TNF-α-related optic neuropathy

Key points at a glance

Key points of this disease

• An optic neuropathy that occurs as a side effect of TNF-α inhibitors (etanercept, infliximab, adalimumab, etc.).
• It develops during treatment for autoimmune diseases such as rheumatoid arthritis, Crohn’s disease, and psoriasis, and presents with optic neuritis-like symptoms (acute vision loss, positive RAPD, optic disc swelling).
• In new users with no history of demyelinating disease, the incidence of optic neuritis is estimated at 5 to 10 per 100,000 people.
• Reports are most common with etanercept; it is less frequent with infliximab and adalimumab.
• Treatment is mainly to stop the drug and switch to an alternative therapy, and corticosteroids may also be used.
• Brain MRI may show demyelinating findings in the brain and spinal cord, and attention is needed to the association with multiple sclerosis.
• It is important to screen for a history and family history of demyelinating disease before starting treatment.

1. What is TNF-α-related optic neuropathy?

TNF-α-related optic neuropathy is optic nerve damage that occurs in connection with the use of tumor necrosis factor alpha (TNF-α) inhibitors. It is classified as drug-induced demyelinating or non-demyelinating optic neuropathy.

TNF-α (tumor necrosis factor alpha) helps regulate the pro-inflammatory cytokine cascade. It is released by activated monocyte-lineage immune cells and exerts pro-inflammatory effects by binding to TNFR1 and TNFR2 (TNF receptors).

Types of TNF-α inhibitors

The main TNF-α inhibitors are divided into two types by mechanism of action.

Classification	Drug name (abbreviation)	Binding target
Monoclonal antibodies	Infliximab (INF), adalimumab (ADA), certolizumab (CZP), golimumab (GLM)	Soluble + membrane-bound TNF-α
Soluble receptor	Etanercept (ETA)	Binds to TNF-α and inactivates it

These drugs are widely used to treat rheumatoid arthritis, Crohn’s disease, spondyloarthritis, inflammatory bowel disease, psoriasis, and atherosclerosis. In ophthalmology, they are also used to treat noninfectious uveitis.

Epidemiology

The incidence of optic neuritis in new users without a history of demyelinating disease is estimated at 5 to 10 per 100,000 people¹⁾. In the SABER (Safety Assessment of Biologic ThERapy) study, three cases of optic neuritis were reported among more than 60,000 new TNF-α inhibitor users at a median of 123 days (range 37-221 days), and the authors concluded that there was no major difference in incidence compared with non-biologic DMARD users¹⁾.

Q What types of TNF-α inhibitors are there?

A

TNF-α inhibitors are classified into two types: monoclonal antibodies and soluble receptors. Monoclonal antibodies include infliximab, adalimumab, certolizumab, and golimumab, while the soluble receptor is etanercept. Etanercept acts differently from the other drugs because it directly binds to TNF-α and inactivates it.

2. Main symptoms and clinical findings

Subjective symptoms

• Acute vision loss: Often affects only one eye.
• Eye pain: Pain with eye movement, similar to optic neuritis, may occur.
• Neurological symptoms: May be accompanied by confusion, ataxia, dysesthesia, paresthesia, and other symptoms.

Clinical findings (findings confirmed by the doctor during the examination)

• Optic disc: Normal or swollen. One case of bilateral optic disc edema related to golimumab has been reported.
• RAPD (relative afferent pupillary defect): Positive.
• Head MRI findings: Demyelination of the brain or spinal cord may be seen. Associated with confusion, ataxia, dysesthesia, optic neuritis, facial nerve palsy, and hemiparesis.
• Frequency by drug: Onset has been reported most often with etanercept. The frequency is lower with infliximab and adalimumab²⁾. In a case series of 15 cases, the breakdown was 8 infliximab, 5 etanercept, and 2 adalimumab²⁾.
• Skin symptoms: May be accompanied by skin adverse reactions resembling a neutropenic allergic reaction.

3. Causes and risk factors

The direct cause of this disease is the use of TNF-α inhibitors (such as etanercept, infliximab, and adalimumab).

The risk of developing the condition increases if any of the following apply.

• Family history of demyelinating disease
• History of multiple sclerosis (MS)
• History of optic neuritis
• History of transverse myelitis
• History of Guillain-Barré syndrome

TNF-α inhibitors can also cause orbital inflammation (orbital myositis) in addition to optic nerve damage. It may develop 1 week to 6 months after treatment starts, and it can be difficult to distinguish it from orbital inflammation related to the underlying disease (rheumatoid arthritis or inflammatory bowel disease).

Prevention and daily care

Before starting TNF-α inhibitor treatment, be sure to tell your doctor about any family or personal history of demyelinating disease (multiple sclerosis, optic neuritis, transverse myelitis, or Guillain-Barré syndrome). Regular eye examinations are recommended during treatment. If you notice changes in vision or eye pain, see an ophthalmologist promptly.

Q What screening is needed before using TNF-α inhibitors?

A

Before treatment begins, it is recommended to check for any personal or family history of demyelinating disease (multiple sclerosis, optic neuritis, transverse myelitis, or Guillain-Barré syndrome). In patients with these risk factors, the indication for treatment should be considered carefully. Regular eye examinations during treatment are also important.

4. Diagnosis and testing

Diagnosis is based on a history of TNF-α inhibitor use and clinical findings similar to optic neuritis.

