methoxazole therapy and 4 showed effects within 24 hours. Three patients had histories of rechallenge with trimethoprim-sulfamethoxazole, and in each case acute iritis recurred within 24 hours of reinstitution of therapy. Five patients had additional evidence of an adverse reaction manifest as cutaneous involvement, stomatitis, glossitis, conjunctival and scleral injection, and granulomatous hepatitis.
In addition to uveitis, retinal hemorrhage has been associated with the use of trimethoprim-sulfamethoxazole. Colon et al reported a patient who developed bilateral intermediate uveitis and intraretinal hemorrhages after the use of trimethoprim-sulfamethoxazole. Kristinsson et al reported a patient who developed bilateral anterior uveitis after taking trimethoprim-sulfamethoxazole and bilateral anterior uveitis and retinal hemorrhages after the use of trimethoprim alone. Hence, it is possible that trimethoprim could have played an etiologic role in some of the cases of uveitis and retinal hemorrhage associated with the use of trimethoprim-sulfamethoxazole.
Ocular Hypotensive Drugs
Betaxolol is a cardioselective [beta]1 adrenergic receptor blocker used in the treatment of ocular hypertension and glaucoma. Jain reported a patient who developed bilateral anterior uveitis 3 weeks after starting to take betaxolol 0.5% twice daily in both eyes for ocular hypertension. The uveitis resolved over a period of 4 weeks after stopping the betaxolol and with the administration of topical fluorometholone.
Brimonidine is a selective α2 adrenergic receptor agonist that is used in the treatment of ocular hypertension and glaucoma. Byles et al reported 4 patients who developed acute granulomatous anterior uveitis 11 to 15 months after using brimonidine 0.2% twice daily. The uveitis resolved rapidly after stopping the brimonidine and after taking topical steroids. In all patients, on rechallenge with brimonidine in 1 eye, the uveitis recurred within 3 weeks only in the eye that had received the rechallenge with brimonidine. Subsequently, additional reports have appeared implicating the use of topical brimonidine in the development of granulomatous anterior uveitis.[43–46] In those reports the patients developed anterior uveitis after a prolonged use of brimonidine similar to the cases reported by Byles and colleagues.
Pilocarpine and Other Cholinergic Drugs
A faint flare is often seen in association with the use of cholinergic drugs.[47,48] In addition, posterior synechiae may form with the use of cholinergics, especially with the long-acting acetylcholinesterase inhibitors. Jain et al reported a patient who developed granulomatous iridocyclitis and posterior synechiae after using 1% pilocarpine twice daily for 13 months. The uveitis resolved shortly after stopping the pilocarpine drops and with the administration of betamethasone drops.
Metipranolol is a nonselective [beta] adrenergic receptor blocker used in the treatment of ocular hypertension and glaucoma. Akingbehin and Villada reported the occurrence of 56 episodes of granulomatous anterior uveitis in 26 eyes of 15 patients who were being treated with metipranolol. Metipranolol used at a concentration of 0.6% was implicated in 54 of those 56 episodes, whereas 0.3% metipranolol was implicated in the other 2 episodes. There was an increase in intraocular pressure in 30 of the 56 episodes. The time duration from the start of metipranolol therapy to the onset of the first episode of anterior uveitis ranged from 2 to 31 months. The episodes were treated by discontinuing the metipranolol and also, in the majority of the cases, with the institution of topical steroid therapy. The eyes recovered fully except for 3 eyes that developed posterior synechiae. In another report, Melles and Wong reported 2 patients who developed granulomatous anterior uveitis after taking 0.3% metipranolol. The uveitis in those patients was also associated with an increase in intraocular pressure and it resolved after the discontinuation of the metipranolol. One of the patients was inadvertently rechallenged and had a recurrence of the iritis. Conversely, however, a retrospective cohort study by Beck et al on 1928 patients using 0.3% metipranolol found no cases of uveitis among treated patients indicating the rarity of this adverse effect of metipranolol when used at a concentration of 0.3%.
