Anterior uveitis is the most common form of uveitis, accounting for more than 90% of cases in a community-based practice. Incidence in the United States varies by age, from approximately 7 cases per 100,000 person-years in persons aged 14 years and younger up to approximately 220 per 100,000 persons aged 65 years and older.
Because uveitis may occur secondary to inflammation of the cornea and/or sclera, it is important for the physician to evaluate these structures carefully to rule out primary keratitis or scleritis. Inflammation of the sclera and the cornea is covered in depth in BCSC Section 8, External Disease and Cornea; see also Chapter 7.
Acute Nongranulomatous Anterior Uveitis
The classic presentation of acute anterior uveitis is the sudden onset of pain, redness, and photophobia that can be associated with decreased vision. Fine keratic precipitates (KPs) dust the corneal endothelium in most cases. Active disease is characterized by anterior chamber cells and variable flare. Severe cases may show a protein coagulum in the aqueous or, less commonly, a hypopyon (Fig 8-1). Occasionally, a fibrin net forms across the pupillary margin (Fig 8-2), potentially producing a seclusion membrane and iris bombé. Iris vessels may be dilated, and, on rare occasions, a spontaneous hyphema occurs. Cells may also be present in the anterior vitreous. Fundus lesions are not characteristic, although uveitic macular edema and disc edema may be noted. Occasionally, intraocular pressure (IOP) may be elevated because of trabeculitis, blockage of the trabecular meshwork by debris and cells, or pupillary block.
The inflammation usually lasts several days to weeks, up to 3 months. Two patterns may occur. In the first type, the attack is acute and unilateral, with a history of episodes alternating between the 2 eyes; this pattern is typical for HLA-B27–associated anterior uveitis. Either eye may be affected, but recurrence is rarely bilateral. The second pattern is acute and bilateral.
Corticosteroids are the mainstay of treatment to eliminate inflammation, prevent cicatrization, and minimize damage to the uveal structures. Topical corticosteroids are the first line of treatment, and administration every 1–2 hours is often needed. If necessary, periocular or oral corticosteroids may be used for severe episodes. Initial attacks may require all 3 routes of administration, particularly in severe cases.
Ocular morbidity can be reduced by timely diagnosis, aggressive initial therapy, and patient adherence. In cases with a recurrent course, maintenance therapy with low-dose topical corticosteroids may be needed.
Corticosteroid-sparing drugs, such as antimetabolites, and others may be needed for long-term therapy in chronic or frequently recurrent anterior uveitis. Tumor necrosis factor (TNF) inhibitor therapy has been effective in recalcitrant anterior uveitis, particularly in HLA-B27–positive patients. Cycloplegic agents can relieve pain and can break and prevent formation of synechiae. They can be given topically or with conjunctival cotton pledgets soaked in tropicamide, cyclopentolate, or phenylephrine hydrochloride (Fig 8-3).
HLA-B27 is a major histocompatibility complex (MHC) class I antigen present in approximately 8% of the general population in the United States. Approximately 40%–50% of patients with acute anterior uveitis are HLA-B27 positive. Thus, although patients with recurrent anterior nongranulomatous uveitis should be tested for HLA-B27, the presence of HLA-B27 alone does not provide an absolute diagnosis. Further, the precise trigger for acute anterior uveitis in HLA-B27–positive persons remains unclear.
Several autoimmune diseases known collectively as the seronegative spondyloarthropathies are strongly associated with both acute anterior uveitis and HLA-B27. Patients with these diseases, by definition, do not test positive for rheumatoid factor. The seronegative spondyloarthropathies include
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ankylosing spondylitis (AS)
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reactive arthritis syndrome
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inflammatory bowel disease
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psoriatic arthritis
These entities are sometimes clinically indistinguishable, and all may be associated with spondylitis and sacroiliitis. Women are more likely than men to experience atypical spondyloarthropathies.
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Van Gelder RN. Diagnostic testing in uveitis. Focal Points: Clinical Modules for Ophthalmologists. San Francisco: American Academy of Ophthalmology; 2013, module 6.
