The eye involvement in monogenic autoinflammatory diseases: literature review and update J. Sota1, A. Vitale1, C. Fabiani2, B. Frediani1, D. Rigante3, G.M. Tosi4, M.E. Zannin5, L. Cantarini1

1Research Centre of Systemic Auto- ABSTRACT leading to the up-regulation of proin- inflammatory Diseases, Behçet’s Disease Monogenic autoinflammatory diseases flammatory cytokines, especially inter- and Rheumatology- (AIDs) are rare entities characterised leukin (IL)-1β and tumour necrosis fac- Collaborative Centre, Department of Medical Sciences, Surgery and Neuro- by improper activation of the innate im- tor (TNF)-α (1, 2). The most common Sciences, University of Siena; mune system. This in turn determines monogenic autoinflammatory disorders 2Department of Ophthalmology, recurrent episodes of systemic inflam- include familial Mediterranean fever Humanitas Clinical and Research Centre, mation characterised by fever, which is (FMF), TNF receptor-associated peri- Rozzano (Milan); variously combined with a wide range odic syndrome (TRAPS), mevalonate 3Institute of Paediatrics, Università Cattolica Sacro Cuore, Fondazione Poli- of inflammatory manifestations involv- kinase deficiency (MKD), idiopathic clinico Universitario “A. Gemelli”, Rome; ing the skin, joints, serous membranes, granulomatous diseases, and cryopyrin- 4Ophthalmology Unit of the Department gastrointestinal tract, and central nerv- associated periodic syndrome (CAPS) of Medicine, Surgery and Neuroscience, ous system. As shown by research ef- (Table I). CAPS includes three differ- University of Siena; forts conducted during the last decade, ent clinical phenotypes: familial cold 5Department of Paediatrics, University of Padova, Italy. the eye is not exempt from the systemic autoinflammatory syndrome (FCAS), Jurgen Sota*, MD inflammatory process and may be in- Muckle-Wells syndrome (MWS), and Antonio Vitale*, MD volved in almost all of the most frequent chronic infantile neurologic cutane- Claudia Fabiani, MD AIDs, with several distinct peculiarities. ous and articular (CINCA) syndrome. Bruno Frediani, MD Ocular affections may severely impact These show increasing severity, with Donato Rigante, MD patients’ quality of life due to orbital FCAS being the least severe and CIN- Gian Marco Tosi, MD Maria E. Zannin, MD , impairment of , and/ CA the most severe. From a clinical Luca Cantarini, MD, PhD or long-term, sight-threatening compli- point of view, AIDs occur most often *J. Sota and A. Vitale have contributed cations. Consequently, in the context of during childhood, however, the delayed equally to this paper. a multidisciplinary team, ophthalmolo- onset of symptoms during adulthood Please address correspondence to: gists should be aware of ocular mani- has commonly been reported (3, 4). Luca Cantarini, MD, PhD, festations related to these disorders as All AIDs are characterised by recurrent Research Centre of Systemic Auto- they may have a dominant diagnostic fever episodes and increased inflamma- inflammatory Diseases, Behçet’s Disease weight in patients with a challenging tory markers variously combined with and Rheumatology-Ophthalmology Collaborative Uveitis Centre, presentation as well as a salient role skin rash and inflammatory episodes Department of Medical Sciences, in therapeutic choice in sight-threat- affecting the joints, serous membranes, Surgery and Neurosciences, ening situations. This review describes gastrointestinal tract, eyes, and cen- University of Siena, Rheumatology a variety of aspects of ophthalmologic tral nervous system (5). Conversely, a Unit, Policlinico “Le Scotte”, involvement in AIDs, looking at both complete wellbeing with normal acute viale Bracci 1, 53100 Siena, Italy. E-mail: [email protected] well-recognised eye manifestations as phase reactants characterise inter-crit- Received on November 27, 2017; accepted well as rarely reported ocular presen- ical periods (6). However, AIDs can on December 7, 2017. tations, with a particular focus on the sometimes acquire a chronic course, Clin Exp Rheumatol 2018; 36 (Suppl. 110): recent literature. especially in cases related to low-pen- S44-S53. etrance mutations, which often lead to © Copyright Clinical and Introduction adult-onset manifestations and incom- Experimental Rheumatology 2018. Autoinflammatory diseases (AIDs) plete or atypical phenotypes (7). Taken embrace an expanding group of rare together, the rarity of AIDs and their Key words: autoinflammatory disorders characterised by seemingly relatively low knowledge among physi- diseases, uveitis, , unprovoked episodes of self-limited cians along with the broad spectrum of pigmentosa, inflammatory attacks with no infec- possible clinical presentations and the tious agents, autoreactive T cells or au- need for a careful and correct genotype- toantibodies observed. The pathogen- phenotype correlation, may complicate esis of AIDs is hallmarked by genetic the differential diagnosis in patients Funding and competing interests mutations of proteins involved in the with suspected AIDs thus causing a de- on page S-52. modulation of the innate immunity and lay in diagnosis (8-10).

S-44 Clinical and Experimental Rheumatology 2018 Ocular involvement in AIDs / J. Sota et al.

Table I. Genetic and clinical features of the main autoinflammatory diseases.

AID Gene/Locus Inheritance Protein Fundamental clinical clues

FMF MEFV/16p13.3 AR Pyrin Fever, serositis, arthralgia or arthritis generally affecting large joints, erysipela-like rash, amyloidosis in untreated patients

TRAPS TNFRSF1A/12p13 AD Tumour necrosis factor Fever, migrating erythematous skin rash, muscle pain in the form of receptor 1 fasciitis, , periorbital oedema, arthralgia or arthritis, serosal involvement, amyloidosis

MKD MVK/12q24 AR Mevalonate kinase Fever, polymorphous rash, arthralgia, abdominal pain, diarrhoea, lymph node enlargement, splenomegaly, aphtosis

MA MVK/12q24 AR Mevalonate kinase Psychomotor retardation and growth delay, progressive cerebellar ataxia, dysmorphisms, vision deficits, MKD symptoms

FCAS NLRP3/1q44 AD Cryopyrin Fever, cold-induced urticarial rash, conjunctivitis, arthralgia

MWS NLRP3/1q44 AD Cryopyrin Fever, urticarial rash, conjunctivitis, , arthralgia, sensorineural deafness, amyloidosis

CINCA NLRP3/1q44 AD Cryopyrin Fever, urticarial skin rash, uveitis, , deforming arthritis mainly involving large joints, chronic aseptic meningopathy, sensorineural hearing loss, amyloidosis

Blau syndrome NOD2/16q12.1-13 AD Nucleotide-binding Arthritis, skin rash, granulomatous inflammatory ocular involvement oligomerisation domain 2

AD: autosomal dominant; AID: autoinflammatory disease; AR: autosomal recessive; CINCA: chronic infantile neurologic cutaneous and articular syn- drome; FCAS: familial cold autoinflammatory syndrome; FMF: familial Mediterranean fever; MA: mevalonic aciduria; MEFV: MEditerranean FeVer; MKD: mevalonate kinase deficiency; MVK: mevalonate kinase; MWS: Muckle-Wells syndrome; NLRP3: NACHT, LRR and PYD domains-containing protein 3; NOD2: nucleotide-binding oligomerisation domain 2; TNFRSF1A: tumour necrosis factor receptor super family 1A ; TRAPS: tumour necrosis factor-associated periodic syndrome.

