An Update on Noninfectious Retinal Vasculitis

Retinal vasculitis (RV) is an entity which encompasses the inflammation of retinal vessels. The inflammation can occur as an isolated ocular disease or be associated with systemic inflammatory diseases. The annual incidence of RV is about 1–2 cases per 10,000 population [1]. Isolated cases of RV may occur in a small proportion (3%) of the cases [2]. Also, RV occurring in conjunction with systemic vasculitis is seen in much fewer cases (1.4%) [3].

The disease can be diffuse or involve only arteries, veins, or capillaries. The vessels in the macular area may be inflamed, leading to visual loss. In contrast, the involvement of the vessels in the retinal periphery may lead to a peripheral leakage without any effect on the vision [4]. The disease is diagnosed clinically on a detailed dilated fundus examination and appears as perivascular infiltration, intraretinal hemorrhages, or cotton-wool spots highlighting the abnormalities of the retinal vessels. Fundus fluorescein angiography (FFA) can highlight perivascular leakage and staining, leading to the diagnosis of RV. Retinal vascular inflammation can occur due to infectious or noninfectious etiologies [5]. The pathogenesis, pathology, and treatment of noninfectious RV vary significantly compared to infectious RV.

The most common causes of RV secondary to systemic diseases include Behcet’s disease (BD), multiple sclerosis (MS), and systemic lupus erythematosus (SLE) [6]. The involvement of retinal vessels without any underlying systemic inflammatory disease is known as primary RV. In about 17% of the cases, underlying etiology is not evident on a detailed workup [3]. However, patients with initial, negative laboratory work may develop systemic disease during the follow-up period. Some authors have highlighted in their study that 3.5% of the patients with RV developed systemic disease during the follow-up [7].

RV is a sight-threatening ocular disease with varied clinical presentations and etiologies, and managing the disease can be challenging. The sight-threatening complications include macular edema, vascular occlusions, retinal ischemia, neovascularization, vitreous hemorrhage, tractional retinal detachment, and neovascular glaucoma [3‒6, 8]. The current review discusses various causes of noninfectious RV and updates in their management.

The exact pathophysiological changes occurring in cases of noninfectious vasculitis are difficult to ascertain. Animal models have been developed to study the pathophysiology of RV [9]. The manifestations like perivenular sheathing and cuffing have been attributed to a type-III hypersensitivity reaction [10]. The typical terms used to describe findings in RV, like “periarteritis” and “periphlebitis,” point towards the perivascular location of the inflammation. A break in the blood-retinal barrier secondary to inflammation in autoimmune and systemic diseases may be central to the pathogenesis in noninfectious RV [11]. An increased expression of intracellular adhesion molecules and increased recruitment of inflammatory cells around the retinal vessels has been noted by researchers. Lee et al. [12] noted increased interferon-beta, E-selectin, and s-intracellular adhesion molecules in serum samples of the patients with RV. Histopathological studies have highlighted the presence of lymphoma cells in the vicinity of retinal veins in patients with RV secondary to lymphomas [12, 13]. Hughes and colleagues [1] pointed out that noninfectious RV is an autoimmune condition. However, a previous microbial infection, as a cause of an exaggerated immune response, cannot be ruled out. The genetic susceptibility of both HLA associations and cytokine polymorphisms may influence the auto-reactivity.

Sarcoidosis is a multisystem disease with protean clinical manifestations. The condition is characterized by the presence of noncaseating granulomas in various organs. Ocular involvement can be the initial presentation of sarcoidosis in up to 80% of the patients [14]. Retinal vascular involvement can occur in most patients, along with the typical choroidal (granulomas) and vitreous involvement (snowballs and snow banking). Inflammation of the retinal venous system, in the form of sheathing, is one of the most common presentations of sarcoidosis. The typical, segmental, vascular sheathing cuffing with exudation, known as “candle-wax dripping,” can be seen in about 40% of the patients [15, 16]. Although vascular involvement is not primarily obstructive, ischemic changes, vascular occlusions, and neovascularization can also occur [17]. Vasculitis, accompanied by retinal hemorrhages and retinal edema, can be recognized clinically and on multimodal imaging (Fig. 1) [18].

The neovascularization of the optic disc and the peripheral retina is typical after capillary closure/dropout. Other complications include vitreous hemorrhage, ischemia, and tractional retinal detachment. In addition to routine ocular examination, serial fundus photographs and FFA are used to evaluate the disease activity. Optical coherence tomography angiography has recently been used to assess the inflammatory activity in patients with sarcoid-associated RV [18].