Prostaglandin analogs, including latanoprost, travoprost, and bimatoprost, are widely used in the treatment of ocular hypertension and glaucoma. The use of latanoprost has been implicated in some cases of uveitis, although this is somewhat controversial.[54,55] Warwar et al carried out a retrospective study on 163 eyes of 94 patients who were taking latanoprost and reported that 8 of those eyes had anterior uveitis and 2 of the eyes developed cystoid macular edema. In another study, Smith et al retrospectively reviewed the charts of 527 patients on latanoprost and found that 5 of 505 patients with no prior history of uveitis developed a mild delayed uveitis while on latanoprost. However, they did not find worsening of uveitis after starting latanoprost in 9 patients who had an active uveitis at the time of initiation of latanoprost therapy.
In addition to latanoprost, the 2 other commonly used prostaglandin analogs, namely travoprost[58–62]and bimatoprost,[63,64] have also been implicated in some cases of anterior uveitis. In 1 report, Faulkner and Burk reported a patient in whom acute anterior uveitis developed just after 5 doses of travoprost. Chiam reported another case in whom bilateral granulomatous uveitis developed after taking travoprost for 2 months. The uveitis resolved with the discontinuation of the travoprost and with the initiation of topical steroids. On rechallenge of 1 eye with travoprost, uveitis recurred in that eye. Parentin reported a patient who developed unilateral granulomatous anterior uveitis 1 week after starting to take bimatoprost in the affected eye. The uveitis resolved over a period of 2 weeks after the discontinuation of the bimatoprost and without the need to use topical steroids. In another report, Packer et al described a patient who developed symptoms within 1 hour of the first dose of bimatoprost and was diagnosed with nongranulomatous anterior uveitis. The bimatoprost was discontinued and the uveitis resolved with topical steroid therapy. As this risk is fairly low, however, the authors commonly utilize prostaglandin analogs as topical hypotensive agents of last resort as part of maximal-tolerated medical therapy before indication of surgical management of uveitic glaucoma.
Bisphosphonates, such as etidronate, pamidronate, alendronate, risedronate, and zoledronate, are analogs of pyrophosphate that retard the formation and dissolution of hydroxyapatite crystals in skeletal and nonskeletal tissues.They inhibit bone resorption and are indicated for the treatment of osteoporosis. In a literature review reported by Rey et al,18 patients developed ocular side effects within 24 to 48 hours of initiation of an infusion of bisphosphonate. The most common manifestation was anterior uveitis and the majority of the cases had bilateral involvement. Discontinuation of the bisphosphonate and initiation of steroid therapy resulted in a favorable outcome. Anterior uveitis has been reported after the administration of pamidronate, alendronate, risedronate, and zoledronate.[67,68] Fraunfelder and Fraunfelderreviewed data from the spontaneous reporting systems of the National Registry of Drug-Induced Ocular Side Effects, the Food and Drug Administration, and the World Health Organization and reported that there were 66 cases of uveitis associated with pamidronate and 19 cases of uveitis associated with alendronate. In addition to being implicated in the development of uveitis, some bisphosphonates have been associated with scleritis[69–72] or orbital inflammation.[73,74]
Antitumor Necrosis Factor α (Anti-TNF-α) Agents
The anti-TNF-α agents etanercept, infliximab, and adalimumab have been implicated in the development of uveitis in a few anecdotal reports.[75–79] Lim et al reviewed all cases of uveitis associated with etanercept, infliximab, and adalimumab reported to national databases between 1998 and 2006, after excluding patients with underlying disease likely to be associated with uveitis. Overall, in that review, there were 43 cases of uveitis associated with etanercept, 14 associated with infliximab, and 2 associated with adalimumab. After normalizing for the estimated number of patients treated with each medication, etanercept was associated with a greater number of uveitis cases than infliximab (odds ratio, 5.375; P<0.001) and adalimumab (odds ratio, 8.6; P<0.01), whereas no such association was found between adalimumab and infliximab (odds ratio, 1.6; P> 0.5). It is possible that, rather than causing uveitis, etanercept is simply less effective than the other TNF-α blockers in preventing the development of uveitis in susceptible patients.
