Immunomodulatory Therapy in Noninfectious Posterior Uveitis
Four treatment approaches from which to choose.
Omar Saleh, MD • Aleksandr Kagan Do • Yoreh Barak, MD • Henry J. Kaplan, MD, FACS
Immunomodulatory therapy (IMT) is an important tool in our therapeutic armamentarium to control intraocular inflammation in patients with noninfectious posterior uveitis who are intolerant or unresponsive to local or systemic corticosteroids. By offering a corticosteroid-sparing approach, these medications may save many patients from the adverse effects of chronic corticosteroid use.1
The ability of IMT to control intraocular inflammation, improve vision, avoid the adverse effects of prolonged corticosteroid use, and achieve long-term remission in noninfectious posterior uveitis is well accepted.2-8 However, most evidence concerning the efficacy and safety of IMT in uveitis comes from anecdotal reports or retrospective reviews.
The Multicenter Uveitis Steroid Treatment (MUST) trial represents a landmark in uveitis because it is a multicenter, randomized, prospective clinical trial involving 23 clinical centers comparing the effectiveness and safety of a novel local therapy (an intraocular fluocinolone acetonide implant) with systemic therapy.38 This trial showed that patients in the systemic treatment arm (corticosteroids plus immunosuppression) generally tolerated treatment and had no long-term adverse consequences, as well as that there was no difference in visual acuity between the two treatment groups at two years.39
Nevertheless, the decision to use systemic therapy in uveitis patients requires careful patient selection and expertise in the field. It carries with it the responsibility to monitor the patient meticulously for potential adverse effects.
|Omar Saleh, MD, Aleksandr Kagan, DO, and Yoreh Barak, MD, are fellows in the Department of Ophthalmology and Visual Sciences at the University of Louisville in Kentucky. Henry J. Kaplan, MD, FACS, is Evans Professor of Ophthalmology and chair of the Department of Ophthalmology and Visual Sciences at the University of Louisville. None of the authors reports any financial interest in any products mentioned in this article. Dr. Kaplan can be reached via e-mail at firstname.lastname@example.org.|
We will briefly review the clinical evidence to date concerning the use of four classes of systemic IMT in noninfectious posterior uveitis: alkylating agents, anti-metabolites, leukocyte signaling inhibitors, and biologics.
The longest history of systemic immune suppression in posterior uveitis exists with alkylating agents. Although they are not frequently used today because of their serious systemic adverse effects, they can be sight-saving in recalcitrant intraocular inflammatory diseases, with careful patient selection and strict follow-up.
Cyclophosphamide is highly effective and is considered the first-line therapy in the control of severe intraocular inflammation secondary to Wegener granulomatosis, polyarteritis nodosa, rheumatoid arthritis, and relapsing polychondritis.18-20 Chlorambucil has been used to control sight-threatening inflammation in Behçet's disease and sympathetic ophthalmia.21,22
Long-term remission with these drugs can be obtained if they are used at moderate dosage for at least one year after intraocular inflammation has been controlled.23 Alternatively, a short-term, high-dose pulse regimen for three to six months can be employed.24
When alkylating agents are used, a complete blood count and urinalysis should be obtained at the onset of treatment and then weekly until a stable dose is reached, after which it can be extended to monthly or longer. If significant bone marrow suppression is seen, therapy should be interrupted until the counts have recovered, and then therapy may be resumed at a lower dose. If hematuria occurs, cyclophosphamide should be discontinued.
