Ocular Changes in Children With Familial Mediterranean Fever: The Effect of Subclinical Inflammation?

DOI: https://doi.org/10.21203/rs.3.rs-1905417/v1

Abstract

Purpose: Elevation of acute phase reactants during attack is an important indicator of acute inflammation in Familial Mediterranean Fever (FMF). However, the disease course also involves inflammation in remission period. Subclinical inflammation is a major etiological factor for organ involvement of the disease. The eye is one of the target organs in the course of FMF.

Methods: The study included 51 patients with FMF in remission period for at least 3 months and 51 age-matched healthy individuals. Intraocular pressure, axial length, peripapillary retinal nerve fiber layer (RNFL) thickness, central macular thickness, and subfoveal choroidal thickness were assessed for patient and control groups using spectral domain optical coherence tomography (SD-OCT). Patients were grouped according to disease severity scores, and laboratory and ocular findings were compared.

Results: Serum amyloid A, C-reactive protein and fibrinogen were higher and temporal inferior RNFL was thinner in the patient group than in the control group (p<0.05). Central macular, submacular choroidal,  nasal and temporal thicknesses were lesser in the patient group than in the control group, but there was no statistically significant difference between the groups (p>0.05). On the other hand, a positive correlation was found between proteinuria and axial length in the patient group.

Conclusion: Subclinical inflammation is one of the factors responsible for important changes in the eye in FMF. Some changes that occur in the early period can become more prominent with a longer duration of the disease. Follow-up from childhood to adulthood would enable revealing the effects of subclinical inflammation in these patients.

Introduction

Familial Mediterranean Fever (FMF) is an inflammatory disease characterized by self-limited attacks of fever and serositis, affecting the peritoneum, pleura, joints and other organs [1]. While inflammation that exacerbates during attacks is the main cause of amyloidosis and permanent changes, subclinical inflammation that persists in the attack-free periods causes damage to many organs and tissues.

The disease is inherited as an autosomal recessive trait. The gene responsible for FMF was called MEFV (Mediterranean Fever) by the International FMF Consortium [2]. The MEFV gene encodes a protein, known as pyrin or marenostrin [3]. This protein is involved in the regulation of inflammation through autoregulatory effects on leukocytes [4]. In FMF, the role of pyrin in the regulation of innate immunity is inhibited due to missense mutations in the MEFV gene that change the structure and function of pyrin [5]. FMF-associated pyrin mutations activate the caspase-1 enzyme, causing the release of interleukin (IL)-1β [6]. IL-1β regulates the activation and production of tumor necrosis factor-alpha (TNF-α). These proinflammatory cytokines cause chronic inflammation in FMF [7]. While the course of the disease consists of attacks due to inflammation, the disease goes into spontaneous remission between attacks and the symptoms resolve [8]. However, despite colchicine treatment, both C-reactive protein (CRP) and serum amyloid A (SAA) levels are high in 30–90% of patients, indicating that subclinical systemic inflammation persists in the attack-free periods [9]. Moreover, increased levels of other inflammatory markers; IL-6, IL-8, IL-10, IL-12, IL-17 and IL-18 were reported in the attack-free periods [9, 10]. This ongoing inflammatory process also negatively affects the eye tissues rich in vascular structures. Disease-related changes occur in retinal and choroidal vascular structures because FMF triggers vasculopathy and inflammation [11]. Especially the choroid was reported to be more susceptible to the effects of inflammatory and vascular systemic diseases compared to other eye tissues [12]. In addition, IL-1β, the release of which increases during the disease, can activate TNF-α, and together they can affect retinal structures [6, 7, 12].

Studies on retinal and choroidal changes are limited in patients with FMF [11, 13]. Invasive eye studies are very limited due to the risk of serious complications, making non-invasive methods become important. Spectral-domain optical coherence tomography (SD-OCT) is a non-invasive, non-contact, transpupillary imaging modality for investigating retinal structures. Newly developed software for SD-OCT that uses an 830-nm infrared light source has increased our ability to image the choroid. Since Spaide et al. described enhanced depth imaging (EDI)-OCT, CT has been studied in many chorioretinal diseases using this technology [14]. This method allows for revealing changes in the eye tissue in detail. The present study, considering that the damage caused by FMF during the attacks continues between the attacks, assessed the changes in peripapillary retinal nerve fiber layer (RNFL) thickness and choroidal vascular structure of children using SD-OCT and examined the ocular effects of subclinical inflammation.

