and ocular surface of patients with dry eye disease. Curr. Eye Res. 37, 12–17 (2012).
Maurice, M. M. et al. Defective TCR-mediated signaling in synovial T cells in rheumatoid arthritis. J. Immunol. 159, 2973–2978 (1997).
Pierer, M. et al. Clonal expansions in selected TCR BV families of rheumatoid arthritis patients are reduced by treatment with the TNFα inhibitors etanercept and infliximab. Rheumatol. Int. 31, 1023–1029 (2011).
Wolf, F., Schargus, M., Feuchtenberger, M. & Geerling, G. Correlation of tear film osmolarity and rheumatic disease activity in patients with rheumatoid arthritis [3787]. Presented at the Association of Research in Vision and Ophthalmology 2011 meeting.
Knox Cartwright, N. E., Tole, D. M., Georgoudis, P. & Cook, S. D. Peripheral ulcerative keratitis and corneal melt: a 10-year single center review with historical comparison. Cornea 33, 27–31 (2014).
Tong, L. et al. Impact of symptomatic dry eye on vision-related daily activities: the Singapore Malay Eye Study. Eye (Lond.) 24, 1486–1491 (2010).
Buchholz, P. et al. Utility assessment to measure the impact of dry eye disease. Ocul. Surf. 4, 155–161 (2006).
Hengge, U. R., Ruzicka, T., Schwartz, R. A. & Cork, M. J. Adverse effects of topical glucocorticosteroids. J. Am. Acad. Dermatol. 54, 1–15; quiz 16–8 (2006).
Petznick, A. et al. Autologous plasma eyedrops prepared in a closed system: a treatment for dry eye. Eye (Lond.) 27, 1102 (2013).
Pan, Q. et al. Autologous serum eye drops for dry eye. Cochrane Database of Systematic Reviews, Issue 8. Art. No.: CD009327. http://dx.doi.org/10.1002/14651858.CD009327.pub2.
Quinto, G. G., Campos, M. & Behrens, A. Autologous serum for ocular surface diseases. Arq. Bras. Oftalmol 71, 47–54 (2008).
Dogru, M. & Tsubota, K. Pharmacotherapy of dry eye. Expert Opin. Pharmacother. 12, 325–334 (2011).
Liu, J., Kuszynski, C. A. & Baxter, B. T. Doxycycline induces Fas/Fas ligand-mediated apoptosis in Jurkat T lymphocytes. Biochem. Biophys. Res. Commun. 260, 562–567 (1999).
Jap, A. & Chee, S. P. Immunosuppressive therapy for ocular diseases. Curr. Opin. Ophthalmol. 19, 535–540 (2008).
Iaccheri, B. et al. Rituximab treatment for persistent scleritis associated with rheumatoid arthritis. Ocul. Immunol. Inflamm. 18, 223–225 (2010).
Gottenberg, J. E. et al. Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann. Rheum. Dis. 64, 913–920 (2005).
US National Library of Medicine. ClinicalTrials.gov [online], (2013).
Okanobo, A., Chauhan, S. K., Dastjerdi, M. H., Kodati, S. & Dana, R. Efficacy of topical blockade of interleukin-1 in experimental dry eye disease. Am. J. Ophthalmol. 154, 63–71 (2012).
Amparo, F. et al. Topical interleukin 1 receptor antagonist for treatment of dry eye disease: a randomized clinical trial. JAMA Ophthalmol. 131, 715–723 (2013).
Brown, C., Toth, A. & Magnussen, R. Clinical benefits of intra-articular anakinra for persistent knee effusion. J. Knee Surg. 24, 61–65 (2011).
Sadrai, Z. et al. PDE4 inhibition suppresses IL-17-associated immunity in dry eye disease. Invest. Ophthalmol. Vis. Sci. 53, 3584–3591 (2012).
Semba, C. P. et al. Lifitegrast 5.0% ophthalmic solution reduces ocular surface staining and improves symptoms in patients with dry eye disease: results of a phase 3 study [abstract 2669]. Presented at Association of Research in Vision and Ophthalmology 2013 meeting.
West, K. CP-690550, a JAK3 inhibitor as an immunosuppressant for the treatment of rheumatoid arthritis, transplant rejection, psoriasis and other immune-mediated disorders. Curr. Opin. Investig. Drugs 10, 491–504 (2009).
Huang, J. F. et al. Immunomodulatory effect of the topical ophthalmic Janus kinase inhibitor tofacitinib (CP-690550) in patients with dry eye disease. Ophthalmology 119, e43–e50 (2012).
Liew, S. H. et al. Tofacitinib (CP-690550), a Janus kinase inhibitor for dry eye disease: results from a phase 1/2 trial. Ophthalmology 119, 1328–1335 (2012).
Li, J. et al. Therapeutic efficacy of trehalose eye drops for treatment of murine dry eye induced by an intelligently controlled environmental system. Mol. Vis. 18, 317–329 (2012).
Corvaisier, M. et al. IL-26 is overexpressed in rheumatoid arthritis and induces proinflammatory cytokine production and TH17 cell generation. PLoS Biol. 10, e1001395 (2012).
Hirota, K. et al. Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model. J. Exp. Med. 204, 2803–2812 (2007).
Kochi, Y. et al. A regulatory variant in CCR6 is associated with rheumatoid arthritis susceptibility. Nat. Genet. 42, 515–519 (2010).
Serrano Hernandez, A. Helper (TH1, TH2, TH17) and regulatory cells (Treg, TH3, NKT) in rheumatoid arthritis [Spanish]. Reumatol. Clin. 5 (Suppl. 1), 1–5 (2009).
Toh, M. L., Kawashima, M., Hot, A. & Miossec, P. Role of IL-17 in the TH1 systemic defects in rheumatoid arthritis through selective IL-12Rβ2 inhibition. Ann. Rheum. Dis. 69, 1562–1567 (2010).
van Hamburg, J. P. et al. TH17 cells, but not TH1 cells, from patients with early rheumatoid arthritis are potent inducers of matrix metalloproteinases and proinflammatory cytokines upon synovial fibroblast interaction, including autocrine interleukin-17A production. Arthritis Rheum. 63, 73–83 (2011).
Acknowledgements
L.T. is supported by the Singapore National Research Foundation under its clinician scientist award NMRC/CSA/045/2012 and administered by the Singapore Ministry of Health's National Medical Research Council, and by the Singapore Biomedical Research Council BMRC 10/1/35/19/670. S.A. is supported by the NMRC Singapore Translational Research (STAR) Award NMRC/STaR/020/2013, Duke-National University of Singapore and Singapore Health Services.
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Tong, L., Thumboo, J., Tan, Y. et al. The eye: a window of opportunity in rheumatoid arthritis?. Nat Rev Rheumatol 10, 552–560 (2014). https://doi.org/10.1038/nrrheum.2014.85
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DOI: https://doi.org/10.1038/nrrheum.2014.85
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