sirolimus and Uveitis--Posterior

Local therapeutics play an important role in the management of infectious and noninfectious uveitis (NIU) as well as certain masquerade syndromes. This review highlights the established therapeutics and those under investigation for the management of uveitis.. An injectable long-acting fluocinolone acetonide insert was recently approved by the Food and Drug Administration for the treatment of NIU affecting the posterior segment. Intravitreal methotrexate, sirolimus, and anti-vascular endothelial growth factor (VEGF) agents are being evaluated for efficacy in NIU. Intravitreal foscarnet and ganciclovir are important adjuncts in the treatment of viral retinitis as are methotrexate and rituximab for the management of vitreoretinal lymphoma.. Local injectable steroids with greater durability are now available for NIU but comparative efficacy to other treatment modalities remains to be determined. Local steroid-sparing immunosuppressive agents are undergoing evaluation for efficacy in NIU as are anti-VEGF agents for uveitic macular edema. Local antivirals may improve outcomes in cases of viral retinitis. Local chemotherapeutics can help induce remission in vitreoretinal lymphoma.

Topics: Anti-Infective Agents; Drug Implants; Eye Infections, Bacterial; Fluocinolone Acetonide; Glucocorticoids; Humans; Immunosuppressive Agents; Methotrexate; Panuveitis; Rituximab; Sirolimus; Uveitis, Intermediate; Uveitis, Posterior

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.

Topics: Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Humans; Immunosuppressive Agents; Intravitreal Injections; Panuveitis; Sirolimus; Uveitis, Intermediate; Uveitis, Posterior

To evaluate the efficacy and safety of intravitreal sirolimus in the management of noninfectious uveitis of the posterior segment (NIU-PS).. Combined analysis of 2 phase 3, randomized, double-masked, multinational, 6-month studies.. Adults with active NIU-PS (intermediate uveitis, posterior uveitis, or panuveitis; defined as vitreous haze [VH] ≥1.5+ on modified Standardization of Uveitis Nomenclature scale).. Patients were randomized 1:1:1 to receive intravitreal sirolimus 44 μg (n = 208), 440 μg (n = 208), or 880 μg (n = 177) on days 1, 60, and 120. Patients discontinued medications for NIU-PS except for systemic corticosteroids, which were tapered according to protocol. Enrollment in the 880-μg group was terminated after interim results found no significant difference in efficacy compared with the 440-μg dose.. The primary efficacy end point was the percentage of patients with VH of 0 at month 5 in the study eye without the use of rescue therapy. Secondary efficacy end points included VH of 0 or 0.5+, corticosteroid-tapering success, and changes in best-corrected visual acuity (BCVA). Safety measures included ocular and nonocular adverse events.. A total of 592 patients were randomized. Significantly higher proportions of patients treated with 440 μg compared with 44 μg intravitreal sirolimus achieved VH of 0 (21.2% vs. 13.5%; P = 0.038) and VH of 0 or 0.5+ (50.0% vs. 40.4%; P = 0.049) at month 5. Best-corrected visual acuity was stable (absolute change <5 ETDRS letters) or improved >5 letters in 80.1% and 80.2% of patients in the 440-μg and 44-μg groups, respectively. At month 5, corticosteroids were tapered successfully in 69.6% and 68.8% of patients in the 440-μg and 44-μg groups, and among these patients, VH of 0 or 0.5+ was achieved by 43.5% and 28.1% in the 440-μg and 44-μg groups. Both doses were generally well tolerated. Mean changes from baseline intraocular pressure (IOP) in the study eye at each analysis visit were minimal in all treatment groups.. Intravitreal sirolimus 440 μg improved ocular inflammation, as measured by VH, compared with the 44-μg dose, with minimal impact on IOP, while preserving BCVA.

