Uveitis

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2] Basir Gill, M.B.B.S, M.D.[3]

Uveitis specifically refers to inflammation of the middle layer of the eye, termed the “uvea“. In common usage, it may refer to an inflammatory process involving the interior of the eye. The uvea consists of the iris, ciliary body, and choroid; it provides most of the blood supply to the retina. Uveitis may occur unilaterally or bilaterally, affect the anterior, intermediate, or posterior segment of the eye, may be infectious or non infectious, and granulomatous or non-granulomatous. The exact pathogenesis of uveitis is not fully understood. It is thought that uveitis is mediated by a genetic predisposition and an acquired cross immunity to infectious agents, or cross immunity to self-antigens due to underlying autoimmune diseases. Common causes of uveitis include seronegative spondyloarthropathy, sarcoidosis, juvenile idiopathic arthritis, systemic lupus erythematosus, Behçet syndrome, multiple sclerosis, AIDS, syphilis, and tuberculosis. Uveitis must be differentiated from other diseases such as conjunctivitis, endophthalmitis, or scleritis. A history of cigarette smoking is associated with all etiologies and subtypes of uveitis. Uveitis is estimated to be responsible for approximately 10% of the blindness in the United States. If left untreated uveitis can progress to permanent vision loss or result in complications such as cataracts, glaucoma, and retinal detachment. A history of an underlying associated condition along with symptoms of eye pain, redness, photophobia, floaters, and blurry vision is strongly suggestive of uveitis. There are no specific laboratory or physical examination findings associated with uveitis. Imaging modalities may assist in diagnosing an underlying condition, though have no diagnostic utility for uveitis itself. Slit lamp test is the diagnostic modality of choice. Other ophthalmologic studies may assist in further characterizing the disease. Mainstay medical therapy is by high dose corticosteroids. Targeted antimicrobials may be required to treat an underlying infection. Surgical intervention is reserved for managing complications of uveitis such as cataract surgery or glaucoma surgery. The only indicated guideline for screening is in patients suspected of or diagnosed with juvenile idiopathic arthritis. Prompt treatment of a potential underlying infection may help prevent development of uveitis.

Uveitis was first discovered by Hippocrates, a Greek physician, and was a well known to other major medical physicians, such as Galen and Aëtius of Amida. In 1952, corticosteroids were used to treat uveitis for the first time.^[1]

Uveitis is best described using various, concurrent classification systems. Uveitis may be classified according to anatomical location into 4 subtypes, depending on which part of the uvea is primarily affected: anterior, intermediate, posterior, and panuveitis. Based on the duration of symptoms it may be further sub-classified as acute or chronic. Upon further investigation, uveitis may be classified according to histological features of the inflammation such as granulomatous or non-granulomatous. Additionally, uveitis may be described by the laterality of the condition (unilateral or bilateral). Finally, uveitis may be classified by general underlying systemic causes such as infectious, autoimmune, drug-induced, or idiopathic.^{[2][3][4][5][6]}

The healthy eye maintains immune privilege, limiting responses to self and foreign antigens through the blood–retina barrier, regulatory T cells, and anti-inflammatory cytokines such as TGF-β and IL-10.^[7][8] Noninfectious uveitis results from loss of immune tolerance to retinal proteins, causing aberrant T-cell activation.^[7][8] Infectious uveitis arises when pathogens breach the blood–retina barrier and may amplify inflammation via antigenic mimicry.^[8] In both forms, MHC class II–mediated antigen presentation activates CD4+ T cells, which differentiate into Th1 and Th17 cells that infiltrate ocular tissues and secrete IFN-γ, IL-2, and IL-17, driving recruitment of inflammatory cells and resulting in chorioretinitis, vasculitis, and edema. ^{[7][8][9][10]}

Common causes of uveitis include seronegative spondyloarthropathy, sarcoidosis, juvenile idiopathic arthritis, systemic lupus erythematosus, Behçet syndrome, multiple sclerosis AIDS, syphilis, and tuberculosis.^[6][11]

Uveitis must be differentiated from other diseases that cause conjunctival injection, eye pain, photophobia, or visual disturbance. Masquerade syndromes, which are ophthalmic disorders that clinically present as either an anterior or posterior uveitis but are not primarily inflammatory, must be differentiated from uveitis. As uveitis manifests in a variety of clinical etiologies, differentiation must also be established in accordance with the particular subtype.^{[12][6][13][14]}

Worldwide, the prevalence of uveitis ranges from 38 to 714 per 100,000 persons. The prevalence among different subtypes of uveitis varies greatly. Anterior, chronic, non-granulomatous and non-infectious subtypes are more commonly seen than others. The worldwide incidence of uveitis ranges from 17 to 52 per 100,000 persons per year. The age, sex, and race distribution is also dictated by the prevalence of the underlying cause within those demographic groups. Uveitis is associated with 3% to 10% of vision impairment in the US and Europe, and up to one-fourth of blindness in low- and middle-income countries.^{[5][6][11][15]}

