Treatment of non-infectious retinal vasculitis

Abstract

Retinal vasculitis (RV) refers to an entity in which the retinal vasculature is inflamed, frequently with indications of inflammation elsewhere in the eye. Non-infectious RV can be idiopathic or associated with systemic disease, ocular conditions, and malignancy. It can also be classified based on the vessel affected: artery, vein, or both. Due to the lack of strong evidence-based treatment trials and algorithms for RV, physicians must often rely on their experience, which creates great variability in treating this entity. This article provides an overview of various treatment modalities used in the management of non-infectious RV, with a focus on immunomodulatory therapies. We outline a potential stepwise approach of starting with steroids to control the acute inflammation and subsequently changing to immunomodulatory therapy (IMT) for long-term treatment.

Introduction

Retinal vasculitis (RV) is among the one of the most sight-threatening ophthalmic diseases. This review will describe one important yet poorly understood category of ocular disease: non-infectious RV, and how to treat it. RV refers to a set of diseases in which the retinal vasculature is inflamed, frequently with indications of inflammation elsewhere in the eye. Non-infectious RV may present alone or associated with other ocular inflammatory diseases, such as idiopathic, intermediate, posterior, and panuveitis, and systemic conditions, such as sarcoidosis, lupus, polyarteritis nodosa, multiple sclerosis (MS), and Behçet’s disease (BD). ¹ Primary (idiopathic) RV is the term given to inflammation of the retinal vasculature with no infectious etiology, systemic disease, or concomitant ocular disease. RV can lead to severe and irreversible vision loss.

Although RV is rarely associated with systemic vasculitis, it can still be associated with systemic diseases. As a result, conducting an extensive review of systems, medical and social history, and evaluation is essential to rule out any systemic disease association. Patients with RV undergo a thorough diagnostic evaluation, which is often expensive and unrevealing. Painless decrease in vision, blurry vision, flashes, and floaters are among the most common, presenting symptoms described by patients with RV. ² Potential vision-threatening sequelae are vascular occlusion and retinal ischemia, for which the pathophysiology is thought to be either thrombotic or obliterative secondary to inflammatory cell infiltration. ³

This review aims to present and discuss the most frequently used treatments for RV, and to provide the best ways to classify this poorly understood disease. We seek to provide clinicians with a guide for making the diagnosis and summarize potential treatment options.

Classification

The classification of RV can be challenging. Part of this difficulty comes from the different diagnostic criteria used by rheumatologists and ophthalmologists. Rheumatologists classify vasculitis based on the affected vessel size and histology, usually requiring a biopsy. This is not easily accomplished in the eye. ⁴ Instead, ophthalmologists diagnose it based on retinal vessel leakage that can be observed on a fundoscopic exam and ancillary testing, including intravenous fluorescein angiography (IVFA). Clinical findings on funduscopic exam associated with RV may include infiltrates, sheathing along the vessels, intraretinal hemorrhage, and cotton-wool spots.^5–7

Non-infectious RV can be idiopathic or associated with systemic disease, ocular disease, and malignancy. Idiopathic RV is further classified into ischemic and non-ischemic forms, from which ischemic RV portends a significantly worse visual outcome. ⁸ The most common systemic inflammatory diseases associated with RV are BD, sarcoidosis, and MS. ⁶ Other systemic conditions that are also associated with RV include systemic lupus erythematosus (SLE) and polyangiitis with granulomatosis.^9–11 RV associated with ocular diseases include pars planitis, Eales’ disease, Birdshot chorioretinopathy (BSCR), and idiopathic retinal vasculitis aneurysms and neuroretinitis (IRVAN). Cases of RV are reported in patients with malignant conditions, including acute leukemia, ocular, or central nervous system (CNS) lymphoma, Hodgkin’s lymphoma, metastatic B cell lymphoma, and pineal germinoma.^12–20 Given this, malignancy should be considered in the differential diagnosis in patients unresponsive to treatment for RV.

