Intravitreal Sirolimus for the Treatment of Noninfectious Uveitis: Evolution through Preclinical and Clinical Studies

In recent decades, the treatment paradigm for noninfectious intermediate uveitis, posterior uveitis, and panuveitis, a group of intraocular inflammatory diseases, has included systemic and local (periocular or intraocular) corticosteroids, biologics, and other steroid-sparing immunomodulatory therapy agents. Recently, an intravitreal formulation of sirolimus, an immunosuppressant that inhibits the mammalian target of rapamycin, a key regulator of cell growth in the immune system, was developed. On the basis of this mechanism and the local method of delivery, it was hypothesized that intravitreal sirolimus can improve ocular inflammation in patients with noninfectious intermediate uveitis, posterior uveitis, and panuveitis, with minimal systemic exposure and systemic adverse events (AEs). This review summarizes the pharmacokinetics, efficacy, and safety results of intravitreal sirolimus from 3 preclinical studies and 4 phase 1–3 clinical studies. Preclinical studies in rabbits showed that 22 to 220 μg intravitreal sirolimus results in sustained release of sirolimus in the vitreous for 2 months or more, with systemic concentrations below the threshold for systemic immunosuppression (approximately 8 ng/ml). Subsequently, 2 phase 1 studies (n = 50 and n = 30) established that intravitreal sirolimus improves ocular inflammation in humans. Further investigation in phase 2 and 3 studies (n = 24 and n = 347, respectively) suggested that 440 μg has the best benefit-to-risk profile. In the phase 3 study, the proportion of patients who showed complete resolution of ocular inflammation at month 5 was significantly higher in the 440-μg group than in the 44-μg group (22.8% vs. 10.3%; P = 0.025, Fisher exact test). In addition, 47 of 69 patients (68.1%) who were treated with systemic corticosteroids at baseline discontinued corticosteroid use at month 5. No sirolimus-related systemic AEs were reported in phase 1–3 studies. Collectively, these preclinical and clinical study data of intravitreal sirolimus support the therapeutic rationale of treating noninfectious uveitis with a local mammalian target of rapamycin inhibitor and suggest that 440 μg intravitreal sirolimus has the potential to be an effective and well-tolerated anti-inflammatory and corticosteroid-sparing treatment for noninfectious intermediate uveitis, posterior uveitis, and panuveitis

Posterior segment manifestations of human immunodeficiency virus/ acquired immune deficiency syndrome

Ocular manifestations can occur in up to 50% of human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS) patients and posterior segment involvement is the most common presentation. The posterior segment manifestations of AIDS can be divided into four categories: retinal vasculopathy, opportunistic infections, unusual malignancies and neuro-ophthalmologic abnormalities. Retinal microvasculopathy and cytomegalovirus (CMV) retinitis are the most common manifestations, even in the era of highly active anti-retroviral therapy (HAART). Highly active anti-retroviral therapy has been shown to cause regression of CMV retinitis, reduce the incidence of CMV-related retinal detachments, and prolong patient survival. Immune recovery uveitis is a new cause of vision loss in patients on HAART. Diagnosis and treatment are guided by the particular conditions and immune status of the patient

Effect of combination antiretroviral therapy on cytomegalovirus retinitis

Purpose: To study the various changes in the course of cytomegalovirus (CMV) retinitis following combination antiretroviral treatment. Methods: Combination antiretroviral treatment was given to 12 patients with active CMV retinitis following which all anti-CMV medications were discontinued once the CD4 cell counts were> 100/mm3 for 3 months. Results: The median CD4 cell count increased from 36.5/mm3 (range, 3-74/mm3) at baseline to 175.5/mm3 (range, 97-410/mm3) at 3 months. No patient had reactivation of CMV retinitis or developed extraocular CMV infection during median follow-up of 16.7 months. In one patient with peripheral active CMV retinitis, the retinitis resolved completely and remained so throughout the follow-up period without specific anti-CMV treatment. Five (41.7%) patients had immune recovery vitritis. Conclusion: Patients receiving combination antiretroviral treatment following treatment for CMV retinitis have better control of CMV retinitis but immune recovery vitritis is a common sequelae. Reactivation of CMV retinitis is common in patients who discontinue combination antiretroviral treatmen

Chronic NonInfectious Uveitis of the Posterior Segment: Current and Future Approaches to Individualize Management

Uveitis involving the posterior segment is a sight-threatening condition that can be associated with multiple underlying ocular and systemic diseases. Accurate diagnosis is the foundation for selecting treatment that can preserve vision and is guided by the findings of a thorough history, clinical examination, laboratory testing, and imaging. Evaluation and management of posterior uveitis varies globally, however, because of geographic/ethnic variation in its causes, differences in local practices, and varying access to diagnostic modalities and treatments. This case-based program captures the highlights of a roundtable discussion, in which an international panel of uveitis subspecialists provides their expert perspectives on the diagnosis and management of uveitis involving the posterior segment, including the role of emerging diagnostic techniques and new and emerging therapies. The cases are from the files of Sunil K. Srivastava, MD.This educational activity is intended for European, Asia/Pacific, and US ophthalmologists caring for patients with noninfectious uveitis of the posterior segmentThe New York Eye and Ear Infirmary of Mount Sinai designates this enduring material for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity

