Uveitis

Physicians classify uveitis using the Standardization of Uveitis Nomenclature (SUN) Working Group system, established in 2005 and universally accepted worldwide. The SUN system classifies uveitis by three axes: the primary anatomic location of inflammation inside the eye, the course of the disease over time (acute, recurrent, or chronic), and the grade of disease activity. Each axis guides different aspects of prognosis and treatment.

Anterior uveitis is the most common type, accounting for 45–93% of all uveitis cases across global studies. The inflammation is located primarily in the anterior chamber—the fluid-filled space between the cornea and the iris. Anterior uveitis typically presents with a painful, red, light-sensitive eye. Important named forms include:

• Idiopathic chronic anterior uveitis: This is the most common type overall; no identifiable systemic cause is found even after a thorough evaluation.
   
• HLA-B27-associated acute anterior uveitis: unilateral, acute, and often recurrent; strongly linked to a group of joint and spine diseases called seronegative spondyloarthropathies, including ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and inflammatory bowel disease–associated arthritis. These carry the HLA-B27 genetic marker. More than two uveitis episodes dramatically increase the risk of the patient developing ankylosing spondylitis over time.
   
• Juvenile idiopathic arthritis-associated uveitis (JIA-U): the most dangerous form in children. Unlike other anterior uveitides, JIA-U causes no pain and no redness—the eye looks completely normal from the outside. It is detected only on slit-lamp examination, making scheduled screening mandatory for all children with juvenile idiopathic arthritis (JIA). Up to 45% of children with JIA already have serious ocular complications by the time they reach their first ophthalmology visit.
   
• Fuchs heterochromic iridocyclitis (Fuchs uveitis syndrome): a chronic, low-grade, typically unilateral uveitis associated with a subtle color change in the affected iris (heterochromia). It does not respond to corticosteroids in the typical way and generally carries a favorable long-term prognosis.
   
• Tubulointerstitial nephritis and uveitis (TINU) syndrome: a form that affects both the kidneys and eyes simultaneously; predominantly affects adolescent females (75% female; median onset age 15 years). Kidney inflammation precedes eye inflammation in 65% of cases.
   
• Sarcoidosis-associated, Behcet disease-associated, and other systemic disease-linked anterior uveitides: These all carry specific clinical and laboratory features that direct their management.

Intermediate uveitis accounts for approximately 10–15% of all uveitis cases. The primary site of inflammation is the vitreous—the gel filling the back of the eye—and the peripheral retina. It typically presents with floaters and blurred vision, but little or no pain or redness. The most common form is pars planitis—an idiopathic (cause unknown) intermediate uveitis named for the area of peripheral retina involved. Its classic examination findings are “snowball” opacities (white fluffy aggregates in the inferior vitreous) and “snowbank” (an organized white exudate over the pars plana). Mean pediatric onset is 7.8 years. Approximately 25–35% of mild pars planitis cases require no treatment and resolve on their own. Intermediate uveitis is also associated with multiple sclerosis, sarcoidosis, and Lyme disease.

Posterior uveitis accounts for 15–30% of diagnoses. The inflammation primarily involves the retina and/or the choroid and is typically painless. Patients most commonly report floaters, visual field defects (blank or dark spots in vision), and blurred vision. Major named forms include:

• Birdshot chorioretinopathy: bilateral; characterized by scattered cream-colored oval lesions distributed around the optic nerve, resembling buckshot on the retina. Strongly associated with the HLA-A29 genetic marker (present in more than 95% of patients). Predominantly affects middle-aged Caucasian adults. Causes slow, progressive damage, including night blindness and color vision loss.
   
• Toxoplasmic retinochoroiditis: the most common infectious posterior uveitis worldwide, caused by the parasite Toxoplasma gondii. The hallmark examination finding is a white focal retinal lesion with surrounding haze (“headlight in fog”) adjacent to an older pigmented scar from a prior episode.
   
• Acute posterior multifocal placoid pigment epitheliopathy (APMPPE): This is a self-limited form that typically follows a viral illness in young adults and resolves completely without treatment.
   
• Multiple evanescent white dot syndrome (MEWDS), punctate inner choroiditis (PIC), multifocal choroiditis with panuveitis (MFCPU), and serpiginous choroiditis (SC): These are named by their imaging patterns on the retina; each has a distinct prognosis and management.

