Treatment of Noninfectious Uveitis: Current Options and Agents in Development
A review of the available and forthcoming treatments
JOSE R. MAYA, MD • MOSTAFA HANOUT, MD • PETER MAI, MS • NITHYA RAJAGOPALAN • KATHLEEN E. GUINN, BS • MOHAMMAD A. SADIQ, MBBS • YASIR J. SEPAH, MBBS • QUAN D. NGUYEN, MD, MSC
Jose R. Maya, MD, Mostafa Hanout, MD, and Mohammad A. Sadiq, MBBS, are postdoctoral research fellows of the Stanley M. Truhlsen Eye Institute at the University of Nebraska Medical Center (UNMC) in Omaha. Peter Mai, MS, Nithya Rajagopalan, and Kathleen E. Guinn, BS, are research assistants at UNMC. Yasir J. Sepah, MBBS, and Quan D. Nguyen, MD, MSc, are on the faculty of the Truhlsen Eye Institute. None of the authors reports any financial interest in any of the products mentioned in this article. Dr. Nguyen can be reached via e-mail at email@example.com.
Uveitis accounts for 10% of the visual impairment in the Western world. In the United States alone, approximately 30,000 cases of legal blindness reported annually are due to uveitis.1
Additionally, an approximate annual cost of more than $225 million is associated with the medical care for uveitis patients.2 Anterior uveitis is the most common form of uveitis and accounts for 65% to 70% of all the cases of uveitis.
This index review focuses primarily on the current therapeutic options for noninfectious uveitis (NIU), with a brief overview of the indications for these agents and the side effects of which clinicians must be aware.
Although corticosteroids have remained the first line of treatment for ocular inflammation, their long-term use is associated with systemic and local adverse effects, such as cataract formation, glaucoma, and a multitude of metabolic disorders, including weight gain, hypertension, hypercholesterolemia, atherosclerosis, and osteoporosis.3
Research has shown that 28% to 59% of uveitis patients will develop visual loss that requires therapy beyond corticosteroids. Numerous studies have attempted to develop a therapeutic option that would allow clinicians to limit the use of corticosteroids in managing the signs and symptoms of ocular inflammation and as an adjunct therapy when required.
Issues With Long-term Use
The use of steroid-sparing agents is indicated if chronic steroid usage (no less than 7.5 mg of prednisone or equivalent daily) is necessary to control inflammation. Immunomodulatory therapy (IMT), including antimetabolites, calcineurin inhibitors, alkylating agents, and biologics, for example, are effective and appropriate, but their usage is also not without risks.
Patients treated with these agents require thorough and experienced clinical oversight. We recommend strict adherence to such a guideline to avoid the development of long-term complications, which can arise from the use of corticosteroids or IMT.
Antimetabolites are agents that hinder cellular metabolism, which affects normal cell growth and proliferation. Antimetabolites to treat immunological diseases are warranted because rapidly proliferating T- and B-lymphocytes are especially vulnerable to inhibition of cellular metabolism.
Methotrexate (MTX) is an excellent first choice for patients with NIU because of its once-weekly dosing and manageable cost. It has specifically shown effectiveness in treating Behfet’s disease and ankylosing spondylitis.
Methotrexate impairs the function of intracellular folic acids, reducing cellular metabolism.4 Taylor et al reported that the intravitreal route of administration of MTX was effective in controlling intraocular inflammation. In addition, it increased visual acuity in almost 80% of patients.5
Although MTX has a favorable safety profile, adverse events may include hepatotoxicity and rare incidences of hepatic cirrhosis. MTX is also not appropriate for use during pregnancy and while breast feeding.
As a purine analog, azathioprine (AZA) inhibits DNA replication and RNA transcription, impeding T- and B-lymphocyte proliferation.4,6 Studies have shown that AZA is effective when used in conjunction with steroids in the treatment of Adamantiades-Behfet disease (ABD) and serpiginous choroidopathy.
Azathioprine is also potent in refractory cases of Vogt-Koyanagi-Harada (VKH) syndrome, in which a complete response to systemic corticosteroids does not occur, or a very high dose of corticosteroids is necessary to obtain the desired therapeutic effects.6
The adverse events associated with AZA toxicity include bone marrow suppression and hepatotoxicity.6
Mycophenolate mofetil (MMF; CellCept, Genentech, South San Francisco, CA) is an excellent alternative to MTX and has proved effective in treating Behfet’s disease, juvenile rheumatoid arthritis (JRA), and systemic lupus erythematosus.
