Ophthalmological manifestations in autoimmune diseases: Overcoming diagnostic and therapeutic challenges

Abstract

Autoimmune diseases frequently present with ophthalmological manifestations, posing significant diagnostic and therapeutic challenges. This review delved into the complex interplay between autoimmunity and ocular health, highlighting common manifestations such as uveitis, keratitis, and optic neuritis. We explored advanced diagnostic tools and techniques to improve early detection and accurate diagnosis. Additionally, the review addressed current therapeutic strategies, emphasizing the need for tailored treatments to manage ocular symptoms effectively while minimizing systemic side effects. By overcoming these challenges we aimed to enhance patient outcomes and quality of life for those affected by autoimmune-related eye diseases.

Key Words: Autoimmune diseases; Ophthalmological manifestations; Uveitis; Keratitis; Optic neuritis; Scleritis; Episcleritis; Diagnosis; Biomarkers; Management; Therapeutic challenges

Core Tip: Early detection of symptoms related to ocular manifestations in autoimmune diseases, leading to vision-threatening conditions such as uveitis and optical neuritis, is critical for preventing irreversible damage. Advanced diagnostic tools and useful serological biomarkers offer improved accuracy but remain underutilized. Effective management requires balancing symptom control with minimizing immunosuppression risks and emphasizes a multidisciplinary approach involving ophthalmologists and rheumatologists. Continued research is vital to address unmet clinical needs and optimize outcomes.

INTRODUCTION

Autoimmune diseases are a group of disorders in which the immune system mistakenly targets the body’s own cells, tissues, or organs, resulting in chronic inflammation and tissue damage[1]. These diseases are mostly systemic and involve multiple organ systems with various presentations. Simply, they are not homogenous when it comes to variables like their pathogenesis, symptoms, and prevalence.

The global burden of autoimmune diseases is high with studies showing that it affects approximately 5% of the United States population and around 5%-10% of the industrialized world population[2,3]. One of the organ systems frequently affected by autoimmune diseases is the eye, which is particularly vulnerable due to its immune-privileged status (Figure 1). Ophthalmological manifestations often reflect underlying systemic activity and at times precede the systemic symptoms of the condition. Common complications involving the eye include dry eye disease in Sjörgen’s syndrome (SS), uveitis in ankylosing spondylitis (AS), scleritis, episcleritis, and keratitis in rheumatoid arthritis (RA), and retinal vasculitis in systemic lupus erythematosus (SLE) and granulomatosis with polyangiitis (GPA). The conditions mentioned above and many others can range from mild ocular symptoms to severe complications threatening the patient’s vision. Early detection and treatment of ocular symptoms are important for preventing irreversible damage and improving outcomes[3].

Figure 1 Blood-ocular barrier maintains the immune-privileged status of the eye by restricting the entry of blood-borne substances. It consists of two main components: The inner blood-retinal barrier formed by tight junctions between retinal endothelial cells and supported by Müller glial cells, which regulate fluid and ion balance and the outer blood-retinal barrier composed of tight junctions between retinal pigment epithelial cells adjacent to the choroid, controlling molecular exchange between the retina and the systemic circulation.

Due to the nature of ophthalmological conditions and the vast differential diagnosis, diagnosing ocular manifestations as part of a systemic condition remains challenging. Advances in diagnostic techniques, both in imaging and laboratory, including optical coherence tomography (OCT), OCT angiography (OCTA), functional imaging, and serological biomarkers like aquaporin 4 (AQP4), have improved diagnostic accuracy, but their use is not widespread yet. When treating these conditions, clinicians should aim to strike a balance between controlling the symptoms and minimizing the adverse effects of immunosuppression, highlighting the need for ongoing research[4-6].

The aim of this review was threefold. Our objective was to delve deeper into the available advanced diagnostic tools and discuss the challenges clinicians face when treating patients with autoimmune diseases. We aimed to discuss current therapeutic and emerging approaches focusing on unmet clinical needs and to highlight the importance of a multidisciplinary approach involving rheumatologists, ophthalmologists, and other clinical and research specialists to optimize patient outcomes. This review provided a comprehensive understanding of the topics mentioned earlier.

SEARCH STRATEGY

The research strategy for this paper focused on a comprehensive review of the literature to explore ocular manifestations in autoimmune diseases. PubMed, MEDLINE, Scopus, and Web of Science databases were utilized to gather evidence-based data. Key topics included diagnostic challenges, advances in imaging technologies, and therapeutic approaches like corticosteroids (CS) and biologics. Emphasis was placed on multidisciplinary management and the integration of biomarkers in diagnostics.

The search terms included combinations of the following keywords with Boolean operators: (“ophthalmological manifestations” OR “ocular manifestations” OR “eye involvement”) AND (“autoimmune diseases” OR “autoimmune disorders” OR “systemic autoimmune diseases”) AND (“diagnosis” OR “diagnostic challenges” OR “diagnostic tools”) AND (“therapy” OR “treatment” OR “therapeutic challenges” OR “immunotherapy”) AND (“uveitis” OR “keratitis” OR “optic neuritis” OR “dry eye syndrome”) AND (“biomarkers” OR “imaging techniques” OR “optical coherence tomography” OR “OCT”). The search was limited to articles published in English and included original research, clinical trials, and review articles focusing on the role of ophthalmological involvement in autoimmune diseases.

Articles were critically reviewed for relevance, methodology, and outcomes. This approach ensured a robust synthesis of current knowledge while identifying gaps for future research managing ocular involvement in autoimmune disease.

COMMON OPHTHALMOLOGICAL MANIFESTATIONS IN AUTOIMMUNE DISEASES AND THEIR PATHOPHYSIOLOGY

Autoimmune inflammatory diseases are able to affect nearly every part of the eye and orbit, sometimes presenting as the first or single manifestation of an underlying systemic disease[7]. Ophthalmic involvement may appear either preceding or during active disease or years after the diagnosis[8]. Common manifestations include orbital or intraocular symptoms (e.g., uveitis, keratitis) or adnexal inflammation [e.g., optic neuritis (ON)] and often render emergencies requiring urgent treatment[9]. An observational cross-sectional study performed by Cifuentes-González et al[10] concluded that the most common ocular manifestation of autoimmune disease, reported in approximately 1 out of 3 patients (30.86%), was dry eye sensation[10]. The eye is historically recognized as an immune-privileged tissue. Ocular immune privilege is mediated by physical barriers, such as the blood-ocular barrier or the absence of lymphatic drainage from the anterior chamber, and immunoregulatory molecules, which protect the eye from local inflammatory processes[11]. Disruption of this protective environment by autoimmune conditions, often in the background of vasculitis or multisystemic disease, can result in a range of minor to vision-threatening symptoms that frequently are underestimated in general clinical practice[8].