Panuveitis involves all three anatomic compartments—the anterior chamber, vitreous, and retina/choroid—simultaneously. It is the most visually devastating form and carries the highest risk of permanent vision loss. Major forms include:

• Vogt–Koyanagi–Harada (VKH) disease: bilateral granulomatous panuveitis in which the immune system attacks melanin-containing cells in the choroid, skin, inner ear, and hair follicles. Associated with HLA-DRB1*04. VKH has four clinical phases: a prodromal phase resembling meningitis (headache, neck stiffness, hearing changes, tinnitus, fever); an acute uveitic phase with bilateral blurred vision, fluid under the retina, and disc swelling; a convalescent phase marked by skin depigmentation (vitiligo) and white eyelashes; and a chronic recurrent phase.
   
• Behcet disease panuveitis: a systemic vasculitis causing recurrent, severe, nongranulomatous panuveitis, often with a visible layer of white cells at the base of the anterior chamber (hypopyon). Associated with the HLA-B51 gene and most common in populations from the historic “Silk Road” geographic corridor. Males have a worse visual prognosis than females.
   
• Sympathetic ophthalmia: bilateral granulomatous panuveitis developing weeks to years after a penetrating injury or surgery to one eye. The damaged eye’s uveal proteins enter the circulation and trigger an immune attack on the otherwise uninjured fellow eye.
   
• Blau syndrome: caused by a NOD2 gene gain-of-function mutation; presents before age 5 with the triad of skin rash, arthritis, and uveitis. Autosomal dominant inheritance.

Uveitis is also classified by its time course. Acute uveitis begins suddenly and resolves within three months. Recurrent uveitis consists of repeated episodes separated by at least three months of being free of inflammation without treatment. Chronic uveitis is the most challenging form—inflammation persists and returns within three months of reducing or stopping treatment, requiring long-term suppression. Certain conditions, such as JIA-associated uveitis and Behcet disease, are almost always chronic.

Uveitis results from immune-mediated intraocular inflammation—an abnormal immune response directed against the tissues of the eye. The eye is normally an immune-privileged site, protected by physical barriers (the blood-retinal barrier) and active immune tolerance mechanisms (called anterior chamber-associated immune deviation—ACAID) that prevent the immune system from mounting destructive inflammatory attacks inside the eye. Uveitis occurs when these protective systems are overcome.

Noninfectious causes account for 67–90% of uveitis in developed countries. The fundamental mechanism is T-cell-driven: CD4+ T-cells differentiate into pathogenic Th1 and Th17 effector cells that attack intraocular tissues. Th1 cells release IFN-gamma, driving macrophage activation and granuloma formation. Th17 cells release IL-17, recruiting neutrophils and causing tissue damage. The inflammatory cytokines tumor necrosis factor (TNF)-alpha, IL-6, and IL-17A are particularly central—which explains why anti-TNF biologic therapies are so effective in uveitis. T-cells specifically targeting the eye’s own proteins—including S-antigen (retinal arrestin) and interphotoreceptor retinoid-binding protein (IRBP)—have been identified in the blood of uveitis patients, confirming the autoimmune mechanism.

Specific autoimmune mechanisms differ by disease. In HLA-B27-associated uveitis, the HLA-B27 molecule presents specific peptides to T-cells and may trigger endoplasmic reticulum (ER) stress and the IL-23/IL-17 inflammatory pathway. In VKH disease, T-cells attack melanin-associated proteins in the choroid, skin, and inner ear simultaneously. In sympathetic ophthalmia, penetrating eye trauma exposes normally sequestered uveal proteins to the immune system, generating bilateral autoimmune attack. In Blau syndrome, a gain-of-function mutation in the NOD2 gene causes constitutive (always-on) activation of the NF-kB inflammatory pathway, overproducing pro-inflammatory cytokines and non-caseating granulomas. The most common identified autoimmune causes of uveitis include HLA-B27-associated spondyloarthropathy (the most common known cause in the developed world), JIA, sarcoidosis, Behcet disease, VKH disease, and birdshot chorioretinopathy. Approximately 34% of cases at tertiary uveitis centers remain idiopathic—presumed autoimmune but without an identified trigger.

Uveitis primarily affects working-age adults (20 to 60 years) and has a female predominance, with women accounting for 56.8% of noninfectious uveitis cases. Risk varies significantly by the underlying disease subtype.

