Systemic lupus erythematosus (SLE) is a chronic, autoimmune, connective tissue disorder of multiple organ systems (joints, skin, kidneys, and brain, among others) affecting about 20-150 patients per 100,000 people. It typically has a relapsing and remitting clinical course. The eye is frequently involved in SLE [1], and the disease may cause ocular involvement by several mechanisms including immune complex deposition in the basement membrane of small blood vessel endothelial cells [1]. Ocular complications have been reported in up to one-third of patients with SLE [2]. Ocular manifestations can be associated with significant morbidity and may play a role as a marker for systemic disease activity. The onset of disease is usually between the late teens and early 40s and women have a nine-fold higher incidence of the disease in comparison to men [34]. SLE can affect various parts of the eye from the orbit and external eye to the retina and optic nerve [25]. This review will show the various ocular manifestations of SLE and discuss treatment options for eye problems.

The pathogenesis of SLE is complex and incompletely understood. Environmental factors and hormonal influences, among other factors, may be involved in the development of lupus. SLE is associated with defects in the innate and adaptive immune systems, apoptotic clearance, cytokines, T-cell signaling and B-cell immunity [6]. Ischemic retinal vasculitis with vascular occlusion is a serious complication resulting in severe visual loss and late complications including neovascular glaucoma [7]. The exact mechanism of vascular occlusion remains unclear; however, some suggested possible pathogenic mechanisms include immune-complex deposition, complement activation with microvascular thrombosis and fibrinoid degeneration of the vascular wall [8]. Many elements of the immune system are involved in the pathogenesis of lupus, and autoantibodies appear to play a key role. Cellular death by apoptosis may expose self-antigens that are normally sequestered inside cells to antigen presenting cells (APCs), thus initiating a harmful immune response. T and B lymphocytes are then activated via various cellular interactions leading to the production of high-affinity autoantibodies. APCs release cytokines and other inflammatory factors that contribute to the immune reaction [91011]. As such, many treatments have been developed targeting T cells and B cells.

The clinical diagnosis of SLE is based on the presence of four of the 11 features listed by the American College of Rheumatology classification criteria [1213]. The presence of four criteria indicates a diagnosis of SLE, serially or simultaneously, during the course of the disease. The revised criteria include: (1) malar rash, (2) discoid rash, (3) skin photosensitivity, (4) oral ulcers, (5) nonerosive arthritis, (6) serositis, (7) renal involvement, (8) neurological disorder, (9) hematologic disorder, (10) immunologic disorder, and (11) positive antinuclear antibodies. The presence of 4 of these 11 criteria confirms the diagnosis of SLE and yields a sensitivity of 85% and a specificity of 95% for SLE [14].

One-third of SLE patients have ophthalmic involvement and the most common ocular problem is keratoconjunctivitis sicca. SLE can affect various ocular structures including the cornea, conjunctiva, episclera, sclera, retina, uveal tract, optic nerve, vasculature, orbit, and adnexa. A summary of SLE ocular manifestations is given in Table 1. The prevalence and visual prognosis differ among each involved structure.

SLE treatment varies depending on the organs involved and the severity of disease. Because of the systemic nature of the disease involving multiple organs, collaboration among the involved specialists (ophthalmologists, rheumatologists, nephrologists, dermatologists) is often required for tailored therapy for each patient.

Traditional treatment options for SLE include non-steroidal anti-inflammatory drugs, corticosteroids, anti-malarial drugs and other immunosuppressive agents. Corticosteroids are the mainstay acute treatment for treating ocular SLE. Corticosteroids are fast acting and effective in short-term use; however, corticosteroid-sparing agents should be considered for long-term therapy [26].

For patients with mild disease, NSAIDs and antimalarials are chosen for treatment [422]. Antimalarials, such as chloroquine and hydroxychloroquine, have been reported to be effective in treating SLE; however, the antimalarial drugs are associated with dose-related retinal toxicity. Retinal toxicity remains a concern, with ongoing debate with regard to how best to monitor patients taking antimalarials.

In 2011 the American Academy of Ophthalmology (AAO) suggested the recommendations for chloroquine and hydroxychloroquine screening. The AAO recommends a baseline examination within the first year of use and annual screening for 5 years of use [27].

Plasmapheresis can be performed to eliminate circulating immune complexes and autoantibodies [28]. A variety of systemic immunosuppressants have demonstrated efficacy in treating ocular SLE. These therapies include methotrexate, mycophenolate mofetil, cyclosporine A, azathioprine, chlorambucil and cyclophosphamide [2930]. High-dose intravenous (IV) cyclophosphamide has been known to play a role in the treatment of SLE, especially in severe cases such as lupus nephritis, central nervous system lupus and vasculitis [31]. Some patients revealed refractory features [32]. In addition, generalized immunosuppression can result in serious side-effects including bone marrow suppression, hepatotoxicity and risk of infection. Biologics SLE involves production of multiple autoantibodies, each of which has been targeted as a potential immunotherapy. Thus, recently several biologic agents, targeting specific components of the immune system, are being evaluated for the treatment of SLE.

New biologic agents are playing an important role in the management of SLE (Table 2).

Because lupus is a multi-organ disease, an important step for the treatment is the assessment of disease activity across multiple systems. The SLE Disease Activity Index and British Isles Lupus Assessment Group (BILAG) index are the most widely used diagnosis systems [33]. Although systemic medication is required to treat the underlying disease, the ocular manifestations of SLE require additional local therapy in some cases. For example, keratoconjunctivitis sicca, the most common ocular manifestation of SLE, can be treated with artificial tears, punctal plugs and topical cyclosporine. Laser photocoagulation has been applied for the treatment of vaso-occlusive lupus retinopathy. Vitrectomy can also be performed in proliferative retinopathy with vitreous hemorrhage or tractional retinal detachment resulting from ocular ischemia [34]. In addition, anti-vascular endothelial growth factor has recently proven to be effective in the treatment of ischemic lupus retinopathy [2323]. Topical corticosteroids may be adequate for the treatment of anterior uveitis, or corneal ocular manifestations associated with SLE [4]. The presence of scleral, orbital, retinal, choroidal or neurological manifestations requires systemic therapy [5].

SLE is a potentially life-threatening multisystem disease that is commonly associated with ocular manifestations. This paper reviews recent advances in our understanding of the pathogenesis, diagnosis, and treatment of SLE. A better understanding of SLE pathophysiology will facilitate development of more effective treatment options. Although many new biologic treatments have been evaluated in the past decade, clear guidelines for treating SLE have not been established. A high clinical suspicion for lupus should be maintained for early diagnosis. Treatment of ophthalmic involvement should be selected via collaboration with a lupus specialist. More research is needed in order to determine which therapy and/or combination of therapies will provide the best outcome for SLE patients.