C. Stephen Foster

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.

Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel.

PURPOSE To provide recommendations for the use of immunosuppressive drugs in the treatment of patients with ocular inflammatory disorders. PARTICIPANTS A 12-person panel of physicians with expertise in ophthalmologic, pediatric, and rheumatologic disease, in research, and in the use of immunosuppressive drugs in patient care. EVIDENCE Published clinical study results. Recommendations were rated according to the quality and strength of available evidence. PROCESS The panel was convened in September of 1999 and met regularly through May 2000. Subgroups of the panel summarized and presented available information on specific topics to the full panel; recommendations and ratings were determined by group consensus. CONCLUSIONS Although corticosteroids represent one of the mainstays in the management of patients with ocular inflammation, in many patients, the severity of the disease, the presence of corticosteroid side effects, or the requirement for doses of systemic corticosteroids highly likely to result in corticosteroid complications supports the rationale for immunosuppressive drugs (for example, antimetabolites, T-cell inhibitors, and alkylating agents) being used in the management of these patients. Because of the potential for side effects, treatment must be individualized and regular monitoring performed. With careful use of immunosuppressive drugs for treatment of ocular inflammatory disorders, many patients will benefit from them either with better control of the ocular inflammation or with a decrease in corticosteroid side effects.

Serious Complications of Topical Mitomycin-C after Pterygium Surgery

BACKGROUND The use of topical mitomycin (mitomycin-C) as a medical adjunct to pterygium and glaucoma surgery is increasing. METHODS The authors report on a series of 10 patients who experienced serious, vision-threatening complications associated with the use of this drug after pterygium surgery. RESULTS Complications included severe secondary glaucoma (4 patients), corneal edema (3 patients), corneal perforation (1 patient), corectopia (2 patients), iritis (8 patients), sudden onset mature cataract (2 patients), scleral calcification (1 patient) and incapacitating photophobia and pain (8 patients). Two patients required penetrating keratoplasties and a third required three lamellar keratoplasties. Another patient underwent four additional surgeries including a conjunctival Z-plasty, scleral patch grafting, and conjunctival autografting before his intractable pain and photophobia resolved 15 months after the original surgery. Because of these complications, 6 patients required a total of 20 return visits to the operating room after their original pterygium surgery. In 5 eyes, visual acuity remained at 20/200 or less. Three of the six patients with the most severe complications had concomitant chronic external diseases (rosacea [3 patients], ichthyosis [1 patient], keratitis sicca [1 patient]). CONCLUSION The authors urge extreme caution in the use of mitomycin. If mitomycin is used, the lowest possible concentration should be applied for the shortest time period in an effort to avoid these complications. A prospective multicenter study of the ophthalmic use of this medication is needed.

Dexamethasone Intravitreal Implant for Noninfectious Intermediate or Posterior Uveitis

OBJECTIVE To evaluate the safety and efficacy of 2 doses of dexamethasone intravitreal implant (DEX implant) for treatment of noninfectious intermediate or posterior uveitis. METHODS In this 26-week trial, eyes with noninfectious intermediate or posterior uveitis were randomized to a single treatment with a 0.7-mg DEX implant (n = 77), 0.35-mg DEX implant (n = 76), or sham procedure (n = 76). MAIN OUTCOME MEASURE The main outcome measure was the proportion of eyes with a vitreous haze score of 0 at week 8. RESULTS The proportion of eyes with a vitreous haze score of 0 at week 8 was 47% with the 0.7-mg DEX implant, 36% with the 0.35-mg DEX implant, and 12% with the sham (P < .001); this benefit persisted through week 26. A gain of 15 or more letters from baseline best-corrected visual acuity was seen in significantly more eyes in the DEX implant groups than the sham group at all study visits. The percentage of eyes with intraocular pressure of 25 mm Hg or more peaked at 7.1% for the 0.7-mg DEX implant, 8.7% for the 0.35-mg DEX implant, and 4.2% for the sham (P > .05 at any visit). The incidence of cataract reported in the phakic eyes was 9 of 62 (15%) with the 0.7-mg DEX implant, 6 of 51 (12%) with the 0.35-mg DEX implant, and 4 of 55 (7%) with the sham (P > .05). CONCLUSIONS In patients with noninfectious intermediate or posterior uveitis, a single DEX implant significantly improved intraocular inflammation and visual acuity persisting for 6 months. Application to Clinical Practice Dexamethasone intravitreal implant may be used safely and effectively for treatment of intermediate and posterior uveitis. Trial Registration clinicaltrials.gov Identifier: NCT00333814.

