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Ophthalmologists and rheumatologists frequently miscommunicate in consulting on patients with retinal vasculitis. This report seeks to establish a common understanding of the term, retinal vasculitis, and to review recent papers on this diagnosis.
1) The genetic basis of some rare forms of retinal vascular disease have recently been described. Identified genes include CAPN5, TREX1, and TNFAIP3; 2) Behçet’s disease is a systemic illness that is very commonly associated with occlusive retinal vasculitis; 3) retinal imaging including fluorescein angiography and other newer imaging modalities has proven crucial to the identification and characterization of retinal vasculitis and its complications; 4) although monoclonal antibodies to IL-17A or IL-1 beta failed in trials for Behçet’s disease, antibodies to TNF alpha, either infliximab or adalimumab, have demonstrated consistent benefit in managing this disease. Interferon treatment and B cell depletion therapy via rituximab may be beneficial in certain types of retinal vasculitis.
Retinal vasculitis is an important entity for rheumatologists to understand. Retinal vasculitis associated with Behçet’s disease responds to monoclonal antibodies that neutralize TNF, but the many other forms of non-infectious retinal vasculitis may require alternate therapeutic management.
Few terms create as much misunderstanding as retinal vasculitis. A rheumatologist classifies vasculitis on the basis of the size of the vessel affected, its location, and the associated histological changes. Usually this classification requires a biopsy; occasionally the diagnosis is based on imaging such as an abdominal angiogram. A diagnosis of vasculits indicates documented or presumed damage of the vessel wall.
In contrast, an ophthalmologist diagnoses retinal vasculitis on the basis of perivascular infiltrates on a dilated eye examination and imaging usually in the form of a fluorescein angiogram. Vasculitis can be suggested by a finding such as an intraretinal hemorrhage, which indicates an abnormality of a retinal vessel, or a cotton wool spot indicative of local retinal ischemia. A biopsy is a rarity due to the potential damage caused by a retinal biopsy. Angiography is consistent with retinal vasculitis if fluorescein stains the vessel wall or leaks beyond the vessel. This leakage demonstrates increased vascular permeability, which is a very different threshold for diagnosing vasculitis compared to vessel wall destruction on histopathology.
This review focuses on new developments in the understanding and treatment of retinal vasculitis. However, before summarizing those papers, we begin with a summary of some basic concepts relative to retinal vasculitis so that the reader will be armed with the background to appreciate the recent literature. These concepts include:
Recent developments related to retinal vasculitis can be divided into (1) new insights into pathogenesis, (2) epidemiology and complications, (3) imaging, and (4) treatment.
Very rare genetic causes of retinal vascular inflammatory disease are now being recognized and may help better elucidate the pathogenesis of certain types of retinal vasculitis. ADNIV (autosomal dominant neovascular inflammatory vitreoretinopathy), a condition that results in anterior chamber and vitreous inflammation, as well as retinal and iris neovascularization, is caused by mutations in Calpain 5 7, a calcium-dependent cysteine protease coded by the CAPN5 gene. A mouse model of uveitis resulting from a mutation in calpain 5 has been described 8. Several different mutations of calpain 5 can result in ophthalmic disease 7. The neovascularization that occurs in ADNIV might be secondary to ischemia rather than an intrinsic disease of retinal vasculature. In addition to ADNIV, another inherited retinal vasculopathy is caused by mutations in TREX1, an exonuclease 9 . Polymorphisms in TREX1 have been associated with predisposition to systemic lupus erythematosus (SLE)10 . Mutation in TREX1 can cause abnormal retinal and cerebral vasculature and retinal ischemia. The syndrome has been labelled retinal vasculopathy with cerebral leukodystrophy9 . Mutations of the same gene cause Aicardi-Goutieres Syndrome11. A novel Behçet’s-like autoinflammatory disease was recently reported due to mutations in TNFAIP3 (tumor necrosis factor alpha-induced protein 3) leading to A20 haploinsufficiency and increased expression of NF-κB–mediated inflammatory cytokines12. Patients present early in life with oral ulcers, pathergy, dermal abscesses, chorioretinal scarring, and macular fibrosis secondary to retinal vasculitis.
