Non-infectious uveitis--current therapies and drugs in the pipeline.
(1 CET POINT)
Uveitis is a disease associated with inflammation of one or more tissues of the uvea (see Figure 1). Uveitis in the posterior segment of the eye can affect adjacent structures such as the retina, vitreous, optic nerve head and retinal blood vessels. (1)
Uveitis is estimated to have an annual incidence of 17-52 and a prevalence of 38-714 cases per 100,000 population. (2) Patients with this condition report symptoms of pain, photophobia and blurred vision. If left untreated, uveitis may lead to raised intraocular pressure and loss of vision. (3) It has been reported that approximately a third of uveitis patients suffer from severe visual impairment. (4)
A grading system was established in 2005 to classify uveitis based on the anatomical location of the inflammation; (3) these are anterior, intermediate or posterior uveitis, where inflammation is located in the anterior segment, vitreous humour or the choroid/ retina, respectively. The grading system also includes a fourth class of uveitis: pan-uveitis, where inflammation is widespread across the entire uveal tract, retina and vitreous humour. Patients with pan-uveitis are most likely to lose their vision. (4)
A summary of the different classifications of uveitis and the site of inflammation is provided in Table 1. The most common form in Western countries is anterior uveitis. (5)
The aetiology for this condition varies with age, geographical location and environmental and genetic factors. (5) For example, the most common type in children below 16 years of age is paediatric parasitic anterior uveitis, whereas in patients above the age of 60 it is herpetic anterior uveitis. (6) Therefore, an understanding of the different types and aetiologies of uveitis amongst various populations helps in the diagnosis and treatment of this condition. There are a large number of different causes for uveitis, but these can be subdivided into two main categories; infectious, or non-infectious. The former is of viral (cytomegalovirus or syphilis), bacterial (bartonella) or parasitic (toxoplasmosis) origin. (1) Therefore, it is important to treat the underlying cause as well as the inflammation in infectious uveitis. On the other hand, in non-infectious or immunemediated uveitis, treatment is aimed at managing ocular inflammation. In both instances, it is vital to control the ocular inflammation, as delaying treatment could lead to complications such as glaucoma, secondary to raised intraocular pressure. Current and emerging therapies for treatment will now be discussed.
Aims of therapy and scientific rationale
Ideally, therapy should be designed to treat inflammation effectively, with minimal costs and adverse effects and ease of application to encourage patient compliance. Although, the underlying mechanisms and pathophysiology of uveitis is not fully understood, it has a strong correlation with immune-mediated diseases. Therefore, treatment of non-infectious uveitis is aimed at suppressing the immune, as well as inflammatory response. Treatment of infectious uveitis of bacterial, viral, fungal or parasitic origin is treated with the appropriate antimicrobial drug in addition to corticosteroids and cycloplegics.
Since their first use in the 1950s, corticosteroids have been shown to be effective in the treatment of non-infectious uveitis. (7) However, corticosteroids can elicit both ocular and systemic side effects irrespective of their route of administration. Although, the risk of developing systemic side effects is higher with oral or parenteral routes, significant systemic absorption may occur following topical, periocular or intraocular administration. The most common side effects of corticosteroid use are cataracts and secondary glaucoma. Therefore, it is essential to monitor intraocular pressure during therapy. With the topical route of administration, the likelihood of developing secondary glaucoma is dependent on the potency of the corticosteroid. (8) Table 2 (page 78) lists some of the available topical corticosteroids. Other side effects associated with corticosteroids administered via different routes include: topical--blurred vision, allergy and punctate keratopathy; periocular--proptosis, central retinal artery occlusion and haemorrhage; intraocular --vitreous floaters and retinal detachment; and systemic myopia and exophthalmia. (9)
[FIGURE 1 OMITTED]
The route of administration and choice of corticosteroid varies with type and severity of uveitis. Some cases of anterior uveitis are treated with topical corticosteroids,10 with doses ranging from one drop daily to one drop hourly depending on the extent of ocular inflammation. It is important to note that rebound ocular inflammation may develop secondary to sudden withdrawal or rapid tapering of the topical corticosteroid; this can be avoided by gradual tapering as well as patient counselling and compliance. (11) Intermediate uveitis, posterior uveitis, panuveitis or uveitis associated with a high risk of vision loss tend to be treated using periocular, intravitreal, oral or intravenous corticosteroids. Periocular and intravitreal corticosteroids have been proven to be efficacious in treating uveitis. (12,13) Fluocinolone acetonide intravitreal implant (Retisert, Bausch & Lomb, Rochester, New York) was the first implant to be approved for the treatment of chronic non-infectious posterior uveitis. The implant provides a gradual