An immunosuppressant and prodrug of mycophenolic acid, MMF inhibits purine synthesis, hindering T- and B-lymphocyte proliferation. The drug also interferes with antibody synthesis and cellular adhesion to the vascular endothelium.4
Although uncommon, adverse effects of MMF toxicity include hepatotoxicity, opportunistic infections, leukopenia, and lymphoma. Its relatively favorable safety profile, however, supports its use over AZA among the antimetabolites, especially in organ transplantation and uveitis.7
Calcineurin is a calcium- and calmodulin-dependent protein phosphatase. When activated, it upregulates interleukin (IL)-2 expression and successively promotes cell growth and the proliferation of T-lymphocytes.
Calcineurin inhibitors effectively block proliferation and additional cytokine release, thus making them a powerful clinical tool against NIU.
Clinicians have used cyclosporine A (CsA) in combination with MMF in birdshot retinochoroidopathy with an acceptable safety profile.8 By forming a complex with calcineurin, CsA inhibits calmodulin binding with Ca+2-activated phosphatase activity of calcineurin.
The adverse events associated with the use of cyclosporine include nephrotoxicity, hypertension, gum hyperplasia, and paresthesia, among others.9
Tacrolimus is an exceptionally viable macrolide immunosuppressant that is more potent then CsA and shows fewer systemic side effects.10 Researchers have reported its use in posterior uveitis, even in patients refractory to cyclosporine.11
The systemic side effects related to tacrolimus are nephrotoxicity, hyperesthesia, hypertension, tremor, gastrointestinal symptoms, and central nervous system alterations.10
These agents are among the most potent immunosuppressive therapies available. Physicians should reserve these drugs for recalcitrant cases and severe, sight-threatening uveitis cases.12
Alkylating agents interfere in cell replication and cell division within resting and dividing T- and B-lymphocytes in the peripheral blood.12 The physician must seriously consider the powerful toxic effects of these agents in the renal, hematopoietic, gastrointestinal, gonadal, and central nervous systems. Each of these agents has a characteristic set of toxicities that clinicians must take into account.
Cyclophosphamide is indicated in only the most severe cases due to its frequent adverse effects. Despite these effects, it is useful in treating many systematic autoimmune diseases that cause NIU, including systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis.
This agent undergoes activation to produce active phosphoramide mustard, which cross-links DNA and reduces the proliferation of T- and B-lymphocytes. Recently, a new protocol of intravenous cyclophosphamide in severe noninfectious posterior uveitis and other ocular inflammatory diseases showed a high rate of sustained remission of disease in 91.7% of patients.13
The most common systemic side effect with cyclophosphamide treatment is hemorrhagic cystitis. The drug also increases the risks of bladder cancer, myelosuppression, and sterility.
Oncologists use chlorambucil (Leukeran, GlaxoSmithKline, Philadelphia, PA) in chronic lymphocytic leukemia and lymphoma. Ophthalmologists can also use it in selected cases of uveitis and ocular inflammatory diseases, such as ocular cicatricial pemphigoid.
Chlorambucil is well tolerated by most patients, but its effectiveness is less predictable. Anemia and thrombocytopenia are common side effects.
BIOLOGIC RESPONSE MODIFIERS
These natural or synthetic molecules target regulating cytokines or cellular receptors. They include monoclonal antibodies and recombinant forms of natural inhibitory molecules.
Clinicians have used these agents, off-label in most cases, in patients with refractory ocular inflammation, including sarcoidosis, birdshot retinopathy, and Behçet’s disease.14
Most of these agents target tumor necrosis factor (TNF)-alpha. The body produces this proinflammatory cytokine in response to acute and chronic inflammation, and it plays a very important role in the inflammatory cascade.15
However, doctors should reserve their use for uveitis refractory to traditional immunosuppressants. We discuss several agents commonly employed in the management of uveitis and ocular inflammatory diseases below.
Infliximab (Remicade, Johnson & Johnson, New Brunswick, NJ) is a chimeric monoclonal immunoglobulin G antibody against TNF-alpha. Its efficacy was shown by the maintenance of visual acuity, control of ocular inflammation, and reduction in corticosteroid doses in children with NIU and adults with ABD.16
A prospective, multicenter trial in Japan reported some level of improvement in 92% of patients and the absence of ocular attacks in 44% of patients treated with infliximab in refractory uveitis related to ABD.16 These findings have led to infliximab becoming a first-line therapy in Japan for the treatment of ABD.
