Introduction

Familial Mediterranean fever (FMF) is one of the most prevalent periodic monogenic autoinflammatory diseases affecting select ethnic groups (Jewish, Armenian, Turkish and Arabic) living around the Mediterranean basin. The prevalence is around 1/500 in Armenians and 1/1000 in Turks. The clinical manifestations in decreasing order include peritonitis, fever, arthritis, pleuritis, myalgia, erysipelas-like rash, and amyloidosis. This genetic disorder results from pathogenic mutations located on the short arm of chromosome 16p13.3 [1,2,3,4,5,6,7,8,9,10,11,12,13,14].

Ocular involvement in FMF is quite uncommon [1,2,3,4,5,6,7,8,9]. Retinal vasculitis has been reported in a few cases with FMF mostly as pictures and perspectives [10, 11] or letter [12] or briefcase reports [13, 14]. We analyzed the clinical presentation of retinal vasculitis or retinal vascular occlusion in the context of FMF in a retrospective multicenter collaborative study.

Materials and methods

Uveitis specialists practising around the Mediterranean basin and senior authors (cited on Google Scholar) that published on ocular findings in FMF were invited to collaborate. Excel sheet was filled by the collaborators in an anonymous fashion. The study received institutional review board approval (AMM) and followed the tenets of the declaration of Helsinki. Patients were diagnosed clinically according to the Tel Hashomer criteria. Variables included inflammatory blood markers, initial vision, final vision, follow-up time, therapy type dosage and duration. Exclusion criteria included infectious causes like tuberculosis and autoimmune disorders such as Behçet’s disease, periarteritis nodosa, IgA vasculitis, lupus, and rheumatoid arthritis. Snellen spectacle-corrected visual acuity was converted to logMAR for statistical analyses. Paired student t-test was calculated to measure the change in visual acuity at the last follow-up. This case series was combined with previously reported cases (PubMed Central and Google Scholar using the search terms retinal vasculitis or retinal vascular occlusion AND FMF before June 2021).

Results

This is a retrospective review of 16 cases of FMF associated with retinal vasculitis (Table 1) (including 3 published cases) [12,13,14] from Belgium (1 case), Canada (1 case), Japan (1 case), Morocco (1 case), UK (1 case), Lebanon (2 sisters), Turkey (9 cases) involving 13 centres with one case of central retinal artery occlusion (Turkey, 1 case). The mean age at onset of the retinal vasculitis was 29.5 ± 13.4 (range 9–62), and the mean age at onset of FMF was 18.4 ± 16.0 (range 1–56). There was a total of 9 women and 7 men, 15 Caucasian and 1 Asian. Family history of FMF was present in 8 patients, absent in 7 patients, and not mentioned in 1 patient. FEVR mutations were not registered in 5 cases but were positive in 11 cases: M680I (3 cases), M694V (3 cases), V726A (2 cases), M694I (1 case), and R761H (1 case having also M694V mutation), and not specified (2 cases). There was a negative workup for antinuclear antibody, antineutrophil cytoplasmic antibody, anti-cyclic citrullinated peptide, rheumatoid arthritis latex, purified protein derivative skin test, chest radiograph and brain magnetic resonance imaging (except one patient had occipital lesion from vasculitis). Erythrocyte sedimentation rate was elevated in 8 patients, while C-reactive protein was elevated in a single patient. Behcet’s disease was excluded by the rheumatology consultant and by the absence of recurrent oral and genital ulcers.

Table 1 Clinical parameters of subjects with retinal vasculitis and FMF (NLP No light perception; LP Light perception; HM Hand motion; NA Not available; R Right; L Left; RL right and left eye; CF Counting finger; FMF Familial Mediterranean fever; MEFV gene Gene responsible for FMF).