Physicians also classify RV based on the vessel affected: artery, vein, or both. Arterial involvement is associated with diseases, such as IRVAN, SLE, and granulomatosis, with polyangiitis. Some notable conditions with venous involvement include BD, sarcoidosis, pars planitis, BSCR, MS, and Eales’ disease. ⁷ Although BD affects both arteries and veins, retinal involvement of veins has been more commonly reported. Sarcoidosis, though not considered a true vasculitis, causes an inflammatory response primarily around veins, resulting in the occlusion of the small vessels. ⁷ Evidence of both artery and vein involvement can be idiopathic, a part of systemic disease, or associated with malignancy.

Treatment

Treatment for RV is determined by the cause of the vasculitis and its severity. The main goals in managing patients with RV are rapid control of intraocular inflammation, prevention of recurrent attacks, and achieving complete remission with preservation of vision. Unfortunately, therapeutic guidelines for patients with RV are lacking due to a paucity of well-designed randomized clinical trials. Recommended therapeutic options include anti-inflammatory regimens involving systemic corticosteroids in the short term and local steroids, if necessary, followed by steroid-sparing therapy using immunosuppressive medications, including chemotherapeutic (disease-modifying antirheumatic drugs or DMARDs) or biologic agents for the long term. ²¹

Immunosuppressants

Immunosuppressive medications, such as glucocorticoids, are required to treat acute episodes of inflammation. Glucocorticoids are the mainstay of treatment for RV in the absence of infection. Ali et al. ² compared the course of non-infectious RV in 56 patients, reporting prednisone as more commonly used (68%) compared with periocular triamcinolone injections (28%) and intravitreal triamcinolone injections (4%). In this study, the authors did not comment on the adverse effects of local or systemic steroids but mentioned that smoking was associated with worse visual outcome and that patients who presented before the age of 40 years were more likely to require a steroid-sparing agent. ² Steroids are given orally when RV is severe and occurs bilaterally. Intravitreal steroid implants can be used when the inflammation is stubborn despite systemic steroids, systemic steroids are poorly tolerated, or if the inflammation causes macular edema. The use of periocular or intraocular steroids can prevent systemic side effects but have potential side effects, including the risk of glaucoma and cataracts. ²²

Systemic steroids remain the mainstay of treatment for non-infectious RV, particularly during an acute flare for preventing vision loss. In a retrospective cohort study conducted by Sharief et al., ²³ 236 eyes were observed to have RV, and systemic steroids were used in 168 eyes with a reduction in vision loss and preventing further complications, such as macular edema or retinal ischemia compared with those eyes with vasculitis that did not use steroids. It is important to eventually consider steroid-sparing therapies for the treatment of patients once their acute flares have resolved. Side effects from systemic steroids include risk of infection, adrenal crisis, muscle weakness, cushingoid appearance, and delayed wound healing.

Local steroid therapy is especially used in the setting of RV with concurrent uveitis or with other ocular conditions. In a case series of 12 eyes with Eales’ disease, 10 out of the 12 eyes (83.3%) treated with intravitreal triamcinolone acetonide (IVTA) showed reduction in late leakage of retinal vessels on fluorescein angiography. ²⁴ Two of the eyes in this study did develop significant rise in intraocular pressure after IVTA. Because the duration of IVTA is short, intravitreal dexamethasone implant is thought by many to produce a more sustained effect than IVTA but was comparable with IVTA at 8 weeks in decreasing the central subfield thickness in uveitic macular edema.^25–27 There are case reports that suggest that the addition of intravitreal dexamethasone implant improved visual outcomes, macular edema, and resolution of RV, in entities, such as BD-associated uveitis and RV, and in IRVAN.^28,29 There were some elevations in intraocular pressure noted in some of these reports, following the use of the steroid implant.

The use of fluocinolone acetonide implants provide even a longer duration of action and are reasonable to consider for non-infectious RV. In a retrospective case series by Bajwa et al., ³⁰ 11 patients with BSCR intolerant of immunomodulatory therapy (IMT) underwent surgery for fluocinolone acetonide implant. At 3-year follow-up, no patient had any sign of ocular inflammation, and there was more than 20% decrease in central retinal thickness in patients with macular edema. At baseline, 54% of patients were on IMT, which decreased to 14% of patients at 3-year follow-up. Most commonly reported adverse events were cataract formation in every patient and increased intraocular pressure in over half of the patients. ³⁰ Despite the high success rate of corticosteroid therapy in treating acute inflammation and flare-ups, some cases of RV may be steroid-dependent, or patients may not be able to tolerate the adverse side effects.

