INTRODUCTION — Rheumatoid arthritis (RA) is a common and chronic systemic inflammatory disease of unknown etiology that primarily involves joints. Extraarticular manifestations are also observed, including ophthalmic involvement. Several forms of eye disease can occur in patients with RA, and the clinical course of the ocular disease may be quite variable.
The importance of the early diagnosis of ophthalmic disease in the patient with RA cannot be overemphasized, since it permits the timely management of potentially serious sight-threatening complications. The presence of ocular disease may also be an indication of ongoing systemic disease activity [1,2]. However, ocular involvement, in particular severe dry eye, may exist independently from severe articular disease and should be evaluated in all patients with RA regardless of extra-ophthalmic manifestations [3].
Issues relating to the ocular manifestations of RA are discussed in this review. The anatomy of the relevant structures is depicted in the figure (figure 1). The articular and other nonarticular clinical manifestations of this disorder are discussed separately. (See "Clinical manifestations of rheumatoid arthritis" and "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis".)
INDICATIONS FOR URGENT REFERRAL TO AN OPHTHALMOLOGIST — Urgent referral to an ophthalmologist with expertise in the management of ocular inflammation or cornea-external diseases of the eye should be carried out in patients with rheumatoid arthritis (RA) who present with any of the following:
●Significant change in visual acuity over a period of several days or weeks, which may represent severe corneal or scleral disease
●Moderate to severe ocular pain
●New-onset ocular redness that is progressive
Importantly, severe eye disease can occur in patients with RA even without substantial (and sometimes just minimal) ophthalmic symptoms. The two most dreaded ophthalmic complications in patients with RA are necrotizing scleritis (see 'Scleritis' below) and corneal melting (see 'Corneal inflammation and melting' below), although the incidence of each appears to have decreased considerably with the adoption of more effective systemic therapeutic agents; use of these therapies has led to reduced rates of nonarticular complications, including in the eye. However, patients with severe RA and those at particularly high risk of mucosal desiccation (eg, those with secondary Sjögren's syndrome [SS] and older adults) are still prone to develop severe corneal melts from ocular surface dryness and inflammation.
CORNEAL DISEASE — Corneal involvement in patients with rheumatoid arthritis (RA) is a significant complication in those with Sjögren's and sicca syndromes. Corneal inflammation unrelated to dry eye and involving corneal melting may also infrequently occur.
Sjögren's and sicca syndromes — The characteristic features of Sjögren's syndrome (SS) are defined by the presence of dry eyes and dry mouth and are termed keratoconjunctivitis sicca (KCS) and xerostomia, respectively.
SS may be either primary or secondary, with RA being the most common underlying condition in secondary disease. While serologic abnormalities such as anti-Ro/SSA antibodies may be present in the setting of secondary SS, they are not required for diagnosis. Labial salivary gland biopsy is mostly utilized for the diagnosis of primary SS. The presence of dry eye should be excluded in all patients with RA. (See "Diagnosis and classification of Sjögren's syndrome".)
KCS, as a manifestation of lacrimal gland pathology, is the most common ophthalmic manifestation of RA; estimates of its frequency range widely given the lack of high-quality studies and depending upon the definition of dry eye, occurring in as many as approximately 15 to 40 percent of patients [4,5]. Symptomatic and objective signs of KCS are central to the diagnosis of SS, and whenever in doubt, an ophthalmologist should be consulted.
Severe dry eye may exist independently from severe articular disease and is not always due to SS. Dry eye should be evaluated in all patients with RA regardless of extra-ophthalmic manifestations [3].
Clinical features of ocular disease — Patients with SS often complain of dryness, foreign body sensation, burning, or photophobia. Since ocular surface lubrication is maintained by a balance between fluid secretion and loss (largely by evaporation), patients with KCS have an aggravation of symptoms with exposure to dry or windy environments (which increase evaporative loss of the tear film). There are no features of SS that are specific or characteristic of RA.
Slit lamp examination of patients with KCS reveals conjunctival injection, decreased tear meniscus, and devitalized surface epithelial cells that stain with Lissamine green or fluorescein dyes (figure 2 and picture 1). Filamentary keratitis, a condition in which epithelial debris and strands with adherent mucus attach to the corneal surface, is a particularly painful and bothersome consequence of KCS (picture 2). A Schirmer's test may be of diagnostic value but is notoriously unreliable.