In 2015, case reports and small series added to the differential diagnosis for retinal vasculitis. It was reported to occur subsequent to vaccination for influenza 1 and in a patient who had both malaria and Dengue Fever 13. Intravitreal injection of vancomycin as is done in some centers after cataract surgery has been rarely associated with retinal vasculitis 14. Patients with birdshot chorioretinopathy 15 and uveitis in association with psoriasis 16 were also noted to have a predisposition to retinal vasculitis.
A relatively common cause of retinal vasculitis in India is known as Eales’ Disease. A recent report performed PCR for Mycobacterium tuberculosis DNA and detected it in 39% of patients with Eales’ disease 17. The vasculitis is generally believed to be a hypersensitivity response to mycobacterial antigen rather than an active infection.
A report from Israel characterized 45 patients with retinal vasculitis18. About two thirds had an associated systemic disease. This is far higher than a report from our own center 3. The difference is accounted for by the much higher prevalence of Behçet’s disease in Israel since Behçet’s disease accounted for more than 70% of the systemic illness among patients with retinal vasculitis.
A series of over 6000 patients with Behçet’s disease from Iran concluded that 58% had eye disease and about one third had retinal vasculitis 19. The slight male predominance and the relative frequency of specific organ involvement was similar in Iran to what had been reported in countries such as Turkey, Germany, and Japan.
A series of 132 patients with Behçet’s disease from an eye center in Saudi Arabia found that panuveitis was the most common presentation 20. The study noted that 26% of patients had retinal vasculitis at presentation.
Our own group has looked for correlations between clinical signs of retinal vasculitis or patient characteristics and outcome measures 21. We found that neovascularization was more common in occlusive retinal vasculitis. We found that a complication known as an epiretinal membrane was more common in patients who had intraretinal hemorrhage or cotton wool spots as opposed to a finding known as vascular sheathing. Smoking correlated with a worse prognosis. Patients who were less than 40 years of age appeared to have more severe disease as judged by the likelihood that immunosuppressive therapy beyond corticosteroids would be prescribed as treatment. We also found that while only 1.4% of retinal vasculitis patients had systemic vasculitis, approximately 25% had some type of associated systemic disease, with sarcoidosis and Behçet’s disease being the most common 3. Other systemic diseases that can be associated with retinal vasculitis include Vogt-Koyanagi-Harada syndrome, multiple sclerosis, psoriatic arthritis and inflammatory bowel disease based our findings.
As alluded to above, retinal vasculitis is generally defined by ophthalmologists as a disruption in the blood-retinal barrier as noted by retinal vascular leakage on fluorescein angiography and/or perivascular infiltrates on dilated fundus examination, usually in the presence of other signs of intraocular inflammation such as infiltrating leukocytes into the vitreous, anterior chamber, retina or choroid. Various ophthalmic imaging modalities aid in the identification of several features of retinal vasculitis including: extent and location of retinal vascular leakage (ultra widefield-fluorescein angiography); location and extent of retinal or choroidal lesions (fundus photography, optical coherence tomography or OCT, widefield autofluorescence); and presence of complications associated with retinal vasculitis including cystoid macular edema and retinal neovascularization (OCT and Ultra widefield-fluorescein angiography). For instance, in a patient with Behçet’s disease associated retinal vasculitis with untreated disease, the extent of retinal infiltration, retinal vasculitis, and associated cystoid macular edema can be illustrated readily without retinal biopsy on ultra widefield fluorescein angiography, fundus imaging, and OCT (Figure 1). The diagnosis of Behçet’s disease in this patient was made after presentation with panuveitis, oral ulceration and a pustular rash (Figure 1), all of which resolved with treatment with oral prednisone, azathioprine, and infliximab (Figure 2).
Recent imaging findings in retinal vasculitis include the association of retinal vasculitis with suprachoroidal fluid on enhanced depth imaging OCT in patients with Birdshot choroidopathy 22. Errera et al. recently reported that adaptive optics imaging in retinal vasculitis detected perivascular infiltrates not seen on other standard imaging modalities such as fluorescein angiography and fundus photography 23. Mesquida et al. demonstrated retinal vasculitis on ultra widefield-fluorescein angiography that was not otherwise clinically evident in Behçet’s disease in 28 of 33 eyes (84.8%), with the most common angiographic finding being diffuse vascular leakage 24.