A history of cigarette smoking is associated with all etiologies and subtypes of uveitis.^[16] Some underlying causes have specific potent risk factors for developing uveitis such as seronegative spondyloarthropathies, immunosuppression, sarcoidosis, and juvenile idiopathic arthritis.^[13] Geographic variation in etiology and presentation is driven by differences in infection burden, air pollution, tobacco smoking, and genetic background. ^[17][18]

There is insufficient evidence to recommend routine screening for uveitis for the general population. For patients diagnosed with or suspected of having juvenile idiopathic arthritis (JIA), screening guidelines have been recommended by the American Academy of Pediatrics (AAP) and the British Society of Paediatrics and Rheumatology (BSPAR).^[19][20]

If left untreated, uveitis can progress to permanent vision loss. Complications of uveitis include cataracts, glaucoma, macular edema, and retinal detachment. With appropriate treatment, most attacks of anterior uveitis resolve within days to weeks, however, relapses are common. Inflammation related to posterior uveitis may last from months to years and may cause permanent vision damage, even with treatment. ^{[21][22][4][23][24]}

Obtaining a complete history is an important aspect of making a diagnosis of uveitis. It provides insight into cause, precipitating factors, and associated underlying conditions. Uveitis can present unilaterally or bilaterally. Symptoms may develop acutely or insidiously, and may vary depending on the underlying etiology of the uveitis. Acute uveitis attacks are more commonly symptomatic and affect the anterior chamber. Symptoms of anterior uveitis include eye pain, eye redness, and photophobia. Intermediate, posterior, and panuveitis commonly present with floaters, blurry vision, and impaired vision. Chronic uveitis usually has an indolent courses and may not present with eye pain or redness.^[6]

A complete medical history and comprehensive eye examination must be performed by an optometrist or ophthalmologist to properly diagnosis uveitis. Eye examination of patients with uveitis is usually remarkable for eye redness and increased or decreased intraocular pressure. Depending on the affected anatomy of the uvea, “snowbanking” or optic disc edema may be seen on dilated fundus exam, and mutton fat keratic precipitates on slit lamp test may also be appreciated.^[25][26] A complete physical examination can provide insight into the cause, and associated underlying conditions.

There is no single international consensus diagnostic algorithm, and the investigations are tailored to, Regional infection prevalence, comorbidities and immunosuppression, and clinical presentation.^[15] The presence of certain non-specific laboratory findings, in the presence of uveitis, may be suggestive of certain underlying causes. Examples of tests that may demonstrate abnormal findings include CBC, ESR, CRP, complete metabolic panel, iron studies, and serology titers.^{[27][28][29][30][31]} Immunocompromised patients, particularly those with HIV, require comprehensive infectious screening including for CMV, Candida and other opportunistic pathogens.^{[32][33][34][35]}

There are no diagnostic x ray findings associated with uveitis. Positive x ray findings may be found in underlying conditions such as sarcoidosis^[36], tuberculosis^[37], and seronegative spondyloarthropathies^[38][39].

There are no diagnostic CT scan findings associated with uveitis. The presence of certain CT findings, in the presence of uveitis, may be suggestive of specific underlying causes such as inflammatory bowel disease^[40][41][42], sarcoidosis^[43][44], and Behcet’s disease^[45][46].

There are no diagnostic MRI findings associated with uveitis. The presence of certain MRI findings, in the presence of uveitis, may be suggestive of specific underlying causes such as sarcoidosis, multiple sclerosis, Behcet’s disease, syphilis, and joint abnormalities in seronegative spondyloarthropathies.^{[47][48][49][50][39]}

There are no diagnostic ultrasound findings associated with uveitis.

There are no other diagnostic imaging findings associated with uveitis.

Other diagnostic studies associated with uveitis include slit lamp test and ocular tonometry. The slit lamp test is considered a gold standard modality in diagnosing uveitis. While intraocular pressure may increase or decrease depending on the anatomical location and severity of the inflammation, slit lamp test findings are relatively more consistent. Common slit lamp test findings include presence of inflammatory cells in the anterior chamber, keratic precipitates, and mutton fat precipitates. Slit lamp test findings associated with anatomical location include snowbanking in intermediate uveitis (e.g., pars planitis), snowballing in vitritis, and retinal edema in posterior uveitis.^[6][51]

Noninfectious anterior uveitis is treated first-line with topical prednisolone acetate 1% with intensive dosing and taper ^[5], with rimexolone showing comparable efficacy ^[52]; periocular or intravitreal corticosteroids are second-line when topical therapy is inadequate and systemic therapy is undesirable.^[53][54][55] Moderate-to-severe intermediate, posterior uveitis, and panuveitis require systemic and/or intravitreal corticosteroids with immunosuppression ^[15], typically oral prednisone or IV methylprednisolone for severe disease, achieving rapid remission in many patients. ^[56][57]

