Ocular Manifestations of Familial Mediterranean Fever (FMF)
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Introduction
Familial Mediterranean Fever (FMF) is a monogenic autoinflammatory disorder caused by pathogenic variants in the MEFV gene, which encodes the inflammasome sensor pyrin. It is characterized by recurrent, self-limited attacks of fever and serosal inflammation involving the peritoneum, pleura, synovium, and, in some patients, the pericardium. Between attacks, many patients exhibit persistent subclinical inflammation that contributes to long-term organ damage, most notably AA amyloidosis of the kidney and other organs.[1]
FMF is endemic in populations around the Mediterranean basin, including people of Turkish, Armenian, Arab, and non-Ashkenazi Jewish descent, although migration has led to global distribution. Colchicine dramatically reduces the frequency and intensity of attacks and is the cornerstone of prophylactic therapy; however, colchicine-resistant or non-adherent patients remain at risk for ongoing inflammation and amyloidosis.[1]
Ocular manifestations of FMF are uncommon compared with other autoinflammatory syndromes, but reported lesions include episcleritis, anterior and posterior uveitis, posterior scleritis, retinal vasculitis, dry eye disease, and amyloid-related adnexal and conjunctival deposits.[1] Because these findings may herald uncontrolled systemic disease or evolving amyloidosis, recognition of FMF-related eye disease is clinically important, particularly in patients from endemic populations or with a strong family history. [1] This article reviews the current understanding of the pathophysiology, spectrum of ocular involvement, diagnostic approach, and management strategies for patients with FMF who develop ophthalmic manifestations.
Etiology and Pathophysiology
FMF results from mutations in the MEFV gene on chromosome 16p13.3, which encodes pyrin, a cytosolic protein expressed mainly in myeloid cells.[2] Pyrin participates in innate immune sensing by assembling the pyrin inflammasome in response to alterations in Rho GTPase signaling and cytoskeletal dynamics.[2] Activated pyrin recruits ASC and caspase-1, leading to cleavage of pro–interleukin-1β (IL-1β) and pro–IL-18 into their active forms and to gasdermin-D–mediated pyroptosis.[2]
Pathogenic MEFV variants (classically M694V, M680I, V726A, M694I and others) lower the threshold for inflammasome activation so that otherwise innocuous stimuli can trigger excessive IL-1β release and recurrent inflammatory attacks.[3] Experimental models and human studies demonstrate that IL-1β is a central driver of FMF autoinflammation and that pyrin dephosphorylation in FMF monocytes is sufficient to trigger inflammasome activation, in contrast to healthy controls.[3]
Persistent or inadequately controlled inflammation promotes deposition of serum amyloid A–derived fibrils (AA amyloidosis), particularly in the kidneys but also in the gastrointestinal tract, heart, and other organs.[4] Homozygosity for the M694V mutation and certain SAA1 genotypes markedly increase amyloidosis risk. Amyloid can deposit in vascular walls and periocular tissues, altering vessel integrity and local tissue architecture.[4]
From an ophthalmic standpoint, several mechanisms are relevant:
- Systemic vasculitis and endothelial dysfunction can involve episcleral, retinal, and choroidal vessels, producing episcleritis, retinal vasculitis, or occlusive microangiopathy.
- Autoinflammatory involvement of the uveal tract may trigger episodes of anterior, intermediate, or posterior uveitis and, in rare cases, posterior scleritis.
- Chronic systemic inflammation and amyloid deposition in the conjunctiva, eyelids, lacrimal glands, trabecular meshwork, and orbital tissues may lead to dry eye, mechanical ptosis, secondary glaucoma, or other structural changes.
Taken together, these mechanisms explain why ocular manifestations tend to arise in patients with long-standing or poorly controlled FMF, severe genotypes, or established amyloidosis.