• Edad: Uveitis can affect all age groups, including children (incidence 4.3 per 100,000), but peak incidence is in adults aged 20 to 50 years.
   
• Systemic autoimmune or inflammatory disease: HLA-B27-positive individuals with spondyloarthropathy have a 25–80% lifetime risk of uveitis, depending on the specific condition. Up to 25% of children with oligoarticular JIA develop uveitis. Thirty to 60% of patients with sarcoidosis develop eye disease. Ankylosing spondylitis carries a 25–40% lifetime risk of uveitis.
   
• Human leukocyte antigen (HLA) genetic markers: HLA-B27 drives anterior uveitis in seronegative spondyloarthropathy. HLA-A29 is present in over 95% of birdshot chorioretinopathy patients. HLA-DRB1*04 is associated with VKH disease.
   
• Race and ethnicity: HLA-B27-associated uveitis is most common in non-Hispanic white populations. VKH disease predominantly affects Asian, Hispanic, Native American, and Middle Eastern patients. Sarcoid uveitis is more common in Black/African American patients (43.68% of sarcoid uveitis cases in U.S. databases). Behcet disease is most common along the historic “Silk Road” geographic corridor.
   
• Pregnancy: provides partial protection during the second and third trimesters; flare rate approximately one per year during pregnancy versus 2.4 per year outside it, due to the Th2 immune shift of pregnancy. This protection reverses postpartum and is lost within six months. Preeclampsia reverses the protection—incidence rate ratio 2.96 after delivery with preeclampsia.

There is no population-wide screening program for uveitis in the general public. Targeted screening is directed at high-risk populations—most importantly, children with juvenile idiopathic arthritis. The most critical screening reality in uveitis is the asymptomatic nature of JIA-associated uveitis: the eye looks perfectly normal from the outside, yet slit-lamp examination reveals ongoing intraocular inflammation causing progressive structural damage. Because 45% of children with JIA already have serious ocular complications by the time of their first ophthalmology visit, the screening schedule cannot be treated as optional. The gold-standard screening test is slit-lamp biomicroscopy—an examination using a high-powered slit beam of light to directly view the anterior chamber and grade inflammatory cell count (0 to 4+ cells) and protein leakage (0 to 4+ flare).

The screening frequency for JIA-associated uveitis is determined by risk category. Children who meet all four highest-risk criteria—antinuclear antibody (ANA)-positive, JIA onset before age 7, JIA duration of four years or less, and oligoarticular or related JIA subtype—must be examined by slit lamp every three months. Moderate-risk children are examined every six months; lower-risk categories annually. Screening must begin at the time of JIA diagnosis, not when symptoms appear, because the inflammation causing damage has no visible warning signs. A stepwise surveillance approach for all patients includes educating patients and parents to recognize warning signs of flares (new floaters, redness, pain, light sensitivity, sudden visual change), periodic slit-lamp screening at an appropriate frequency, and supplemental imaging (optical coherence tomography—OCT, fluorescein angiography, visual field testing) when abnormalities are detected.

The hallmark symptoms of uveitis depend almost entirely on where in the eye the inflammation is occurring. Anterior uveitis typically presents with the classic triad of a painful, red, light-sensitive eye. Posterior and intermediate forms are often entirely painless, with floaters and visual blur as the primary complaints. JIA-associated uveitis and Fuchs uveitis syndrome present with a completely symptom-free, painless, white eye—detectable only through scheduled slit-lamp examination. This wide variability in presentation is why many patients with posterior or pediatric uveitis go undiagnosed for extended periods.

• Deep, aching ocular pain: often described as periorbital, worsened by light exposure
   
• Photophobia (intense light sensitivity): from ciliary spasm as the inflamed ciliary body reacts to light
   
• Ciliary flush: a ring of redness around the cornea (perilimbal injection) rather than the diffuse conjunctival redness of conjunctivitis
   
• Blurred vision: from inflammatory cells and protein floating in the anterior chamber
   
• Tearing
   
• Small or poorly dilating pupil (miosis): from sphincter spasm
   
• Hypopyon: a visible white layer of inflammatory cells settling at the bottom of the anterior chamber, visible as a white crescent at the base of the cornea; characteristic of severe anterior uveitis, particularly Behcet disease and severe HLA-B27-associated episodes
   
• JIA-U exception: completely asymptomatic, painless, white eye. No redness, no pain. Detected only by slit-lamp. Band keratopathy (a white horizontal calcium deposit across the cornea) may become visible as a sign of longstanding undetected inflammation.