DMARDs are first-line steroid-sparing systemic therapy for noninfectious posterior uveitis, and adalimumab is second line for refractory disease. ^{[58][59][60][61][62][63][64]} Corticosteroid treatment carries significant risk of cataract, glaucoma, and ocular hypertension ^{[5][54][65][66]}. Infectious uveitis requires pathogen-directed antimicrobial therapy first, with corticosteroids used only as adjuncts and never alone; gram-positive organisms predominate in endophthalmitis^{[67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86]}

There is no indication for surgical intervention in uveitis. Surgical management of uveitis is most commonly reserved for management of complications of uveitis or, rarely, for diagnostic purposes. Common complications of uveitis requiring surgery include cataract surgery, glaucoma surgery, or band keratopathy. Common indications for the diagnostic utility of surgery in uveitis include vitreous tap, vitreous biopsy, and posterior uveal biopsy.^[87]

Appropriate treatment of an underlying disorder may help to prevent uveitis in persons with a systemic infection or inflammatory disease.

There are no secondary prevention methods associated with uveitis.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2]

Uveitis was first discovered by Hippocrates, a Greek physician, and was well known to other major medical physicians, such as Galen and Aëtius of Amida. In 1952, corticosteroids were used to treat uveitis for the first time.^[1]

• Uveitis is an ancient disease.
• Uveitis was first discovered by Hippocrates, a Greek physician, and was well known to other major medical physicians, such as Galen and Aëtius of Amida.^[1]
• In 1806, Antonio Scarpa, an Italian anatomist, described a uveitis case study and the treatment of the disease for the first time in modern literature.^[2]
• In 1830, William Mackenzie, a Scottish physician, described uveitis for the first time in English medical literature.^[1][3]
• In 1952, corticosteroids were used to treat uveitis for the first time.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2]

Uveitis is best described using various, concurrent classification systems. Uveitis may be classified according to anatomical location into 4 subtypes, depending on which part of the uvea is primarily affected: anterior, intermediate, posterior, and panuveitis. Based on the duration of symptoms it may be further sub-classified as acute or chronic. Upon further investigation, uveitis may be classified according to histological features of the inflammation such as granulomatous or non-granulomatous. Additionally, uveitis may be described by the laterality of the condition (unilateral or bilateral). Finally, uveitis may be classified by general underlying systemic causes such as infectious, autoimmune, drug-induced, or idiopathic.^{[1][2][3][4][5]}

Uveitis can be described according to the following classifications:^[1][2][5]

• Classification by Anatomical Location
  • Anterior uveitis: Iritis, cyclitis or iridocyclitis (inflammation affecting the iris, the ciliary body, or both)
  • Intermediate uveitis: Viritis or pars planitis (inflammation of the the vitreous humor or the pars plana)
  • Posterior uveitis: Choroiditis, retinitis, or chorioretinitis (inflammation of the choroid, the retina, or both)
  • Panuveitis: Inflammation of the entire uvea
• Classification by Duration of Symptoms^[3]
  • Acute: Active uveitis for less than 3 months
  • Chronic: Active uveitis for more than 3 months
• Classification by type of inflammation^[4]
  • Granulomatous: showing granulomatous inflammation on slit lamp test
  • Non-granulomatous showing no granulomatous inflammation on slit lamp test
• Classification by Laterality
  • Unilateral: Single eye involvement
  • Bilateral: Both eyes involvement
• Classification by Etiology^[1][2]
  • Idiopathic: No known cause
  • Infectious: Bacterial, viral, fungal, or parasitic cause
  • Autoimmune/Inflammatory: Caused by a systemic non-infectious inflammatory condition commonly associated with uveitis
  • Drug-Induced: Iatrogenic cause by medications that are associated with incidence of uveitis
    

As uveitis manifests in a variety of clinical etiologies, differentiation must be established in accordance with the classification system for particular subtypes. Etiologies of acute anterior unilateral infectious uveitis must be differentiated from other subtypes that cause conjuctival injection, eye pain, and photophobia such as acute anterior bilateral non-infectious uveitis or chronic anterior uveitis. Diversely, posterior infectious uveitis must be differentiated from other subtypes that cause visual changes such as intermediate non-infectious uveitis and infectious panuveitis. Using the above model, the following is a classification of uveitis, which includes the most common subtypes:

Anterior uveitis can be classified according to the following presentation:^[5][6][7]

• Acute (>3 months of active symptoms)^[3]
  • Unilateral
    • Infectious: Cytomegalovirus, Herpes simplex, Varicella zoster, syphilis
    • Non-infectious: Seronegative spondyloarthropathy, relapsing polychondritis, systemic lupus erythematosus (SLE), Kawasaki disease
  • Bilateral
    • Infectious: Tuberculosis, syphilis
    • Non-infectious: tubulointerstitial nephritis with uveitis (TINU syndrome)
• Chronic (>3 months of active symptoms)^[3]
  • Infectious: Tuberculosis
  • Non-infectious: juvenile idiopathic arthritis, Sjorgen’s Syndrome, sarcoidosis

