Bilateral Retinal Vasculitis as Initial Presentation of Systemic Lupus Erythematosus with Secondary Antiphospholipid Syndrome

Background

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease of undefined etiology with relapsing and remitting course. It is more common among females of childbearing age, with a female-to-male ratio of 9: 1 [1]. The common clinical features are fatigue, arthralgia, malar rash, renal, and neuropsychiatric manifestations. All organs and systems can be affected in SLE, including the eye.

Ocular manifestations were reported in about one-third of patients with SLE, and the percentage is even higher in the presence of antiphospholipid syndrome (APS) [2]. The involvement of eye structures, such as the surface of the eye (25–35%), retina (10%), and optic nerve (1%), is influenced by disease activity [2,3]. In this case report, we present a 34-year-old man with bilateral retinal vasculitis as the initial presentation of SLE with secondary APS.

Case Report

A 34-year-old man, previously healthy, presented to the eye clinic for the first time with painless reduced vision for 3 weeks, starting with the right eye, followed by left eye involvement in the third week. His past surgical history included LASIK refractive procedure for both eyes 1 year before. His family history was positive for multiple sclerosis (MS) in his sister. A review of systems revealed generalized fatigue, myalgia, arthralgias, and weight loss of around 10 kg in the last 3 months.

His vital signs were within normal ranges: temperature 37°C, blood pressure 118/80 mmHg, and a heart rate of 86 beats per minute. On ophthalmic examination, the best corrected visual acuity (BCVA) was 20/40 in the right eye and 20/25 in the left eye. Intraocular pressure (IOP) was 7 and 12 mmHg in the right and left eye, respectively. Examination of the anterior segment was within normal limits and showed bilateral clear vitreous. A fundus exam showed bilateral diffuse multiple cotton-wool spots, dot and blot hemorrhage covering the posterior pole with venous congestion and beading (Figure 1A, 1B). In addition, there was cystoid macular edema (CME) in the fovea of both eyes, confirmed by optical coherence tomography (OCT) of the macula (Figure 2A, 2B). Fundus fluorescein angiography (FFA) with color fundus photographs at the same time (Figure 3A–3D) showed bilateral areas of peripheral and macular hypo-fluorescence and multiple hyper-fluorescent knob-like aneurysmal dilatations with vascular leaking and staining. On physical examination, there was bilateral tenderness over the wrist, elbow, knee, metatarsophalangeal joints, and 2nd and 3rd metacarpophalangeal joints.

The laboratory workup was notable for high erythrocyte sedimentation rate (ESR) at 90 mm/hr (normal range 0–20 mm/h) and prolonged activated partial thromboplastin time (APTT) 66.6 s (normal range 24.6–36.4 s) partially corrected with mixing study indicating the presence of inhibitor such as lupus anticoagulant, which was positive in our case. A rheumatological workup was positive for antinuclear antibody (ANA- IF) of >1: 320 (normal <1: 80), anti-double-stranded DNA of 1: 80 (normal <1: 10), lupus anticoagulant 1.33 (normal range 0.8–1.2%), and rheumatoid factor 128 IU/mL (normal range 0–25 IU/mL). Protein C and S were low at 44 and 30% respectively (normal range 60–170%). Complement C3 was low at 0.76 g/L (normal range 0.9–1.8 g/L); however, C4 was normal at 0.19 (normal range 0.1–0.4 g/L). Extractable nuclear antigen Ab (ENA) was positive for nucleosome, histone, and ribosome PO. All of the following investigations were negative: complete blood count (CBC), renal function test (RFT), liver function test (LFT), activated protein C resistance (APCR), and antithrombin III (ATIII). In addition, anti-cyclic citrullinated peptide (CCP), C-ANCA, P-ANCA, and VDRL all were negative. The antiphospholipid syndrome (APS) antibodies were weakly positive anti-β2-glycoprotein IgG 30 (normal range <5 U/ML), IgM 20 (normal range <5 U/ML); anti-cardiolipin IgG 36 (normal range <10 U/ML), and IgM 20 (normal range <7 U/ML). Routine urine test results and protein-to-creatinine ratio (ACR) were within normal ranges, indicating no renal involvement.

A diagnosis of SLE was made by the rheumatology team based on the clinical presentations and laboratory investigations. The patient received intravenous methylprednisolone 1g/day for 5 days and was discharged on oral prednisone 1 mg/Kg/day with a tapering regimen. One month later, the patient was admitted to the hospital with deep vein thrombosis (DVT) in his right leg. The antiphospholipid syndrome (APS) antibodies were repeated after 12 weeks and were still weakly positive anti-β2-glycoprotein IgG 6 (normal range <5 U/ML), IgM 7 (normal range <5 U/ML); anti-cardiolipin IgG 11 (normal range <10 U/ML), and IgM 8 (normal range <7 U/ML). However, repeated lupus anticoagulant after 12 weeks was still high at 1.5% (normal range 0.8–1.2%).