Intraocular cilia associated with perforating injury

<b>Purpose:</b> To report a case series of penetrating injury complicated by occurrence of intraocular cilia. <b>Methods:</b> Retrospective analysis of charts of 11 eyes of 11 patients with penetrating injury and intraocular cilia, presenting between September 1978 and November 1998. Ten eyes underwent surgery for trauma-related problems such as cataract, vitritis, retinal detachment etc., at which time intraocular cilia were removed. One eye did not have surgery and continues to harbour cilia at the posterior perforation site. <b>Results:</b> Metallic wire was responsible for injury in 6 of 11 eyes with intraocular cilia. Five eyes had significant intraocular inflammation. The cilia were located in the anterior segment in 4 eyes; in the posterior segment in 6 eyes and in both in one eye. At the last follow up, 72.7&#x0025; had 6/18 or better vision. Poor vision in the rest was due to recurrent retinal detachment (2 eyes) and macular scarring (1 eye). <b>Conclusion:</b> Intraocular cilia are more commonly associated with injury by a metallic wire. The presentation and management of an injured eye does not seem to be influenced by the presence of cilia in the eye

Current approaches to diagnosis and management of ocular lesions in human immunodeficiency virus positive patients

Human immunovirus infection in India is rapidly increasing. Ocular lesions due to highly active antiretroviral therapy have been well recognized. Acquired immunodeficiency syndrome can affect all parts of the eye. However, posterior segment lesions are the most common and of these, Human immunodeficiency virus retinopathy and cytomegalovirus retinitis predominate. Often clinical examination can establish the diagnosis of many ocular lesions in acquired immunodeficiency syndrome; therefore, ophthalmologists need to be aware of the more common ones. Various drugs in different routes can used to treat cytomegalovirus retinitis. Highly active antiretroviral therapy has remarkably reduced systemic and ocular morbidity among acquired immunodeficiency syndrome patients. To facilitate care of these patients aseptic precautions for ophthalmic care personnel are now well established and therefore ophthalmologist should not hesitate to provide ophthalmic care to acquired immunodeficiency syndrome patients

Polypoidal choroidal vasculopathy: Pearls in diagnosis and management

Polypoidal choroidal vasculopathy (PCV) is increasingly recognized as an important cause of exudative maculopathy in Asians as against Wet age-related macular degeneration in Caucasians. A panel of retinal experts methodically evaluated pertinent updated literature on PCV with thorough PubMed/MEDLINE search. Based on this, the panel agreed upon and proposed the current consensus recommendations in the diagnosis (clinical and imaging), management and follow-up schedule of PCV. Diagnosis of PCV should be based on the gold standard indocyanine green angiography which demonstrates early nodular hyperfluorescence signifying the polyp with additional features such as abnormal vascular network (AVN). Optical coherence tomography is an excellent adjuvant for diagnosing PCV, monitoring disease activity, and decision-making regarding the treatment. Current treatment modalities for PCV include photodynamic therapy, anti-vascular endothelial growth factor agents, and thermal laser. Choice of specific treatment modality and prognosis depends on multiple factors such as the location and size of PCV lesion, presence or absence of polyp with residual AVN, amount of submacular hemorrhage, presence or absence of leakage on fundus fluorescein angiography, visual acuity, and so on. Current recommendations would be invaluable for the treating physician in diagnosing PCV and in formulating the best possible individualized treatment strategy for optimal outcomes in PCV management

Comparison of RetCam and Smartphone-Based Photography for Retinopathy of Prematurity Screening

This study aimed to compare the clinical performance between a smartphone-based fundus photography device and a contact imaging device for retinopathy of prematurity (ROP) screening. All patients were first examined with binocular indirect ophthalmoscopy (BIO), which served as the reference standard. The patients were then assessed by two devices. Imaging quality, ability to judge the zone and stage of ROP, agreement with the BIO results, vital signs, and pain scores were compared between these two devices. In total, 142 eyes of 71 infants were included. For the smartphone-based fundus photography, image quality was graded excellent or acceptable in 91.4% of examinations, although it was still significantly inferior to that of the contact imaging device (p &lt; 0.001). The smartphone-based fundus photography images had moderate agreement with the BIO results regarding the presence or absence of plus disease (Cohen&rsquo;s &kappa; = 0.619), but evaluating the zone (p &lt; 0.001) and stage (p &lt; 0.001) of ROP was difficult. Systemic parameters, except for heart rate, were similar between the two imaging devices (all p &gt; 0.05). In conclusion, although the smartphone-based fundus photography showed moderate agreement for determining the presence or absence of plus disease, it failed to identify the zone and stage of ROP