Patients who are steroid-dependent or experience adverse side effects may be treated with steroid-sparing therapies. Cyclophosphamide is one agent that is sometimes used for RV associated with systemic disease. A previous case of SLE-associated RV was treated with pulsed intravenous cyclophosphamide combined with high-dose pulse intravenous corticosteroids. ¹⁰ This resulted in a recovery of vision and reversal of angiographically visible pathology. This agent is not used more frequently due to the multiple side effects associated with it, including bone marrow suppression, infertility, hemorrhagic cystitis, alopecia, and possibly carcinogenic. Cyclosporine and azathioprine are also commonly used agents in the treatment of RV. ³¹ In a longitudinal study of 295 patients with BD, Davatchi et al. ³² showed a combination of intravenously pulsed cyclophosphamide, orally administered azathioprine, and oral prednisolone as the best treatment choice for RV before opting for biologic agents. There were improvements in visual acuity, ocular inflammation, and disease activity noted for these patients. Interestingly, no ocular side effects occurred in this cohort, but the general side effects with azathioprine and cyclophosphamide were noted with no patient stopping the treatment protocol early. ³²

Methotrexate (MTX) has been widely used in treating ocular inflammatory diseases for the past two decades due to its efficacy, low cost, and tolerable safety profile. Low-dose intermittent intravitreal MTX is beneficial in treating RV associated to BD, juvenile idiopathic arthritis (JIA)-associated iridocyclitis, and sarcoidosis in patients refractory to steroids. ³³ A recent study determined the efficacy of intravenous MTX in combination with intravenous methylprednisolone in patients with severe, sight-threatening ocular inflammation, such as RV, scleritis, posterior uveitis, and panuveitis, in which they all achieved remission; the only adverse effect reported was leukopenia. ³⁴ In addition, Bae and Lee ³³ demonstrated a significant reduction in aqueous humor levels of the associated cytokines IL-6 and IL-8 after intravitreal MTX in patients with steroid-refractory RV.

Mycophenolate mofetil can also be used to treat intraocular inflammation. A retrospective study reported the effective control of inflammation in 65% of patients treated with mycophenolate for several etiologies, including RV, BSCR, pars planitis, and JIA. ³⁵ In this study, mycophenolate mofetil as monotherapy was able to achieve a steroid-sparing effect in 54% of patients; side effects occurred in 10 patients (18%), including diarrhea, fatigue, nausea, anemia, and leukopenia. Al-Moujahed et al. ³⁶ showed the efficacy of adding oral mycophenolate mofetil to a multidrug treatment regimen with intravenous infliximab infusions and intravenous methylprednisolone. It provided long-term immunosuppression after infliximab was weaned off in a 12-year-old patient with occlusive RV from BD.

Biologics

Biological drugs, such as cytokines and monoclonal antibodies targeting inflammatory mediators or receptors, have been produced to treat many immune-mediated disorders over the last three decades. In terms of anti-inflammatory potential, there is growing evidence that these novel medicines may outperform traditional immunosuppressive medications.

Interferon-alpha

Interferon-alpha (IFN-α) is one of the earliest cytokines with anti-proliferative, anti-angiogenetic, and immunomodulatory effects. Many studies have shown that IFN-α can be used to manage inflammation and treat RV over the last few years. IFN-α has been used for ocular involvement in BD as a subcutaneous injection or in combination with azathioprine, showing improvement in visual acuity, resolution of RV, and macular edema.^37–39 Becker et al. ⁴⁰ studied the effect of subcutaneous injections of INF-α in nine patients with MS refractory to corticosteroids. Vasoproliferative changes and visual acuity resolved in all patients, proving IFN-α beneficial and effective. In this study, the most reported side effects were only noted in three patients and include dizziness, tremor, and myopathy. Before starting a patient on INF-α, it is essential to lower the corticosteroid dose to avoid antagonistic effects. Steroids reduce the activity of NF-kB, a molecule that upregulates the sensitivity of cells to IFN-α. ⁴¹ Compared with tumor necrosis factor-alpha (TNF-α) antagonists, IFN-α has kept patients in remission even after treatment is stopped, in studies done in BD refractory to other therapies. ⁴²