BD is a chronic multisystem disorder characterized by recurrent non-granulomatous inflammation. BD can cause severe ocular and systemic complications [19]. The systemic manifestations include mucosal tissue ulcerations, erythema nodosum, arthritis, respiratory tract involvement, pericarditis, meningoencephalitis, and dural sinus thromboses. Ocular involvement includes anterior uveitis, mobile hypopyon, optic atrophy, papilledema, and occlusive RV [20]. The classic triad of BD includes oro-genital ulcers, skin, and eye involvement. Ocular involvement generally manifests within 2 years of disease onset and occurs in 70–85% of the patients, while retinal involvement (retinal lesions and vasculitis) can occur in up to 50–93% of the cases [21]. Ocular involvement in BD can also manifest as a potentially blinding bilateral panuveitis. The initial involvement may be limited in the form of anterior or posterior uveitis. Still, during the later/advanced stages of the disease, panuveitis is the most common form of ocular disease. RV associated with full-thickness retinal infiltrates is a common occurrence in BD. These lesions generally heal without significant scarring and pigmentation. RV in BD can involve retinal arteries, veins, and capillaries (Fig. 2). Branch vein occlusions, retinal hemorrhages, and macular edema are more common in BD than central retinal vein occlusions [22]. Often, BD has a chronic or recurrent course requiring long-term treatment with systemic immunosuppression.

The FFA findings include diffuse vascular leakage (capillary involvement), peripheral ischemia, neovascularization of the disc and elsewhere, macular edema, vascular staining, vein occlusions, and macular ischemia. The typical FFA finding in BD is a “fern-like pattern” of diffuse vascular leakage during late phases. The complications of RV in BD include optic disc ischemia, macular ischemia, neovascularization, vitreous hemorrhage, tractional retinal detachment, and phthisis bulbi [23]. Recent reports have shown an increased incidence of venous thrombotic events (VTEs) in patients with BD [24, 25]. The two most common VTEs reported in BD are superficial subcutaneous thrombophlebitis and deep vein thrombosis. The increased incidence of VTE in BD has been attributed to persistent inflammation, predisposing to thromboembolic phenomenon [26]. However, the exact mechanism is not known. Similar to BD, an increased incidence of VTE has been documented in polymyalgia rheumatica and giant cell arteritis. Increased incidence of VTE in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides has also been reported recently in the literature [27].

Patients with systemic auto-inflammatory diseases rarely develop RV. The literature shows that the incidence of RV in the setting of systemic vasculitic illness is very low [22]. Granulomatosis with polyangiitis (GPA) is one of the ANCAs associated with systemic vasculitides. Ocular and orbital involvement can be seen in more than half of the patients with ANCA positivity [28]. The various ocular manifestations in GPA include orbital cellulitis, peripheral ulcerative keratitis, conjunctivitis, episcleritis, scleritis, dacryocystitis, and dacryoadenitis [29]. The retinal involvement in GPA may range from benign cotton-wool spots to sight-threatening retinal vascular occlusions [30]. The compression of the central retinal vessels secondary to inflammation of tissues in the orbit can lead to vascular occlusions [31]. The occlusions can also occur due to vasculitis secondary to inflammatory activity in GPA [32]. GPA-associated RV is characterized by necrotizing vasculitis with or without immune complex deposition.

RV in GPA can involve any subset of the retinal vessels [30]. The common retinal findings in GPA include retinal hemorrhages, cotton-wool spots, perivascular infiltrates, and focal arterial and venous infarctions. Retinal ischemia and neovascularization can develop in some cases [33]. The treatment includes high-dose intravenous corticosteroids and systemic immunosuppression, depending on the severity of the disease.

As highlighted previously, RV is a rare occurrence in system vasculitides, and most of the reported literature is in the form of isolated case reports and case series. Microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and Takayasu’s arteritis (TA) are rare ANCA-associated vasculitides with low incidence rates in the population [34]. In a series by Lin et al. [35], out of the 14 patients, only two had RV associated with EGPA and MPA. Partal et al. [36] reported a child with severe visual loss, combined retinal arterial and venous occlusion secondary to EGPA. Similar cases have been reported by Sánchez-Vicente et al. [37] and Nikandish and Saremi [38], and TA is a systemic vasculitic disease primarily involving large vessels like the aorta and its branches. The primary pathology involved in TA is granulomatous panarteritis with intimal proliferation and defects in the elastic lamina. Ocular involvement in TA is reported to be higher than in patients with EGPA and MPA [39].