Ocular involvement in AIDs may have is represented by recurrent episodes of main optic coherence Tomography (SD- distinct peculiarities (Table II). Figure 1 fever generally lasting 48–72 hours, OCT) (23). Although no significant dif- illustrates some of the most representa- inflammation of one or more serosal ferences were found between FMF pa- tive eye lesions of monogenic AIDs. membranes, a non-destructive arthritis tients and a control group, the authors Ocular affections may severely impact usually involving one large joint of the highlighted the necessity to perform the quality of life due to orbital pain, lower limbs, and skin manifestations ocular evaluation during FMF attacks. impairment of visual acuity and/or mostly in the form of erysipelas-like In this regard, Gundogan et al. carried long-term, sight-threatening complica- rash (21). Over time, this basilar clinical out a prospective case-controlled clini- tions. Hence, an increased awareness of phenotype of FMF has been expanded cal study evaluating CT during acute AIDs is warranted among ophthalmolo- with other clinical features including attacks in 50 patients suffering from gists in order to achieve an early diag- ocular involvement. The earliest pa- FMF (14). This study identified a sig- nosis and optimal ocular management. per on ophthalmologic affections was nificantly thicker in FMF pa- The last decade has seen a number of published in 1959 by Michaelson and tients compared with healthy controls. interesting findings published on ocular colleagues, who described dotted le- Moreover, CT was positively corre- involvement in AIDs (11-20). Herein, sions consistent with colloid bodies on lated with inflammatory biomarkers, we review the current knowledge on routine funduscopic examination in 13 and especially C-reactive protein. The this issue and provide a broad overview out of 23 patients; slit-lamp microscopy systemic inflammatory process during on the possible presentations of ocular subsequently localised the lesions in the acute attacks and the following increase affections in these rare diseases. Bruch’s lamina (22). Another patient of vascular permeability, choroidal ves- displayed an ocular fundus with a solid- sels enlargement and exudation may be Familial Mediterranean fever looking mulberry-like mass thought to responsible for the increase in CT with FMF is an autosomal recessive autoin- originate from an adjacent colloid body more impact during acute attacks rather flammatory disorder caused by muta- (22). In 2014, a Turkish working group than during symptom-free intervals tions of the MEFV gene, encoding the investigated retinal and choroidal thick- (14). However, other authors have sug- pyrin protein. This immunoregulatory ness (CT) in 30 FMF children by meas- gested the possible occurrence of con- molecule, also known as marenostrin, uring each subject’s right eye at the fo- founding factors behind the increase of is involved in the regulation of inflam- vea and horizontal nasal and temporal CT including the high body temperature mation, cytokine production, and apop- quadrants at 500 mm intervals to 1500 during attacks and possible toxic conse- tosis. The cardinal phenotype of FMF mm from the foveal using spectral-do- quences of treatment on choroidal tis-

Clinical and Experimental Rheumatology 2018 S-45 Ocular involvement in AIDs / J. Sota et al.

Table II. Current knowledge on ocular involvement in monogenic autoinflammatory diseases.

Disease First Author, year (ref) Patients with Mutations Ocular description ocular involvement/ Sample size

Michaelson, 1959 (22) 14/24 NK Fundal lesions resembling colloid bodies in Bruch membrane

Erdurmus, 2014 (23) 30 pts NK No pathological changes in choroidal thickness during well-being periods Gundogan, 2016 (14) 50 pts NK Increased choroidal thickness during acute attacks Georgakopoulos, 2016 (27) 1/1 M694V/0 Acute posterior multifocal placoid pigment epitheliopathy

FMF Kosker, 2016 (16) 4/100 3 hom M694V 1 het M694V/M680I Yazici, 1982 (28) 1/1 NK Acute AU and episcleritis Yazici, 2014 (20) 6/6 NK 1 posterior scleritis, 2 AU, 1 IU, 2 PU Ocular complications: CME, epiretinal membranes, BK, , , and retinal ischaemia Petrushkin, 2015 (30) 1/1 NK IU

Toro, 2000 (33) 11/25 NK Conjunctivitis and PE Lachmann, 2014 (8) 71/158 NS (less likely to carry R92Q) 35 conjunctivitis, 32 PE, 20 periorbital pain Halligan, 2006 (35) 1/1 R92Q swelling and subepithelial, anterior stromal whorl-like deposits consistent with the concomitant Fabry

TRAPS disease Rösen-Wolff, 2001 (34) 3/3 2 C30R Conjunctivitis, /papillitis 1 T50M

Prietsch, 2003 (39) 3/3 2 hom A334T, 1 het A334T Nuclear cataract, retinal dystrophy, and optic atrophy plus 72insT* Simon, 2004 (40) 4/5 2 het V377I/W62X and progressive tapetoretinal degeneration 1 het A334T/H20P 1 het A334T/W62X Balgobind, 2005 (37) 1/1 Compound het 421insG* RP and A334T

MKD Wilker, 2010 (41) 1/1 NK RP-like and punctate cataract Siemiatkowska, 2013 (18) 3 pts 1 hom A334T RP and posterior subcapsular cataract 2 het I268T/A334T Kellner, 2017 (15) 2/2 het H20P/A334T RP and early onset of cataract Durel, 2016 (38) 3/23 NS 3 conjunctivitis, 2 uveitis, 2/23 1 optic neuritis 1/23

Dollfus, 2000 (43) 31 pts NK Papilledema, pseudopapilledema and optic atrophy; chronic AU, vitritis, vasculitis; BK, stromal infiltration, corneal neovascularisation, cataract. Rigante, 2010 (44) 1/1 NK Post-inflammatory retinal dystrophy Terrada, 2011 (45) 1/1 D303N Bilateral anterior, nummular, stromal ; bilateral papilledema Hirano, 2015 (46) 1/1 D303N Stromal keratitis and uveitis, pale , sheathed retinal arteries, yellowish deposits in the posterior pole Kawai, 2013 (47) 1/1 D303N Conjunctival and episcleral injection plus bilateral optic disc swelling and retinal vascular sheathing around the optic disc Alejandre, 2014 (49) 3/3 R260W Conjunctivitis, , uveitis Naz Villalba, 2016 (48) 1/1 T348M Bilateral papilledema Oberg, 2013 (63) 2/2 R260W, T436A Conjunctivitis, AU, bilateral papilledema and PanU Shakeel, 2007 (50) 1/1 A439V AU CAPS Espandar, 2014 (51) 3/3 NK Bilateral central stromal scarring with diffuse anterior stromal white blood cell infiltration Levy, 2015(7) 97/136 NS Conjunctivitis, uveitis, atrophy, cataract, glaucoma, papilledema Eroglu, 2016 (13) 6/14 I572F, Y570H, G569R, Papilledema, optic atrophy, scleritis, severe iridoscleritis, 2 patients with T436A, uveitis 1 genetically negative patient Mehr, 2016 (10) 8/18 M662T, I572F, Y570C, Papilledema T436N, R260W, 2 patients with T348M, 1 patient not tested Sobolewska, 2016 (19) 24/29 A439V in 15 patients, Conjunctivitis, uveitis, ocular rosacea 9 genetically negative patient

S-46 Clinical and Experimental Rheumatology 2018 Ocular involvement in AIDs / J. Sota et al.

