Systemic lupus erythematosus (SLE) is a systemic, autoimmune, connective tissue disorder that can detrimentally affect multiple organ systems including the eye. The disease often presents with a relapsing and remitting course affecting roughly 20–150 people per 100 000 . SLE is nine times more prevalent in women, most often affecting Asian and African women in their reproductive years [1,2][1,2]. There is some evidence that there are predisposing genetic, epigenetic, environmental and infectious factors for SLE as well as immunoregulatory factors . Up to one-third of SLE patients experience some kind of ocular manifestation .
Different ocular structures can be affected by SLE including the cornea, conjunctiva, episclera, sclera, retina, uveal tract, optic nerve, vasculature and orbit [3,4][3,4]. A variety of treatments can be utilized to treat SLE including, nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarials, corticosteroids, immunomodulatory agents and biologics. Initial treatment with corticosteroids is common; however, corticosteroid-sparing therapy should be employed early in the course of the disease to avoid the harmful side-effects associated with long-term high-dose corticosteroid use . This review will discuss the various ocular manifestations of SLE and discuss the current therapies being used to treat the condition.
SLE is known to be associated with defects in the innate and adaptive immune systems, apoptotic clearance, cytokines, T-cell signaling and B-cell immunity [6▪▪]. Retinal vasculopathy and related vascular occlusion are serious complications associated with SLE that result in vision loss in 55% of cases [7▪]. The exact mechanism of vascular occlusion remains unclear; however, several theories have been postulated. Some suggest that pathogenesis involves immune-complex deposition, complement activation with microvascular thrombosis and fibrinoid degeneration of the vascular wall [7 ▪ ,8][7 ▪ ,8]. Several autoantibodies have been found to be associated with SLE including anti-Ro, La, Sm, phospholipid, nucleosome, N-methyl-D-aspartic acid receptor and α-actinin . Although autoantigens against nuclear components are strongly associated with SLE, not all SLE patients test positive for antinuclear antibodies [4,9 ▪ ][4,9 ▪ ].
B-cell intolerance has been shown to play a major role in SLE's autoimmune response [7 ▪ ,10][7 ▪ ,10]. Autoimmune abnormalities cause apoptotic nuclear fragments to accumulate such as double and single-stranded DNAs and RNA binding nuclear antigens and nonnuclear fragments [11▪▪]. These self-antigens are presented on the cell surface by antigen-presenting cells (APCs) which are subsequently detected by T cells. T cells then trigger B cells to produce self-antibodies. APCs release cytokines and other inflammatory factors which contribute to the immune reaction [11▪▪]. Several animal studies have also supported the theory that T-cell and B-cell interactions play a significant role in the pathogenesis of SLE [11 ▪▪ ,12,13 ▪ ][11 ▪▪ ,12,13 ▪ ][11 ▪▪ ,12,13 ▪ ]. Thus, many therapies have been developed which target T cells and B cells.
The diagnostic criteria for SLE have long been debated . The most recent diagnostic criteria were formulated by the Systemic Lupus International Collaborating Clinics (SLICC). According to the SLICC, at least four of 17 defined criteria must be met in order to definitively diagnose SLE [1,14,15][1,14,15][1,14,15]. At least one clinical criterion and one immunologic criterion should be met. Otherwise, the patient must have biopsy-proven lupus nephritis accompanied by antinuclear antibodies or antidouble-stranded DNA antibodies . The SLE clinical and immunologic criteria can be seen in Table 1. Oddly enough, ocular abnormalities are not part of the diagnostic criteria. However, any part of the eye can be affected by SLE .
SLE can affect multiple ocular structures including the periorbita, adnexa, eye and optic nerve. The prevalence and severity differ among each structure.
External ocular structures
Although, orbital vasculitis, myositis and panniculitis are not common ocular manifestations, they have been reported in some SLE cases. Orbital inflammation and vasculitis result in vision loss due to ischemic injury in the optic nerve and increased intraocular pressure due to neovascular glaucoma . When present, orbital myositis is accompanied by pain, globe restriction, periorbital swelling and proptosis . In addition, creatine kinase, aldolase and myoglobin levels are often elevated . Subcutaneous orbital involvement, although rare, can be associated with enophthalmos and ‘melting’ of orbital structures . Periocular skin can also be affected by SLE. Raised, scaly and atrophic lesions are associated with discoid lupus erythematosus. In some cases, the lesions appear on the eyelids and can easily be mistaken for blepharitis and/or eczema [3,4][3,4].
