Curr Allergy Asthma Rep (2014) 14:409 DOI 10.1007/s11882-013-0409-1

AUTOIMMUNITY (TK TARRANT, SECTION EDITOR)

Noninfectious Immune-Mediated Uveitis and Ocular Inflammation Jennifer Pan & Manuj Kapur & Rex McCallum

Published online: 15 December 2013 # Springer Science+Business Media New York 2013

Abstract Noninfectious uveitis encompasses a diverse group of ocular inflammatory disorders that share an underlying immune etiology and may be associated with systemic disease or confined primarily to the eye. Uveitis is commonly classified by anatomical location of inflammation into anterior, intermediate, posterior, and panuveitis. The treatment of noninfectious uveitis consists of corticosteroids, immunosuppressive agents, and surgically placed steroid implants. We review the epidemiology, immunopathology, and clinical features of several noninfectious immune-mediated uveitides, including HLA-B27 acute anterior uveitis, juvenile idiopathic arthritis, intermediate uveitis, sarcoidosis, Behcet’s disease, VogtKoyanagi-Harada syndrome, sympathetic ophthalmia, and white dot syndromes. We also discuss the stepwise approach to medical treatment of immune-mediated uveitis as well as the characteristics, safety, and efficacy of immunosuppressive agents used to treat ocular inflammatory disease.

Keywords Uveitis . Ocular inflammation . Systemic disease . Iritis . HLA-B27 . Pars planitis . Posterior uveitis . Panuveitis . Corticosteroid . Immunomodulatory therapy . Steroid implant This article is part of the Topical Collection on Autoimmunity J. Pan Texas Tech University Health Sciences Center – Paul L. Foster School of Medicine, El Paso, TX 79905, USA e-mail: [email protected] M. Kapur University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX 77555-1106, USA e-mail: [email protected] R. McCallum (*) University of Texas Medical Branch at Galveston, 301 University Blvd., Galveston, TX 77555-0133, USA e-mail: [email protected]

Introduction Uveitis, an intraocular inflammatory disease, is the fifth leading cause of visual impairment and blindness in the United States [1]. Uveitis encompasses a diverse group of ocular disorders and is estimated to cause 10–15 % of all cases of blindness in the United States [2]. Uveitis may be classified as anterior, intermediate, posterior, or panuveitis based on the anatomical involvement of the eye. Anterior uveitis is inflammation of the anterior chamber and is the most common form of uveitis, with varying patterns of reported incidence in worldwide literature [3]. Intermediate uveitis is defined as inflammatory cells in the vitreous humor (pars planitis, posterior cyclitis, and hyalitis). Posterior uveitis involves inflammation of the retina/choroid (choroiditis, chorioretinitis, retinitis). Panuveitis is inflammation of all three parts of the uvea, i.e. the anterior chamber, vitreous humor, and choroid or retina [4]. While individual forms of uveitis may be distinguished based on anatomical involvement of the uveal tract, uveitis may also be classified by etiology of inflammation. The major causes of uveitis are infections, systemic immune-mediated disease, and autoimmune syndromes confined primarily to the eye (Table 1). Other etiologies include post-traumatic, postsurgical, and lens-induced and drug-induced uveitis. The progressive decrease in visual acuity associated with uveitis is attributed to complications such as cystoid macular edema, cataract formation, secondary glaucoma, vitreous opacities, and retinal scars. Cystoid macular edema is the most frequent complication and is an important cause of irreversible visual impairment and blindness in patients with uveitis [2]. Among the types of uveitis classified by anatomical site, panuveitis has the worst visual prognosis due to more widespread inflammation. While anterior uveitis has a better visual prognosis than panuveitis and posterior uveitis, it is the most common form of uveitis and can lead to blindness if not treated appropriately [3]. Of the systemic diseases, juvenile

409, Page 2 of 8 Table 1 Major subsets of uveitis based on etiology of inflammation