The ophthalmic manifestations and diagnosis of SS are described in detail separately. (See "Clinical manifestations of Sjögren's syndrome: Exocrine gland disease" and "Diagnosis and classification of Sjögren's syndrome".)
Treatment recommendations — The treatment of the ophthalmic manifestations of SS is described in detail separately. (See "Treatment of dry eye in Sjögren's syndrome: General principles and initial therapy" and "Treatment of moderate to severe dry eye in Sjögren's syndrome".)
Corneal inflammation and melting — In addition to KCS, corneal involvement in RA may involve significant inflammation, frequently in association with anterior scleritis but sometimes without scleritis (picture 3). Symptoms vary and may range from substantial to minimal discomfort, despite the presence of severe disease. Such corneal involvement is rare in RA, occurring in less than 1 percent of patients.
One study, for example, found that 43 percent of patients with scleritis had associated corneal involvement [1]. A corneal "melt" refers to the clinical characterization of collagen breakdown initiated by significant inflammation in the corneal extracellular matrix.
The incidence of corneal melting appears to have decreased considerably with the adoption of more effective systemic therapeutic agents, particularly the tumor necrosis factor (TNF) inhibitors and other biologics; use of these therapies has led to reduced rates of extraarticular manifestations of RA, including in the eye. However, patients with severe RA, and those at particularly high risk of mucosal desiccation (eg, those with secondary SS and older adults) are still prone to develop severe corneal melts from ocular surface dryness and inflammation.
The severity of the corneal inflammation often parallels the severity of the scleritis but can occur in eyes with little scleral inflammation. However, these entities probably represent different manifestations of similar pathologic processes whose common denominator is collagenolysis. This process may be due in part to the upregulation of inflammatory cytokines; these molecules subsequently trigger corneal cells to produce a number of proteolytic enzymes that can effectively degrade the extracellular matrix [6,7].
There are a number of descriptive terms that depict various stages and extent of corneal inflammation in RA. These include stromal keratitis, sclerosing keratitis, keratolysis, marginal furrowing or guttering, and peripheral ulcerative keratitis (PUK) [8].
The most common form of corneal melt in RA is PUK. This disorder is not exclusive to RA and may be observed in those with a variety of other systemic immune-mediated conditions, including the vasculitides (eg, granulomatosis with polyangiitis). In PUK, adjacent conjunctival and episcleral tissues reveal an abundance of lymphocytes and macrophages [9]. These cells, particularly macrophages, may release significant quantities of inflammatory cytokines and proteases that can exacerbate the stromal breakdown.
Management of corneal melt by the ophthalmologist may involve both medical and surgical interventions, and patients should be treated by an expert in the management of ocular inflammation or cornea-external diseases of the eye. Removal of the inciting inflammatory cells may explain the beneficial effect of conjunctival resection [10]. Ongoing rheumatoid keratitis, as well as corneal scarring from antecedent corneal disease, may require transplantation; however, the visual and survival prognoses of these grafts tend to be relatively poor [11].
Corneal infection — Corneas compromised by an inadequate tear film are also susceptible to infection. Patients with poor corneal surface, as occurs in RA, are at increased risk of corneal infection. Cases of corneal melting that are progressive and difficult to control should, therefore, be cultured (and recultured if necessary) to exclude microbial disease. Most cases of bacterial corneal ulcers in patients with RA and SS are associated with Gram-positive organisms, particularly Staphylococcus and Streptococcus species [12].
EPISCLERITIS — Episcleritis may be a manifestation of rheumatoid arthritis (RA), occurring in less than 1 percent of ambulatory patients in one series [1]. On the other hand, nearly 6 percent of those patients presenting with episcleritis to an ophthalmology clinic had RA [1].
Episcleritis is typically acute in onset, with patients describing discomfort rather than pain (picture 4). The disorder is usually benign and self-limiting and is discussed in detail separately. (See "Episcleritis".)
