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Controlled evaluation of loteprednol etabonate and prednisolone acetate in the treatment of acute anterior uveitis. Loteprednol Etabonate US Uveitis Study Group.

PURPOSE: To compare the safety and efficacy of loteprednol etabonate 0.5% ophthalmic suspension with prednisolone acetate 1.0% ophthalmic suspension in reducing the ocular signs and symptoms associated with acute anterior uveitis. METHODS: Two prospective studies were conducted in sequence. Both were parallel, randomized, double-masked, active-controlled comparisons conducted at academic or private practice clinics in the United States. Efficacy was evaluated by the proportion of patients with a score of 0 for key signs and symptoms of uveitis. Intraocular pressure was increased regularly. The first study involved up to 42 days of treatment, starting with a dose of eight times per day. The second study involved up to 28 days of treatment, starting with a dose of 16 times per day. RESULTS: In the first study (N = 70), the proportion of patients achieving resolution by the final visit was anterior chamber cell (74% loteprednol etabonate, 88% prednisolone acetate, P = .194) and flare (71% loteprednol etabonate, 81% prednisolone acetate, P = .330). In the second study (N = 175), the proportion of patients achieving resolution by the final visit was anterior chamber cell (72% loteprednol etabonate, 87% prednisolone acetate, P = .015) and flare (66% loteprednol etabonate, 82% prednisolone acetate, P = .017). In both studies, intraocular pressure increase of more than 10 mm Hg was observed more frequently in patients receiving prednisolone acetate (seven patients) than those receiving loteprednol etabonate (one patient). CONCLUSIONS: Although a clinically meaningful reduction of signs and symptoms was noted in both treatment groups, loteprednol etabonate was less effective than prednisolone acetate in both of these controlled studies. However, the more favorable profile of loteprednol etabonate with respect to intraocular pressure increase may make it useful in many patients.

Acute Disease↗

Synthetic lipid A-induced uveitis and endotoxin-induced uveitis--a comparative study.

Endotoxin-induced uveitis (EIU) is an animal model of ocular inflammation induced by lipopolysaccharide (LPS). The lipid A (LA) region of the LPS chemical structure is believed to be responsible for virtually all the biological activities induced by LPS. The aim of this study was to perform a more detailed investigation of the potency of LA in reproducing EIU. Various doses of either LPS or LA were injected into the footpad of an inbred strain of Lewis rat and the inflammation patterns were compared by assessing the protein concentration, by cytological study, and by determining the inflammatory cell content in samples of aqueous humor obtained during 96-hour follow-up. Evaluation of the cell number and protein concentration ratio of both groups showed the LA-stimulated group presented a higher ratio than the LPS group (Welch's t-test, (P < 0.00001). It was noteworthy that even the injection of high doses of LPS could not reproduce the level of cellular infiltration induced by LA. Histological study confirmed the enhanced cellularity in the LA group, neutrophils being predominant in both the LPS- and the LA-stimulated groups. The divergent findings in these two models of uveitis may be valuable to further investigations of the process of inflammatory cell migration into the anterior chamber of the eye.

Animals↗

[Acute recurrent uveitis and idiopathic interstitial nephritis-- a nosologic entity (tubulo-interstitial nephritis and uveitis)].

So far 34 cases of idiopathic acute tubulo-interstitial nephritis and uveitis (TINU syndrome) have been reported by nephrologists. The patients have mainly been girls and only female adults. The authors describe a 53-year-old woman with this nosological entity, presenting with a granulomatous anterior uveitis and chronic course of nephritis. This is the first such case reported. All other cases described in the literature are compared and an attempt is made to locate the immune deficiency.

Acute Disease↗

[Secondary glaucoma and uveitis: hypertensive uveitis (author's transl)].

The secondary rise of i.o. pressure in uveitis may lead to a true secondary glaucoma or to hypertensive uveitis. The etiology of the endogenous inflammation does not seem to play a role. Pathogenetically the occlusion of the pupil with the formation of iris bombé and the obliteration of the chamber angle by exudate are important factors, while the hypersecretion of aqueous humor plays a minor role. Medical treatment consists in mydriatics and steroids. Surgical treatment depends on the pathogenetic mechanism and consists either in sector iridectomy or a filtering procedure.

Behcet Syndrome↗

Immunologic and biochemical properties of several retinal proteins bound by antibodies in sera from animals with experimental autoimmune uveitis and uveitis patients.