• Floaters: the most prominent symptom; dark, moving spots or strings in the visual field caused by inflammatory cells floating in the vitreous gel
   
• Blurred or hazy vision: from vitreous cloudiness (vitritis)
   
• No or minimal pain and no significant redness: distinguishing intermediate from anterior uveitis

• Visual field defects (scotomas): fixed blind or dark spots in the visual field corresponding to areas of retinal involvement
   
• Floaters
   
• Blurred vision
   
• Photopsia (flashing lights): from photoreceptor irritation
   
• Color vision changes
   
• Entirely painless: the eye appearing externally normal, while significant retinal damage may be occurring

Panuveitis combines symptoms from all three locations—pain, redness, and light sensitivity from anterior involvement alongside floaters, visual field defects, and visual blur from posterior involvement. It carries the highest risk of blindness of any uveitis category.

• VKH disease: prodromal phase: flu-like illness, orbital pain, neck stiffness, sensorineural hearing loss, tinnitus, headache, and fever preceding the eye symptoms by days to weeks. Later convalescent phase: skin depigmentation (vitiligo), whitening of eyelashes, eyebrows, and scalp hair (poliosis), and the characteristic orange discoloration of the fundus called “sunset glow fundus.”
   
• Behcet disease: recurrent painful oral ulcers (canker sores), genital ulcers, erythema nodosum (tender red skin nodules), and joint pain. The oral ulcers are often the earliest and most consistent sign that the eye inflammation is related to Behcet.
   
• TINU syndrome: fatigue, fever, flu-like illness, and flank or back pain from kidney inflammation, with blood in the urine (hematuria). In 65% of cases, the kidney symptoms precede the eye symptoms.
   
• JIA-associated uveitis: active or prior joint swelling and pain are the context for detection. The eye disease itself causes no symptoms until complications develop.

Sustained or repeated uveitis inflammation—and in some cases the medications used to treat it—leads to a range of structural complications that are the primary causes of permanent vision loss. In JIA-U, which carries among the highest complication rates of any uveitis form:

• Posterior subcapsular cataract (clouding of the back surface of the lens): 23–83% of JIA-U patients; causes glare and progressive vision loss
• Glaucoma (optic nerve damage from elevated eye pressure): 17–28% of JIA-U patients; causes permanent visual field loss
• Posterior synechiae (adhesions between the iris and the lens): 18–44% of JIA-U patients; distorts the pupil, can trigger angle closure and acute intraocular pressure (IOP) spikes
• Band keratopathy (calcium deposits on the cornea): 14–46% of JIA-U patients; causes corneal glare and opacity
• Cystoid macular edema (fluid accumulation in the central retina): 2–30% of JIA-U patients; the most common cause of central vision loss in uveitis overall
• Epiretinal membrane: scar tissue on the retinal surface causing metamorphopsia (image distortion)
• Retinal vasculitis: vessel inflammation causing hemorrhage, ischemia, and retinal neovascularization in severe cases
• Legal blindness (vision of 20/200 or worse): 5–15% of patients with uveitis despite treatment

Uveitis is diagnosed by an ophthalmologist—ideally a uveitis specialist—often in collaboration with a rheumatologist when systemic disease is suspected. Diagnosis involves two parallel processes: characterizing the intraocular inflammation by examination and imaging, and identifying the underlying cause through systemic workup. The most critical initial distinction is infectious versus noninfectious uveitis, because the treatments are fundamentally different and giving immunosuppressants to a patient with unrecognized active infection can be catastrophic. Masquerade syndromes—particularly intraocular lymphoma—must also be excluded before committing to long-term immunosuppression.

• Slit-lamp biomicroscopy: The gold-standard diagnostic tool. The ophthalmologist uses a high-powered slit beam of light to directly examine the anterior chamber and grade the number of inflammatory cells (0 to 4+ cells per high-powered field) and the degree of protein leakage into the aqueous fluid (flare, 0 to 4+). The size and shape of keratic precipitates on the cornea provide diagnostic clues: fine, star-shaped precipitates suggest nongranulomatous uveitis (HLA-B27, JIA); large, greasy “mutton-fat” precipitates indicate granulomatous disease (sarcoidosis, VKH, sympathetic ophthalmia). The slit lamp also detects posterior synechiae, peripheral anterior synechiae, hypopyon, band keratopathy, and lens changes.
   