However, some researchers have questioned the efficacy of this drug in maintaining remission after its withdrawal.17 The systemic adverse effects to consider are malignancy, tuberculosis, multiple sclerosis, and lupus-like reactions.
Adalimumab (Humira, AbbVie, Inc., North Chicago, IL) is a fully humanized monoclonal antibody that targets TNF. Its effectiveness was shown in treating severe forms of VKH disease, ABD, JRA-associated uveitis and pediatric uveitis.18
Clinically, this drug has shown good safety and efficacy profiles. Additionally, subcutaneous delivery provides a less expensive and less immunogenic therapeutic option, compared to infliximab.19
The most common side effect is local erythema at the site of injection. Rare systemic side effects consist of serious infections, demyelinating diseases, and drug-induced lupus.
Adalimumab is especially useful in cases of sight-threatening childhood uveitis, in infliximab-allergic patients, and in resistant NIU with poor response to other therapies.19
This immunomodulatory cytokine (Roferon, Genentech) has proved a valuable treatment option, especially in ABD and refractory cases of chronic posterior uveitis.20 Systemic adverse events include flu-like symptoms, leukopenia, and alopecia.
Case reports have shown the soluble recombinant IL-1 receptor antagonist anakinra (Kineret, Sobi, Inc., Stockholm, Sweden) to be useful in cases of posterior uveitis associated with CINCA syndrome. It has also proved useful in selective cases of uveitis.21 The systemic side effects include neutropenia, particularly in combination with TNF-blocking agents, and serious infections.
PRECAUTIONS WITH IMT
The use of IMT agents mandates thorough patient evaluation and counseling to help reduce the risk of associated adverse events. Physicians who prescribe such medications should have the expertise of safety monitoring and managing the reported associated toxicities.22
The ophthalmologist initiating IMT should rule out any active or latent infection, as well as any hepatic, renal, or hematologic disease. Many IMT agents are potentially teratogenic, so the physician should screen and counsel patients to avoid pregnancy. Detection of drug toxicity can mandate dose reduction or even discontinuation of a certain agent.22
Routine Blood Work
The treatment team should monitor complete blood count very closely in patients on MMF. Patients on MTX will need CBC and liver function tests every four to six weeks. Dose reduction or discontinuation can reverse detected hepatotoxicity.23
Calcineurin inhibitors, such as cyclosporine A and tacrolimus, can impair renal function. Dose adjustment or complete cessation of the drug may be indicated if the creatinine level increases by 30% or more.24
Grave adverse events, including increased risk of malignancy, sterility, and myelosuppression, have been associated with cyclophosphamide and chlorambucil.25 Patients may consider sperm banking prior to treatment because of the high risk of infertility, and they should undergo CBC on a monthly basis.
Side Effect Prevention and Screening
High water intake is necessary to decrease the risk of developing hemorrhagic cystitis. Prophylactic trimethoprim-sulfamethoxazole can protect against opportunistic pneumocystis pneumonia infections.25
The risk of serious opportunistic infections particularly increases with the use of biologic response modifiers. As a result, patients should undergo proper screening for tuberculosis before starting treatment.
Clinicians treating inflammatory ocular diseases should have a no-tolerance policy for any degree of inflammation. The efficacy of systemic treatment with corticosteroids is well known and mandated in certain cases.
However, many ophthalmologists do not follow the acceptable maintenance dose of 7.5 mg/day of prednisone or its equivalent. These doctors must consider the proper use of IMT in cases in which they cannot control the inflammation with an acceptable maintenance dose of corticosteroids.26
Tailored treatment is now possible given an increasing understanding of the immune response. Clinician scientists continue to work on characterizing the various phenotypes associated with different types of uveitis to diagnose and treat them effectively. At the same time, the correct use of corticosteroids and IMT allows for better results in patients. RP
1. Nussenblatt RB. The natural history of uveitis. Int Ophthalmol. 1990;14:303-308.
2. Suttorp-Schulten MS, Rothova A. The possible impact of uveitis in blindness: a literature survey. Br J Ophthalmol. 1996;80:844-848.
3. Fel A, Aslangul E, Le Jeunne C. [Eye and corticosteroid’s use]. Presse Med. 2012;41:414-421.
4. Jabs DA, Rosenbaum JT. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2001;131:679.
5. Taylor SR, Banker A, Schlaen A, et al. Intraocular methotrexate can induce extended remission in some patients in noninfectious uveitis. Retina. 2013 Apr 23. [Epub ahead of print]
6. Kayama T, Otsuka A, Miyachi Y, Kabashima K. Improvement of anti-TNF-H antibody-induced pustular psoriasis by azathioprine. Eur J Dermatol. 2012;22:565-566.