release of corticosteroid over a 30-month period. However, it requires surgical placement and has been associated with an increased risk of raised intraocular pressure and cataract formation. (14) Other slow-release intravitreal implants include Iluvien (fluocinolone acetonide) and Ozurdex (dexamethasone). Further, the intravitreal route of administration is associated with rare but sight-threatening complications, such as retinal detachment, endophthalmitis and haemorrhage. (15) Patients receiving oral corticosteroids should be made aware of the potential risks and advised against abrupt withdrawal. Oral side effects include weight gain, hypertension, corticosteroid-induced diabetes, dyslipidaemia and osteoporosis. The latter signifies the importance of calcium and vitamin D supplementation. (16) To reduce the risks of corticosteroid use, non-corticosteroids-related therapeutics including intravitreal methotrexate, anti-vascular endothelial growth factor treatments and intravitreal sirolimus, have been recently developed. (17)
Non-steroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs (NSAIDs) act by inhibiting the cyclo-oxygenase enzyme and have anti-inflammatory therapeutic effects. Unlike corticosteroids, NSAIDs do not cause cataract formation or elevated intraocular pressure, thus providing a potential anti-inflammatory alternative with a better safety profile. However, it is important to note that the efficacy of NS AID monotherapy has not been well established and that topical administration and ocular clearance pathways prevent the delivery of sufficient amounts for the treatment of posterior segment uveitis. (18,19) An example of such an NSAID is diclofenac, which has demonstrated low intraocular levels following topical administration due to rapid vitreous elimination. Intravitreal administration has been trialled to circumvent this effect where using a less soluble salt of diclofenac demonstrated a prolonged elimination half-life,20 and thus the potential to use this NSAID. However, intravitreal injections are not a preferred route of administration and are associated with sight-threatening adverse effects such as retinal detachment, endophthalmitis and haemorrhage. (15) Larger studies are needed to evaluate the role of intraocular NSAIDs and provide further information on the ideal regimen, duration of treatment and safety of long-term therapy.
Mydriatics and cydoplegics
Topical cydoplegics/mydriatic eye drops are used to control pain caused by ciliary muscle spasm which frequently occurs with acute anterior uveitis and to break or prevent synechiae. (21) A synechia is an ocular condition which involves adhesion of the iris to either the cornea (anterior synechia) or to the lens (posterior synechia). Antimuscarinic agents dilate the pupil (mydriasis) and paralyse the ciliary muscle (cycloplegia), relieving pain for the patient. They vary in potency and duration of action, with the effects of cyclopentolate hydrochloride 1% lasting up to 24 hours compared to homatropine hydrobromide or atropine sulfate whose effects can continue for up to three or seven days, respectively. Atropine sulfate is mainly used in the prophylaxis of posterior synechiae and to relieve ciliary spasm in anterior uveitis.
Immunosuppressant drugs include antimetabolites, alkylating agents, some antibiotics and specific adjuvants. Table 3 lists some classes and examples of drugs with immunosuppressant activity. (9) The Systemic Immunosuppressive Therapy for Eye Disease (SITE) multicentre retrospective cohort study conducted on patients with non-infectious ocular inflammation showed that oral methotrexate at a maintenance dose of 15-25mg once a week, (22) and azathioprine at a dose of 1-2mg/ kg/day (maximum daily dose of Smg/kg), (23) were both moderately effective in controlling ocular inflammation. Another antimetabolite that has shown effective activity in ocular inflammation, is mycophenolate mofetil. (24) However, all of these antimetabolites take a month to several months to achieve a therapeutic effect and are associated with undesirable side effects. The common side effect with all three antimetabolites is gastrointestinal upset. Mycophenolate mofetil and azathioprine are also commonly associated with bone marrow suppression. (16) There are strict controls available for patients initiated and maintained on methotrexate, such as its contraindication in patients with hepatic disorders, monthly monitoring of blood count and liver function tests, and concomitant administration of folic acid lmg to minimise the risk of developing side effects including gastrointestinal upset and fatigue. (16)
Alkylating agents, such as cyclophosphamide and chlorambucil, act by suppressing B-cell function, consequently reducing leukocyte count. They are used to maintain remission following the discontinuation of corticosteroid therapy. (25) However, both alkylating agents are associated with serious side effects such as anaemia, teratogenicity, thrombocytopenia, infertility, infection, and in the case of cyclophosphamide, the development of secondary malignancies. Chlorambucil has been associated with the following side effects: bone marrow suppression; opportunistic infections and sterility. Therefore, strict monitoring during therapy is key with both of these agents. Other agents, such as cyclosporine, (26) and rapamycin (also known as sirolimus), (27) have also shown anti-inflammatory activity in non-infectious uveitis.