A recent systematic review and meta-analysis showed that about 4% of patients with TA developed RV [40]. The RV associated with ANCA-associated vasculitides can be severe and refractory to the treatment. Initiation of aggressive treatment strategies and monoclonal antibodies can lead to remissions in even the severe forms of the disease [40].

SLE is another systemic vasculitis that results in arthritis, myocarditis, nephritis fever, and Raynaud’s phenomenon [41, 42]. Ocular involvement in SLE is highlighted by retinopathy that is reported to affect 30% of patients. Retinopathy manifests as cotton-wool spots, frosted branch angiitis (FBA), retinal bleeding, and vascular fibrosis [41, 43‒46]. In addition, optic nerve atrophy due to RV may occur. Vitreous hemorrhage can occur due to retinal neovascularization in up to 40% of SLE retinopathy patients. Larger retinal vessel disease can lead to retinal central arterial occlusion [47]. Apart from RV, usually there are no intraocular signs of inflammation such as vitreous haze or vitreous cells in SLE.

The rare clinical triad of microvasculopathy in the brain and retina associated with hearing loss in young women was first described in 1979 as Susac’s syndrome (SS) [48]. The exact pathogenesis is not known, but the auto-inflammatory endothelial damage to the vessel walls, causing ischemic infarcts, has been attributed to be central to the disease process [49]. The endothelial damage leads to vascular occlusions, leading to ischemia and thus affecting the vascular supplies of the brain, retina, and cochlea, resulting in the specific symptoms of the disease. The complete triad may be evident in only 15% of the patients at the initial presentation [50]. This can lead to significant delays in the diagnosis and institution of specific therapies. Neurological involvement manifesting as encephalopathy is the primary symptom in most cases. The disease can be associated with headache, dementia, low concentration levels, disorientation, and behavioral changes [50]. Hearing loss occurs due to microvascular occlusions at the level of the vascular supply of the vestibulocochlear system. The most common symptoms include sensorineural hearing loss followed by tinnitus, vertigo and nystagmus [50].

The typical ocular symptoms include decreased vision, visual field defects, and photopsia. In contrast, ocular findings include arteriolar narrowing, perivascular infiltrates, yellowish arterial plaques (Gass plaques), retinal pallor, cotton-wool spots, and optic disc hyperemia [51, 52]. The ocular disease may manifest as multiple branch retinal artery occlusions without clinically apparent RV or uveitis. However, FFA in these cases can demonstrate underlying inflammation in the form of vascular and segmental perivascular leakage [52‒54]. Bagaglia et al. [53] have highlighted the role of multimodal imaging and optical coherence tomography angiography in SS. Papasavvas et al. [54] highlighted the abrupt disruption and segmental interruption of arterial flow on FFA as a pathognomonic finding of SS in their series. The treatment of SS depends on the severity of the neurological disease. The treatment modalities include high-dose corticosteroids, immunosuppressive drugs, and monoclonal antibodies. However, the disease may require treatment for a more extended period to achieve remission [52, 53].

The administration of vaccines (immunization) can lead to the development of multiple systemic adverse events (AEs). Considering the magnitude of COVID-19 vaccinations worldwide, an increased number of AEs have been reported [55].

The ocular AEs reported after administration of different types of COVID-19 vaccines include de novo episodes of uveitis (anterior, posterior, and panuveitis), reactivation of uveitis, multiple evanescent white dot syndromes, Vogt-Koyanagi-Harada-like disease, and vascular occlusions [55‒60]. Although rare, RV has been reported after COVID-19 and influenza vaccinations (Fig. 3) [55, 61]. Li et al. [62] also reported diffuse bilateral RV (presenting as FBA) in a patient with a recent history of COVID-19 vaccination. Testi et al. [63], in their multicentric study, had 2 patients with RV secondary to COVID-19 vaccination. Two mechanisms of auto-immunity leading to RV and vascular occlusions have been postulated, one being the hypersensitivity reaction and immune complex deposition related to the vaccine, the other being the inflammatory damage induced by the adjuvants used to enhance the efficacy of the vaccines [64].