Epidemiology and Risk Factors
FMF is most prevalent in the eastern Mediterranean, where carrier rates for MEFV variants may exceed 1 in 5 in some communities, and the disease is a leading cause of hereditary periodic fever.[5] Although ophthalmic involvement is considered rare and is usually reported as isolated case reports or small series, recent reviews suggest that almost all major classes of ocular inflammation have been described in FMF, with uveitis and posterior scleritis being the most vision-threatening phenotypes.[5] In the largest dedicated series to date, Yazici et al. identified 6 FMF patients with ocular inflammation in a tertiary center; posterior uveitis and anterior uveitis each accounted for one-third of cases, and posterior scleritis and episcleritis comprised the remainder.[5]
Patients with more severe systemic disease appear to be at greater risk for ocular manifestations.[6] Homozygous M694V and other high-risk MEFV genotypes are associated with earlier onset FMF, more frequent attacks, and a higher incidence of AA amyloidosis, all of which correlate with cumulative inflammatory burden. Poor adherence to colchicine, colchicine resistance, and persistently elevated acute-phase reactants despite treatment also mark patients who may be vulnerable to extra-articular complications, including ocular disease.[6]
Age at onset may influence the pattern of ocular involvement. Pediatric studies using OCT and choroidal vascularity metrics suggest that even children with clinically quiescent FMF exhibit subtle posterior segment changes, indicating that chronic subclinical inflammation can affect ocular tissues early in the disease course. Adults with long-standing FMF and documented amyloidosis are more likely to develop adnexal or conjunctival amyloid deposits and secondary ocular complications related to renal failure or systemic hypertension.[7]
Table 1. Selected Risk Factors for Ocular Involvement in Familial Mediterranean Fever
| Risk Factor | Rationale / Association |
|---|---|
| Homozygous high-risk MEFV variants (e.g., M694V/M694V) | Linked to severe phenotype, frequent attacks, and increased amyloidosis risk. |
| Persistent systemic inflammation or colchicine resistance | Indicates inadequate control of IL-1–driven autoinflammation. |
| Established AA amyloidosis | Predisposes to vascular and periocular amyloid deposition and systemic hypertension. |
| Long disease duration | Increases cumulative inflammatory burden and structural tissue damage. |
| Pediatric onset with chronic subclinical inflammation | Associated with measurable microstructural retinal and choroidal changes on imaging. |
Classification of Ocular Manifestations
Ocular involvement in FMF spans multiple anatomical sites and reflects the interplay between autoinflammation, vascular dysfunction, and, in some patients, AA amyloid deposition. A structured classification helps distinguish primary inflammatory manifestations from those related to systemic complications such as hypertension or amyloidosis.[8] Reported categories include adnexal disease, ocular surface abnormalities, uveitis across the full spectrum (anterior to panuveitis), retinal vascular disease, neuro-ophthalmic involvement, and amyloid-related ocular infiltration.[8]
Table 2. Anatomical Categories of Ocular Manifestations in FMF
| Category | Examples | Distinctive Features |
|---|---|---|
| Ocular adnexa | Eyelid amyloid, lacrimal gland infiltration | Related to systemic AA amyloidosis in advanced disease |
| Ocular surface | Conjunctival amyloid, dry eye | May be initial finding in amyloidosis |
| Anterior segment | Episcleritis, anterior uveitis | Reflects autoinflammatory activity |
| Intermediate/posterior uveal tract | Vitritis, posterior scleritis, posterior uveitis | Seen in more severe or uncontrolled FMF |
| Retinal/vascular involvement | Retinal vasculitis, vein occlusions | Often linked to vascular inflammation or amyloid angiopathy |
| Neuro-ophthalmic involvement | Optic neuropathy, papilledema | May arise from vasculitis, inflammation, or systemic complications |
Ocular Adnexal and Anterior Segment Manifestations
Ocular adnexal and anterior segment findings in FMF arise from autoinflammation or from secondary AA amyloid deposition in periocular tissues. These manifestations may precede visceral amyloidosis and can signal chronic disease activity or inadequate systemic control.[9]
Conjunctival and Eyelid Amyloidosis
Conjunctival amyloid commonly appears as yellow to pink, waxy, thickened deposits, often located in the fornices or bulbar conjunctiva. Patients may experience irritation, foreign body sensation, or spontaneous subconjunctival hemorrhage due to vessel fragility.[10] Eyelid involvement may lead to nodular thickening, mechanical ptosis, or distorted lid contour. These findings strongly correlate with longstanding systemic inflammation and frequently occur in individuals with concomitant renal amyloidosis.[10]
Episcleritis and Scleritis
Episcleritis can present during FMF inflammatory flares, producing sectoral redness and mild discomfort.[11] Scleritis, though less frequent, is clinically significant and presents with deep, persistent pain and diffuse or nodular scleral inflammation. Posterior scleritis has been documented in FMF and may be associated with severe systemic disease. Its detection requires B-scan ultrasonography when clinical suspicion is high.[11]
Anterior Uveitis
Anterior uveitis in FMF manifests with pain, photophobia, conjunctival injection, and anterior chamber inflammation.[12] Both granulomatous and non-granulomatous patterns have been reported. Uveitis typically corresponds with periods of active systemic inflammation or inadequate colchicine response. Complications such as posterior synechiae, cataract, and secondary glaucoma may arise with recurrent or poorly controlled episodes.[12]
Tear Film Dysfunction and Dry Eye
Dry eye symptoms can result from lacrimal gland involvement, ocular surface amyloid deposition, or chronic inflammation altering meibomian gland function. Patients report burning, fluctuating vision, and discomfort, and Schirmer testing may reveal reduced tear production.
Table 3. Key Anterior/Adnexal Manifestations and Associated Clinical Clues
| Manifestation | Characteristic Clues | When to Suspect |
|---|---|---|
| Conjunctival amyloid | Waxy deposits, recurrent hemorrhage | Longstanding FMF, renal amyloidosis |
| Eyelid amyloid | Nodular thickening, ptosis | Systemic amyloid infiltration |
| Episcleritis | Sectoral redness, mild pain | During inflammatory FMF flares |
| Scleritis | Deep pain, diffuse/nodular inflammation | Severe or uncontrolled FMF |
| Anterior uveitis | Cells/flare, photophobia | Active autoinflammatory phase |
| Dry eye syndrome | Reduced tear film, irritation | Lacrimal gland or surface involvement |
Intermediate, Posterior, and Panuveitis
Posterior segment involvement in FMF reflects heightened systemic autoinflammation and occasional vascular compromise. These manifestations are less common than anterior findings but carry greater risk for permanent visual impairment. They arise either from primary inflammatory pathways (uveitis, posterior scleritis) or from structural/vascular damage linked to systemic amyloidosis.