In Figure 2, we present the basic anatomy of the human eye, highlighting its many structures while labeling different conditions that can affect the eye and their locations.

Figure 2 Anatomy of the human eye and locations of the most common manifestations of autoimmune diseases that affect the eye.

Uveitis in autoimmune diseases

Intraocular inflammation of the uvea (uveitis) is an important manifestation of various autoimmune diseases[9]. Uveitis can affect the iris, ciliary body, or choroid and is classified according to anatomical involvement into anterior, intermediate, posterior, and panuveitis[12]. Several autoimmune diseases are commonly linked to uveitis. Sarcoidosis is especially noteworthy with uveitis presenting in 20%-50% of affected patients, often preceding systemic symptoms[13]. Anterior uveitis is the most common form and typically presents as either acute or chronic granulomatous iridocyclitis, marked by keratic precipitates and synechiae as seen in Table 1[7,9]. Posterior uveitis is the second most common manifestation and is typically characterized by retinal vasculitis, vitreous snowballs, or choroidal granulomas[14]. Uveitis in sarcoidosis can cause a high degree of discomfort for the patient, including redness, pain, epiphora, photophobia, or even a reduction in visual acuity[15]. Complications include macular edema, glaucoma, cataracts, and occasionally Horner’s syndrome[16]. The pathogenesis of these ocular manifestations is related to high levels of T helper 1 Lymphocytes in the eye, leading to a proinflammatory cascade and the formation of granulomas[17]. In cases of ocular sarcoidosis, differential diagnosis is important and must include tuberculosis and other granulomatous diseases with tuberculin skin tests and chest X-rays aiding in this direction[18,19].

Table 1 Frequently encountered ocular diseases and manifestations associated with autoimmune diseases, their clinical symptoms, their differential diagnoses, and the most common complications.

Condition/manifestation	Primary location	Clinical features	Common autoimmune diseases	Non-autoimmune/differential diagnoses	Complications	Ref.
Uveitis	Uvea (iris, ciliary body, choroid)	Redness, pain, photophobia, blurred vision, floaters	RA, SS, BD, CD, UC, MS, celiac, sarcoidosis	HSV, VZV, CMV, toxoplasmosis, TB, trauma, leukemia, Lyme disease	Macular edema, glaucoma, cataracts, Horner’s syndrome	[7,9,12-27,60-63]
Keratitis	Cornea	Redness, photophobia, blurred vision, pain, FB sensation	RA, SS, SLE, celiac, Hashimoto’s, vasculitis	HSV, HHV-6, fungi, bacteria, trichiasis, trauma	Ulceration, perforation, corneal thickening	[9,17,21,30-38,61,62,64]
Optic neuritis	Optic nerve	Visual impairment (unilateral or bilateral), pain with eye movement	MS, NMO, MOG-AD, sarcoidosis, SLE, SS	Syphilis, TB, Lyme disease, compressive lesions, toxins	Blindness, demyelination, optic atrophy	[40-42,46-53,65]
Episcleritis	Episcleral tissue	Mild pain, redness, irritation	RA, SS, CD, UC, dermatomyositis	Syphilis, Lyme disease, TB, HZV, hypersensitivity reactions	Generally self-limiting	[16,54,56,66-70]
Scleritis	Sclera	Severe pain, photophobia, possible vision loss	RA, SS, CD, UC, GPA, PAN, BD	Monkeypox, TB, HZV, syphilis, post-op, bisphosphonates	Necrotizing inflammation, retinal vasculitis, vision loss	[10,16,54-59,62,66,67,71]
Keratoconjunctivitis sicca	Cornea/Conjunctiva	Dryness, photophobia, gritty sensation	RA, SS, CD, celiac, GBS, MG, GD, Hashimoto’s, psoriasis, SSc	Medications, meibomian gland dysfunction, environment, HIV/AIDS	Corneal damage, infection risk	[72,73]
Conjunctivitis	Conjunctiva	Redness, edema, lacrimation, discomfort	RA, CD, psoriasis, celiac	Allergens, irritants, viruses (e.g., SARS-CoV-2, flavivirus)	Persistent inflammation, scarring	[61,62,74,75]
Blepharitis	Eyelids	Burning, photophobia, irritation, redness	RA, CD, MG, psoriasis	Staph, VZV, meibomian dysfunction, rosacea	Chronic discomfort, eyelid scarring	[76,77]
Retinal vasculitis	Retina	Floaters, scotoma, color vision changes	RA, SS, BD, CD	CMV, TB, syphilis, Lyme disease, flavivirus	Vision loss, retinal ischemia	[60,61,78]
Macular edema	Macula	Blurry vision, micro/macropsia, color impairment	RA, BD, GBS, DM1	RVO, tumors, trauma, radiation	Vision loss, distortion	[79,80]
Choroiditis	Choroid	Floaters, metamorphopsia, central vision loss	RA	TB, vector-borne infections	Vision distortion, scarring	[60,81]
Photophobia	Nonspecific	Light intolerance	SS, GBS, Hashimoto’s	Migraine, TBI, optic/chiasmal pathology	Underlying diagnosis-dependent	[82,83]
Retinal detachment	Retina	Flashes, floaters, shadow over vision	RA, BD, UC, MS, SSc	Trauma, tumors, medications	Vision loss	[84]
Vitreal/retinal hemorrhage	Vitreous/retina	Floaters, cobwebs, haziness	BD, MS, GBS, dermatomyositis	Endocarditis, trauma, PCV, flavivirus	Vision loss	[62,72,77,85]
Retinal vein occlusion	Retina	Vision loss, RAPD	BD, UC, celiac, dermatomyositis	Polycythemia vera, thrombophilia, drugs	Edema, hemorrhage, ischemia	[86]
Glaucoma	Optic nerve	Progressive vision loss, dark adaptation delay	BD, MS, GD, DM1	Ocular HTN, steroids, surgery, trauma	Irreversible blindness	[87]
Corneal ulcers	Cornea	Pain, redness, photophobia, discharge	SS, CD, celiac	Bacteria, HHV-6, trauma	Vision loss, perforation	[71,72]
Diplopia	EOMs/CNS	Double vision	GBS, MG, GD, Hashimoto’s, SSc, dermatomyositis	Orbital mass, refractive error, neuromuscular issues	Falls, impaired depth perception	[88,89]
Optic atrophy	Optic nerve	Vision loss, field defects	BD	Ischemic, infectious, compressive, toxic	Permanent vision loss	[65]
Cataracts	Lens	Blurry vision, glare, color desaturation	CD, Celiac, MS, DM1, psoriasis, SSc, dermatomyositis	Corticosteroids, trauma, radiation	Progressive vision loss	[90]

