Tumor Necrosis Factor Blockers
Tumor Necrosis Factor Blockers, commonly referred to as TNF-blockers, have become increasingly popular over the last decade as a treatment option for refractory non-infectious uveitis. In the article below we review the history of these drugs and the evidence supporting their use.
General Pathology/Pathophysiology/Mechanism of Action
Tumor Necrosis Factor (TNF) is a term used to describe a family of cytokines that have in common the ability to stimulate other cells to undergo programmed cell death, or apoptosis. The members of the TNF family include TNF-alpha, which has been demonstrated to be an important cytokine in the initiation and propagation of the normal and aberrant immune response, via mechanisms ranging from stimulation of other cytokines, to inflammatory cell recruitment, to alteration of vascular permeability.
The first TNF blocker on the world market was infliximab (Remicade, Centocor), closely followed by etanercept (Enbrel, Amgen), both in 1998. Adalimumab (Humira, Abbott) followed in 2002. These three drugs have all been studied for eye diseases, while the two newer entries into the market, golimumab (Simponi, Centocor) and certolizumab (Cimzia, UCB), have not been studied in eye inflammatory disease. Hence, the remainder of discussion below will focus on the former three biomedicines.
Etanercept is a fusion protein, with Fc portion of a human IgG1 molecule fused to two P75 receptor domains for TNF, As a soluble molecule it is able to capture and neutralize free TNF in a biologic milieu, but unlike the other TNF blockers which are monoclonal antibodies, it cannot bind cell-surface expressed TNF. Etanercept also binds Lymphotoxin A, formerly known as TNF-beta; the monoclonal antibodies bind TNF-alpha only with high avidity.
Etanercept is delivered as a twice-weekly subcutaneous injection, though more recently a once-weekly formulation has been used. It is a fusion protein comprised of the Fc portion of a human IgG1 molecule and two P75 receptor fragments for TNF. In addition to binding TNF-alpha, Etanercept is able to bind lymphotoxin-A (formerly known as TNF-beta). As a fusion protein it is able to bind free TNF but is unable to bind TNF expressed on cell surfaces and is unable to bind complement.
Infliximab is a chimeric (human-murine) monoclonal antibody. Like the other monoclonal antibodies in this class, it binds TNF-alpha exclusively and is able to so with both free and cell-surface expressed TNF-alpha. Infliximab is administered intravenously in three loading doses at weeks 0, 2, and 6, and then administered every 4-8 weeks.
Adalimumab is similar to infliximab in that it is a monoclonal antibody, but differs in that it is a fully human molecule, and in that it is administered subcutaneously every 2 weeks, though some clinicians use this medication weekly. Patients may elect to draw up adalimumab and inject it subcutaneously via syringe, pre-filled pen, or prefilled pen in a citrate free formulation that is noted to be less painful.
Use in Treatment of Inflammatory Eye Disease
Favorable efficacy has been shown for the use of antagonists of TNF in the treatment of ocular inflammatory disease. The best efficacy appears to be provided by the antibody based therapies, while the receptor decoy agent (etanercept) shows reduced efficacy. There has been some suggestion in the literature and anecdotally that etanercept may precipitate episodes of uveitis, but recent syntheses of the evidence have suggested that while etanercept may be less effective in preventing the development of incident eye disease, it probably is not a causative factor.
The choice of agent is not clear cut. Infliximab has the longest track record in inflammatory ocular disease, but is administered by intravenous infusion. Adalimumab and other newer agents are given subcutaneously, making administration at home convenient, and reducing costs. Direct comparisons between the various TNF inhibitors has not been carried out, thus the choice of agent remains largely one of physician choice. Adalimumab is the first and currently only FDA approved biologic for non-infectious intermediate, posterior, and panuveitis in adults and children 2 years of age and older.
Currently, expert panel recommendations regarding anti-TNFa agents and their use in treating ocular inflammatory disease are as follows: 1. Infliximab and adalimumab can be considered first-line therapy for treatment of ocular manifestations of Behçet's disease. 2. Infliximab and adalimumab can be considered second-line therapy for the treatment of JIA associated uveitis. 3. Infliximab and adalimumab can be considered as potential second-line for the treatment of severe ocular inflammatory conditions ( posterior uveitis, panuveitis, severeHLA-B27 associated uveitis, and scleritis) in patients who have failed antimetabolites or calcineurin inhibitors. 4. Infliximab and adalimumab are preferred over etanercept. 
