REVIEWS The eye: a window of opportunity in rheumatoid arthritis? Louis Tong, Julian Thumboo, York Kiat Tan, Tien-Yin Wong and Salvatore Albani 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 autoimmunemediated. 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 (T H)-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. Tong, L. et al. Nat. Rev. Rheumatol. advance online publication 10 June 2014; corrected online 25 June 2014; doi:10.1038/nrrheum.2014.85

Introduction

Singapore Eye Research Institute, Singapore National Eye Center, 11 Third Hospital Avenue, 168751, Singapore (L.T., T.‑Y.W.). Department of Rheumatology and Immunology, Singapore General Hospital, Outram Road, 169608, Singapore (J.T., Y.K.T.). SingHealth/Duke-NUS Translational Immunology and Inflammation Centre, 20 College Road, 169856, Singapore (S.A.).

Rheumatoid arthritis (RA) is the most common sys­ temic autoimmune disease, affecting approximately 1% of the population.1,2 Over the years, various advances in the molecular understanding of RA have occurred, inclu­d ing involvement of inflammatory and auto­ immune pathways that lead to tissue damage.3–5 Despite the systemic nature of the disease, most RA research is focused on the synovial and cartilage tissues. Only lately have investigations into the immunology of ocular surface inflammation that leads to dry eye improved.6–8 Here, we underscore the similarities among the patho­ genic pathways affecting various target organs in systemic RA, including ocular surface dysfunctions, in particu­ lar dry eye. We also describe evidence of the immuno­ pathogenic pathways particular to the ocular surface in the course of systemic auto­immunity in RA. Advanced imaging tools (such as MRI or ultra­sono­graphy) enable direct visualization and accurate measure­ment of jointspecific inflammation, at the same time,9 tools that determine the severity of ocular disease (such as levels of cytokines in tears, impres­sion cyto­logy, automated grading of conjunctival hyperae­mia and in vivo imag­ ing of immune cells and lymphatics) have advanced the study of ocular surface immun­ology.10 Knowledge of shared and organ-specific processes should shape em­erging and future therapeutic approaches to dry eye. For those pathways that are shared between ocular and systemic effects, it is important to emphasize that

Correspondence to: L.T. louis.tong.h.t@ snec.com.sg

Competing interests The authors declare no competing interests.

the accessibility of the ocular surface could offer a unique opportunity to noninvasively assess systemic pathogenic mechanisms. This knowledge, once vali­ dated, might provide useful biomarkers to monitor and even predict disease progression in RA.

Immune system of the ocular surface The ocular innate and adaptive immune defences serve to protect the eye against pathogens and other immune insults. However, excessive activation of the immune sys­tem leads to inflammation and auto­immunity. In the absence of overt ocular insults, therefore, various mechanisms need to be in place to maintain a somewhat suppressed immune system. Several immunological mechanisms operate to sup­ press innate immunity in the eye.6,7 These mechanisms include production of the anti-inflammatory cytokine IL‑13, the absence and/or suppression of HLA-DR (CLII), HLA-B7 and CD40, autophago­cytosis and, pos­ sibly, the sequestration of auto­reactive antigens. The avascular state of the normal central cornea also helps to prevent activation of innate immune pathways. 11–13 Levels of many alarmins in RA have been found to be elevated in dry eye. The S100A8 and S100A9 proteins are normally expressed by human corneal and limbal epithelial cells,14 and have been found to be upregu­lated in the tears of patients with dry eye. 15 However, these proteins have not been detected specifically in patients with RA and dry eye. In people with RA without ocular symptoms, the num­­­ber of antigen-presenting Langerhans cells in

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REVIEWS Key points ■■ Rheumatoid arthritis (RA) is associated with severe ocular surface complications such as scleritis ■■ RA is the most common autoimmune disease associated with dry eye syndrome ■■ 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 ■■ 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 ■■ Systemic treatment of RA counteracts ocular complications; topical, targeted treatment of ocular surface inflammation with less toxicity could be possible for RA

the cen­tral and peripheral cornea were increased com­ pared with individuals without RA. This finding suggests a heightened state of the innate immune system even without overt ocular disease.16 We hypothesize that this condition, together with a previous immune signature (such as memory T cells from articular damage in RA), can trigger ocular surface inflammation that is often clinically more severe than in idiopathic dry eye.17,18 Similar mechanisms operate to suppress the activa­ tion of the adaptive immune response. These include the negative selection of autoreactive T‑cell clones, the pres­ ence of suppressive CD4+ regulatory T cells in the lamina propria of the conjunctiva, the suppressive CD8+ cyto­ toxic T cells and the quiescent dendritic or Langerhans cells within the conjunctival epithelia. The immunetolerant state conferred by the eye-associated lymphoid tissue was also maintained by immature macrophages or monocytes in the deep stroma of the conjunctiva.7 As the ocular surface has a critical role in defence against microbes and other insults, local immune sup­ pression that is prescribed for autoimmune dis­e ases should ideally be highly targeted, based on inter­ference of known disease-mediating pathways, so as not to c­ompromise this critical physiological role.