RA: Rheumatoid arthritis; SS: Sjögren’s syndrome; BD: Behçet’s disease; CD: Crohn’s disease; UC: Ulcerative colitis; MS: Multiple sclerosis; SLE: Systemic lupus erythematosus; NMO: Neuromyelitis optica; MOG-AD: Myelin oligodendrocyte glycoprotein antibody-associated disease; GPA: Granulomatosis with polyangiitis; PAN: Polyarteritis nodosa; GBS: Guillain–Barré syndrome; MG: Myasthenia gravis; GD: Gaucher disease; SSc: Systemic sclerosis; DM1: Diabetes mellitus 1; HSV: Herpes simplex virus; VZV: Varicella zoster virus; CMV: Cytomegalovirus, TB: Tuberculosis; HHV-6: Human herpesvirus 6; HZV: Herpes zoster virus; AIDS: Acquired immunodeficiency syndrome; SARS-CoV-2: Severe acute respiratory syndrome coronavirus 2; RVO: Retinal vein occlusion; TBI: Traumatic brain injury; PCV: Polypoidal choroidal vasculopathy; HTN: Hypertension; FB: Foreign body; RAPD: Relative afferent pupillary defect; EOM: Extraocular movements; CNS: Central nervous system.

RA is another autoimmune disease frequently associated with uveitis, particularly anterior uveitis[20]. Ocular symptoms usually precede joint involvement, including pain, photophobia, redness without discharge, and decreased vision[21]. Although the exact mechanism linking RA and uveitis is not fully understood, one transcription factor, signaling transducer and activator of transcription 3 (STAT3), is shown to play an important role in the pathogenesis of the symptoms[22]. According to Escobar et al[22], STAT3 is needed for the differentiation of Th17 CD4+ cells, which in turn produce interleukin (IL) 17 but also for the expression of microRNA155 (miR-155) in the same type of cells. In their study miR-155 and STAT3-deficient mice failed to develop experimental autoimmune uveitis. Thus, it became evident that STAT3 and miR-155 form an axis that sets the ground for the pathogenesis of uveitis through IL-17.

Moreover, Behçet’s disease frequently causes recurrent uveitis, characterized by non-granulomatous necrotizing obliterative retinal vasculitis that can affect any part of the uvea[23]. Posterior and panuveitis are the most common forms while typical complaints include blurred vision, photophobia, pain, and conjunctival hyperemia[24]. Ocular symptoms usually do not precede systemic manifestations, but their significance should not be overlooked as severe complications such as retinal lesions, cataract, and glaucoma can arise[8,25,26]. Intense inflammation (hypopyon) can be seen in around 20% of patients with ocular involvement and is associated with a poor prognosis of blindness.

Finally, other autoimmune diseases, such as AS and multiple sclerosis (MS), have also been associated with uveitis; in AS anterior uveitis is present in 20%-40% of patients in developed countries[12] while intermediate uveitis is common in MS[27]. More specifically, uveitis in MS is thought to be secondary to inflammation of the central nervous system (CNS), but the exact mechanism is still under investigation.

In general proinflammatory cytokines, most importantly IL-6, play an important role in developing immune-related uveitis. Murray et al[28] revealed that in some autoimmune uveitis, the levels of IL-6 in the aqueous humor are drastically elevated without a similar increase in serum levels[28]. Moreover, Ooi et al[29] showed that IL-6 anti-TGF-β activity could counteract the fine balance of the anterior chamber-associated immune deviation, which is crucial for maintaining ocular immune privilege.

Keratitis in autoimmune diseases

Keratitis, or inflammation of the cornea, can also be manifested in various autoimmune diseases. In SS lacrimal gland dysfunction can result in keratoconjunctivitis sicca (KCS) [or dry eye syndrome (DES)] due to abnormal tear film function[30]. Patients experience photosensitivity, itching, and foreign body sensations, which worsen during low blinking rates[31]. Complications of untreated KCS are severe and may include corneal ulceration and in some cases perforation[21]. Early diagnosis is therefore important to prevent such consequences.

KCS is also common in SLE, affecting more than one-third of patients[9]. KCS in SLE often coincides with the development of secondary SS. According to Chen et al[32], symptom severity correlates with anti-dsDNA antibody titers and low C3 Levels. Corneal involvement in SLE may also present as erosions, keratoendothelitis, or peripheral ulcerative keratitis (PUK)[33] with typical manifestations including painful eyes, hyperlacrimation, and blurred vision. However, in a great percentage of patients, the disease remains silent until complications arise, thus underscoring the importance of regular eye examinations for SLE patients. Interestingly, Monov et al[34] recently described a rare case of retinal vasculitis as the first manifestation of SLE, implying that the inclusion of ocular manifestations among the classification criteria for SLE would enable earlier establishment of the diagnosis and therapeutic interventions[34].

In RA DES results from immune-mediated damage to the lacrimal glands by B and T lymphocytes[35]. Symptoms include roughness, redness, and impaired vision[17], and studies have shown that KCS is present in 29% of patients with RA while bilateral PUK is found in 10% of cases[21,36,37].