Table II. continued

Disease First Author, year (ref) Patients with Mutations Ocular description ocular involvement/ Sample size

Arvesen, 2017 (53) 1/1 R334Q Granulomatous uveitis Milman, 2009 (58) 4/4 T605N AU, bilateral PanU, , scleritis, corneal opacities, retinal disruption Jimenez-Martinez, 2011 (56) 1/1 M513R BK and PanU Raiji, 2011 (59) 1/1 D382E Numerous small, white, corneal subepithelial ovoid opacities and conjunctival nodules and later a fulminant PanU Zeybek, 2015 (60) 1/1 P507S Granulomatous AU Kim, 2016 (57) 2/2 H480R AU, multiple mild subepithelial opacities on both eyes along with focal posterior Jain, 2016 (55) 1/1 E667K Right eye: non-granulomatous AU with vitreous haemorrhage Left eye: chronic AU, multiple granuloma, and

BS complicated cataract Achille, 2016 (62) 1/1 het P268S/SNP5 Bilateral granulomatous PanU Carreño, 2015 (11) 9/9 6 het R334Q/wt 5 PanU, 3 AU, 1 IU 1 het Q809K/wt Optic nerve and retinal features: pale optic disc in 6 eyes, 1 het H520Y/wt indistinct margins in 6 eyes, sheathed optic disc vessels in 4 1 compound het E383D*/D390V eyes, nodular excrescences in the peripapillary area in 13 eyes, hypopigmentation in 6 eyes and mixed hypo- and hyperpigmentation in 7 eyes Ebrahimiadib, 2016 (12) 6/6 E600A Bilateral non-granulomatous PanU, bilateral retinal vasculitis, papillitis and scleritis Rosé, 2015 (17) 25/31 NS AU, IU, 64% active vitreous inflammation, 18% active chorioretinitis, 5% active retinal vasculopathy. Complications: 64% synechiae, 55% cataract, 36% IOP, 23% BK, 14% macular oedema, 9% .

AU: anterior uveitis; BK: ; BS: Blau syndrome; CAPS: cryopyrin associated periodic fever; CME: cystoid macular oedema; FMF: familial Mediterranean fever; het: heterozygous; hom: homozygous; IOP: increased ; IU: ; KC: keratoconus; MKD: meva- lonate kinase deficiency; NK: not known; NS: not specified for patients with ocular involvement; PanU: panuveitis; PE: periorbital oedema; PU: posterior uveitis; pts: patients; RP: ; TRAPS: tumour necrosis factor receptor-associated periodic syndrome; wt: wild type. *not found in Infevers (http://fmf.igh.cnrs.fr/ISSAID/infevers/). sues (24, 25). In particular, a disruption prevalence of KC was higher in FMF Cystoid macular oedema, epiretinal of microtubules within retinal nerve patients than in a control group; 4 out membranes, band keratopathy, cataract, fibre layer axons was manifested asa of 100 FMF patients were affected by branch retinal vein occlusion, neovas- reduced birefringence on scanning laser KC, whereas none of the 300 patients cularisation, and glaucoma were also polarimetry without abnormalities on in the control group were affected (16). reported as ocular complications. It is retinal nerve fibre layer thickness meas- Furthermore, when compared with the noteworthy that 3 out of 6 patients pre- ured by OCT (26). highest prevalence reported in the lit- sented a relapsing course, in line with An interesting case report presented the erature, FMF was shown to be a pre- the recurrent nature of FMF (20). How- association of FMF with acute poste- disposing factor for the development ever, 2 patients were also diagnosed rior multifocal placoid pigment epithe- of KC, especially in patients carrying with Behçet’s disease (BD), as FMF liopathy (APMPPE) in a patient with homozygous mutations (16). and BD can coexist (29). A second case bilateral blurred vision and scotomata. With reference to uveal tract inflam- of intermediate uveitis was reported by As APMPPE was believed to be caused mation, Yazici and Pazarli described a Petrushkin et al. who described a female by an occlusive choroidal vasculitis, patient with FMF who developed acute patient with FMF complaining from and given the increased frequency of anterior uveitis in the left eye and epis- sudden in the right eye (30). In vasculitis in FMF patients, the authors cleritis ten months later (28). Because of any case, a careful diagnostic approach presumed there was a link between the two different forms of eye involve- is warranted in patients with FMF and APMPPE and FMF (27). ment, the authors were tempted to spec- uveitis in order to rule out concomitant FMF is also considered to be a predis- ulate a possible relationship between systemic disorders that may clinically posing factor for the development of ocular inflammation and FMF. Follow- overlap with FMF (20, 21). keratoconus (KC), especially in patients ing this, a case series on FMF patients carrying homozygous mutations of the with ocular involvement described 2 TNF receptor-associated periodic MEFV gene. A possible interaction be- cases with anterior uveitis, 2 with poste- syndrome tween FMF and KC was identified in rior uveitis, 1 with intermediate uveitis, TRAPS, the most common among the 2016 by Kosker et al. who showed the and 1 case with posterior scleritis (20). autosomal dominant AIDs, is caused

Clinical and Experimental Rheumatology 2018 S-47 Ocular involvement in AIDs / J. Sota et al.