In 19 eyes (omitting Case 13 that received laser pan-retinal photocoagulation only) of 15 patients with FMF and retinal vasculitis treated with oral or local corticosteroid, logMAR initial spectacle-corrected visual acuity improved from 1.51 ± 1.30 (Snellen equivalent 6/194 or 20/647) to 0.23 ± 0.40 (Snellen equivalent 6/10.5 or 20/34) (paired t-test p < 0.001) after a mean follow-up of 29.0 ± 34.9 months (range 1–120). Nine eyes had initial corrected visual acuity below 6/60 or 20/200: No light perception (1 eye), light perception (2 eyes), hand motion (1 eye), counting finger near the face (3 eyes), and counting finger at 1.5 m (2 eyes). Visual recovery was absent in 2 eyes that underwent solely laser pan-retinal photocoagulation (PRP) and was either partial in 5 eyes or full in 14 eyes that received systemic or local therapies. The left eye was involved in 7 patients, the right eye in 4 patients, and both eyes in 5 patients. Eleven patients (14 eyes) received oral corticosteroid (initial prednisone 1 mg/kg/day) tapered slowly over a mean of 6.9 ± 6.6 months (range 1–24). Fast tapering of oral corticosteroid as sole therapy resulted in recurrence of the retinal vasculitis in 2 cases. Concomitant immunosuppression was given in 7 eyes (4 patients) (azathioprine 1 mg/kg/d alone in 3 eyes, methotrexate with adalimumab followed by cyclosporine in 2 eyes and cyclophosphamide 500 mg/d in 2 eyes). Five patients (7 eyes) did not receive oral corticosteroid: one patient received methotrexate 15 mg/m2/d with adalimumab 40 mg biweekly then maintained on cyclosporine A 3 mg/kg/d, one patient had an increase in the colchicine dosage, one patient received intravitreal bevacizumab with an increase in the colchicine dosage, one patient underwent pan-retinal photocoagulation, and two patients received intraocular dexamethasone implant. All patients were maintained on oral colchicine (0.5mg–2.5 mg/d) with one subject developing retinal vasculitis 7 months after discontinuing the drug.

Frosted branch angiitis (FBA) occurred in 11 patients (13 eyes) including 2 sisters (Figs. 13) (grandparents and parents are first cousins) while a milder form of retinal vasculitis occurred in 5 patients (8 eyes). In a few cases, the initial presentation mimicked other entities delaying proper diagnosis and prompt treatment. In one case (Case 13), the initial diagnosis was central retinal vein occlusion hence pan-retinal photocoagulation was offered initially. Also in Case 10, the initial diagnosis was demyelinating disease (optic neuritis and central nervous system vasculitis) with a very prompt response to systemic corticosteroid while the correct diagnosis was retinal and central nervous system vasculitis from FMF.

Fig. 1: Comparison between a color fundus montage and a fluorescein angiographic image of the posterior pole.
figure 1

Frosted branch angiitis of the left eye in a 31-year-old Caucasian woman with FMF (case 1) of one-year duration and visual recovery from hand motion to 6/7.5 (20/25) after 2 years of oral corticosteroid with azathioprine.

Fig. 2: Comparison between a color fundus image and a fluorescein angiographic image of the posterior pole.
figure 2

Frosted branch angiitis of the left eye in two Caucasian sisters with FMF (Case 5 top, Case 6 bottom). FMF was diagnosed at age 2 years in both sisters. The parents and grandparents are first cousins. FBA responded to oral corticosteroids tapered over 6–8 months with the recovery of vision.

Fig. 3: Comparison between a color fundus image and a fluorescein angiographic image of the posterior pole.
figure 3

Frosted branch angiitis in the right eye of a 33-year-old Caucasian woman with FMF (Case 11) initial vision of 6/480 (20/1600) improving to 6/15 (20/50) up to the last follow-up 36 months after a single intravitreal dexamethasone implant.

Besides retinal vasculitis, two eyes developed central retinal artery occlusion or branch retinal artery occlusion [15] both well-controlled by a short course of oral corticosteroid.