Anterior ocular structures
Keratoconjunctivitis sicca is commonly seen in SLE patients. In fact, this is the most common ocular manifestation, found in up to one-third of patients . Clinical indications include discomfort, forniceal foreshortening, symblepharon formation and exposure keratopathy [3,18 ▪ ][3,18 ▪ ]. In addition, proinflammatory markers can be seen in patients’ tear film. As a consequence of dry eye, corneal scarring, ulceration and filamentary keratitis can occur as well as decreased visual acuity .
Other anterior ocular manifestations include peripheral ulcerative keratitis (PUK), scleritis and episcleritis. PUK, a corneal manifestation, often indicates the presence of active vasculitis . Another corneal disease associated with SLE is cataract . Scleritis is a vision-threatening ocular manifestation that requires immediate therapy . Scleritis is rarely necrotizing but can manifest as nodular or diffuse, affecting both the anterior and/or posterior segments of the eye . Figure 1 illustrates a case of scleritis in a patient with SLE who was seen at Massachusetts Eye Research and Surgery Institution. Anterior uveitis has also been reported in some patients with SLE [4,20 ▪ ][4,20 ▪ ].
Posterior ocular structures
Lupus retinopathy is a common manifestation of the systemic disease, occurring in up to 29% of patients [3,7 ▪ ][3,7 ▪ ]. Retinopathy is first evidenced by small intraretinal hemorrhages and cotton wool spots . Even with treatment, retinopathy is associated with visual acuity deterioration . Vascular occlusion can be visualized via fundus fluorescein angiography, and manifests as widespread arteriolar or branch retinal artery occlusion accompanied by retinal ischemia and neovascularization [3,9 ▪ ][3,9 ▪ ]. When larger retinal vessels are affected, retinal and optic disc infarction can lead to neovascularization as well [7▪]. Although not seen in many other retinal vasculitic disorders, central retinal artery and/or vein occlusion can result secondary to SLE [7 ▪ ,8][7 ▪ ,8]. Retinal vasculitis is associated with poor visual outcome and has an acute presentation. In most of the cases, retinal vasculitis is accompanied by antiphospholipid antibodies . Retinal manifestations are often indicative of systemic disease in other organ systems. For example, retinal disease strongly correlates with central nervous system and renal disease [3,21 ▪ ][3,21 ▪ ].
Lupus choroidopathy with retinal detachment, although rare, is seen with central nervous system vasculitis and nephropathy and requires aggressive systemic treatment . A case report by Chin et al.[22▪] describes a case of lupus accompanied by polypoidal choroidal vasculopathy. Another rare ocular manifestation of SLE is optic nerve disease including optic neuritis and ischemic optic neuropathy. SLE patients with optic nerve damage have poor visual acuity which may or may not improve with treatment depending on the patient .
Ocular imaging is paramount for monitoring choroidal and retinal disease. Indocyanine green angiography is more useful for detecting choroidal disease, whereas fluorescein angiography is useful for detecting retinal, macular and optic nerve disease . Figure 2 illustrates retinal vasculitis and choroidal disease in a 35-year-old woman with lupus-associated antiphospholipid syndrome and lupus retinochoroidopathy seen at Massachusetts Eye Research and Surgery Institution.
SLE treatment varies depending on the location and severity of disease. Because of the systemic nature of the disease, treatment may be difficult and collaboration among specialists (ophthalmologists, rheumatologists, nephrologists, dermatologists and so on) is often required.
Corticosteroids are the mainstay acute treatment for treating ocular SLE. Corticosteroids are fast acting and effective; however, high-dose corticosteroids should only be used in the short term. If long-term therapy is required, corticosteroid-sparing agents should be administered . Aggressive systemic therapy is crucial for treating the systemic condition.