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Infectious

Systemic immune-mediated disease

Syndromes confined primarily to the eye

Endophthalmitis

HLA-B27 acute anterior uveitis

Anterior uveitis

-bacterial

-Ankylosing spondylitis

-HLA-B27 AAU

-fungal

-Reactive arthritis

-Idiopathic HLA-B27 negative anterior uveitis

Herpetic uveitis

-Inflammatory bowel disease

-Fuchs’ heterochromic iridocyclitis

-HSV

-Psoriatic arthropathy

-Posner–Schlossman syndrome

-VZV

-Undifferentiated spondyloarthropathy

-Lens-associated uveitis

-EBV

Juvenile idiopathic arthritis

Intermediate and Posterior Uveitis

-CMV

Sarcoidosis

-Sympathetic ophthalmia

HIV

Behcet’s disease

-Intermediate uveitis

HTLV-1

Vogt-Koyanagi-Harada syndrome

-White dot syndromes

Whipple’s disease

Polyarteritis Nodosa

Onchocerciasis

Necrotizing vasculitis

idiopathic arthritis and sarcoidosis have the worst visual prognosis and are the most frequent causes of bilateral visual loss [2]. Uveitis associated with HLA-B27 tends to affect the anterior chamber and has a relatively better visual prognosis than uveitis associated with other systemic diseases. HLAB27 anterior uveitis is the most common identifiable cause of anterior uveitis and generally considered to have a good visual prognosis [3].

Anterior Uveitis Associated with Systemic Disease Understanding the epidemiology of uveitis helps predict the likelihood of a systemic association and order appropriate diagnostic testing and treatment. Anterior uveitis, the most common form of uveitis, is strongly associated with HLAB27 and its spectrum of seronegative spondyloarthropathies. HLA-B27 Acute Anterior Uveitis HLA-B27 acute anterior uveitis (AAU) is the most common identifiable cause of anterior uveitis and is defined as inflammation of the anterior chamber that occurs in association with the HLA-B27 antigen [3]. HLA-B27 AAU is a distinct inflammatory disorder and includes HLA-B27 AAU with only ocular features as well as HLA-B27 AAU-associated systemic disease. HLA B27 AAU is the most common cause of hypopyon uveitis and more commonly affects males between the ages of 20–40 [5]. Ocular features include an acute onset of unilateral, non-granulomatous AAU characterized by significant cellular and protein extravasation into the aqueous humor, including fibrin and hypopyon in the anterior chamber. Recurrences are common and can occur in the contralateral eye. Between 49 and 84 % of patients with HLA-B27-positive AAU have an associated systemic disease [3]. The seronegative spondyloarthropathies are the most common systemic

diseases associated with HLA-B27 positive AAU. These include ankylosing spondylitis, reactive arthritis, psoriatic arthritis, spondylitis associated with inflammatory bowel disease, isolated acute anterior uveitis, and undifferentiated spondyloarthropathy. Between 20 and 40 % of patients with either ankylosing spondylitis or reactive arthritis develop acute anterior uveitis, while 7–16 % of patients with psoriatic arthritis and 2–9 % of patients with inflammatory bowel disease may develop acute anterior uveitis. Uveitis associated with psoriatic arthritis or inflammatory bowel disease is more common in females, bilateral, posterior to the lens, and chronic in duration [6, 7]. HLA-B27 AAU may occur as a distinct autoimmune syndrome confined to the eye or in association with a systemic illness. Therefore, it is important to recognize that AAU may be a manifestation of an underlying systemic illness. A detailed history and a positive review of systems in AAU patients should guide appropriate laboratory testing, including HLA-B27. HLA-B27 AAU is associated with a variety of ocular complications. Common anterior segment complications include posterior synechiae, cataract formation, ocular hypertension, glaucoma, and chronic anterior uveitis. Posterior segment complications may result in visual impairment and require aggressive medical and surgical management, including systemic immunosuppressive therapy and pars plana vitrectomy for control of inflammation and preservation of vision [8]. Therefore, all spondyloarthritic patients with symptomatic ocular involvement, including redness, pain, or photophobia, should be referred to an ophthalmologist. However, screening eye exams are routinely low shield in spondyloarthritic patients without ocular involvement.