Sera from guinea pigs and rabbits with and without experimental autoimmune uveitis (EAU) induced by immunization with retina, choroid, optic nerve, retinal rod outer segments (ROS) and purified bovine S-antigen were tested for the ability to immunoprecipitate 125I-labeled, detergent-solubilized bovine retinal proteins. The results demonstrate that three major protein antigens with m.w. of 50,000 (p50), 35,000 (p35) and 27,000 (p27) and several minor activities between 30,000 and 60,000 m.w. are recognized by antibodies from these animals. The p50 component was immunoprecipitated by sera from animals immunized with whole retina homogenate, the high speed supernatant of whole retina homogenate, ROS, and S-antigen, and has been identified as S-antigen in competition experiments. The p35 band appeared when sera were used that were raised against antigen preparations containing membrane-bound retinal protein, i.e., whole retina homogenate, ROS, and washed ROS, and thus appears to be an ROS membrane protein. The p27 band was found when sera raised against ROS, washed ROS, optic nerve and whole retina homogenate were used, suggesting it is a membrane-bound antigen common to ROS and optic nerve. Serum from animals immunized with homologous choroid did not immunoprecipitate a detectable product. S-antigen and p35 were also precipitated by some uveitis patient sera. Because S-antigen is also an ROS protein as is rhodopsin, a putative uveitogenic retinal antigen, ROS appear to be an unusually rich source of autoantigenic proteins. S-antigen was also shown to be synthesized in the retina, and the primary translation product was indistinguishable from purified S-antigen by SDS-PAGE, thus eliminating the possibility that it is derived from or is cross-reactive with the 67,000 m.w. rhodopsin kinase.

Animals↗

Increased nitric oxide production in endotoxin-induced uveitis. Reduction of uveitis by an inhibitor of nitric oxide synthase.

Nitric oxide (NO) has been implicated in the pathogenesis of several inflammatory diseases. In the present study, we investigated the potential role of NO in an ocular model of inflammation, endotoxin-induced uveitis (EIU), in Lewis rats. Injection of LPS in one footpad induces severe uveitis after 16 h, which is accompanied by an increase of NO in the aqueous and vitreous humors, as evaluated by nitrite assay. Reverse transcriptase-PCR experiments reveal a large increase of inducible NO synthase (iNOS) mRNA in the iris/ciliary body, from 2 to 24 h after LPS treatment. In the retina, maximal increase of iNOS mRNA was detected 16 h after LPS treatment. Two i.p. injections of the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME), which inhibits nitrite release in the aqueous and vitreous humors, profoundly reduce clinical and histologic inflammation in EIU rats. These results implicate the NO pathway in the pathogenesis of EIU and demonstrate the possibility of modulating this inflammatory disease by injection of a NOS inhibitor.

Amino Acid Oxidoreductases↗

Tubulo-interstitial nephritis-uveitis (TINU)-syndrome with posterior uveitis.

A case of TINU-syndrome with complications in the posterior segment is reported. A 15-year old boy presented, eight months after an acute tubulo-interstitial nephritis, a bilateral anterior uveitis, followed by an unilateral posterior uveitis with papillitis. The treatment with oral and topical corticosteroids was successful.

Acute Disease↗

Experimental melanin-protein induced uveitis (EMIU) is the sole type of uveitis evoked by a diversity of ocular melanin preparations and melanin-derived soluble polypeptides.

Experimental melanin-protein induced uveitis (EMIU) is a CD4 T cell-mediated disease involving the choroid and iris, but sparing the retina. The present study was designed to solubilize uveitogenic antigen from melanin granules without enzymatic digestion, and to investigate some of its elements by comparison with different purified melanin preparations. Many melanin surface-derived polypeptides with molecular weights ranging from 1 to > 100 kDa were obtained by extractions of the prepurified granules with hot lithium dodecyl sulfate (LDS). The mixture was electrophoretically separated into seven subfractions, each containing many components and capable of evoking the typical features of EMIU after footpad immunization of Lewis rats. The five low-molecular-weight fractions between M, 1 kDa and 30 kDa exhibited most pathogenicity which was evenly distributed among the fractions. Highly uveitogenic material remained in the melanin preparations even after multiple exhaustive extractions with LDS, and represented about 70% of the detectable protein. The uveal pathogen (UP-X) thus proved to be antigenically stable, and the major part of the pathogenic material was strongly bound to the granule surface layer. Concentrated urea solution was also capable of extracting many uveitogenic melanin polypeptides, but in a different composition than LDS did, and less effectively. Human choroidal melanin provided an LDS-soluble fraction with low pathogenicity. A single intraperitoneal injection of bovine melanin polypeptides together with pertussis toxin, but without footpad immunization in Freund's complete adjuvant, evoked EMIU as well. In all experiments, no uveitis except EMIU was observed, indicating that only one type of uveitogenic epitope was present in a wide variety of carrier molecules. An explanation for this phenomenon is discussed.