Intermediate may present with unilateral or bilateral involvement. It can be classified according to the following etiologies^[5][6][7]

• Infectious: Lyme disease, Whipple’s disease
• Non-infectious: multiple sclerosis, sarcoidosis, tubulointerstitial nephritis with uveitis (TINU syndrome), lymphoma

Posterior uveitis may present with unilateral or bilateral involvement. It can be classified according to the following most common etiologies:^[5][6][7]

• Infectious: Toxoplasmosis, Cytomegalovirus, Tuberculosis, Syphilis, Toxocariasis, Herpes simplex, Varicella zoster, cat scratch disease
• Non-infectious:Vogt-Koyanagi-Harada syndrome, systemic lupus erythematosus, granulomatosis with polyangitis, Behcet’s disease, birdshot chorioretinopathy, lymphoma

Panuveitis may present with unilateral or bilateral involvement. It can be classified according to the following most common etiologies:^[5][6][7]

• Infectious: Tuberculosis, syphilis
• Non-infectious: Juvenile idiopathic arthritis, Behcet’s disease, sarcoidosis, Vogt-Koyanagi-Harada syndrome, Sjorgen’s Syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2]

The healthy eye possesses immune privilege, which suppresses immune responses to both endogenous retinal antigens (such as S-antigen) and exogenous antigens. This immune privilege is maintained by the blood–retina barrier, cellular mechanisms including regulatory T cells, and cytokine-mediated mechanisms involving transforming growth factor beta and interleukin-10.^[1][2]

Uveitis is mediated by a genetic predisposition and an acquired cross immunity to infectious agents, or cross immunity to self-antigens due to underlying autoimmune diseases. It is estimated that 35% to 50% of cases of uveitis are idiopathic.^[3][4] Development of uveitis is hypothesized to be the result of a genetic predisposition for acquiring the disease; contributions of several human leukocyte antigen (HLA) alleles are most commonly implicated.^[4][5]This includes HLA-B27 in seronegative spondyloarthropathies, HLA-A29 in birdshot chorioretinopathy, HLA-B51 in Behcet syndrome and multiple sclerosis, HLA-B8, HLA-DR15, and HLA-DR2.^[4][5]

Initiation of Uveitis

Noninfectious uveitis is hypothesized to result from reduced immune tolerance to retinal proteins, leading to inappropriate immune activation within the eye. In infectious uveitis, pathogenic organisms breach the blood–retina barrier and initiate inflammation; pathogen-derived antigens may resemble retinal proteins, a process known as antigenic mimicry, which can exacerbate the inflammatory response.^[1][2] Infectious uveitis is hypothesized to be secondary to a T-cell mediated hypersensitivity reaction resulting in immunoactivating cytokine production by proliferating Tн17 and Tн1 cells.^[5][6] A similar mechanism is hypothesized for autoimmune etiologies of uveitis with the exception of an unknown source of the triggering antigen.^{[7][8][9][10]}

Antigen Presentation and T-Cell Activation

The prevailing mechanism in both infectious and noninfectious uveitis involves antigen presentation via major histocompatibility complex class II molecules, leading to activation of naïve CD4⁺ T cells. In infectious uveitis, antigen presentation is initiated by pathogen-derived antigens, whereas in noninfectious uveitis it is initiated by ocular autoantigens.^[1][2]

Effector T-Cell Response

Upon activation, naïve CD4⁺ T cells differentiate predominantly into Th1 and Th17 subsets, which migrate to the retina and uveal tissues. These effector T cells play a central role in sustaining intraocular inflammation.^[1][2]

Cytokine Cascade and Innate Immune Recruitment

Activated Th1 and Th17 cells release proinflammatory cytokines, including interferon-gamma, interleukin-2, and interleukin-17, triggering a cytokine cascade that recruits innate immune cells such as macrophages and neutrophils into ocular tissues.^[2]

Inflammatory Tissue Injury

The accumulation of inflammatory cells and sustained cytokine signaling result in tissue damage, manifesting as chorioretinitis, retinal vasculitis, and edema, which contribute directly to visual dysfunction in uveitis.^[2]

The retina’s immune privilege relies on the blood-retina barrier, which shields

ocular tissue proteins from the systemic immune system. This protective

mechanism can be compromised, leading to autoimmune reactions. Within the

retina, Tregs marked by CD4+, CD25+, and FoxP3+ identifiers contribute to

immune tolerance by emitting neuropeptides and anti-inflammatory cytokines.

These Tregs can suppress other T cells that have escaped elimination in the

thymus during development and have the potential to react against

self-antigens, producing cytokines, TGFβ, and IL-35 to reduce inflammation.

