How does Fingolimod (FTY720) cause macular edema?

From the Guidelines

Fingolimod can cause macular edema by disrupting the blood-retinal barrier through its effects on sphingosine-1-phosphate (S1P) receptors. Fingolimod (brand name Gilenya) is an oral medication used to treat relapsing forms of multiple sclerosis that works by binding to S1P receptors on lymphocytes, preventing them from leaving lymph nodes. However, these same S1P receptors are present on vascular endothelial cells in the retina. When fingolimod binds to these receptors, it can increase vascular permeability by disrupting tight junctions between endothelial cells in the retinal vasculature. This increased permeability allows fluid to leak from blood vessels into the macula, causing it to swell (macular edema).

The risk of macular edema is approximately 0.4% in patients taking fingolimod and typically occurs within the first 3-4 months of treatment, as seen in patients with MS with up to 5 years of ozanimod treatment in an OLE that enrolled patients from phase 1–3 trials 1. Patients with diabetes or a history of uveitis have a higher risk. Regular ophthalmologic examinations are recommended before starting fingolimod and at 3-4 months after initiation. If a patient develops visual symptoms such as blurred vision or decreased visual acuity while on fingolimod, they should be promptly evaluated for macular edema, which typically resolves after discontinuation of the medication.

Some key points to consider:

• The incidence of macular edema appeared to be low in clinical trials, with ≤0.6% reported in patients with UC for up to 142 weeks in the phase 3 True North OLE and in pooled phase 2 and phase 3 UC trials examining ozanimod over 2196 patient-years of exposure 1.
• Most cases of macular edema occurred in patients with pre-existing risk factors or comorbid conditions.
• Treatment with anti-VEGF agents, such as bevacizumab, ranibizumab, aflibercept, brolucizumab, and faricimab, may be effective in treating macular edema, as demonstrated in patients with diabetic macular edema 1.
• Regular monitoring of liver enzymes and function, as well as assessment of respiratory function, is recommended during treatment with ozanimod, but these are not directly related to the mechanism of macular edema caused by fingolimod.

From the FDA Drug Label

Macular Edema: Increases the risk of macular edema. Obtain a baseline evaluation of the fundus, including the macula, near the start of treatment with fingolimod. Conduct an evaluation of the fundus, including the macula, 3 to 4 months after treatment start, periodically while on therapy and any time there is a change in vision. Consider discontinuing fingolimod if macular edema develops. Diabetes mellitus and uveitis increase the risk. (5. 4) Advise patients that fingolimod capsules may cause macular edema, and that they should obtain an eye exam near the start of treatment with fingolimod, have their eyes monitored periodically by an eye care professional while receiving therapy, and contact their healthcare provider if they experience any changes in their vision while taking fingolimod Inform patients with diabetes mellitus or a history of uveitis that their risk of macular edema is increased [see Warnings and Precautions (5. 4)].

The exact mechanism by which fingolimod causes macular edema is not directly stated in the provided drug labels. However, it is clear that fingolimod increases the risk of macular edema, particularly in patients with diabetes mellitus or a history of uveitis.

• Key points:
  • Fingolimod increases the risk of macular edema.
  • Patients should have a baseline eye exam and regular monitoring.
  • Diabetes and uveitis increase the risk.
  • Discontinuation of fingolimod should be considered if macular edema develops. 2

From the Research

Mechanism of Fingolimod-Associated Macular Edema

• Fingolimod, a sphingosine 1-phosphate modulator, acts on its receptors to affect immune cell accumulation, neuronal function, and vascular permeability 3.
• The drug decreases brain volume and increases vascular permeability, resulting in increased macular volume and damage to the blood-retinal barrier, which causes an increased risk for macular edema 3.
• Fingolimod's anti-inflammatory properties decrease various cytokines, including interleukin (IL)-1B and IL-6, but its effects on vascular permeability and the blood-retinal barrier contribute to the development of macular edema 3.

Risk Factors for Fingolimod-Associated Macular Edema

• A daily dosage of 0.5 mg of fingolimod has an increased association with macular edema 3.
• Cystoid macular edema is more common in older individuals suffering from comorbidities affecting the retina, such as diabetes, or those undergoing ophthalmological surgeries 3.
• Patients with a history of relapsing-remitting multiple sclerosis are at risk of developing macular edema while taking fingolimod 4, 5, 6, 7.

Clinical Presentation and Treatment

• Fingolimod-associated macular edema can present with symptoms such as blurred vision and can be diagnosed using spectral domain optical coherence tomography (SD-OCT) 4, 7.
• Treatment options for macular edema include nonsteroidal anti-inflammatory drugs, acetazolamide, triamcinolone, ketorolac, corticosteroids, and intravitreal procedures 3, 4, 5, 7.
• Discontinuation of fingolimod therapy is often necessary to resolve macular edema, and regular ophthalmary examinations are recommended for patients taking the drug 3, 7.