Ocular inflammation in RA RA can cause episcleritis, peripheral ulceratitive kerati­ tis, corneal melts, anterior nodular scleritis, necrotizing scleritis (scleromalacia perforans), conjunctival nodules and, more rarely, optic neuritis, anterior ischaemic optic neuropathy and retinal vasculitis.19,20 In one study, 107 of 243 (44%) patients with scleritis were found to have an underlying systemic disease. Of these 107 patients, 14% had their systemic conditions diagnosed as a result of the initial eye evaluation, and 8.4% developed a sys­ temic disease during follow-up, which means that the ocular surface complications facilitated or preceded the systemic diagnosis. The most frequent rheumatic disease in this study was RA (15.2% or 37 of 243 patients with scleritis).21 In some patients with RA, disease activity can last only 2–5 years (often because of early or aggres­sive therapy).22,23 Nevertheless, the relationship of ocular com­ plications to the overall duration of activity and natu­ral history of RA is still not known. Dry eye, unlike scleritis, might not be limited to late-phase RA. Increased collabo­ ration between ophthalmologists and rheumatologists

might be necessary, and indeed some ocular manifes­ tations could be included in the regularly revised RA d­iagnostic criteria24 in the future. Immunological profiles that distinguish between each of the clinical ocular surface disease entities in RA are limited. Dry eye disease, for which the immunological basis is described later, is the most commonly encoun­ tered ocular manifestation of RA.25 Consequently, we will focus here mostly, but not exclusively, on RA‑associated dry eye and immune-mediated animal models of ocular surface inflammation.

Clinical evidence The most common example of ocular surface inflam­ mation is dry eye. Dry eye is a multifactorial disease of the tear and ocular surface associated with symptoms, potential damage to the ocular surface, hyperosmolarity of tears and increased inflammation.26 Despite the pos­ sibility of diverse triggering factors, it has been found that systemic immunological factors and endocrino­logical status of the patient are also important. In human dry eye, the role of immune factors extend to both Sjögren’s and non-Sjögren’s syndromes, but the primary or se­condary nature of these factors might need to be determined.26 The ocular surface damage and visual impairment in a patient with RA and dry eye is often more severe than in idiopathic dry eye.17 The pathology of dry eye is immune-mediated, with dysregulation of the antigenpresenting cells (APCs), afferent limbs and efferent limbs of the immune response.6,27 Patients with RA who have dry eye commonly develop secondary Sjögren’s syndrome, with lymphocytic infiltra­ tion and destruction of acini in the lacrimal glands. The clinical severity of these cases of dry eye resembles those from primary Sjögren’s syndrome (in terms of clinical symptoms and corneal epithelial damage as evidenced by corneal fluorescein dye staining) more than those in idiopathic dry eye. In addition, the infiltration of the larimal gland with lymphocytes in RA was also not distin­ guishable from those in microscopic sections of lacrimal glands obtained from patients with primary Sjögren’s syn­ drome.25,28–30 These features suggest that there might be some autoimmune mechanisms causing dry eye common to more than one systemic autoimmune disease. In a study of 72 patients with RA, 10% satisfied the Japanese criteria for secondary Sjögren’s syndrome (dry eye and dry mouth), but as high as 90% had dry eye symptoms.25 Corneal epitheliopathy was found to be more severe in patients with RA than other patients with dry eye in a clinic-based study; this pattern of involvement on the cornea was more generalized, and often extended to the superior zone of the cornea.17 Such clinical signs might alert an experienced clinician to the possibility of underlying systemic inflammation. A study using 2D-DIGE (difference gel electro­ phoresis) proteomics to test the tear fluid from patients with dry eye syndrome associated with RA 31 found protein levels of lactotransferrin to be downregulated, which is a finding similar to those in idiopathic dry eye.32,33 Three proteins were found to be upregulated,

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REVIEWS Pathological mediators

Driving chronic ocular surface inflammation

Pathological events

Conjunctival intraepithelial NK cells

Antigenpresenting cell

T cell

IL-6

Plasmacytoid dendritic cell IL-1β IL-26? TNF IL-23?

