Drug Induced Uveitis

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Introduction

Uveitis is usually caused by autoimmune or infectious causes, but sometimes systemic or topical drugs can lead to intraocular inflammation. Drug-induced uveitis is a relatively rare occurrence, but can be missed as a cause of ocular inflammation.

Etiology and Epidemiology

Drug-induced uveitis is a relatively rare occurrence and is reported to represent less than 0.5 % of cases in a tertiary referral uveitis clinic [1]. The time between medication use and occurrence of symptoms varies, ranging from a few days to months. Common symptoms include: pain, photophobia, blurred vision, and redness. The cause for drug-induced inflammation is not well known. Postulates include direct and indirect mechanisms. Direct mechanisms are typically seen soon after medication use, typically occurring with topical or intracamerally instilled drugs. Indirect mechanisms include immune complex deposition in uveal tissues, immune reactions to antigens released from antibiotic-induced death of microorganisms, or an alteration of melanin’s ability to scavenge free radicals [2].

In the late 1980s, Naranjo et al [3] proposed a set of criteria to establish a causality of adverse drug effects:

  • The reaction is frequently described and documented
  • Recovery of symptoms occurs when the drug is tapered or discontinued
  • Other causes for symptoms have been excluded
  • Symptoms worsen when the dose of the drug is increased
  • The adverse event is documented by objective evidence
  • Similar effects occur in a patient with similar drugs
  • Symptoms recur with re-challenge of the suspected drug


Note that not all these criteria have to be fulfilled. If the drug is suspected of inducing uveitis, then the proposed solutions are to stop the offending drug and/or switch medications. Drug-induced uveitis typically resolves within weeks with discontinuation of the offending agent and treatment of the ocular inflammation.

Systemic Medications

Rifabutin

Rifabutin is used for the treatment and prophylaxis of the Mycobacterium avium complex (MAC) infection in HIV-positive patients. Symptoms of anterior uveitis with or without hypopyon, intermediate uveitis or posterior uveitis may occur between 2 weeks to 7 months following start of therapy [4]. Uveitis has been reported to occur with this drug alone [5] as well in combination of other anti-microbial agents such as azithromycin, erythromycin, clarithromycin, ethambutol, and fluconazole. Symptoms have presented after doses as low as 300 mg/day and can recur with re-challenge [6] [7] [8]. Uveitis can also increase in severity with elevation of dose.

Symptoms

Unilateral or bilateral - pain, redness, photophobia, blurred vision

Signs

Conjunctival injection, keratic precipitates, anterior chamber cell/flare with or without hypopyon, vitreous cell, perivascular retinal infiltrates [9]

Treatment

Discontinue rifabutin

  • Treat inflammation with topical steroids and cycloplegic agents

Prognosis

  • Most cases resolve within 1-2 months of discontinuation of rifabutin and administration of topical corticosteroids


Cidofovir

Cidofovir, a DNA polymerase inhibitor, is administered intravenously and intravitreally for the treatment of cytomegaloviral (CMV) retinitis. Anterior uveitis has been reported in 26-52% of patients with CMV retinitis after intravenous treatment after a median of 4-11 doses of intravenous cidofovir [10] [11] [12]. Hypotony and uveitis have also been reported in a patient with non-ocular CMV infection (encephalitis) [13]. This patient had a normal fundus exam, suggesting a direct effect on the ciliary body [13][14]. Uveitis has also been reported in patients receiving intravitreal cidofovir for treatment of CMV retinitis. One case series reported anterior uveitis in 26% of patients after a single intravitreal injection. Concomitant use of systemic probenecid decreased the frequency of inflammation [15]. The risk of cidofovir-associated uveitis is increased with a history of CMV retinitis [11], treatment with highly active antiretroviral therapy (HAART) and with rising CD4 counts [16]. Because of its association with immune recovery uveitis, cidofovir should probably not be used if immune recovery is expected [17].

