Ocular manifestations of rheumatoid arthritis

Ocular manifestations of rheumatoid arthritis

Author
Reza Dana, MD, MPH, MSc

Section Editors
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Jonathan Trobe, MD

Deputy Editor
Paul L Romain, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2016. &#124 This topic last updated: Jul 06, 2015.

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. 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 on ophthalmologist with expertise in the management of ocular inflammation or corneal-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
●Moderate to severe ocular pain
●New-onset redness that is progressive
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 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 infrequently occur also.
Sjögren's and sicca syndromes — Although no consensus definition of Sjögren's syndrome (SS) exists, the classic triad of this syndrome consists of the following:
●Mucosal dryness. Dry eyes and dry mouth are termed keratoconjunctivitis sicca (KCS) and xerostomia, respectively.
●Positive (minor salivary gland) biopsy.
●Serologic evidence of autoantibodies.
SS may be either primary or secondary, with RA being the most common underlying condition in secondary disease. (See "Diagnosis and classification of Sjögren's syndrome".)
KCS, as a manifestation of lacrimal gland pathology, is the most common ophthalmic manifestation of RA, occurring in as many as 15 to 25 percent of patients [4]. Symptomatic and objective signs of KCS are central to the diagnosis of SS, and whenever in doubt an ophthalmologist should be consulted.
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).
Physical examination — Slit lamp examination of patients with KCS reveals conjunctival injection, decreased tear meniscus, and devitalized surface epithelial cells that stain with Rose Bengal or fluorescein dyes (picture 1 and picture 2). 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 3). A Schirmer's test may be of diagnostic value but is notoriously unreliable. (See "Diagnosis and classification of Sjögren's syndrome".)
Treatment recommendations — Therapeutic options for KCS of any cause always include the use of artificial tear substitutes. We strongly prefer nonpreserved preparations, since they can be used frequently with no adverse effect from the usual preservatives found in topical preparations. Patients with significant mucus overproduction or filamentary keratitis are best treated with topical acetylcysteine (10 percent) as a mucolytic agent (this can be specially prepared for ophthalmic use in most well-equipped pharmacies). Topical cyclosporine-A, when used twice daily for a prolonged period (greater than three to four months), may significantly decrease dry eye symptoms, decrease ocular surface inflammation, and, in some cases, enhance lacrimation [5].
In patients with severe KCS, punctal occlusion is the treatment of choice, since it is a highly effective method for maximizing the preservation of tears. This technique involves sealing of the lacrimal puncta, which are the openings to the nasolacrimal ducts that drain the tears. Our usual approach is to begin with preliminary temporary occlusion, using collagen or silicone plugs (picture 4) to ensure that punctal occlusion does not result in excess tear accumulation (epiphora) and to avoid a permanent change in the small minority of patients who might regain near-normal lacrimal function with appropriate therapy. When indicated, laser or handheld thermal cautery energy can be used for a more permanent closure. It is important to realize that punctal occlusion is a tear preservation strategy; as a result, it is of little benefit, unless supplemented with artificial lubricants, in those with minimal to no tear production.
The use of slow-release artificial inserts may provide continuous lubrication without surgical intervention; these inserts also require some wetting of the ocular surface prior to becoming clinically beneficial.
Oral muscarinic agents, including pilocarpine, have become increasingly popular in the treatment of exocrine dysfunction in this disorder. While both oral pilocarpine and cevimeline have been approved for use in dry mouth in SS, only pilocarpine has been approved for use in dry eye. Common side effects of pilocarpine include those from cholinergic stimulation, including gastrointestinal disturbance and sweating. Initially, we usually begin pilocarpine at a dose of 5 mg twice daily, which is gradually increased over several weeks to 20 to 25 mg/day in divided doses, if adequately tolerated. While patients may get significant relief from xerostomia, efficacy with KCS is more variable. (See "Treatment of dry eye in Sjögren's syndrome".)
In some patients, these conservative measures are inadequate to control the KCS, which can be complicated by nonhealing epithelial defects (picture 5). Among those with such defects, expert management by a cornea and external disease specialist is mandatory. Treatment usually consists of the judicious use of a bandage contact lens and, if necessary, a tarsorrhaphy (lid closure procedure). Not infrequently, particularly in cases of secondary SS, severe KCS is associated with corneal melting; in this setting, systemic immunosuppression may be required.
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 6). 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 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 proinflammatory 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 [Wegener’s]). In PUK, adjacent conjunctival and episcleral tissues reveal an abundance of lymphocytes and macrophages [9]. These cells, particularly macrophages, may release significant quantities of proinflammatory cytokines and proteases that can exacerbate the stromal breakdown.
Removal of these 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 Staphylococcusand 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 presenting to an ophthalmology clinic had RA [1].
Episcleritis is typically acute in onset, with patients describing discomfort rather than pain (picture 7). 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]. The reported incidence of scleritis in patients with rheumatoid arthritis (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].
Issues related to scleritis are discussed in detail separately. The following discussion reviews those features of scleritis specific to RA. (See "Clinical manifestations and diagnosis of scleritis" and "Treatment of scleritis".)
Patients with scleritis associated with RA are older and tend to have bilateral disease more often than those with scleritis due to non-rheumatoid 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 8).
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 9).
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 recommendations — Although topical medications may provide 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 [14]:
●In mild cases, we usually begin with an NSAID alone. We have the most experience with indomethacin (slow release formulation at 75 mg BID), diflunisal (250 to 500 mg BID), and naproxen (375 to 500 mg twice daily).
●In moderately severe disease (eg, severe diffuse or nodular scleritis), we usually begin with prednisone at 1 mg/kg per day. The response to therapy is monitored closely and altered as necessary.
●In necrotizing disease or disease unresponsive to the above measures, we add methotrexate (10 to 20 mg/week) to prednisone. An alternative regimen consists of supplementing prednisone with oral cyclophosphamide (1 to 2.5 mg/kg per day). Remission is usually achieved in the first three weeks, after which the prednisone is tapered.

