Ocular manifestations of familial Mediterranean fever

Key Points at a Glance

Key Points of This Disease

• Familial Mediterranean fever (FMF) is a monogenic autoinflammatory disease caused by MEFV gene mutations.
• Ocular symptoms are relatively rare, but various lesions such as episcleritis, uveitis, posterior scleritis, and retinal vasculitis have been reported.
• Severe genotypes (e.g., M694V homozygotes) and colchicine-resistant cases have a higher risk of ocular complications.
• Control of systemic inflammation with colchicine is most important for preventing ocular complications.
• In long-standing cases complicated by serum amyloid A-related amyloidosis, amyloid deposition in the conjunctiva and eyelids and secondary glaucoma may occur.
• Early ophthalmologic consultation and optimization of systemic treatment can improve visual prognosis.

1. Ocular manifestations of familial Mediterranean fever

Familial Mediterranean Fever (FMF) is an autosomal recessive autoinflammatory disease caused by mutations in the MEFV gene located on the short arm of chromosome 16 (16p13.3). It is characterized by recurrent episodes of fever and serositis involving the peritoneum, pleura, and synovium. It is common among populations around the Mediterranean basin, including Turks, Armenians, Arabs, and non-Ashkenazi Jews.

Ocular manifestations of familial Mediterranean fever are less frequent compared to other autoinflammatory syndromes. However, recent reports have documented nearly all major categories of ocular inflammation in FMF [3]. Yazici et al. reported six FMF patients with ocular inflammation at a tertiary care center. Posterior uveitis and anterior uveitis each accounted for one-third, with the remainder being posterior scleritis and episcleritis [2].

Colchicine is the cornerstone of familial Mediterranean fever treatment and dramatically reduces the frequency and intensity of attacks [1]. However, in patients with colchicine resistance or poor adherence, the risk of persistent inflammation and AA amyloidosis remains.

Q Which populations are most commonly affected by familial Mediterranean fever?

A

It is common among populations around the Mediterranean, such as Turks, Armenians, Arabs, and non-Ashkenazi Jews. In some communities, the carrier rate of MEFV mutations exceeds 1 in 5 people. Due to migration, it has spread worldwide.

2. Main symptoms and clinical findings

Subjective symptoms

Ocular symptoms of familial Mediterranean fever vary depending on the site of the lesion.

• Eye pain and redness: Seen in episcleritis and anterior uveitis. Scleritis involves deep, persistent pain.
• Photophobia: Occurs with anterior uveitis.
• Floaters and blurred vision: Occur in intermediate and posterior uveitis, reflecting vitreous opacities.
• Vision loss: Prominent in posterior uveitis, retinal vasculitis, macular edema, and optic neuritis.
• Burning sensation and foreign body sensation: Recognized as dry eye symptoms. Caused by amyloid deposition in the lacrimal gland or chronic inflammation.
• Transient darkening and diplopia: Symptoms associated with papilledema or cranial nerve palsy.

Clinical Findings

Ocular manifestations in familial Mediterranean fever involve multiple anatomical sites, reflecting the interplay of autoinflammation, vascular dysfunction, and AA amyloid deposition.

Anterior Segment Lesions

Episcleritis: Sectoral hyperemia and mild discomfort. Appears during inflammatory flares.

Scleritis: Deep, persistent pain. Presents with diffuse or nodular inflammation.

Anterior uveitis: Cells and flare in the anterior chamber, photophobia. Both granulomatous and non-granulomatous patterns have been reported.

Posterior segment lesions

Posterior uveitis: Inflammation of the choroid and retina. May cause vision loss due to macular lesions.

Posterior scleritis: Presents with choroidal folds and serous retinal detachment. T-sign may be observed on ultrasound [4].

Retinal vasculitis: Shows perivascular sheathing and leakage on fluorescein angiography.

The correspondence between major ocular complications and their sites of occurrence is shown below.