• Dilated fundus examination with indirect ophthalmoscopy: Examines the vitreous, retina, choroid, and optic disc under pupil dilation. Reveals snowballs and snowbank in pars planitis, subretinal fluid and disc swelling in VKH, birdshot lesions, retinal vasculitis, choroidal lesions, and optic nerve involvement.
   
• Goldmann applanation tonometry: the gold standard for measuring intraocular pressure (IOP); performed at the slit lamp. Elevated IOP raises concern for inflammatory glaucoma; abnormally low IOP suggests ciliary body shutdown from severe inflammation.

• Optical coherence tomography (OCT): the most sensitive tool for detecting subclinical macular edema before it becomes symptomatic. OCT provides high-resolution cross-sectional images of every retinal layer, detecting cystoid macular edema, epiretinal membrane, subretinal fluid, and retinal atrophy. Retinal nerve fiber layer thickness monitoring tracks glaucomatous progression.
   
• Fluorescein angiography (FA): Intravenous fluorescein dye is injected and serial retinal photographs are taken. Detects retinal vasculitis (vessel leakage, staining, occlusion), macular edema, optic disc inflammation, and retinal neovascularization.
   
• Indocyanine green angiography (ICGA): superior to fluorescein angiography for visualizing the choroidal blood vessels. ICG dye binds plasma proteins and is retained in the choroid, making it ideal for detecting hidden choroidal infiltrates in VKH disease and sarcoidosis. The “dark dots” seen on ICGA in birdshot chorioretinopathy are pathognomonic (disease-defining) for that condition.
   
• Fundus autofluorescence (FAF): images the metabolic activity of the retinal pigment epithelium using its natural fluorescence. Correlates with active disease in serpiginous choroiditis, birdshot, and VKH. Used for monitoring geographic disease activity and treatment response.
   
• B-scan ultrasonography: used when a dense cataract or vitreous hemorrhage prevents direct visualization of the retina. Detects vitreous opacities, retinal detachment, choroidal thickening, and intraocular tumors that could be masquerading as uveitis.
   
• Anterior segment OCT (AS-OCT): High-resolution imaging of the anterior chamber structures detects peripheral anterior synechiae (adhesions between iris and cornea), narrow angles, and aqueous cell burden.

Two tests are mandatory in every new uveitis evaluation regardless of clinical presentation, because both syphilis and tuberculosis can mimic any form of uveitis, are fully treatable, and would be seriously worsened by immunosuppression: syphilis serology (rapid plasma reagin—RPR or venereal disease research laboratory—VDRL plus confirmatory fluorescent treponemal antibody absorption—FTA-ABS) and tuberculosis screening (QuantiFERON®-TB Gold interferon gamma release assay or PPD skin test), plus a chest X-ray. TB screening is also mandatory before initiating any immunosuppressive or biologic therapy. Additional targeted tests are ordered based on the clinical picture:

• HLA-B27 typing: for any adult with recurrent acute anterior uveitis; identifies spondyloarthropathy risk
   
• ANA: for any child with anterior uveitis; identifies JIA-associated risk
   
• Serum angiotensin-converting enzyme (ACE) and lysozyme: for bilateral granulomatous uveitis; elevated in approximately 60% of sarcoidosis cases (note: normally elevated in children, limiting utility in pediatric patients)
   
• High-resolution CT of the chest: detects hilar lymphadenopathy and pulmonary nodules in sarcoidosis and TB
   
• Urine beta-2-microglobulin: markedly elevated in TINU syndrome from proximal tubular kidney damage; a specific diagnostic test for this adolescent presentation
   
• HLA-A29 typing: for any patient with bilateral posterior uveitis and cream-colored posterior lesions; present in over 95% of birdshot chorioretinopathy cases
   
• Toxoplasma immunoglobulin G (IgG) and immunoglobulin M (IgM) serology: for any posterior uveitis with the “headlight in fog” lesion adjacent to an old scar
   
