Use In Uveitis Research Articles

Biologics in the Treatment of Uveitis.

To provide an overview of biologics that are used to treat noninfectious uveitis, including their different targets, modes of actions, and indications. A review of recent and well-established literature was used to present the biochemical and pathophysiological background of biologics and to provide an account of evidence-based decision making for their use, not only in noninfectious uveitis in general, but with special regard to indications for their use in particular types of uveitis. Extensive clinical data for adalimumab shows that it is currently the only approved biologic for the treatment of uveitis. However, there is sufficient evidence to argue that many other biologics, notably TNF-α inhibitors, certain Interleukin inhibitors, Interferons, and B cell and T cell inhibitors, are also suitable for use in uveitis. Biologics have revolutionized the treatment of noninfectious uveitis and are now considered indispensable. They are used in cases of insufficient response to or intolerance of conventional immunosuppressive agents. However, they can also be indicated as a first-line therapy for certain types of uveitis (e.g., Behçet's disease). TNF-α inhibitors are the most commonly used biologics in the treatment of uveitis.

MODERN OPPORTUNITIES IN UVEITIS TREATMENT

Uveitis is a heterogeneous group of inflammatory diseases of the choroid and adjacent structures. The pathophysiology of uveitis may be different. The treatment approach of infectious and non-infectious uveitis or masquerade syndrome is also different, but the correction of immune disorders of any uveitis should play a leading role. Infectious etiology requires the pathogen eradication with adequate antimicrobial therapy. Therapy of noninfectious uveitis based on the suppression of the local immune response. Depending on the activit y of the inflammatory process it may require system or topical anti-inflammatory and/or immunosuppressive treatment with corticosteroids or immunomodulatory therapeutic agents. The main groups of drugs are presented with the immunosuppressive alkylating agents, corticosteroids, antimetabolites, T-cell inhibitors and biological modulators of the immune response. They can reduce the amount and intensit y of recurrence, the number of complications, decrease the dose of corticosteroids or even replace them in the case of the development of side effects and resistance. An alternative uveitis treatment is extracorporal efferent-quantum hemocorrection methods. The most commonly used is plasmapheresis based on the removal of plasma with dissolved mediators of inflammation, immune complexes, antibodies, exoand endotoxins. Treatment should be pathogenetically oriented and localized to the affected tissue in order to maximize the ratio of efficacy / side effect. Often, however, this can’t be achieved. So the search continues to develop new therapies for use in uveitis that aim to suppress inflammatory activit y, prevent accumulation of damage, and preserve visual function for patients with the minimum possible side effects.

Biologicals in uveitis

Most noninfectious uveitis appears to be autoimmune or autoinflammatory in nature, requiring treatment with immunosuppressive and/or anti-inflammatory drugs. Inflammatory uveitis is a difficult condition to treat. Recently, a new class of drugs obtained by a biological process and therefore defined as biologics has been successfully used in the treatment of immune-mediated rheumatic diseases. These drugs target different proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), and IL-6 or immune effector cells including B- and T-lymphocytes. The success in rheumatology of the TNF-α inhibitors adalimumab (ADA) and infliximab (IFX) over the past several years has led to their use in uveitis, in particular in patients with Behcet's disease and for early use in patients with juvenile idiopathic arthritis who have not benefitted from methotrexate. The first experience with anti-TNF inhibitors etanercept, IFX, and ADA gave us excellent results in uveitis. Other newer biologics approved by the United States Food and Drug Administration for rheumatic diseases are emerging treatments for uveitis. These include the anti-CD20 inhibitors rituximab, the anti-TNF inhibitors certolizumab and golimumab, the IL-6 inhibitor tocilizumab, the IL-1 inhibitor anakinra, the cytotoxic T-lymphocyte antigen 4 inhibitor abatacept. Uveitis, a significant cause of ocular morbidity worldwide, is undergoing major changes as biologic therapies have entered into the field. We used PubMed and CrossRef (Google) search engine as the main source of information. In this review, we outline the ideal characteristics of drugs for uveitis and review the data to support the use of current and emerging biological therapies in this context.