Birdshot chorioretinopathy (BSCR) is a potentially blinding ocular disorder involving retinal and choroidal vessels without systemic involvement [65]. The disease manifests as bilateral, symmetrical, posterior uveitis characterized by multiple hypopigmented choroidal lesions associated with RV. The choroiditis lesions are mostly centerd around the optic disc, while vasculitis primarily involves the large retinal vessels (predominantly retinal veins). Previously, authors have highlighted RV as an essential criterion for diagnosing BSCR [66‒68]. A strong association of the disease with the HLA-A 29 antigen has been noted in the literature [69].

The typical hypofluorescent dots at the choroid level can be seen on ICGA as a sign of active choroidal inflammation. Since the choroid is primarily involved, ICGA is a more sensitive imaging modality to detect choroidal lesions. In the early 1980s, Gass reported the diffuse narrowing of retinal vessels, vascular tortuosity, perivascular hemorrhages, and optic disc swelling in patients with BSCR [70]. FFA helps assess the extent of retinal vascular involvement and inflammatory activity in BSCR. Agrawal et al. [65] have reported a significantly smaller venule-to-arteriole ratio in patients with BSCR. The authors highlighted the role of this modality in the follow-up of patients with BSCR. In 20% of the cases, the disease may be self-limiting, while recalcitrant cases require corticosteroids and immunomodulator therapy [70].

FBA is a rare clinical entity characterized by severe inflammation of the retinal vessels. The disease primarily involves an exaggerated immune response, leading to a severe form of RV. The severe sheathing of the retinal vessels produces an appearance similar to the “frosted branches of a tree.” [71] The disease primarily involves retinal veins and is known as acute retinal periphlebitis. FBA is characterized by acute visual loss, retinal sheathing, retinal edema, and vitritis, with varying degrees of anterior uveitis. FFA shows diffuse vascular leakage without signs of stasis or occlusion [71]. FBA can be idiopathic or associated with ocular and systemic diseases.

The ocular entities associated with FBA include cytomegalovirus retinitis, HIV retinopathy, and toxoplasma chorioretinitis. At the same time, SLE, Crohn’s disease, large cell lymphoma, and acute lymphoblastic leukemia (ALL) have been described as systemic causes of FBA [72]. Kleiner categorized patients with FBA into three groups. The first group represents patients with leukemia and lymphoma, the second includes infectious, viral, and autoimmune diseases, and the third includes idiopathic cases [73]. There has been significant debate about whether FBA is a clinical sign or, per se, a clinical entity on its own [74]. An unusual case of SLE relapse presenting as FBA has been reported in the literature [24]. A recent report highlights that idiopathic FBA and secondary FBA occur almost equally; however, idiopathic FBA has more bilateral occurrence than secondary FBA [72]. FBA can present with severe inflammation and severely reduced visual acuity; however, treating the underlying cause and administering oral corticosteroids in idiopathic cases results in an excellent visual outcome.

Drug-induced vasculitis has also been widely reported, especially after intravitreal drug delivery [75]. Serious AEs like hemorrhagic occlusive retinal vasculitis have been reported following the injection of aminoglycosides (gentamycin and amikacin), vancomycin, mitomycin-C, cefuroxime, rituximab, and brolucizumab into the vitreous cavity [75‒80]. The disease presents with severe visual loss, retinal hemorrhages, and occlusive vasculitis. Type-III and IV hypersensitivity reactions have been thought to play a key role in the pathogenesis of hemorrhagic occlusive retinal vasculitis. Delayed drug toxicity and the role of antidrug antibodies have also been implicated as a possible cause of this sight-threatening entity. However, the exact mechanism is not clear. The treatment includes aggressive therapy with systemic and local corticosteroids after excluding infectious etiology [77]. Also, the development of RV after treatment with systemic anticancer drugs like dabrafenib and trametinib has been reported [81].

Tsui et al. [82] reported a patient with leukemia who developed vasculitis while on treatment with Ipilimumab. Pembrolizumab has also been reported to induce RV as a spectrum of uveitis [83]. It becomes pertinent to acquire a good drug history in patients with vasculitis treated for systemic diseases.

Idiopathic retinal vasculitis, aneurysms, and neuroretinitis is a rare sight-threatening disease of unknown etiology [84]. The disease is characterized by predominant arterial involvement, formation of aneurysms, peripheral retinal vascular involvement, capillary nonperfusion, neovascularization, and macular exudation [85]. The early stages of the disease may be asymptomatic; however, during the late stages, the disease may lead to significant visual loss. Young females are the predominant group affected. The disease’s specific systemic associations and etiology have not yet been identified. However, associations with tuberculosis and fungal infections have been proposed [86‒88]. Samuel et al. [85] were the first to classify the disease based on clinical features.