Site	Major lesions	Clinical features
Anterior segment	Episcleritis / anterior uveitis	Corresponds to inflammatory flare
Posterior segment	Posterior uveitis / posterior scleritis	Common in severe cases
Retinal blood vessels	Vasculitis, venous occlusion	Endothelial dysfunction involved

Q When are ocular symptoms of familial Mediterranean fever likely to occur?

A

They tend to appear during periods of systemic inflammation or when colchicine is insufficiently effective. Episcleritis occurs with inflammatory flares, while posterior segment lesions are more common in poorly controlled chronic cases.

3. Causes and Risk Factors

Ocular symptoms of familial Mediterranean fever are based on excessive activation of the pyrin inflammasome caused by MEFV gene mutations. The main pathogenic mechanisms are the following three.

• Systemic vasculitis/vascular endothelial dysfunction: Affects the vessels of the episclera, retina, and choroid, causing episcleritis and retinal vasculitis.
• Autoinflammatory lesions of the uvea: Induces anterior, intermediate, and posterior uveitis or posterior scleritis.
• AA amyloid deposition: Amyloid accumulation in the conjunctiva, eyelids, lacrimal glands, trabecular meshwork, etc., leads to structural changes such as dry eye, ptosis, and secondary glaucoma.

The main factors that increase the risk of ocular lesions are as follows.

• Homozygosity for high-risk MEFV mutations (e.g., M694V/M694V): Associated with severe phenotype, frequent attacks, and increased risk of amyloidosis.
• Colchicine-resistant or persistent systemic inflammation: Indicates uncontrolled IL-1-driven autoinflammation.
• Confirmed AA amyloidosis: Predisposes to vascular and periocular amyloid deposition and systemic hypertension.
• Long disease duration: Cumulative inflammatory burden increases tissue damage.
• Childhood-onset chronic subclinical inflammation: Associated with retinal and choroidal microstructural changes detectable by OCT.

Prevention and Daily Care

• If diagnosed with familial Mediterranean fever, do not discontinue colchicine on your own. Suppressing systemic inflammation directly prevents ocular complications.
• Have regular eye examinations. Especially if you have frequent attacks or have amyloidosis, early eye changes can be detected.
• If you experience eye pain, redness, vision loss, floaters, or other unusual eye symptoms, see an ophthalmologist promptly.

4. Diagnosis and Examination Methods

Diagnosis of ocular symptoms associated with familial Mediterranean fever is based on a thorough ophthalmologic examination considering the history of the systemic disease. Ocular findings alone often do not show a pattern specific to familial Mediterranean fever, so differential diagnosis is important.

Ophthalmologic Examination

• Slit-lamp examination: Check for cells and flare in the anterior chamber, keratic precipitates, and posterior synechiae. In episcleritis and scleritis, evaluate the pattern and depth of redness.
• Fundus examination: Check for choroidal lesions, vascular sheathing, hemorrhage, and papilledema associated with posterior uveitis or retinal vasculitis.
• Fluorescein angiography (FA): In retinal vasculitis, leakage of fluorescein from vessel walls is observed. It is also useful for evaluating retinal vein occlusion.
• Optical coherence tomography (OCT): Detects macular edema (intraretinal cystoid spaces, diffuse thickening). Enhanced depth imaging OCT (EDI-OCT) can detect choroidal thickening and microstructural changes even in clinically quiescent patients [5].
• B-mode ultrasonography: Performed when posterior scleritis is suspected. Check for the T sign (fluid accumulation between the sclera and optic nerve sheath).

Systemic evaluation and differential diagnosis

Confirmation of MEFV gene mutations and monitoring of acute-phase reactants such as CRP and SAA (serum amyloid A) are the mainstays of systemic disease assessment.

Since the ocular symptoms of familial Mediterranean fever are nonspecific, differentiation from the following diseases is necessary.

