TNF Inhibitors for Uveitis: Balancing Efficacy and Safety

KEYWORDS::

• adalimumab
• biologics
• demyelination
• etanercept
• infliximab
• multiple scleroisis
• ocular Inflammation

The treatment of noninfectious uveitis traditionally has involved the use of local and systemic corticosteroids in the short term,^1,2 together with systemic noncorticosteroid immunosuppressive agents^3–9 in patients requiring stronger or more sustained immunosuppression. Therapeutic options beyond corticosteroids have included anti-metabolites, such as methotrexate, azathioprine, and mycophenolate mofetil; leukocyte signaling inhibitors, such as cyclosporine and tacrolimus; and, infrequently, the alkylating agents cyclophosphamide and chlorambucil, which are generally reserved for the most severe vision threatening or life-threatening conditions. While the choice of particular agents requires careful consideration of a given patient’s underlying condition and treatment history, and all patients need to be monitored closely for drug-induced side effects, the judicious use of corticosteroids together with these more established “disease-modifying” or “corticosteroid-sparing” agents allows for prompt and continued control of inflammation in most patients with uveitis.^1–9

The introduction of biologic therapies over a decade ago has revolutionized the treatment of rheumatologic disease, particularly moderate to severe systemic conditions, such as rheumatoid arthritis, inflammatory bowel disease, and the various spondyloarthropathies. These agents have been used more recently off-label to treat relatively small cohorts of patients with refractory uveitis.^10–13 By far, most experience has been gained with the tumor necrosis factor (TNF) inhibitors,¹⁴ which are currently available in one of five forms: infliximab (Remicade), a chimeric murine-human full-length monoclonal antibody given by intravenous infusion; etanercept (Enbrel), an antibody Fc-TNF receptor fusion protein injected subcutaneously; adalimumab (Humira) and golimumab (Simponi), fully humanized full-length monoclonal antibodies given as subcutaneous injections; and certolizumab (Cimzia), a fully humanized Fab antibody fragment linked to polyethylene glycol to extend drug half-life, which is also administered subcutaneously. Infliximab, etanercept, and adalimumab have each been used to treat a wide range of uveitic disorders,^10–14 with particularly good results noted in patients with moderate to severe Behçet disease^15,16 and juvenile idiopathic arthritis.¹⁷ Experience with golimumab and certolizumab, however, is still quite limited.

Despite the clear efficacy and promise of TNF inhibitors, their use is not without risk.^18,19 Safety data from both large, randomized clinical trials and postmarketing surveillance highlights the potential for the development of infusion or injection site reactions, of drug-induced autoimmune disease, such as systemic lupus erythematosus or vasculitis, and of opportunistic infections, most notably tuberculosis and severe fungal infections. Isolated cases of aplastic anemia, exacerbation or development of demyelinating disease, worsening of preexisting heart failure, and lymphoma have also been described, although whether the anti-TNF therapy contributed directly to the occurrence of these events remains unknown. Generally, the rate of adverse events reported with the various TNF inhibitors has been similar, except for etanercept, which appears uniquely associated with increased risk of developing uveitis.²⁰

Two articles in this issue of Ocular Immunology & Inflammation highlight just how much remains unknown regarding the potential risks of anti-TNF therapy in patients with uveitis. The first report, by Papadia and Herbort,²¹ describes a 38-year-old man with ankylosing spondylitis and recurrent HLA-B27-associated anterior uveitis who developed a central scotoma due to occipital demyelination while on infliximab. Magnetic resonance imaging (MRI) performed shortly after the onset of the patient’s symptoms showed multiple areas of increased signal in the periventricular white matter and corpus callosum, as well as a large lesion in the occipital area. The patient’s infliximab was discontinued and after 1 month his scotoma resolved. The second report, by Li and colleagues,²² describes a 39-year-old Caucasian woman who developed optic neuritis and demyelinating disease while on adalimumab for chronic, bilateral, granulomatous iridocyclitis, multifocal choroiditis, and chest X-ray findings consistent with sarcoidosis—although a confirmatory biopsy was never obtained. An MRI obtained shortly after presentation revealed numerous periventricular and subcortical lesions consistent with a demyelinating process. Vision remained poor in the eye with optic neuritis despite discontinuation of the adalimumab and treatment with intravenous methylprednisolone and interferon beta 1a for presumed multiple sclerosis.

The authors of both reports clearly state that the occurrence of isolated cases of de novo demyelination in patients receiving TNF inhibitors provides no direct evidence for causality. In fact, evidence in support of such an association is contradictory. On the one hand, high levels of TNF have been observed in the cerebral spinal fluid and in central plaques in animals with autoimmune encephalomyelitis,^23,24 and TNF inhibition was shown to decrease the severity of the disease in such models.²⁵ Moreover, both clinical trials¹⁸ and large pharmacovigilance databases²⁶ have failed to identify a statistically significant increase in the risk of developing demyelinating disease as compared to controls and the population at large, respectively.²⁷ On the other hand, however, at least two early phase trials of TNF inhibition in patients with multiple sclerosis reported an increase in the number of central nervous system (CNS) lesions associated with treatment.^28,29

So how should those who care for patients with uveitis integrate such case reports into their treatment paradigms? First, it should be emphasized that TNF inhibitors represent a tremendous advance in the treatment of moderate to severe autoimmune disease, including refractory uveitis, in patients who either cannot tolerate or are incompletely responsive to nonbiologic immunosuppressive agents. Such enthusiasm needs to be balanced, however, by the fact that we simply do not know whether systemic TNF inhibition confers increased risk of developing or exacerbating demyelinating disease. Given the relatively large selection of other biologic and nonbiologic immunosuppressive agents, we would tend toward the conservative.²⁷ We discourage the use of a TNF inhibitor in patients with preexisting demyelinating disease, and would recommend discontinuing anti-TNF therapy in a patient who develops evidence of optic nerve or CNS demyelination while on such an agent. We would also advise caution when considering a TNF inhibitor in patients with idiopathic intermediate uveitis, since a sizable proportion of these patients either have, or will go on to develop, evidence of central demyelination. In addition, it is important to remember that TNF inhibitors are contraindicated in patients with preexisting heart failure, malignancy, or active infection,¹⁸ and that all patients considered for anti-TNF therapy should be screen for tuberculosis, hepatitis B, hepatitis C, and human immunodeficiency virus (HIV) infection prior to initiating therapy. Those with exposure to tuberculosis or hepatitis B can be treated concurrently with isoniazid or lamivudine, respectively, with close monitoring of serum aminotransferases.^29,30 HIV-positive patients without advanced immunosuppression have been treated with anti-TNF therapy, but great caution is recommended.³¹ Treatment with anti-TNF agents is not recommended for patients with hepatitis C.³⁰ Lastly, we would encourage larger and longer trials of anti-TNF agents in patients with ocular inflammatory disease, and remind those who treat such patients to continue to document and report, either in the literature or to local health authorities—such as the FDA’s Adverse Events Reporting System (AERS; www.fda.gov)—adverse events that occur in patients receiving biologic therapies.

ACKNOWLEDGEMENTS

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.