Infectious endophthalmitis. Review of 36 cases.

A three-year retrospective study of 36 cases of infectious endophthalmitis seen at a large referral eye center between 1977 and 1980 was conducted. The criterion for infectious endophthalmitis was the culture of microorganisms from aqueous or vitreous on at least two media. The most frequent pathogen was Staphylococcus epidermis; it was isolated from 18 (50%) of the cases. In cases of infectious endophthalmitis following recent cataract extraction, S. epidermidis was isolated from 10 to 17 eyes (58.8%). Complete loss of visual function occurred in 16 of the 36 eyes (44.4%); a visual acuity of 20/400 or better as recorded in 15 eyes (41.6%) and 20/100 or better in eight (22.2%). Fifty percent of the cases were treated with vitrectomy and intraocular antibiotics. Poor visual outcome was associated with gram-negative organisms or delay of vitrectomy more than 24 hours after the initial diagnosis. In cases of postoperative S. epidermidis endophthalmitis, the most favorable visual outcomes were associated with use of intraocular antibiotics and vitrectomy; 80% of cases so treated had a final visual acuity of 20/400 or better and 60% had a visual acuity of 20/100 or better.

Mitomycin eye drops as treatment for pterygium.

The authors used an antineoplastic-antibiotic agent, mitomycin, in the form of eye drops as adjunctive treatment for primary and recurrent pterygia after surgical excision. Sixteen primary and four recurrent pterygia were treated with 1.0 mg/ml mitomycin eye drops, 14 primary and 10 recurrent pterygia were treated with 0.4 mg/ml mitomycin eye drops, and 18 primary pterygia were treated with placebo eye drops. Postoperative follow-up for the eyes treated with mitomycin eye drops ranged from 3 to 34 weeks (mean, 23 weeks). One of 44 pterygia treated with mitomycin recurred after 5 months (recurrence rate, 2.3%), whereas 16 of 18 primary pterygia treated with placebo eye drops developed postoperative granulomas and recurrent pterygia with a mean postoperative period of 6 weeks (recurrence rate, 88.9%). Topical mitomycin (1.0 mg/ml) caused conjunctival irritation, excessive lacrimation, and mild superficial punctate keratitis. These topical side effects were minimized with the 0.4 mg/ml mitomycin dosage. No systemic toxicity was noted with either dosage. The authors believe that mitomycin eye drops is a safe and effective adjunct to surgical excision in the treatment of primary or recurrent pterygia, or both.

Mortality rate in rheumatoid arthritis patients developing necrotizing scleritis or peripheral ulcerative keratitis. Effects of systemic immunosuppression.

We performed a nonrandomized clinical trial comparing the ocular and systemic efficacy of cytotoxic immunosuppression with steroidal and nonsteroidal anti-inflammatory therapy in the care of 34 patients with rheumatoid arthritis who developed peripheral ulcerative keratitis and/or necrotizing scleritis. Nine of the 17 patients managed with conventional therapy died of a vascular-related event during the ten-year period of the study. In 13 of the 17 patients, the ocular inflammatory process progressed, and in 5 patients extraocular, although nonlethal, vasculitic lesions developed. One of 17 patients treated with long-term immunosuppressive therapy died during the ten-year follow-up period, and this death occurred after cytotoxic therapy was withdrawn. None of the patients on immunosuppressive regimens developed extraocular vasculitis while taking the drug, and none had progression of the ocular destructive lesion. The results of this study emphasize that the eye is a sensitive indicator for potentially lethal occult systemic vasculitis in patients with rheumatoid arthritis who develop peripheral ulcerative keratitis or necrotizing scleritis. Our mortality data strongly suggest that the use of cytotoxic drugs may alter favorably the general as well as the ocular prognosis in these patients.