Antimetabolites now enjoy favor as a first choice of treatment with IMT in most cases of posterior uveitis. Methotrexate, mycophenolate mofetil, and azathioprine have been used in combination with other drugs or as monotherapy in the management of posterior uveitis.
|IMT AGENT||MECHANISM OF ACTION||MAJOR ADVERSE REACTIONS||COST AND COMMENTS|
|Blocks purine synthesis and 5- aminoimidazole-4-carboxamide ribonucleotide (AICAR), thus increasing anti-inflammatory adenosine concentrations at sites of inflammation and inhibiting T-cell activation.40,41||Gastrointestinal upset (10% to 25%), hepatotoxicity (15%), pneumonitis, dermatitis, stomatitis, and alopecia. No increase in risk of malignancy.||$87 for 72 tablets.|
Alcohol is strictly prohibited while on methotrexate.
|Inhibits lymphocyte proliferation by blocking inosine monophosphate dehydrogenase (IMPDH) and suppressing de novo purine synthesis. Also inhibits antibody production.||Upset stomach and diarrhea. No increased risk of new malignancy.42||$400 for one month; $220 for generic formulation.|
|Antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins. Decreases the proliferation of immune cells.||GI upset, bone marrow suppression, and hepatotoxicity.||Initially weekly and subsequent monthly tests for CBC and LFT.|
|Inhibits calcineurin in leukocytes, which decreases the production of interleukin-2.||Hypertension (50%), nephrotoxicity (25%), malignancies.43||Approximate monthly cost for oral treatment: $126.|
|Cross-links DNA by active metabolites, which interfere with the growth of normal and neoplastic cells.||Bone marrow suppression, hemorrhagic cystitis, carcinogenesis, teratogenicity, alopecia.||Chlorambucil may have a better safety profile. Chlorambucil is commonly used for the treatment of chronic lymphocytic leukemia.|
|Chimeric monoclonal antibody against TNF-alpha.||Infusion reaction, lupus-like syndrome, vascular thrombosis, congestive heart failure, demyelinating disease, tuberculosis reactivation, increased risk of malignancies.||$761 per injection. Concomitant methotrexate treatment is recommended to suppress lupuslike syndrome.|
|Recombinant human IgG1 monoclonal antibody specific for human TNF. Binds specifically to TNF-alpha and blocks interaction with p55 and p75 cell-surface TNF receptors.||Injection reaction, increased risk of nonmelanoma skin cancers, reactivation of TB and histoplasmosis, congestive heart failure.||$1,167 per injection.|
|Monoclonal antibody directed against the CD20 antigen expressed on B cells.||Infusion reaction, reactivation of hepatitis B, tumor lysis syndrome.||$582 per 10 mg/mL 10mL vial.|
|Consists of two identical TNF “receptors” linked together. Binds lymphotoxin (TNF-beta) in addition to soluble TNF-alpha.||Injection reaction (33%), reactivation of TB and histoplasmosis, CHF. Dosing is twice a week.||$110 per injection.|
Methotrexate showed favorable efficacy and safety in the treatment of sarcoidosis-associated panuveitis, chronic vitritis, and retinal vasculitis, especially in corticosteroid-resistant patients.9,10 However, in the Systemic Immuno-suppressive Therapy for Eye Diseases (SITE) study, methotrexate was most successful in patients with anterior uveitis and scleritis.11
Reports on the use of mycophenolate mofetil in posterior uveitis are not common. It has been used in combination with corticosteroids and with other immunosuppressive drugs in intraocular inflammation with reportedly good results.12,13 Additionally, the efficacy of monotherapy in various inflammatory eye conditions, including posterior uveitis, was favorable with a satisfactory safety profile.14
The efficacy of azathioprine in posterior uveitis has been variable. In a placebo-controlled trial of 73 patients with Behçet's disease, azathioprine was thought to be effective in decreasing the incidence of posterior uveitis in those patients without ocular involvement, as well as disease in the second eye in those patients with unilateral disease.15
However, other studies with azathioprine in Behçet's disease, as well as sympathetic ophthalmia, were not favorable.7 In the SITE study, azathioprine was most effective in eyes with intermediate uveitis.16 Patients on antimetabolites should be monitored with a CBC and liver function tests (LFTs) every one to three months. With mycophenolate mofetil, a CBC should be obtained every two weeks during dose titration and less frequently afterwards.