Fig. 1. Representative eye lesions in the monogenic autoinflammatory disorders. (A) Swelling and peripapillary retinal oedema with haemorrhagic papillitis. (B) Retinal vasculitis. (C-D) Diffuse microvascular choriocapillaris vasculitis showing leakage of fluorescein during fluorescein retinal angiography. (E-F) Diffuse anterior necrotising scleritis resulting in scleromalacia. (G) with scleral thinning. (H) Diffuse anterior non-necrotising scleritis. (I) Granulomatous anterior uveitis. (J) Posterior irido-capsular synechiae. (K-L) in the anterior chamber. From Bascherini et al. 2015 (5). by mutations in the TNFRSF1A gene, patients identified periorbital oedema, was identified at physical examination, which encodes for the 55 kDa type-1 re- periorbital pain, and conjunctivitis in while an ophthalmologic examination ceptor of TNF-α. From a clinical point 20%, 13%, and 22% of 158 subjects, revealed subepithelial, anterior stromal of view, this syndrome is characterised respectively (8). Moreover, periorbital whorl-like deposits, which is a charac- by recurrent inflammatory episodes oedema tended to be significantly more teristic finding of Fabry disease. The lasting several weeks with a various common in paediatric patients as well authors suggested that the two genetic combination of the following symp- as in adults with a disease onset during diseases may interact, potentially wors- toms: fever, migrant erythematous childhood. With regard to genotype- ening the clinical phenotype (35). rash, myalgia, lymphadenopathy, artic- phenotype correlations, eye manifesta- ular symptoms mainly represented by tions were less frequently encountered Mevalonate kinase deficiency arthralgia, pleuritic and abdominal pain in patients carrying the R92Q low-pen- The second most important autoin- that may sometimes lead to exploratory etrance mutation (8). flammatory disorder with recessive laparotomy (31, 32). Ophthalmologic A sporadic case of optic neuritis/papil- inheritance is represented by MKD, features have contributed to further ex- litis has also been reported in a German determined by mutations in the MVK pand the heterogeneous phenotype of patient harbouring the C30R mutation gene. The MVK gene encodes for me- TRAPS. Periorbital oedema and con- who also developed fever, arthritis, skin valonate kinase, a crucial enzyme for junctivitis are the most common ocular rash myocarditis, and occasional diar- the nonsteroidal isoprenoids biosyn- manifestations. In this regard, Toro et rhoea (34). thesis, which in turn determines protein al. described conjunctivitis and/or peri- An interesting association between prenylation. The described metabolic orbital oedema in 11 out of 50 TRAPS TRAPS and Fabry disease was re- defect triggers innate immunity hyper- patients in a study conducted on 16 ported by Halligan and colleagues in responsiveness ultimately leading to re- families (33). Accordingly, based on which a 9-year-old boy presenting current multi-systemic inflammatory at- data from the Eurofever/EUROTRAPS with symptoms consistent with TRAPS tacks classically characterised by fever, international registry, the largest case was found to carry the R92Q mutation painful adenopathy, arthralgia, rash, and series currently published on TRAPS (35). Among others, eyelid swelling abdominal pain that may sometimes

S-48 Clinical and Experimental Rheumatology 2018 Ocular involvement in AIDs / J. Sota et al. require surgical examinations for pos- MKD can even be misdiagnosed as exhibited opacification and nu- sible acute abdomen. Currently, more nonsyndromic RP, which might rep- clear cataract within 1–2 days (42). In than 200 sequence variants of the MVK resent the presenting feature in such particular, water and sodium accumu- gene have been associated with MKD, patients. In this regard, a proband of lated in the lenses, which lost soluble with most of them being single-nucle- Dutch origin with RP was found to carry gamma crystallin proteins and potas- otide polymorphisms that lead to mis- MVK mutations in a study by Siemiat- sium. Meanwhile, lenses lost the capac- sense mutations. To date, the disease is kowska and colleagues; the MVK gene ity to concentrate a potassium analogue considered as a phenotypic continuum was subsequently tested in the patient’s (86Rb), possibly due to a slow poisoning of increasing severity according to the family and in a large cohort of patients of the cation pump, an effect on mem- degree of residual enzymatic activity. It with nonsyndromic, genetically un- brane integrity or both (42). ranges from the milder form, hyper IgD solved RP (18). This study identified 3 Other ocular manifestations, including syndrome (HIDS), to the most severe subjects from 2 families with nonsyn- uveitis and optic neuritis, have been variant known as mevalonic aciduria dromic RP who were found to have a reported. An observational multicentre (MA) (Table I). In its severest vari- mutation in the MVK gene. A detailed study aimed at classifying clinical and ant, the clinical phenotype may also be medical history revealed a mild form biological features of MKD in adult- expressed by facial dimorphisms and of MKD despite a significantly lowered hood reported 3 patients with conjuncti- central nervous system involvement mevalonate kinase activity, leading to vitis, 2 of them with uveitis, and 1 case including seizures, ataxia, myopathies, misdiagnosis even among expert clini- of optic neuritis (38). and psychomotor retardation (36). cians (18). Ophthalmologic features have contrib- Recently, 2 brothers of German extrac- Cryopyrin-associated periodic uted to MKD clinical heterogeneity as tion with a compound heterozygous syndromes its clinical spectrum continues to ex- MVK mutation (H20P/A334T) were CAPS represents a group of monogenic pand (15, 18, 37-41). In a study by Pri- described in the first paper reporting an AIDs caused by de-novo or dominantly etsch et al., which investigated 3 MA association of MKD and RP with early inherited gain-of-function missense patients with retinal dystrophy (RD), cataract development (15). As for the mutations of the NLRP3 gene. CAPS cataract accompanied RD in 2 siblings cases illustrated by Siemiatkowska and encompasses three overlapping syn- while optic atrophy was a supplementa- colleagues (18), a relatively mild phe- dromes sharing general anchor points ry finding in the third patient (39). Ocu- notype was reported despite the severe and presenting an increasing disease lar involvement, along with ataxia and effects of the A334T mutation, further severity that ranges from FCAS, the short stature, became predominant in suggesting the probable influence of milder form, to CINCA, the most se- patients surviving infancy, suggesting additional genetic and environmental vere variant (13). an age-dependent phenotype expres- factors on disease manifestation. An increasing number of studies have sion. For all these reasons, Prietsch et On this basis, the currently proposed explored the inflammatory eye involve- al. suggested ocular electrophysiology pathogenetic mechanism behind the ment in patients with CAPS. In this as an integral part of diagnostic evalua- non-random association between MKD regard, a relevant study on 136 CAPS tion in order to detect retinal disorders and RP resides in an impaired isopre- patients has been recently published in patients with MA (39). Simon et al. nylation, which probably interferes with the aim to retrospectively analyse also reported progressive blindness due with macromolecules that are essential demographic, genetic, and clinical data, to tapetoretinal degeneration and cata- for the function of photoreceptors (37). and to investigate genotype-phenotype ract in 4 patients with MKD (40). It is noteworthy that most of the MKD correlations (7). Ophthalmologic in- As supported by several reports in the patients with concomitant RP harbour volvement was described in 71% of medical literature (15, 18, 37), retinitis the A334T (c.1000G>A) in exon 10 of the patients. Specifically, 9 patients pigmentosa (RP) is the most notewor- the MKV gene (15, 18, 37, 39, 40), thus presented uveitis and 87 had conjunc- thy ocular disease connected to MKD, suggesting a potential genotype-phe- tivitis; in 16 cases, ocular manifesta- and particularly to MA. Night blindness notype correlation. Therefore, ophthal- tions were deemed severe and reported with funduscopic and full-field electro- mological examination and instrumen- as impaired vision (n=8), optic nerve retinogram findings suggestive of RP tal ocular evaluation should be recom- atrophy (n=6), cataract (n=4), and was reported in a patient with MKD mended for all patients with MKD. glaucoma (n=2). Although not statisti- (37). In addition, RP-like retinopathy The identification of cataract represents cally explored, severe ophthalmologic connected with MA was diagnosed an interesting finding, which deserves manifestations were more frequent in on the basis of Goldmann visual field attention in MKD patients (15, 39-41). carriers of rare variants. Papilledema, constrictions and full-field electroreti- A possible explanation for cataract reported as neurologic manifestation, nogram after a patient complained of could be a direct toxic effect of meva- was identified in 29 patients (7). and decreased peripheral lonic acid rather than an osmotically- With respect to the clinical features of vision; ophthalmologic evaluation also induced opacification. Indeed, young CINCA, a nonpruritic urticarial skin revealed findings fitting with punctate rat lenses cultured for up to 4 days in rash, generally occurring before the 6th cataracts (41). a medium containing mevalonic acid month of life, is usually the present-