Symptoms

Pain, redness, photophobia, tearing and decreased vision

Signs

Unilateral/bilateral non-granulomatous anterior uveitis with or without keratic precipitates, posterior synechiae, hypopyon, and anterior vitreous cell

  • Possible severe and fibrinous uveitis, accompanied by hypotony [14]>

Treatment/Prognosis

Discontinuation of cidofovir

  • Aggressive topical steroid and cycloplegic agents
  • Outcomes are variable with potential for permanent structural complications such as posterior synechiae and hypotony

Bisphosphonates

Bisphosphonates are used to inhibit bone resorption in patients with osteoporosis. They are also used to manage hypercalcemia associated with osteolytic bone cancer, metastatic disease to bone, and Paget’s disease of bone [18]. Inflammation has been reported after both nitrogen and non-nitrogen-containing bisphosphonates and also after intravenous or oral use. The interval between exposure and symptoms tends to be shorter with intravenous administrations, with onset as early as 6 hours after IV administration and several days after oral use [19]. Most reports of uveitis or scleritis have been after pamidronate disodium [18][19][20] [21], but inflammation has also been reported after zoledronate [22], alendronate sodium [18][23], risedronate sodium [18], and etidronate sodium [18]. Bisphosphonates stimulate 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 which results in the development of uveitis or scleritis [19][21]. 17 cases of unilateral scleritis and one case of bilateral scleritis were reported within 6 hours to 2 days after intravenous pamidronate sodium injection in one series, with positive dechallenge and rechallenge data [20]. In 16 of these cases the inflammation was anterior, and in one case, it was posterior [20]. In general, the bisphosphonate must be discontinued for scleritis to resolve, even with medical management [21]. Uveitis is generally bilateral with onset in the first 48 hours of drug exposure. In many patients, the drug must be discontinued, with favorable resolution after a short course of topical steroids [20].

Symptoms

  • Unilateral or bilateral - redness, pain, photophobia, blurred vision

Signs

Conjunctivitis

  • Episcleritis
  • Scleritis
  • Iritis - anterior chamber reaction with cell/flare

Treatment

Nonspecific conjunctivitis seldom requires treatment; NSAID eye drops may provide symptomatic relief

  • Episcleritis can be treated with topical NSAIDs or steroid drops
  • Anterior uveitis can vary in severity, and may be treated with topical or systemic steroids depending on severity. In most cases, bisphosphonates must be discontinued to resolve
  • In cases of scleritis, bisphosphonates must be discontinued, regardless of anti-inflammatory therapy [19]

Prognosis

  • Resolves with medical management and discontinuation of bisphosphonates

Sulfonamides

Sulfonamides are a primary treatment of many bacterial infections, including urinary tract infections, otitis media, bronchitis, sinusitis, and pneumonia. Ocular side effects are common, with reported symptoms and signs including visual disturbances, keratitis, conjunctivitis, periorbital edema [24], and rarely uveitis. 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 [24]

Symptoms

  • Pain, redness, light sensitivity, vision changes

Signs

Unilateral/bilateral acute iritis

  • Autoimmune dysfunction such as Stevens-Johnson syndrome

Treatment/Prognosis

Discontinuation of sulfonamide in severe uveitis

  • Treatment of iritis with topical steroids and cycloplegic agents

Moxifloxacin

Moxifloxacin is a fourth-generation fluoroquinolone used for the treatment of acute bacterial sinusitis, acute bacterial exacerbation of chronic bronchitis, community acquired pneumonia, complicated and uncomplicated skin and skin structure infections, and complicated intra-abdominal infections [25]. The first case of systemic moxifloxacin-induced uveitis was described in 2004 in a 77 year-old woman treated for pneumococcal pneumonia who developed bilateral acute anterior uveitis and pigment dispersion [26]. Multiple cases have been reported since [27], with similar presentations. The relationship between systemic fluoroquinolone treatment and the occurrence of uveitis has been considered "possible", according to World Health Organization criteria, in a recent retrospective analysis of 40 case reports [28]. Moxifloxacin was suspected in 25 of these cases. The presence of both iris transillumination and pigment dispersion appears specific to this syndrome.

Signs/Symptoms

Bilateral eye pain, photophobia, +/-redness

  • Acutely, bilateral aqueous cells with significant pigment dispersion, endothelial dusting, +/- posterior synechiae, segmental iris transillumination, +/- increased IOP
  • Residual diffuse iris transillumination defects and mydriasis after treatment of acute signs and symptoms

Treatment

  • Discontinue moxifloxacin
  • Topical steroids as needed for aqueous cell

Topical Agents

Metipranolol

Metipranolol is a topical, non-selective β1/β2 blocker used in the treatment of glaucoma that reduces intraocular pressure via decreased aqueous humor production. It is the most common beta-blocker to cause uveitis [29] [30], although the incidence is still rare.