Memory TCRζ dim T cells

Migration of TH17 cells to lacrimal glands and ocular surface

CCR-6+ TH17 cell

IL-15 IL-22 IL-21

IL-17A Cytokine Chemoattractant for committed TH17 and neutrophils Effector

IL-6 IL-8 IFN-γ

MMP-1

MMP-3

Breach in self-tolerance

Proteolysis of tight junctions Ocular surface epitheliopathy

Figure 1 | TH17 cell polarisation in RA‑associated ocular surface inflammation. Schematic of the regulation of TH17 cell polarisation in ocular surface inflammation associated with RA.52,94–99 NK cells are involved in the activation of plasmacytoid dendritic cells, which have a role in antigen presentation in the ocular surface (middle). The roles of some cytokines, although described in systemic RA, are still uncertain in the ocular surface (indicated by ‘?’). The role of mediators is shown on the left, whereas the corresponding pathological events are shown on the right. The TH17 pathway regulation in the ocular surface is not completely understood, and some regulatory steps are inferred from the systemic or articular domains. Abbreviations: MMP, matrix metalloproteinase; NK (cell), natural killer (cell); RA, rheumatoid arthritis; TCR, T‑cell receptor; TH17 (cell), type 17 T helper (cell).

ecto-ADP ribosyltransferase 5 precursor, Rho-related GTP-binding protein and RhoJ precursor. Ulceration and melting of the cornea are common in severe ocular surface inflammation of any origin, including severe dry eye. A study assessing corneal and conjunctival biopsy samples of 13 patients with RA and corneal ulceration found that the conjunctival epithe­ lial cells of these patients showed strong expression of HLA-DR and DP antigens. In addition, the corneal stromal fibroblasts in these samples strongly expressed lysosomal elastase. The study authors stated that this elastase mediated the degradation of the corneal tissue, causing the corneal melts.34 In a study of 24 patients with RA treated with sys­ temic prednisone (starting with 1 mg/kg before adopt­ ing a tapering scheme), and methotrexate (0.3 mg/kg per week) until remission of systemic disease activity, ocular examination and investigations related to ocular immune markers were performed prior to systemic treatment and after remission. In the 12 patients with secondary Sjögren’s syndrome, corneal dendritic cell density and tear levels of IL‑1α, IL‑6, IL‑8 and TNF were elevated prior to systemic treatment, and these cytokines levels, especially IL‑1α and IL‑6, were respon­ sive (decreased) once RA was controlled with systemic treatment. Systemic treatment did not substantially affect these parameters in another 12 patients with RA without secondary Sjögren’s syndrome.35 This study shows that

systemic treatment of RA benefits the ocular effects of RA, suggesting that common inflammatory mediators exist in systemic and ocular RA. Inflammatory mediators such as TNF are elevated in the joints36 and tears35 in patients with RA. The impor­ tance of TNF in this context was illustrated by clinical improvement in sight-threatening ocular surface disease in RA such as scleritis and peripheral ulcerative keratitis after treatment with infliximab (a monoclonal antibody against TNF).37 This finding was again corroborated by other studies that found improvement of these condi­ tions with other types of anti-TNF agents (adalimumab, certolizumab and golimumab).38 Furthermore, some soluble immune elements involved in RA might be differentially regulated at the ocular surface. The levels of IL‑17 in tears were raised in patients with autoimmune keratitis associated with RA.39 In the serum, however, IL‑17 levels were not increased in patients with dry eye associated with RA compared with those with chronic graft versus host dis­e ase. 40 These findings imply that inflammation in the ocular surface is not just a result of upregulation of circulatory cytokines due to systemic RA, but that local immune responses are also involved. In fact, there might be a complex cascade of events leading to type 17 T helper (TH17) cell activation (Figure 1). Unfortunately, certain molecules involved in the TH17 pathway are not as well characteriz­ed in the ocular surface as in the joint. Despite the fact that retinal vasculitis is not a feature of RA, retinal vascular calibre in patients with RA has been linked to systemic inflammatory factors in two clinic-based studies 41,42 and one population-based study. 43 These patients did not have uveitis or evi­ dence of intraocular inflammation, but retinal vascular calibre was increased in patients with RA and associated with increased C‑reactive protein levels. 41 Eyes with wider retinal veins were associated with higher serum C‑reactive protein, IL‑6 and amyloid A levels than eyes with narrower veins.43