Intermediate uveitis manifests with vitreous cells, haze, and peripheral snowballs. Patients often report floaters and blurred vision.[13] This manifestation typically coincides with subacute or chronic systemic inflammation rather than acute febrile attacks. Without adequate systemic control, intermediate uveitis may progress to posterior uveitis or panuveitis. Posterior uveitis in FMF may present with choroidal lesions, focal or multifocal retinitis, or associated vasculitis. Inflammation can lead to photopsias, scotomas, or central vision changes when the macula is involved. Posterior uveitis tends to occur in patients with recurrent inflammatory attacks or suboptimal colchicine response.[13] Posterior scleritis, although rare, is one of the most characteristic posterior complications reported in FMF. Clinical signs may include pain, decreased vision, and choroidal folds or serous retinal detachment. Diagnosis relies heavily on ultrasonography, which may show a T-sign, and on careful exclusion of infectious causes.[13] Panuveitis represents diffuse inflammation involving the anterior chamber, vitreous, retina, and choroid. It is typically associated with chronic systemic inflammation, colchicine non-responsiveness, or underlying amyloidosis. Visual prognosis depends on the extent of retinal and vascular involvement as well as response to systemic anti-inflammatory therapy.[13]
Table 4. Posterior Segment Manifestations and Their Primary Mechanisms
| Manifestation | Mechanism | Clinical Implications |
|---|---|---|
| Intermediate uveitis | Persistent autoinflammation | Risk of progression to posterior involvement |
| Posterior uveitis | Choroidal/retinal inflammation | Potential macular involvement and vision loss |
| Posterior scleritis | Deep scleral inflammation | May mimic orbital disease; requires imaging |
| Panuveitis | Global intraocular inflammation | High risk for complications (CME, glaucoma) |
Retinal and Vascular Manifestations
Retinal involvement in FMF is uncommon but clinically important because it reflects either immune-mediated vasculitis or microvascular dysfunction associated with chronic systemic inflammation. These complications may present during active FMF flares or insidiously in patients with poorly controlled disease. Visual prognosis depends on the degree of macular involvement and the presence of ischemic vascular changes.[14]
Retinal Vasculitis
Retinal vasculitis may affect arterioles, venules, or both, producing perivascular sheathing, leakage on fluorescein angiography, and scattered intraretinal hemorrhages. Patients may report blurred vision, floaters, or paracentral scotomas.[15] Vasculitis in FMF is typically non-occlusive, but severe inflammation can result in capillary dropout or ischemia, particularly in individuals with prolonged systemic inflammation.[15]
Retinal Vein and Artery Occlusions
Retinal vascular occlusions, though rare, have been reported in FMF and may be related to endothelial dysfunction, inflammatory hypercoagulability, or amyloid angiopathy. Branch retinal vein occlusion is more frequently described than arterial occlusion and presents with sudden unilateral visual decline, venous engorgement, and macular edema. Arterial occlusions may manifest as acute, profound vision loss with retinal whitening and relative afferent pupillary defect.[16]
Macular Edema
Macular edema can occur secondary to vasculitis or retinal vein occlusion. OCT typically shows intraretinal cystic spaces or diffuse thickening. Persistent edema may reflect inadequate systemic control and can significantly limit central vision even after inflammation is quiet.[17]
Choroidal and Chorioretinal Changes
Choroidal thickening and subtle structural alterations have been detected in pediatric and adult FMF patients through enhanced-depth OCT imaging. These findings likely reflect microvascular remodeling from chronic low-grade inflammation. In some cases, chorioretinal lesions may accompany posterior uveitis.[18]
Table 5. Retinal and Vascular Findings in FMF and Their Pathophysiologic Basis
| Manifestation | Pathophysiologic Basis | Major Clinical Concern |
|---|---|---|
| Retinal vasculitis | Autoinflammatory vascular injury | Risk of ischemia and vision distortion |
| Retinal vein occlusion | Endothelial dysfunction, inflammation | Macular edema and vision loss |
| Retinal artery occlusion | Severe vascular compromise | Sudden profound visual decline |
| Macular edema | Leakage from inflamed/compromised vessels | Persistent central visual impairment |
| Choroidal changes | Chronic subclinical inflammation | Structural alteration detectable on OCT |
Neuro-Ophthalmic Manifestations
Neuro-ophthalmic findings in FMF typically arise from inflammatory injury to the optic nerve, meningeal involvement, or secondary systemic complications such as hypertension or renal failure. Although uncommon, these manifestations require prompt evaluation due to the risk of irreversible visual loss.[19]
Optic Neuritis
Optic neuritis associated with FMF presents with decreased visual acuity, impaired color discrimination, and visual field defects.[20] The optic nerve may appear swollen in the acute phase or pale once axonal loss has occurred. Mechanisms include immune-mediated demyelination or inflammatory ischemia. Symptoms may parallel systemic flares or appear in the context of colchicine-resistant disease.[20]
Papilledema