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Wakefield D, Chang JH, Amjadi S, Maconochie Z, Abu El-Asrar A, McCluskey P. What is new HLA-B27 acute anterior uveitis? Ocul Immunol Inflamm. 2011;19(2):139–144.
HLA-B27–related diseases
Ankylosing spondylitis AS ranges in severity from asymptomatic to crippling. Symptoms of this disorder include lower back pain and morning stiffness. Up to 90% of patients with AS test positive for HLA-B27, although most HLA-B27–positive individuals do not develop the disease. The chance that an HLA-B27–positive patient will develop spondyloarthritis or eye disease is 1 in 4. Family members may also have AS or anterior uveitis. Often, persons with anterior uveitis lack symptoms of back disease.
The ophthalmologist may be the first physician to suspect AS in an individual patient. Symptoms or family history of back problems together with HLA-B27 positivity suggest the diagnosis. Sacroiliac imaging studies should be obtained when indicated by a suggestive history of morning lower back stiffness that improves with exertion. Patients should be informed of the risk of deformity and referred to a rheumatologist. Pulmonary apical fibrosis and cardiovascular disease (aortic valvular insufficiency) may also develop.
Nonsteroidal anti-inflammatory agents (NSAIDs) are the mainstay of systemic treatment for AS. Sulfasalazine may be used in patients whose joint disease is not controlled with NSAIDs, and it may reduce the frequency of uveitis recurrences. However, TNF inhibitors are gaining favor for second-line treatment in recalcitrant cases given their rapid therapeutic effect and overall efficacy. Ophthalmologists should also recognize that early diagnosis is important because nonpharmacologic interventions such as exercise, physical therapy, and smoking cessation may help slow disease progression.
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Braun J, Baraliakos X, Listing J, Sieper J. Decreased incidence of anterior uveitis in patients with ankylosing spondylitis treated with the anti-tumor necrosis factor agents infliximab and etanercept. Arthritis Rheum. 2005;52(8):2447–2451.
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Monnet D, Breban M, Hudry C, Dougados M, Brézin AP. Ophthalmic findings and frequency of extraocular manifestations in patients with HLA-B27 uveitis: a study of 175 cases. Ophthalmology. 2004;111(4):802–809.
Reactive arthritis syndrome Reactive arthritis syndrome, formerly known as Reiter syndrome, consists of the classic diagnostic triad of nonspecific urethritis, polyarthritis, and conjunctival inflammation, often accompanied by nongranulomatous anterior uveitis. The HLA-B27 marker is found in approximately 50%–75% of patients. The condition constitutes less than 2% of all spondyloarthropathies and occurs most frequently in young adult men, although 10% of patients are female.
Episodes of diarrhea or dysentery without urethritis can trigger reactive arthritis syndrome. Ureaplasma urealyticum as well as Chlamydia, Shigella, Salmonella, and Yersinia species have all been implicated as triggering infections, although pathogens cannot be isolated from affected joints. Arthritis begins within 30 days of infection in 80% of patients. The knees, ankles, feet, and wrists are affected asymmetrically and in an oligoarticular (4 or fewer joints) distribution. Sacroiliitis is present in as many as 70% of patients.
In addition to the classic triad, 2 other conditions are considered major diagnostic criteria:
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keratoderma blennorrhagicum: a scaly, erythematous, irritating disorder of the palms and soles of the feet (Fig 8-4)
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circinate balanitis: a persistent, scaly, erythematous, circumferential rash of the distal penis
Extraarticular findings such as nail bed pitting, oral ulcers, conjunctivitis, uveitis, and constitutional symptoms help establish a diagnosis of reactive arthritis syndrome. Most cases resolve after a short episode. Occasionally, the disease becomes chronic. Eye involvement occurs in approximately 20%. Conjunctivitis is the most common eye finding associated with this disease, and it is usually mucopurulent and papillary. Punctate and subepithelial keratitis may also occur, occasionally leaving permanent corneal scars. Acute nongranulomatous anterior uveitis occurs in up to 10% of patients and may become bilateral and chronic.