Evidence from animal studies Collagen-induced arthritis model The closest animal model for human RA that has ocular manifestations is based on an autoimmune response against administration of type II collagen into the joints of mice.44,45 As in humans, susceptibility to RA in mice depends on MHC regions (equivalent to HLA in humans). Articular disease can be transferred with serum from CIA mice. Pathogenesis in the recipient mice is owing to transferred autoantibodies rather than T cells.46,47 In this model, male DBA/1J mice were immunized with bovine type II collagen (emulsified in complete Freund’s adjuvant) intradermally at the base of the tail. Mice were challenged after 21 days with type II colla­ gen (with incomplete Freund’s adjuvant) at the tail, back of the neck or around the eye. The mice with second­ ary challenge around the eye showed anterior scleral inflammation, characterized by increased infiltration of immune cells (CD4+ and CD11b+, but not CD11c+) in the

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REVIEWS anterior sclera and thickening of the sclera. The central cornea and posterior segment of the eye remained unaf­ fected. These mice have also been shown to have depo­ sition of plasma cells (CD138+), complement C3 and immunoglobulins IgG and IgM in the anterior sclera.48 The tear function and presence of dry eye were not explored in this scleritis model. Dessication dry eye model A mouse model of dry eye has been developed by scopo­lamine injection and fan blowing in a dessicat­ ing environ­m ent; notably, it is actually possible to con­fer the dry eye disease phenotype to a nude mouse with­out expo­sure to dessicating stimuli after adop­tive trans­fer of CD4+ T cells from a mouse with dry eye.49,50 Interest­ingly, this transfer model does not work with T cells from an arthropathic mouse. In this model, de­ssication-stress promotes the differentiation of T cells into TH17 cells.51 CD4+ T cells co-cultured with den­ dri­tic cells and epithelial explants from mice with dry eye expressed increased levels of IL‑17A, IL‑17F, IL‑22, CCL20, and retinoic acid receptor-related orphan receptor-γ (ROR‑γ), as well as increased numbers of IL‑17-producing T cells. Generation of T H17 cells in the ocular sur­face is, therefore, likely to be medi­ated by dendritic cells. Intra­epithelial natural killer cells in the conjunctival membrane also promote TH17 differen­ tiation and loss of epithelial barriers in dry eye. 52 The antigen trigger­ing the immune response is not known. Nevertheless, the disease is immune-mediated as it can be acquired by adoptive transfer of CD4+ T cells.49 The phenotype can be rescued by concurrent transfer of regu­latory T cells from a unstimulated mouse, suggest­ ing that the formation of the dry eye phenotype required a regulatory-T-cell defect. Dessicating stress promotes the expression of type 1 T helper (TH1) chemokines and chemokine receptors in the ocular surface of C57BL/6 mice.53 CCL3 (also known as MIP‑1α), CCL4 (also known as MIP‑1β), CXCL9 (also known as MIG) and CXCL10 (also known as IP‑10) were increased in the corneal and conjunctival epithelia of the mice. At the same time, levels of RANTES, CXCL9 and CXCL10 were increased in the conjunctiva. The expression of the TH1 chemokine receptor CCR5 was also increased, together with its ligands CCL3 and CCL4 in the cornea and conjunctiva of these mice. Levels of the transcripts encoding TH2 chemokine receptor CCR3 and ligands CCL7 (also known as MCP3) and eotaxin‑1 were also increased. The T  cells from the draining lymph nodes of de­s sication-induced dry eye in mice were analysed by another group. The investigators found markedly higher expression of CD69 and CCR5 by these T cells than T cells from control mice. Interfering with corneal epithelial programmed cell death 1 ligand 1 (PD‑L1, with blocking antibodies, or in homozygous PD‑L1knockdown mice) increased the levels of dry-eye-­ associated inflammation in these mice, by increasing the expression of chemokine ligands and increased T‑cell homing to the ocular surface.54

