Infliximab

From EyeWiki


Infliximab for Treatment of Uveitis

Infliximab (Brand name: Remicade) is a mouse/human chimeric, monoclonal anti-tumor necrosis factor α (TNF-α) antibody1. Along with etanercept (Enbrel) and adalimumab (Humira), these drugs make up the TNF-α antagonists. TNF-α is a key molecule of the body’s immune defense system. Elevated levels of TNF-α occur at the site of inflammation and is responsible for the pathology of many diseases. Infliximab is a monoclonal antibody that specifically binds TNF-α antigen with high affinity and prevent its proinflammatory effects1.

Overview

Uveitis is a sight-threatening condition that involves inflammation of the entire or individual components of the uvea, which is divided into the iris, ciliary body, and choroid2. The Standardization of Uveitis Nomenclature (SUN) Working Group created a classification of uveitis in 2005 based on the anatomic site of inflammation3. Thus, uveitis is divided by location into anterior uveitis (or iridocyclitis), intermediate uveitis (or pars planitis), posterior uveitis, and panuveitis. Primary uveitis refers to intraocular inflammation of unclear etiology, and secondary uveitis refers to uveitis due to infectious or noninfectious diseases4. Common causes of infectious secondary uveitis include Lyme disease, cytomegalovirus, herpes zoster, and toxoplasmosis. Noninfectious secondary uveitis is typically associated with immune-mediated systemic conditions including sarcoidosis, juvenile idiopathic arthritis, and inflammatory bowel disease2,4.

The pathogenesis of uveitis is not well established, but it is thought to occur predominantly due to a helper T-cell response initiating the production of cytokines, TNF-α, and vascular endothelial growth factor (VEGF)5-6. Systemic production of these products can damage the blood-retinal barrier and lead to exposure of the inner eye to an immune attack7-9. TNF-α may be associated with anterior chamber cells and flare, which suggests that it may be an initiating factor in the pathogenesis of uveitis9.

The goal of treatment of noninfectious uveitis is to control inflammation and to prevent the devastating sequelae of chronic inflammation, such as loss of vision. Initial treatment of noninfectious uveitis is typically with topical or intraocular corticosteroids. Systemic treatment is generally reserved for patients with inflammation resistant to initial therapies. Systemic treatment options include oral glucocorticoids, immunosuppressive agents, and biologics, such as anti-tumor necrosis factor alpha agents and VEGF inhibitors. The most common immunomodulary agents used include methotrexate, cyclosporine, and mycophenolate mofetil. Anti-TNF-α antagonists have been used in the treatment of refractory uveitis and in some cases of pediatric uveitis. Infliximab, one of the TNF-α inhibitors, is commonly used for a variety of rheumatologic disease. There has been increasing evidence for the use of infliximab as an off-label treatment of uveitis4.

Role of Tumor Necrosis Factor α (TNF-α)

Tumor necrosis factor α (TNF-α) is a proinflammatory cytokine in the body produced by many different types of immune cells, including macrophages, T-cells, mast cells, granulocytes, and natural killer (NK) cells. TNF-α can serve as a ligand or a receptor. Its production leads to NF-κB production, cell activation, or apoptosis, depending on the type of cell it acts upon. It plays a role in the inflammatory cascade by inducing the production of other inflammatory cytokines, such as IL-1, interferon gamma, and IL-2. The production of TNF-alpha is highly regulated, and can be initiated by various stimuli, including infections, trauma, hypoxia, and cytokines. It is barely detectable in quiescent cells. At low doses, TNF-α augments the body’s immune response against infections. However at higher doses, TNF lead to excess inflammation and organ damage. Acute release of large amounts of TNF can lead to septic shock1.

Figure 1. Structure of TNF-α antagonists[1]

Mechanism of Action of Infliximab

Immune-mediated diseases all share a common pathologic mechanism involving TNF-α. Removing TNF-α from the site of inflammation is a therapeutic goal. Infliximab is an IgG monoclonal antibody, meaning it is derived from B cells that clonally express copies of a heavy chain and light chain which are linked covalently to form a unique antibody molecule. With this structure, infliximab binds strongly to circulating and membrane-bound TNF-α ligands in order to inhibit the action of TNF-α1.