In some uveitis patients, peripheral vascular leakage is isolated (without diffuse vascular leakage), but the significance of this finding remains unclear. Our group found that peripheral vascular leakage on ultra widefield-fluorescein angiography occurred at a higher prevalence in patients thought to be clinically active compared to those with well-controlled disease (p=0.001), and that complications such as macular edema and optic disc leakage were associated with peripheral vascular leakage 25. Another emerging imaging modality, OCT angiography, is able to quantitate flow within blood vessels without the use of intravenous fluorescein dye such as that used in fluorescein angiography. Using OCT angiography, we find that retinal vascular flow is diminished in retinal vasculitis patients compared to age-similar normal subjects (Investigative Ophthalmology and Visual Science, 2015;56(7): 3359 (abstract)).
The treatment for retinal vasculitis depends on the cause of the vasculitis and its severity. In the setting of an infection, retinal vasculitis should be treated by managing the underlying infection. Retinal vasculitis secondary to anti-phospholipid antibodies might require anti-coagulation. Some forms of retinal vasculitis cause minimal disruption of visual function and do not require therapy.
While initial results were promising 26,27, biologics directed at either IL-1 beta or IL-17A, have recently failed to meet the primary endpoint in clinical trials for uveitis in general and for Behçet’s disease specifically28,29. (The failure of neutralization of IL-1 beta in the treatment of Behcet’s disease is based on a press release from July, 2015; https://www.google.com/webhp?sourceid=chrome-instant&ion=1&espv=2&ie=UTF-8#q=gevokizumab%20uveitis).
Adalimumab was studied by Abbvie in two randomized, controlled trials for uveitis (not specifically retinal vasculitis), VISUAL I and VISUAL II. Both trials have been reported in abstract form at the 2015 annual meeting of the American College of Rheumatology. In the first trial, active uveitis was studied. The second trial enrolled patients with controlled inflammation who were oral corticosteroid dependent. In both trials, the primary endpoint was time to treatment failure. Both trials met their primary endpoint. All immunomodulatory therapy approved by the US Food and Drug Administration to date represents a form of corticosteroid. Abbvie will seek vision threatening, non-infectious uveitis as an indication for the use of adalimumab. If successful, rheumatologists would have improved ease to prescribe adalimumab for retinal vasculitis. The inhibition of TNF has been extremely successful in the management of Behçet’s disease and associated retinal vasculitis. In Japan, regulatory authority has approved infliximab specifically for the treatment of Behçet’s disease and recent American Uveitis Society recommendations state that “infliximab and adalimumab can be considered as first-line immunomodulatory agents for the treatment of ocular manifestations of Behçet’s disease”30.
Several recent studies from different ethnic cohorts have addressed the long-term effects of TNF inhibition in Behçet’s ocular disease: the first from a Spanish registry31 and the second from a Japanese registry32. In the Spanish study, 124 patients with uveitis refractory to conventional immunosuppressants were treated with either open-label infliximab or adalimumab. Over the course of one year, ocular inflammation, visual acuity, and steroid doses rapidly improved with 67.7% of patients achieving clinical remission. The number of patients with retinal vasculitis decreased from 89 (143 eyes) to 8 (13 eyes). In the Japanese study, 164 consecutive patients treated with infliximab for more than one year were retrospectively studied. The frequency of ocular inflammatory attacks was reported in the year prior to infliximab and compared to the year after infliximab and a significant reduction was observed. Similarly, visual acuity also improved. Relapses were frequent and typically responded to higher doses of infliximab. The frequency of retinal vasculitis was not specifically stated
The efficacy of TNF inhibition for Behçet’s disease has been confirmed in a retrospective study from a French registry that included 124 patients with Behçet’s disease 33. Of those with ophthalmic disease considered to be “severe or refractory”, 96% had a complete or partial response to TNF inhibition. Several different monoclonal antibodies to TNF appeared to show comparable benefit. Interestingly, the diagnosis of retinal vasculitis was associated with a statistically significant reduction in responsiveness, odds ratio 0.33, range 0.12 to 0.89.