• Lyme disease serology (enzyme-linked immunosorbent assay—ELISA followed by Western blot): for intermediate or panuveitis in patients from endemic regions of the northeastern and midwestern United States
   
• HIV testing: for posterior uveitis in any patient with CMV retinitis pattern or with other features of immunocompromise

Most noninfectious intermediate, posterior, and pan-uveitides are not curable—the underlying autoimmune condition remains lifelong. The treatment goal is complete suppression of inflammation to grade zero (no detectable cells in the anterior chamber; no vitreous haze) because any level of persistent inflammation doubles the risk of visual impairment and triples the risk of legal blindness in conditions like JIA-U. Not every uveitis requires medication—self-limited forms such as APMPPE, MEWDS, and mild pars planitis may be observed without treatment. When treatment is needed, a stepwise approach escalates from local eye drops through regional injections to systemic immunosuppression to biologic agents based on the anatomic location, severity, and response. Multidisciplinary collaboration—between ophthalmologist, rheumatologist, and other subspecialists—is essential for optimal outcomes. Your care team will tailor the treatment approach to your specific uveitis subtype, disease activity, and overall health.

For anterior uveitis, corticosteroid eye drops are the first-line treatment. Prednisolone acetate 1% ophthalmic suspension is the standard agent, applied very frequently at initial presentation (as often as every hour) and tapered as the inflammation resolves. Difluprednate 0.05% (Durezol®) is a more potent topical corticosteroid reserved for severe anterior uveitis and for macular edema; it carries a higher risk of elevated eye pressure and cataract formation. Cycloplegic drops—atropine 1%, scopolamine, or cyclopentolate—are a mandatory companion to corticosteroid drops in acute anterior uveitis. They prevent and break the iris adhesions (posterior synechiae) that form as a complication of inflammation, and they relieve the painful ciliary spasm that causes photophobia.

For intermediate, posterior, or panuveitis—and for anterior uveitis not adequately controlled by topical drops alone—corticosteroids are delivered directly to the posterior eye. Sub-Tenon (periocular) injection of triamcinolone acetonide into the space around the eye reaches the posterior segment without entering the eye itself; effects last six to eight weeks. Intravitreal (inside the eye) injection of triamcinolone acetonide is more effective than periocular injection for macular edema—confirmed by the POINT Trial. Three U.S. Food and Drug Administration (FDA)-approved sustained-release intravitreal implants provide longer-duration therapy. The dexamethasone intravitreal implant (Ozurdex®, 0.7 mg) is a biodegradable implant injected in the clinic via needle that releases dexamethasone over approximately six months; the Phase 3 HURON trial demonstrated 47% of treated eyes reached grade-zero vitreous haze at eight weeks versus 12% with sham. The fluocinolone acetonide intravitreal insert, FDA-approved in 2018, delivers sustained corticosteroid release for approximately three years through an injected (not surgical) insert. The fluocinolone acetonide intravitreal implant 0.59 mg (Retisert®) is a surgically placed sustained-release implant (see Surgery section below), FDA-approved for noninfectious posterior uveitis.

Oral prednisone is used for severe, bilateral, or posterior disease requiring rapid systemic control. The initial dose is typically 1 mg/kg/day (maximum 60 mg/day), tapered toward the lowest effective dose. Long-term oral corticosteroids at doses below 7.5 mg per day are acceptable for maintenance per the seven-year MUST Trial, but doses above this threshold carry cumulative toxicity: weight gain, hypertension, diabetes, osteoporosis, Cushing’s syndrome, mood disturbance, and increased infection risk. Intravenous methylprednisolone pulse therapy (1 g per day for three days) is reserved for rapid control of severe acute disease and is always followed by oral prednisone and a steroid-sparing agent. Per guidelines, the corticosteroid taper should begin no later than two weeks after starting a steroid-sparing immunosuppressive agent.

When corticosteroids cannot be tapered to safe long-term doses, conventional steroid-sparing immunosuppressive agents (also called disease-modifying antirheumatic drugs—DMARDs) are added. All are used off-label for uveitis. The three main antimetabolite options are methotrexate, mycophenolate mofetil, and azathioprine.

