Hypersensitivity Uveitis
M. Levent Civelek
Debra A. Goldstein
Howard H. Tessler
HYPERSENSITIVITY REACTIONS
When an immune response occurs and causes tissue damage, it is referred to as a hypersensitivity reaction. In the 1960s, British immunologists Coombs and Gell originally classified hypersensitivity reactions into four types, and, recently, a fifth and sometimes a sixth are also added. Although our understanding of the immune system has dramatically changed since the 1960s, the classification of Coombs and Gell remains almost unchanged; it is still used and valid.1
TYPE I: IMMEDIATE HYPERSENSITIVITY
Type I hypersensitivity is mediated by IgE antibodies. Antigen binds to two molecules of IgE or IgG attached to a receptor site (Fc) on the surface of a basophil or a mast cell and results in the degranulation of these cells. Type I ocular hypersensitivity usually results in primarily external disease, but “seasonal iritis” and retinal edema have been described in severe cases of hay fever.2,3,4
IgE antibodies specific for retinal S antigen (S-Ag) are detected early in experimental S-Ag induced uveitis in rats. The role of mast cells in the induction of experimental autoimmune uveoretinitis (EAU) is also supported by several studies: (1) mast cell degranulation occurs before the onset of EAU,5 (2) EAU is inhibited by drugs that affect mast cells,6,7 and (3) the number of mast cells in rat choroid,8 iris, and ciliary body9 is correlated with the susceptibility of rats to EAU. But according to a study in 2002, instillations of antiallergic agents, such as cromolyn sodium, tranilast, levocobastine hydrochloride, pemirolast potassium, and ibudilast, did not inhibit flare elevation in a rabbit study, whereas single instillation of betamethasone inhibited 88% of aqueous flare elevation. It is unlikely that antiallergic agents inhibit flare elevation and affect disruption of the blood–aqueous barrier.10
TYPE II: CYTOTOXIC ANTIBODY
Cytotoxic antibodies mediate type II reactions. IgG or IgM bind to antigen on the surface or basement membranes of target cells, resulting in cell death (e.g., ocular cicatricial pemphigoid and Mooren’s ulcer).
Extraocular manifestations of sympathetic ophthalmia (SO) and Vogt-Koyanagi-Harada (VKH), such as vitiligo, poliosis, alopecia, dysacusis, and central nervous system symptoms consistent with irritation of the meninges (which contains melanin), appear to be caused by a reaction to melanin.11,12 Sugita et al.13 suggested that SO and VKH may be autoimmune diseases directed toward the MART-1 peptide of melanocytes. In SO and VKH disease, anti-melanin autoantibodies and melanin-sensitized lymphocytes have been demonstrated in the peripheral blood.14 Serum antibodies to retinal antigens have been detected15 to be consistent with this disease being mediated, at least in part, by a type II hypersensitivity.
TYPE III: IMMUNE COMPLEXES
Type III reactions cause tissue injury by precipitation and deposition of immune complexes. Antigen-antibody complexes can initiate the complement cascade, which attracts macrophages, neutrophils, and platelets, and causes tissue damage. The uvea is highly vascularized, and its blood supply has been said to resemble that of the renal cortex. Because immune complexes can be deposited in the renal glomerulus, they may also accumulate in the uvea. Systemic lupus erythematosus (SLE) retinopathy, rheumatoid sclerouveitis, sarcoidosis, retinal vasculitis, chronic idiopathic uveitis, Behçet’s syndrome, rheumatoid arthritis, Wegener’s granulomatosis, and lens induced uveitis may be due, in part, to type III hypersensitivity reactions; immune complexes have been observed in patients having these diseases.16,17,18,19
TYPE IV: DELAYED-TYPE (CELL MEDIATED) HYPERSENSITIVITY
In contrast to the previous three reactions, no immunoglobulins are involved in type IV reactions, and the hypersensitivity is mediated directly through T cells. This reaction is triggered when antigen is presented to T lymphocytes by antigen presenting cells (APCs), which results in cytokine (lymphokine) release or lymphocyte stimulation. Examples of type IV reactions include contact dermatitis (eczema) and corneal graft rejection. Type IV reactions may play a role in ocular toxoplasmosis, herpetic uveitides, sympathetic ophthalmia, pars planitis, and birdshot retinochoroidopathy.21
TYPE V: STIMULATORY ANTIBODY
In type V hypersensitivity, IgG antibodies are directed toward cell-surface antigens and have a stimulatory effect on their target. An example is long-acting thyroid stimulator (LATS) antibody. LATS is directed toward a portion of the hormone receptor and mimics the function of thyroid-stimulating hormone. Maternal stimulating antithyroid IgG antibodies are able to cross the placenta and may cause neonatal hyperthyroidism.4,22
TYPE VI: ANTIBODY DEPENDENT CELL-MEDIATED CYTOTOXICITY (ADCC)
Type VI reactions are sometimes classified as a subgroup of type II hypersensitivity reactions. Target cells coated with antibody are destroyed by specialized killer cells (NK cells, killer T cells, macrophages), which bear receptors for the Fc portion of the coating antibody (Fc receptors). These receptors allow the killer cells to bind to the antibody-coated target (tumor rejection and defense against parasites). This cytotoxic reaction is complement independent.