The major criteria include RV, aneurysmal dilations, and neuroretinitis, while minor criteria include peripheral capillary nonperfusion, neovascularization, and macular exudation. The disease is classified into various stages (five stages) depending on the presence of different clinical findings. The presence of aneurysms, neuroretinitis, RV, and macular exudation is characterized as stage I, while the presence of peripheral capillary nonperfusion is classified as stage II disease. Stage III includes neovascularization and vitreous hemorrhage, while anterior segment neovascularization is classified as stage IV disease. Neovascular glaucoma is classified as stage V disease. The initial stages may be asymptomatic; however, the disease may progress to sight-threatening stages. Different treatment modalities are available based on the clinical stage. The initial stages may be managed with pan-retinal photocoagulation, cryotherapy, and systemic corticosteroids; however, stages with neovascularization and vitreous hemorrhage may require anti-VEGF agents and pars plana vitrectomy (PPV) [85]. Cheema et al. [89] showed that initiating systemic infliximab therapy improved macular exudation in their series. Use of dexamethasone implant and immunosuppressive therapy has also been advocated in the literature for the management of the disease [90, 91]. Samuel et al. [85] highlighted that early initiation of treatment in idiopathic retinal vasculitis, aneurysms, and neuroretinitis cases leads to better visual outcomes and prognosis.

A thorough clinical examination and use of multimodal imaging can lead to early diagnosis and play an important role in managing the disease. Delays in diagnosis and initiating therapy can lead to severe visual loss.

Masquerade is defined as a group of ocular diseases which present with features of intraocular inflammation but do not belong to the categorization of uveitis as such. Masquerade syndrome occurs more frequently in the extremes of age (children and elderly population). Masquerades are classified into two subtypes: neoplastic and non-neoplastic [92]. The non-neoplastic uveitis masquerades include diseases like retinal detachment, retinitis pigmentosa, coats disease, retained intraocular foreign bodies, and ocular ischemic disease [93]. Primary vitreoretinal lymphomas (PVRLs) are the most common etiology for neoplastic masquerade syndromes. Uveal lymphoid infiltrations and infiltrations secondary to systemic lymphomas should also be considered [93]. The diagnosis can be challenging. A detailed history, clinical review of systems, multimodal imaging, and relevant systemic investigations can help in early diagnosis of this entity. Also, specific surgical interventions like diagnostic vitrectomy, vitreous cytological analysis, and tests like IL6 to IL10 quotient help establish the diagnosis [94].

Retinal involvement in ALL patients has been reported previously [95]. The retinal vascular manifestations in patients with leukemia include cotton-wool spots and white-centered retinal hemorrhages. Retinal involvement can also occur as “leukemic retinopathy.” The disease features of leukemic retinopathy occur secondary to severe anemia rather than leukemic infiltration [84]. Severe translucent perivascular infiltration has also been reported in ALL [96‒100]. RV in patients with T-cell leukemia is rare. Merle et al. [100] screened 300 seropositive patients with T-cell leukemia, and RV was noted in a single patient only, highlighting the very low incidence of the disease. Similar case reports highlighting RV in leukemia have been reported [100‒103]. Two of these reports highlight that the Human T-cell lymphotropic virus type 1 associated disease masqueraded as severe necrotizing RV and retinitis [102, 103]. Unusual cases of leukemia presenting as FBA have also been reported in the literature [99, 104].

PVRL generally masquerades as vitritis and retinal or subretinal infiltration (Fig. 4) [93]. Katoch et al. [105] reported a patient with PVRL in whom vitritis and RV manifested before the appearance of the typical subretinal deposits. Sonne et al. [106] also reported an unusual case of PVRL presenting as occlusive vasculitis. Similar reports with diffuse, occlusive RV have been reported in the literature [107]. Diffuse vasculitis and vascular sheathing have also been reported in a patient with diffuse systemic B-cell lymphoma [108].

An unusual case with metastatic adenocarcinoma initially presenting as vasculitis and posterior pseudo-hypopyon has been reported by Kawali et al. [109] A rare recurrence of metastatic cutaneous melanoma following therapy presenting as vitreous involvement and RV has also been reported. Although rare, these entities should be considered in the differential diagnosis of RV in patients with malignancies [110].