Clinical and Experimental Rheumatology 2018 S-49 Ocular involvement in AIDs / J. Sota et al. ing sign. The urticarial rash is often in a CAPS patient with conjunctival manifestations were positively corre- followed by articular manifestations and episcleral injection in both eyes, lated with headache and skin rash and responsible for joint and bone deformi- and inflammatory cells in the anterior were significantly more frequent in ge- ties over the long-term. Additional chamber; the patient also had bilateral netically positive subjects than in their features may expand the protean spec- optic disc swelling and retinal vascular genetically negative relatives. trum with neurological abnormalities, sheathing around the optical discs (47). A severe form of ocular involvement including, chronic aseptic meningitis A focus on ocular manifestations was may even occur in patients with FCAS, and sensory organ involvement with carried out in a two-centred descriptive the mildest form of CAPS. An associa- progressive sensorineural hearing loss study, which described clinical and ge- tion between FCAS and keratitis was and (43). Several types of netic features in a large cohort of Turk- reported in 2014, with bilateral corneal ocular involvement have also been de- ish paediatric patients with CAPS (13). scars and leukocyte infiltration on slit scribed in the CINCA syndrome. An Among the initial clinical findings, eye lamp examination described in 3 family international collaborative descriptive affections were identified in 6 out of 14 members with FCAS (51). case-report study carried out on 31 pa- children. Three of these patients, clas- Ocular involvement in MWS and FCAS tients found optic disc changes as the sified as suffering from severe CAPS, can be as severe as that usually attrib- most common ocular finding in CINCA exhibited papilledema and optic atro- uted to CINCA (48, 51). Indeed, careful (43). Indeed, 84% of enrolled subjects phy; 2 patients showed uveitis and the ocular assessment may reveal serious presented with optic disc abnormalities remaining patient had a severe irido- issues, including interstitial keratitis including fluorescein angiogram-doc- scleritis. One of the patients with uvei- and uveitis, which may necessitate the umented optic disc oedema in 13 out tis had no mutations (13). use of biologic agents to avoid ocular of 31 cases, papilledema in 7 out of 31 A recent study, which described epi- complications (48). patients, and moderate to severe diffuse demiological, clinical, and treatment optic atrophy in 9 out of 31 cases. The characteristics of 18 Australian patients Blau syndrome involvement of the posterior segment affected by CAPS, identified papillede- Both the familial and sporadic forms was less frequent, with macular oede- ma in 7 out of 8 CINCA patients and of the dominantly inherited granuloma- ma found in 4 patients, retinal vasculitis in 1 out of 8 patients diagnosed with tous AIDs, defined as Blau syndrome in 3 patients, focal choroiditis in 1 pa- MWS; this resolved after biologic treat- (BS) and early-onset (EOS) tient, and vitritis in 4 patients. Anterior ment in 75% of cases (10). Similarly, respectively, are caused by gain-of- pole abnormalities were also described: bilateral papilledema was identified in function mutations in the nucleotide 13% of patients exhibited dry eye and a MWS patient, which improved after oligomerisation domain (NOD)-2 gene, 42% displayed corneal involvement in 3 months’ treatment (48). Ophthalmo- mainly identified in the NATCH region the form of band keratopathy, stromal logical examination on 3 family mem- (Table I) (3, 52). Typically, outbreaks infiltration, corneal vascularisation, and bers with MWS identified reticulated occur during childhood and are charac- cataract (43). On this basis, ophthal- mid-stromal changes without corneal terised by non-caseating inflammatory mologists should be familiar with the opacification in the proband and bilat- granulomatous structures in the skin, complex ocular profile of CINCA and eral central corneal opacification in her joints, and uveal regions (3). Blurred constitute an integral part in the man- mother and younger sister; an analysis vision, ocular pain, and agement team. Notably, complicated of their personal history showed that are the most common ophthalmologi- sight-threatening events, such as post- they had also suffered from episcleritis, cal complaints (53). BS carries a severe inflammatory retinal dystrophy, may keratitis, and uveitis (49). ocular morbidity (17) and is associ- severely impair visual acuity (44). The first association of MWS with an- ated with a poor visual outcome (54). Corneal infiltrates were first reported by terior uveitis was described in 2007 Patients harbouring the R334W and Terrada et al. in a patient with CINCA when Shakeel and Gouws reported a R334Q mutations seem to be particu- in which biomicroscopy re- patient carrying the A439V mutation larly prone to developing panuveitis vealed bilateral anterior nummular stro- who complained of photophobia and and have a worse visual prognosis (54). mal keratitis, and a fundus examination blurred vision with keratic precipi- However, novel mutations reported was evocative of bilateral papilledema tates and hypopyon (50). The A439V in several case reports and small case (45). This last finding justified a perma- mutation was also identified in a ret- series of patients with BS have also nent visual loss due to optic nerve fibre rospective, observational cohort study highlighted an important impairment of alteration despite a dramatic ophthal- specifically focused on ocular symp- visual function (12, 53, 55-60). mologic improvement. Corneal infiltra- toms in 37 members of a 5-generation The first report of the T605N mutation in tion has also been reported by Hirano et family (19). Eye involvement, repre- the NOD2 gene was described in 4 mem- al. who described stromal keratitis and sented by conjunctivitis followed by bers of a Norwegian family with BS, who uveitis in a female patient with CIN- anterior uveitis, was the second most showed a wide range of eye involvement CA (46). Of note, both patients were common finding after musculoskeletal comprising bilateral panuveitis, anterior found to harbour the D303N mutation affections; ocular rosacea was also de- uveitis, scleritis, retinal disruption, and a (45, 46). This mutation was also found scribed in 8 patients. Ophthalmologic case of (58).