Indications and Uses

Infliximab is used to treat several systemic inflammatory conditions, including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis and Crohn’s disease. It has been reported to be effective for the treatment of uveitis associated with juvenile idiopathic arthritis (JIA), Behcet’s disease, sarcoidosis, Vogt-Koyanagi-Harada syndrome, and Takayasu disease.

Infliximab may also be effective for birdshot retinochoroidopathy, recalcitrant uveitis, cystoid macular edema, pars planitis, multifocal choroiditis, HLA B-27 related anterior uveitis and idiopathic uveitis10. The pathologic events in these diseases include the induction of cytokines, such as IL-1 and IL-6, as well as acute phase reactants like C reactive protein.

Juvenile idiopathic arthritis

Uveitis is the most common extraarticular presentation of JIA, with the most common form being chronic anterior uveitis11. It is important to control inflammation to decrease the risk of vision loss. Initial treatment includes topical glucocorticoids, however the use of long-term topical glucocorticoids can lead to cataracts and increased intraocular pressures. Thus, to maintain inflammation control patients are often given systemic therapy in the form of methotrexate or monoclonal TNF-α inhibitors. Infliximab and adalimumab are the preferred TNF-α inhibitors over etanercept12.

Behcet’s disease

Behcet’s disease is a chronic multisystem disease manifesting as ocular, oral, cutaneous, genital, vascular, and neurologic lesions13. Ocular manifestations occur in 70% of patients and manifests as bilateral panuveitis. This can occur as recurrent inflammatory attacks with episodes of remission. Repetitive attacks can result in permanent ocular tissue damage14. Many studies have shown uveitis secondary to Behçet’s disease to be especially responsive to infliximab15-17. In Japan, infliximab is approved as first-line treatment for ocular Behçet’s disease. An expert panel has recommended FDA approval for first-line treatment of ocular manifestations of Behçet’s disease18.

Administration and Dosing

Infliximab must be given intravenously by infusion. It has a half-life of 8 to 10 days and a clearance of 11 mL/hour. Administration typically begins at a dosage of 3 to 5 mg/kg at weeks 0, 2, and 6, and then every 4-8 weeks depending on disease control. The dose and frequency can be increased up to 10 mg/kg every 4 weeks based on patient response and side effects19,20. After achieving clinical remission, the infusion interval can be slowly prolonged; there is limited evidence regarding the ideal protocol for extending infusion intervals and eventually discontinuing the drug. As recommended by the American College of Rheumatology, infliximab is commonly given with another immunosuppressive drug, such as methotrexate. This may reduce the risk of allergic reactions or antibody production against the chimeric monoclonal antibody, and allows for a smaller dose to be used20,21.

Safety

Side effects

The most common side effects of infliximab are respiratory infections, headache, rash, coughing, fatigue, and stomach pain22. During infusion, patients may experience discomfort around the infusion site, fever or chills, itching or allergic skin rash, chest pain, and changes in blood pressure.

Serious Infections

There is a reported increased risk of infection in patients treated with TNF-α inhibitors. Prior to therapy, patients must receive up to date vaccinations and should be screened for hepatitis B, hepatitis C, and HIV. There is a greater chance for the reactivation of latent TB in patients taking infliximab and adalimumab as compared to other TNF-α inhibitors22. Screening for latent TB with tuberculin skin tests and/or chest radiographs prior to starting therapy is recommended for all TNF-α antagonists23. Patients with serpiginous choroidopathy, which may be associated with TB, should be monitored cautiously10.

Malignancy and other syndromes

An increased rate of lymphomas and systemic lupus erythematous-like syndromes have also been reported, but their associated with TNF-α antagonists as opposed to the underlying disease is controversial1, 24. Patients should be counseled to immediately report any symptoms to their physician.

Autoantibody formation

Because infliximab is a chimeric mouse-human monoclonal antibody, there is a chance that prolonged treatment with infliximab may lead to new autoantibody formation24-26. To reduce this risk, patients may be given combination therapy with methotrexate or similar agent to suppress the immune system and decrease the chance of autoantibody formation26.

Limitations

Infliximab is not FDA approved for uveitis or ocular inflammation. It is currently FDA approved for Crohn’s disease, ulcerative colitis, rheumatoid arthritis, psoriatic arthritis and plaque psoriasis, and ankylosing spondylitis.

Infliximab is contraindicated in patients with underlying malignancy and immune compromised status. It is also expensive and has limited long-term safety data.

