Familial Mediterranean fever is typically described as an autoinflammatory disease that can involve joints, skin, muscles, and kidneys; however, it is a predisposing factor for a variety of different inflammatory diseases involving other organs and systems [17]. Ocular inflammation is an uncommon entity reported in FMF [18]. In this study, five pediatric FMF patients with various OIDs were presented. Although uveitis and optic neuritis have been reported before, to the best of our knowledge, the first cases of ROM and acquired Brown’s syndrome observed in patients with FMF in the literature have been introduced [10, 19].
In this study, five cases with an OID among a cohort of 512 pediatric FMF patients seem as a meaningful frequency for the coexistence of both diseases. Although the overall prevalence of ocular inflammatory diseases is not known, the highest prevalence of pediatric noninfectious uveitis reported in the literature (0.03%) is lower than the frequency of uveitis in our cohort (0.39%) [20]. On the other hand, the risk of OID in FMF seems low compared to the frequency of other inflammatory diseases [21]. The etiology of OIDs includes infections, autoimmune, inflammatory, and malignant diseases; however, idiopathic inflammation constitutes the majority of cases [22]. Ocular inflammation has been infrequently observed in FMF and reported OIDs are not unique to this inflammatory syndrome. Besides, other concurrent diseases with FMF such as juvenile idiopathic arthritis or Behçet’s disease may complicate the definition of the underlying cause of OIDs. To date, ten cases with uveitis, eight with scleritis, three with optic neuritis, and three with frosted branch angiitis have been reported among OIDs in patients with FMF (Table 2). A recent study indicated foveal vascular abnormalities during an attack-free period in children with FMF whereas increased choroidal thickness with a significant correlation of C-reactive protein was found during an acute FMF attack in another study [23, 24]. In this study, investigations to find out the etiology of the diagnosed OID excluded all known secondary causes of OIDs. None of the patients had any other associated disease with FMF. Ocular inflammation was bilateral in four of the cases and all OIDs had recurrent and chronic courses. Moreover, one of the patients with uveitis had bilateral panuveitis that is an infrequent type of pediatric uveitis [25]. In two of the patients, typical FMF attacks and recurrences of OIDs were temporally associated. Based on these observations and case series in the literature, we may postulate that OIDs observed in FMF patients may be associated with increased inflammation of FMF. Substantial overlap between pathogenic mechanisms of both diseases seems possible.
Table 2
Summary of patients with familial Mediterranean fever concurrent with ocular inflammatory diseases in the medical literature
Author, year [reference] | No. of patients | Mutation | Type of OID (no. of patients) | Course of OID (no. of patients) | Other concurrent inflammatory diseases (no. of patients) | Treatment (no. of patients) |
Yazici, 1982 [30] | 1 | Unknown | Anterior uveitis and episcleritis | Recurrent | None | Colchicine, NSAIDs, systemic and topical steroids |
Scharf, 1985 [31] | 2 | Unknown | Episcleritis | One episode defined (2/2) | None | Colchicine, NSAIDs, topical steroids |
Hirsh, 1990 [32] | 1 | Unknown | Panuveitis | Recurrent | None | Colchicine (dose increased), systemic and topical steroids, surgery |
Lossos, 1993 [19] | 2 | Unknown | Optic neuritis | One episode defined (2/2) | None | Colchicine, systemic steroids (1) |
Akman, 2001 [9] | 2 (siblings) | Unknown | Panuveitis (1) Episcleritis (1) | Recurrent | None | Colchicine, NSAIDs, systemic and topical steroids, photocoagulation (1) |
Ozaltin, 2001 [13] | 1 | M694V/M694V | Anterior uveitis | One episode defined | None | Colchicine |
Berestizschevsky, 2008 [12] | 1 | Unknown | Episcleritis | One episode defined | None | Colchicine (dose increased), NSAIDs, systemic and topical steroids, mitomycin C, surgery |
Akalin, 2010 [27] | 1 | M694V/M694V | Episcleritis | One episode defined | None | Colchicine, systemic and topical steroids |
Satoh, 2010 [33] | 1 | Unknown | Frosted branch angiitis | One episode defined | None | Colchicine, systemic steroids |
Yazici, 2014 [10] | 6 | Unknown | Anterior uveitis (2) Posterior uveitis (2) Intermediate uveitis (1) Posterior scleritis (1) | Recurrent or chronic (5/6) | Behçet’s disease (2) | Colchicine, systemic and topical steroids, methotrexate (1), mitomycin C (1), cyclosporine A (2), photocoagulation (2), surgery for cataract (2) |
Petrushkin, 2015 [29] | 1 | Unknown | Intermediate uveitis | One episode defined | None | Colchicine (dose increased) |
Basaran, 2016 [14] | 1 | M694V/M694V | Optic neuritis | Recurrent | None | Colchicine (dose increased), systemic steroids, anakinra, kanakinumab |
Ozates, 2016 [11] | 1 | M694V/M694V | Frosted branch angiitis | Recurrent | None | Colchicine, systemic steroids, azathioprine, laser |
Chan, 2018 [34] | 1 | V726A | Frosted branch angiitis | One episode defined | None | Colchicine, systemic steroids |
Mansour, 2019 [35] | 1 | Unknown | Posterior scleritis | One episode defined | None | Colchicine, systemic steroids |
NSAID: Nonsteroidal Anti-Inflammatory Drug, OID: Ocular Inflammatory Disease |
Previous studies have thoroughly studied the genotype and phenotype correlation in FMF and shown that identified mutations do not always correlate with the clinical manifestations. On the other hand, carrying M694V mutation has been associated with a relatively severe disease course, an early disease onset, and a higher risk for concomitant diseases [26, 27]. Strikingly, M694V mutation has been the most frequently reported mutation in patients with FMF and OIDs in the literature [11, 13, 14, 28]. However, although the role of several inflammasomes has been discovered in the pathogenesis of several OIDs, the pyrin inflammasome has not been shown to be involved in any OIDs to date [29]. In the current study, all patients presented with typical FMF attacks at early ages and carried at least one M694V mutation.
Colchicine may not be effective in associated inflammatory diseases with FMF such as sacroiliitis and vasculitis and additional therapies to colchicine are usually needed [5, 27]. In the literature, several studies and case reports presented that topical and systemic corticosteroids and other immunosuppressants in addition to colchicine were needed to control ocular inflammation in FMF patients because of their recurrent and chronic courses (Table 2). Some rare instances recovered by regular use or an increased dose of colchicine [13, 30]. Similar to the literature, all of our patients experienced OIDs while on colchicine. Although three of them benefitted from systemic corticosteroids during the acute presentation of OID, ocular inflammation recurred after the withdrawal of steroids. An increased dose of colchicine and the addition of anti-IL-1 therapy in two of them provided a long-term remission. Unfortunately, both patients with uveitis experienced several recurrences and ocular complications despite the use of different immunosuppressants.
Limitations of our study could be its retrospective nature. Future multi-centered studies involving larger numbers of FMF patients may help to examine possible associations between FMF and ocular inflammation. Moreover, molecular studies for the identification of pathogenic pathways linking FMF to OIDs need further investigations.
In conclusion, there is insufficient data to indicate whether FMF is a disease that causes ocular inflammation. However, increased frequency of OIDs in FMF as per the pediatric population and relapsing and chronic course of OIDs occasionally with concurrent FMF attacks suggest that this inflammatory syndrome especially those carrying M694V mutations may be a predisposing factor for OIDs. Any ocular symptoms in patients with FMF should alert physicians for the coexistence of OIDs. Because OIDs are not specific for FMF, all possible underlying causes should be excluded.