• Behçet’s disease: Acute recurrent uveitis with oral and genital ulcers. Characterized by hypopyon and fern-like fluorescein leakage on fluorescein angiography. HLA-B51 is positive in about 50% of cases.
• Sarcoidosis: Granulomatous findings such as mutton-fat keratic precipitates, iris nodules, and snowball vitreous opacities. Elevated ACE and bilateral hilar lymphadenopathy are supportive findings.
• HLA-B27-associated uveitis: Acute recurrent anterior uveitis. Associated with ankylosing spondylitis and inflammatory bowel disease.

Key points for differentiation

In familial Mediterranean fever, history of fever and serositis, family history, and ethnic background are important clues. MEFV gene testing leads to a definitive diagnosis. Coexistence with Behçet’s disease has also been reported, so attention should be paid to overlap of both diseases.

5. Standard Treatment

Treatment for ocular complications of familial Mediterranean fever consists of two main pillars: control of systemic inflammation and local anti-inflammatory therapy for the eye.

Systemic Treatment

Colchicine

Colchicine is the first-line drug for treating familial Mediterranean fever, aimed at preventing attacks and suppressing the progression of amyloidosis. It is usually administered continuously at 0.5–1.5 mg/day (often 1 mg/day). Adequate control of systemic inflammation with colchicine is most important for preventing the onset of ocular complications.

Anti-IL-1 Therapy (for Colchicine-Resistant Cases)

If colchicine alone does not provide sufficient effect, IL-1 inhibitors are considered. This treatment directly targets the excessive release of IL-1β, which is central to the pathology of familial Mediterranean fever.

Local Ocular Treatment

Depending on the ocular inflammatory findings, the following local treatments are performed as appropriate. The treatment principles follow those for other non-infectious uveitis.

• Steroid eye drops: Used for anterior segment inflammation. Adjust from 1 to 8 times daily depending on the degree of inflammation, and taper as inflammation subsides. Be aware of the side effect of increased intraocular pressure.
• Mydriatic eye drops: Aimed at preventing posterior synechiae. Use mydriatics such as tropicamide while inflammatory cells are present in the anterior chamber.
• Local steroid injection: If posterior segment inflammation is severe, consider sub-Tenon injection of triamcinolone acetonide.
• Vitrectomy: May be necessary for epiretinal membrane or vitreous hemorrhage.

Management of Complications

• Secondary glaucoma: For elevated intraocular pressure due to posterior synechiae or amyloid deposition, drug therapy (beta-blocker eye drops, carbonic anhydrase inhibitors) or surgical therapy (trabeculectomy, etc.) is performed.
• Complicated cataract: For cataracts caused by chronic inflammation or steroid use, surgery is considered after sufficient resolution of inflammation.

Precautions in Treatment

• Systemic administration of steroids may cause severe relapse after tapering or discontinuation of an inflammatory attack, so they must be used with caution.
• Regular monitoring is essential for elevated intraocular pressure and cataracts associated with long-term steroid use.
• Self-discontinuation of colchicine impairs systemic inflammation control and increases the risk of ocular complications.

Q If I take colchicine, will I not develop eye symptoms?

A

Colchicine dramatically reduces the frequency of attacks but does not guarantee complete prevention. In colchicine-resistant patients or those with poor adherence, extra-articular complications including ocular symptoms may occur. Continued regular ophthalmologic examinations are important.

6. Pathophysiology and Detailed Mechanisms

Familial Mediterranean fever is a condition in which pathogenic mutations in the MEFV gene lower the activation threshold of the pyrin inflammasome. Pyrin is a cytoplasmic protein primarily expressed in myeloid cells, and it assembles the inflammasome in response to changes in Rho GTPase signaling.

Activated pyrin recruits ASC and caspase-1. Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active forms, leading to gasdermin D-mediated pyroptosis (inflammatory cell death). Pathogenic MEFV mutations (such as M694V, M680I, V726A, M694I) lower the activation threshold. As a result, even normally harmless stimuli can trigger excessive IL-1β release and inflammatory attacks.

The mechanism of inflammation in ocular tissues is summarized as follows.