Discussion

Table 1 collected a total of 16 cases having FMF who developed retinal vasculitis (21 eyes) and besides an additional case of central retinal artery occlusion (1 case) and branch retinal artery occlusion (1 case). It seems that FMF is primarily involved in the pathogenesis of retinal vasculitis and needs to be included in the differential of retinal vasculitis and especially with FBA. Similarly, vasculitis can involve other sites such as the central nervous system [16], the heart [17], the skin and the kidneys [18]. The pathogenesis of FMF-associated vasculitis remains still unknown but includes increased serum proinflammatory cytokines (IL-6, IL-18, and INF-γ) and exuberant IL-1β production [19].

FBA consists of a florid translucent retinal perivascular sheathing with variable uveitis, macular oedema and visual loss, Fluorescein angiography shows normal arterial and venous flow and profuse dye leakage from sheathed vessels. FBA may be idiopathic or associated with Behçet’s disease, Crohn’s disease, lupus or infectious aetiology (cytomegalovirus, herpes simplex type 2, toxoplasmosis, tuberculosis) and blood dyscrasias. Additional retinal findings may include intraretinal haemorrhages, hard exudates, and serous exudative detachments of the macula and periphery. A proposed mechanism of retinopathy involves immune complex deposition in retinal vessels [10,11,12,13]. Other theories pointed toward an autoimmune response often triggered by exposure to an infectious agent. Patients complain of sudden onset of blurred vision, central scotomas, floaters, and photopsia, and most patients respond to systemic corticosteroid therapy with good recovery of visual acuity. Vitreous haemorrhage is an additional cause of visual loss in FBA being noted in 10 eyes in the current series. The temporal association between the fever, abdominal pain and the visual loss in immunocompetent young subjects coupled with the prompt response to systemic corticosteroid and absence of retinitis rule out CMV as the cause of FBA.

Kölber et al. [15] described a 14-year-old boy with FMF of 12 years duration and controlled on oral colchicine who developed quadrantic visual field loss. Branch retinal occlusion was documented on intravenous fluorescein angiography. Complete workup (coagulation screen, protein electrophoresis, HLA for Behçet’s disease) was negative. There was a rapid decrease of the scotoma on initiation of corticosteroid. In the current case series, one patient had FMF-related central retinal artery occlusion responding to corticosteroid therapy. These 2 cases of retinal artery occlusion in young subjects insinuate the idea that some FMF patients exhibit increased vascular morbidity from the prothrombotic condition of massive or covert inflammation that can manifest in an increased intima-media thickness of the carotid artery, enhanced atherosclerosis, hyperfibrinogenemia, and risk of stroke in very young subjects [20].

On chromosome 16.p13.3, the FMF gene, also known as MEFV, encodes the protein pyrin that modulates the activity of target proteins directly involved in inflammation. Cekin et al. [21] did not find any mutations in 55% of 514 Turkish patients with FMF. Five of the most commonly found mutations were M694V (48%), E148Q (18%), M680I (15%), V726A (12.5%) and P369S (3.3%)in the Turkish study (514 patients). Five of the most commonly found mutations were M694V (41.3%), V726A (27.6%), M680I (18.2%), E148Q (5.3%), R761H (3.4%) in the Armenian study (10,370 patients) [22]. The frequency of symptoms in that Turkish series [21] was as follows: abdominal pain (76%), fever (58%), arthritis (28%) and chest pain (19%). M694V or M680I mutant alleles had the highest frequency of FMF symptoms. In contrast, patients carrying the E148Q or V726A mutant allele showed few clinical FMF symptoms. In other studies, FMF-associated vasculitis was associated with the M694V allele [21]. M694V mutations appear to be of high penetrance, with earlier onset and more severe phenotypes in general FMF symptoms, and probably as well in retinal vasculitis as shown here.