The efficacy of leukocyte-signaling inhibitors, such as cyclosporine, in posterior uveitis was first demonstrated in the late 1980s. Nussenblatt and colleagues reported on their effectiveness in several posterior uveitides: Behçet's disease, Vogt-Koyanagi-Harada syndrome (Figure 1), sarcoidosis, and sympathetic ophthalmia.17 Their effectiveness in controlling inflammation, with noninferiority to systemic corticosteroids, was reported in a randomized, controlled clinical trial of 56 patients with intractable intermediate and posterior uveitis.
In addition, the authors found increased effectiveness if these drugs were used with other IMT agents. Baseline blood pressure, CBC, and a complete metabolic panel should be obtained and monitored biweekly during dose titration and monthly thereafter.
Over the past few years, biologic agents have been added to our therapeutic armamentarium. Preliminary reports on the efficacy of antibodies to tumor necrosis factor, such as infliximab, have been promising.
Infliximab has been used in Behçet's disease resistant to other immunosuppressive agents, as well as in juvenile idiopathic arthritis (JIA), ankylosing spondylitis, Wegener granulomatosis, sarcoidosis, and Crohn's disease25-27 It is considered by some authors to be the therapy of choice for severe sight-threatening uveitis secondary to Behçet's disease.28
In a prospective clinical trial by Suhler et al.,29 infliximab achieved therapeutic success in 77% of patients at one year in refractory uveitis in Behçet's disease, birdshot chorioretinopathy, idiopathic panuveitis, and panuveitis associated with sarcoidosis. However, three patients developed thromboembolism, two a drug-related lupus-like illness, and one each a solid malignancy and congestive heart failure. At two years, one additional patient developed a lupus-like illness, and two developed fatal solid malignancies. In addition, 75% of patients developed elevated antinuclear antibody titers.
Other TNF-α inhibitors, while not as extensively studied, have also shown efficacy in the control of intraocular inflammation. Adalimumab was first reported for refractory Behçet's uveitis in 2007.30 Since then, it has been used favorably in uveitis associated with JIA, ankylosing spondylitis, Vogt-Koyanagi-Harada, and birdshot chorioretinopathy.31,32,33
Although infliximab, compared to the other anti-TNF-α agents, seems to achieve the best control of posterior uveitis in Behçet's disease,34,35 it is associated with very serious side effects.36 In children with JIA-associated uveitis, adalimumab seems to be tolerated better, and it may be more suitable for this group of patients.37
Before initiating infliximab or adalimumab therapy, patients are required to undergo tuberculosis testing and to receive hepatitis B vaccinations. CBC and LFT are performed at baseline and then monthly (adalimumab) or before every injection (infliximab). Newer biologics, directed at interleukin 2, CD20, etc., have not yet been used extensively in posterior uveitis at this time.
Table 1 provides a brief overview of the mechanisms of action, side effects, and approximate costs of some of the medications used for IMT. Moreover, the authors recommend references 7, 8, and 39 for comprehensive guidance on the use, monitoring, and efficacy of different immunosuppressive medications in the treatment of ocular inflammation.
In summary, IMT plays an important role in the management of posterior uveitis and provides an alternative to long-term corticosteroid use. However, there are few randomized, clinical trials associated with IMT comparing their effectiveness and adverse side effects. The importance of conducting comparative clinical trials, such as MUST, in noninfectious posterior uveitis cannot be overemphasized. Future reviews on IMT in uveitis will hopefully have more substantive clinical data to offer. RP
1. Kruh J, Foster CS. Corticosteroid-sparing agents: conventional systemic immunosuppressants. Dev Ophthalmol. 2012;51:29-46.
2. Samson CM, Waheed N, Baltatzis S, et al. Methotrexate therapy for chronic noninfectious uveitis: analysis of a case series of 160 patients. Ophthalmology. 2001;108:1134-1139.