Multicenter Study of Intravitreal Dexamethasone Implant in Noninfectious Uveitis: Indications, Outcomes, and Reinjection Frequency

To identify clinical outcomes and treatment patterns of intravitreal dexamethasone implant (Ozurdex; Allergan, Inc) in noninfectious uveitis in the clinical setting. Multicenter retrospective cohort study. Eighty-two eyes (63 patients) receiving 142 implant injections over 35 months were included. Treatment indication, uveitis diagnosis, visual acuity, intraocular pressure, vitreous haze score, central retinal thickness by optical coherence tomography, phakic status, number of injections, time to reinjection, systemic treatments, and complications data were collected. Time to visual acuity and vitreous haze score improvement as per the Standardization of Uveitis Nomenclature guidelines were also determined. The probability of visual acuity improvement (≥0.3 logarithm of the minimal angle of resolution units improvement) was 39% at 1 month, 49% at 3 months, 52% at 6 months, and 58% at 12 months. Eyes with baseline vitritis (vitreous haze score ≥+0.5, n = 45) had a probability of vitreous haze score improvement (2-step decrease or change from +0.5 to 0) at 2 weeks of 41%, at 1 month 63%, at 3 months 73%, at 6 months 79%, and at 12 months 88%. In eyes that completed 12-month follow-up (n = 54), 40.7% underwent 2 injections (mean time to second injection of 6.6 ± 1.9 months) and 11.2% required ≥3 injections (mean time to third injection of 11 ± 1.5 months). Dexamethasone implant use in uveitis provides favorable visual acuity and vitreous haze score outcomes but requires repeated injections, an important consideration when choosing intraocular treatment as a route to controlling uveitis.

Pharmacotherapy for uveitis: current management and emerging therapy

Uveitis, a group of conditions characterized by intraocular inflammation, is a major cause of sight loss in the working population. Most uveitis seen in Western countries is noninfectious and appears to be autoimmune or autoinflammatory in nature, requiring treatment with immunosuppressive and/or anti-inflammatory drugs. In this educational review, we outline the ideal characteristics of drugs for uveitis and review the data to support the use of current and emerging therapies in this context. It is crucial that we continue to develop new therapies for use in uveitis that aim to suppress disease activity, prevent accumulation of damage, and preserve visual function for patients with the minimum possible side effects.

Topical tacrolimus nanoemulsion, a promising therapeutic approach for uveitis

Uveitis is a sight threatening inflammatory disorder that affects all ages and remains a significant cause of visual loss. Inflammatory activity plays an important role in the whole pathogenesis of uveitis. Treatment of uveitis is mainly driven by corticosteroids that have potential side effects. Recent investigations demonstrated that tacrolimus inhibits T-cell proliferation and suppresses release of inflammatory cytokines. Since tacrolimus is a definite immunosuppressive agent, and since inflammatory process has been involved in uveitis, the compound must have effect on the progression of uveitis through reduction in inflammatory activity. Even results of the clinical trials demonstrate that tacrolimus have useful role in treatment of sight threatening uveitis that is refractory to other therapy. Studies also indicate that long term use of tacrolimus is well tolerated. However, its use in uveitis is limited because of its poor physico-chemical properties including poor aqueous solubility and high molecular weight (822Da). Therefore, we have proposed that tacrolimus nanoemulsion administered topically is a promising therapeutic approach to treat uveitis. Based on previous evidences, we have hypothesized that nanoemulsion formulation of tacrolimus can improve efficacy and safety profile of tacrolimus.

Laser flare photometry and its use in uveitis

Intraocular inflammation causes disruption of the blood–ocular barriers and entry of proteins and inflammatory cells into the aqueous humor. Slit-lamp examination allows only a subjective and arbitrary grading of cells and flare (protein) in the anterior chamber. Laser flare photometry is the only objective and quantitative method to reliably measure intraocular inflammation. Flare measurements by laser flare photometry enables exact monitoring of both acute and chronic uveitic entities. Recent studies showing the predictive value of flare levels for disease outcomes have revolutinized therapeutic approach in uveitis, placing flare to the center of inflammatory parameters to be targeted for better outcomes.