Antivascular Endothelial Growth Factor Agents
Pieramici et al first reported a patient who developed unilateral anterior nongranulomatous uveitis and posterior synechiae 3 weeks after receiving the fourth dose of bevacizumab for neovascular age-related macular degeneration in the affected eye after the 3 initial injections were uneventful. The uveitis resolved within a week after receiving topical steroid therapy. Kay et al carried out a retrospective case series on a cohort of 978 consecutive bevacizumab injections and found that 7 eyes of 6 patients developed noninfectious uveitis (with anterior chamber and vitreous cellular reaction) after bevacizumab intravitreal injections. All patients developed symptoms within 1 day of injection. There was no hypopyon and the inflammation resolved rapidly after topical steroid therapy. A few other articles have also reported the occurrence of acute anterior uveitis after injection with intravitreal bevacizumab or ranibizumab.[83–85] Glading et al reported 2 cases of anterior and posterior uveitis that occurred 4 weeks or more after the first intravitreal injection of aflibercept. Both of those patients had received other vascular endothelial growth factor inhibitors before aflibercept administration without signs of inflammation.
Knopf reported a patient who had a complicated cataract surgery with resultant uveitis and who developed a relapse of inflammation after a subsequent influenza vaccination. Four months after an apparently complete recovery from the postcataract surgery uveitis the patient received an influenza vaccine. Within 2 weeks after the vaccination the patient had a recrudescence of the ocular inflammation accompanied by cystoid macular edema and reduced vision. The authors suggested that the patient might have underwent “immune priming” as a result of the cataract surgery, a process that might have predisposed the patient to develop an immune-mediated uveitis after the influenza vaccine. Blanche et alreported a case of uveitis that became evident 48 hours after an initial vaccination with influenza. The patient received an inactivated vaccine and developed bilateral anterior and posterior uveitis. The uveitis responded to topical steroid therapy and the patient was weaned off steroid drops after 90 days of therapy. Wells and Gargreported a patient who developed symptoms within 1 day after receiving an influenza vaccination. The patient was diagnosed with bilateral panuveitis that responded well to local and systemic steroid therapy.
Hepatitis B Vaccine
Fraunfelder et al examined spontaneous reports from the National Registry of Drug-Induced Ocular Side Effects, the World Health Organization, and the Food and Drug Administration collected between 1982 and 2009 to evaluate for any association between hepatitis B vaccination and uveitis. Thirty-two cases of uveitis occurring after hepatitis B vaccine were reported to these databases. The number of days until uveitis was reported after vaccination ranged between 1 and 15 days. The uveitis was reported to occur after the first vaccination in 15 patients, after the second vaccination in 3 patients, and after the third vaccination in 3 patients.
Human Papilloma Virus (HPV) Vaccine
Holt et al examined spontaneous reports from the National Registry of Drug-Induced Ocular Side effects, World Health Organization, and Food and Drug Administration to evaluate the association between HPV vaccination and uveitis. A total of 24 case reports of uveitis associated with HPV vaccination were identified. The time from HPV vaccination to reported uveitis ranged from 0 to 476 days (median, 30 d).
Measles, Mumps, and Rubella (MMR) Vaccine
Islam et al reported 2 patients who developed bilateral nongranulomatous anterior uveitis 4 and 6 weeks after receiving an MMR vaccine. Both patients responded to steroid therapy but required several months of treatment. In another report, Ferrini et al presented a patient who developed unilateral anterior uveitis 3 months after receiving an MMR vaccination. The patient also had iris heterochromia, rubeosis, seclusio pupillae, and a dense nuclear cataract and cortical cataract in the affected eye. Aqueous humor analysis showed the presence of more rubella-specific immunoglobulin G in the affected eye than in the unaffected one with a Goldmann-Witmer coefficient of 1.69 for the affected eye. The inflammation responded well to systemic and local steroid therapy.