Inflammatory bowel disease Ulcerative colitis and Crohn disease (granulomatous ileocolitis) are both associated with acute anterior uveitis. Up to 12% of patients with ulcerative colitis and 2.4% of patients with Crohn disease develop acute anterior uveitis. Occasionally, bowel disease is asymptomatic and follows the onset of uveitis. Twenty percent of patients with inflammatory bowel disease have sacroiliitis; of these, 60% are HLA-B27 positive. Patients with both acute anterior uveitis and inflammatory bowel disease (IBD) are more likely to be HLA-B27 positive and have sacroiliitis. Patients with IBD may also develop sclerouveitis, but these individuals are more commonly HLA-B27 negative, have symptoms resembling rheumatoid arthritis, and usually do not develop sacroiliitis. HLA-B27–negative IBD patients may also be more likely to develop intermediate uveitis.
Psoriatic arthritis The diagnosis of psoriatic arthritis is made according to findings of typical cutaneous changes (Fig 8-5), terminal phalangeal joint inflammation (Fig 8-6), and ungual involvement. Twenty percent of patients may have sacroiliitis, and IBD occurs more frequently than would be expected by chance. Up to 25% of patients develop anterior uveitis, which tends to be insidious and bilateral; it is also more likely to be chronic than is the uveitis associated with other spondyloarthropathies. Risk is particularly high in psoriatic spondylitis patients. Uveitis may be more severe in HLA-B27–positive patients. Treatment consists of cycloplegic and mydriatic agents and corticosteroids, which are usually given topically. In severe cases, periocular or systemic corticosteroids may be required, and chronic cases may need immunomodulatory therapy (IMT).
Anterior uveitis in patients with psoriasis without arthritis has distinct clinical features. The mean age of onset is older than in idiopathic or HLA-B27–associated uveitis and may be bilateral and of longer duration. Posterior segment involvement can be present.
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de Azevedo Fraga NA, Paim de Oliveira MF, Follador I, de Oliveira Rocha B, Rêgo VR. Psoriasis and uveitis: a literature review. An Bras Dermatol. 2012;87(6):877–883.
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Egeberg A, Khalid U, Gislason GH, Mallbris L, Skov L, Hansen PR. Association of psoriatic disease with uveitis: a Danish nationwide cohort study. JAMA Dermatol. 2015;151(11):1200–1205.
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Sampaio-Barros PD, Pereira IA, Hernández-Cuevas C, et al; RESPONDIA Group. An analysis of 372 patients with anterior uveitis in a large Ibero-American cohort of spondyloarthritis: the RESPONDIA Group. Clin Exp Rheumatol. 2013;(4):484–489.
Tubulointerstitial nephritis and uveitis syndrome
Tubulointerstitial nephritis and uveitis (TINU) syndrome occurs predominantly in adolescent girls and women up to their early 30s; the mean age of onset is 21 years. Uveitis is typically a bilateral, nongranulomatous, anterior uveitis. Ocular symptoms and findings are more severe in patients with recurrent disease, with development of fibrin, posterior synechiae, larger KPs, and, rarely, hypopyon. Posterior segment involvement is rare but may include vitritis, multifocal chorioretinal lesions, and retinal vascular leakage as well as optic nerve and macular edema (Fig 8-7).
Patients may present with ophthalmic findings before systemic symptoms and tubulointerstitial nephritis develop. More commonly, however, patients present with systemic symptoms before the development of uveitis. The following criteria are required for a clinical diagnosis of TINU syndrome:
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abnormal serum creatinine level or decreased creatinine clearance
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abnormal urinalysis findings, with increased β2-microglobulin level, proteinuria, presence of eosinophils, pyuria or hematuria, urinary white cell casts, and normoglycemic glycosuria
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associated systemic illness, consisting of fever, weight loss, anorexia, fatigue, arthralgias, and myalgias; there may also be abnormal liver function, eosinophilia, and an elevated erythrocyte sedimentation rate
The etiology remains unclear. Seroreactivity against retinal and renal antigens has been demonstrated. The syndrome has been reported to be strongly associated with HLA-DRB1*0102. The predominance of activated CD4+ (helper) T lymphocytes in the kidney interstitium suggests a role for cellular immunity. Renal biopsies have shown severe interstitial fibrosis. TINU syndrome is very responsive to treatment with high-dose oral corticosteroids. Some patients with a prolonged course may require IMT.