Anti-TNFα

TNF-α is a cytokine that contributes to retinal damage and inflammation in various immune-mediated diseases. Infliximab, a chimeric monoclonal antibody, is one of the most well-studied drugs in this class for patients resistant to other immunosuppressive drugs. Sharma et al. ⁴³ studied 60 patients resistant to conventional IMTs who received infliximab and demonstrated compelling results in treating RV with 100% of patients receiving remission within 12 months of therapy. The side effects of infliximab in this study included leukopenia, diarrhea, and recurrent respiratory or soft tissue infections. Infliximab has significantly reduced the mean number of relapses and extended the length of remission during RV in BD, compared with conventional immunosuppression, including azathioprine, MTX, and cyclosporine. ⁴⁴ Furthermore, it has effectively led to RV resolution in patients with BD and IRVAN.^45,46 Infliximab was also used in six pediatric cases of idiopathic RV refractory to MTX, etanercept, and daclizumab. ⁴⁷ It achieved a reduction of ocular and intraocular inflammation after the first intravenous dose and allowed all patients to discontinue topical steroid therapy and discontinue systemic corticosteroids without a relapse.

Adalimumab (ADA) is a monoclonal IgG1 antibody self-administered via subcutaneous injection, which aids in achieving a more stable serum concentration. In patients with BD, intraocular inflammation has been effectively treated with ADA. ⁴⁸ Olivieri et al. ⁴⁹ reported successful treatment of RV in patients with BD who failed treatment with intravenous infliximab due to infusion reactions or lack of efficacy with infliximab. In this study, there were no side effects observed with adalimumab when patients were switched to it. Switching between TNF-α agents, after failure of one agent or infusion reactions, has been an alternative option studied in the last few years. Successful switching of infliximab to adalimumab in patients with BD has been reported, by achieving remission and prevention of relapse.^50,51

Another TNF-α inhibitor that successfully treats refractory RV in patients with BD is golimumab (GLM). Mesquida et al. ⁵² showed the benefits of GLM infusion t for a patient who developed resistance to infliximab infusions after 14 months of treatment. In addition, Fabiani et al. ⁵³ reported the efficacy of GLM infusions every 4 weeks in reducing the number of uveitis relapses and resolution of active RV in five patients with BD.

Anti-interleukin-6

IL-6 is a cytokine used to assess disease activity and has been linked to the pathogenesis of immune-mediated diseases, including non-infectious uveitis and RV. Tocilizumab (TCZ) is an anti-IL-6 receptor antibody currently approved for treating giant cell arteritis and rheumatoid arthritis refractory to anti-TNF drugs. A case report of a 33-year-old patient with idiopathic panuveitis and RV experienced significant improvements in retinal vascular leakage following treatment with intravenous TCZ. ⁵⁴ Six months after completion of the TCZ treatment, the patient, however, experienced a recurrence in ocular inflammation. Interestingly, in a case series of 11 patients with refractory BD-associated uveitis, TCZ proved to be efficacious, showing rapid improvement and maintenance in all ocular parameters, with complete remission in eight out of 11 patients. ⁵⁵ In this study, two patients had to be withdrawn from the study while receiving TCZ infusions due to an infusion reaction or impairment in their arthritis. ⁵⁵

Anti-interleukin-1

IL-1 is another crucial proinflammatory cytokine, and suppression of this cytokine has garnered much interest in treating RV. Three anti-IL-1 agents have been studied in RV treatment, including anakinra, canakinumab, and gevokizumab. Anakinra and canakinumab were used in a multicenter retrospective observational study of 19 patients with BD-associated uveitis. ⁵⁶ IL-1 inhibition induced a significant reduction in the relapse rate, providing long-term control of ocular inflammation in refractory and long-lasting cases; there were no adverse events seen in 12 months of therapy for these patients. Another anti-IL-1 agent used in the literature for treating RV is gevokizumab, a recombinant humanized antibody that binds to interleukin-1 beta (IL-1 beta). Gul et al. ⁵⁷ reported seven patients with BD-associated posterior uveitis or RV that proved resistant to azathioprine and cyclosporine tolerated a single infusion of gevokizumab well. The treatment was associated with rapid clinical responses in all patients and complete resolution of intraocular inflammation in 14 days. This effect was observed despite discontinuation of other immunosuppressive agents and without the need to increase the doses of corticosteroids.