Current Research

A 6.5-year retrospective cohort study showed 72 of 88 (81.8%) of patients with refractory uveitis achieved clinical remission with infliximab treatment; 84.7% of the patients achieved remission at 6 months, and 37.5% of the patients were able to discontinue all additional topical or oral therapies within 180 days of beginning infliximab therapy. Of the patients who achieved clinical remission, only five were successfully tapered off infliximab to achieve infliximab-free long-term remission during the course of the study, suggesting that prolonged maintenance dosing for infliximab may be necessary to maintain remission. 17 (19.3%) patients had to discontinue treatment secondary to serious side effects27..

A 2-year prospective trial of infliximab treatment for refractory uveitis had initial remission in 24 of 31 patients (77%). Of these patients, 60% retained effectiveness in the first year and 60% in the second year. 6 of 31 (19.4%) patients had to discontinue treatment due to serious side effects. 3 of 31 patients developed drug-induced lupus28.

A retrospective longitudinal case series of 31 patients with chronic noninfectious uveitis treated with infliximab achieved corticosteroid-sparing control of inflammation in 33.3% of patients at 3 months, 60.7% at 6 months, and 60.9% at 12 months. The median time to sustained control of inflammation was 63 days29.

Studies have shown infliximab to be more effective than etanercept in the treatment of uveitis19, 30. As reported in the Systemic Immunosuppressive Therapy for Eye Disease (SITE) Cohort Studies, one study may indicate that infliximab and adalimumab are potentially more effective or quicker at controlling inflammation than conventional corticosteroid-sparing drugs (methotrexate, cyclosporine, azathioprine, cyclophosphamide)19. It should be noted that the definitions of treatment success, dosing regimen, severity of disease in the study population, and other factors vary between the referenced published reports.

Conclusions

Infliximab is an effective treatment for refractory uveitis. It appears to have a relatively low rate of treatment-ending adverse events, although there is limited long-term safety data. Long-term maintenance therapy with infliximab may be needed to maintain remission. Given the high cost, possibly severe adverse effects, and limited long-term safety data, infliximab is not recommended as first-line therapy, but off-label use may be very useful when conventional therapy has failed or has been poorly tolerated.

Additional Resources

http://www.uveitis.org/

https://nei.nih.gov/health/uveitis/uveitis

https://www.mayoclinic.org/diseases-conditions/uveitis/symptoms-causes/syc-20378734

References

1. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117:244-79.

2. Dunn JP. Uveitis. Prim Care. 2015;42(3):305–323.

3. Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140:509–516.

4. Sukumaran S, Marzan K, Shaham B, Reiff A. High dose infliximab in the treatment of refractory uveitis: does dose matter? ISRN Rheumatol. 2012:765380. doi: 10.5402/2012/765380. Epub 2012 Jan 5. PubMed PMID: 22389806; PubMed Central PMCID: PMC3263752.

5. Muhaya M, Calder VL, Towler HMA, Jolly G, McLauchlan M, Lightman S. Characterization of phenotype and cytokine profiles of T cell lines derived from vitreous humour in ocular inflammation in man. Clinical and Experimental Immunology. 1999;116(3):410–414.

6. Calder VL, Shaer B, Muhaya M, et al. Increased CD4+ expression and decreased IL-10 in the anterior chamber in idiopathic uveitis. Investigative Ophthalmology and Visual Science. 1999;40(9):2019–2024.

7. Richards JC, Tay-Kearney ML, Murray K, Manners P. Infliximab for juvenile idiopathic arthritis-associated uveitis. Clinical and Experimental Ophthalmology. 2005;33(5):461–468.

8. Rosenbaum JT, Howes EL, Rubin RM, Samples JR. Ocular inflammatory effects of intravitreally-injected tumor necrosis factor. American Journal of Pathology. 1988;133(1):47–53.

9. De Vos AF, Van Haren MC, Verhagen C, Hoekzema R, Kijlstra A. Tumour necrosis factor-induced uveitis in the Lewis rat is associated with intraocular interleukin 6 production. Experimental Eye Research. 1995;60(2):199–207.

10. Rosenbaum J, Pasadhika S. Update on the use of systemic biologic agents in the treatment of noninfectious uveitis. Biologics: Targets and Therapy. 2014; 8: 67-81. doi:10.2147/btt.s41477.