PUK is associated with systemic vasculitis syndromes such as ANCA-associated vasculitis (AAV) and polyarteritis nodosa[38]. It is associated with the deposition of immune complexes in the periphery of the cornea, conserving the central cornea due to the lack of blood supply[39]. Typical symptoms include pain, redness, frequent lacerations, and blurred vision, but the diagnosis is made by slit lamp examination of crescent-shaped ulcers[21].

ON in autoimmune diseases

ON is an acute inflammatory condition that causes optic nerve demyelination, often causing permanent visual impairment. It is most commonly associated with MS, optic myelitis (NMO), and myelin oligodendrocyte glycoprotein antibody disease (MOG-AD)[40]. ON may also be associated with other inflammatory diseases such as sarcoidosis, SLE, or SS[41]. MS-related ON is typically unilateral with a favorable prognosis and visual recovery over weeks to months[42] while NMO-associated ON is more severe, often bilateral, and can result in blindness[40].

The mechanism of the development of optic nerve damage involves demyelination and axonal injury with anti-AQP4 antibodies or anti-myelin oligodendrocyte glycoprotein playing a central role while at the same time serving as biomarkers. AQP4 is a water channel expressed on the surface of astrocytes in the CNS[43]. Axonal injury is mediated by AQP4 antibodies with the involvement of the complement system, eventually leading to astrocytic lysis[44]. This damage was also shown to be independent of complement participation[45].

Moreover, ON in MOG-AD and NMO is more extensive than in MS, involving more optic nerve segments and often involving the anterior optic nerve in MOG-AD and the posterior optic chiasm or tract in NMO[46,47]. The authors of three separate studies[47-49] reported that optic chiasm involvement occurred in the majority (60%-75%) of patients with NMO but is less common in MOG-AD and rare in MS. Consecutively, radiological differences can help differentiate these diseases as patients with NMO and MOG-AD have more extensive optic nerve involvement. Magnetic resonance imaging is important for diagnosing ON and distinguishing it from noninflammatory optic neuropathy while contrast-enhanced orbital imaging can help differentiate demyelinating disease[50].

Additionally, longitudinally extensive ON lesions are a key feature of NMO and MOG-AD, whereas MS typically shows shorter lesion involvement[51]. A study by Dunker et al[52] showed that lesions greater than 17.5 mm or involving the intracanalicular portion of the optic nerve are associated with poorer visual outcomes[52]. On the other hand a more recent study by Kupersmith et al[53] suggested that the shorter the lesion, less than 17.5 mm, the better the recovery[53].

Scleritis and epicondylitis in autoimmune diseases

Similarly, although less frequently, episcleritis and scleritis can occur in autoimmune disease[8]. Scleritis (inflammation of the sclera) presents with severe eye pain, photophobia, and possible vision loss. In contrast episcleritis (inflammation of the tissue between the sclera and conjunctiva) is usually less uncomfortable and has a slower course[54].

Scleritis, especially in RA and GPA, can result in serious complications such as necrotizing inflammation[55] and retinal vasculitis leading to visual loss[56]. It usually presents with discharge, photophobia, and decreased visual acuity as opposed to episcleritis, which is characterized by mild pain, irritation, and redness limited to a single area of the eye[57]. GPA-associated scleritis presents with severe bilateral pain and diffuse inflammation with anterior scleritis being the most common[58]. Systemic vasculitides such as polyarteritis nodosa and Behçet’s disease are also associated with scleritis[54]. Prompt diagnosis and treatment are important because of the sight-threatening nature of scleritis and its association with systemic diseases[59].

A summary of ocular manifestations associated with autoimmune diseases is presented in Table 1, emphasizing the most common clinical symptoms and complications of conditions like uveitis, keratitis, and ON. The main autoimmune diseases and non-autoimmune diseases that may cause uveitis (i.e., uveitis associated with autoimmune diseases[7,9,12], in sarcoidosis[13-17], tuberculosis[18-19], rheumatoid arthritis[20,21], experimental autoimmune uveitis[22], uveitis in Behçet disease[23-26], multiple sclerosis[27]; viral infections[60-63]), keratitis (autoimmune diseases[9], sarcoidosis[17], rheumatoid arthritis[21], Sjögren Syndrome[30-32], SLE[33,34], rheumatoid arthritis[35-38], viral infections[61,62,64], ON (management[40-42] multiple sclerosis[46-49], visual performance[53], optic atrophy[65], episcleritis (associated with sarcoidosis[16], noninfectious[54], systemic disease[56], infections[66-70], scleritis (rheumatological diseases[10], sarcoidosis[16], noninfectious and systemic[54-59], viral infections[62,66,67,71]), KCS cornea[72,73], conjunctivitis[61,62,74,75], blepharitis[76,77], retinal vasculitis[60,61,78], macular edema[79,80], choroiditis[60,81], photophobia[82,83], retinal detachment[84], vitreal/retinal hemorrhage[62,72,77,85], retinal vein occlusion[86], glaucoma[87], corneal ulcers[71,72], diplopia[88,89], optic atrophy[65], and cataracts[90] and their complications are presented in Table 1.

CHALLENGES IN DIAGNOSING AUTOIMMUNE-RELATED OCULAR CONDITIONS

Current diagnostic methods for diagnosing ocular symptoms related to autoimmune disease

Eye involvement in the context of systemic autoimmune disease can prove to be a severe sight-threatening complication. Therefore, early diagnosis and timely management are required even in asymptomatic patients. Early screening should ideally include an ophthalmologic examination as an integral part of routine multisystemic assessment of the patient with the autoimmune disease. However, the commonly offered methods of traditional eye examination have several potential limitations.

A significant rate-limiting issue arises from the lack of specificity in the traditionally encountered tests. Thus, the lack of standardized diagnostic criteria makes it essential to approach each patient with a history of (poly) autoimmunity with a high degree of suspicion. Diagnosis is often made on the basis of clinical examination combined with the patient’s history and commonly relies on the exclusion of numerous disease mimickers. A careful anamnesis and clinical examination can often be followed by testing visual fields, whereas more specific imaging modalities can also be offered in conjunction with autoantibody serologic testing. As dry eye sensation is the most commonly encountered manifestation of autoimmune disease, a Schirmer test can be provided early on to quantify tear break-up time and lacrimal lake[8,91]. Imaging modalities include OCT, fluorescein angiography (FA), and fundus autofluorescence. Electrophysical tests include full-field electroretinography[8].