Anti-vascular endothelial growth factor

Vascular endothelial growth factor (VEGF) is strongly linked to ocular neovascularization, angiogenesis, and vascular permeability. Given this, suppression of VEGF within the eye is emerging as a new option for all retinal diseases characterized by the high levels of VEGF due to retinal ischemia. ⁵⁸ Bevacizumab is a one of the anti-VEGF agents that could be used in the treatment of RV. Andreanos et al. ⁵⁹ reported a case of hemorrhagic occlusive retinal vasculitis (HORV) after prophylactic intracameral vancomycin on cataract surgery. They administered intravitreal bevacizumab, achieving rapid visual acuity restoration and no signs of neovascularization. In 2004, a rare case of RV and central retinal vein occlusion associated with Crohn’s disease was treated with a combination of oral prednisone, mercaptopurine, and intravitreal bevacizumab, achieving complete resolution of the disease. ⁶⁰ In this case, intravitreal bevacizumab was used to help treat the complications related to the central vein occlusion. Adverse events, however, have been associated with the use of bevacizumab, including cataract formation, elevated intraocular pressure, retinal artery occlusion, ocular hemorrhage, and hematogenous retinal detachment. ⁶¹ A second anti-VEGF used for the treatment of RV is ranibizumab. There was a case of rapidly progressing IRVAN that was treated with intravitreal injections of ranibizumab and ultimately achieved immediate regression of neovascularization and improvement in visual acuity. ⁶²

Lymphocyte-targeted therapies

Rituximab, an antibody against CD20, has been recently studied for the treatment of refractory cases of RV. A case of severe SLE-associated RV refractory to steroid therapy was successfully treated with a combination of plasmapheresis, IV rituximab, and intravitreal ranibizumab. ⁶³ Rituximab has also been effective in cases of severe BD-associated RV refractory to prednisolone, azathioprine, and etanercept.^32,64 In a case of severe lupus-associated RV, rituximab infusions were implemented together with oral prednisolone and cyclophosphamide infusions, ultimately achieving resolution of cotton-wool spots, retinal hemorrhages, and improvement in visual acuity in both eyes. ⁶⁵

Alemtuzumab, an anti-CD52 antibody therapy, has a predominant effect of T-cell depletion. It has been used to achieve remission in BD poorly controlled by conventional therapy. ⁴² A study in 2015 investigated the effect of alemtuzumab on patients with refractory and relapsing BD. ⁶⁶ In total, 84% of patients achieved partial or complete remission, and the most commonly seen side effect was symptomatic thyroid disease in 25% of the patients.

Daclizumab inhibits intraocular inflammation by targeting the CD25 member of the IL-2 receptor complex. In 2007, a randomized, placebo-controlled, double-masked clinical trial did not show any benefit of daclizumab infusions compared with placebo in BD-associated inflammatory eye disease. ⁶⁷ In 2008, a retrospective review of patients with BSCR refractory to conventional therapy, however, showed effective results of daclizumab in stabilizing vision and decreasing inflammation in many patients. ⁶⁸ Two patients experienced side effects, which included transaminitis, leukopenia, and diarrhea.