For most of the uveitic entities, it remains uncertain which type of hypersensitivity reaction is involved. Uveitic disorders associated with hypersensitivity can be categorized into those associated with exogenous antigens (i.e., those found in the environment) and those associated with endogenous antigens (i.e., those found in the eye).
EXOGENOUS ANTIGENS
ENVIRONMENTAL ANTIGENS
Association between hypersensitivity to environmental antigens (e.g., allergies) and uveitis has been documented. Cases of uveitis have been reported in association with allergies to food,23,24 dust,23 ragweed,24 trees and grasses,25 cat, caterpillar, and tarantula hair.26,27,28,29,30
In 1904, Saemisch31 first used the term ophthalmia nodosa to describe the granulomatous nodules formed on the conjunctiva and iris in response to caterpillar hairs or sensory setae. Iritis, occasionally with formation of iris nodules and vitritis, is also described after ocular reaction to caterpillar hairs.32 Ophthalmia nodosa can also be caused by tarantula hairs. Tarantulas are occasionally kept as pets and are usually harmless, but, if threatened, they eject their dorsal barbed hairs with the hair of their hind legs. These hairs are capable of embedding into cornea and skin and inciting an inflammatory reaction. It is usually hard to detect those hairs in the cornea. Even with hairs in the anterior corneal stroma only, anterior uveitis with mutton fat deposits on endothelium may be seen.29 One patient is reported to have developed small peripheral choroidal lesions after 6 months.30 Extensive dissection of the cornea or sclera to remove the hairs is not recommended because successful management is obtainable with topical steroids (Fig. 1).
 Fig. 1 Ophthalmia nodosa. Slit lamp photograph of left eye of a 13-year-old boy who developed a red and painful eye after playing with his pet tarantula. Note the granulomatous keratic precipitates (black arrows) and subepithelial opacity (white arrow). There was also a mild anterior chamber reaction. |
An asthmatic patient has been described who developed a well-demarcated area of choroiditis after several bouts of urticaria. The authors felt that this was due to IgE-mediated release of vasoactive amines, which have been reported to trigger vasculitic syndromes.32
Bee and wasp stings of the cornea have been associated with significant ocular pathology. Uveitis has been observed after corneal bee sting33 and wasp bite.34 Bee venom is a complex toxin composed of several compounds with different actions. Toxicity is related to nonenzymatic polypeptide toxins (mellitin, apamin, iminimine) and enzymes (phospholipase A and B, hyaluronidase). Mellitin can cause depigmentation of the iris (heterochromia iridis), noted in cases of bee sting.35 Mellitin also causes the release of serotonin, histamine, and other chemical mediators of inflammation. Apamin is a neurotoxin that blocks neurotransmission, and internal ophthalmoplegia and sector iridoplegia have been reported as neurotoxic effects of apamin after corneal bee sting. Optic neuritis, papilledema, and optic atrophy have occurred following bee stings to the other parts of the body.36 The mechanism is thought to be focal demyelination of the optic nerve caused by an acute allergic reaction to the bee venom. Enzymes in the venom have high molecular weight and are highly antigenic, accounting for the immunologic injury to the eye following stings. Type I hypersensitive reaction takes place, with release of chemical mediators of inflammation and manifested by such findings as conjunctival injection, chemosis, and corneal edema.33 Corticosteroids alone, or in conjunction with cycloplegics and antibiotics, are used in corneal bee stings; antihistamines can be included in case of chemosis and conjunctival injection.
The cases above are unusual. In general, the association between allergies and uveitis is rare. Van Metre37 reported no cases due to allergy among 556 cases of uveitis studied. In a series of 1500 cases, Kimura26 did not find any statistically significant association between contact allergy and uveitis. These results also reflect our clinical experience.
INFECTIOUS AGENTS
Infectious causes (e.g., tuberculosis, syphilis, and toxoplasmosis) of uveitis are well known; however, uveitis associated with hypersensitivity to infectious agents is seldom recognized clinically.