Juvenile Idiopathic Arthritis (JIA) JIA is the most common chronic rheumatologic disease in children [9]. Chronic asymptomatic bilateral anterior uveitis is

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the most frequent extra-articular symptom of JIA. Positive ANA is the most common serological abnormality in JIA, and ANA-positive, RF-negative oligoarthritic patients with JIA have an increased risk of uveitis [10]. Typically, such chronic anterior uveitis is insidious in onset and persists longer than 3 months. Majority of patients develop uveitis 4–7 years after the onset of JIA. Chronic inflammation of the anterior chamber in patients with JIA-associated uveitis may result in complications such as band keratopathy, posterior synechiae, cataract formation, secondary glaucoma, cystoid macular edema, and cyclitic membrane with hypotony [11]. Of these, glaucoma is an under-diagnosed cause of irreversible visual loss in such patients. Posterior synechiae, active anterior chamber inflammation, and intraocular surgery are associated with increased incident of vision loss [12]. JIA-associated uveitis can last for decades, long after the joint disease has disappeared, and sight-threatening complications such as cataract formation and glaucoma are often refractory to medical treatment and require surgical management. Due to the asymptomatic presentation of JIA-associated uveitis, JIA children with early onset oligoarthritis, rheumatoid factor negative polyarthritis, or ANA positivity need close and regular follow-up. These patients should have a baseline ophthalmologic exam within 1 month of the diagnosis of the arthritis with follow-up exam as outlined in Table 2 [13]. Early detection and prompt treatment of patients with mild JIA-associated uveitis is associated with a good visual prognosis [14]. Intermediate Uveitis Intermediate uveitis is characterized by inflammation in the peripheral retina, vitreous base, and pars plana region of the ciliary body. Pars planitis, sometimes called peripheral uveitis, is the most common subset of intermediate uveitis and is characterized by inflammatory debris over the pars plana. Intermediate uveitis presents as blurred vision, floaters, and Table 2 Frequency of ophthalmologic exams in JIA patients with oligo/ polyarthritis ANA Age of onset (years) + + + + + – – –

≤6 ≤6 ≤6 >6 >6 ≤6 ≤6 >6

Duration of disease (years)

Exam frequency (months)