SCLERITIS — Compared with episcleritis, scleritis is associated with a more ominous prognosis with respect to ocular morbidity and associated extraarticular manifestations [2,3,13]. Issues related to scleritis are discussed in detail separately. The following discussion reviews those features of scleritis specific to rheumatoid arthritis (RA). (See "Clinical manifestations and diagnosis of scleritis" and "Treatment of scleritis".)
Clinical features — The reported incidence of scleritis in patients with RA has ranged from 0.7 to 6.3 percent, although as many as 33 percent of all patients presenting to an ophthalmologist with scleritis may have associated RA [1]. The true frequency is unknown but likely lower; most of the estimates rely upon data from selected referral populations in specialty clinics.
Patients with scleritis associated with RA are older and tend to have bilateral disease more often than those with scleritis due to nonrheumatoid conditions [3]. Diffuse anterior scleritis is the most common and least severe form of scleritis (with or without RA) and usually responds well to systemic immunosuppressive therapy (picture 5).
Scleritis is usually characterized by severe, constant, boring pain that worsens at night or in the early morning hours and radiates to the face and periorbital region. The extraocular muscles insert into the sclera, thus ocular movements exacerbate the pain associated with scleral inflammation. The pain generally limits activity and often prevents sleep. Additionally, patients may report headache; watering of the eye; ocular redness, particularly in patients with non-necrotizing anterior scleritis; and photophobia, which is variably present. Symptoms may vary depending upon the severity of scleritis that is present and whether there is tissue necrosis. When there is tissue necrosis in severe disease, there is loss of peripheral innervation, which leads to "paradoxic" lessening of symptoms. (See "Clinical manifestations and diagnosis of scleritis", section on 'Ocular symptoms'.)
Necrotizing scleritis remains a dreaded ophthalmic complication of RA, although the incidence of necrotizing scleritis has decreased considerably with the adoption of better systemic agents in the long-term management of RA patients.
Severe scleritis can present with advanced necrotizing disease (scleromalacia perforans), in which there may be minimal to no symptoms since the nerves have also degenerated. Histopathology of the affected area is consistent with a rheumatoid nodule, with granulomatous changes and fibrinoid necrosis [14,15]. Necrotizing scleritis without inflammation (scleromalacia perforans) is characterized by severe thinning of the sclera in an otherwise clinically uninflamed and painless "white" eye. Since such patients do not typically complain of ocular discomfort, it is essential for clinicians taking care of patients with longstanding RA to examine behind the eyelids to fully examine the eyes to identify the asymptomatic thinning of the sclera that often appears bluish (from the subjacent choroid) (picture 6). (See "Clinical manifestations and diagnosis of scleritis", section on 'Ocular symptoms'.)
Patients with RA and scleritis may have more advanced joint disease and extraarticular manifestations than those without scleritis [1,3]. Scleritis (particularly the inflammatory necrotizing subtype) in the patient with RA may also reflect underlying systemic vasculitis [1,2,13]. Because of the general increase in disease activity, RA patients with scleritis appear to have a higher mortality in the absence of immunosuppressive therapy [1-3].
Treatment — Patients suspected of scleritis should be referred to an ophthalmologist with expertise in the evaluation and management of ocular inflammation or cornea-external diseases for collaborative treatment of this condition together with the patient's rheumatologist or another expert comfortable in the management and monitoring of patients on immunomodulatory treatments. Collaborative management is important due to the myriad of complications that may ensue from systemic immune suppression, as well as from the underlying disease; this arrangement will hopefully ensure that the regimen can be tailored to the patient's response and that iatrogenic complications can be handled expeditiously.
Management issues of particular importance in patients with RA are reviewed here, and a more detailed overview of the treatment of scleritis is presented separately. (See "Treatment of scleritis".)
Although topical medications, such as topical steroids (eg, prednisolone acetate 1%), may provide some symptomatic relief, systemic therapy is required to treat and reverse the course of scleritis or corneal ulcerative disease in patients with RA. The therapy needs to be individualized according to the severity of the patient's condition and comorbidities, response to therapy, and side effects. Therapeutic failure is defined as persistent inflammation after two to three weeks of therapy or progression of the scleritis to a more severe variant.