For patients with mild disease, NSAIDs and antimalarials are utilized for treatment [3,16][3,16]. Antimalarials, such as chloroquine and hydroxyl chloroquine, have been reported to be effective in treating SLE. However, these therapies can cause irreversible vision loss as a result of drug-induced maculopathy and should, therefore, be used with caution [3,23][3,23]. For patients exhibiting ocular manifestations associated with highly active disease, that is retinal vasculitis, nephritis and choroiditis, rapid and more aggressive therapy is required .
A variety of systemic immunosuppressants have demonstrated efficacy in treating ocular SLE. These therapies include methotrexate, mycophenolate mofetil, cyclosporine A, azathioprine, chlorambucil and cyclophosphamide [3,24,25 ▪▪ ][3,24,25 ▪▪ ][3,24,25 ▪▪ ]. 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 [26,27 ▪▪ ][26,27 ▪▪ ]. After being treated with immunosuppressant, many patients exhibit refractory disease [11 ▪▪ ,28][11 ▪▪ ,28]. In addition, generalized immunosuppression can lead to negative side-effects including bone marrow suppression, hepatotoxicity and risk of infection .
SLE involves production of multiple autoantibodies, each of which has been targeted as potential immunotherapy. Thus, recently several biologic agents, targeting specific components of the immune system, are being evaluated for the treatment of SLE. Belimumab is the first biologic agent that was approved for use in SLE by the Federal Drug Administration in 2011 [28,29][28,29]. Belimumab's mode of action is to defuse B-lymphocyte stimulator's biological activity [28,30][28,30].
Current research has suggested that therapies targeting B cells including rituximab, ocrelizumab and epratuzumab are useful for treating SLE [11 ▪▪ ,31][11 ▪▪ ,31]. These therapies avoid the negative side-effects associated with corticosteroid therapy and untargeted immunosuppression [11▪▪]. Rituximab, a B-cell depleting therapy, was one of the first biologics used to treat SLE . Rituximab has also been used in combination with cyclophosphamide in patients with refractory SLE . In severe SLE cases, pulsed sequential plasmapheresis and rituximab has improved retinal vascular occlusion . Two clinical trials were conducted to evaluate rituximab's ability to treat active lupus and lupus nephritis [34,35][34,35]. However, rituximab is not yet approved for use in SLE specifically.
Epratuzumab is an anti-CD22 IgG1 monoclonal antibody. CD22 is a desired target for therapy because it plays a role in B-cell development and survival . A study by Dorner et al. demonstrated that treatment with epratuzumab in SLE patients results in a decrease in peripheral B cells by 35–40%. Other clinical trials support the fact that treatment with epratuzumab showed clinical benefit in SLE patients [37 ▪▪ ,38][37 ▪▪ ,38].
Because T cells play a role in the pathogenesis of SLE, several therapies have been developed to target them. Abatacept, another immunomodulatory drug, is targeted against T-cell signaling [6▪▪]. Other biologic agents targeting T cells include ruplizumab, toralizumab and rigerimod [6▪▪]. Abetimus is also being evaluated for the treatment of SLE. Abetimus (LJP-394) is administered intravenously and blocks specific B-cell antidouble-stranded DNA antibodies .
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 used for retinal vascular occlusion and resultant ischemia. Vitrectomy can also be used to treat ocular diseases resulting from ocular ischemia [9 ▪ ,24][9 ▪ ,24]. In addition, anti-vascular endothelial growth factor has recently proven to be effective against vasoocclusion and vasculitis in patients with SLE [39,40][39,40]. Topical corticosteroids may be adequate to treat anterior uveitis, or corneal ocular manifestations associated with SLE (4). However, treatment of the underlying disease is of utmost importance. The presence of scleral, orbital, retinal, choroidal or neurological manifestations requires systemic therapy (4).
Current treatment has been inadequate in maintaining low disease activity and inducing remission in SLE patients. Unfortunately, many drugs that have undergone clinical trials for SLE have shown a lack of efficacy or have caused detrimental side-effects. A better understanding of the pathophysiology of SLE will enable researchers to develop more effective treatment options. Although many new biologic treatments have been undergoing evaluation in the last decade, clear guidelines for treating SLE are lacking. More research is needed in order to determine which therapy and/or combination of therapies will provide the best outcome for SLE patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
1. Choudhary MM, Hajj-Ali RA, Lowder CY. Gender and ocular manifestations of connective tissue diseases and systemic vasculitides. J Ophthalmol 2014; 2014:403042.