Recent therapies: subcutaneous repository corticotropin injection

Target molecules of recent resurgence include melanocortin peptides, such as adrenocorticotropic hormone (ACTH). ACTH not only stimulates cortisol production but also has anti-inflammatory properties by binding to melanocortin receptors on immune cells. ⁶⁹ It has been approved to treat immune-mediated diseases, including SLE, rheumatoid arthritis, sarcoidosis, MS, and inflammatory processes of the eye. In 2021, the first prospective study of patients with RV treated with repository corticotropin injection (RCI) showed that it was effective and well tolerated by patients. ²¹ The results reported more than 50% improvement in RV disease activity by week 12 in half of the eyes and complete resolution of RV in seven eyes in a mean time of 17.1 weeks. In this study, two eyes experienced elevations in intraocular pressure, and three eyes were noted to have formation of cataracts; one patient had to stop the medication due to an injection site reaction. In another case, a patient with idiopathic panuveitis and RV was treated with an injection of ACTH gel and achieved a rapid and adequate control of retinal vascular leakage, macular edema, and optic nerve inflammation. ⁵⁴

Drug-associated RV

Drug-associated RV is a rare adverse effect that can lead to vision loss. Because many patients take multiple medications, drug-associated vasculitis can be challenging to detect. One of the most reported medications associated with this entity is brolucizumab. A patient with neovascular age-related macular degeneration (nAMD) developed retinal arterial occlusion and vasculitis 4 weeks after intravitreal brolucizumab. ⁷⁰ Intravitreal dexamethasone implant improved visual acuity, but residual peri-vascular leakage remained. In 2020, a case series reported RV in 26 eyes of 25 patients (88% female) after treatment with brolucizumab, in which 92% were associated with intraocular inflammation. In total, 12 eyes (46%) had a final VA of 20/200 or worse. None of the patients had a history of anti-VEGF-associated ocular inflammation; hence, a careful examination for the signs of active inflammation before brolucizumab injection was recommended. ⁷¹ Systemic and local steroid therapy has been shown to be effective in the resolution of brolucizumab-associated RV in patients with age-related macular degeneration. ⁷²

Rituximab-associated retinal occlusive vasculitis developed in a patient with ocular lymphoma and ultimately resolved with systemic steroids. ⁷³ Witkin et al. ⁷⁴ reported a case series of HORV after cataract surgery associated with intraocular vancomycin, in which systemic and local steroids, intravitreal injections of anti-VEGF, and pan-retinal photocoagulation were recommended and effective in treatment of the patient. New-onset RV associated with the use of infliximab was reported in a case of Crohn’s-related spondyloarthritis. After the patient’s 12th infusion of infliximab, the patient developed acute onset blurry vision and RV, which resolved with laser retinal photocoagulation and peribulbar corticosteroid injection.

There was a case report that came out in 2020 that discussed RV associated with ipilimumab in a patient with chronic myeloid leukemia; the patient was ultimately treated with an intravitreal injection of dexamethasone implant and reported improvement in their visual acuity. ⁷⁵ In addition, in 2021, a rare case of a levonorgestrel intrauterine device-associated RV was reported. ⁷⁶ After the device was removed and intravenous methylprednisolone treatment started, the patient went into visible remission of any signs and symptoms of ocular inflammation. Therefore, drug-associated RV can have many presentations and sight-threatening complications. A thorough medical review must be done to assess recent changes in the patient’s medications to assess if there may be a medication-associated RV, affecting a patient’s visual acuity.

Conclusion

Non-infectious RV is a potentially vision-threatening inflammatory condition that can be idiopathic or associated with systemic disease, malignancy, or ocular inflammatory conditions. Currently, treatment information is extrapolated from non-randomized clinical trials, case series, and case studies. Due to this and the lack of strong evidence-based medicine, physicians must rely on clinical reasoning and their familiarity with different treatment options when deciding on the appropriate agent to use. This can result in great variability when treating patients based on clinicians’ preferences.

Randomized clinical trials are prospective studies that measure the effectiveness of a new intervention or treatment. In these studies, the randomization reduces the ability to have bias and provides a rigorous tool to study cause–effect relationships between an intervention and outcome. Researchers carefully select the population, interventions to occur, and outcomes of interest and select participants to be either in the intervention or placebo group. These studies represent the gold standard for effective research; however, they can prove challenging in inflammatory eye disease, given the rarity of the condition and the clinical heterogeneity that accompanies the condition. Many of these conditions can occur in the context of systemic conditions that have their own treatment protocols or in isolation of those, as solely ocular inflammation. Therefore, to perform these studies, it is important to take the patient’s systemic condition into account, prior treatments or interventions that have been trialed for the patient, and the outcomes that are being measured in a systematic manner to draw effective conclusions from the study.