The dessication mouse model might or might not be relevant to dry eye in RA. Nevertheless, should these multiple immunological disturbances (T H17 cells, chemokines and receptors) also occur in the context of human dry eye (with or without RA), they could poten­ tially form links to systemic immune processes. As such, these immune alterations could help to explain why ocular surface inflammation becomes more severe when the same immunological components are disturbed in systemic autoimmune disease. Aire dry eye model Balb/c mice deficient in the autoimmune regulator (Aire) gene provide a model of autoimmune-mediated aq­u eous-deficient dry eye disease. 55 This condition resembles human autoimmune dry eye, such as in Sjögren’s syndrome and to some extent, RA. In these mice, the cornea developed punctate epithelial kerati­ tis similar to human dry eye, as early as 4 weeks of age. This keratitis progressed to filamentary keratitis, which is a condition found in severe human dry eye. CD4+ T cells infiltrated the cornea and the eyelid by 4 weeks. As in human dry eye, the number of mucus-secreting Goblet cells quantified by Periodic acid–Schiff staining decreased, whereas the transcripts of genes responsible for fibrosis and inflammation (that is, genes encoding SPRR1b, IFN‑γ and IL‑1β) increased compared with heterozygous controls. In these mice, kinetic studies show lymphocytic infil­ tration in the lacrimal glands with multiple foci of CD4+ and CD8+ T cells, as well as IgD+ B cells. In adop­tive trans­ fer studies, mature lymphocytes from draining lymph nodes were transferred into immunodeficient (SCID or RAG) mice. Mice receiving transferred Aire-deficient CD4+ and CD8+ T cells and IgD+ B cells had lacrimal and salivary gland pathology, but recipients that received wild-type control lymphocytes did not. Adoptive trans­ fer of Aire-deficient lymphocytes into immuno­deficient hosts failed to induce Sjögren’s sy­ndrome, showing that the disease was T‑cell dependent. In further experiments,56 the same group showed that Aire mutation in TCRα-deficient mice (which results in absence of T cells, failed to induce dry eye disease); in particular, TH1-polarized CD4+ T cells were found to be important in the pathogenesis of dry eye. In Aire-knockout mice, macrophages (F4/80 +) and T cells infiltrated into the corneal stroma, the limbus and the lacrimal glands, in addition to invasion by T cells.57 Depletion of local macrophages using subconjunctival injection of clodronate liposomes reduced ocular surface topical fluorescein dye staining (indicating less ocular surface damage) and subepithelial fibrosis. Systemic depletion of macrophages by intraperitoneal injection of liposomes reduced lacrimal gland inflammation and the function of tear secretion. These results indi­ cate that macro­phages are essential in the induction of T-cell-mediated damage to the ocular surface in dry eyes. Other mouse models that focus on specific molecules involved in inflammatory pathways are available. One such example is the STAT3-deficient mouse model,

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REVIEWS Table 1 | Immunological homeostasis in the physiology of the normal ocular surface and extraocular tissues Type of immune tolerance

Ocular surface

Extraocular tissues

Innate Immunity

Production of anti-inflammatory cytokine IL‑13 Absence and/or suppression of HLA-DR (CLII), HLA-B7 and CD40 Autophagocytosis Sequestration of unknown antigen?

Existence of barriers (sequestration of antigens) Avascularity, lack of lymphatics Paucity of innate immune cells (macrophages, mast cells and dendritic cells) in joints Lack of TLR4 signalling

Adaptive immunity

Negative selection of autoreactive T‑cell clones Suppressive CD4+ regulatory T cells (lamina propria) Suppressive CD8+ cytotoxic T cells (intraepithelial) Dendritic and/or Langerhan cells (epithelium) Immature macrophages and/or monocytes (deep stroma)

Central: positive selection, cells with no affinity to self-antigens die by neglect (apoptosis); negative selection or anergy, deletion of T cells and B cells (e.g. T cells with high affinity of self MHC) Peripheral: Anergy-induced, activation-induced and peripheral suppression cell death; acquired tolerance (e.g. oral or mucosal tolerance)

Abbreviations: MHC, major histocompatibility complex; TLR, Toll-like receptor.

