TNF-alpha Related Optic Neuropathy

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Article initiated by:

Andrew Go Lee, MD, Emma Stenz, Nagham Al-Zubidi, MD, Peter W. Mortensen, MD, Subahari Raviskanthan, MBBS, Ayesha Abid

All contributors:

Nagham Al-Zubidi, MD, Ayman Okla Suleiman, MD, Peter W. Mortensen, MD, Subahari Raviskanthan, MBBS

Assigned editor:

Ayman Okla Suleiman, MD

Review:

Assigned status Up to Date

 by Ayman Okla Suleiman, MD on October 4, 2024.

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Disease Entity

Elevated tumor necrosis factor-alpha (TNF-α) production and downstream receptor signaling may play a role in the pathogenesis of several autoimmune diseases (e.g., rheumatoid arthritis, Crohn disease, atherosclerosis, spondyloarthritis, inflammatory bowel disease, and psoriasis). TNF-α has an instrumental role in orchestrating the cytokine cascade in pro-inflammatory responses and has been proposed as a therapeutic target for autoimmune disease.

TNF-α is primarily secreted by activated monocytic immune cells and exerts its action by binding to tumor necrosis factor receptor 1 (TNFR1) and tumor necrosis factor receptor 2 (TNFR2), leading to pro-inflammatory effects. TNF-α inhibitors, which antagonize either TNF-α directly or its receptor, are therefore used to treat these autoimmune inflammatory diseases. Infliximab (INF), adalimumab (ANA), certolizumab (CZP) and golimumab (GLM) are monoclonal antibodies that function by binding to soluble and membrane forms of TNF-α, thereby neutralizing its pathological pro-inflammatory effects. Etanercept (ETA) is a soluble TNF-α receptor that binds and inactivates TNF-α, thereby decreasing the amount available for binding to its cellular surface receptor.

Disease

TNF-α inhibitors, while effective for reducing the pro-inflammatory cascades involved in autoimmune pathogenesis, have several severe documented side effects including adverse skin reactions and both acute and delayed infusion reactions, which resemble a neutropenic allergic response. With regards to their neurologic effects, TNF-α inhibitors have been associated with demyelinating and non-demyelinating central nervous system (CNS) disease. . Further details on signs and symptoms can be found in section 2.3

Risk Factors

Proposed risk factors for TNF alpha optic neuritis may include a family history of demyelinating disease, prior MS, prior optic neuritis, transverse myelitis, and Guillain-Barre syndrome.

Pathophysiology

The effects of anti-TNF-α agents in patients with autoimmune diseases has been associated with drug-induced anti-double stranded deoxyribonucleic acid (anti-dsDNA) antibody production and drug-induced systemic lupus erythematosus (SLE). Anti-TNF-α treatment in multiple sclerosis (MS) has led to immune activation and worsened disease burden. Though the mechanism is not completely understood, it is believed that TNF may downregulate the adaptive immune response and consequently attenuate the T-cell receptor signaling which could prevent autoimmunity. Thus, by inhibiting TNF-α, a corresponding increase in autoimmunity due to overactivation of T cell activity may cause an increased susceptibility to SLE. One such case study described a woman who demonstrated drug-induced SLE on etanercept. She was switched to corticosteroids and hydroxychloroquine sulfate, after which her skin lesions disappeared. Further, patients who take etanercept and infliximab were found to have an increased risk of lupus. When switched to an alternative TNF alpha antagonist, they no longer had recurrence of their lupus symptoms.

Primary Prevention

Prevention is mainly to switch the patient to an alternative TNF alpha antagonist as noted above. Further, screening at risk patients and monitoring ophthalmic function is another way to avoid TNF-α associated optic neuropathy.

Diagnosis

Screening for demyelination or signs of an adverse response after initiating therapy is how diagnosis is often made.

Ophthalmic examination

Ophthalmic examination is recommended for all patients on this therapy with particular attention paid to any signs of optic neuritis or demyelination.

Signs and Symptoms

Any changes in vision after initiating therapy should be thoroughly investigated by an ophthalmologist. Further as noted above, patients who have adverse skin reactions might be experiencing a neutropenic allergic response.

Cranial magnetic resonance imaging (MRI) has shown demyelination in the brain or spinal cord associated with confusion, ataxia, dysesthesia, paresthesia, optic neuritis, facial nerve palsy, and hemiparesis. The clinical presentations are more common with etanercept and less frequently for infliximab and adalimumab.

Optic neuritis has been reported after etanercept, infliximab, and adalimumab use. The optic neuropathy presents like optic neuritis (acute, unilateral loss of vision, relative afferent pupillary defect, and a normal or swollen optic nerve). One case of bilateral optic disc edema has been associated with the TNF-α inhibitor golimumab. Overall, the incidence of optic neuritis among new users of anti-TNF-α agents without previous demyelinating condition has been estimated at 5–10 per 100,000 persons.

Differential diagnosis

Multiple TNF-α inhibitors have been associated with optic neuropathy that can mimic optic neuritis. Clinicians should be aware of the possibility of TNF- α associated optic neuropathy. Whether these cases are causal or coincidental remains ill defined. Screening for optic neuropathy should always be standard of care in patients who are on the therapy and present with any visual changes, palsy, confusion, or signs of optic neuritis.

Management

General treatment

Treatment includes switching the patient to an alternative therapy. Patients might be given a corticosteroid or another TNF-α inhibitor.