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Immunological features of BS at aque- and ocular findings in 31 BS patients hypo-pigmentation accompanied by ous humour, vitreous and blood levels (17). A total of 25 patients (81%) had nodular excrescences in the peripap- were initially analysed in 2011 in a BS ocular involvement and all patients pre- illary area were also noted in 6 and 7 patient with non-pruritic cutaneous rash sented with anterior uveitis during their eyes, respectively. The nodular aspect and polyarthritis, who subsequently de- disease course. Posterior and interme- was related to the granulomatous nature veloped bilateral band keratopathy and diate uveitis were recorded in 72% and of the inflammatory process and was panuveitis (56). The particular ocu- 52% of these patients, respectively, and also identified in patients with ante- lar milieu enriched in IL-6 and IL-8, active vitreous inflammation was iden- rior uveitis. It was concluded that optic along with a differential expression of tified in 64% of the cohort. Synechiae nerve abnormalities can be more often chemokine receptors on T cells, were and cataract complications were identi- associated with BS than previously rec- found to be related to the novel M513R fied in more than half the patients with ognised and screening for mutations in mutation in the NOD2 gene. anterior uveitis; the NOD2 gene, in cases of characteris- Numerous small and white corneal and band keratopathy were recorded in tic retinal and optic disc changes, was subepithelial opacities and conjuncti- 36% and 23% of patients, respectively. recommended (11). Ocular inflamma- val nodules were observed in a 2.5-year Complications of posterior uveitis in- tion and joint involvement represent the old female, previously misdiagnosed as cluded macular oedema, optic atrophy, main clue that guide therapy, as early an atypical juvenile idiopathic arthritis, and retinal detachment (17). treatment is required to prevent articu- who presented with a complicated oph- Unlike skin rash, which is usually the lar sequelae and visual loss (12, 54, 59). thalmologic history (59). The patient earliest feature of BS, eye disease rarely later developed a fulminant refractory constitutes the presenting symptom and Conclusions panuveitis. Based on the clinical pres- is usually the last of the triad to emerge Considering their protean clinical spec- entation, genetic testing was performed (54, 56, 57, 59, 60). However in select- trum, AIDs are rare entities that may which confirmed the diagnosis of BS ed cases, uveitis may precede other dis- present to a wide variety of care profes- and identified the D382E mutation, ease manifestations (55) or even repre- sionals, including ophthalmologists. On which had been reported only once pre- sent the first sign of BS, which may be the basis of current knowledge, ocular viously in the literature (59). later diagnosed via genetic testing. As involvement in AIDs should not be dis- Similarly, Zeybek et al. illustrated the a case in point, genetic and molecular regarded and ophthalmologists should case of a 5-year old male initially diag- testing in a family with 7 members af- be aware of ocular manifestations re- nosed with juvenile idiopathic arthritis fected with refractory uveitis revealed a lated to these disorders. Indeed, dif- and found thereafter to have BS in the novel mutation converting glutamate to ferential diagnosis may be challenging light of granulomatous anterior uveitis alanine in amino acid 600 (E600A) and even among expert clinicians (9) and revealed at an ophthalmologic exami- an increased basal activity of NOD2, re- recognition of peculiar features may nation; genetic testing determined the spectively (12). In 6 out of the 7 symp- represent the turning point. In addition, identification of a novel P507S muta- tomatic family members, uveitis was ocular examination can reveal a seri- tion in the fourth exon of NOD2 gene the first disease manifestation and all of ous involvement, such as uveitis and (60). them suffered from panuveitis, although interstitial keratitis, even in the con- The mutational spectrum of BS has re- with a non-granulomatous type. It was text of mild AIDs phenotypes (48, 51). cently been expanded with further novel postulated that in this subset of BS with In these cases, a prompt and careful mutations identified. Specifically, 2 sib- adult onset and uveitis dominancy, the multisystem workup including ocular lings who developed erythematous skin E600A mutation was responsible for a examination can considerably improve rashes and uveitis were found to carry higher penetrance of uveitis and an ear- the patients’ prognosis and quality of the novel H480R mutation in the NOD2 ly onset of ocular involvement (12). To- life. To this extent, the ophthalmologist gene (57). Interestingly, although uvei- gether, these data suggest that atypical may have a dominant diagnostic weight tis is generally the last BS manifesta- or incomplete forms of BS/EOS should and a salient role on therapeutic choice, tion to emerge (54, 56, 57, 59, 60), one be taken into account as possible diag- thus bringing considerable benefits to of the siblings displayed an early onset noses when facing chronic granuloma- disease evolution. However, as almost ocular involvement. In addition, the tous uveitis (62). all available studies are small case se- NOD2 common variant, P268S/SNP5, Furthermore, other ocular structures, ries or present a retrospective design, was identified as potentially associated such as the optic nerve and retinal tis- many critical issues remain unsolved with chronic uveitis in a study of 25 sues, may be affected in BS. In a study and further research on this topic is re- Italian patients suffering from inflam- which specifically examined optic quired to clarify unmet needs for strong matory eye involvement compared with nerve and in 17 eyes from 9 BS evidence-based conclusions. 25 healthy controls (61). patients, indistinct disc margins were The first international, prospective co- identified in 6 eyes, and optic nerve Acknowledgments hort study of BS was a 3-year, multi- head pallor in 6 eyes; 4 eyes exhibited The authors acknowledge Dr Melanie centre, observational study designed sheathed optic disc vessels (11). Hypo- Gatt for Health Publishing & Services to report baseline articular, functional, pigmentation and a mixed hyper- and Srl, for her English language assistance.

Clinical and Experimental Rheumatology 2018 S-51 Ocular involvement in AIDs / J. Sota et al.