As we have already pinpointed, the complex and usually nonspecific symptomatology of autoimmune ophthalmic involvement further hinders and delays the diagnosis. Additionally, early ophthalmic involvement may not yield significant findings, and eye examination may remain unremarkable without pathognomonic features[92]. Similarly, the variable nature of autoimmune disease progress makes it difficult to predict the timeline of ophthalmic involvement. For example ocular involvement can occur early on, coinciding with initial disease diagnosis or even years after disease establishment[8].

As evidenced by Table 1, many autoimmune diseases can exhibit similar ocular manifestations. For instance KCS can occur in primary SS or secondary SS in the context of RA. ON, retinal vasculitis, and uveitis are also some frequently encountered autoimmune manifestations of various systemic diseases. This overlap can prove to be quite a conundrum, especially in the case of polyautoimmunity in which a causal relationship will be difficult to establish[93]. Additionally, the impact of various medications employed in treating autoimmune diseases further complicates the effect-causality question. For example CS and hydroxychloroquine can mediate glaucoma and retinopathy evolution, respectively[94]. Consequently, the rarity and the extremely variable nature of ophthalmic involvement make it necessary that the patient is routinely evaluated by a multidisciplinary team, including ophthalmologists, rheumatologists, and other specialists. The emphasis should be on a personalized approach for monitoring and effectively managing each patient[8,93].

The utilization of various imaging modalities, including OCT, FA, color fundus photography, and OCTA, constitutes an integral part of the diagnosis and management of autoimmune disorders targeting the eye. These methods aim to improve diagnostic accuracy, add prognostic value, and improve treatment planning.

OCT provides a high-resolution image of the retina and the choroid plexus, and subsequently it can effectively highlight structural abnormalities and change secondary to autoimmune processes. Currently, OCT is also employed to document disease progression as in the cases of ON and autoimmune retinopathy according to retinal thickness changes[95]. As an OCT evolution OCTA can additionally map changes involving both superficial and deep retinal microvascular networks, optic disc perfusion, and choroidal vasculature flow, which may not be apparent in traditional OCT. For instance OCTA in patients with MS reveals reduced retinal plexus densities, preferentially involving the superficial vascular networks[96].

OCTA can additionally quantify changes in the retinal and choroidal microvasculature by measuring the foveal avascular zone extent and describing the density, caliber, complexity, and perimeter indices of microcirculation. OCTA findings in patients with SLE ocular involvement were consistent with enlargement of the foveal avascular zone and reduced density of the parafoveal vessels of the deep retinal capillary plexus. An inverse relationship between the SLE index and parafoveal vessel density in deep retinal capillary plexus has also been established. OCT can also detect choroidal involvement based on choroidal thickening and subretinal fluid, particularly in the presence of antiphospholipid antibodies[97,98].

Both OCT and OCTA provide insightful although different details for assessing ocular manifestations. While OCT has an advantage in assessing structural components, OCTA also has an advantage in capturing the minute details of vascular networks without being able to detect vascular leakage. Using both modalities together improves the precision of diagnosis and the effectiveness of disease progression monitoring.

The inability of OCTA to assess active inflammation through blood vessel leakage detection necessitates complementary imaging with FA. FA allows for the visualization of blood flow in the retina and choriocapillaris following the injection of a fluorescent dye into the systemic circulation. This examination can pinpoint areas of blockage and dye leakage in the retinal vasculature that can prompt the diagnosis of retinal vasculitis, which is commonly encountered in autoimmune processes. Another benefit of FA lies in its ability to diagnose complications of autoimmune diseases associated with neovascularization and macular edema.

FA in patients with SLE demonstrated macular edema and the formation of epiretinal membranes. FA was able to measure disease activity based on the early subclinical changes in the retinas of patients with SLE. In RA FA can detect signs of vasculitis and retinal inflammation, including lack of capillary perfusion and capillary leakage while it can also indicate macular changes, including macular edema. Similar findings can be replicated by OCTA, which can detect vascular changes, including retinal capillary loss and caliber changes[97,99].

Biomarkers used in the differential diagnosis of ophthalmic manifestations of autoimmunity

The presence of specific autoantibodies in the sera of patients can narrow down the differential diagnoses, optimize treatment, and monitor disease activity. However, scientific knowledge surrounding the correlation of systemic biomarkers with ocular involvement in autoimmune diseases is limited. Nevertheless, among symptomatic patients with autoimmune eye manifestations, some inflammatory biomarkers and antibodies are present. A specific category of biomarkers can be found in tear fluid. It was therefore suggested that these tear film biomarkers, including lactoferrin and lysozyme, could indicate ocular surface inflammation encountered in SS. Inflammatory biomarkers, such as matrix metalloproteinase 9, can diagnose inflammation like KCS. Another useful application of biomarkers found in ocular fluids (vitreous, aqueous humor, tears) could be in the elucidation of the pathogenetic mechanisms and serve as a measure to monitor the response to therapy[100].

The prognostic value of biomarkers can be supported by the results of the study published by Cifuentes-González et al[10] in which they concluded that the presence of rheumatoid factor as well as anti-cyclic citrullinated peptide antibodies correlated closely with the incidence of severe sight-threatening complications, including PUK, sclerosing keratitis, and scleritis. Similarly, in AAV positive proteinase-3 ANCA antibodies were associated with anterior segment involvement, whereas in patients with myeloperoxidase-ANCA, the optic nerve was more commonly affected. Moreover, polyautoimmunity was shown to have a positive correlation with the presence of antinuclear antibodies (ANAs), IgG, and IgM anti-cardiolipin antibodies, anti-Smith antibodies, anti-ribonucleoproteins antibodies, and anti-Sjögren syndrome-related antigen A. Reduced concentrations of C3 additionally had predictive value for the occurrence of photophobia (P = 0.05)[10]. The presence of TRab (thyrotropin receptor autoantibodies) is frequently encountered in the serum of patients with eye pain, correlating with Grave's ophthalmopathy[101]. Red eye and diplopia were accompanied by positivity for both PR3 antibodies and myeloperoxidase-ANCA antibodies in patients with AAV[10,102].