Ocular inflammation can occur secondary to many systemic inflammatory diseases including inflammatory bowel disease, ankylosing spondylitis, psoriasis, Behget's disease, juvenile idiopathic arthritis and rheumatoid arthritis. The Food and Drug Administration (FDA) has approved many biologic agents for the treatment of these diseases and, therefore, it is no surprise that some of these agents have been trialled, off-label, for the treatment of uveitis. (28,29) For example, infliximab and rituximab have received FDA approval for use in the treatment of rheumatoid arthritis. They both differ in their mechanisms of action; infliximab binds and blocks both circulating and membrane-bound TNF-[alpha], whereas rituximab acts against the B-cell antigen, CD20. The off-label use of infliximab has received a large volume of interest after demonstrating efficacious effects in patients with Behcet's uveitis, (30-31) a systemic disorder characterised by recurrent mouth ulcers and intraocular inflammation. Rituximab has been trialled on patients with severe uveitis associated with juvenile idiopathic arthritis refractory to topical or systemic cyclosporine, immunosuppressants and at least one TNF-a inhibitor. The study showed that rituximab could inactivate uveitis in these patients for a long period of time (six to nine months). (32) Side effects associated with rituximab include hypersensitivity reaction, serious infections and tuberculosis. (33) Many other biologies have also been trialled in patients who have uveitis including: etanercept, adalimumab and daclizumab.
The aforementioned biologies differ to each other in their mechanisms of actions, where etanercept and adalimumab are TNF-a blockers, and daclizumab is a T-lymphocyte inhibitor. However, antibodies that have been produced from part human or have no human DNA, for example infliximab, may cause immunemediated hypersensitivity reactions which, depending on their severity, may be treated with antihistamines and / or corticosteroids. Other reported side-effects associated with biologies include: headache, altered lipid levels, and increased risk of infection and malignancy. (33) Cost is another limitation to the use of biologies in the treatment of uveitis as they are very expensive, with unit prices ranging from hundreds to thousands of pounds. (34)
Corticosteroids and immunomodulatory therapy are extensively used in the treatment of non-infectious uveitis. However, as mentioned above, in the longterm these are associated with serious side effects. For this reason, extensive research is ongoing with the aim of developing new therapeutic agents that are efficacious and have better safety profiles. Examples under current assessment in clinical trials include: mTOR inhibitors; fully humanised antibody biologies; glucocorticoid receptor antagonists; recombinant humanised antibodies; and CD28 inhibitors. (35)
Due to the complexity of the pathophysiology of uveitis, current treatment is limited to the use of therapeutics associated with serious side effects. This has led to the development of novel therapies, which aim to stop or reduce inflammation in patients and minimise the need for immunosuppressant therapy.
Exam questions and references
Under the enhanced CET rules of the GOC, MCQs for this exam appear online at www.optometry.co.uk. Please complete online by midnight on 11 November 2016. You will be unable to submit exams after this date.
Course code: C-52471 Deadline: 11 November 2016
* Understand current treatment therapies for uveitis (Group 6.1.11) Be aware of the latest research relating to emerging treatment options for uveitis (Group 2.5.3)
* Understand the latest treatment options for uveitis (Group 4.1.3)
* Be aware of the different approaches for treating uveitis (Group 8.1.3)
Dr. Naba Elsaid is a pharmacists and a lecturer
Dr Naba Elsaid PhD, MPharm and Dr Zeeheh Elsaid PhD, MPharm In clinical pharmaceutics at the University of Hertfordshire. She obtained her PhD from UCL School of Pharmacy.
Dr. Zeeneh Elsaid is a pharmacist and research fellow at UCL School of Pharmacy. Her research focus is the design and development of novel drug delivery systems.
Table 1 Classification of uveitis Type of uveitis Location State of inflammation Anterior Iris Iritis Ciliary body Anterior cyclitis Iris and ciliary body Iridocyclitis Intermediate Vitreous Vitritis Hyalitis Pars planitis Posterior Choroid Choroiditis Retina Retinitis Neuroretinitis Choroid and retina Chorioretinitis Retinochoroiditis Pan-uveitis All of the above All of the above Table 2 Prednisolone acetate 1% Prednisolone sodium phosphate 0.1-0.5% Fluorometholone 0.1% Rimexolone 1% Loteprednol etabonate 0.5% Table 3 Immunosuppressive drugs Table 3 Class Examples Antimetabolites Azathioprine Methotrexate Mycophenolate mofetil Alkylating agents Cyclophosphamide Chlorambucil Antibiotics Cyclosporine Tacromimus Rapamycin Dapsone Adjuvants Bromocriptine Ketoconazole Colchicine
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|Author:||Elsaid, Naba; Elsaid, Zeeheh|
|Date:||Oct 1, 2016|
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