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Ali A, Rosenbaum JT. TINU (tubulointerstitial nephritis uveitis) can be associated with chorioretinal scars. Ocul Immunol Inflamm. 2014;22(3):213–217.
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Mackensen F, Billing H. Tubulointerstitial nephritis and uveitis syndrome. Curr Opin Ophthalmol. 2009;20(6):525–531.
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Mandeville JT, Levinson RD, Holland GN. The tubulointerstitial nephritis and uveitis syndrome. Surv Ophthalmol. 2001;46(3):195–208.
Glaucomatocyclitic crisis
Glaucomatocyclitic crisis, also known as Posner-Schlossman syndrome (PSS), usually manifests as a recurrent unilateral, mild, acute nongranulomatous anterior uveitis. Symptoms are vague: discomfort, blurred vision, and halos. Signs include markedly elevated IOP, corneal edema, KPs, low-grade cell and flare, and a slightly dilated pupil. Episodes last from several hours to several days, and recurrences are common over many years. Historically treatment has been topical corticosteroids and antiglaucoma medications, including, if necessary, systemic carbonic anhydrase inhibitors. Recent studies suggest cytomegalovirus (CMV) as a possible cause of PSS, with distinct genotypes of CMV being associated with PSS and anterior uveitis as opposed to retinitis. Corneal endotheliitis, linear KPs, and male preponderance are more common among CMV-associated PSS. An anterior chamber tap can be done to confirm the diagnosis of CMV by polymerase chain reaction testing. There may be a possible role for antiviral therapy in such cases.
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Chee SP, Jap A. Presumed Fuchs heterochromic iridocyclitis and Posner-Schlossman syndrome: comparison of cytomegalovirus-positive and negative eyes. Am J Ophthalmol. 2008;146(6):883–889.
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Oka N, Suzuki T, Inoue T, Kobayashi T, Ohashi Y. Polymorphisms in cytomegalovirus genotype in immunocompetent patients with corneal endotheliitis or iridocyclitis. J Med Virol. 2015;87(8):1441–1445.
Lens-associated uveitis
An immune reaction to lens material may result in ocular inflammatory disease. This reaction may follow disruption of the lens capsule (traumatic or surgical), termed phacoantigenic uveitis, or leakage of lens protein through the intact lens capsule in mature or hypermature cataracts, termed phacolytic uveitis (Figs 8-8, 8-9). The exact mechanism of lens-induced uveitis, although unknown, is thought to represent an immune reaction to lens proteins. Experimental animal studies suggest that altered tolerance to lens protein leads to the inflammation, which usually has an abrupt onset but occasionally occurs insidiously. Patients previously sensitized to lens protein (eg, after cataract extraction in the fellow eye) can experience inflammation within 24 hours after capsular rupture.
Phacoantigenic uveitis Phacoantigenic uveitis was previously termed phacoanaphylactic uveitis. This nomenclature is incorrect because anaphylaxis involves immunoglobulin E (IgE), mast cells, and basophils, none of which are present in the more appropriately termed phacoantigenic uveitis. Clinically, patients exhibit an anterior uveitis that may be granulomatous or nongranulomatous. Small or large KPs are usually present. Anterior chamber reaction varies from mild (eg, postoperative inflammation involving a small amount of retained cortex) to severe (eg, traumatic lens capsule disruption); hypopyon may be present. Posterior synechiae are common, and IOP is often elevated. Inflammation in the anterior vitreous cavity is common, but fundus lesions do not occur.