11. Foeldvari I, Nielsen S, Kummerle-Deschner J, et al. Tumor necrosis factor-alpha blocker in treatment of juvenile idiopathic arthritis-associated uveitis refractory to second-line agents: results of a multinational survey. J Rheumatol. 2007; 34(5):1146-50.

12. Angeles-Han ST, Ringold S, Beukelman T, Lovell D, et al. 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis. Arthritis Care & Research. 2019; 1-14.

13. Wong RC, Ellis CN, Diaz LA. Behcet's disease. Int J Dermatol. 1984;23:25-32

14. Ohno S, Nakamura S, Hori S, et al. Efficacy, safety and pharmacokinetics of multiple administration of infliximab in Behçet's disease with refractory uveoretinitis. J Rheumatol. 2004;31(17):1362-8.

15. Sfikakis PP, Kaklamanis PH, Elezoglou A, et al. Infliximab for recurrent, sight-threatening ocular inflammation in Adamantiades-Behcet disease. Ann Intern Med. 2004;140(5):404–406.

16. Tugal-Tutkun I, Mudun A, Urgancioglu M, et al. Efficacy of infliximab in the treatment of uveitis that is resistant to treatment with the combination of azathioprine, cyclosporine, and corticosteroids in behçets disease: An open-label trial. Arthritis & Rheumatism. 2005; 52(8): 2478-2484. doi:10.1002/art.21231.

17. Clarke G, Jabs DA, Read RW, et al. Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology. 2014;121(3):785-796. doi: 10.1016/j.ophtha.2013.09.048.

18. Martel JN, Esterberg E, Nagpal A, & Acharya NR. Infliximab and Adalimumab for Uveitis. Ocular Immunology and Inflammation. 2012;20(1):18-26. doi:10.3109/09273948.2011.633205.

19. Reddy AK, & Albini TA. A Review of Biologics for Uveitis. Retina Today. 2015. http://retinatoday.com/2015/10/a-review-of-biologics-for-uveitis/. Accessed February 24, 2018.

20. Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendation for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2012; 64(5): 625-639. doi: 10.1002/acr.21641.

21. Keystone EC. Safety of biologic therapies: an update. J Rheumatol Suppl, 2005;32:8-12.

22. Carmona L, Gómez-Reino JJ, Rodríguez-Valverde V, Montero E, Pascual-Gómez EM, et al. Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. Arthritis Rheum. 2005;52:1766-1772

23. Antoni C, Braun J. Side effects of anti-TNF therapy: current knowledge. Clin Exp Rheumatol. 2002;20(Suppl 28):S152–S157.

24. Suhler EB, Smith JR, Wertheim MS, Lauer AK, Kurz DE, Pickard TD, Rosenbaum JT. A Prospective Trial of Infliximab Therapy for Refractory Uveitis. Archives of Ophthalmology. 2005;123(7):903-12. doi:10.1001/archopht.123.7.903.

25. Louis M, Rauch J, Armstrong M, Fitzcharles MA. Induction of autoantibodies during prolonged treatment with infliximab. J Rheumatol. 2003;30(12):2557-2562.

26. Kruh JN, Yang P, Suelves AM, Foster CS. Infliximab for the treatment of refractory noninfectious uveitis: a study of 88 patients with long-term follow-up. Ophthalmology. 2014;121(1):358-364. doi: 10.1016/j.ophtha.2013.07.019.

27. Suhler EB, Smith JR, Giles TR, et al. Infliximab therapy for refractory uveitis: 2-year results of a prospective trial [letter]. Arch Ophthalmol. 2009;127:819-822. doi:10.1001/archophthalmol.2009.141.

28. Martel JN, Esterberg E, Nagpal A, & Acharya NR. Infliximab and Adalimumab for Uveitis. Ocular Immunology and Inflammation. 2012;20(1):18-26. doi:10.3109/09273948.2011.633205.

29. Galor A, Perez VL, Hammel JP, & Lowder CY. Differential Effectiveness of Etanercept and Infliximab in the Treatment of Ocular Inflammation. Ophthalmology. 2006; 113(12):2317-2323. doi:10.1016/j.ophtha.2006.04.038.

30. Foeldvari I, Nielsen S, Kummerle-Deschner J, et al. Tumor necrosis factor-alpha blocker in treatment of juvenile idiopathic arthritis-associated uveitis refractory to second-line agents: results of a multinational survey. J Rheumatol. 2007; 34(5):1146-50.
  1. 1 Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther. 2008;117:244-79.