Although rare, other unusual entities causing RV have also been reported. A large series with 44 eyes with HLA B27 uveitis showed that about half of the eyes had posterior segment involvement. Among the 22 eyes, 41% had a disc leakage, while 32% had peripheral. Vascular leakage documented on FFA [111]. Attia et al. [112] reported a rare case with HLA B 27 related uveitis presenting with RV, neovascularization and vitreous hemorrhage.

Other rare associations include RV occurring in association with IgA nephropathy and uveitis [113]. Kang et al. [114] reported ischemic RV in a patient with adult onset Henoch-Schonlein purpura. The patient was managed with retinal photocoagulation and reperfusion of the macular capillary bed secondary to regenerative angiogenesis was noted.

Systemic sclerosis is a multisystem disease characterized by severe hypertension, renal dysfunction, and autoimmune hemolytic anemia. Although rare, ocular involvement presenting as RV has been reported in multiple case reports [115, 116]. The ocular disease is characterized by the development of occlusive RV in these cases [117]. Systemic corticosteroids led to the control of inflammation in almost all the cases. In most cases, pan-retinal photocoagulation will be required to take care of the peripheral capillary nonperfusion to prevent neovascularization.

MS is a rare cause of RV. This disease is characterized by chronic progressive neurological impairment due to demyelination [15, 118]. Ocular inflammation may occur during the course of the disease and may have a waxing and waning course. Optic neuritis is the most common manifestation and is typically unilateral [15, 118‒120]. The inflammation can be either granulomatous or non-granulomatous anterior uveitis or present as other forms such as intermediate uveitis/pars planitis, retinitis, or retinal periphlebitis. RV has been reported in 11% of cases of MS [15, 121]. FFA can show perivascular and optic disc leakage in these cases. Most patients have excellent visual recovery, though permanent vision loss can happen to variable degrees [121‒123].

Acute multifocal hemorrhagic RV (Blumenkranz syndrome) is another entity characterized by acute visual loss from anterior uveitis, multifocal RV, capillary nonperfusion, hemorrhages on the retina, optic disc swelling, and vitreous cells. This entity can have complications resulting from retinal neovascularization, resulting in vitreous hemorrhage. The etiology of Blumenkranz syndrome is unknown [124].

The treatment of noninfectious RV varies considerably as compared to infectious RV. Managing infectious RV primarily involves the administration of antimicrobial agents like antibiotics, antifungal, antiviral, and antiparasitic agents. However, treating noninfectious RV mainly involves administering corticosteroids and steroid-sparing immunosuppressive drugs (systemic and oral route). The treatment may also include the management of underlying systemic disease. The local delivery of the drugs can be in the form of intravitreal steroid implants and depot steroid injections (sub-tenons). Whereas the severe forms of ocular disease or systemic involvement may require pulse intravenous high-dose corticosteroids, disease-modifying anti-rheumatic drugs, monoclonal antibodies, and TNF-alpha inhibitors [125, 126]. Biologic agents may be required in cases with refractory RV, patients intolerant to systemic corticosteroids, and those with concomitant severe systemic vasculitis. However, recent trials have shown that monoclonal antibodies (IL-1beta and IL-17 A) effectively control inflammation on a short-term basis but could not meet the primary end-point of long-term control of inflammation in BD [127].

Regarding specific disease entities, the treatment of BD involves the administration of systemic corticosteroids and immunosuppressive drugs. Various drugs used for BD include interferon alpha, cyclophosphamide, TNF-alpha antibodies, methotrexate, and azathioprine [128, 129]. Monoclonal antibodies against TNF are most effective in treating BD. As per the 2018 European League Against Rheumatism (EULAR) Standing Committee for Clinical Affairs, the treatment in BD depends on the severity of the disease. The severe cases require high-dose oral corticosteroids with biological agents such as infliximab or interferon alpha. Intravitreal steroid implant can be used for cases which require unilateral supplementation in addition to systemic therapy [130]. The local treatment of the ocular disease involves using drugs like intravitreal steroid implants and anti-VEGF agents [22]. RV in GPA and other ANCA-associated vasculitides may be associated with life-threatening illnesses. The treatment of sight and life-threatening diseases may require the administration of drugs like rituximab and cyclophosphamide. Systemic administration of methotrexate and mycophenolate mofetil may be required for long-term control of the disease [131]. Anti-VEGF agents are essential in managing macular edema and neovascular complications of RV. Treating complications like retinal ischemia and neovascular glaucoma requires pan-retinal photocoagulation, and end-stage complications like tractional retinal detachment may require PPV surgery [132].