≤4 >4 >7 ≤4 >4 ≤4 >4 N/A

Every 3 Every 6 Every 12 Every 6 Every 12 Every 6 Every 12 Every 12

JIA Juvenile idiopathic arthritis, N/A not applicable

findings consistent with vitreous inflammation, retinal vasculitis, and macular edema. Some cases are marked by a unique opacified ridge in the peripheral retina, known as a “snowbank,” and aggregates of inflammatory cells in the inferior vitreous, known as “snowballs” [15]. Complications of intermediate uveitis include posterior subcapsular cataract, secondary glaucoma, hemorrhage, and tractional retinal detachment. Visual loss is most commonly caused by chronic macular edema or secondary glaucoma. Intermediate uveitis is frequently associated with various HLA associations, the most common being HLA-DR, which is observed in 67–72 % of patients [16]. The most significant association is with the DR15 alelle, which is also associated with multiple sclerosis. Although intermediate uveitis is not usually associated with systemic disease, 17 % of patients with intermediate uveitis develop multiple sclerosis and approximately 27 % of patients with multiple sclerosis develop intermediate uveitis [17]. Because of its association with multiple sclerosis, patients who initially present with intermediate uveitis should be evaluated for MS with a thorough neurologic history and exam in addition to a brain MRI in patients at great risk for MS [18]. Posterior Uveitis Sarcoid Uveitis Sarcoidosis is a chronic granulomatous disease of unknown etiology that can involve many organs, including the lungs, eyes, skin, lymph nodes, liver, spleen, and central nervous system. Approximately 20 % of patients with sarcoid initially develop eye disease, which can take on many forms, including uveitis, dry eyes, optic neuritis, lid inflammation, or orbital disease [19]. A negative Mantoux test supports the clinical diagnosis of sarcoidosis, although the gold standard in diagnosis is histopathological evidence of noncaseating granulomas. More than 25 % of patients with systemic sarcoidosis develop ocular disease [19]. The anterior chamber is most commonly affected, and up to 66 % of patients with sarcoid ocular disease present with iritis or iridocyclitis with mutton fat keratic precipitates on the corneal endothelium (Fig. 1). Anterior segment exam may reveal conjunctival granulomas, iris nodules, and posterior synechiae. The posterior chamber is involved in 25 % of patients and is frequently associated with retinal vasculitis, which may be either perivascular or involve retinal vascular changes [20]. Yellowish-gray nodular lesions may appear in the choroid or outer retina, and vitreous cells or “snowball” opacities may be present. Patchy retinal periphlebitis seen as perivascular sheathing on clinical exam may also be evident. Panuveitis occurs in 6–33 % of patients with sarcoidosis and is considered a poor prognostic factor in patients with sarcoidosis [21]. Incisional biopsy of

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Vogt-Koyanagi-Harada Syndrome

Fig. 1 Patient with granulomatous uveitis with mutton fat keratic precipitates. (Courtesy of Dr. Glenn Jaffe, Duke Eye Center, Duke University Medical Center, Durham, NC, USA)

conjunctival granulomas is useful in confirming the diagnosis of sarcoidosis, particularly in patients that initially present with sarcoid uveitis.

Behcet’s Disease Behcet’s disease is an occlusive vasculitis of unknown etiology marked by chronic, relapsing multisystemic inflammation. Behcet’s disease remains a clinical diagnosis characterized by recurrent eye inflammation, oral ulcers, and genital ulcers. The etiology of Behcet’s disease is unknown, but inflammation may be triggered by a heat-shock protein, phosphoantigen, or superantigen in susceptible HLA-B51 or positive individuals [22]. Ocular disease occurs in a high proportion of patients, and up to 80 % of patients with Behcet’s disease develop uveitis [23]. Ocular manifestations tend to occur 2–3 years after initial systemic symptoms and can be associated with blindness in 50–90 % of patients [24]. Uveitis is often the dominant manifestation of this disease and typically presents as bilateral nongranulomatous iridocyclitis. However, the majority of patients with Behcet’s uveitis present with recurrent panuveitis. Additionally, necrotizing obliterative retinal vasculitis with retinal neovascularization is also a frequent manifestation of Behçet's disease [25]. It affects the posterior segment more often and more severely than the anterior chamber. Behcet’s uveitis typically leads to blindness if the eye inflammation is not treated [24]. Although it is found worldwide, Behcet’s disease is particularly common in Japan and is responsible for 11–20 % of blindness acquired before middle age in Japan [26]. Although aggressive treatment of Behcet’s disease with systemic corticosteroids has improved visual outcomes in some patients, the visual prognosis of Behcet’s uveitis generally remains guarded. However, the introduction of biologic agents such as infliximab has been shown to improve the uveitis as well as the mean visual acuity in the majority of patients [27].