Stevens-Johnson syndrome and toxic epidermal necrolysis: A review of the literature

OBJECTIVE To perform a comprehensive review of Stevens-Johnson syndrome and toxic epidermal necrolysis. DATA SOURCES A MEDLINE search was performed for the years 1975 to 2003 using the keywords Stevens-Johnson syndrome and toxic epidermal necrolysis to identify relevant articles published in English in peer-reviewed journals. STUDY SELECTION All clinical studies that reported on 4 or more patients, review articles, and experimental studies that concerned disease mechanisms were selected and further analyzed. Clinical reports that included fewer than 4 patients were selected only if they were believed to carry a significant message about disease mechanism or therapy. RESULTS Stevens-Johnson syndrome and toxic epidermal necrolysis seem to be variants of the same disease with differing severities. A widely accepted consensus regarding diagnostic criteria and therapy does not exist at present. Despite the recent experimental studies, the pathogenic mechanisms of these diseases remain unknown. Although progress in survival through early hospitalization in specialized burn units has been made, the prevalence of life-long disability from the ocular morbidity of Stevens-Johnson syndrome and toxic epidermal necrolysis has remained unchanged for the past 35 years. Further progress depends on modification of the acute phase of the disease rather than continuation of supportive care. The available published evidence indicates that a principal problem in the pathogenesis is immunologic and that immunomodulatory intervention with short-term, high-dose intravenous steroids or intravenous immunoglobulin holds the most promise for effective change in survival and long-term morbidity. CONCLUSIONS The results of this review call for a widely accepted consensus on diagnostic criteria for Stevens-Johnson and toxic epidermal necrolysis and multicenter collaboration in experimental studies and clinical trials that investigate disease mechanisms and novel therapeutic interventions, respectively.

Analysis of the Acute Ophthalmic Manifestations of the Erythema Multiforme/Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Disease Spectrum

PURPOSE To evaluate the epidemiology, possible etiologic factors, complications encountered, and treatment administered to a group of patients with ocular involvement in the erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum who were seen at two large tertiary referral centers over a 34-year period. METHODS Hospital records from 1960 to 1994 at the Massachusetts General Hospital and Shriners Hospital for Crippled Children were reviewed for patients with erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis. Only patients fulfilling specific clinical diagnostic criteria and those who received a diagnosis by a dermatologist were included in the review. RESULTS A total of 366 patients with erythema multiforme, Stevens-Johnson syndrome, or toxic epidermal necrolysis were identified. Drugs were the most commonly identified etiologic factor in all three conditions: sulfonamides were the most frequently identified agents. Eighty-nine patients (24%) had ocular manifestations at the time of their acute hospital stay. Ocular involvement was seen in 9% of patients with erythema multiforme, in 69% with Stevens-Johnson syndrome, and in 50% with toxic epidermal necrolysis. The ocular problems were more severe in patients with both Stevens-Johnson syndrome and toxic epidermal necrolysis. There was no significant difference between the number of patients who were treated with systemic steroids and those who were not (P = 0.42). CONCLUSIONS The erythema multiforme/Stevens-Johnson syndrome/toxic epidermal necrolysis disease spectrum remains an important cause of severe visual loss in a significant number of patients. Systemic steroids used during the acute phase of the disease appear to have no effect on the development of ocular manifestations. Studies on the acute immunopathogenic mechanisms occurring in these disease are warranted if more effective therapies are to be found.

Methotrexate therapy for chronic noninfectious uveitis: analysis of a case series of 160 patients.

PURPOSE To evaluate the outcomes of patients with chronic noninfectious uveitis unresponsive to conventional antiinflammatory therapy who were treated with methotrexate. DESIGN Retrospective noncomparative interventional case series. PARTICIPANTS All patients with chronic noninfectious uveitis treated with methotrexate at a single institution from 1985 to 1999. METHODS Charts of patients seen on the Ocular Immunology & Uveitis Service at the Massachusetts Eye & Ear Infirmary were reviewed. Patients with chronic uveitis of noninfectious origin treated with methotrexate were included in the study. MAIN OUTCOME MEASURES Control of inflammation, steroid-sparing effect, visual acuity, adverse reactions. RESULTS A total of 160 patients met the inclusion criteria. Control of inflammation was achieved in 76.2% of patients. Steroid-sparing effect was achieved in 56% of patients. Visual acuity was maintained or improved in 90% of patients. Side effects requiring discontinuation of medication occurred in 18% of patients. Potentially serious adverse reactions occurred in only 8.1% of patients. There was neither long-term morbidity nor mortality caused by methotrexate. CONCLUSIONS Methotrexate is effective in the treatment of chronic noninfectious uveitis that fails to respond to conventional steroid treatment. It is an effective steroid-sparing immunomodulator, is a safe medication, and is well tolerated.