A recent retrospective case series of 25 patients with ocular inflammatory disease explored the use of weekly adalimumab after failing treatment with adalimumab every other week dosing. Authors found that at 6 months 14/25 (56%) of patients had treatment success and 13/24 (54%) had treatment success at 12 months. 
Considerations Prior to Use
Treatment with anti TNFa agents should not be initiated with patients with active infections, especially tuberculosis. Careful exclusion of the possibility of latent TB must be accomplished before beginning therapy with TNF antagonists. TNF antagonists may worsen congestive heart failure and demyelinating disease. In uveitis patients who may have multiple sclerosis, especially those with pars planitis, an MRI of the brain is advisable prior to initiating therapy with TNF blockers. The role of TNF blockers in increasing the risk of some malignancies is an area of concern with some published reports suggesting a potential increased risk of cancer-specific mortality in exposed patients. As with all systemic immunosuppressives, careful consideration of the potential risks and benefits are indicated in patients with a history of malignancy. 
Special attention must also be paid to patients with history of hepatitis B carrier state, psoriasis, as well as congestive heart failure. Anti-TNFa agents may cause new or worsening psoriasis, active hepatitis infection, and new or worsening heart failure. It is imperative that patients be screened for hepatitis B status prior to initiation of TNF antagonists.
As with all immunosuppressives, ongoing surveillance for the development of infectious complications is mandatory, as well as monitoring for effectiveness of agent. Reduced effectiveness over time may occur due to the development of antibodies to infliximab (anti-idiotypic antibodies). Concomitant use of antimetabolites such as methotrexate may ameliorate or delay this process, which may also be managed by increasing the dose of infliximab in patients unable to tolerate adjunctive immunosuppression. Specific monitoring usually comprises of measurement of complete blood count, metabolic panel, and liver panel at each infusion for infliximab and every six months for adalimumab, although more frequent monitoring is often required (every 1-2 months) when patients are on other adjunctive immunosuppressives. Some clinicians order ANAs with infusions to monitor for the development of drug-associated lupus erythematosus (DLE), an uncommon but serious complication. 85% of patients develop positive ANAs, which are not uniformly associated with decreased effectiveness of the drug or the occurrence of any side effects. In patients with an elevated ANA and symptoms consistent with DLE, a dsDNA antibody test is confirmatory. DLE patients are treated with discontinuation of the offending drug and oral corticosteroids if needed.
Development of infectious complications, as noted previously, may be devastating. DLE, as discussed above, is usually reported as uncommon, though one case series in uveitis noted an incidence of 10%. Risk of malignancy may increased by as much as three-fold. Demyelinating disease may be worsened or perhaps caused by therapy, and congestive heart failure is worsened by TNF antagonists.
- ↑ Cordero-Coma M, Sobrin L. Anti-tumor necrosis factor-α therapy in uveitis. Surv Ophthalmol. 2015 Nov-Dec;60(6):575-89.
- ↑ Cordero-Coma M, Yilmaz T, Onal S. Systematic review of anti-tumor necrosis factor-alpha therapy for treatment of immune-mediated uveitis. Ocul Immunol Inflamm. 2013;21(1):19-27.
- ↑ 3.0 3.1 Levy-Clarke G, Jabs DA, Read RW, Rosenbaum JT, Vitale A, Van Gelder RN. Expert panel recommendations for the use of anti-tumor necrosis factor biologic agents in patients with ocular inflammatory disorders. Ophthalmology. 2014 Mar;121(3):785-96.e3.
- ↑ Lee J, Koreishi, AF, Zumpf, KB, Minkus CL, Goldstein, DA. Success of Weekly Adalimumab in Refractory Ocular Inflammatory Disease. Ophthalmology. 2020 Apr. [Epub ahead of print].
- ↑ 5.0 5.1 Humira FDA Highlights of Prescribing Information. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/125057s0110lbl.pdf
- ↑ Rheumatology (Oxford). 2009 Jul;48(7):716-20. doi: 10.1093/rheumatology/kep080. Epub 2009 May 4. Anti-TNF-induced lupus. Williams EL1, Gadola S, Edwards CJ.