Papilledema in FMF is typically linked to elevated intracranial pressure rather than direct optic nerve inflammation. [21]Potential contributors include renal impairment from AA amyloidosis, hypertension, and, less commonly, central nervous system inflammatory involvement. Patients may describe headaches, transient visual dimming, or diplopia. Fundus examination reveals bilateral optic disc edema with preserved visual acuity early in the course.[19]
Cranial Nerve Palsies
Cranial neuropathies, particularly abducens nerve palsy, may occur due to increased intracranial pressure or inflammatory involvement of the meninges. Patients present with binocular horizontal diplopia and impaired abduction. These deficits generally resolve with treatment of the underlying systemic condition.[20]
Visual Pathway and CNS Involvement
Rarely, FMF-related neuroinflammation or amyloid deposition affects the optic tract or occipital cortex, producing homonymous visual field defects. MRI may show meningeal enhancement, parenchymal lesions, or other evidence of CNS involvement.[19]
Table 6. Neuro-Ophthalmic Presentations of FMF
| Presentation | Key Clinical Marker | Underlying Mechanism |
|---|---|---|
| Optic neuritis | Decreased vision, dyschromatopsia | Inflammatory or ischemic injury |
| Papilledema | Bilateral disc edema | Elevated intracranial pressure |
| CN VI palsy | Diplopia, limited abduction | ICP-related or meningeal inflammation |
| Homonymous field defects | Congruent visual field loss | CNS parenchymal involvement |
Amyloidosis-Related Ocular Disease
AA amyloidosis is a major long-term complication of FMF resulting from persistent elevation of serum amyloid A. Ocular tissues may accumulate amyloid fibrils, particularly in patients with longstanding disease or inadequate colchicine responsiveness. These manifestations may represent early evidence of systemic amyloid deposition.
Conjunctival Amyloidosis
Conjunctival involvement presents as localized, waxy, yellow-pink deposits that may cause chronic irritation, subconjunctival hemorrhage, or cosmetic concerns. The fragility of amyloid-infiltrated vessels can predispose to recurrent bleeding.
Eyelid and Adnexal Amyloid Deposits
Amyloid infiltration of the eyelids may cause nodularity, mechanical ptosis, or altered lid contour. Lacrimal gland involvement can impair tear production, contributing to secondary dry eye symptoms. Histologic confirmation is often required when adnexal masses are present.
Trabecular Meshwork and Secondary Glaucoma
Amyloid deposition within the trabecular meshwork may increase outflow resistance and lead to secondary open-angle glaucoma. Elevated intraocular pressure may persist despite control of systemic inflammation, necessitating pharmacologic or surgical intervention.
Retinal and Choroidal Amyloid Angiopathy
Amyloid deposition in retinal or choroidal vessels can compromise vascular integrity, predisposing to ischemia, vessel wall thickening, or subtle chorioretinal changes. These findings typically occur in patients with established systemic amyloidosis and correlate with renal involvement.
Table 7. Ocular Sites of Amyloid Deposition in FMF
| Ocular Site | Clinical Effect | Systemic Correlation |
|---|---|---|
| Conjunctiva | Waxy deposits, recurrent hemorrhage | Often first visible sign of amyloidosis |
| Eyelids | Ptosis, nodularity | Advanced systemic deposition |
| Lacrimal gland | Tear deficiency | Sicca symptoms |
| Trabecular meshwork | Elevated IOP | Secondary glaucoma |
| Retinal/choroidal vessels | Vascular thickening, ischemia | Occurs with widespread amyloid angiopathy |
Diagnostic Evaluation
Evaluation of ocular involvement in Familial Mediterranean Fever (FMF) requires recognizing that findings may arise from autoinflammatory mechanisms, vasculitic injury, or systemic AA amyloidosis. Because FMF can mimic a range of infectious, autoimmune, and autoinflammatory ophthalmic diseases, diagnosis relies on synthesizing systemic history, ocular examination, and multimodal imaging. A thorough evaluation is essential for distinguishing FMF-related inflammation from entities such as Behçet disease or sarcoidosis, which occur in similar geographic populations and may present with nearly identical posterior segment findings.[22]
Clinical History and Systemic Assessment
A comprehensive history is foundational. Clinicians should document frequency and duration of febrile FMF attacks, presence of chest or abdominal pain, colchicine use and adherence, treatment response, known MEFV genotype, and whether the patient has developed systemic amyloidosis.[23] Patients with high-risk genotypes (e.g., M694V homozygosity) or those exhibiting colchicine resistance are more likely to display persistent inflammatory activity, which correlates with the development of ocular disease. Inquiry into visual symptoms—including episodic blurred vision, floaters, photophobia, ocular redness, diplopia, or transient visual obscurations—helps guide suspicion toward anterior uveitis, posterior uveitis, vasculitis, or neuro-ophthalmic involvement. Because amyloidosis frequently impairs renal function long before ocular deposition appears, systemic fluid retention, proteinuria, or hypertension should raise concern for vascular involvement affecting the retina or optic nerve.[23]
Ophthalmic Examination