Vogt-Koyanagi-Harada syndrome (VKH) is a presumably autoimmune disease characterized by chronic bilateral granulomatous panuveitis associated with various cutaneous, auditory, and central nervous system symptoms. VKH is the second leading cause of uveitis in Japan, after Behcet’s syndrome, and tends to affect darkly pigmented races, particularly Hispanics and Asians [28]. VKH has a strong HLA class II association, specifically with the HLA-D locus and DR4 allele [29]. Current data suggest that VKH is a T helper cellmediated autoimmune attack against melanocytic antigens common to the uvea, skin, inner ear, and central nervous system. Like Behcet’s disease, VKH remains a clinical diagnosis marked by 3 of the following 4 symptoms in the absence of trauma: (1) bilateral chronic iridocyclitis; (2) chorioretinal lesions, optic neuritis, posterior uveitis with thickening of the choroid, and exudative serous retinal detachments; (3) neurological signs of tinnitus, neck stiffness, and/or CSF pleocytosis; or (4) cutaneous findings of alopecia, poliosis, or vitiligo [30]. At the onset of disease, patients with VKH present with auditory and neurological symptoms such as severe headache, neck stiffness, and tinnitus. The neurological symptoms are followed by an acute bilateral uveitic phase marked by the onset of decreased vision and findings of diffuse choroiditis and exudative serous detachments. Late ocular findings of VKH include chorioretinal depigmentation scars, subretinal fibrosis, and recurrent or chronic bilateral panuveitis. Overall, 60 % of patients with VKH achieve vision of 20/30 or better [31].

Specific Syndromes Confined to the eye Although many forms of uveitis are associated with systemic inflammatory or infectious disease, a variety of uveitis syndromes occur without extraocular manifestations. Among the syndromes previously discussed, HLA-B27 acute anterior uveitis with only ocular involvement and idiopathic H-B27negative anterior uveitis are marked by inflammation restricted to the eye. The following syndromes are also uniquely confined to the eye. Sympathetic Ophthalmia Sympathetic ophthalmia (SO) is an autoimmune condition in which penetrating trauma to one eye (exciting eye) causes sight-threatening inflammation in the contralateral eye (sympathizing eye). SO is a rare disease with a reported incidence of 0.19 and 0.07 % following accidental and surgical trauma, respectively [32]. SO typically presents as bilateral panuveitis characterized by granulomatous mutton-fat keratic

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precipitates, aqueous cell and flare, vitreous cells, prominent choroidal thickening, and papillitis [33]. Retinal detachment, subretinal neovascularization, and vasculitis are uncommon, but may occur in conjunction with anterior chamber inflammation. In 65 % of cases, the onset of inflammation is between 2 and 8 weeks following trauma, and 90 % of cases occur within 1 year of trauma to the exciting eye [34]. There are no definitive tests to confirm the diagnosis of SO, but a history of ocular trauma or intraocular surgery combined with clinical signs of bilateral granulomatous panuveitis supports its diagnosis. Routine tests are performed to rule out other causes of granulomatous panuveitis, such as VKH syndrome and sarcoidosis, that mimic SO. The visual prognosis in SO varies and depends on the extent of intraocular inflammation. White dot Syndromes The white dot syndromes encompass a group of posterior uveitides of unknown etiology manifested by multiple white dots in the deep layers of the retina, retinal pigment epithelium, or choroid. Patients with white dot syndrome present with distorted vision, known as metamorphopsia, due to retinal injury, as well as sudden blurring of vision associated with photopsia, floaters, and scotomata. This group of disorders includes punctuate inner chorioretinopathy (PIC), presumed ocular histoplasmosis syndrome (POHS), acute multifocal posterior placoid epitheliopathy (AMPPE), multiple evanescent white dot syndrome (MEWDS), multifocal choroiditis (MFC) with panuveitis, and birdshot choroidopathy. Punctate inner chorioretinopathy (PIC) typically occurs in myopic young women and presents with an acute bilateral loss of vision, light flashes, and scotomata associated with small yellow-white lesions of the inner choroid and retinal pigment epithelium [35]. The hallmark of PIC is the absence of inflammatory cells in the vitreous and anterior chamber. PIC and presumed ocular histoplasmosis (POHS) syndrome present with the same clinical signs, but POHS is associated with H. capsulatum infection and is usually seen in areas where Histoplasma is endemic, such as Ohio-Mississippi valleys [36]. The clinical triad associated with POHS is peripapillary atrophy, punched-out lesions in the retina, and choroidal neovascular membrane involved the macula, without a vitritis. Acute multifocal posterior placoid epitheliopathy (AMPPE) presents as acute bilateral loss of vision in young patients following a viral prodrome and is associated with the sudden appearance of multiple large yellow-white, flat inflammatory lesions in the retinal pigment epithelium [37]. AMPPE may have a self-limited clinical course with spontaneous recovery of vision in most cases, especially if the primary lesions spare the fovea. AMPPE may be associated with cerebral vasculitis, erythema nodosum, and sensorineural deafness, suggesting an underlying microvasculopathy in the pathogenesis of this condition [38]. The cerebral vasculitis can