In non-necrotizing disease, such as diffuse or nodular scleritis, induction of remission is usually first attempted with systemic glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs), depending upon the severity of the scleritis [16]:
●In mild cases of non-necrotizing scleritis, we suggest initiating treatment with an NSAID alone. We have the most experience with indomethacin (slow release formulation at 75 mg twice daily), diflunisal (250 to 500 mg twice daily), naproxen (375 to 500 mg twice daily), and flurbiprofen (100 mg three times daily). (See "Treatment of scleritis", section on 'Nonsteroidal antiinflammatory drugs'.)
The use and adverse effects of NSAIDs are described in detail separately. (See "NSAIDs: Therapeutic use and variability of response in adults" and "Nonselective NSAIDs: Overview of adverse effects" and "Overview of COX-2 selective NSAIDs".)
●In moderately severe disease (eg, severe diffuse or nodular scleritis), we suggest prednisone (1 mg/kg per day) or equivalent. The response to therapy is monitored closely and altered as necessary, depending upon the severity of disease and the response to therapy. The use and adverse effects of glucocorticoids are described in more detail separately. (See "Treatment of scleritis", section on 'Glucocorticoids' and "Major side effects of systemic glucocorticoids".)
●In necrotizing disease or disease unresponsive to the above measures, we suggest adding immunosuppressive drug therapy such as methotrexate (15 to 25 mg/week) to prednisone. An alternative regimen consists of supplementing prednisone with oral cyclophosphamide (1 to 2.5 mg/kg per day) and is typically reserved for the most severe cases of necrotizing disease.
Control of the disease is usually achieved in the first three weeks of treatment, after which the prednisone is tapered. Methotrexate is used in the same fashion as in RA, and oral cyclophosphamide as in patients with systemic vasculitis, as described in detail separately. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Major side effects of low-dose methotrexate" and "General principles of the use of cyclophosphamide in rheumatic diseases" and "General toxicity of cyclophosphamide in rheumatic diseases".)
In addition, we have the most experience with cyclosporine (2 to 5 mg/kg per day) and azathioprine (1 to 2 mg/kg per day). Often, multiple agents need to be added (eg, azathioprine or cyclosporine to prednisone) or one drug may have to be substituted for another (eg, methotrexate to cyclophosphamide) to achieve an adequate response and to maintain disease quiescence [2,3,17].
Agents that suppress tumor necrosis factor (TNF)-alpha or CD20 (eg, rituximab) have shown efficacy in treating RA, including its severe ophthalmic complications such as scleritis [18,19]. However, there is no consensus among ophthalmologists about the best timing and regimens for use of biologics in treating RA-related ocular disorders, and their use for ocular indications remains an empirical one. There is a lack of data regarding the efficacy of other biologic agents and the oral Janus kinase inhibitors in these patients. (See "Overview of biologic agents and kinase inhibitors in the rheumatic diseases".)
Other experts prefer, in addition to oral glucocorticoids, to intensify conventional DMARD therapy (eg, optimizing methotrexate orally or parenterally (see "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration')); and/or adding or switching a biologic DMARD (eg, a TNF inhibitor or other biologic); or using a small molecule Janus kinase inhibitor (eg, tofacitinib) before trying oral cyclophosphamide [20]. This is based upon the efficacy of these agents in RA and concern regarding the potential toxicities of cyclophosphamide. (See "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy".)
In a retrospective report from two centers in the Netherlands of 104 patients with scleritis (one-third had underlying systemic diseases; 13 percent had RA), stepwise treatment included NSAIDs as the first choice, oral glucocorticoids if NSAIDs failed, and glucocorticoid-sparing immunosuppressive agents (usually methotrexate) if the glucocorticoid dose could not be reduced to <10 mg daily [21]. Oral glucocorticoids were used in 62 percent of the patients, usually in combination with NSAIDs and/or local steroid therapy; methotrexate was used in 35 percent of patients. Treatment with oral glucocorticoids was successful in 30 percent of patients in whom they were used, and treatment with methotrexate was successful in 47 percent of those receiving this agent.