Funding 12. EBRAHIMIADIB N, SAMRA KA, DOMINA AM 26. FORTUNE B, WANG L, CULL G, CIOFFI GA: This paper is part of a supplemental is- et al.: A Novel NOD2-associated Mutation Intravitreal colchicine causes decreased and Variant Blau Syndrome: Phenotype and RNFL birefringence without altering RNFL sue supported by an unrestricted grant Molecular Analysis. Ocul Immunol Inflamm thickness. Invest Ophthalmol Vis Sci 2008; from Novartis Farma, Italy through a 2016; 15: 1-8. 49: 255-61. service agreement with Health Publish- 13. EROGLU FK, KASAPCOPUR O, BESBAS N et 27. GEORGAKOPOULOS CD, ANTONOPOULOS I, ing & Services Srl. Health Publishing al.: Genetic and clinical features of cryopy- MAKRI OE, VASILAKIS P, LIOSSIS SN, ANDO- rin-associated periodic syndromes in Turk- NOPOULOS AP: Acute posterior multifocal & Services Srl provide editorial assis- ish children. Clin Exp Rheumatol 2016; 34 placoid pigment epitheliopathy in a patient tance. Article Processing Charges were (Suppl. 102): S115-S20. with familial Mediterranean fever. Clin Exp also funded by Novartis Farma, Italy. 14. GUNDOGAN FC, AKAY F, UZUN S, OZGE G, Optom 2016; 99: 385-7. TOYRAN S, GENC H: Choroidal Thickness 28. YAZICI H, PAZARLI H: Eye involvement in a Changes in the Acute Attack Period in Pa- patient with familial Mediterranean fever. J Competing interests tients with Familial Mediterranean Fever. Rheumatol 1982; 9: 644. L. Cantarini has received consultancies Ophthalmologica 2016; 235: 72-7. 29. WATAD A, TIOSANO S, YAHAV D et al.: Be- and speaker’s fees from Novartis and 15. KELLNER U, STOHR H, WEINITZ S, FARMAND hçet’s disease and familial Mediterranean G, WEBER BHF: Mevalonate kinase deficiency fever: Two sides of the same coin or just an SOBI. The the other authors declare no associated with ataxia and retinitis pigmento- association? A cross-sectional study. Eur J competing interests. sa in two brothers with MVK gene mutations. Intern Med 2017; 39: 75-8. Ophthalmic Genet 2017; 38: 340-4. 30. PETRUSHKIN HJ, KARAGIANNIS DA, BIRD References 16. KOSKER M, ARSLAN N, ALP MY et al.: As- A, JAWAD AS: Intermediate uveitis associated sociation Between Keratoconus and Famil- with familial Mediterranean fever. Clin Exp 1. RIGANTE D, LOPALCO G, VITALE A et al.: ial Mediterranean Fever in Turkey. Rheumatol 2015; 33 (Suppl. 94): S170. Untangling the web of systemic autoinflam- 2016; 35: 77-80. 31. KIRRESH A, EVERITT A, KON OM, DASGUPTA matory diseases. Mediators Inflamm 2014; 17. ROSE CD, PANS S, CASTEELS I et al.: Blau R, PICKERING MC, LACHMANN HJ: Trapped 2014: 948154. syndrome: cross-sectional data from a mul- without a diagnosis: Tumour necrosis fac- 2. RIGANTE D, VITALE A, LUCHERINI OM, ticentre study of clinical, radiological and tor receptor-associated periodic syndrome CANTARINI L: The hereditary autoinflam- . Rheumatology . Pract Neurol matory disorders uncovered. Autoimmun Rev functional outcomes (Ox- (TRAPS) 2016; 16: 304-7. 2014; 13: 892-900. ford) 2015; 54: 1008-16. 32. RIGANTE D, LOPALCO G, VITALE A et al.: 18. SIEMIATKOWSKA AM, van den BORN LI, 3. CANTARINI L, IACOPONI F, LUCHERINI OM Key facts and hot spots on tumor necrosis et al.: Validation of a diagnostic score for the VAN HAGEN PM et al.: Mutations in the me- factor receptor-associated periodic syn- diagnosis of autoinflammatory diseases in valonate kinase (MVK) gene cause nonsyn- drome. Clin Rheumatol 2014; 33: 1197-207. adults. Int J Immunopathol Pharmacol 2011; dromic retinitis pigmentosa. Ophthalmology 33. TORO JR, AKSENTIJEVICH I, HULL K, DEAN 24: 695-702. 2013; 120: 2697-705. J, KASTNER DL: Tumor necrosis factor re- 4. SAYARLIOGLU M, CEFLE A, INANC M et al.: 19. SOBOLEWSKA B, ANGERMAIR E, DEUTER ceptor-associated periodic syndrome: a nov- Characteristics of patients with adult-onset C, DOYCHEVA D, KUEMMERLE-DESCHNER el syndrome with cutaneous manifestations. familial Mediterranean fever in Turkey: J, ZIERHUT M: NLRP3 A439V Mutation in a Arch Dermatol 2000; 136: 1487-94. analysis of 401 cases. Int J Clin Pract 2005; Large family with cryopyrin-associated peri- 34. ROSEN-WOLFF A, KRETH HW, HOFMANN 59: 202-5. odic syndrome: description of ophthalmolog- S et al.: Periodic fever (TRAPS) caused 5. BASCHERINI V, GRANATO C, LOPALCO G et ic symptoms in correlation with other organ by mutations in the TNFalpha receptor 1 al.: The protean ocular involvement in mo- symptoms. J Rheumatol 2016; 43: 1101-6. (TNFRSF1A) gene of three German patients. nogenic autoinflammatory diseases: state of 20. YAZICI A, OZDAL P, YUKSEKKAYA P, ELGIN Eur J Haematol 2001; 67: 105-9. the art. Clin Rheumatol 2015; 34: 1171-80. U, TEKE MY, SARI E: Ophthalmic manifesta- 35. HALLIGAN C, HEESE BA, MELLOR G, 6. FEDERICI S, CAORSI R, GATTORNO M: The tions in familial Mediterranean fever: a case MICHELS VV, REED A: A boy with fever and autoinflammatory diseases. Swiss Med Wkly series of 6 patients. Eur J Ophthalmol 2014; whorl keratopathy. J Rheumatol 2006; 33: 2012; 142: w13602. 24: 593-8. 1210-1. 7. LEVY R, GERARD L, KUEMMERLE-DE- 21. PETRUSHKIN H, STANFORD M, FORTUNE F, 36. FAVIER LA, SCHULERT GS: Mevalonate ki- SCHNER J et al.: Phenotypic and genotypic JAWAD AS: Clinical Review: Familial Medi- nase deficiency: current perspectives. Appl characteristics of cryopyrin-associated pe- terranean Fever-An Overview of Pathogen- Clin Genet 2016; 9: 101-10. riodic syndrome: a series of 136 patients esis, Symptoms, Ocular Manifestations, and 37. BALGOBIND B, WITTEBOL-POST D, FREN- from the Eurofever Registry. Ann Rheum Dis Treatment. Ocul Immunol Inflamm 2016; 24: KEL J: Retinitis pigmentosa in mevalonate 2015; 74: 2043-9. 422-30. kinase deficiency. J Inherit Metab Dis 2005; 8. LACHMANN HJ, PAPA R, GERHOLD K et al.: 22. MICHAELSON I, ELIAKIM M, EHRENFELD 28: 1143-5. The phenotype of TNF receptor-associated EN, RACHMILEWITZ M: Fundal changes re- 38. DUREL CA, AOUBA A, BIENVENU B et al.: autoinflammatory syndrome (TRAPS) at sembling colloid bodies in recurrent poly- Observational Study of a French and Belgian presentation: a series of 158 cases from the serositis (periodic disease). AMA Arch Oph- multicenter cohort of 23 patients diagnosed in Eurofever/EUROTRAPS international regis- thalmol 1959; 62: 1-4. adulthood with mevalonate kinase deficiency. try. Ann Rheum Dis 2014; 73: 2160-7. 23. ERDURMUS M, BEKDAS M, DEMIRCIOGLU Medicine (Baltimore) 2016; 95: e3027. 9. LIDAR M, GIAT E: An Up-to-date Approach F, SOYDAN A, GOKSUGUR SB, KISMET E: 39. PRIETSCH V, MAYATEPEK E, KRASTEL H et to a Patient with a Suspected Autoinflamma- Retinal and choroidal thickness in children al.: Mevalonate kinase deficiency: enlarging tory Disease. Rambam Maimonides Med J with familial Mediterranean fever. Ocul Im- the clinical and biochemical spectrum. Pedi- 2017; 8: e0002. munol Inflamm2014; 22: 444-8. atrics 2003; 111: 258-61. 10. MEHR S, ALLEN R, BOROS C et al.: Cryopy- 24. KAYA A, AKSOY Y, SEVINC MK, DINER O: 40. SIMON A, KREMER HP, WEVERS RA et al.: rin-associated periodic syndrome in Austral- Temperature Control Function of the Cho- Mevalonate kinase deficiency: Evidence for a ian children and adults: Epidemiological, roid May Be the Reason for the Increase in phenotypic continuum. Neurology 2004; 62: clinical and treatment characteristics. J Pae- Choroidal Thickness during the Acute Phase 994-7. diatr Child Health 2016; 52: 889-95. of Familial Mediterranean Fever. Ophthal- 41. WILKER SC, DAGNELIE G, GOLDBERG MF: 11. CARRENO E, GULY CM, CHILOV M et al.: Op- mologica 2016; 235: 123. Retinitis pigmentosa and punctate cataracts tic nerve and retinal features in uveitis asso- 25. KOSKER M, BICER T, CELIKAY O, GURDAL in mevalonic aciduria. Retin Cases Brief Rep ciated with juvenile systemic granulomatous C: Choroidal Changes in Patients with Famil- 2010; 4: 34-6. disease (Blau syndrome). Acta Ophthalmol ial Mediterranean Fever. Ophthalmologica 42. CENEDELLA RJ, SEXTON PS: Probing cata- 2015; 93: 253-7. 2016; 235: 184. ractogenesis associated with mevalonic aci-