Furthermore, retinal pigment epithelium and retinal cells express certain

proteins on their surfaces that deactivate lymphocytes, thereby regulating

ocular inflammation. Disease is typically associated with major

histocompatibility complex class II molecule–mediated presentation of

autoantigens or cross-reactive foreign peptides to naive T cells. Activated CD4+

T cells differentiate into CD4+ TH1 and TH17 cells that migrate to the affected

tissue, recruiting inflammatory cells and producing tissue damage. T cells

differentiate into CD4+ TH1 and TH17 cells, producing IFNγ and IL-17,

respectively. These facilitate the recruitment and activation of downstream

cytokine release and innate inflammatory response, such as IL-6, TNF, and

granzyme B (a protease involved in programmed cell death), which in turn can

lead to vasculitis and edema.21,22

IFNγ indicates interferon gamma; TGFβ, transforming growth factor beta.

TNF, tumor necrosis factor; Treg, regulatory T cell.^[11]

The following conditions are associated with uveitis:^[3][4][12]

• Seronegative spondyloarthropathy
• Sarcoidosis
• Multiple sclerosis
• Inflammatory bowel disease
• Systemic lupus erythematosus (SLE)
• Behçet’s syndrome
• Birdshot retinochoroidopathy
• Juvenile idiopathic arthritis (JIA)
• Vogt-Koyanagi-Harada syndrome
• Fuch’s heterochromic iridocyclitis
• Lymphoma
• Lyme Disease
• Acquired immunodeficiency syndrome (AIDS)
• Herpes simplex
• Varicella Zoster
• Cytomegalovirus
• Syphilis
• Toxoplasmosis
• Toxocariasis
• Tuberculosis
• Rubella
• Cat scratch disease (Bartonella spp.)

On gross pathology, redness of the eye and dilated cilliary vessels are common yet non-specific findings in uveitis. The following are images of the gross pathology of uveitis:^[13][14]

• 
  Uveitis with pus in the anterior chamber
• 
  Anterior Uveitis

On microscopic histopathological analysis, lymphocytic infiltration, monocytic infiltration, epitheloid cells, and granulomatous inflammation of the uveal structures are characteristic findings of uveitis. The following are images of the microscopic pathology of uveitis:^[15]

• 
  Uveitis with infiltration of lymphocytes
• 
  Uveitis with granulomatous inflammation and infiltration of the choroid by lymphocytes and macrophages

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2]

Common causes of uveitis include seronegative spondyloarthropathy, sarcoidosis, juvenile idiopathic arthritis, systemic lupus erythematosus, Behçet syndrome, multiple sclerosis, AIDS, syphilis, and tuberculosis.^[1][2]

Uveitis may be caused by either systemic inflammatory diseases, localized infectious diseases, or isolated syndromes confined to the eye. No specific diagnosis is made in approximately one-half of cases. However, uveitis is often associated with human leukocyte antigen (HLA) alleles such as HLA-B27, HLA-A29, HLA-B51, HLA-B8, HLA-DR15, HLA-DR2.^[1][2][3]

Systemic autoimmune disorders that can cause uveitis include:^[1][2][4]

• Ankylosing spondylitis
• Behçet’s disease
• Inflammatory bowel disease
• Juvenile rheumatoid arthritis
• Kawasaki disease
• Multiple sclerosis
• Psoriatic arthritis
• Reiter’s syndrome
• Sarcoidosis
• Systemic lupus erythematosus
• Whipple disease

Infectious diseases that can cause uveitis include:^[1][2][5]

• Toxocariasis
• Toxoplasmosis
• Tuberculosis
• Syphilis
• Leptospirosis
• Brucellosis
• Herpes simplex
• Varicella zoster
• Presumed ocular histoplasmosis syndrome
• Lyme disease
• Cytomegalovirus
• Rubella
• Cat scratch disease (Batronela spp.)

Isolated eye disorders that can cause uveitis include:^[1][2][6]

• Vogt-Koyanagi-Harada syndrome
• Acute posterior multifocal placoid pigment epitheliopathy
• Birdshot retinochoroidopathy

The cause of uveitis may vary depending on the anatomical location affected:^[1][2]

• Anterior uveitis may be associated with autoimmune diseases, but most cases occur in healthy people for unapparent reasons. The disorder may affect only one eye. It is most common in young and middle-aged people.

• Intermediate uveitis usually occurs in young men and is generally not associated with any other disease. In most cases, the cause is unknown.^[7] However, some evidence suggests it may be linked to Crohn’s disease and possibly multiple sclerosis.^[8]

• Posterior uveitis may develop in people who have an autoimmune disease or who have had a systemic (body-wide) infection. The most common cause of posterior uveitis is infections resulting from toxoplasmosis.^[9]