The clinical eye exam must be comprehensive. Slit-lamp evaluation can detect conjunctival or eyelid amyloid deposition, episcleritis, scleritis, keratic precipitates, flare, and anterior chamber inflammation. Gonioscopy may reveal early trabecular meshwork infiltration in patients with suspected amyloid-related glaucoma.[24] Dilated fundus examination is crucial for identifying vitritis, retinal vasculitis, chorioretinal lesions, macular edema, or signs of optic nerve inflammation or papilledema. Because FMF patients may exhibit subtle posterior findings during quiescent systemic phases, careful comparison with prior fundus photographs (if available) may help detect microprogression. An intraocular pressure assessment is necessary at each visit because both inflammatory and amyloid-mediated mechanisms can lead to secondary open-angle glaucoma.[24]
Imaging Studies
Optical coherence tomography (OCT) is indispensable for quantifying macular edema, assessing disruption of the ellipsoid zone, and measuring choroidal thickness, which may be increased in chronic autoinflammation.[25] Enhanced-depth OCT can highlight early amyloid-related alterations in the choroidal vasculature. Fluorescein angiography (FA) allows visualization of perivascular leakage, capillary nonperfusion, or late staining typical of retinal vasculitis. Indocyanine green angiography (ICG) offers additional insights into choroidal circulation, especially when deeper choroidal lesions suggest posterior scleritis or amyloid angiopathy. In suspected posterior scleritis, B-scan ultrasonography is essential, revealing characteristic T-sign or scleral thickening even when fundus visualization is obscured. MRI of the brain and orbits is indicated in patients with optic neuritis, papilledema, or unexplained visual field defects, particularly when systemic hypertension or renal failure may complicate the picture.[25]
Laboratory Testing
Laboratory studies help contextualize ocular findings within systemic FMF activity. Elevated ESR or CRP supports active inflammation, although levels may fluctuate independently of ocular disease.[26] Renal function tests and 24-hour urine protein quantification or spot protein-to-creatinine ratio are crucial for detecting early amyloidosis, which directly influences ocular prognosis. While no laboratory test confirms FMF-related uveitis, clinicians must exclude infections such as tuberculosis and syphilis, as well as autoimmune conditions like sarcoidosis, ANCA-associated vasculitis, or systemic lupus erythematosus. In complex cases, conjunctival or eyelid biopsy can confirm amyloid deposition, aiding in differentiating FMF-associated amyloidosis from other causes of conjunctival infiltration.[26]
Table 8. Diagnostic Tools and Their Primary Role in FMF Ocular Evaluation
| Modality | Primary Role |
|---|---|
| OCT | Quantifies macular edema; detects choroidal thickening and photoreceptor disruption |
| Fluorescein angiography | Identifies vasculitis, leakage, capillary nonperfusion |
| Indocyanine green angiography | Evaluates choroidal circulation, amyloid angiopathy |
| B-scan ultrasound | Detects posterior scleritis or scleral thickening |
| MRI brain/orbits | Assesses optic nerve inflammation and intracranial pathology |
| Renal and inflammatory markers | Detect systemic activity and amyloidosis risk |
Management
Management of ocular involvement in FMF relies on suppressing systemic autoinflammation, addressing local ocular pathology, and preventing irreversible tissue damage. Because FMF spans the autoinflammatory spectrum, treatment strategies often mirror those used in other IL-1–mediated conditions but must be tailored to the patient’s systemic status, degree of amyloidosis, and ocular phenotype.
Systemic Therapy
Colchicine is the foundational therapy for FMF, reducing frequency of febrile attacks and preventing AA amyloidosis when taken consistently. Patients with ocular disease often have evidence of inadequate systemic control—whether from non-adherence, toxicities limiting dose escalation, or genetic resistance. In such cases, IL-1 inhibitors (anakinra, canakinumab, or rilonacept) have demonstrated marked efficacy in suppressing autoinflammatory activity, reducing acute-phase reactants, and preventing further end-organ involvement, including ocular inflammation.[27] Because IL-1 blockade directly targets the pathogenic inflammasome overactivation in FMF, it is increasingly considered in patients presenting with recurrent or vision-threatening ocular disease. Systemic corticosteroids may be used briefly during severe attacks but should not substitute for disease-modifying therapy, as they do not prevent amyloid formation.[27]
Ocular Anti-Inflammatory Treatment
Anterior uveitis is typically managed with topical corticosteroids and cycloplegics, titrated to response. Posterior uveitis, retinal vasculitis, or posterior scleritis often require systemic corticosteroids to rapidly control intraocular inflammation. However, corticosteroids must be paired with effective systemic FMF therapy to prevent rebound inflammation.[28] For patients with persistent macular edema or inflammatory vitreitis despite systemic control, periocular steroid injections or intravitreal corticosteroids may be considered, recognizing the increased risk of ocular hypertension in amyloid-infiltrated trabecular meshwork. Long-term steroid monotherapy should be avoided due to cumulative toxicity.[28]
Management of Amyloidosis-Related Disease