Our recommendations follow Dr Foster’s ‘step-ladder’ approach for ocular inflammatory diseases, starting with systemic steroids to control the inflammation and subsequently changing to IMT for long-term treatment. ⁷⁷ Glucocorticoids are typically the first-line agent. When quiescence of ocular inflammation is dependent on glucocorticoids, this; however, requires escalation to IMT (Figure 1). In cases in which inflammation, pain, or visual outcomes have not improved in RV immediately within a few weeks of glucocorticoid therapy, it may be necessary to re-evaluate and consider treatment escalation with the use of concomitant periocular or intravitreal steroids. If there is a recurrence of RV on tapering of glucocorticoid therapy, this literature review supports MTX as a good starting point for treating non-infectious RV requiring a steroid-sparing agent if there are no contraindications. If MTX is ineffective or not tolerated by the patient, a different antimetabolite, such as mycophenolate or azathioprine, can be used. If antimetabolites are ineffective or not tolerated, treatment may need to be switched to another class of IMT, such as TNF-α inhibitors. A multi-modal approach may be needed for RV treatment, including concomitant use of local steroid treatment with steroid-sparing agents. More studies are required to further refine the treatment algorithm for non-infectious RV, based on clinical response and tolerance of the medication.

Figure 1.

Schematic diagram reviewing how to approach a patient with non-infectious RV.

When a patient presents with non-infectious RV, it is important to determine if it is in the context of a systemic condition, concurrent uveitis, or idiopathic without any uveitis or systemic association. In all three scenarios, it is important to start with systemic steroids (1 mg/kg/day up to 80 mg/day) for controlling the inflammation. If symptoms are improving, then they are tapered, and IMT is started for steroid-sparing therapy, such as a disease-modifying antirheumatic drug (DMARD). If steroids are not improving the symptoms, periocular or intravitreal injection of steroids can be used in patients with concurrent uveitis or primary RV; intravenous (IV) steroids can be considered in those with systemic disease in addition to periocular steroids. In patients with idiopathic RV or concurrent uveitis that do not respond to periocular or intravitreal injections, therapy is escalated to a DMARD, with antimetabolites typically being used as first-line agents. Other types of DMARDs or biologics may need to be trialed depending on the response to therapy. In patients with primary RV or RV with concurrent uveitis that respond to steroids, steroids can be subsequently tapered, and the patient can be monitored. If there is a recurrence, then the patient should be restarted on steroids with initiation of IMT. MTX is often used as the first-line IMT due to its efficacy, affordability, and oral formulation. Comorbid autoimmune conditions may guide IMT choice. Alternate IMT, such as a biologic (e.g. TNF-α or CD20 inhibitors), is often considered if initial IMT is unable to resolve underlying vasculitis.

One difficulty in establishing algorithms for RV is that when it is associated with certain disease entities, there may be controversy in treating some of the manifestations in those entities. For example, if TNF-α inhibitors appear to be the next line of therapy for a patient with RV and optic neuritis with BD refractory to steroids and conventional immunosuppression, there is potential to aggravate CNS demyelination and worsen the optic neuritis. ⁷⁸ Therefore, it is important to consider each entity and its manifestations carefully when deciding on the appropriate therapy. This review has several limitations. Due to the low prevalence of this disease, it is difficult to find studies with previously established treatment algorithms for RV; hence, this review aimed to provide a possible approach for the management of non-infectious RV for clinicians. Other limitations include the paucity of well-designed randomized clinical trials and the wide array of treatment approaches depending on the clinicians’ specialties, such as retina, uveitis, or rheumatology.

Literature search

This review was compiled using articles identified by searching PubMed from the last 20 years. The following keywords were used for the search: ‘retinal vasculitis’; ‘non-infectious retinal vasculitis’; ‘retinal vasculitis and treatment’; ‘retinal vasculitis and steroids’; ‘retinal vasculitis and biologics’; and ‘retinal vasculitis and immunomodulatory’. We included all relevant articles in English. Non-English articles were included if English abstracts were available.