3. Süllü Y, Oge I, Erkan D, Aritürk N, et al. Cyclosporin-A therapy in severe uveitis of Behçet's disease. Acta Ophthalmol Scand. 1998;76:96-99.
4. Greenwood AJ, Stanford MR, Graham EM. The role of azathioprine in the management of retinal vasculitis. Eye (Lond). 1998;12:783-788.
5. Rosenbaum JT. Treatment of severe refractory uveitis with intravenous cyclophosphamide. J Rheumatol. 1994;21:123-125.
6. Posarelli C, Arapi I, Figus M, et al. Biologic agents in inflammatory eye disease. J Ophthalmic Vis Res. 2011;6:309-316.
7. Durrani K, Zakka FR, Ahmed M, et al. Systemic therapy with conventional and novel immunomodulatory agents for ocular inflammatory disease. Surv Ophthalmol. 2011;56:474-510.
8. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol. 2000;130:492-513.
9. Dev S, McCallum RM, Jaffe GJ. Methotrexate treatment for sarcoid-associated panuveitis. Ophthalmology. 1999;106:111-118.
10. Shah SS, Lowder CY, Schmitt MA, et al. Low-dose methotrexate therapy for ocular inflammatory disease. Ophthalmology. 1992;99:1419-1423.
11. Gangaputra S, Newcomb CW, Liesegang TL, et al. Methotrexate for ocular inflammatory diseases. Ophthalmology. 2009;116:2188-2198.e1.
12. Daniel E, Thorne JE, Newcomb CW, et al. Mycophenolate mofetil for ocular inflammation. Am J Ophthalmol. 2010;149:423-432.
13. Larkin G, Lightman S. Mycophenolate mofetil. A useful immunosuppressive in inflammatory eye disease. Ophthalmology. 1999;106:370-374.
14. Baltatzis S, Tufail F, Yu EN, et al. Mycophenolatemofetil as an immunomodulatory agent in the treatment of chronic ocular inflammatory disorders. Ophthalmology. 2003;110:1061-1065.
15. Yazici J, Pazarli H, Barnes CG, et al. A controlled trial of azathioprine in BehÇet's syndrome. N Engl J Med. 1990;322:281-285.
16. Pasadhika S, Kempen JH, Newcomb CW, et al. Azathioprine for ocular inflammatory diseases. Am J Ophthalmol. 2009;148:500-509.
17. Nussenblatt RB, Palestine AG, Chan CC, et al. Randomized, double-masked study of cyclosporine compared to prednisolone in the treatment of endogenous uveitis. Am J Ophthalmol. 1991;112:138-146.
18. Brubaker R, Font RL, Shepherd EM. Granulomatous sclerouveitis. Regression of ocular lesions with cyclophosphamide and prednisone. Arch Ophthalmol. 1971;86:517-524.
19. Fauci AS, Doppman JL, Wolff SM. Cyclophosphamide induced remissions in advanced polyarteritis nodosa. Am J Med. 1978;64:890-894.
20. Hoang-Xaun T, Foster CS, Rice BA. Scleritis in relapsing polychondritis. Response to therapy. Ophthalmology. 1990;97:892-898.
21. Tessler HH, Jennings T. High-dose short-term chlorambucil for intractable sympathetic ophthalmia and Behçet's disease. Br J Ophthalmol. 1990;74:353-357.
22. Mudun BA, Ergen A, Ipcioglu SU, et al. Short-term chlorambucil for refractory uveitis in Behçet's disease. Ocul Immunol Inflamm. 2001;9:219-229.
23. Mamo JG. Treatment of Behcet disease with chlorambucil. A follow-up report. Arch Ophthalmol. 1976;94:580-583.
24. Goldstein DA, Fontanilla FA, Kaul S, et al. Long-term follow-up of patients treated with short-term high-dose chlorambucil for sight-threatening ocular inflammation. Ophthalmology. 2002;109:370-377.
25. Baughman RP, Bradley DA, Lower EE. Infliximab in chronic ocular inflammation. Int J Clin Pharmacol Ther. 2005;43:7-11.