In another case series from a single institution of 40 patients with inflammatory scleritis managed over five years (nearly half had systemic disease; 15 percent had RA), control of scleritis was achieved in 95 percent [22]. NSAIDs and prednisone were the most commonly used agents during the first few months of treatment, with methotrexate and cyclophosphamide use increasing later in the course of treatment.
Surgery — Surgical management is usually not necessary in patients with RA and scleritis. However, the late diagnosis of necrotizing disease with severe scleral thinning or impending globe perforation may require urgent surgical management. Surgical tectonic grafts of corneoscleral tissue or fascia lata may be required [23]. As a general rule, surgery should not be performed until appropriate medical management has been instituted, since surgery can incite even more ocular destruction. In patients with large scleral defects or perforations, pulse intravenous glucocorticoids and cyclophosphamide may be necessary [23].
OTHER OCULAR DISORDERS — Anterior uveitis, in the absence of scleritis, is not significantly more common in rheumatoid arthritis (RA) than in the general population (figure 3) [24]. However, anterior or posterior uveitis can be found contiguous to anterior or posterior scleritis, respectively, and is termed "sclerouveitis." Sclerouveitis may be seen in patients with RA.
Several other ocular disorders, particularly those resulting from therapy, may be observed in patients with RA:
●Tissue edema and intraocular inflammation secondary to scleritis may cause glaucoma by altering the anatomy and functional outflow of the eye's aqueous drainage system. Glucocorticoid therapy can also lead to increases in intraocular pressure and to glucocorticoid-induced glaucoma. (See "Major side effects of systemic glucocorticoids", section on 'Ophthalmologic effects' and "Open-angle glaucoma: Epidemiology, clinical presentation, and diagnosis".)
●Ocular inflammation and its treatment by local or systemic glucocorticoids may lead to cataracts. (See "Major side effects of systemic glucocorticoids", section on 'Ophthalmologic effects' and "Cataract in adults".)
●Retinal pigment epithelial toxicity may be due to the administration of hydroxychloroquine; all patients should be monitored regularly for this adverse effect. (See "Antimalarial drugs in the treatment of rheumatic disease".)
●Older disease-modifying therapies for RA, including gold salts and penicillamine, have been associated with ocular abnormalities. Among those previously treated with gold salts, patients may show deposition of gold particles (ocular chrysiasis) in the corneal stroma and the lens capsule of the eye that may have a dramatic appearance on biomicroscopy, but it does not affect vision and is not an indication for cessation of therapy [25]. Gold has also been implicated as a cause of the Miller Fisher syndrome, which is characterized by bilateral external ophthalmoplegia, generalized areflexia, and ataxia [26]. Penicillamine therapy has also been implicated as a potential cause of optic neuropathy [27].
●Posterior pole morbidity is rare. Venous stasis retinopathy has been described in one patient as part of a hyperviscosity syndrome secondary to polyclonal gammopathy [28].
●Other rare complications include cranial nerve palsies, geniculocortical blindness [29], and orbital apex syndrome resulting from orbital rheumatoid nodules [30].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)
SUMMARY AND RECOMMENDATIONS
●The early diagnosis of ophthalmic disease in patients with rheumatoid arthritis (RA) is of high importance because of the need for timely management of potentially serious and sight-threatening complications. In some patients, it may be an indication of ongoing systemic disease activity, although there is not necessarily a direct correlation between the eye and systemic disease. The clinical course of ocular disease in RA is quite variable. (See 'Introduction' above.)
●Patients with significant change in visual acuity over a period of several days or weeks, moderate to severe ocular pain, or new-onset redness that is progressive should be referred for urgent evaluation to an ophthalmologist with expertise in the management of ocular inflammation or cornea-external diseases. (See 'Indications for urgent referral to an ophthalmologist' above.)
●Corneal involvement is common in RA, primarily from Sjögren's syndrome (SS), but corneal inflammation unrelated to dry eye, and involving corneal melting, may also infrequently occur. There is some evidence suggesting that patients with poor corneal surface, as occurs in RA, have increased risk of corneal infection, most often with Gram-positive organisms such as Staphylococcus or Streptococcus. (See 'Corneal disease' above and 'Corneal infection' above.)