Topics: Aged; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Intraocular Pressure; Intravitreal Injections; Male; Posterior Eye Segment; Sirolimus; Tomography, Optical Coherence; Uveitis, Posterior

To examine the association between visual function response (VFR) and inflammation reduction in active noninfectious uveitis of the posterior segment (NIU-PS).. Phase 3 SAKURA Study 1 randomized 347 subjects in a double-masked fashion to receive injections of intravitreal sirolimus 44 μg (n = 117); 440 μg (n = 114); or 880 μg (n = 116) every other month. Vitreous haze (VH) response, a measure of inflammation reduction, was defined as a VH score of 0 or 0.5+ at month 5 based on the modified Standardized Uveitis Nomenclature Scale. Visual function was assessed with best-corrected visual acuity (BCVA) and the National Eye Institute (NEI) Visual Function Questionnaire-25 (VFQ-25). In this post-hoc analysis, principal component analysis was used to reduce the information in the multidimensional visual function outcome to a restricted number of independently relevant VFR measures. Minimal clinically important differences (MCID) for the VFQ-25-derived components were based on the standard error of measurements. Overall VFR was defined as either a BCVA improvement of ≥2 lines, or an improvement exceeding the MCID in the VFQ-25 based visual function measures.. The VFQ-25 composite score (VFQCS) and mental health subscale score (VFQMHS) were retained as relevant VFRs, with MCIDs of 4.3 and 11.7 points, respectively. A vitreous haze response was significantly associated with each VFR measure: VFQCS (odds ratio [OR] = 2.23; P = 0.0004); VFQMHS (OR = 2.84; P < 0.0001); BCVA (OR = 2.60; P = 0.0009), and overall VFR (OR = 2.65; P < 0.0001).. Inflammation reduction to a VH score of 0 or 0.5+ was significantly associated with improved visual function. Achieving a VH response of 0 or 0.5+ is a patient-relevant outcome.

Topics: Double-Blind Method; Eye Infections; Female; Humans; Immunosuppressive Agents; Inflammation; Intravitreal Injections; Male; Middle Aged; Patient Reported Outcome Measures; Sickness Impact Profile; Sirolimus; Surveys and Questionnaires; Uveitis, Posterior; Visual Acuity; Vitreous Body

The efficacy and action mechanism of everolimus in the treatment of experimental autoimmune uveoretinitis (EAU) was analyzed. Disease was induced in B10.RIII mice by immunization with human interphotoreceptor-retinoid-binding protein peptide 161-180 (hIRBPp161-180). Everolimus was administered by oral gavage (5 mg/kg/d) beginning either two days before or 14 days after immunization. Everolimus significantly reduced the histopathological uveitis score compared to sham-treated mice. To examine the effect on the antigen-specific immune response, proliferation ([(3)H]-thymidine test) and delayed-type hypersensitivity (DTH) response were measured. Furthermore, content of T-helper-1, -2, and -17 cytokines were analyzed intraocularly (Bead Array) and in cell culture supernatants from splenocytes (sandwich ELISA). To study the effect on the humoral immune response the presence of antigen-specific serum antibodies was tested (indirect ELISA). The DTH, the humoral immune response, the proliferation of splenocytes and the intraocular Th1, Th2, Th17 cytokine content and in vitro production of Th1 and Th17 cytokines were impaired after everolimus treatment. The study of CD4+CD25+FoxP3+ regulatory T cells (T(reg)) in peripheral blood, draining lymph nodes, and spleen by flow cytometry showed an increased number of splenic T(reg) in mice of the everolimus therapy group. Furthermore the T(reg) of these mice had a higher suppressive capacity than cells from sham-treated mice. These results indicate that the immunosuppressive effect of everolimus on EAU was associated with the suppression of pathogenic effector responses and induction of regulatory T cells.

Topics: Animals; Antibodies; Autoimmune Diseases; Cell Proliferation; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Everolimus; Eye Proteins; Flow Cytometry; Forkhead Transcription Factors; Hypersensitivity, Delayed; Immunosuppressive Agents; Mice; Retinitis; Retinol-Binding Proteins; Sirolimus; Spleen; T-Lymphocytes, Regulatory; Uveitis, Posterior