Histologically, a zonal granulomatous inflammation is centered at the site of lens injury. Neutrophils are present around the lens material with surrounding lymphocytes, plasma cells, epithelioid cells, and occasional giant cells.
Treatment consists of topical and, in severe cases, systemic corticosteroids, as well as cycloplegic and mydriatic agents. Surgical removal of all lens material is usually curative. When small amounts of lens material remain, corticosteroid therapy alone may be sufficient to allow resorption of the inciting material. It is important to differentiate some of these entities from postoperative endophthalmitis.
Phacolytic uveitis Phacolytic uveitis (or phacolytic glaucoma, as it is frequently referred to) involves an acute increase in IOP caused by clogging of the trabecular meshwork by macrophages engorged with lens proteins leaking through the intact capsule of a hypermature cataract. The diagnosis is suggested by the presence of elevated IOP, refractile bodies in the aqueous (representing lipid-laden macrophages), and a lack of KPs and synechiae. Therapy includes pressure reduction, often through use of osmotic agents and topical medications, followed quickly by cataract extraction. An aqueous tap may reveal swollen macrophages.
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Kalogeropoulos CD, Malamou-Mitsi VD, Asproudis I, Psilas K. The contribution of aqueous humor cytology in the differential diagnosis of anterior uvea inflammations. Ocul Immunol Inflamm. 2004;12(3):215–225.
Postoperative inflammation: infectious endophthalmitis
Infectious endophthalmitis must be included in the differential diagnosis of postoperative inflammation and hypopyon. Infection with low-virulence organisms such as Propionibacterium acnes and Staphylococcus epidermidis as well as fungal species can cause delayed or late-onset endophthalmitis after cataract surgery. Infectious endophthalmitis is discussed in more detail in Chapter 12.
Postoperative inflammation: intraocular lens–associated uveitis
Intraocular lens (IOL)–associated uveitis ranges from mild inflammation to the uveitis-glaucoma-hyphema (UGH) syndrome. Surgical manipulation results in breakdown of the blood–aqueous barrier, leading to vulnerability in the early postoperative period. IOL implantation can activate complement cascades and promote neutrophil chemotaxis. This leads to cellular deposits on the IOL, synechiae formation, capsular opacification, and anterior capsule phimosis. Retained lens material from extracapsular cataract extraction can exacerbate the usual transient postoperative inflammation. Rarely, iris chafing caused by the edges or loops of IOLs on either the anterior or the posterior surface of the iris can result in mechanical irritation and inflammation. The motion of an iris-supported IOL or anterior chamber IOL (ACIOL) can cause intermittent corneal touch and lead to corneal endothelial damage or decompensation, low-grade anterior uveitis, peripheral anterior synechiae, recalcitrant glaucoma, and macular edema (Figs 8-10, 8-11). These lenses should be removed and exchanged when penetrating keratoplasty is performed.
Irritation of the iris root by an intraocular implant can cause UGH syndrome. Flexible ACIOLs are less likely than older rigid ACIOLs to cause UGH syndrome. Because ACIOL use is rare, UGH syndrome is encountered most commonly with sulcus placement of a single-piece hydrophobic acrylic IOL (something that should never be intentionally done). The syndrome can occur even with the appropriate placement of a 3-piece IOL in the sulcus. Ultrasound biomicroscopy or anterior segment optical coherence tomography (OCT) can be helpful in evaluating lens position in cases of chronic pseudophakic uveitis. Many cases can be managed with topical corticosteroids only, although some may require IOL explantation or repositioning. UGH syndrome and chronic uveitis are also discussed in BCSC Section 11, Lens and Cataract.
In general, the more biocompatible the IOL material, the less likely it is to incite an inflammatory response. Irregular or damaged IOL surfaces as well as polypropylene haptics have been associated with enhanced bacterial and leukocyte binding and should be avoided in patients with uveitis. In general, acrylic IOLs appear to have excellent biocompatibility, with low rates of cellular deposits and capsular opacification. Persistent postoperative anterior uveitis (postsurgical uveitis) is very rare and occur more commonly in eyes experiencing intraoperative complications. Foldable implant materials have also been found to be well tolerated in many patients with uveitis.