• Review of medication history: If optic neuritis-like symptoms appear after use of a TNF-α inhibitor, consider this disease.
• Ophthalmic examination: Recommended for all patients receiving treatment. Carefully look for signs of optic neuritis and demyelination.
• Head MRI: An essential test for detecting demyelinating lesions in the brain and spinal cord.

Differential diagnosis

• Differentiation from optic neuritis: Several TNF-α inhibitors are known to cause optic neuropathy that mimics optic neuritis. In some cases, it is unclear whether this is causal or coincidental.
• Orbital inflammation due to the underlying disease: rheumatoid arthritis and inflammatory bowel disease themselves can cause orbital inflammation, and it can sometimes be difficult to distinguish this from a drug side effect.
• MOGAD (MOG antibody-associated disease): TNF-α inhibitor therapy has been reported to be rarely associated with the onset of MOGAD.

5. Standard treatment

Treatment for this condition is handled in the following order.

• Discontinuation of the causative drug: the first step. Stop the TNF-α inhibitor.
• Switching to an alternative therapy: changing to a drug with a different mechanism of action is the basic approach. Switching to another TNF-α inhibitor may also be considered with careful judgment.
• Corticosteroid therapy: used to reduce inflammation. Case reports of infliximab-induced optic neuritis have described improvement in visual function with intravenous steroids³⁾. In cases of adalimumab-associated optic neuritis, partial or complete recovery of vision has also been reported with drug discontinuation and short-term steroid treatment⁴⁾.
• If drug-induced SLE is present: there are reports that skin lesions disappeared after switching to steroids plus hydroxychloroquine sulfate.
• If orbital inflammation (orbital myositis) is present: there are reports of complete remission with drug discontinuation and systemic steroid treatment.

Treatment considerations

There are reports that lupus symptoms did not recur after switching to another TNF-α inhibitor, while it is known that the risk of lupus is higher in patients using etanercept and infliximab. Any medication change should be made only after thorough discussion with the treating physician.

Q If TNF-α-related optic neuropathy develops, can you return to the same type of medicine?

A

In principle, stopping the causative drug is recommended. Switching to another TNF-α inhibitor has been reported not to cause recurrence of lupus symptoms and may be considered with careful judgment. However, taking the risk of recurrence into account, if possible, changing to a drug with a different mechanism of action is preferable.

6. Pathophysiology and detailed disease mechanism

Several mechanisms are thought to be involved in the development of TNF-α-related optic neuropathy.

• Drug-induced autoimmunity: Use of TNF-α inhibitors can promote production of anti-dsDNA antibodies, and drug-induced SLE (systemic lupus erythematosus) may develop.
• Overactivation of T cells: TNF-α normally contributes to downregulation of adaptive immunity (reduction of T-cell receptor signaling). Inhibiting TNF-α is thought to cause excessive T-cell activity and enhance autoimmune responses.
• Effects in patients with MS: Anti-TNF-α treatment is known to trigger immune activation and worsen disease burden in multiple sclerosis (MS) ⁵⁾. In a review that compiled 122 central nervous system demyelinating events, the reported distribution was 50 infliximab cases (41%), 57 etanercept cases (47%), 19 adalimumab cases (16%), and 1 golimumab case (1%) ⁵⁾.
• Effects on the blood-retinal barrier (BRB): TNF-α is known to disrupt tight junctions and increase BRB permeability, and increased permeability of the inner BRB (iBRB) caused by intravitreal TNF-α administration has been demonstrated in vitro. Increased permeability of the retinal pigment epithelium (RPE) has also been reported.
• Paradoxical effects of etanercept: Although etanercept is meant to neutralize TNF-α, it can sometimes show a “paradoxical adverse effect” that interferes with normal immune responses and triggers autoimmune diseases such as uveitis⁶⁾. This is thought to be due to an imbalance in cytokine regulation, and etanercept is known to be more likely than other TNF-α inhibitors (infliximab and adalimumab) to cause uveitis⁶⁾.
• Association with MOGAD: TNF-α inhibitor therapy has been reported to be rarely associated with the onset of MOG antibody-associated disease (MOGAD).
• Lupus risk: In patients using etanercept and infliximab, the risk of lupus is higher, and there have been reports of no lupus recurrence after switching to another TNF-α antagonist.

---

7. References

1. Winthrop KL, Chen L, Fraunfelder FW, et al. Initiation of anti-TNF therapy and the risk of optic neuritis: from the Safety Assessment of Biologic ThERapy (SABER) Study. Am J Ophthalmol. 2013;155(1):183-189.e1. PMID: 22967869.
2. Simsek I, Erdem H, Pay S, Sobaci G, Dinc A. Optic neuritis occurring with anti-tumour necrosis factor alpha therapy. Ann Rheum Dis. 2007;66(9):1255-1258. PMID:17456525; PMCID:PMC1955135.
3. Dermawan A, So K, Venugopal K, Picardo S. Infliximab-induced optic neuritis. BMJ Case Rep. 2020;13(12):e238182. PMID: 33370961.
4. Kim A, Saffra N. A case report of adalimumab-associated optic neuritis. J Ophthalmic Inflamm Infect. 2012;2(3):145-147. PMID: 22271346.
5. Kemanetzoglou E, Andreadou E. CNS Demyelination with TNF-α Blockers. Curr Neurol Neurosci Rep. 2017;17(4):36. PMID: 28337644.
6. Susanna FN, Pavesio C. A review of ocular adverse events of biological anti-TNF drugs. J Ophthalmic Inflamm Infect. 2020;10(1):11. PMID: 32337619.