2. El-Shereef RR, Mohamed AS, Hamdy L. Ocular manifestation
of systemic lupus erythematosus
. Rheumatol Int 2013; 33:1637–1642.
3. Palejwala NV, Walia HS, Yeh S. Ocular manifestations of systemic lupus erythematosus
: a review of the literature. Autoimmune Dis 2012; 2012:290898.
4. Read RW. Clinical mini-review: systemic lupus erythematosus
and the eye. Ocul Immunol Inflam 2004; 12:87–99.
5. Foster CS, Vitale A. Diagnosis and Treatment of Uveitis. 2nd ed. 2013; Delhi: India: Jaypee Brothers Medical Publishers, 814–825.
6▪▪. Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus erythematosus
. Lancet 2014; 384:1878–1888.
This article provides a review of SLE in its entirety.
7▪. Talat L, Lightman S, Tomkins-Netzer O. Ischemic retinal vasculitis
and its management. J Ophthalmol 2014; 2014:197675.
This article describes retinal vasculitis, an important ocular manifestation of SLE and describes how it can be treated.
8. Yen YC, Weng SF, Chen HA, Lin YS. Risk of retinal vein occlusion in patients with systemic lupus erythematosis: a population-based cohort study. Br J Ophthalmol 2013; 97:1192–1196.
9▪. Fouad el A, Hanane M, Mounir B, et al. Severe ischemic retinopathy in a patient with systemic lupus erythematosus
without antiphospholipid syndrome: a case report. Saudi J Ophthalmol 2015; 29:169–171.
This case report describes a case of lupus retinopathy in the absense of antiphospholipid syndrome. This is interesting because antiphospholipid syndrome is usually associated with lupus retinopathy.
10. Rajadhyaksha AG, Mehra S, Nadkar MY. Biologics in SLE: the current status. J Assoc Physicians India 2013; 61:262–267.
11▪▪. Kamal A, Khamashta M. The efficacy of novel B cell biologics as the future of SLE treatment: a review. Autoimmun Rev 2014; 13:1094–1101.
This is an overview of new B-cell-targeting therapies that may provide benefit to SLE patients.
12. Chan O, Schlomchik MJ. A new role for B cells in systemic autoimmunity: B cells promote spontaneous T cell activation in MRL-lpr/lpr mice. J Immunol 1998; 160:51–59.
13▪. Konya C, Paz Z, Tsokos GC. The role of T cells in systemic lupus erythematosus
: an update. Curr Opin Rheumatol 2014; 26:493–501.
This review provides an updated and more in-depth look at the role T-cells play in lupus pathogenesis.
14. Yu C, Gershwin ME, Chang C. Diagnostic criteria for systemic lupus erythematosus
: a critical review. J Autoimmun 2014; 48–49:10–13.
15. Petri M, Orbai AM, Alarcón GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus
. Arthritis Rheum 2012; 64:2677–2686.
16. Nguyen QD, Foster CS. Systemic lupus erythematosus
and the eye. Int Ophthalmol Clin 1998; 38:33–60.
17. Kono S, Takashima H, Suzuki D, et al. Orbital myositis associated with discoid lupus erythematosus. Lupus 2014; 23:220–222.
18▪. Resch MD, Marsovszky L, Németh J, et al. Dry eye and corneal langerhans cells in systemic lupus erythematosus
. J Ophthalmol 2015; 2015:543835.
This review discusses dry eye, the most common ocular manifestation of SLE.
19. Alderaan K, Sekicki V, Magder LS, Petri M. Risk factors for cataracts in systemic lupus erythematosus
(SLE). Rheumatol Int 2015; 35:701–708.
20▪. Hong-Kee N, Mei-Fong C, Azhany Y, Zunaina E. Antiphospholipid syndrome in lupus retinopathy. Clin Ophthalmol 2014; 8:2359–2363.
Article indicated why testing for antiphospholipid syndrorme is useful and discusses the implications of lupus retinopathy.