Table 2 | Immunological landscapes when immune activation occurs in the eye and joint in rheumatoid arthritis Pathology

Ocular surface

Systemic immune response

Clinical syndromes

Keratoconjunctivitis sicca (secondary Sjögren’s syndrome), episcleritis, peripheral ulcerative keratitis, corneal melts, necrotizing scleritis (scleromalacia perforans), optic neuritis, anterior ischaemic optic neuropathy The clinical signs of dry eye are often severe, similar to dry eye from primary Sjögren’s syndrome; lacrimal gland infiltration with lymphocytes also not distinguishable

Articular: synovial swelling, cartilaginous damage, fibrosis and fusion of joints (e.g. carpometacarpal joints and cervical joints) Extra-articular: pneumonitis, pleuritis, pericarditis, subcutaneous nodules

Innate immunity

Increased HLA-DR and co-stimulatory molecules in professional APCs (dendritic cells) and conjunctival epithelial cells Danger signals expressed (S100A8, S100A9, neutrophil components LL‑37, extracellular DNA, decrease tear nuclease [e.g. lipocalin]) TLR4, TLR9 and TAM signalling, type I IFN response (link to adaptive immunity) Upregulation of CCR5 in CD4+ cells Upregulation of ICAM1 in epithelial cells and vascular endothelial cells Secretion of chemokines into tears (CCL3, CCL4 and CCL5)

Mechanism of damage highly related to the massive infiltration of the innate immune cells (including macrophages, neutrophils, mast cells and dendritic cells) into joints Cytokine networks augment disease (e.g. IL-17 from complement 5a receptor expressing macrophages augments migration of innate immune cells and production of other proinflammatory cytokines such as IL-6, TNF, RANKL and IL-1) Expression of S100A8 alarmins

Adaptive immunity

TNF, IL‑6 and IL‑1β secreted into tears TH1 differentiation, IFN‑γ production MMP production: loss of epithelial permeability TGF-β: fibrosis Dendritic cells and intraepithelial NK cells Promotion of TH17 differentiation: IL‑17A, IL‑17F-producing T cells Defect in TREG cells

Oligoclonal T‑cell infiltration important for initiation of disease, HLA-DR‑B1 association Loss of regulatory capability by TREG cells Hyperproliferation of synovial fibroblasts important for joint damage, increased osteoclasts (stimulated by RANKL) Humoral response (by B cells) sufficient for arthritis inflammation phase (e.g. rheumatoid factor and anticitrullinated peptide antibodies)

Abbreviations: APC, antigen-presenting cell; CCL, CC-ligand; ICAM1, intercellular adhesion molecule 1; IFN, interferon; MMP, matrix metalloproteinase; NK (cell), natural killler (cell); RANKL, TNF ligand superfamily member 11 (also known as receptor activator of nuclear factor κ‑B ligand); TAM, Tyro3, Axl and Mer; TGF‑β, transforming growth factor β; TH (cell), helper T cell; TLR, Toll-like receptor; TREG (cell), regulatory T cell.

which is characterized by dacryoadenitis and formation of Sjögren’s-syndrome-like autoantibodies.58

Ocular versus systemic immunology The components of the immune system in a normal, healthy eye and joint are described in Table 1. Table 2 shows the features that are found in the systemic and ocular immune landscapes in the context of RA, high­ lighting the similarities in both profiles; for example, the involvement of alarmins such as S100A8 and Toll-like receptor (TLR) signalling. However, many acute-phase reactions are nonspecific and, by themselves, do not constitute proof of identical mechanisms in systemic and ocular inflammation.

Differentiation of lymphocytes and expression of related cytokines found in ocular surface studies have been previously described in systemic studies in RA.59 More­over, the disease mediators that induce tissue damage in the ocular surface are also those that affect the joint (such as Fas, IL‑2, IL-6, IL-8, matrix metallo­ proteinase [MMP], nitric oxide, reactive oxygen species, TGF‑β and TNF).60,61 Some critical steps of mmune signalling (from innate to adaptive) occur in ocular and systemic RA. Some molecules (TLR, IL-1R) have been evaluated in both systems,62–66 but others (for example, TAM or Tyro3, Axl and Mer)67 have not yet been evaluated in the context of the ocular surface. Some of the cytokines produced

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REVIEWS Stress

Professional antigenpresenting cell (Langerhans)

Autoantigen mimics environmental antigen

Epithelial cell

Defect in autophagy Disease epitope inducing positive selection of autoreactive clones

IL-1β

HLA-DR

TNF

Change in adhesion molecules

S100A9

Facilitates chemotaxis

Histones Extracellular DNA Alarmin signalling

Eye-related lymphoid tissue Loss of self-tolerance

Therapeutic approaches

Tissue-specific pairing Low affinity Lymphocyte

Glycam1

L-selectin

ICAM-1

Regional/systemic lymphocytes Leukocyte trafficking

Postcapillary high endothelial venule

Lymph node

High affinity LFA-1

immuno­logy of the ocular surface and the joint in RA. Ideally, a global immune profile of the ocular surface and systemic immunology should be monitored longi­ tudinally, including the changes before and after treat­ ment. Knowledge of local immune disturbances of the ocular surface might be useful as such investigations could reveal biomarkers that point to a need for rheu­ matological referral, either to make a fresh diagnosis of RA, to facilitate early control of RA, or, increasingly, to support the use of topical drugs that have been evalu­ ated in the systemic context. In addition, as scleritis can manifest before joint disease, molecular mechanisms of inflammation in the eye could identify pathogenic mechanisms in the joints and other organs.

