Nitrogen-containing bisphosphonates are known to cause a systemic acute phase reaction, including the development of transient influenza-like symptoms, in approximately 30% of patients following the first intravenous infusion [49]

Nitrogen-containing bisphosphonates are known to cause a systemic acute phase reaction, including the development of transient influenza-like symptoms, in approximately 30% of patients following the first intravenous infusion [49]. with anti-vascular endothelial growth factor (anti-VEGF) agents has increased the prevalence and recognition of drug-induced uveitis. The mechanism(s) underlying drug-induced uveitis BT-11 are generally unclear, although both inflammatory and toxic reactions have been suggested to play a role [1-3]. As such, for each agent summarized below, we BT-11 only discuss the mechanism of drug-induced uveitis when specific studies have provided additional insight. This review highlights both well-established and recently reported systemic, topical, intraocular, and vaccine-associated causes of drug-induced uveitis. Although many drugs have been reported as causing uveitis, only those drugs with multiple independent publications to help confirm causation were further ranked. Using an algorithm originally proposed by Naranjo and associates, we quantitatively describe the association of various drugs to uveitis as definite, probable, possible, and doubtful (Table?1) [4]. Naranjo scores of 9 or higher imply a definite association, scores of 5 to 8 a probable association, scores of 1 1 to 4 a possible association, and scores of 0 make an association doubtful. Table?2 lists the drugs most strongly associated with uveitis. Table?3 provides a list of those reviewed in the current paper and their likelihood of causing uveitis based on the Naranjo scoring system. In addition, the likelihood of causation per the Naranjo criteria is listed in parentheses next to the name of the medication in each subsection. Current updates regarding specific agents may be found at http://www.eyedrugregistry.com. Table 1 The Naranjo scoresheet for assessing the association between a medication and an adverse reaction complex (MAC), typically for immunocompromised patients and particularly those infected by the HIV. It is most commonly associated with anterior uveitis with hypopyon (Figure?1), although intermediate uveitis, panuveitis, and retinal vasculitis have been reported [18,19]. Open in a separate window Figure 1 Slit-lamp photograph of hypopyon uveitis. A 17-year-old Eritrean girl who was on rifabutin for recurrent MAC prophylaxis developed anterior uveitis with a hypopyon. The patient also had retinal vasculitis. The inflammation completely resolved following cessation of rifabutin. Photograph courtesy of H. Nida Sen, MD, MHS (see [18]). Most of our understanding of rifabutin-induced uveitis BT-11 comes from cases series reported in the early- to mid-1990s [20-23]. Saran and associates described the clinical features of seven individuals with HIV/AIDS who received between 300 to 600 mg of rifabutin daily along with clarithromycin and fluoconazole, and the majority of individuals also received concomitant ethambutol. In this statement, five individuals presented with acute hypopyon uveitis 51 to 393 days (median 79 days) after starting the medications. All individuals eventually developed bilateral anterior uveitis. Vision recovered to 20/30 in all individuals within 3 weeks of starting topical corticosteroid treatment only, although three of the five individuals required rifabutin dose reduction and/or discontinuation. In a larger group of 24 individuals on 600 mg of rifabutin per day along with clarithromycin and ethambutol, Shafran and colleagues described the development of ocular irritation and redness in 75% and 54% of individuals, respectively, after a median of 42 days of rifabutin use. Photophobia occurred in 33% of individuals, and a hypopyon developed in 29% of individuals [24]. In the same study, individuals who have been on a lower dose of rifabutin (300 mg/day time) seldom developed uveitis, and when it occurred, it required at least 7 weeks of medication use for the uveitis to develop. Skinner and Blaschke consequently confirmed that drug-related uveitis was unusual at the recommended dose of 300 mg/day time [25]. Risk factors for the development of rifabutin-associated uveitis include dose and duration of rifabutin therapy, low body excess weight, and use of concomitant medications, including clarithromycin and ritonavir [21]. Inside a multivariate analysis of individuals taking 600 mg of rifabutin daily, Shafran and colleagues found that uveitis occurred in 64% of individuals weighing less than 55 kg, in 45% of individuals 55 to 65 kg, and in only 14% of individuals weighing over 65 kg [24]. Several medications, such as clarithromycin and ritonavir, may exacerbate rifabutin-related side effects such as uveitis through inhibition of hepatic cytochrome P-450 [26-28]. Although systemic azoles, such as fluoconazole, also inhibit cytochrome P-450, Shafran and associates found no evidence that concurrent use of systemic azoles improved the risk of uveitis [21]. Rifabutin-induced uveitis likely results from direct rifabutin toxicity. The association between rifabutin and uveitis is definitely supported by an