Esmaeli-Gutstein and Winkelman reported a patient who developed unilateral anterior uveitis 7 days after receiving a live attenuated varicella vaccine. The patient also had developed a generalized vesicular skin rash 2 days after receiving the vaccine. The patient was successfully treated with systemic acyclovir and topical steroids with a quick response. Sham and Levinson reported a patient with a previous history of herpes zoster dermatitis in the area of distribution of the ophthalmic division of the trigeminal nerve and anterior uveitis (treated at the time with a course of systemic valacyclovir and long-term topical steroids) who developed unilateral anterior uveitis 3 weeks after receiving a herpes zoster vaccination. The patient had weaned off topical steroids 7 months before receiving the vaccine. The uveitis that occurred after the herpes zoster vaccination responded well to systemic valacyclovir and topical steroids. Gonzales et al reported a patient who developed acute retinal necrosis 1 month after receiving a varicella vaccine while on immunosuppressive treatment. In that patient, polymerase chain reaction assay performed on a vitreous aspirate was positive for a strain of varicella zoster virus similar to the one used in the vaccine.
Diethylcarbamazine is a piperazine derivative that is used in the treatment of filariasis, loiasis, and tropical eosinophilia. It was used previously in the treatment of onochcerciasis but has been replaced with ivermectin for this indication. Diethylcarbamazine treatment for onchocerciasis often resulted in ocular and systemic complications. The reported ocular complications including anterior uveitis and chorioretinitis were believed to be associated with circulating immune complexes.
Myers and Fraunfelder reported a patient who developed bilateral anterior uveitis while on ovulation induction therapy with clomiphene. The patient was treated with topical steroids successfully but developed a recurrence of the bilateral anterior uveitis on rechallenge with clomiphene 3 months later.
Avadhani et al reported a patient who developed acute anterior uveitis within a couple of hours after the topical administration of podophyllum, a drug used for the treatment of warts. The condition resolved with topical steroids. The uveitis recurred when the patient again used podophyllum 2 months later.
Quinidine is a stereoisomer of quinine used in the treatment of cardiac arrhythmia. Spitzbergreported 2 patients who developed bilateral anterior uveitis several days after beginning systemic quinidine therapy. Both patients exhibited Koeppe nodules. The uveitis responded to a short course of topical steroid therapy. Subsequently, additional reports have implicated quinidine in cases of anterior uveitis.[101,102]
Topiramate is a sulfamate-substituted monosaccharide that was initially approved for the treatment of epilepsy. It is also indicated in the treatment of migraine headache. Katsimpris et al reported the occurrence of bilateral anterior uveitis and angle closure glaucoma in a patient after the systemic administration of topiramate. Jabbarpoor et al reported the development of bilateral anterior uveitis with hypopyon formation in a patient after the systemic administration of topiramate for migraine headache. The topiramate was discontinued and the inflammation resolved after topical and systemic steroid therapy.
Tuberculin is an extract of M. tuberculosis used in skin testing to identify the presence of past or current tuberculosis infection. One form of tuberculin in common use is purified protein derivative (PPD), which contains the active protein fraction of tuberculin. Burgoyne et al reported the development of acute panuveitis that progressed to bilateral serous retinal detachments after the administration of a PPD skin test. The skin reaction was done 13 days before the onset of the symptoms and was intensely positive showing an induration of 29 mm at 48 hours. The condition recurred 8 years later when the PPD skin test was repeated. The repeat PPD test showed an induration of 70 mm at 48 hours and was administered 8 days before the onset of symptoms. Both episodes of uveitis responded to steroid therapy. Interestingly, the patient did not have any clinical evidence of ocular or systemic tuberculosis.
Many drugs are associated with the development of uveitis in susceptible patients although, often, the pathogenetic mechanisms are not clear. The onset of uveitis can be immediate or delayed by interval that could be several months after the administration of the inciting drug. The uveitis caused by drugs typically resolves without major sequelae if prompt treatment, including the discontinuation of the offending agent and the institution of steroid therapy, is undertaken. The ophthalmologist should keep in mind the recent medications as possible causes of uveitis whenever evaluating an existing patient or a new patient with uveitis. Therefore, it is important to review the past and current medication history of the patient, especially when evaluating a new patient or when managing a patient returning with a recurrence.