Although the specific cause of uveitis remains unknown in many patients, the initiating stimuli for intraocular inflammation can be divided into two major pathways: an antigen specific (infectious agent) immune-mediated inflammatory response and a nonspecific inflammatory response (which is nonantigen specific).
Endotoxin-induced uveitis (EIU) is an animal model for nonantigen-specific stimulus induced ocular inflammation. In Lewis rats, intravenous, intraperitoneal, and intrafootpad endotoxin injection38 or intraocular endotoxin injection39 are demonstrated to induce EIU. According to kinetic studies, inflammatory cells migrate first into the eye about 6 hours after endotoxin injection, and ocular inflammation peaks approximately 18 hours later. Inflammation is related to the release of cytokines from activated cells. Tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), IL-6, and IL-8 are inflammatory mediators that appear to be stimulated by endotoxin. Those cytokines and other inflammatory molecules can start the inflammatory cascade with breakdown of the blood-aqueous and blood-retinal barriers, leading to additional cellular infiltration of the eye.40
Antigen-specific ocular immune responses may also take place and are divided into cell-mediated and humoral responses. Both of these require processing of the antigen by specialized antigen-presenting cells (APC). It has been postulated that this results from molecular mimicry between part of the DNA of the various organisms and a portion of HLA-B27, although this is still controversial.
Immune responses against infectious agents may cross-react against ocular antigens and induce uveitis. For example, researchers noted homology between yeast histone and S-Ag.41 A number of forms of uveitis follow an infectious disease but do not seem to be caused by direct infection. Reiter’s syndrome is associated with HLA-B27 haplotype. Uveitis in these patients may occur after gram-negative dysentery or after nongonococcal urethritis, as a result of chlamydia trachomatis and ureaplasma urealyticum.40
Post-streptococcal syndrome is an autoimmune disorder precipitated by infection with group A streptococci. The pathologic process is thought to stem from a cross-reaction between antibodies, sensitized lymphocytes, or both, generated against streptococcal antigens with the tissues of the host.42 Manifestations include acute rheumatic fever (ARF), post streptococcal reactive arthritis (PSRA), and acute glomerulonephritis. Recurrent anterior uveitis can occur in patients with a history of post-streptococcal syndrome who have repeated group A streptococcal infection. The intraocular inflammation follows a time course similar to that of the other manifestations of the syndrome, such as recurrent rheumatic fever.43,44 PSRA differs from ARF, in which evidence of carditis is not usually seen and the response of arthritis to aspirin is poor. Two adult patients with PSRA, both of whom developed uveitis, were recently described.45
There are probably multiple initiating infectious stimuli for inflammation in the uvea. Uveitis may result from the replication of the microbes, the host’s hypersensitivity to the components of the microbe, or both. Unfortunately, the exact mechanism of uveitis in humans is still unknown.40
DRUG-INDUCED UVEITIS
Drug-induced uveitis is a relatively rare occurrence (reported to be less than 0.5 % in a tertiary referral uveitis clinic).46 Drug-induced uveitis is almost always reversible within weeks of discontinuation of the causative agent and treatment of the inflammation.
Naranjo et al.47 proposed the following seven criteria to establish causality of adverse events by drugs:
The reaction is a frequently described event that is well documented.
Recovery occurs upon withdrawal of the drug.
Other possible causes for the event have been excluded.
The reaction becomes more severe when the dose of drug is increased.
The adverse event is documented by objective evidence.
Similar effects can occur in a given patient with similar drugs.
The event recurs on rechallenge with the suspected drug.
Several drugs have anecdotally been noted to cause uveitis in single case reports. Very few drugs that have been reported to cause uveitis have had causality confirmed by elimination of confounding variables, double-blind challenge, or rechallenge testing.