S-52 Clinical and Experimental Rheumatology 2018 Ocular involvement in AIDs / J. Sota et al.

duria. Curr Eye Res 1998; 17: 153-8. 49. ALEJANDRE N, RUIZ-PALACIOS A, GARCIA- patient caused by a novel NOD2 mutation. 43. DOLLFUS H, HAFNER R, HOFMANN HM et APARICIO AM et al.: Description of a new Int J Immunogenet 2011; 38: 233-42. al.: Chronic infantile neurological cutaneous family with cryopyrin-associated periodic 57. KIM W, PARK E, AHN YH et al.: A familial and articular/neonatal onset multisystem in- syndrome: risk of visual loss in patients case of Blau syndrome caused by a novel flammatory disease syndrome: ocular mani- bearing the R260W mutation. Rheumatology NOD2 genetic mutation. Korean J Pediatr festations in a recently recognized chronic (Oxford) 2014; 53: 1095-9. 2016; 59: S5-S9. inflammatory disease of childhood. Arch 50. SHAKEEL A, GOUWS P: Muckle-Wells syn- 58. MILMAN N, URSIN K, RODEVAND E, NIEL- Ophthalmol 2000; 118: 1386-92. drome: another cause of acute anterior uvei- SEN FC, HANSEN TV: A novel mutation in the 44. RIGANTE D, STABILE A, MINNELLA A et tis. Eye (Lond) 2007; 21: 849-50. NOD2 gene associated with Blau syndrome: al.: Post-inflammatory retinal dystrophy in 51. ESPANDAR L, BOEHLKE CS, KELLY MP: First a Norwegian family with four affected mem- CINCA syndrome. Rheumatol Int 2010; 30: report of keratitis in familial cold autoinflam- bers. Scand J Rheumatol 2009; 38: 190-7. 389-93. matory syndrome. Can J Ophthalmol 2014; 59. RAIJI VR, MILLER MM, JUNG LK: Uveitis in 45. TERRADA C, NEVEN B, BODDAERT N et al.: 49: 304-6. Blau syndrome from a de novo mutation of Ocular modifications in a young girl with 52. YAO Q: Nucleotide-binding oligomerization the NOD2/CARD15 gene. J AAPOS 2011; cryopyrin-associated periodic syndromes re- domain containing 2: structure, function, and 15: 205-7. sponding to interleukin-1 receptor antagonist diseases. Semin Arthritis Rheum 2013; 43: 60. ZEYBEK C, BASBOZKURT G, GUL D, DEMIR- anakinra. J Ophthalmic Inflamm Infect 2011; 125-30. KAYA E, GOK F: A new mutation in blau syn- 1: 133-6. 53. ARVESEN KB, HERLIN T, LARSEN DA et al.: drome. Case Rep Rheumatol 2015; 2015: 46. HIRANO M, SEGUCHI J, YAMAMURA M et al.: Diagnosis and Treatment of Blau Syndrome/ 463959. Successful resolution of stromal keratitis and Early-onset Sarcoidosis, an Autoinflamma- 61. MARRANI E, CIMAZ R, LUCHERINI OM et uveitis using canakinumab in a patient with tory Granulomatous Disease, in an Infant. al.: The common NOD2/CARD15 variant chronic infantile neurologic, cutaneous, and Acta Derm Venereol 2017; 97: 126-7. P268S in patients with non-infectious uvei- articular syndrome: a case study. J Ophthal- 54. PILLAI P, SOBRIN L: Blau syndrome-associ- tis: a cohort study. Pediatr Rheumatol Online mic Inflamm Infect2015; 5: 34. ated uveitis and the NOD2 gene. Semin Oph- J 2015; 13: 38. 47. KAWAI M, YOSHIKAWA T, NISHIKOMORI R, thalmol 2013; 28: 327-32. 62. ACHILLE M, ILARIA P, TERESA G et al.: HEIKE T, TAKAHASHI K: Obvious optic disc 55. JAIN L, GUPTA N, REDDY MM et al.: A Novel Successful treatment with adalimumab for swelling in a patient with cryopyrin-associ- Mutation in Helical Domain 2 of NOD2 in severe multifocal choroiditis and panuveitis ated periodic syndrome. Clin Ophthalmol Sporadic Blau Syndrome. Ocul Immunol In- in presumed (early-onset) ocular sarcoidosis. 2013; 7: 1581-5. flamm2016: 1-3. Int Ophthalmol 2016; 36: 129-35. 48. NAZ VILLALBA E, GOMEZ de la FUENTE E, 56. JIMENEZ-MARTINEZ MC, CRUZ F, GROMAN- 63. OBERG TJ, VITALE AT, HOFFMAN RO, BOHN- CARO GUTIERREZ D et al.: Muckle-Wells syn- LUPA S, ZENTENO JC: Immunophenotyping SACK JF, WARNER JE: Cryopyrin-associated drome: a case report with an NLRP3 T348M in peripheral blood mononuclear cells, aque- periodic syndromes and the eye. Ocul Immu- mutation. Pediatr Dermatol 2016; 33: e311-4. ous humour and vitreous in a Blau syndrome nol Inflamm2013; 21: 306-9.

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