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result in a high mortality rate. Therefore, any patient with AMPPE with suspected neurologic involvement warrants prompt investigation for central nervous system involvement [39]. Multiple evanescent white dot syndrome (MEWDS) is a rare disorder that presents with sudden vision loss, scotoma, and photopsia in young women following a viral prodrome. MEWDS is characterized by the presence of small white lesions deep in the outer retina or at the level of the RPE and foveal granularity. MEWDS is distinguished from other white dot syndromes by the granular appearance of the macula and the absence of vitreous inflammation. The disorder is selflimited and has an excellent visual outcome with spontaneous recovery of vision within 6–7 weeks. Multifocal choroiditis with panuveitis is characterized by multiple choroidal lesions in addition to anterior uveitis and vitritis [40]. It tends to affect myopic young women, who present with decreased central vision associated with metamorphopsia, floaters, scotomas, and photopsia. Birdshot choroidopathy is an uncommon chronic, bilateral, posterior uveitis associated with multiple ovoid, creamcolored subretinal lesions that resemble tiny birdshot pellets. Birdshot choroidopathy more commonly affects females around the age of 50 who present with night blindness, reduction in peripheral vision, floaters, and photopsia. Although visual acuity tends to be fairly good at initial presentation, central vision loss may develop in the presence of cystoid macular edema. Of patients with this disorder, 95 % possess the HLA-A29 antigen [41].

Treatment The approach to treating noninfectious immune-mediated uveitis varies depending upon the anatomical location of the inflammation and is generally not affected by the etiology of the uveitis. In most cases, the treatment of noninfectious uveitis follows a stepwise approach, beginning with corticosteroid therapy to quickly control inflammation. Corticosteroids may be given topically, through local injection, intraocular injection, or systemically. Although excellent at suppressing initial inflammation, corticosteroids are not curative, and chronic use is associated with adverse ocular and systemic side effects. Well-known ocular side effects include the development of cataracts, glaucoma, central serous retinopathy, and activation of herpes simplex virus [1]. Patients who are unable to taper off corticosteroid therapy without having recurrence of their uveitis should be strongly considered for alternative therapy to avoid the devastating effects of chronic corticosteroid use [42]. More aggressive immunomodulatory therapy with immunosuppressive agents (ISA) is required if the patient continues to have chronic or recurrent active inflammation. ISA represent the final step in the stepwise approach to