Cardiovascular	Kawasaki disease, Wegener granulomatosis
Chemical / poisoning	No underlying causes
Dermatologic	Vitiligo, Psoriasis
Drug Side Effect	Certolizumab pegol, etidronate, fomivirsen sodium, latanoprost, metipranolol, medrysone,nivolumab, pembrolizumab, rifabutin, trametinib, vemurafenib
Ear Nose Throat	No underlying causes
Endocrine	No underlying causes
Environmental	No underlying causes
Gastroenterologic	Ulcerative colitis, Crohn’s disease
Genetic	Blau syndrome, Granulomatous arthritis of childhood, Incontinentia pigmenti, Synovitis granulomatous with uveitis and cranial neuropathies
Hematologic	Lymphoma
Iatrogenic	No underlying causes
Infectious Disease	Brucellosis, Cat scratch fever, Epstein-Barr virus, Herpes simplex, Herpes zoster, HTLV-1, Lepromatous leprosy, Leptospirosis, Lyme disease, Malaria, Mycobacterium tuberculosis, Ocular bartonellosis, Onchocerciasis, Presumed ocular histoplasmosis syndrome, Secondary syphilis, Syphilis, Toxocariasis, Toxoplasma, Toxoplasmosis, Tuberculosis, West nile virus, Whipple disease , AIDS
Musculoskeletal / Ortho	Granulomatous arthritis of childhood, Ankylosing spondylitis, Juvenile chronic arthritis, Juvenile rheumatoid arthritis, Polychondritis, Rheumatoid disease, Still disease, juvenile-onset
Neurologic	Tropical spastic paraparesis, Multiple sclerosis
Nutritional / Metabolic	No underlying causes
Obstetric/Gynecologic	No underlying causes
Oncologic	Lymphoma
Opthalmologic	Acute retinal necrosis syndrome, Alezzandrini syndrome, Birdshot retinochoroidopathy, Fuchs’ heterochromic cyclitis, Heerfordt-Waldenstroem syndrome, Ocular ischemic syndrome, Pars planitis, Scleritis, Tubulointerstitial nephritis and uveitis, Systemic ophthalmitis, Intraocular foreign body
Overdose / Toxicity	No underlying causes
Psychiatric	No underlying causes
Pulmonary	No underlying causes
Renal / Electrolyte	Tubulointerstitial nephritis and uveitis
Rheum / Immune / Allergy	Ulcerative colitis, Ankylosing spondylitis, Autoimmune uveitis, Behcet disease, Crohn’s disease, Hypocomplementemic urticarial vasculitis syndrome, Juvenile chronic arthritis, Juvenile rheumatoid arthritis, Kawasaki disease, Multiple sclerosis, Polychondritis, Psoriasis, Reiter syndrome, Rheumatoid disease, Sarcoidosis, Still disease, juvenile-onset, Sympathetic ophthalmitis, Systemic lupus erythematosus, Vogt-Koyanagi-Harada syndrome, Wegener granulomatosis
Sexual	No underlying causes
Trauma	Trauma
Urologic	No underlying causes
Dental	No underlying causes
Miscellaneous	Intraocular foreign body

Acute retinal necrosis syndrome AIDS Alezzandrini syndrome Ankylosing spondylitis Autoimmune uveitis Behcet disease Birdshot retinochoroidopathy Blau syndrome Brucellosis Certolizumab pegol Cat scratch fever Crohn’s disease Epstein-Barr virus Etidronate Fomivirsen sodium Fuchs’ heterochromic cyclitis Granulomatous arthritis of childhood Heerfordt-Waldenstroem syndrome Herpes simplex Herpes zoster HTLV-1 Hypocomplementemic urticarial vasculitis syndrome Incontinentia pigmenti Intraocular foreign body Juvenile chronic arthritis Juvenile rheumatoid arthritis Kawasaki disease Lepromatous leprosy Leptospirosis Lyme disease Lymphoma Malaria Medrysone Multiple sclerosis Mycobacterium tuberculosis

Ocular bartonellosis Ocular ischemic syndrome Onchocerciasis Pars planitis Polychondritis Presumed ocular histoplasmosis syndrome Psoriasis Reiter syndrome Rheumatoid disease Rifabutin Sarcoidosis Scleritis Secondary syphilis Still disease, juvenile-onset Sympathetic ophthalmitis Synovitis granulomatous with uveitis and cranial neuropathies Syphilis Systemic lupus erythematosus Toxocariasis Toxoplasma Toxoplasmosis Trauma Tropical spastic paraparesis Tuberculosis Tubulointerstitial nephritis and uveitis Ulcerative colitis Vemurafenib Vitiligo Vogt-Koyanagi-Harada syndrome Wegener granulomatosis West nile virus Whipple disease

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2]

Uveitis must be differentiated from other diseases that cause conjunctival injection, eye pain, photophobia, or visual disturbance. Masquerade syndromes, which are ophthalmic disorders that clinically present as either an anterior or posterior uveitis but are not primarily inflammatory, must be differentiated from uveitis. As uveitis manifests in a variety of clinical etiologies, differentiation must also be established in accordance with the particular subtype.^[1][2][3][4]

Uveitis must be differentiated from other diseases that cause conjunctival injection, eye pain, photophobia, or visual disturbance. Masquerade syndromes, which are ophthalmic disorders that clinically present as either an anterior or posterior uveitis but are not primarily inflammatory, must be differentiated from uveitis. As uveitis manifests in a variety of clinical etiologies, differentiation must also be established in accordance with the particular subtype.^[1][2][3][4]