One of the most important factors in the success of cataract surgery is aggressive control of intraocular inflammation in the perioperative period. For further discussion and illustrations, see Chapter 14 and BCSC Section 11, Lens and Cataract.
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Ozdal PC, Mansour M, Deschênes J. Ultrasound biomicroscopy of pseudophakic eyes with chronic postoperative inflammation. J Cataract Refract Surg. 2003;29(6):1185–1191.
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Patel C, Kim SJ, Chomsky A, Saboori M. Incidence and risk factors for chronic uveitis following cataract surgery. Ocul Immunol Inflamm. 2013;21(2):130–134.
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Roesel M, Heinz C, Heimes B, Koch JM, Heiligenhaus A. Uveal and capsular biocompatibility of two foldable acrylic intraocular lenses in patients with endogenous uveitis—a prospective randomized study. Graefes Arch Clin Exp Ophthalmol. 2008;246(11):1609–1615.
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Taravati P, Lam DL, Leveque T, Van Gelder RN. Postcataract surgical inflammation. Curr Opin Ophthalmol. 2012;23(1):12–18.
Drug-induced uveitis
Some drugs are associated with the development of intraocular inflammation. These include rifabutin (an antibiotic used in the treatment of Mycobacterium avium-intracellulare infection), systemic fluoroquinolones (especially moxifloxacin, which may induce iris depigmentation and uveitis), bisphosphonates, sulfonamides, diethylcarbamazine (an antifilarial drug), and oral contraceptives. Paradoxically, certain TNF inhibitors (eg, etanercept, adalimumab) have also been associated with new-onset uveitis, psoriasis-like rash (Fig 8-12), and a systemic sarcoid-like syndrome. Vaccines such as BCG vaccine and influenza vaccines, as well as the purified protein derivative used in the tuberculin skin test, have also been implicated in the development of uveitis. Intravesical BCG vaccine (sometimes used in the treatment of bladder cancer) can result in uveitis that may be immune-mediated or infectious. More recently, a spectrum of intraocular inflammation—ranging from mild anterior uveitis to retinal vasculitis, choroiditis, and Vogt-Koyanagi-Harada (VKH) syndrome–like panuveitis—has been associated with cancer immunotherapy, particularly with immune checkpoint inhibitors (Fig 8-13).
Numerous topical antiglaucoma medications have been associated with uveitis. These include metipranolol (a nonselective beta-blocking drug used in the treatment of glaucoma), acetylcholinesterase inhibitors, prostaglandin F2α analogues, and brimonidine (α2-adrenergic agonist). While prostaglandin analogues have been suggested to induce or worsen macular edema, evidence is anecdotal, and these glaucoma drops are generally used in uveitis patients when other topicals are not sufficient to lower IOP. Drugs that are injected directly into the eye have also been associated with uveitis. These medications include antibiotics, urokinase (a plasminogen activator), cidofovir (a cytosine analogue effective against CMV) and vascular endothelial growth factor (VEGF) inhibitors. Treatment generally involves topical corticosteroids and cycloplegic drugs, if necessary. Recalcitrant cases may require cessation or tapering of the offending medication.
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Conrady CD, Larochelle M, Pecen P, Palestine A, Shakoor A, Singh A. Checkpoint inhibitor-induced uveitis: a case series. Graefes Arch Clin Exp Ophthalmol. 2018;256(1):187–191.
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Cunningham ET Jr, Pasadhika S, Suhler EB, Zierhut M. Drug-induced inflammation in patients on TNF-α inhibitors. Ocul Immunol Inflamm. 2012;20(1):2–5.
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Horsley MB, Chen TC. The use of prostaglandin analogs in the uveitic patient. Semin Ophthalmol. 2011;26(4–5):285–289.
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Moorthy RS, London NJ, Garg SJ, Cunningham ET Jr. Drug-induced uveitis. Curr Opin Ophthalmol. 2013;24(6):589–597.
Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.