David S. Chu

Effects of AIN457, a Fully Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis

A human antibody to interleukin-17A is well tolerated and may be effective in the treatment of psoriasis, rheumatoid arthritis, and noninfectious uveitis. Stopping Inflammation in Its Tracks Inflammation—characterized by redness, swelling, and pain and derived from the Latin word inflammare (to set on fire)—is the body’s principal defense against infection and injury. Once the infection has been squelched by the immune system, the inflammatory response is usually switched off. Sometimes, however, immune cells activated during inflammation elude the “off switch,” resulting in tissue destruction and various diseases—including cancer, rheumatoid arthritis, and skin disorders such as psoriasis. Cytokines that activate immune cells are key drivers of inflammation. To address whether blocking one of these cytokines, interleukin-17A (IL-17A), might be a useful therapeutic strategy for treating inflammatory diseases, Hueber and colleagues used a human monoclonal antibody (AIN457) against IL-17A to treat patients in three small proof-of-concept trials for psoriasis, rheumatoid arthritis, and uveitis (eye inflammation). Their results demonstrate that IL-17A participates in these diseases and that the antibody against this cytokine may be an effective therapeutic agent. The proinflammatory cytokine IL-17A is produced by T helper 17 (TH17) cells and affects many different cell types including macrophages and dendritic cells of the immune system, as well as epithelial, endothelial, and skin cells. IL-17A has been implicated in psoriasis, rheumatoid arthritis, and uveitis, but its exact role is unclear. The etiologies and symptoms of these three diseases are very different. TH17 and TH1 cells have been implicated in both psoriasis (characterized by excessive turnover of skin cells resulting in scaly skin patches) and uveitis (intraocular inflammation that can lead to vision loss). In contrast, in the autoimmune disease rheumatoid arthritis, autoreactive T and B cells together with autoantibodies promote prolonged inflammation, ultimately resulting in the destruction of cartilage and bone. In their three proof-of-concept trials, Hueber and co-workers treated a total of 60 patients with the human monoclonal antibody AIN457 at different doses and observed no major adverse effects. Although the trials were small and the results were preliminary, improvements were seen in all three disease groups. Psoriasis patients receiving AIN457 showed reduced scaly skin patches, decreased production of inflammatory cytokines, and a reduction in T cells infiltrating the skin lesions compared with placebo-treated patients. After receiving infusions of AIN457, rheumatoid arthritis patients exhibited reduced inflammation of the synovial joints as shown by improvements in three different clinical scores compared with placebo-treated patients. Meanwhile, patients with uveitis treated with AIN457 showed improved visual acuity, reduced ocular inflammation, or a reduced need for steroid drugs after 8 weeks. These encouraging results warrant larger clinical trials to assess further the safety and efficacy of AIN457 for treating psoriasis, rheumatoid arthritis, and uveitis and perhaps other inflammatory diseases in which IL-17A has been implicated. Interleukin-17A (IL-17A) is elaborated by the T helper 17 (TH17) subset of TH cells and exhibits potent proinflammatory properties in animal models of autoimmunity, including collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental autoimmune uveitis. To determine whether IL-17A mediates human inflammatory diseases, we investigated the efficacy and safety of AIN457, a human antibody to IL-17A, in patients with psoriasis, rheumatoid arthritis, and chronic noninfectious uveitis. Patients with chronic plaque-type psoriasis (n = 36), rheumatoid arthritis (n = 52), or chronic noninfectious uveitis (n = 16) were enrolled in clinical trials to evaluate the effects of neutralizing IL-17A by AIN457 at doses of 3 to 10 mg/kg, given intravenously. We evaluated efficacy by measuring the psoriasis area and severity index (PASI), the American College of Rheumatology 20% response (ACR20) for rheumatoid arthritis, or the number of responders for uveitis, as defined by either vision improvement or reduction in ocular inflammation or corticosteroid dose. AIN457 treatment induced clinically relevant responses of variable magnitude in patients suffering from each of these diverse immune-mediated diseases. Variable response rates may be due to heterogeneity in small patient populations, differential pathogenic roles of IL-17A in these diseases, and the different involvement or activation of IL-17A–producing cells. The rates of adverse events, including infections, were similar in the AIN457 and placebo groups. These results support a role for IL-17A in the pathophysiology of diverse inflammatory diseases including psoriasis, rheumatoid arthritis, and noninfectious uveitis.