Basement membrane

Figure 2 | Pathogenesis of ocular surface inflammation in RA. Schematic showing the probable pathogenesis of ocular surface inflammation3,7 in RA.5 Many of these processes have an equivalent function in the joint. Abbreviations: ICAM, intercellular adhesion molecule 1; LFA, lymphocyte function associated antigen 1; RA, rheumatiod arthritis.

by activation of T cells in both the ocular surface and the joint (IL‑6, IL‑12, IFN‑γ) are well known,68–70 but others have not been assessed in the ocular surface (IL‑23 and IL‑17). Immunological tolerance in the eye is altered in inflam­mation of ocular surface (Figure 2). Increas­ingly, the role of TH17 cells in inflammation of the ocular surface in dry eye has been speculated to be involved in dry eye (Figure 1), although some regulatory points have not been studied and are suggested on the basis of studies of systemic inflammation in RA. One question that arises is whether there is clinical evidence that systemic inflammation in RA is related to ocular surface inflammation. In a study of 87 patients with RA, 30 with and 57 without dry eye,71 it was found that tear osmolarity correlated with RA disease activity score (DAS28), but not with concentrations of C‑reactive protein or rheumatoid factor. These findings suggest that ocular surface inflammation might have some predictive value in the management of the systemic disease in RA, although a longitudinal study is required to determine whether levels of tear inflammation markers follow the same temporal profile as systemic disease indicators. One must remember that some aspects of ocular immunity have not been fully explored and these areas could shed light on the differences between the

Different therapeutic strategies are necessary for distinct types of ocular surface involvement in RA.19 In patients with corneal melts secondary to RA, aggressive systemic anti-inflammatory treatment can reduce ocular morbid­ ity.72 In patients with RA who have mild-to-moderate dry eye, symptomatic treatment with copious lubricants and, if necessary, immune-modulation with topical ciclosporin will probably suffice.19 The common mani­ festation of dry eye in RA25 is not trivial because dry eye symptoms have been found to be associated with dif­ ficulty performing activities of daily living 73 and indi­ viduals with moderate dry eye report that their condition affected quality of life, with these effects on quality of life comparable to those as a result of moderate angina.74 Current treatment of various forms of ocular sur­ face dis­e ase includes corticosteroids and ciclosporin (reviewed previously).19 The use of topical cortico­steroids is associated with increased intraocular pressure and sight-threatening glaucoma.75 In more severe disease, use of autologous serum or plasma might deliver the neces­ sary anti-inflammatory and immunosuppressive pro­ teins to the ocular surface.76–78 MMP can be inhibited by drugs such as doxycycline.79 Doxycycline can also induce apoptosis of T cells during the immune response in the context of dry eye.80 None of these existing strategies are adequate or satisfactory for the more severe ocular surface inflammation in RA, such as severe dry eye (in which symptoms and corneal epithelio­p athy are not responsive to conventional treatment), peripheral ulcer­ ative keratitis or scleritis. These severe m­anifestations remain a clinic­al challenge. Using the knowledge gained in immunological studies, one can target ocular surface inflammation in several ways. Potential therapeutic strategies explored in systemic RA could have a role in the treatment of RA-associated ocular conditions should the under­lying pathogenic mechanisms overlap. Anti-TNF strategies, using for example, the inhibitor etanercept or the immuno­globulin can be used in treatment of ocular-­surface inflamma­ tion in RA.81 Treatment with rituximab, a monoclonal antibody against CD20 (a B-cell marker), has also been shown to be effective in the treatment of scleritis.82 Although rituximab is not routinely used to treat dry eye, it has been reported to improve dry eye symptoms