Signs/Symptoms

  • Unilateral/Bilateral granulomatous and non-granulomatous anterior uveitis
  • Keratic precipitates
  • Anterior chamber cell with cell/flare
  • Iris nodules may be present [31] [32]

Treatment/Prognosis

  • Treatment of iritis with topical steroids and cycloplegic agents with resolution of symptoms typically in 3-5 weeks
  • Discontinuation of metipranolol

Brimonidine

Brimonidine tartrate is a highly selective α2 adrenoreceptor agonist that lowers intraocular pressure by reducing aqueous production and increasing uveoscleral aqueous outflow. It is used as a long-term glaucoma treatment, and is typically well tolerated. The most common ocular adverse event is allergic reaction, severe enough to warrant discontinuation of the drop in 7% to 15% of patients [33] [34]. Conjunctival follicles have been reported in 8% of patients [33][34]. Anterior uveitis secondary to brimonidine is rare and typically develops 11-15 months after initiation of therapy [35]. The uveitis may be granulomatous [36].

Signs/Symptoms

  • Redness, photophobia, blurred vision - keratic precipitates, posterior synechiae, iris nodules, anterior chamber cell/flare

Treatment/Prognosis

  • Discontinuation of brimonidine
  • Topical steroids and cycloplegic agents generally treat and resolve inflammation and symptoms

Prostaglandin-Analogues

Prostaglandin-analogues are used to treat open-angle glaucoma and ocular hypertension, and act via increasing uveoscleral outflow. They are the newest class of hypotensive agents and often first-line treatment of glaucoma and ocular hypertension. In one case series, iritis was seen in 4.9% of patients treated with latanoprost within 6 months of starting the medication [37]. This study also reported a 2.1% incidence of cystoid macular edema, with a previous history of CME, iritis, intra-operative vitreous loss, or anterior chamber intraocular lens being risk factors. Other case reports have showed uveitis caused by bimatoprost [38] and travoprost [39].

Signs/Symptoms

  • Pain, redness, decreased vision
  • Mild anterior chamber reaction, CME

Treatment/Prognosis

  • Resolution of iritis within 1-2 weeks of discontinuation
  • Topical steroids may be necessary
  • CME may require therapy, and take longer to resolve

Drug-Induced Tubulointerstitial Nephritis and Uveitis (TINU) syndrome

TINU syndrome is a distinct entity that was initially reported primarily in young women, although there is likely no female preponderance and all ages may be affected [40]. The renal disease is characterized by acute interstitial nephritis with a predominantly T-lymphocyte infiltrate, whereas the ocular disease is most often a bilateral anterior uveitis that may occur before, simultaneous with, or after the onset of renal disease. Cell-mediated immune dysfunction has been implicated in the pathogenesis of TINU syndrome, but a cause has not yet been identified [41].

TINU has been described in case reports following flurbiprofen [42] and the Chinese herb “Goreisan” [43]. In one review of TINU, 24% of cases occurred in patients after antibiotic use, often to treat respiratory infections, and 18% of patients reported recent use of an NSAID [44].

Signs/symptoms

Systemic illness lasting ≥ 2 weeks with fever, weight loss, anorexia, malaise, fatigue, rash, abdominal or flank pain, arthralgias, or myalgias. Associated laboratory evaluation may demonstrate anemia, elevated liver function tests, eosinophilia, and elevated Westergren erythrocyte sedimentation rate [40]

  • Bilateral anterior uveitis with or without intermediate uveitis or posterior uveitis
  • Acute interstitial nephritis (AIN) based on histopathology (renal biopsy) or clinical features (elevated serum creatinine or decreased creatinine clearance, increased urinary beta-2 microglobulin, low grade proteinuria, hematuria or pyuria in the absence of infection, urinary white cell casts, or normoglycemic glucosuria
  • Onset of uveitis usually occurs prior to renal disease, but can occur following the renal disease

Treatment/Prognosis

  • Discontinue offending agent
  • Topical steroids for anterior uveitis
  • Oral steroids with or without steroid-sparing immunosuppression may be necessary for uveitis and renal disease
  • While a large majority of the cases are limited in duration, recurrences are not uncommon. Some patients may also develop chronic uveitis [40]

Acknowledgements

  • Article co-authored by Panagiotis Alexakos

Additional Resources

References

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