Colchicine is a tricyclic alkaloid administered in Behçet’s disease, pericarditis and atrial fibrillation. On July 29, 2009, colchicine won Food Drug Administration approval as a stand-alone drug for the treatment of familial Mediterranean fever. Colchicine impairs neutrophil recruitment migration and function, prevent activation of macrophage (TNF-α receptor expression) and interrupt granule release in mast cells with the end result being decreased levels of the proinflammatory cytokines IL-1β, IL-6, IL-18, and IFNγ [23].

The standard therapy of retinal vasculitis remains the maintenance of an adequate dosage of oral colchicine (1 mg daily). While on maintenance therapy, colchicine lowered CRP to within normal levels in the current study (except in one patient who discontinued the drug). Colchicine is well-known to normalize the CRP level in many inflammatory disorders [24]. A decrease in the dose [1, 12] or discontinuation of the medication results in a flare-up of ocular inflammation. When retinal vasculitis is mild and is caught early, an increase in colchicine dosage may adequately and solely control the inflammation [1, 12]. When the vasculitis is severe with visual decline, systemic corticosteroid for several months can control the vasculitis and prevent recurrences, albeit with a slow taper. When the retinal vasculitis is severe, systemic immunosuppression can supplement the oral corticosteroid (Cases 1, 2, 4 and 9). The indications for longer-term steroid use in FMF are protracted febrile myalgia (a sort of vasculitis), protracted arthritis (belongs to the spectrum of spondyloarthropathy of FMF), and ocular inflammation (scleritis, retinal vasculitis). Panretinal photocoagulation alone did not alter the downhill natural course, while intraocular dexamethasone did control retinal vasculitis in 2 patients. Of note is that severe forms of FBA can be accompanied by an irreversible visual loss in case of delayed control of inflammation.

The current study suffers from a retrospective nature, short follow-up in many cases, absence of virological studies (human immunodeficiency virus, cytomegalovirus, herpes virus), serology for toxoplasma, or work up for either Crohn’s disease or blood dyscrasias. Also, there is a lack of a uniform therapeutic strategy because of changing vasculitis regimens over the past decade. Moreover, retina specialists may be geared for laser pan-retinal photocoagulation or intravitreal injections of vascular endothelial growth factor antagonists if FBA is mistaken for retinal venous occlusion (Case 13) [8]. Conservatively, uveitis specialists most often would initiate therapy with oral corticosteroids. However more recently there is a trend for use of intraocular dexamethasone implants or newly approved immunomodulators. Of note is that FMF can rarely present with serositis without fever [25] and that it can involve patients not originating around the Mediterranean basis such as Japan [25] or China [26]. Despite the early presentation of FMF, occasionally late presentations can occur [25] as in the current series and especially so in countries such as Japan or China [24].

In conclusion, FBA with severe visual loss as well as milder forms of retinal vasculitis is associated with FMF. Prompt systemic or local therapy with corticosteroid or dexamethasone implant alone or with concomitant systemic immunosuppression can restore vision. Colchicine therapy remains the best prophylactic tool to prevent retinal vasculitis. The current case series highlights the importance of the recognition of the association of FBA with FMF even outside the endemic areas of FMF.

Summary

What is known about this topic

  • Frosted branch angiitis is caused by infections (cytomegalovirus, Toxoplasma gondii).

  • Frosted branch angiitis is associated with Behcet disease, lupus and Crohn’s disease.

What this study adds

  • Frosted branch angiitis can be associated with familial Mediterranean fever in the absence of concomitant infection or autoimmune disease.

  • Frosted branch angiitis can present with severe visual loss in the context of familial Mediterranean fever either from retinal vasculitis and/or the presence of vitreous haemorrhage.

  • Prompt and prolonged therapy for several months with systemic corticosteroids is sight-saving.

  • Life-long colchicine therapy is essential in the control and prevention of retinal (or systemic) vasculitis in familial Mediterranean fever.