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REVIEWS in 3 of 6 patients after 4 weeks of treatment for primary Sjögren’s syndrome.83 This finding was from a retro­ spective survey of rituximab use in rheumatic diseases over a mean follow-up period of 8.3 months (range 2–26 months). Two patients with Sjögren’s syndrome were started on rituximab because of lymphoma, and the others because of the refractory nature of Sjögren’s syn­ drome. Although 14 patients with RA were included in this survey, clinical outcome of dry eye was not reported. A double-blind, randomized placebo-controlled phase II clinical trial of the safety and tolerability of rituximab for dry eye in Sjögren’s syndrome was completed in January 2013,84 although the results have not yet been published. The IL‑1 receptor antagonist (IL-1Ra) is a prom­ ising approach to inhibit inflammation66 and, when admini­stered as eyedrops, has been shown to be effec­ tive in inhibiting inflammation in a mouse model of dry eye,85 and the symptoms of dry eye in humans.86 These examples demonstrate an immune strategy previously exploited in the treatment of RA by injection IL-1Ra into joints87 and now exploited in the ocular surface. Treatment with phosphodiesterase type‑4 can reduce TH17-cell-mediated ocular surface inflammation in an experimental animal model of dry eye.88 To antagonize leukocyte trafficking, a small-­molecule inhibitor of LFA‑1 is being evaluated in dry eye in a phase III study.89 Targeting signalling pathways is another promising strategy; for example, cytokine signal­ling can be suppressed by Janus kinase (JAK) inhibitors. 90 Tofacitinib (CP‑690550), a JAK inhibitor has been found to be safe and efficacious in reducing dry eye signs, symp­ toms and tear proinflammatory markers in a phase I/II trial of patients with dry eye disease,91,92 although these were not patients with RA and dry eye. Protection of the ocular surface might also involve use of carbohydrates such as trehalose, which can reduce MMP activation.93 The toxicity of these treatments might be limited by using topical administration. In patients with RA who have corneal epithelio­pathy from dry eye, resulting in impaired vision-related quality of life, these treatments might be warranted, even without articular disease.

Conclusions To think of RA as merely a disease of the joint is mis­ leading. Despite the advances described in this Review, ques­tions concerning the nature of the immune response 1.

2.

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in the ocular surface remain. For example, is there a primary defect in the lymphoid tissue of the eye in patients with RA who have ocular surface inflamma­ tion? Why is the ocular surface phenotype transferrable by adoptive transfer of T cells when the articular disease is not? As such, it might be worth studying the evolu­ tion of the im­munology of the ocular surface in patients with RA. Advances in imaging of the retinal blood vessels have introduced the possibility of noninvasive monitoring of subclinical inflammation in the eye, and using that approach as a possible indicator of systemic inflamma­ tion. Before these measures are used routinely, more longi­tudinal research and determination of sensitivity and specificity are required. Exciting new discoveries have shown promise in the treatment of patients with RA and ocular surface dis­ ease. Provided that the ocular surface has not been com­ plicated by an extraneous condition such as infectious keratitis, the immunological disturbances in the ocular surface might interact with systemic immune factors in RA to produce different ocular surface inflamma­ tory phenotypes. This aspect of the natural history of RA requires further studies and collaboration and has implications for the management of patients by ophthalmo­logists and rheumatologists. Specific molecu­ lar intervention in one or more immune pathways could have an increased effect in reducing ocular surface inflam­mation and, therefore, improve clinical outcomes. Topi­cal and regional application of new therapies could be effective because of the location of the tissue damage in ocular surface disease, and this feature might also limit the number of systemic adverse effects. Review criteria Articles reviewed were selected by searches of the PubMed, MEDLINE and Cochrane databases using any of the search terms “Sjögren”, “dry eye”, “scleritis”, “ocular surface disease”, “autoimmune disease”, “ocular surface inflammation”, “imaging”, “cornea” and “conjunctiva” in combination with “rheumatoid arthritis”, and additional references identified by a thorough search of the reference lists of all directly relevant articles. For the latest development in the field, conference abstracts were identified through the Association of Research in vision and ophthalmology webpage (www.arvo.org).

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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. Author contributions L.T. researched data for the article. All authors made equal contribution to substantial discussion of content, writing and reviewing/editing the manuscript before submission.

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REVIEWS CORRECTION The eye: a window of opportunity in rheumatoid arthritis Louis Tong, Julian Thumboo, York Kiat Tan, Tien-Yin Wong and Salvatore Albani Nat. Rev. Rheumatol. advance online publication 10 June 2014; doi:10.1038/nrrheum.2014.85 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.

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