Treatment of amyloid-related ocular disease focuses on both symptom relief and preventing progression. Conjunctival amyloid deposits that interfere with comfort or vision may be surgically debulked; however, recurrence is common unless systemic inflammation is controlled.[29] Lacrimal gland involvement leading to dry eye requires aggressive lubrication and, in some cases, punctal occlusion or anti-inflammatory surface therapy. Glaucoma resulting from amyloid infiltration of the trabecular meshwork may be refractory to topical medications and require filtering surgery or glaucoma drainage devices. Retinal or choroidal amyloid angiopathy is managed by optimizing systemic therapy, although visual recovery may be limited once ischemia occurs.[29]
Treatment of Retinal and Vascular Complications
Macular edema is managed according to etiology: inflammatory edema requires systemic control, whereas edema from venous occlusion may benefit from anti-VEGF therapy. In retinal artery occlusion, visual prognosis is poor, but addressing underlying systemic drivers (hypertension, amyloidosis) is essential for preserving the fellow eye. Retinal vasculitis responds best to high-potency systemic anti-inflammatory therapy combined with colchicine or IL-1 inhibition to stabilize vascular integrity.[30]
Monitoring During Treatment
Patients receiving corticosteroids, IL-1 inhibitors, or combination therapy require scheduled follow-up to evaluate intraocular pressure, lens clarity, retinal thickness, and response to therapy. Because amyloidosis can evolve silently, regular systemic monitoring—particularly of renal function—is equally important.[31]
Prognosis, Differential Diagnosis, and Long-Term Monitoring
Prognosis
The visual prognosis in FMF varies based on the severity of ocular involvement, degree of systemic inflammatory control, and whether AA amyloidosis has developed. Anterior segment manifestations such as episcleritis or mild anterior uveitis generally resolve without lasting visual impairment when systemic disease is managed effectively.[21] In contrast, posterior segment involvement—including posterior uveitis, vasculitis, and posterior scleritis—carries a substantially higher risk of lasting visual sequelae due to ischemia, macular edema, retinal atrophy, or optic neuropathy. Amyloidosis-related disease often progresses insidiously and may reflect advanced systemic involvement, making timely recognition essential. Early initiation of IL-1 blockade in colchicine-resistant patients substantially improves long-term outcomes, reducing attack frequency and decreasing the likelihood of ocular complications.[21]
Differential Diagnosis
FMF-associated ocular inflammation overlaps clinically with several conditions that are endemic in similar regions or share similar inflammatory mechanisms. Behçet disease is the most important mimicker and must be excluded in patients presenting with retinal vasculitis or panuveitis; the presence of recurrent oral or genital ulcers, pathergy, or aggressive occlusive vasculitis favors Behçet disease. Sarcoidosis may produce granulomatous uveitis and periphlebitis, accompanied by pulmonary or lymphatic involvement visible on imaging. [32]Tuberculosis can produce multifocal choroiditis or vasculitis and requires testing in high-prevalence settings. Syphilis, toxoplasmosis, and viral retinitides (HSV, VZV, CMV) all can resemble posterior uveitis associated with FMF, making serologic and imaging evaluation imperative. Distinguishing FMF-related posterior scleritis from idiopathic or infectious scleritis requires careful systemic correlation, as FMF-associated disease often coincides with heightened inflammatory markers.[32]
Long-Term Monitoring
Because FMF is a lifelong autoinflammatory condition with potential for cumulative vascular and tissue damage, patients with ocular involvement require long-term surveillance even when asymptomatic. Follow-up should include periodic slit-lamp and fundus examination, OCT for macular or choroidal monitoring, and intraocular pressure measurement. Fluorescein angiography is appropriate for patients with a history of retinal vasculitis or unexplained visual loss.[33] Systemic monitoring includes assessing acute-phase reactants, renal function, and colchicine adherence, all of which influence ocular prognosis. In patients treated with IL-1 inhibitors, routine evaluation for injection-site reactions, infection, and systemic inflammatory markers is necessary. Education on recognizing early ocular symptoms—including new floaters, photophobia, or visual distortion—is critical, as timely management can prevent irreversible damage.[33]
Table 9. Key Elements of Long-Term Monitoring in FMF Patients with Ocular Disease
| Monitoring Focus | Clinical Purpose |
|---|---|
| Visual acuity and symptom review | Detect recurrent inflammation or subtle visual decline |
| Slit-lamp and fundus examinations | Identify active uveitis, vasculitis, or amyloid deposits |
| OCT imaging | Monitor macular edema, photoreceptor integrity, and choroidal changes |
| Intraocular pressure | Detect steroid response or amyloid-related glaucoma early |
| Renal and inflammatory markers | Assess systemic amyloidosis risk and FMF activity |
| Colchicine and IL-1 inhibitor adherence | Prevent relapse and progression of ocular inflammation |
References
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- ↑ 1.0 1.1 1.2 1.3 Sönmez HE, Batu ED, Özen S. Familial Mediterranean fever: current perspectives. J Inflamm Res. 2016 Mar 17;9:13-20. doi: 10.2147/JIR.S91352. PMID: 27051312; PMCID: PMC4803250.