The patient was also diagnosed with secondary APS. He was then started on hydroxychloroquine 400 mg once daily, mycophenolate mofetil 1 g once daily, and warfarin tablets 5 mg once daily. The patient was discharged with rheumatology and ophthalmology follow-up.

One month later, the fundus exam and OCT macula showed residual CME (Figures 1C, 1D and 2C, 2D), and a right eye intravitreal ozurdex injection (dexamethasone intravitreal implant) was given. His vision improved to 20/20 in both eyes. After 7 months, the fundus exam showed neovascularization of the disc (NVD) and neovascularization elsewhere (NVE) in both eyes, and a pan-retinal photocoagulation (PRP) was done for both eyes on multiple sessions. After 1 month, he developed vitreous hemorrhage in the right eye after receiving an increased warfarin dose and right eye IV Lucentis (ranibizumab intravitreal injection). Later, he also developed vitreous hemorrhage in the left eye, and IV Eyelea (aflibercept intravitreal injection) was given. The bilateral vitreous hemorrhage resolved within 1 month.

Eighteen months after his presentation, the fundus exam (Figure 1E, 1F) showed the disappearance of cotton-wool spots, and dot and blot hemorrhage. OCT confirmed the disappearance of CME (Figure 2E, 2F) but showed a wide foveal contour in the right eye and mild atrophic changes in the para-foveal area, indicating ischemic insult. The patient reported significant improvement in his vision and SLE was controlled with regular rheumatology follow-ups.

Discussion

The most common ophthalmic manifestations of SLE are keratoconjunctivitis sicca (dry eye disease), iritis, ciliary body inflammation, and retinal vascular changes [2]. Complications in the posterior segment of the eye, such as the retina, usually precede the other systemic features of the disease [2].

About 10% of patients with SLE have lupus retinopathy; however, the incidence tends to decrease, especially with administration of newer systemic therapies [4]. Lupus retinopathy is likely to appear in the presence of neuropsychiatric lupus, lupus nephritis, and autoimmune hemolytic anemia [5]. Our patient had no other organ involvement in the presentation.

Patients with mild retinopathy might be asymptomatic, whereas severe retinopathy leads to visual deterioration, distortions, and visual field defects [2]. Unlike the majority of SLE patients, loss of vision was the only presenting manifestation in our patient. This presenting manifestation has been reported in multiple previous case reports [6–12], but bilateral presentation has only been reported in 2 previous cases [6,10]. Unlike our patient, it is notable that most of the cases mentioned above were females and only 1 case was male. In addition, central retinal artery occlusion (CRAO) associated with retinal vasculitis was also reported as the presenting manifestation of SLE [10–12]. One study showed that 72% of eyes with SLE retinopathy had retinal neovascularization with sequelae such as vitreous hemorrhage (63%) and retinal detachment (27%) [2]. The most common retinal manifestation of SLE is retinal microangiopathy such as small intraretinal hemorrhages and cotton-wool spots [13].

About 77% of SLE patients with lupus disease of the retina or optic nerve are found to have elevated antiphospholipid antibodies [14]. Although our patient had weakly positive antiphospholipid antibodies, he was diagnosed with secondary APS according to the American College of Rheumatology (ACR) criteria, which increases his risk of lupus disease of the retina and vascular occlusions [15].

The combination of systemic and ocular glucocorticoid therapy is the cornerstone treatment to initially manage the ocular manifestations of SLE. In our case, the vision showed marked improvement after systemic steroid and adjunctive intraocular steroid injections. Long-term treatment with hydroxychloroquine and mycophenolate mofetil is also important to maintain remission of SLE. Retinal involvement can also result as a complication of hydroxychloroquine treatment [16]. The incidence of hydroxychloroquine maculopathy was reported to be less than 1% in the first 5 years; however, CRAO and early hydroxychloroquine maculopathy had been linked in 2 previous case reports [17,12]. Thus, close monitoring and early screening of patients on hydroxychloroquine are important, especially if retinal occlusive vasculopathies are present.

Conclusions

Ocular manifestations may be the initial presentation of SLE and can lead to serious ocular complications. Therefore, early diagnosis and proper management are essential and require cooperation between rheumatologists and ophthalmologists. The combination of systemic and ocular therapy is crucial to treat the ocular manifestations of SLE. The aim of treatment is remission with the minimum possible dose of glucocorticoids. Long-term follow-up is important to monitor and manage the disease and treatment complications.