Uveitis must be differentiated from other diseases that cause conjunctival injection, eye pain, photophobia, or visual disturbance, and include:^[5][6][7]

• Corneal ulceration
• Conjunctivitis
• Closed angle glaucoma
• Corneal abrasion
• Ulcerative keratitis
• Herpes keratitis
• Intraocular foreign body
• Episcleritis or scleritis
• Endophthalmitis
• Radiation-induced keratitis

Masquerade syndromes are ophthalmic disorders that clinically present as either an anterior or posterior uveitis, but are not primarily inflammatory. The following are some of the most common:^[4]

• Anterior segment

• Intraocular foreign body
• Juvenile xanthogranuloma
• Leukemia
• Malignant melanoma
• Retinoblastoma
• Retinal detachment

• Posterior segment

• Lymphoma
• Malignant melanoma
• Multiple sclerosis
• Reticulum cell sarcoma
• Retinitis pigmentosa
• Retinoblastoma
• Syphilis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2]; M Chadi Alraies M.D., MPH [3]

Worldwide, the prevalence of uveitis ranges from 69 to 204 per 100,000 persons. The prevalence among different subtypes of uveitis varies greatly. Anterior, chronic, non-granulomatous and non-infectious subtypes are more commonly seen than others. The worldwide incidence of uveitis ranges from 17 to 52 per 100,000 persons per year. The age, sex, and race distribution is also dictated by the prevalence of the underlying cause within those demographic groups.^[1][2][3]

Worldwide incidence and prevalence of uveitis has been well studied. The epidemiologic data varies greatly by underlying etiology or classification of uveitis.

The reported global prevalence of uveitis ranges widely from 38 to 714 per 100,000 people, reflecting substantial geographic and methodological variability. Uveitis is responsible for 3%–10% of visual impairment in the United States and Europe and has been associated with up to one-quarter of blindness in low- and middle-income countries.^[4]

Several studies have reported prevalence data among a large group of uveitis patients, as follows:

• By anatomy In the United States and Europe, ^{[5][6][7][8][9]}
  • Anterior uveitis is the most common subtype (41%–60%)
  • Posterior uveitis (17%–23%)
  • Intermediate uveitis (9%–15%)
  • Panuveitis (7%–32%)
• By Etiology In high-income countries, 52%–79% of uveitis cases are noninfectious, while 11%–21% are infectious; in contrast, infectious causes account for up to 50% of cases in low- and middle-income countries.^[4][10] In high-income settings, the most common infectious causes include toxoplasmosis (5%–7%) and herpes-related uveitis (5%–15%), whereas tuberculosis-related (8%–13%) and HIV-related (10%–14%) uveitis are more prevalent in low- and middle-income countries.^{[6][11][12][13][14][15][16]} Despite comprehensive evaluation, 27%–51% of uveitis cases remain idiopathic.^{[5][7][17][8][18]} In the United States and Europe, 37%–49% of uveitis cases are associated with systemic inflammatory diseases, most commonly axial spondyloarthritis.^{[5][6][7][17][19][20][21]}
• By Laterality Laterality varies by anatomic subtype: anterior uveitis is more often unilateral (≈53%), whereas intermediate uveitis (79%), posterior uveitis (57%), and panuveitis (75%) are more commonly bilateral.^[22]
• Geographic Contrast The epidemiology of uveitis varies substantially by geography and ethnicity, reflecting differences in genetic susceptibility, environmental exposures, and regional infection prevalence.^[23][24] In regions with a lower prevalence of HLA-B27, such as Japan, panuveitis predominates (≈46%), followed by anterior (38%), posterior (13%), and intermediate uveitis (3%).^[25] Sarcoidosis-associated uveitis is more frequent in Europe and the United States (≈8%–10%), Behçet disease accounts for approximately 30% of uveitis cases in Turkey, and Vogt–Koyanagi–Harada disease is more prevalent in East Asian populations.^{[9][26][27][28][29]}
• By Prognosis In a large US insurance-based cohort, approximately 5% of patients with noninfectious intermediate, posterior, or panuveitis developed blindness or low vision within 5 years.^[30]

Worldwide, the incidence of uveitis ranges from 17 to 52 per 100,000 per year.^[1][2][3]

The age, sex, and race distribution of uveitis is dictated by the prevalence of the underlying cause within those demographic groups.