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medical treatment of ocular inflammatory disease. The goal of treatment is sustained corticosteroid-free control of inflammation even after ISA therapy is discontinued [42]. Noninfectious causes of anterior uveitis are generally treated with topical corticosteroids such as prednisolone acetate (1 %). The frequency for the drops depends upon the intensity of the inflammation. A dilating drop such as scopolamine (0.25 %) or cyclopentolate (1 %) can relieve pain due to spasm of the muscles controlling the pupil and will also help to prevent the formation of posterior synechiae that may interfere with the function of the pupil [43]. Uveitis that is primarily posterior to the lens is generally not responsive to topical medication. Options for initial treatment of intermediate, posterior uveitis, and panuveitis include treatment with periocular injection of a corticosteroid such as triamcinolone (subconjunctival, subtenon, or peribulbar) and/or oral corticosteroids. Intraocular injection of corticosteroids carries greater risk of ocular complications, but provides more rapid and consistent benefit [1]. Corticosteroid intravitreal implants should be considered in patients who require regular periocular injections and immunomodulatory therapy to control their ocular inflammation. In 2005, the U.S. Food and Drug Administration approved two implants for patients with refractory posterior uveitis: Retisert (fluocinolone acetonide) and Ozurdex (dexamethasone). The surgically implanted capsules deliver glucocorticoid into the vitreous humor continuously for about 2.5 years [1]. Complications include cataract, glaucoma, and rarely endophthalmitis. The implants do not cause systemic toxicity and can be effective in certain patients, particularly those with unilateral uveitis and no systemic illness requiring immunosuppression. Oral corticosteroids are reserved for patients with bilateral disease unresponsive to topical medications. A common initial dose is 40–60 mg of prednisone per day, with gradual tapering after response to the lowest dose that control inflammation. If control of inflammation cannot be obtained on doses of less than or equal to 10 mg of prednisone within 6– 12 weeks, additional therapeutic approaches should be undertaken [44]. ISA is generally reserved for bilateral disease requiring oral corticosteroid therapy of greater than 10 mg per day of prednisone [43]. Agents that may be effective include antimetabolites, such as methotrexate, azathioprine, or mycophenylate mofetil; alkylating agents such as cyclophosphamide or chlorambucil; and calcineurin inhibitors, such as cyclosporine or tacrolimus. The choice of ISA escalates in a stepwise approach and should be based on response and treatment patterns of specific uveitic entities. Less aggressive forms of uveitis are typically treated with an oral medication such as methotrexate, azathioprine, or mycophenolate mofetil. More aggressive cases may require cyclophosphamide or one of the calineurin inhibitors. Resistant cases of uveitis may require the addition of an additional medication, such as the tumor

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necrosis factor (TNF) inhibitors, etanercept, infliximab, or adalimumab [44]. In recent literature, anti-CD 20, such as Rituximab, has shown to be effective in the management of refractory uveitis, particularly JIA-associated uveitis [45]. Antimetabolites. Methotrexate has been found to effectively treat a variety of corticosteroid-resistant uveitis syndromes, most notably in anterior uveitis, posterior uveitis, or panuveitis, and mucous membrane pemphigoid [46]. Treatment with methotrexate typically begins with a weekly dose of 10–15 mg, administered orally or intramuscularly, and is titrated to clinical response, up to a maximum of 30 mg per week [42]. Azathioprine, another option, is typically prescribed at an initial dose of 1–2 mg/kg/day orally and is adjusted based on clinical response [46]. Azathioprine has been shown to be particularly effective in the management of corticosteroid-resistant JIA-associated iridocyclitis and intermediate uveitis [47]. Mycophenolate mofetil has been shown to control inflammation in patients with scleritis or JIA-associated uveitis refractory to methotrexate [48]. Treatment with mycophenolate mofetil begins with an initial dose of 500 mg twice a day for 2 weeks, and is increased to the therapeutic dose of 1 g twice a day if tolerated [46]. Immunosuppressive treatment with antimetabolites should be continued until the patient achieves corticosteroid-free remission for a minimum of 1 year. At that time, the dose of chemotherapeutic medication may be slowly tapered with the goal of achieving durable remission following cessation of therapy. Alkylating Agents. Cyclophosphamide is considered first line treatment in patients with uveitis and ocular inflammation secondary to Wegener granulomatosis, polyarteritis nodosa, peripheral ulcerative keratitis, and necrotizing scleritis in rheumatoid arthritis, and relapsing polychondritis [49, 50]. It has also been shown to control inflammation in patients with intermediate uveitis or chronic uveitis associated with systemic lupus erythematosus and Crohn’s disease [51]. Cyclophosphamide is typically administered orally staring at a dose of 1– 2 mg/kg or intravenously at an initial dose of 0.75–1 g/m2 body surface area and is titrated to clinical response at 3- to 4week intervals [46]. Subsequent doses are based on the leukocyte count, with a target of between 3,500 and 4,500 cells/ μL. Once the maintenance dose is established, daily oral therapy or infusions are repeated at 4-week intervals and continued for 1 year after corticosteroid-free remission. Chlorambucil has been successfully used in the stepwise approach to treatment-resistant uveitis, but is rarely used because of side-effect concerns. Chlorambucil is typically begun at an oral dose of 0.1 mg/kg/day and titrated to clinical response every 3 weeks up to a maximum daily dose of 6– 12 mg/day. Like cyclophosphamide, treatment is continued for 1 year after quiescence with the goal of inducing durable remission [46].