Methotrexate (15 mg per week by subcutaneous injection, preferred over oral; up to 25 mg per week) achieves inflammation control in approximately 66% of uveitis patients and corticosteroid-sparing in 58% in the SITE cohort study. Folic acid 1 mg daily is mandatory to reduce methotrexate’s toxicity. Complete blood count (CBC) and liver function tests are monitored every four to six weeks. Methotrexate is hepatotoxic, causes cytopenias, and is teratogenic.

Mycophenolate mofetil (1 g twice daily; up to 1.5 g twice daily) achieves control in approximately 73% and steroid-sparing in 55% in the SITE cohort. Gastrointestinal (GI) side effects (diarrhea) are common. Azathioprine (2 to 3 mg/kg/day) achieves control in approximately 62%. Thiopurine methyltransferase (TPMT) enzyme genotyping before initiation identifies patients at risk of severe bone marrow suppression. Two calcineurin inhibitors—cyclosporine and tacrolimus—work by suppressing T-cell IL-2 production and are effective second-line options, though tacrolimus is generally better tolerated than cyclosporine due to cyclosporine’s hypertension and nephrotoxicity profile. Cyclophosphamide and chlorambucil are powerful alkylating agents reserved for the most severe, refractory cases—they can induce remission in 64–91% of treated eyes within two years, but their cumulative toxicity (infertility, hemorrhagic cystitis, and elevated cancer risk) limits their use to no more than 18 to 24 months.

Adalimumab (Humira®) is the only FDA-approved biologic agent for noninfectious uveitis. It is a fully human anti-TNF-alpha monoclonal antibody given as a subcutaneous injection every two weeks. FDA approval was granted in June 2016 for adults and in 2018 for pediatric patients with noninfectious intermediate, posterior, and panuveitis. The evidence basis is strong: the VISUAL I trial (active uveitis) demonstrated approximately 50% reduction in relapse rate versus placebo with a rapid steroid taper; the VISUAL II trial (quiescent uveitis) showed a similar 50% reduction in relapse risk. The SYCAMORE trial in JIA-associated uveitis was stopped early because adalimumab was so clearly superior to placebo—27% treatment failure versus 60% with placebo. The ADJUVITE pediatric trial showed patients on adalimumab were twice as likely to improve versus placebo at two months.

Infliximab (Remicade®), given by intravenous infusion, is the most commonly used off-label biologic for uveitis and is the first-line recommendation from the American Uveitis Society for Behcet disease-associated uveitis (77–90% success rate). It requires doses of at least 5 mg/kg for uveitis effect and is given every four to eight weeks. In head-to-head comparisons in JIA-U, adalimumab appears slightly superior (60% remission versus 20% for infliximab at two years). Etanercept (Enbrel®)—a soluble TNF receptor rather than a monoclonal antibody—is specifically not recommended for uveitis. It failed to show benefit in a randomized controlled trial for JIA-U and carries an OR of 5.375 for paradoxically inducing or worsening uveitis compared to anti-TNF monoclonal antibodies. The mechanism is different: etanercept does not neutralize membrane-bound TNF-alpha the way antibody-based drugs do.

When TNF inhibitors fail (approximately 30% of patients require further escalation), several other off-label biologics are available. Tocilizumab (Actemra®), an interleukin (IL)-6 receptor inhibitor, showed a 33% response rate at 12 weeks in the Phase 2 APTITUDE trial for JIA-U, though it did not meet its primary endpoint; it remains an option for selected refractory patients, particularly those with baseline cystoid macular edema. Abatacept (Orencia®) blocks T-cell co-stimulation and achieves success in 14–57% of TNF-inhibitor-refractory JIA-U patients. Rituximab (Rituxan®) depletes B-cells and has produced durable remission in long-term follow-up studies of refractory JIA-U at mean follow-up exceeding 44 months. Tofacitinib—a Janus kinase (JAK) inhibitor—has shown promise in case reports of refractory JIA-U. Baricitinib is currently in a Phase 3 clinical trial for childhood uveitis. Secukinumab (anti-IL-17A) failed three separate randomized clinical trials in Behcet disease and other uveitides and is not used.

Patients who are started on biologic therapy require mandatory tuberculosis screening before initiation. Live vaccines are contraindicated during biologic therapy. The goal is a minimum of two years of complete remission (no cells, no corticosteroids) before any attempt to wean immunosuppressive therapy. Relapse rates after stopping treatment are high and vary by disease: 43–57% for Behcet disease, 39–72% for VKH, and 43–82% for JIA-U.