- ↑ 2.0 2.1 2.2 Akin H, Onay H, Turker E, Cogulu O, Ozkinay F. MEFV mutations in patients with Familial Mediterranean Fever from the Aegean region of Turkey. Mol Biol Rep. 2010 Jan;37(1):93-8. doi: 10.1007/s11033-009-9543-1. Epub 2009 May 17. PMID: 19449169.
- ↑ 3.0 3.1 Magnotti F, Lefeuvre L, Benezech S, Malsot T, Waeckel L, Martin A, Kerever S, Chirita D, Desjonqueres M, Duquesne A, Gerfaud-Valentin M, Laurent A, Sève P, Popoff MR, Walzer T, Belot A, Jamilloux Y, Henry T. Pyrin dephosphorylation is sufficient to trigger inflammasome activation in familial Mediterranean fever patients. EMBO Mol Med. 2019 Nov 7;11(11):e10547. doi: 10.15252/emmm.201910547. Epub 2019 Oct 7. PMID: 31589380; PMCID: PMC6835204.
- ↑ 4.0 4.1 Mirioglu S, Uludag O, Hurdogan O, Kumru G, Berke I, Doumas SA, Frangou E, Gul A. AA Amyloidosis: A Contemporary View. Curr Rheumatol Rep. 2024 Jul;26(7):248-259. doi: 10.1007/s11926-024-01147-8. Epub 2024 Apr 3. PMID: 38568326; PMCID: PMC11219434.
- ↑ 5.0 5.1 5.2 Bhatt H, Cascella M. Familial Mediterranean Fever. [Updated 2023 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK560754/
- ↑ 6.0 6.1 Giat E, Livneh A, Lidar M, Bar D, Gilad Dor L, Azem S, Ben-Zvi I, Druyan A. Non-canonical manifestations of FMF in homozygous M694V MEFV genotype: Insights from a large patient cohort. Semin Arthritis Rheum. 2025 Oct;74:152821. doi: 10.1016/j.semarthrit.2025.152821. Epub 2025 Aug 29. PMID: 40902213.
- ↑ Sav NM, Teberik K. Retinal changes in children with Familial Mediterranean Fever: the effect of chronic subclinical inflammation. Pediatr Res. 2025 Jun 6. doi: 10.1038/s41390-025-04195-7. Epub ahead of print. PMID: 40481291.
- ↑ 8.0 8.1 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 Jul-Aug;24(4):593-8. doi: 10.5301/ejo.5000398. Epub 2013 Dec 5. PMID: 24338581.
- ↑ Grossniklaus H, Green W, Luckenbach M, Chan C. Conjunctival lesions in adults. A clinical and histopathologic review. Cornea 1987;6:78–116.
- ↑ 10.0 10.1 Prager AJ, Habib LA, Gambogi T, Busam KJ, Marr BP. Long-Term Follow-Up of 4 Patients with Conjunctival Amyloidosis. Ocul Oncol Pathol. 2018 Sep;4(5):313-317. doi: 10.1159/000485918. Epub 2018 Feb 13. PMID: 30320104; PMCID: PMC6167687.
- ↑ 11.0 11.1 Schonberg S, Stokkermans TJ. Episcleritis. [Updated 2023 Aug 7]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK534796/
- ↑ 12.0 12.1 Agrawal RV, Murthy S, Sangwan V, Biswas J. Current approach in diagnosis and management of anterior uveitis. Indian J Ophthalmol. 2010 Jan-Feb;58(1):11-9. doi: 10.4103/0301-4738.58468. PMID: 20029142; PMCID: PMC2841369.
- ↑ 13.0 13.1 13.2 13.3 Babu BM, Rathinam SR. Intermediate uveitis. Indian J Ophthalmol. 2010 Jan-Feb;58(1):21-7. doi: 10.4103/0301-4738.58469. PMID: 20029143; PMCID: PMC2841370.
- ↑ Anglada-Masferrer N, Bertolani Y, Gutuleac L, Angrill Valls J, Distefano L, Kirkegaard-Biosca E. Familial Mediterranean Fever-Associated Retinal Vasculitis: A Rare Manifestation Successfully Managed with IL-1 Pathway Inhibitors. Ocul Immunol Inflamm. 2024 Nov;32(9):2246-2249. doi: 10.1080/09273948.2024.2317978. Epub 2024 Feb 16. PMID: 38364019.
- ↑ 15.0 15.1 Abu El-Asrar AM, Herbort CP, Tabbara KF. Differential diagnosis of retinal vasculitis. Middle East Afr J Ophthalmol. 2009 Oct;16(4):202-18. doi: 10.4103/0974-9233.58423. PMID: 20404987; PMCID: PMC2855661.
- ↑ Cochran ML, Mahabadi N, Czyz CN. Branch Retinal Vein Occlusion. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK535370/
- ↑ Johari M, Attar A, Eghtedari D, Razavizadegan SA. Characteristics of macular edema associated with retinal vein occlusion showing poor anatomic response to three loading anti-vascular endothelial growth factor injections: an optical coherence tomography analysis. BMC Ophthalmol. 2024 Jan 22;24(1):30. doi: 10.1186/s12886-024-03298-9. PMID: 38254100; PMCID: PMC10801953.