Uveitis can occur at any age but presents most frequently in young and middle-aged adults (20–50 years), who account for approximately 60%–80% of cases.^[4][17][31]The prevalence among age groups varies greatly depending on the underlying etiology. The following is an example of age distribution by underlying etiology:^{[3][32][33][34][35]}

Children: Juvenile rheumatoid arthritis, toxocariasis

Young adults: Behçet’s disease, HLA-B27 antigen associated uveitis, Fuch’s uveitis

Older adults: Vogt-Koyanagi-Harada syndrome, herpes zoster ophthalmicus, and tuberculosis

Overall, uveitis is more common in women, with approximately 57% of cases occurring in females.^[36] Female predominance is particularly pronounced in uveitis associated with multiple sclerosis (≈75% female), juvenile idiopathic arthritis (50%–80% female), and sarcoidosis (55%–64% female), whereas HLA-B27–associated uveitis shows a male predominance (male-to-female ratio ≈1.5:1).^[37] The prevalence of uveitis among one of the sexes depends on the gender distribution of the underlying disorder.^[3]

The prevalence of different etiologies of uveitis vary by race. Caucasians are more affected by HLA-B27 related conditions making HLA-related uveitis highly prevalent in this race group. Alternatively, middle eastern people are more likely affected with Behcet’s disease, making them more likely to have uveitis related to this disease. African Americans are more commonly affected by sarcoidosis, thus sarcoid related uveitis is more common in this group.^{[32][33][34][35]}

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2]

A history of cigarette smoking is associated with all etiologies and subtypes of uveitis.^[1] Some underlying causes have specific potent risk factors for developing uveitis such as seronegative spondyloarthropathies, immunosuppression, sarcoidosis, and juvenile idiopathic arthritis.^[2]

A history of smoking is associated with all etiologies and subtypes of uveitis.^[1] Some underlying causes may have potent risk factors for developing uveitis such as:^[2]

• Acute posterior multifocal placoid pigment epitheliopathy: HLA-B27 or HLA-DR2 alleles, preceding viral illness, underlying vasculitis
  
• CMV retinitis: HIV, CD4 count <50, severe immunosuppression, localized ocular immunosuppression
  
• Necrotizing herpitic retinitis: Immunosuppression
  
• Punctuate inner choroidopathy: Myopia in females, age 18 to 40
  
• Sarcoid uveitis: African American race, age<50
  
• Autoimmune scleritis: Female gender, age 40-60 years
  
• Sympathetic ophthalmia: Ocular trauma with delayed closing of the wound
  
• Acute anterior uveitis: HLA-B27 allele, ankylosing spondylitis, psoraitic arthritis
  
• TINU syndrome: Female gender
  
• Vogt-Koyanagi-Harada syndrome: Hispanic or Japanese race, HLA-DR1 and HLA-DR4 alleles
  
• Drug-induced uveitis: Use of rifabutin, cidofovir, bisphosphonates, sulfonamides, moxifloxacin, metipranolol, brimonidine, prostaglandin analogues, or flurbiprofen

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2]

There is insufficient evidence to recommend routine screening for uveitis for the general population. For patients diagnosed with or suspected of having juvenile idiopathic arthritis (JIA), screening guidelines have been recommended by the American Academy of Pediatrics (AAP) and the British Society of Paediatrics and Rheumatology (BSPAR).^[1][2]

There is insufficient evidence to recommend routine screening for uveitis for the general population.^[3] For patients diagnosed with, or suspected of having juvenile idiopathic arthritis (JIA), screening guidelines have been recommended based on the AAP, Cincinnati Children’s Hospital, and the BSPAR. Screening for uveitis in children with JIA is recommended as follows:

• Patients should be referred at the time of diagnosis or suspicion of JIA, and a slit lamp ophthalmologic examination be performed within one month to 6 weeks of referral. It is recommended that after the initial screening examination, regular follow-up screenings be maintained based on risk category and classification.

For access to the complete American guideline,click here.^[2]

For access to the complete British guideline,click here.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Tarek Nafee, M.D. [2]

If left untreated, uveitis can progress to permanent vision loss. Complications of uveitis include cataracts, glaucoma, macular edema, and retinal detachment. With appropriate treatment, most attacks of anterior uveitis resolve within days to weeks, however, relapses are common. Inflammation related to posterior uveitis may last from months to years and may cause permanent vision damage, even with treatment.^{[1][2][3][4][5]}

If left untreated, uveitis can progress to permanent vision loss. Uveitis is estimated to be responsible for approximately 10% of the blindness in the western world.^[3][4][5]

Possible complications of uveitis include:^[6][7]

• Cataracts
• Glaucoma
• Macular edema
• Retinal detachment
• Synechia
• Vision loss

The prognosis of uveitis varies with the subtype, etiology, severity, duration and responsiveness to treatment.

• The following are favorable prognostic factors:^{[8][9][10][11][12][13][14][15][16][17]}
  
  • Rapid initiation of corticosteroid treatment
  • Good initial visual acuity
  • Good response to standard medical therapy

• The following are poor prognostic factors:^{[8][9][10][11][12][13][14][15][16][17]}
  
  • Chronic disease course
  • Posterior or intermediate uveitis
  • Lack of response to standard medical therapy
  • Complications of uveitis
  • Poor initial visual acuity
  • Isolated ocular uveitis (no underlying systemic disease)

With appropriate treatment, most attacks of anterior uveitis resolve within days to weeks, however, relapses are common. Inflammation related to posterior uveitis may last from months to years and may cause permanent vision damage, even with treatment.^[1][2]

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