In addition to methotrexate and cyclophosphamide, 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 [2,3,15]. Other agents such as anti-CD20 (rituximab) and mycophenolate have been used for treatment of ocular inflammation in RA, but the efficacy of these agents has not been systematically evaluated.

Agents that suppress tumor necrosis factor (TNF)-alpha are useful in treating RA, but as yet there is no consensus among ophthalmologists about the usefulness for RA-related ocular indications. The use of anti-TNF therapies for ocular indications remains an empirical one. (See "Overview of biologic agents in the rheumatic diseases".)
Due to the myriad complications that may ensue from systemic immune suppression, as well as from the underlying disease, we strongly recommend that treatment be a joint venture between the patient's ophthalmologist and rheumatologist; this arrangement will hopefully ensure that the regimen can be tailored to the patient's response and that iatrogenic complications can be handled expeditiously.
The two most dreaded ophthalmic complications in RA are necrotizing scleritis and corneal melting (see 'Corneal inflammation and melting' above). The incidence of both appear to have decreased considerably with the adoption of better systemic agents in the long-term management of RA patients, that have in turn led to lower incidences of nonarticular complications, including in the eye. However, patients with severe RA, and those at particularly high risk of mucosal desiccation (eg, secondary Sjögren’s syndrome), such as older adults, are still prone to develop severe corneal melts from ocular surface dryness and inflammation. If a patient presents with (i) significant change in visual acuity over a period of several days or weeks, (ii) moderate to severe ocular pain, or (iii) new-onset redness that is progressive, a timely referral to an ophthalmologist specializing in the management of ocular inflammation or cornea-external diseases is mandatory.
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 [16]. 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 [16].
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 2) [17]. However, anterior or posterior uveitis can be found contiguous to anterior or posterior scleritis, respectively.
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.
●Ocular inflammation and its treatment by local or systemic glucocorticoids may lead to cataracts. (See "Major side effects of systemic glucocorticoids".)
●Retinal pigment epithelial toxicity may be due to the administration of hydroxychloroquine; all patients should be monitored for this adverse effect via once- to twice-yearly dilated funduscopy, central field screening, and color vision and macular threshold testing. In some patients, electrophysiologic testing is used if other more practical tests are deemed insufficiently sensitive. However, this modality is also imperfect. In one study, for example, the electrooculogram was abnormal in 20 percent of patients with RA not treated with chloroquine [18]. (See "Antimalarial drugs in the treatment of rheumatic disease".)
●Among those administered gold salts, the deposition of gold particles (ocular chrysiasis) in the corneal stroma and the lens capsule of the eye may have a dramatic appearance on biomicroscopy, but it does not affect vision and is not an indication for cessation of therapy [19]. Gold has also been implicated as a cause of the Miller Fisher syndrome, which is characterized by bilateral external ophthalmoplegia, generalized areflexia, and ataxia [20].
●Penicillamine therapy in RA has also been implicated in optic neuropathy [21].
●Posterior pole morbidity is rare. Venous stasis retinopathy has been described in one patient as part of a hyperviscosity syndrome secondary to polyclonal gammopathy [22].
●Other rare complications include cranial nerve palsies, geniculocortical blindness [23], and orbital apex syndrome resulting from orbital rheumatoid nodules [24].
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 asStaphylococcus or Streptococcus. (See 'Corneal disease' above and 'Corneal infection' above.)
●Keratoconjuctivitis 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".)
●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, occurring in between 0.7 and 6.3 percent of patients, 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) and usually responds well to systemic treatment with nonsteroidal antiinflammatory drugs (NSAIDs), glucocorticoids, or more potent immunosuppressive therapy. 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 recommendations' above and 'Surgery' above and "Treatment of scleritis".)
●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.)