Systemic Drug-Induced Uveitis
Rifabutin, a derivate of rifampin, is used to treat or to prevent atypical mycobacterial infections in the immunocompromised host. It has been associated with anterior and posterior nongranulomatous uveitis, with or without hypopyon, which may be extremely severe.48,49,50 Rifabutin-associated uveitis, characterized by white-yellow inflammatory opacities in the inferior and posterior vitreous, has also been described by Chaknis et al.51 They described those lesions in three acquired immunodeficiency syndrome (AIDS) patients who were receiving 300 mg of rifabutin daily for 6 or more months for mycobacterium avium complex (MAC) prophylaxis. Three cases of acute uveitis without hypopyon were reported in patients with AIDS who did not have MAC bacteremia and who were taking prophylactic rifabutin.49 Rifabutin-associated uveitis may be an immune reaction to dead mycobacteria, but MAC associated uveitis (without rifabutin) is very rare, and anterior chamber paracentesis of the hypopyon, in these cases, failed to show any organisms on either aqueous cultures or microscopic examinations.52 Rifabutin reaction is probably not T cell-mediated because a paucity of these lymphocytes is one of the hallmarks of AIDS.48 Rifampin is known to be antigenic itself and after binding with serum and tissue proteins. Antibodies against rifampin can circulate or adhere to cellular surfaces and the antigen-antibody complexes induce an inflammatory reaction.53 The high prevalence, incidence of bilaterality, recurrence of uveitis with rechallenges, increasing severity of inflammation with dose escalation, improvement upon withdrawal, and exclusion of other possible causes of uveitis strongly implicate rifabutin as a cause of uveitis.54
Pamidronate sodium (Aredia), an intravenous bisphosphate, inhibits bone resorption and is used in the management of hypercalcemia associated with malignancy, osteolytic bone metastases, paget disease of the bone, and osteoporosis. Seventeen cases of unilateral scleritis and one case of bilateral scleritis have been reported within 6 hours to 2 days after intravenous pamidronate sodium injection, with positive dechallenge and rechallenge data. In 16 cases this occurred anteriorly and in one case, posteriorly.55 The most frequent ocular side effect of serious clinical importance associated with pamidronate is anterior uveitis; both eyes are affected in most patients and onset is within the first 48 hours of drug exposure. In some patients, the drug had to be discontinued, and the outcome was favorable within a few days after topical corticosteroid therapy.55,56 Pamidronate stimulates the production of a distinct group of T cells, which inhibit bone resorption. The activation of T cells releases cytokines, and this may contribute to an immunologic or toxic reaction in patients who develop uveitis or scleritis.57
A more recently developed oral bisphosphate, alendronate sodium (Fosamax), is 100 to 500 times more potent than amino-bisphosphonates and is being used successfully to prevent and to treat osteoporosis in postmenopausal women. Alendronate has also been associated with bilateral anterior uveitis,58 posterior scleritis, anterior scleritis, and orbital myositis that resolves with anti-inflammatory therapy and discontinuation of alendronate.59 There is no rechallenge data for alendronate. But, because this agent is in the same class as pamidronate, has the same pattern of onset, and requires discontinuation of the drug for the scleritis to resolve, a cause-and-effect relationship seems to be almost certain for alendronate.
A bilateral sudden-onset iritis in association with the use of trimethoprim-sulfamethoxazole has been reported by Tilden et al.60 The bilaterality and the recurrence of inflammation with rechallenge are strong evidence that systemic sulfonamides are a cause, albeit rare, of anterior uveitis. The intraocular inflammation may be the result of direct immunogenicity of sulfonamides or, as in the case of Stevens-Johnson syndrome, the result of a systemic, necrotizing vasculitis.54
Diethylcarbamazine (Ivermectin) is an antifilarial agent effective against Oncocerca volvulus, one of the leading causes of blindness in the world. Diethylcarbamazine rapidly and effectively kills microfilaria. Death of the microfilaria that are present in the cornea and anterior chamber liberates an antigenic load that may result in devastating intraocular inflammation. It is Jarisch-Herxheimer reaction, which is a hypersensitivity response, attributed to liberation of endotoxin-like substances or of flarial antigens from the killed or dying microorganisms. This reaction may exacerbate preexisting ocular inflammation, and prophylaxis with corticosteroids may be helpful.54,61,62
There have been old isolated reports of uveitis associated with oral contraceptives.63 There is one case of bilateral anterior uveitis64 and three cases of bilateral posterior uveitis and vasculitis in patients taking norethynodrel and mestranol. The evidence for causality is extremely weak, and there is no rechallenge data. Given the huge number of women using oral contraceptives, these rare cases may have occurred by chance alone. The pathogenesis of uveitis associated with oral contraceptives, if indeed this is a true entity, is unclear.54 Anterior granulomatous uveitis65 and acute nongranulomatous anterior uveitis66 have been reported in patients with hypersensitivity to quinidine.