●Keratoconjunctivitis sicca (KCS) due to SS is the most common ophthalmic manifestation of RA, occurring in as many as 15 to 25 percent of patients. Symptomatic and objective signs of KCS are central to the diagnosis of SS, and whenever in doubt, an ophthalmologist should be consulted. Patients with SS often complain of dryness, foreign body sensation, burning, or photophobia. A number of interventions can be of benefit in SS. (See 'Sjögren's and sicca syndromes' above and "Treatment of dry eye in Sjögren's syndrome: General principles and initial therapy".)
●Corneal disease in RA may involve significant inflammation, either with or without concurrent scleritis. The severity of the inflammation often parallels the severity of the scleritis but can occur in eyes with little scleral involvement. Peripheral ulcerative keratitis (PUK) is the most common form of corneal melt, the clinical characterization of collagen breakdown initiated by significant inflammation in the corneal extracellular matrix in RA, and may also be seen in other systemic immune-mediated conditions. Treatment may require conjunctival resection, and some severely affected patients eventually require corneal transplantation. (See 'Corneal inflammation and melting' above.)
●Episcleritis may be a manifestation of RA, occurring in less than 1 percent of ambulatory patients. It is typically described as discomfort, rather than pain, which is acute in onset and is usually benign and self-limiting. (See 'Episcleritis' above and "Episcleritis".)
●Scleritis is associated with a more ominous prognosis than episcleritis, with respect to ocular morbidity and associated extraarticular manifestations. Diffuse anterior scleritis is the most common and least severe form of scleritis (with or without RA). (See 'Scleritis' above and "Clinical manifestations and diagnosis of scleritis".)
●Necrotizing scleritis "without inflammation" (scleromalacia perforans) is characterized by severe thinning of the sclera in an otherwise clinically uninflamed and painless "white" eye. Since such patients do not typically complain of ocular discomfort, the examination of patients with longstanding RA involves examining behind the eyelids to examine the eyes fully to identify any asymptomatic thinning of the sclera, which often appears bluish (from the subjacent choroid). (See 'Scleritis' above and "Clinical manifestations and diagnosis of scleritis".)
●Individualized systemic therapy is required to treat and reverse the course of scleritis or corneal ulcerative disease in patients with RA, although topical medications may provide symptomatic relief. Treatment should be a collaborative effort involving the patient's ophthalmologist and rheumatologist. Surgery is usually not necessary, but the late diagnosis of necrotizing disease with severe scleral thinning or impending globe perforation often requires urgent surgical management. (See 'Treatment' above and 'Surgery' above and "Treatment of scleritis".)
Diffuse scleritis in patients with RA usually responds well to systemic drug therapy:
•For patients with mild non-necrotizing scleritis (eg, diffuse or nodular scleritis), we suggest initiating treatment with a nonsteroidal antiinflammatory drug (NSAID) alone rather than prednisone (Grade 2C). We have the most experience with indomethacin (slow release formulation at 75 mg twice daily), diflunisal (250 to 500 mg twice daily), and naproxen (375 to 500 mg twice daily).
•For patients with moderately severe disease (eg, severe diffuse or nodular scleritis), we suggest initial treatment with prednisone (1 mg/kg per day) or equivalent rather than an NSAID (Grade 2C). The response to therapy is monitored closely and altered as necessary, depending upon the severity of disease and the response to therapy.
•For patients with necrotizing disease or disease unresponsive to NSAIDs and glucocorticoids, we suggest adding methotrexate (10 to 20 mg/week) to prednisone (Grade 2C). An alternative regimen consists of supplementing prednisone with oral cyclophosphamide (1 to 2.5 mg/kg per day). Control of the condition is usually achieved in the first three weeks, after which the prednisone is tapered. Some patients require alternative or additional immunosuppressive agents.
●Anterior uveitis, in the absence of scleritis, is not significantly more common in RA than in the general population, but anterior or posterior uveitis can be found contiguous to anterior or posterior scleritis, respectively. Glaucoma can be seen as a consequence of scleritis. Disorders resulting from therapy that may occur in patients with RA include glaucoma or cataracts due to glucocorticoids, as well as retinal toxicity from antimalarials. (See 'Other ocular disorders' above.)