- ↑ Gürbostan Soysal G, Seyyar SA, Dogru V, Saygılı O, Güngör K, Coşkun S. Impact of Familial Mediterranean Fever on Choroidal Tissue: A Study of Choroidal Thickness and Vascularity in Pediatric Patients. Ocul Immunol Inflamm. 2025 Nov;33(9):1922-1928. doi: 10.1080/09273948.2025.2532824. Epub 2025 Jul 15. PMID: 40664204.
- ↑ 19.0 19.1 19.2 Bektaş PC, Kavas Tufan A, Çetin N, Yarar C, Carman KB. Neurological Face of Familial Mediterranean Fever. Turk Arch Pediatr. 2022 Sep;57(5):511-515. doi: 10.5152/TurkArchPediatr.2022.21368. PMID: 35866324; PMCID: PMC9524416.
- ↑ 20.0 20.1 20.2 Başaran Ö, Kavuncu S, Güven A, Uncu N, Acar-Çelikel B, Çakar N. Familial Mediterranean fever associated with optic neuritis, successfully treated with anti-interleukin 1 agents. Turk J Pediatr. 2016;58(3):327-330. doi: 10.24953/turkjped.2016.03.018. PMID: 28266203.
- ↑ 21.0 21.1 21.2 Fonollosa A, Carreño E, Vitale A, Jindal AK, Ramanan AV, Pelegrín L, Santos-Zorrozua B, Gómez-Caverzaschi V, Cantarini L, Fabiani C, Hernández-Rodríguez J. Update on ocular manifestations of the main monogenic and polygenic autoinflammatory diseases. Front Ophthalmol (Lausanne). 2024 Feb 22;4:1337329. doi: 10.3389/fopht.2024.1337329. PMID: 38984133; PMCID: PMC11182141.
- ↑ Salehzadeh F, Yasrebi O, Hosseini Khotbesara M, Hosseini Khotbesara M. Idiopathic uveitis and familial mediterranean Fever: is there any relationship? Autoimmune Dis. 2014;2014:238931. doi: 10.1155/2014/238931. Epub 2014 Jan 30. PMID: 24592325; PMCID: PMC3926436.
- ↑ 23.0 23.1 Shohat M. Familial Mediterranean Fever. 2000 Aug 8 [Updated 2016 Dec 15]. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1227/
- ↑ 24.0 24.1 Tooley AA, Sweetser S. Clinical examination: Eyes. Clin Liver Dis (Hoboken). 2016 Jun 28;7(6):154-157. doi: 10.1002/cld.561. PMID: 31041052; PMCID: PMC6490280.
- ↑ 25.0 25.1 Trichonas G, Kaiser PK. Optical coherence tomography imaging of macular oedema. Br J Ophthalmol. 2014 Jul;98 Suppl 2(Suppl 2):ii24-9. doi: 10.1136/bjophthalmol-2014-305305. PMID: 24934220; PMCID: PMC4208347.
- ↑ 26.0 26.1 Groen-Hakan F, Eurelings L, van Laar J, Rothova A. Relevance of erythrocyte sedimentation rate and C-reactive protein in patients with active uveitis. Graefes Arch Clin Exp Ophthalmol. 2019 Jan;257(1):175-180. doi: 10.1007/s00417-018-4174-7. Epub 2018 Nov 8. PMID: 30411142; PMCID: PMC6323081.
- ↑ 27.0 27.1 Kharouf F, Tsemach-Toren T, Ben-Chetrit E. IL-1 inhibition in familial Mediterranean fever: clinical outcomes and expectations. Clin Exp Rheumatol. 2022 Sep;40(8):1567-1574. doi: 10.55563/clinexprheumatol/obb2ds. Epub 2022 Aug 30. PMID: 36062765.
- ↑ 28.0 28.1 Duplechain A, Conrady CD, Patel BC, et al. Uveitis. [Updated 2023 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK540993/
- ↑ 29.0 29.1 Mathew R, Zeppieri M. Ocular Amyloidosis. [Updated 2024 May 28]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK603727/
- ↑ Kohli P, Tripathy K, Patel BC. Macular Edema. [Updated 2024 Apr 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK576396/
- ↑ Mandapati JS, Metta AK. Intraocular pressure variation in patients on long-term corticosteroids. Indian Dermatol Online J. 2011 Jul;2(2):67-9. doi: 10.4103/2229-5178.85993. PMID: 23130227; PMCID: PMC3481806.
- ↑ 32.0 32.1 Mir A, Ivory C, Cowan J. Concurrence of familial Mediterranean fever and Behçet's disease: a case report and review of the literature. J Med Case Rep. 2023 Oct 22;17(1):438. doi: 10.1186/s13256-023-04185-5. PMID: 37865787; PMCID: PMC10590508.
- ↑ 33.0 33.1 Vofo BN, Amer R. Outer Retina Rupture from Subretinal Blood with Spontaneous Sealing and Visual Recovery in Frosted Branch Angiitis from Familial Mediterranean Fever: A Case Report. Turk J Ophthalmol. 2022 Aug 25;52(4):286-290. doi: 10.4274/tjo.galenos.2022.69337. PMID: 36017544; PMCID: PMC9421930.