Cidofovir (Vistide), a DNA polymerase inhibitor (HPMPC), has been successfully used for the treatment of cytomegalovirus retinitis and acyclovir-resistant herpes virus infections in patients with AIDS. Cidofovir-associated uveitis (CAU) has been described in 25% to 59% of patients receiving intravenous cidofovir.67,68 The uveitis is usually anterior, associated with posterior synechiae and accompanied by hypotony. It may be unilateral or bilateral, is dose related, and the risk is increased with highly active antiretroviral therapy (HAART) and with rising CD4+ cell counts.69 While CAU occurs mostly in eyes with inactive CMV retinitis, bilateral anterior uveitis was reported in an AIDS patient taking cidofovir because of presumed recurrence of CMV encephalitis. The patient was not on
HAART and had no evidence of CMV retinitis or any other abnormality on fundoscopy.70 Recently, several reports have proposed the use of cidofovir as a treatment for infections with the virus known as JC virus (JC are the initials of the first person diagnosed with this virus) that causes progressive multifocal leukoencephalopathy (PML) in patients with AIDS. Tacconelli et al.,71 in 2003, treated AIDS patients receiving HAART with cidofovir for CMV retinitis or PML. Sixty percent of CMV patients had CAU on the same side as the retinitis, whereas no cases were detected among the patients with PML. It is hypothesized that the retinal action of cidofovir is increased by concomitant retinal alteration caused by retinitis, previous mycobacterial disease, or toxoplasmosis. It is also possible that an increase in a patient’s HIV-viremia level (viral load) may result in HIV-associated retinal alteration, which facilitates an increase in the penetration of cidofovir. CAU seems to occur more frequently in patients with retinitis, on HAART, in whom HAART has failed to restore immunity. The concomitant use of probenecid decreases the incidence of uveitis associated with intravitreal and also intravenous cidofovir.72 Probenecid inhibits renal tubular secretion of cidofovir73 and may inhibit secretion from the ciliary body, which shares many of the transport mechanisms in the kidney, resulting in decreased intraocular drug levels.67
Etanercept (Enbrel) inhibits the action of both TNF-α and TNF-α. It is increasingly being used in the management of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. The development of rheumatoid nodules and leukocytoclastic vasculitis is reported with etanercept.74,75 A case of anterior nongranulomatous uveitis was reported in 2003 following subcutaneous etanercept treatment for ankylosing spondylitis.76 The close temporal association of the start of etanercept and the uveitis and challenge-rechallenge data suggests that etanercept might have provoked the anterior uveitis.
Ibuprofen, a noncorticosteroidal anti-inflammatory drug (NSAID), can cause aseptic meningitis. A patient with aseptic meningitis and bilateral nongranulomatous iridocyclitis related to ibuprofen has been reported. And it has been suggested that a hypersensitivity reaction to NSAID should be considered when a patient has neurologic abnormalities after initiation of NSAID therapy in the presence or absence of iridocyclitis.77
Topiramate (Topamax) is an oral sulfamate medication used primarily as an antiepileptic. It is also used in the treatment of bipolar disorders and pain control of migraine. Cases of acute myopia and bilateral angle-closure glaucoma with ultrasound biomicroscopic signs of ciliochoroidal effusion have been reported associated with topiramate use.78,79 Fluid accumulated in the supraciliary space with ciliary body detachment is the main factor producing anterior rotation of the ciliary body. This rotation pushes the iris anteriorly and closes the angle.80 Acute myopia is explained by the forward displacement of the lens caused by supraciliary effusion, although some authors suggest that ciliary body swelling and lens thickening may also play a role.81
Topical Drug-Induced Uveitis
The nonselective β-adrenergic blocking agent metipranolol (Optipranolol) appears to cause granulomatous anterior uveitis with prominent mutton fat82 or medium-sized keratic precipitates83 and can also cause nongranulomatous anterior uveitis.84 In 1991 Akingbehin et al.85 presented 15 patients who developed granulomatous anterior uveitis (GAU) with characteristic mutton-fat keratic precipitates after using metipranolol. Intraocular pressure elevations more than 5 mm Hg above their baseline levels developed in over half of the eyes with GAU. This rise in intraocular pressure with metipranolol-associated uveitis may be due to inflammatory debris blocking the trabecular meshwork. The authors rechallenged 7 of the original 26 patients using 0.3% metipranolol in one eye and 0.5% timolol in the fellow eye for up to 14 days.86 In all of the eyes that were rechallenged with metipranolol, GAU, marked intraocular pressure increase, blepharoconjunctivitis, or periorbital dermatitis developed within 14 days. Two weeks after discontinuing the medication, all the patients had complete resolution of symptoms. Uveitis did not develop in the eyes treated with timolol. Because of the relatively large number of cases, time of onset, corresponding laterality of occurrence to drug treatment, and recurrence upon rechallenge, this report strongly suggests that metipranolol was the cause of uveitis.54 The etiology of intraocular inflammation from metipranolol remains unclear.
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