Treatment of ocular inflammatory disorders with daclizumab

PURPOSE To evaluate the efficacy and safety of daclizumab therapy for patients with various ophthalmologic inflammatory disorders (all having previously failed standard treatment methods). DESIGN Retrospective, nonrandomized case series. PARTICIPANTS Fourteen patients. METHODS Fourteen patients were treated with daclizumab after previously failing standard treatment methods. MAIN OUTCOME MEASURES Inflammation and visual acuity. RESULTS Twelve of 27 (44%) eyes and 5 of 14 (36%) patients had improvement in visual acuity; 9 of 27 (33%) eyes and 5 of 14 (36%) patients had no change in visual acuity; and 6 of 27 (22%) eyes and 4 of 14 (27%) patients had continued visual loss. Based on degree of inflammation, 16 of 27 eyes (59%) had improvement, 3 of 27 (11%) eyes had no change, and 8 of 27 (30%) eyes worsened. CONCLUSIONS Daclizumab is safe and, at least in some patients, appears to be an effective medication in the treatment of ocular inflammatory disorders.

Complications in resident-performed phacoemulsification cataract surgery at New Jersey Medical School

Aim: To describe the complications related to cataract surgery performed by phacoemulsification technique by third-year ophthalmology residents at New Jersey Medical School, who are trained to perform phacoemulsification without any prior experience with extracapsular extraction. Design: Retrospective, observational case series. Methods: A retrospective chart review of 755 patients who underwent cataract surgery by third-year residents between July 2000 and June 2005 at the Institute of Ophthalmology and Visual Science was performed. Details of intraoperative complications (posterior capsular rupture, vitreous loss, subluxation of lens fragments into the vitreous, extracapsular cases converted to phacoemulsification, retinal detachment, vitreous haemorrhage and haemorrhagic choroidals) of the cases done by phacoemulsification technique were recorded. Results were analysed and compared with complication rates reported from other residency programmes and from experienced ophthalmologists. Results: Of 755 cataract surgeries, 719 were performed using phacoemulsification technique. Posterior capsule disruption occurred in 48 (6.7%), vitreous loss in 39 (5.4%) and dislocated lenticular fragments in 7 (1.0%) of 719 cases that underwent phacoemulsification technique. Subsequent pars plana lensectomy was required in 5 (0.7%) cases; 1 case (0.1%) experienced retinal detachment and haemorrhagic choroidal detachment. Conclusion: The residents can perform phacoemulsification well with a very low complication rate, without prior training with extracapsular cataract extraction technique.

Elevated Levels of Interleukin 6 in the Vitreous Fluid of Patients with Pars Planitis and Posterior Uveitis: The Massachusetts Eye & Ear Experience and Review of Previous Studies

Introduction: Although the exact mechanisms that lead to uveitis are not entirely known, the role of cytokines in the pathogenesis of this disease has been shown to be important. Prior studies described the presence of an array of cytokines in the intraocular fluid of patients with uveitis. Review of these studies indicate that Interleukin-6 (IL-6) is present, and animal data suggest the important role of IL-6 in the regulation of ophthalmologic immune responses. Purpose: We investigated whether IL-6, TNF-alpha, IL-1 alpha, beta, IL-2 are present in the vitreous of patients with active intermediate and posterior uveitis. Methods: Vitreous specimens were collected from 23 eyes of patients with active intermediate and posterior uveitis who underwent diagnostic or therapeutic vitrectomies. TNF-alpha, IL-1 alpha and beta, IL-2 and IL-6 were measured by enzyme-linked immunosorbent assay. Eight vitreous fluid samples from eye bank eyes were used as control. Results: IL-6 was higher in the vitreous of patients with uveitis compared to control samples (p = 0.0119). No TNF-alpha, IL-2, IL1-alpha or beta was detected. The levels of IL-6 did not correlate with a specific clinical diagnosis, but patients with pars planitis and panuveitis had the highest levels (p = 0.58) Conclusions: IL-6 is elevated in the vitreous of patients with active intermediate and posterior uveitis.