Similarly, antiphospholipid antibodies can be encountered in some patients complaining of decreased visual acuity. Dry eyes have the most diversity regarding the presence of positive antibodies, especially in patients with SS, including positive anti-Sjögren syndrome-related antigen A, Anti-La, rheumatoid factor, ANAs, salivary protein 1, autoantibodies against muscarinic acetylcholine receptors M3, and autoantibodies against kallikrein 13. In the same context dry eye sensation is associated with the positivity of anti-cyclic citrullinated peptide in the sera of patients with RA while in patients with SLE ANAs and anti-dsDNA were encountered. Ocular involvement with diplopia correlated with the presence of lupus anticoagulants, anti-cardiolipin antibodies, and B2GP in patients with antiphospholipid syndrome while muscarinic acetylcholine receptor positivity was typical for myasthenia gravis[10]. Finally, AQP4-IgG demonstrates 98% specificity for neuromyelitis optica spectrum disorders, aiding differentiation from MS-related ON.

Artificial intelligence in ophthalmic imaging and analysis

With the evolution of artificial intelligence (AI) technologies, the potential for in-depth ophthalmologic analyses is great. Integrating machine-learning and deep-learning technologies with ophthalmic imaging can improve diagnosis, management, and prediction protocols and aid in the decision-making process in clinics. Deep-learning models based on deep neural networks can help classify and predict the evolution of disease. For instance fundus images can be analyzed to screen and quantify the likelihood of ocular involvement in the setting of systemic autoimmune disease. Traditional machine-learning protocols can aid in establishing a correlation between retinal findings or ocular structure and systemic disease. Ocular biomarkers can also be potentially extracted by identifying specific imaging features that indicate the presence of a specific autoimmune disease. AI-assisted image analysis can be used to extract data from OCT and OCTA to analyze changes in retinal vasculature, including vascular tortuosity, length density, area density, bifurcation count, and the arteriole-to-venule caliber ratio[95].

In Figure 3, we present a simple clinical decision-making algorithm to help physicians identify autoimmune disease in patients presenting with isolated ocular symptoms and vice versa.

Figure 3 Diagnostic algorithm for systemic work-up in patients with vision loss suspected of an autoimmune etiology. ON: Optical neuritis; SS: Sjögren's syndrome; RA: Rheumatoid arthritis; MS: Multiple sclerosis; KCS: Keratoconjunctivitis sicca; SLE: Systemic lupus erythematosus; ANA: Anti-nuclear antibodies; RF: Rheumatoid factor; ESR: Erythrocyte sedimentation rate; CRP: C-reactive protein; ACE: Angiotensin converting enzyme; HLA: Human leukocyte antigen.

THERAPEUTIC STRATEGIES FOR MANAGING OCULAR MANIFESTATIONS IN AUTOIMMUNE DISEASES

Reducing overall inflammation and attaining total symptom remission are the two main objectives of managing AI presentations in the eyes. This is essential to avoid worsening symptoms, further deterioration[103-105], and potential permanent blindness[106-110].

First-line approach

Depending on the severity and clinical manifestations of the symptoms, treatment for autoimmune-related uveitis is gradual. Initial management typically starts with topical CS, particularly for anterior disease in which symptoms like eye redness and photophobia are common[111-113]. Additionally, sympathomimetics or parasympatholytics can be used to prevent posterior synechiae by promoting ciliary muscle relaxation through pupil dilation[114]. Concerning more severe manifestations or in the event of inadequacy of topical treatment, systemic CS becomes mandatory. To rapidly reduce inflammation the first-line approach frequently consists of high-dose systemic CS, including prednisone, administered at doses greater than 60 mg daily[113]. An intravenous (IV) burst of high-dose CS with dosages up to 1000 mg/day over 3 days may be used in acute cases[115]. Doctors may opt for aggressive management with higher CS doses to control complications rapidly. Particularly for patients with recurrent or chronic uveitis, the goal of the treatment is to maintain disease control with the lowest possible effective drug dosage to minimize side effects[116]. Following a favorable reaction, the dosage of CS is gradually reduced (tampering) to a maintenance dose of 7.5 mg/day to lower the chance of long-term complications, such as cataract or glaucoma development[113].

Ocular dryness in cases of keratitis can be managed by avoiding dry or windy environments and minimizing activities associated with a low blinking rate[117-119]. Topical CS and lubricating eye drops are used to treat more complicated cases, reduce DES symptoms, and encourage healing. Additionally, systemic immunosuppressants may also be introduced into regimens to manage the underlying inflammation more effectively[117-120]. In cases where patients do not adequately respond to medical therapy and maximal lubrication agents, punctal occlusion-occlusion of the tear drainage system at the level of the puncta lacrimalia proves beneficial.

ON, especially when associated with MS, can be controlled with high-dose IV CS, particularly for acute cases, to reduce inflammation and assist the healing process. Typical regimens include IV methylprednisolone 1 g/day for 3-7 days, followed by oral steroids[121]. Timely intervention is necessary to minimize permanent CNS and visual damage. Therefore, treatment should be started early and in an aggressive manner[122].

Lastly, caution is also necessary for scleritis and episcleritis. Low-dose CS or topical nonsteroidal anti-inflammatory drugs may be effective treatments for episcleritis, which typically resolves independently[105]. Scleritis has a more severe course and can lead to serious problems. Therefore, systemic CS or even immunosuppressive medication may be required[123]. Patients with systemic autoimmune disease are often treated with medications, including mycophenolate mofetil, methotrexate, and azathioprine as we will discuss later.

Immunosuppressants

Although CS is still the mainstay of treatment for ocular symptoms, prolonged use of these medications carries a number of substantial concerns, such as an increased risk of infection and other severe adverse effects (e.g., hyperglycemia, Cushing’s syndrome development)[124]. Consequently, patients with autoimmune ocular involvement benefit greatly from adjunctive therapy. In clinical practice immunosuppressive medications are commonly combined with CS to enhance illness control[103,105,108,110] and reduce dependence[125-128]. The most widely used immunosuppressive agents include methotrexate and mycophenolate mofetil[129-131]. They are chosen due to their effectiveness in controlling inflammation and relatively manageable side effects.