21▪. Vodopivec I, Lobo AM, Prasad S. Ocular inflammation in neurorheumatic disease. Semin Neurol 2014; 34:444–457.
This article discusses how ocular manifestations of SLE can be associated with nervous system involvement.
22▪. Chin YC, Bhargava M, Khor CC, et al. Polypoidal choroidal vasculopathy and systemic lupus erythematosus
. Lupus 2014; 23:319–322.
This case report discusses choroidal diseases that can be associated with SLE.
23. Lopez-Ruiz N, Uribe CE. Chloroquine cardiomyopathy: beyond ocular adverse effects. BMJ Case Rep 2014; pii:bcr2014205751.
24. Silpa-archa S, Lee JJ, Foster CS. Ocular manifestations in systemic lupus erythematosus
. Br J Ophthalmol 2015; pii: bjophthalmol-2015-306629.
25▪▪. Al Hussaini M, Hammouda El, Hammouda AE. Optimizing pharmacotherapy of systemic lupus erythematosus
: the pharmacist role. Int J Clin Pharm 2014; 36:684–692.
This article discusses various new treatment options for SLE.
26. Petri M. Cyclophosphamide: new approaches for systemic lupus erythematosus
. Lupus 2004; 13:366–371.
27▪▪. Croyle L, Morand EF. Optimizing the use of existing therapies in lupus. Int J Rheum Dis 2015; 18:129–137.
Discusses current SLE therapies and provides recommendations that will provide benefit in the future.
28. Touma Z, Urowitz MB, Gladman DD. Systemic lupus erythematosus
: an update on current pharmacotherapy and future directions. Expert Opin Biol Ther 2013; 13:723–737.
29. Navarra SV, Guzman RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus
: a randomized, placebo-controlled, phase 3 trial. Lancet 2011; 377:721–731.
30. Dooley MA, Houssia F, Aranow C, et al. Effect of Belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus 2013; 22:63–72.
31. Reddy V, Jayne D, Close D, Isenberg D. B-cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumab and implications for study design. Arthritis Res Ther 2013; 15 (Suppl 1):S2.
32. Jónsdóttir T, Gunnarsson I, Risselada A, et al. Treatment of refractory SLE with rituximab plus cyclophosphamide: clinical effects, serological changes, and predictors of response. Ann Rheum Dis 2008; 67:330–334.
33. Damato E, Chilov M, Lee R. Plasma exchange and rituximab in the management of acute occlusive retinal vasculopathy secondary to systemic lupus erythematosus
. Ocul Immunol Inflamm 2011; 19:379–381.
34. Rovin BH, Furie R, Latinis K, et al. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum 2012; 64:1215–1226.
35. Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus
: the randomized double-blind, phase II/III systemic lupus erythematosus
evaluation of rituximab trial. Arthritis Rheum 2010; 62:222–233.
36. Dorner T, Kaufmann J, Wegener WA, et al. Initial clinical trial of epratuzumab (humanized anti-CD22 antibody) for immunotherapy of systemic lupus erythematosus
. Arthritis Res Ther 2006; 8:R74.
37▪▪. Wallace DJ, Kalunian K, Petri MA, et al. Efficacy and safety of epratuzumab in patients with moderate/severe active systemic lupus erythematosus
: results from EMBLEM, a phase IIb, randomised, double-blind, placebo-controlled, multicentre study. Ann Rheum Dis 2014; 73:183–190.
This clinical trial demonstrated the benefit of epratuzumab treatment in SLE patients.
38. Hobbs K, Gordon C, Strand V, et al. Efficacy and safety of epratuzumab in patients with moderate/severe flaring systemic lupus erythematosus
: results from two randomized, double-blind, placebo-controlled, multicentre studies (ALLEVIATE) and follow-up. Rheumatology 2013; 52:1313–1322.
39. Lee WJ, Cho HY, Lee YJ, et al. Intravitreal bevacizumab for severe vasoocclusive retinopathy in systemic lupus erythematosus
. Rheumatol Int 2013; 33:247–251.
40. Kurup S, Lew J, Byrnes G, et al. Therapeutic efficacy of intravitreal bevacizumab on posterior uveitis complicated by neovascularization. Acta Ophthalmol 2009; 87:349–352.