Infliximab has also been analyzed for its benefit in treating various forms of retinal vasculitis in a retrospective study from a single center in Boston 34. Using an initial dose of 5 mg/kg, 88% of treated patients were reported to be in remission with this therapy.
Reports on the efficacy of rituximab for retinal vasculitis are sparse. One case report noted resolution of retinal vasculitis after rituximab therapy in a patient who had eosinophilic GPA 5 and a small treatment study of 20 patients suggested that rituximab may be efficacious in patients with Behçet’s. 35 Rituximab has also shown some success in several case reports of patients with SLE and retinal vasculitis. Hickman et al reported the success of rituximab therapy 1g intravenously × 2, two weeks apart, in a patient with severe SLE-associated retinal vasculitis that was refractory to cyclophosphamide and intravenous methylprednisolone 36. Donnithorne et al reported on successful use of rituximab with cyclophosphamide in two female pediatric SLE patients 37.
Subcutaneously injected alpha interferon has been a successful alternative for therapy of Behçet’s disease. This was supported in a study from Korea, but this was based on an experience with only five patients. 38 All patients experienced some benefit after treatment with alpha interferon with 3 patients achieving a complete response. Visual acuity did not improve in the majority of patients, presumably due to irreversible damage. In contrast, a study of 72 patients from the UK revealed disappointing results. In this study, the addition of pegylated interferon-alpha-2b did not result in an overall reduction in corticosteroid or immunosuppressant dose although a post-hoc analysis showed that patients on corticosteroids at baseline had an improved quality of life and decreased corticosteroid dose at one year39. Proponents of alpha interferon as therapy for Behçet’s argue that it is as effective as TNF inhibition, that it avoids the risk of immunosuppression, and that it is capable of inducing long term remission. Those who advocate for TNF inhibition point out that this approach to therapy often improves the sense of well-being in contrast to the flu like symptoms engendered by interferon therapy. Inhibition of TNF is probably more effective than interferon for non-ocular manifestations of Behçet’s disease. And in addition to flu like symptoms, interferon therapy is associated with a variety of side effects including depression and immune mediated disease such as thyroiditis or even uveitis. Paradoxically inhibiting type I interferon is a promising mode of therapy for systemic lupus erythematosus or dermatomyositis. Just as administering type I interferon can be therapeutic and blocking type I interferon can be therapeutic, IL-17 demonstrates a similarly surprising result. In an animal model of T cell mediated uveitis, either giving IL-17 40 or blocking IL-17 41 can be efficacious. This suggests that the immune system seeks homeostatic balance and perturbations in either direction could be therapeutic. An alternative argument is that immune system diseases should be viewed as a spectrum based on immune-pathogenesis with, for instance, multiple sclerosis at one end and rheumatoid arthritis at another. By this argument, successful targeting of a cytokine in one immunological disease should not always extrapolate to the right target in another immune-mediated disease.
Retinal vasculitis is usually identified on the basis of perivascular infiltrates or leakage of dye on a fluorescein angiogram in a patient with other evidence for intraocular inflammation and without another cause of retinal vascular disease. The vast majority of patients with retinal vasculitis do not have a systemic vasculitis. Genetic causes of retinal vascular abnormalities are being identified. Behçet’s disease is often associated with retinal vasculitis. Monoclonal antibodies that neutralize TNF are extremely effective in treating Behçet’s disease.
We are indebted to Steve Planck who helped with the formatting of this manuscript.
Financial support: This work was supported by NIH Grants K to CAH, K08 EY022948 to PL, and NEI Core Grant P30 EY010572. Additional support was received from Research to Prevent Blindness, the Stan and Madelle Rosenfeld Family Trust, and the William and Mary Bauman Foundation. PL has a career development award from Research to Prevent Blindness.
Conflict of interest: JTR consults for Genentech, Xoma, Novartis, Abbvie, and Janssen. The other authors report no conflict of interest.