7. Woodroffe R, Yao GL, Meads C, Bayliss S, Ready A, Raftery J, Taylor RS. Clinical and cost-effectiveness of newer immunosuppressive regimens in renal transplantation: a systematic review and modelling study. Health Technol Assess. 2005;9:1-179, iii-iv.
8. Cervantes-Castaneda RA, Gonzalez-Gonzalez LA, Cordero-Coma M, Yilmaz T, Foster CS. Combined therapy of cyclosporine A and mycophenolate mofetil for the treatment of birdshot retinochoroidopathy: a 12-month follow-up. Br J Ophthalmol. 2013;97:637-643.
9. Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009;4:481-508.
10. Miserocchi E, Modorati G, Foster CS. New treatments in noninfectious uveitis. In: Bandello F, ed. Developments in Ophthalmology. Vol. 51. New York, NY; Karger; 2012;
11. Sloper CM, Powell RJ, Dua HS. Tacrolimus (FK506) in the treatment of posterior uveitis refractory to cyclosporine. Ophthalmology. 1999;106:723-728.
12. Habot-Wilner Z, Lightman S. Immunomodulatory therapy in uveitis. In: Nguyen QD, Rodrigues EB, Farah ME, Mieler WF, eds. Retinal Pharmacotherapy. New York, NY; Saunders Elsevier; 2010:248-258.
13. Suelves AM, Arcinue CA, Gonzalez-Martin JM, Kruh JN, Foster CS. Analysis of a novel protocol of pulsed intravenous cyclophosphamide for recalcitrant or severe ocular inflammatory disease. Ophthalmology. 2013;120:1201-1209.
14. Imrie FR, Dick AD. Biologics in the treatment of uveitis. Curr Opin Ophthalmol. 2007;18:481-486.
15. Kneilling M, Mailhammer R, Hultner L, et al. Direct crosstalk between mast cell-TNF and TNFR1-expressing endothelia mediates local tissue inflammation. Blood. 2009;114:1696-706.
16. Okada AA, Goto H, Ohno S, Mochizuki M; Ocular Behget’s Disease Research Group Of Japan. Multicenter study of infliximab for refractory uveoretinitis in Behcet disease. Arch Ophthalmol. 2012;130:592-598.
17. Adan A, Hernandez V, Ortiz S, et al. Effects of infliximab in the treatment of refractory posterior uveitis of Behcet’s disease after withdrawal of infusions. Int Ophthalmol. 2010;30:577-581.
18. Dobner BC, Max R, Becker MD, et al. A three-centre experience with adalimumab for the treatment of non-infectious uveitis. Br J Ophthalmol. 2013;97:134-138.
19. Diaz-Llopis M, Salom D, Garcia-de-Vicuna C, et al. Treatment of refractory uveitis with adalimumab: a prospective multicenter study of 131 patients. Ophthalmology. 2012;119:1575-1581.
20. Sobaci G, Erdem U, Durukan AH, et al. Safety and effectiveness of interferon alpha-2a in treatment of patients with Behcet’s uveitis refractory to conventional treatments. Ophthalmology. 2010;117:1430-1435.
21. Teoh SC, Sharma S, Hogan A, Lee R, Ramanan AV, Dick AD. Tailoring biological treatment: anakinra treatment of posterior uveitis associated with the CINCA syndrome. Br J Ophthalmol. 2007;91:263-264.
22. Ibraham M, Hannout M, Sepah Y, et al. Judicious use of immunomodulatory agents to manage noninfectious uveitis. Retin Physician. 2010;7(9):51-52, 54-58.
23. Cutolo M, Sulli A, Pizzorni C, Seriolo B, Straub RH. Anti-inflammatory mechanisms of methotrexate in rheumatoid arthritis. Ann Rheum Dis. 2001;60:729-735.
24. Murphy CC, Greiner K, Plskova J, et al. Cyclosporine vs tacrolimus therapy for posterior and intermediate uveitis. Arch Ophthalmol. 2005;123:634-641.
25. Pujari SS, Kempen JH, Newcomb CW, et al. Cyclophosphamide for ocular inflammatory diseases. Ophthalmology. 2010;117:356-365.
26. Nguyen QD, Hatef E, Kayen B, et al. A cross-sectional study of the current treatment patterns in noninfectious uveitis among specialists in the United States. Ophthalmology. 2011;118:184-190.