Childhood chronic anterior uveitis associated with vernal keratoconjunctivitis (VKC): successful treatment with topical tacrolimus. Case series

Uveitis treatment involves topical corticosteroids along with cycloplegic-mydriatics. Particularly severe cases may require systemic corticosteroids and immunosuppressive drugs. Vernal keratoconjunctivitis (VKC) treatment consists of a brief period of topical corticosteroids and/or cyclosporine. In patients refractory to traditional treatment, the use of 0.1% topical ophtalmic FK- 506 (tacrolimus) ointment has been occasionally reported.This is the first report of the coexistence of uveitis and VKC. The documented response to topical tacrolimus eyedrop of uveitis and VKC is also of interest, in particular since to our knowledge there are no published reports on its clinical use in uveitis.

Immunosuppressive activity of a novel peptide analog of alpha-melanocyte stimulating hormone (α-MSH) in experimental autoimmune uveitis

Autoimmune uveitis is an inflammatory disorder of the eye that can lead to pain and vision loss. Steroids and immunosuppressive drugs are currently the only therapeutics for uveitis and have serious ocular and systemic toxicities. Therefore, safer alternative therapeutics are desired. Alpha-melanocyte stimulating hormone (α-MSH) is a neuropeptide that suppresses effector T cell functions, induces regulatory T cells and has beneficial effects in certain autoimmune and transplant models. A novel d-amino acid peptide analog of native α-MSH (dRI-α-MSH) was produced that was protected from protease digestion and had increased selectivity for the melanocortin-1 receptor. Systemic delivery of the dRI-α-MSH analog dramatically suppressed disease progression and retained retinal architecture in the experimental autoimmune uveitis (EAU) model. Local delivery by periorbital injection was equally effective. Importantly, treatment with the novel dRI-α-MSH analog suppressed uveitis with a similar magnitude to the corticosteroid, dexamethasone. Data indicate that the novel dRI-α-MSH analogs show anti-inflammatory activities and have potential therapeutic use in uveitis and other autoimmune diseases.

Biologic agents in the management of inflammatory eye diseases

Biologics are a new class of drugs that comprise recombinant cytokines and monoclonal antibodies directed against selected cell-surface markers. They include the tumor necrosis factor-alpha inhibitors infliximab, etanercept, and adalimumab; the antilymphocyte drugs rituximab and alemtuzumab; the interleukin-2 receptor blocker daclizumab; and recombinant interferon-alpha. This article reviews the rationale and current evidence for their use in uveitis, scleritis, and orbital inflammation.

Infliximab for juvenile idiopathic arthritis‐associated uveitis

Infliximab is a murine-human recombinant antitumour necrosis factor monoclonal antibody recently introduced for the treatment of autoimmune diseases in which tumour necrosis factor is thought to be a key mediator. Its role in the treatment of juvenile idiopathic arthritis-associated uveitis is as yet undefined. Six children with juvenile idiopathic arthritis-associated uveitis, inadequately controlled on currently available therapy, were treated with infliximab between September 2002 and November 2004. All children were required to remain on low-dose immunomodulatory treatment in conjunction with the infliximab. A retrospective review of two electronic databases containing details of ophthalmology and rheumatology visits was conducted. In all six children, institution of infliximab therapy was associated with increased ease of management. Ocular inflammation and intraocular pressure control improved in all. It was also possible to reduce the dose or withdraw some glaucoma, steroid and other immunomodulatory drugs. Two children underwent intraocular surgery without noticeable flare of intraocular inflammation. No patient developed any serious systemic complications attributable to infliximab. Infliximab may be a useful adjunct to the management of refractory juvenile idiopathic arthritis-associated uveitis. In our series it was associated with improved uveitis control and simplification of drug use as well as possibly improving safety of surgical intervention. This study suggests that its role is likely to be in conjunction with maintenance immunomodulatory treatment to provide more optimal disease control. Controlled studies are required to confirm its efficacy and safety, and the potential breadth of its use in uveitis and related disorders.