An outbreak of Fusarium keratitis associated with contact lens use in the northeastern United States.

Purpose: To report an outbreak of Fusarium keratitis in contact lens (CL) wearers in the northeastern United States. Methods: Over a 41-month period, all cases with culture-proven corneal ulceration secondary to Fusarium at 2 tertiary care eye centers were identified through the microbiology departments of each institution, and a retrospective review of charts was performed. Statistical analyses were performed to evaluate a possible association of Fusarium keratitis with specific CL and CL solution brands. Results: Fifteen cases of Fusarium keratitis were reported at the 2 tertiary centers between July 2005 and May 2006 (16.4 cases/yr) compared with 6 cases over the previous 30 months from January 2003 to June 2005 (2.4 cases/yr). All 15 of the more recent cases were CL users, and none had a history of trauma. All 15 patients claimed use of ReNu brand contact lens solution when they developed keratitis. Twelve (80.0%) of 15 patients were Acuvue soft contact lens users. Ten (66.7%) of 15 patients used tap water to rinse their contact lens cases. Six (40.0%) of 15 cases have thus far required corneal transplantation. Conclusions: The incidence of corneal ulceration secondary to Fusarium has increased sevenfold over the reported 11-month period at 2 tertiary eye care centers in the northeastern United States compared with the previous 30 months. There seems to be an association between the recent outbreak of Fusarium keratitis among CL users and the use of ReNu contact lens solution. Medical treatment of Fusarium keratitis may be ineffective, and emergent penetrating keratoplasty (PKP) may be required in some patients. CL users and their physicians should reconsider the risks of CL use and discuss proper lens care techniques.

Molecular characterization, biofilm analysis and experimental biofouling study of Fusarium isolates from recent cases of fungal keratitis in New York State

BackgroundTo characterize Fusarium isolates from recent cases of fungal keratitis in contact lens wearers, and to investigate fungal association with MoistureLoc solution.MethodsWe studied six fungal isolates from recent cases of keratitis in New York State. The isolates were characterized by nucleotide sequencing and phylogenetic analyses of multiple genes, and then typed using minisatellite and microsatellite probes. Experimental fungal biofilm formation was tested by standard methods. MoistureLoc solutions were tested in biofouling studies for their efficacy in elimination of Fusarium contamination.ResultsFusarium solani – corneal ulcers (2 isolates), lens case (1 isolate), and F. oxysporum – corneal ulcer (1 isolate), eye (1 isolate), were recovered from five patients. An opened bottle of MoistureLoc solution provided by a patient also yielded F. solani. Two distinct genotypes of F. solani as well as of F. oxysporum were present in the isolated strains. Remarkably, F. solani strains from the lens case and lens solution in one instance were similar, based on phylogenetic analyses and molecular typing. The solution isolate of F. solani formed biofilm on contact lenses in control conditions, but not when co-incubated with MoistureLoc solution. Both freshly opened and 3-month old MoistureLoc solutions effectively killed F. solani and F. oxysporum, when fungal contamination was simulated under recommended lens treatment regimen (4-hr). However, simulation of inappropriate use (15 – 60 min) led to the recovery of less than 1% of original inoculum of F. solani or F. oxysporum.ConclusionTemporary survival of F. solani and F. oxysporum in MoistureLoc suggested that improper lens cleaning regimen could be a possible contributing factor in recent infections.

The Ocular Immunology and Uveitis Foundation preferred practice patterns of uveitis management.

Ocular inflammatory disease is a leading cause of vision loss worldwide. Uveitis encompasses a wide spectrum of pathology, both with respect to its etiology and the anatomic location within the eye. Inflammation can be confined to the eye and may also be seen systemically. The cornerstone of management of ocular inflammatory disease historically has been corticosteroids, which are invaluable in the immediate control of inflammation; however, corticosteroids are inappropriate for long-term use as they are associated with a wide array of toxic side effects. As we continue to learn more about the various etiologies and elucidate the basic science pathways and mechanisms of action that cause intraocular inflammation, new therapeutic approaches have evolved. They include employment of immunomodulatory agents (corticosteroid-sparing therapies) that have expanded our treatment options for these vision-threatening diseases. These pharmacologics provide therapy for ocular and systemic inflammation in an individualized, patient-tailored, stepladder approach with the ultimate goal of durable, corticosteroid-free remission. We review the preferred practice patterns of a tertiary care center specializing in ocular inflammatory disease.