As far as the masquerades are concerned, management strategies include PPV, radiation therapy, systemic chemotherapy, and intravitreal methotrexate injections [133]. Janus kinase inhibitors are the new drugs being tried to treat refractory cases of uveitis and varied systemic diseases. Janus kinase transducers constitute a group of molecules central to the pathways affecting cytokine functions. The upregulation of these transducers has been implicated in the pathogenesis of various autoimmune diseases [134]. JAK inhibitors have emerged as a novel and effective therapy in the treatment of pediatric BD [135]. Although several reports of the use of JAK inhibitors in noninfectious uveitis are coming up in the literature, their potential role in managing RV has to be explored further [136, 137]. To summarize, the management of noninfectious RV may require a combination of treatment modalities and a multidisciplinary approach.

Adalimumab and infliximab have been found to be highly effective in the treatment of recalcitrant cases of RV [138]. Treatment of recalcitrant case of SLE with adalimumab has been reported recently [43]. The American Uveitis Society also recommends the use of infliximab and adalimumab as first-line therapy for BD associated uveitis and vasculitis [139]. Treatment with rituximab has also been found to be efficacious in patients with RV related to BD and SLE [44, 140].

Lightman et al. [141] showed that administering pegylated interferon alpha-2b could reduce the dose of immunosuppression and corticosteroids with significant improvement in quality of life in patients with BD. However, it is pertinent to closely watch for the development of any AEs like flu-like illness and reactivation of tuberculosis, especially in endemic regions. Anesi et al. [142] showed that subcutaneous repository corticotropin injection was effective and well tolerated in patients with RV. The drug administration showed potential for long-term remission in patients with RV. Complete resolution of RV was seen in seven of 30 eyes at a mean of 17 weeks duration.

Newer entities with RV are being diagnosed based on genetic analysis. A rare form of RV associated with anterior segment inflammation, neovascularization, retinal neovascularization, and vitreous inflammation has been reported secondary to calpain 5 gene mutation. The gene involved encodes calcium-dependent cysteine protease. The disease entity is known as autosomal dominant neovascular inflammatory vitreoretinopathy [143]. Mutation in TREX 1, an exonuclease, leads to a rare retinal vasculopathy. The disease is also associated with abnormalities of the cerebral vasculature, thus known as retinal vasculopathy with leukodystrophy [144].

Another disease with features like BD has been reported. The primary genetic defect occurs in the tumor necrosis factor alpha-induced protein 3. This leads to A 20 haploinsufficiency and increased expression of inflammatory cytokines. The typical features of this disease include younger age at disease onset, oral ulcers, positive pathergy test, skin involvement, chorioretinal scars, and macular fibrosis secondary to RV [145].

Experimental models have also been developed to highlight the role of leukotrienes and VEGF in immune-mediated RV [146]. Similarly, there is an increased interest in proteomics, which will be useful in identifying etiology in so-called “primary or idiopathic” cases of RV.

Noninfectious RV can be caused by several etiologies, many of which may have an important systemic association. It is relevant to appropriately investigate all cases of RV to determine the etiology if possible, and initiate appropriate therapy. Certain cases of noninfectious RV may be complicated by vascular nonperfusion, resulting in retinal neovascularization, vitreous hemorrhage, and structural complications such as tractional retinal detachments. The use of systemic and local immunosuppressive therapies, in addition to surgical techniques such as PPV is necessary in the management of these cases.

Due to the heterogeneity of various populations studied and different study designs and methodologies included in this review, there can be an inherent challenge to derive blanket conclusions. Also, different studies included may have used different definitions for RV, which may induce inconsistencies in the interpretation of results.

The authors report no conflicts of interest. The authors alone are responsible for the content and preparation of this manuscript.

No funding was received for this study.

Nitin Kumar Menia was responsible for review of the literature, analysis, and drafting of the manuscript. Yasmine Alcibahy was responsible for review of the literature, analysis, drafting of the manuscript, and critical review. Francesco Pichi and Piergiorgio Neri were responsible for review of the literature, analysis, and critical review of the manuscript. Aniruddha Agarwal was responsible for conceptualization, review of the literature, analysis, and critical review of the manuscript.