Acute Disease↗

Experimental autoimmune uveitis as animal model for human posterior uveitis.

Uveitis is an intraocular inflammatory disease that mostly affects children and young adults. It is one of the major causes of blindness in young individuals in India and the world. It is responsible for about 10 per cent of total visual impairment. Unfortunately, etiological diagnosis is not evident in a majority of these patients. It is generally felt that autoimmune mechanism may be involved in so called 'idiopathic' cases which has led to search for the putative autoantigens in experimental animal models. It has been demonstrated that experimental autoimmune uveitis (EAU) can be elicited against several retinal proteins in rats, mice and sub-human primates. These include the S-antigen, a major protein on retinal photoreceptor cell, interphotoreceptor retinoid binding protein (IRBP) and several others. There are many similarities between clinical entities and the EAU, but the EAU differs from the clinical conditions in being self-limited, and requiring complete Freund's adjuvant for induction of the disease. The disease can be induced only in susceptible strains. Nevertheless, use of the EAU model has allowed for identification of disease causing epitopes of antigens and evaluation of disease modifying strategies which could be applied in clinical situations. There has been significant progress in this field, but still a lot more is required to be learnt to translate it into clinical practice.

Adult↗

Identification of crystallin family proteins in vitreous body in rat endotoxin-induced uveitis: Involvement of crystallin truncation in uveitis pathogenesis.

Endotoxin-induced uveitis (EIU) is an animal model of acute ocular inflammation. To characterize the mechanism of EIU, we analyzed the infiltration of proteins in the vitreous bodies of rats with EIU and normal rats using 2-DE and micro LC/LC-MS/MS. Twenty spots were identified in vitreous bodies of rats. Eighteen of these spots were members of the crystallin family. The truncated form of beta A4- and beta B2-crystallin were predominant in normal vitreous bodies, but there were intact form of crystallins in lipopolysaccharide-injected rats with EIU. These results suggest that crystallin family proteins are the major group of proteins involved in uveitic vitreous and that C-terminal truncation of beta-crystallins may play a role in EIU-related disease progression.

Amino Acid Sequence↗

Endotoxin-induced uveitis in mice. 1. Induction of uveitis and role of T lymphocytes.

Endotoxin-induced uveitis (EIU) with a high frequency of posterior iris synechiae was induced by the systemic injection of 200 micrograms of endotoxin into C3H/HeN mice, an endotoxin-responsive strain. The cell number and the protein concentration within the aqueous humor began to increase 6 hours after the injection, achieving a peak at 24 hours, and decreased gradually thereafter. Inflammatory cells were observed in the anterior chamber, the vitreous body and near the iris-ciliary body histologically. Most of the inflammatory cells were polymorphonuclear cells. On the other hand, C3H/HeJ mice, an endotoxin-unresponsive strain, showed no increase in either cell number or protein concentration in the aqueous humor after endotoxin administration. Pretreatment of C3H/HeN mice with anti-Thy-1.2 antibody significantly decreased both the cell number and the protein concentration in the aqueous humor and the incidence of the posterior synechiae, as compared with the control group. Anti-CD4 antibody also significantly reduced the severity of EIU, while anti-CD8 antibody had no influence on the disease. Anti-IFN-gamma antibody increased the cell number in the aqueous humor. These observations indicate that T lymphocytes, especially CD4+ T lymphocytes, have an extremely important role in the development of EIU in mice.

Animals↗

Immunological studies of uveitis. 2. Immune complex containing retinal S antigen in patient with chronic intractable uveitis.

A case of chronic uveitis resistant to steroid treatment was reported where plasma exchange therapy, in contrast, had a remarkable effect on reducing the cystoid macular edema and retinal phlebitis. The removed plasma showed an elevated level of immune complex, and Western blotting demonstrated that this immune complex in the plasma contained retinal S antigen.

Adult↗