Methotrexate is typically preferred as a first-line agent for non-infectious inflammatory eye diseases while mycophenolate mofetil is typically favored in chronic cases where prolonged immunosuppression is necessary. Other commonly employed drugs include azathioprine and cyclosporine. Azathioprine is valued for its relative safety in long-term use and is often considered particularly suitable for younger patients[129,132] while cyclosporine (a T cell inhibitor) is widely used worldwide for managing chronic uveitis, even though a study by Kaçmaz et al[133] found that it has significant adverse effects, particularly in older adults. The same study concluded that cyclophosphamide and other alkylating agents, though less commonly used due to their significant toxicity[134,135], can be reserved for severe cases that fail to respond to first-line agents.

Biologics and targeted therapies

Furthermore, the treatment of many illnesses, including autoimmune disease, has been completely transformed by the advent of biologic medicines in recent years[103]. Because these biologics help achieve remission while reducing the need for CS, they are especially beneficial for patients who do not respond well to traditional therapy regimens. Tumor necrosis factor-alpha (TNF-α) inhibitors such as adalimumab have demonstrated significant improvements in visual acuity and inflammation reduction (the usual dose is 40 mg at 2-week intervals)[136]. The possible effectiveness of other biological medicines is also being studied. For instance recent clinical studies have studied IL-6 receptor inhibitors like tocilizumab and sarilumab as possible therapies (the usual dose is 8 mg/kg IV every 4 weeks)[137-140]. Without any unanticipated safety issues, the phase 1/2 STOP-uveitis study found that patients taking tocilizumab had better visual acuity and less vitreous haze[141]. Additionally, non-TNF biologics have been developed mainly for the treatment of RA. However, they are now tested in small clinical trials in ocular inflammatory disease, including inhibition of T cell activation via suppression of growth factor by inhibiting IL-2 receptor signaling with daclizumab, co-stimulation of T cells via a fusion protein of CTLA-4 with abatacept, or inhibiting B cell responses via the anti-CD20mAb rituximab[103].

Concerning NMO-associated disorders, inebilizumab, an anti-AQP4 monoclonal IgG antibody, has shown great promise as shown during a 28-week-long randomized control trial (N-MOmentum trial)[142]. More than 80% of the patients treated reported no attacks after 4 years while most of the attacks occurred during the first year of treatment, implying that long-term use of inebilizumab results in enhanced efficacy. Moreover, no safety concerns were raised during the use of this agent. Another anti-AQP4 antibody, satralizumab, was also proven beneficial in treating NMO spectrum ocular autoimmune disease with more than 70% of patients remaining attack-free after 4 years of treatment[143]. While satralizumab reduces neuromyelitis optica spectrum disorder relapse rates by 70%, its long-term safety profile remains under investigation with upper respiratory infections reported in 15% of trial participants (N-MOmentum trial).

Targeted therapy can be achieved using intravitreal injections of CS or biologic drugs, especially in situations of uveitis and other inflammatory disorders that are severe or resistant to treatment[110]. These techniques can lower the possibility of systemic side effects by directly delivering therapeutic medicines to the impacted ocular tissues.

Successful interdisciplinary therapeutic management for patients presenting with ocular symptoms linked to systemic autoimmune diseases has been documented in a number of examples in the literature. For instance a patient with ocular symptoms associated with an autoimmune disease was given a thorough treatment regimen that included systemic immunosuppressives, high-dose glucocorticoids, rituximab, and intraocular medications such as intravitreal bevacizumab and laser photocoagulation in a case presented by Matijašević et al[144]. After initial high-dose methylprednisolone and reintroduction of hydroxychloroquine, alongside other supportive therapies, the patient achieved full clinical recovery and was referred for routine ophthalmological follow-up. After discharge mycophenolate mofetil was commenced at a daily dose of 2 g, and intravitreal bevacizumab was added for neovascularization prevention. Laser photocoagulation was continued as the prednisone was gradually reduced to 7.5 mg daily. Twelve months later, the patient achieved remission with a maintained visual acuity 20/20 and no visual disturbances.

The management of ocular manifestations in autoimmune diseases must balance the effectiveness of treatment against the potential for adverse effects, particularly with long-term corticosteroid use as evident in Table 2. Revolutionary treatment options are being developed into novel biological drugs targeting immune pathways. Targeted therapy development presents the possibility of improved management of ocular problems as our knowledge of the biology of autoimmune disorders grows. Ultimately, the most suitable management regimen for individuals with autoimmune disease symptoms in the eyes requires a multidisciplinary approach combining rheumatologists, ophthalmologists, and other experts[109]. Through this partnership patients are guaranteed to receive all-encompassing care that considers both their ocular health and systemic disease, improving overall results. Table 2 summarizes the management options for patients presenting with eye symptoms on the background of an autoimmune disease.

Table 2 Ocular symptoms, severity, and treatment strategies in autoimmune diseases.

Ocular symptoms	Sever characteristics	Treatment options	Details	Ref.
Uveitis	Mild/moderate	Topical CS	Initial management for anterior uveitis; reduces redness and photophobia	[111-114]
	Severe	Systemic CS, systemic immunosuppressants	High-dose prednisone (> 60 mg daily); IV CS for acute cases (1000 mg/day for 3 days)	[113,115,125-127]
	Recurrent	Gradual CS taper	Reduce to 7.5 mg/day maintenance to prevent complications like cataracts	[113,116]
Keratitis	Mild	Environmental modifications	Avoid dry/windy conditions; avoid activities with reduced blinking	[117-119]
	Severe	Topical CS, lubricating drops, systemic immunosuppressants	Controls dryness, reduces inflammation	[117-119,125-128]
ON	Acute	High-dose IV CS	IV methylprednisolone 1 g/day for 3-7 days; followed by oral CS	[121,122]
Episcleritis	Mild	Low-dose CS or NSAIDs	Often self-resolving	[105]
Scleritis	Severe	Systemic CS, immunosuppressants	Controls inflammation	[105,123,125-128]
Chronic ocular inflammation	Chronic cases	Immunosuppressive agents	Methotrexate (first line for non-infectious cases), mycophenolate mofetil (chronic use), azathioprine, and cyclosporine	[129-133]
Refractory cases	Resistant to initial treatments	Alkylating agents (e.g., cyclophosphamide)	Reserved for severe, non-responsive cases due to toxicity	[134,135]

This table outlines the ocular symptoms associated with autoimmunity, categorizing them by severity and clinical characteristics. It highlights corresponding treatment options and provides additional details to guide clinical decision-making. The table includes both acute and chronic ocular conditions with specific therapeutic approaches for each. CS: Corticosteroids; IV: Intravenous; NSAIDs: Non-steroidal anti-inflammatory drugs; ON: Optical neuritis.