Retrospective review of methotrexate therapy in the treatment of chronic, noninfectious, nonnecrotizing scleritis.

PURPOSE To determine the effectiveness and steroid-sparing capabilities of methotrexate in the treatment of chronic, noninfectious, nonnecrotizing scleritis. DESIGN Retrospective chart review. METHODS We conducted a retrospective chart review of all patients treated for scleritis between January 1, 2000 and July 31, 2005 at the Institute of Ophthalmology and Visual Science at New Jersey Medical School of the University of Medicine and Dentistry of New Jersey. Outcome measures included inflammation, corticosteroid and methotrexate dosages, visual acuity, and reported side effects. RESULTS Eighteen patients, with a total of 27 affected eyes, were included in the study: 15 women and three men with a mean age of 52 years. Inflammation control was achieved in 11 patients, nine women and two men. Successful corticosteroid sparing was achieved in 10 of the 11 patients, with three patients completely discontinuing corticosteroid use. Visual acuity was maintained or improved in 21 (78%) of 27 affected eyes. Eight patients reported adverse effects, with one patient discontinuing treatment because of unbearable fatigue. The dose of methotrexate ranged from 7.5 to 35 mg weekly. The mean duration of methotrexate therapy was 19 months (standard deviation, 11 months). There were no serious adverse reactions or long-term morbidity caused by methotrexate therapy. CONCLUSIONS Methotrexate seems to be a well-tolerated therapy that can reduce inflammation successfully and can decrease the corticosteroid requirement in the treatment of chronic, noninfectious, and nonnecrotizing scleritis.

Evaluation of Sub-Tenon Triamcinolone Acetonide Injections in the Treatment of Scleritis

PURPOSE To suggest that sub-Tenon triamcinolone acetonide (TA) injections may be a helpful supplement in patients with scleritis. DESIGN Retrospective, interventional case series. METHODS A retrospective chart review was conducted of all patients at our institution receiving sub-Tenon TA injections for scleritis between August 2001 and August 2007. Outcome measures included subjective improvement, presence of inflammation, and adverse events. RESULTS Eleven patients (12 eyes) were included in this study. The mean age was 50 years; 2 patients were male and 9 female. Six patients had systemic autoimmune disease. All patients were receiving systemic medications for scleritis at the time of injection. Mean initial follow-up time was 3 weeks. Ten of 11 patients reported subjective improvement, and 10 patients had improvement in objective inflammation. Three patients had adverse side effects, including ocular hypertension, worsening of cataract, and subconjunctival hemorrhage with periorbital ecchymosis. CONCLUSIONS Sub-Tenon TA injections may be a useful adjunct to achieving transient, partial improvement of subjective pain and objective inflammation in patients with scleritis while awaiting systemic medications to take effect. Adverse events were manageable in this small series.

Transmission at the squid giant synapse was blocked by tetanus toxin by affecting synaptobrevin, a vesicle‐bound protein.

1. The effect of whole tetanus toxin (TeTX) and of its light chain (TeTX L‐chain) on transmitter release was determined by presynaptic pressure‐injection in the squid giant synapse. 2. The results indicate that whole TeTX does not modify transmission while the L‐chain blocks transmission within 20‐30 min. This block does not involve changes in the sodium or potassium conductances responsible for spike generation or the voltage‐dependent presynaptic calcium current responsible for transmitter release. 3. Western blotting of protein fractions from the squid optic lobe demonstrated the presence of a protein which reacted with specific antibodies against mammalian synaptobrevin, a vesicular protein. In addition, this protein was enzymatically cleaved by the L‐chain component of the toxin in a similar fashion to its mammalian counterpart. 4. These results demonstrate that TeTX L‐chain toxin acts directly on a squid synaptobrevin and prevents synaptic release probably by interfering with the docking‐fusion synaptic vesicles at the active zone.