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Calcineurin Inhibitors. Cyclosporine and tacrolimus inhibit T cell activation by inhibiting calcineurin. Cyclosporine has been shown to control inflammation in patients with various causes of intractable uveitis [52]. Treatment begins with an oral dose of 2.5 mg/kg/day once daily and is titrated to clinical response in increments of 50 mg, up to a maximum dose of 5 mg/kg/day. Treatment is continued for 1 year after corticosteroid-free remission. Although fewer data are available to describe its efficacy and optimal duration of therapy, studies have found tacrolimus to be as effective as cyclosporine in treating corticosteroid-resistant uveitis with fewer incidences of side effects such as hypertension and nephrotoxicity [53]. Tumor Necrosis Factor Inhibitors. The role of tumor necrosis factor-alpha (TNF) inhibitors such as infliximab, adalimumab, or etanercept in the management of patients with treatmentresistant uveitis is uncertain. All have been shown to reduce the risk of developing eye inflammation in patients with AAU associated with ankylosing spondylitis [54]. Data supporting the efficacy of infliximab in treatment-resistant uveitis have increased in recent years. Infliximab has been successfully used to treat intractable uveitis associated with Behcet disease, JIA, ankylosing spondylitis, Wegener granulomatosis, sarcoidosis, and Crohn disease [55–57]. Anti-CD 20 Monoclonal Antibody. Rituximab (RTX) is a monoclonal antibody directed against the CD20 antigen expressed on B cells, and widely used in the treatment of non-Hodgkin’s lymphoma and rheumatoid arthritis. There is a growing amount of literature suggesting that it may also be effective in the treatment of most aggressive, recalcitrant, and sight-threatening uveitis including JIA and other uveitis that may not respond to conventional immunosuppressants or TNF inhibitors [45]. Infusion dose seems to vary in the literature, but one particular case series advocated two RTX infusions at a dose of 1,000 mg per infusion, given at 2-week intervals [58]. Systemic methylprednisolone is given to all patients, 30 min prior to each RTX infusion. Relapses in JIA-associated uveitis may occur within 6–9 months, and may be controlled with re-treatment [45].

Conclusions The role of immunosuppressive agents has become increasingly important in the treatment of immune-mediated uveitis, as they have been shown to improve patient outcome and limit exposure to corticosteroids. Interdisciplinary collaboration between ophthalmologists and rheumatologists is recommended for the diagnosis, treatment, and follow-up of patients with immune-mediated uveitis. Visual outcome continues to

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improve as immunomodulating therapies become more sensitive in targeting the mechanisms of ocular autoimmunity associated with uveitic syndromes. Immunosuppressive agents have the potential to target specific mediators of ocular inflammation so that patients may experience long-lasting, corticosteroid-free, durable remission of inflammation. Compliance with Ethics Guidelines Conflict of Interest Rex McCallum has received royalties from UpToDate. Jennifer Pan and Manuj Kapur declare that they have no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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