FUTURE DIRECTIONS

As we described extensively the ophthalmological manifestations of autoimmune diseases are complex and often challenging to diagnose and manage. Also, there are many challenges regarding the variability in disease presentation from mild inflammation to severe vision-threatening complications, complicated diagnosis, and rarely timely treatment.

One major gap in the current knowledge is understanding the precise immunological mechanisms that compel ocular inflammation and how they influence systemic disease. In line with this future perspectives circle around advancing molecular understanding, refining and broadening diagnostic tools, and exploring novel targeted therapies. Novel fields for research for ocular manifestations of autoimmune diseases may include investigation of genetic factors, fine immune and molecular mechanisms, and novel molecules promising to change the current treatment effectiveness[145].

Advancements in diagnostic innovations are also transforming the field. High-resolution imaging modalities, such as OCT and confocal microscopy, enable earlier detection of subtle changes in ocular tissues, allowing for more precise monitoring[146]. Additionally, the identification of novel biomarkers has the potential to predict disease activity and therapeutic responses. However, these tools need to be proven before being applied widely in clinical settings. Therapeutic innovations have also made significant strides. Monoclonal antibodies targeting specific cytokines have shown promise in controlling ocular manifestations in patients with systemic autoimmune diseases[147].

Despite these advances challenges remain, including the risk of adverse effects, treatment resistance, and the need for long-term immunosuppression. Looking ahead, personalized medicine offers significant potential for improving patient care. We can develop more targeted, effective, and safe therapies by combining genetic and molecular profiling with clinical data. Collaboration among specialists, such as rheumatologists, ophthalmologists, and immunologists, is essential in effective management strategies. Furthermore, ongoing research into immune modulation and regenerative therapies provides hope for preventing vision loss and improving the quality of life for patients with autoimmune-related ocular diseases.

IMPACT ON QUALITY OF LIFE AND PATIENT OUTCOMES

Ocular manifestations of autoimmune diseases can substantially impact daily life, including vision, comfort, and quality of life. Certain symptoms, such as dryness, photophobia, or ocular pain, can interfere with daily activities, such as reading, studying, or working, but more serious disorders, such as uveitis or ON, can result in vision loss if not addressed. Managing ocular inflammation and establishing symptom remission is critical for preventing progressive damage and blindness, highlighting the necessity of prompt and successful treatments[103,104].

Early detection and treatment are critical for protecting vision and avoiding additional issues. CS, immunosuppressive drugs, and adjunctive therapy are examples of management options designed to decrease inflammation and reduce long-term harm. As previously stated high-dose CS are critical in acute cases such as ON, whereas maintenance dosages are carefully managed to balance efficacy and side effects[113,121]. Delayed therapy raises the likelihood of irreversible ocular and systemic consequences, emphasizing the importance of early detection. A multidisciplinary approach is required for the best care, which includes coordination between ophthalmologists, rheumatologists, and other experts. This integrated method guarantees that the disease is managed comprehensively, both on an ocular and a systemic level. It also enables personalized treatment strategies, which meet individual patient needs and improve outcomes[109].

We present Table 3, which includes biomarkers that can link ocular symptoms with specific autoimmune disease[148] and their respective specificity and sensitivity[149-153].

Table 3 Comparative biomarker table for ocular autoimmune and infectious disorders.

Condition	Key biomarkers	Sensitivity (%)	Specificity (%)	Comments	Ref.
NMOSD	AQP4-IgG (live cell-based assay)	80%	100%	Highly specific; distinguishes NMOSD from MS-related optic neuritis	[148]
MS-related optic neuritis	No specific serological marker			Diagnosis is clinical and radiological; CSF oligoclonal bands may assist	[149]
MOG-AD	MOG-IgG (cell-based assay)	89.1%	93.3%	Important for recurrent optic neuritis with optic disc edema; often in children/young adults	[150]
Sarcoidosis-associated uveitis	ACE, lysozyme	ACE: 38.2%-84.0%; lysozyme: 60.0%-78.0%	ACE: 83.0%-97.8%; lysozyme: 76.0%-95.0%	Elevated levels support diagnosis; imaging often essential	[151]
TB-associated uveitis	QuantiFERON-TB gold	62%-95%	92%-100%	Latent TB testing critical in endemic areas or atypical uveitis	[152]
Behçet’s disease	HLA-B51			HLA-B51 is the strongest genetic association; supportive rather than diagnostic	[153]

NMOSD: Neuromyelitis optica spectrum disorders; AQP4: Aquaporin-4; MOG-AD: Myelin oligodendrocyte glycoprotein antibody disease antibody; ACE: Angiotensin converting enzyme; TB: Tuberculosis; CSF: Cerebrospinal fluid; MS: Multiple sclerosis; HLA: Human leukocyte antigen.

CONCLUSION

Autoimmune diseases are a heterogeneous group of disorders that significantly impact global health. These diseases often involve multiple organ systems, including the eyes, which are particularly sensitive due to the immune-privileged environment. Ocular manifestations include uveitis, keratitis, and ON, ranging from mild to severe and potentially threatening vision. Early detection and treatment are critical for preventing irreversible damage. Advances in diagnostic tools, such as OCT and serological biomarkers, have improved diagnostic accuracy but are not yet widely implemented in clinical practice. More research is needed in this direction to perfect diagnostic possibilities and improve patient care.

Managing ocular symptoms in autoimmune illnesses requires a delicate balance between symptom control and reducing the negative effects of immunosuppression. New medicines, such as TNF-α inhibitors and IL-6 receptor blockers, provide targeted solutions for refractory cases. More importantly, a multidisciplinary strategy combining ophthalmologists, rheumatologists, and other experts is required to improve patient outcomes. Continued research and innovation are critical for meeting unmet clinical requirements and increasing the quality of treatment for afflicted patients.