26. Bodaghi B, Bui Quoc E, Wechsler B, et al. Therapeutic use of infliximab in sight threatening uveitis: retrospective analysis of efficacy, safety, and limiting factors. Ann Rheum Dis. 2005;64:962-964.
27. Kahn P, Weiss M, Imundo LF, et al. Favorable response to high-dose infliximab for refractory childhood uveitis. Ophthalmology. 2006;113:860-864.
28. Kraus CL, Culican SM. Use of biologic agents in ocular manifestations of rheumatic disease. Int J Rheumatol. 2012;2012:203819.
29. Suhler EB, Smith JR, Giles TR, et al. Infliximab therapy for refractory uveitis: 2-year results of a prospective trial. Arch Ophthalmol. 2009;127:819-822.
30. Mushtaq B, Saeed T, Situnayake RD, et al. Adalimumab for sight-threatening uveitis in BehÇet's disease. Eye (Lond). 2007;21:824-825.
31. Diaz-Llopis M, Garcia-Delpech S, Salom D, et al. Adalimumab therapy for refractory uveitis: a pilot study. J Ocul Pharmacol Ther. 2008;24:351-361.
32. Rudwaleit M, Rodevand E, Holck P, et al. Adalimumab effectively reduces the rate of anterior uveitis flares in patients with active ankylosing spondylitis: results of a prospective open-label study. Ann Rheum Dis. 2009;68:696-701.
33. Tynjala P, Kotaniemi K, Lindahl P, et al. Adalimumab in juvenile idiopathic arthritis—associated chronic anterior uveitis. Rheumatology (Oxford). 2008;47:339-344
34. Evereklioglu C. Ocular Behçet disease: current therapeutic approaches. Curr Opin Ophthalmol. 2011;22:508-516
35. Zakka FR, Chang PY, Giuliari GP, et al. Current trends in the management of ocular symptoms in Adamantiades-Behçet's disease. Clin Ophthalmol. 2009;3:567-579.
36. Suhler EB, Smith JR, Wertheim MS, et al. A prospective trial of infliximab therapy for refractory uveitis: preliminary safety and efficacy outcomes. Arch Ophthalmol. 2005;123:903-912.
37. Biester S, Deuter C, Michels H, et al. Adalimumab in the therapy of uveitis in childhood. Br J Ophthalmol. 2007;91:319-324.
38. Holbrook JT, Kempen JH, Prusakowski NA, et al. Challenges in the design and implementation of the Multicenter Uveitis Steroid Treatment (MUST) Trial - lessons for comparative effectiveness trials. Clin Trials. 2011;8:736-743.
39. Kempen JH, Altaweel MM, Holbrook JT, et al. Randomized comparison of systemic anti-inflammatory therapy versus fluocinolone acetonide implant for intermediate, posterior, and panuveitis: the Multicenter Uveitis Steroid Treatment (MUST) Trial. Ophthalmology. 2011;118:1916-1926.
40. Cronstein BN, Naime D, Ostad E. The antiinflammatory mechanism of methotrexate: increased adenosine release at inflamed sites diminishes leukocyte accumulation in an in vivo model of inflammation. J Clin Invest. 1993;92:2675-2682.
41. Kremer JM. The mechanisms of action of methotrexate in rheumatoid arthritis: the search continues. J Rheumatol. 1994;21:1-5.
42. O'Neill JO, Edwards LB, Taylor DO. Mycophenolate mofetil and risk of developing malignancy after orthotopic heart transplantation: analysis of the transplant registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006;25:1186-1191.
43. Durnian JM, Stewart R, Tatham R, et al. Cyclosporin-A associated malignancy. Clin Ophthalmol. 2007;1:421-430.
44.Cunningham ET Jr, Goldstein DA, Zierhut M. Uveitis treatment trials — a cross-study perspective. Ocul Immunol Inflamm. 2012;20:63-67.