• Vasculitis and endothelial dysfunction: Excessive release of cytokines, primarily IL-1β, damages the vascular endothelium. Inflammation affects the vessels of the episclera, retina, and choroid, causing episcleritis, retinal vasculitis, and occlusive microvasculopathy.
• Direct autoinflammation of the uvea: Overactivation of innate immunity triggers inflammation in uveal tissue. Lesions can occur in any part, from the anterior uvea to panuveitis.
• AA amyloid deposition: Persistent inflammation enhances the production of serum amyloid A (SAA). Amyloid fibers derived from SAA deposit in the conjunctiva, eyelids, lacrimal glands, trabecular meshwork, and retinal vessels, causing structural and vascular damage. M694V homozygotes and specific SAA1 genotypes significantly increase the risk of amyloidosis.

In monocytes from patients with familial Mediterranean fever, dephosphorylation of pyrin alone induces inflammasome activation. This reaction does not occur in healthy individuals. This basic finding supports the central pathogenic role of IL-1β.

Q How does amyloidosis affect the eyes?

A

SAA-derived amyloid fibers produced by persistent systemic inflammation deposit in the conjunctiva (waxy deposits, bleeding), eyelids (nodules, drooping), lacrimal gland (decreased tear production), trabecular meshwork (increased intraocular pressure, secondary glaucoma), and retinal blood vessels (wall thickening, ischemia), causing damage. See also the section on “Causes and Risk Factors”.

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7. Latest Research and Future Prospects (Research-stage Reports)

For patients: Please read this

The following content is currently at the research stage or in clinical trials and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments.

Detection of Subclinical Ocular Lesions by OCT

In a study of children with familial Mediterranean fever in clinical remission, EDI-OCT detected choroidal thickening and microstructural changes [5]. These findings suggest that chronic subclinical inflammation may affect ocular tissues from early stages of the disease. Whether the choroidal vascularity index could serve as an early biomarker for ocular involvement in familial Mediterranean fever warrants further investigation.

Application of Biologic Agents

The efficacy of IL-1 inhibitors (e.g., anakinra, canakinumab) for colchicine-resistant familial Mediterranean fever has been reported [3]. Whether these drugs are also effective in preventing or treating ocular inflammation requires accumulation of clinical data. For non-infectious uveitis in general, adalimumab (anti-TNF-α antibody) has shown a steroid-sparing effect, and its application to familial Mediterranean fever-associated uveitis warrants consideration.

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8. References

1. Petrushkin H, Stanford M, Fortune F, Jawad AS. Clinical Review: Familial Mediterranean Fever-An Overview of Pathogenesis, Symptoms, Ocular Manifestations, and Treatment. Ocul Immunol Inflamm. 2016;24(4):422-430. PMID: 25760918. https://pubmed.ncbi.nlm.nih.gov/25760918/
2. Yazici A, Ozdal P, Yuksekkaya P, Elgin U, Teke MY, Sari E. Ophthalmic manifestations in familial Mediterranean fever: a case series of 6 patients. Eur J Ophthalmol. 2014;24(4):593-598. PMID: 24338581. https://pubmed.ncbi.nlm.nih.gov/24338581/
3. Fonollosa A, Carreño E, Vitale A, et al. Update on ocular manifestations of the main monogenic and polygenic autoinflammatory diseases. Front Ophthalmol (Lausanne). 2024;4:1337329. PMID: 38984133. https://pubmed.ncbi.nlm.nih.gov/38984133/
4. Mansour AM, Khatib L, Mansour HA. Posterior Scleritis in Familial Mediterranean Fever. Case Rep Ophthalmol. 2019;10(1):134-139. PMID: 32231554. https://pubmed.ncbi.nlm.nih.gov/32231554/
5. Gundogan FC, Akay F, Uzun S, Ozge G, Toyran S, Genç H. Choroidal Thickness Changes in the Acute Attack Period in Patients with Familial Mediterranean Fever. Ophthalmologica. 2016;235(2):72-77. PMID: 26637112. https://pubmed.ncbi.nlm.nih.gov/26637112/