association with dose and with the duration of use, as well as bilateral involvement, limited rechallenge data [29], and reversibility with drug discontinuation. Bisphosphonates (Naranjo.Naranjo scores of 9 or higher imply a definite association, scores of 5 to 8 a probable association, scores of 1 1 to 4 a possible association, and scores of 0 help to make an association doubtful. vaccine-associated causes of drug-induced uveitis. Although many drugs have been reported as causing uveitis, only Lamin A/C antibody those medicines with multiple self-employed publications to help confirm causation were BT-11 further rated. Using an algorithm originally proposed by Naranjo and associates, we quantitatively describe the association of various medicines to uveitis as certain, probable, possible, and doubtful (Table?1) [4]. Naranjo scores of 9 or higher imply a definite association, scores of 5 to 8 a probable association, scores of 1 1 to 4 a possible association, and scores of 0 make an association doubtful. Table?2 lists the medicines most strongly associated with uveitis. Table?3 provides a list of those reviewed in the current paper and their probability of causing uveitis based on the Naranjo rating system. In addition, the likelihood of causation per the Naranjo criteria is outlined in parentheses next to the name of the medication in each subsection. Current updates regarding specific providers may be found at http://www.eyedrugregistry.com. Table 1 The Naranjo scoresheet for assessing the association between a medication and an adverse reaction complex (Mac pc), typically for immunocompromised individuals and particularly those infected from the HIV. It is most commonly associated with anterior uveitis with hypopyon (Number?1), although intermediate uveitis, panuveitis, and retinal vasculitis have been reported [18,19]. Open in a separate window Number 1 Slit-lamp picture of hypopyon uveitis. A 17-year-old Eritrean woman who was on rifabutin for recurrent MAC prophylaxis developed anterior uveitis having a hypopyon. The patient also experienced retinal vasculitis. The swelling completely resolved following cessation of rifabutin. Picture courtesy of H. Nida Sen, MD, MHS (observe [18]). Most of our understanding of rifabutin-induced uveitis comes from instances series reported in the early- to mid-1990s [20-23]. Saran and associates described the medical features of seven individuals with HIV/AIDS who received between 300 to 600 mg of rifabutin daily along with clarithromycin and fluoconazole, and the majority of individuals also received concomitant ethambutol. With this statement, five individuals presented with acute hypopyon uveitis 51 to 393 days (median 79 days) after starting the medications. All individuals eventually developed bilateral anterior uveitis. Vision recovered to 20/30 in all individuals within 3 weeks of starting topical corticosteroid treatment only, although three of the five individuals required rifabutin dose reduction and/or discontinuation. In a larger group of 24 individuals on 600 mg of rifabutin per day along with clarithromycin and ethambutol, Shafran and colleagues described the development of ocular irritation and redness in 75% and 54% of individuals, respectively, after a median of 42 days of rifabutin use. Photophobia occurred in 33% of individuals, and a hypopyon developed in 29% of individuals [24]. In the same study, individuals who have been on a lower dose of rifabutin (300 mg/day time) seldom developed uveitis, and when it occurred, it required at least 7 weeks of medication use for the uveitis to develop. Skinner and Blaschke consequently confirmed that drug-related uveitis was unusual at the recommended dose of 300 mg/day time [25]. Risk factors for the development of rifabutin-associated uveitis include dose and duration of rifabutin therapy, low body excess weight, and use of concomitant medications, including clarithromycin and ritonavir [21]. Inside a multivariate analysis of individuals taking 600 mg of rifabutin daily, Shafran and colleagues found that uveitis occurred in 64% of individuals weighing less than 55 kg, in 45% of individuals 55 to 65 kg, and in only 14% of individuals weighing over 65 kg [24]. Several medications, such as clarithromycin and ritonavir, may exacerbate rifabutin-related side effects such as uveitis through inhibition of hepatic cytochrome P-450 [26-28]. Although systemic azoles, such as fluoconazole, also inhibit cytochrome P-450, Shafran and associates found no evidence that concurrent use of systemic azoles improved the risk of uveitis [21]. Rifabutin-induced uveitis likely results from direct rifabutin toxicity. The association between rifabutin and uveitis is definitely supported by an association with dose and with the duration of use, as well as bilateral involvement, limited rechallenge data [29], and reversibility with drug discontinuation. Bisphosphonates (Naranjo score 10, certain) Bisphosphonates are primarily used to treat osteoporosis and to prevent fractures due to malignant bone disease. While they are generally well tolerated [30], several medications in this class have been associated with uveitis. Moreover, bisphosphonates have been mentioned to cause scleritis/episcleritis in some individuals [31]. Intravenous pamidronate sodium is the bisphosphonate.