Materials And Methods

This study was conducted with 51 pediatric patients who were followed up for FMF in the Pediatric Nephrology Department of Düzce University Faculty of Medicine, and 51 age- and gender-matched healthy controls. Detailed consent forms were obtained from all participants and their families. The study was approved by the local ethics committee (Ethics No: 2020/230). FMF was diagnosed according to Tel-Hashomer diagnostic criteria [15]. In addition, disease severity was measured using the International Severity Scoring System for Familial Mediterranean Fever (ISSF) [16]. An ISSF score of ≥ 6 was considered as high disease activity, an ISSF score of 3–5 as moderate disease activity and an ISSF score of ≤ 2 as low disease activity.

All examinations and imaging of the patients were performed when FMF was in remission period for at least three months. The patients were receiving colchicine treatment regularly. The physical examinations of the participants were completely normal. Exclusion criteria were as follows: individuals with an age outside 6–18 years, previous eye surgery or trauma, congenital malformations of the eye, amblyopia, refractive error greater than ± 1 diopter, intraocular pressure of ≥ 21 mmHg, any glaucomatous optic disc changes, history of wearing contact lenses, inflammatory diseases such as strabismus, uveitis, scleritis, corneal scars or ectasia, history of using topical eye drops, optic nerve diseases, amyloidosis, autoimmune and vasculitic diseases, chronic kidney disease, advanced congestive heart failure, and comorbidities such as diabetes and hypertension. In addition, children who could not comply with the measurements were also excluded from the study.

All examinations were conducted on the right eye. Each subject received a general eye examination including best corrected visual acuity test, dilated-pupil fundus examination with a 90-diopter (D) lens, and refractive error measurement with Topcon KR-8100 Auto Kerato-Refractometer (Topcon Corporation, Tokyo, Japan), intraocular pressure (IOP) measurement with non-contact tonometer (Canon TX-20P), axial length (AL) measurement with IOL-Master 700 (Carl Zeiss Meditec, Jena, Germany), as well as macular, retinal nerve fiber layer and choroidal layer thickness measurements using Spectral Domain Optical Coherence Tomography (SD-OCT, Heidelberg Engineering, Heidelberg, Germany). Eye tests and OCT scans were performed by a trained ophthalmologist between 09:00 and 11:00 AM to mitigate potential diurnal variability. The disc margin contour line was drawn manually at the inner edge of the scleral ring by determining 7 points. The RNFL thickness was measured globally (G) and in temporal (T), superotemporal (ST), superonasal (SN), nasal (N), inferotemporal (IT), and inferonasal (IN) sectors. The CT was measured as the perpendicular distance between the hyperreflective outer border of the retinal pigment epithelial layer (automatically detected by the instrument) and the manually drawn sclero-choroidal interface. The RT and CT were measured using the caliper system at 500-µm intervals up to 1.500 mm (one subfoveal, three nasal, and three temporal points) [17].

Blood and urine samples collected from the patients were stored properly and all tests were studied simultaneously. As acute phase reactants, the SAA, CRP, fibrinogen and sedimentation levels were analyzed in all groups. In addition, the spot urine protein-to-creatinine ratio value was used to assess proteinuria. The level of significance for proteinuria in the urine was set to > 0.2.

Statistical Analysis

The distribution of the data was analyzed by the Kolmogorov-Smirnov test and the homogeneity of variance by Levene's test. The groups were compared using the Independent Samples t-test, Welch test, One-Way ANOVA or Mann-Whitney U and Kruskal-Wallis tests, depending on the type of data distribution and the number of groups compared. Categorical variables were analyzed by Pearson's Chi-Square, Fisher's Exact or Fisher-Freeman-Halton tests, depending on the expected value principle. The Pearson’s or Spearman’s correlation analysis was used to examining correlations, depending on the type of data distribution. Descriptive statistics were expressed as mean ± standard deviation, median, quartiles, and minimum-maximum values depending on the type of data distribution, while categorical variables were summarized as numbers and percentages. Statistical analyses were performed using the SPSS version 22 and the level of significance was set to p < 0.05.

Results

The mean age was 12.00 ± 3.30 years in the patient group and 12.11 ± 3.16 years in the control group (p = 0.86). The gender distribution was similar in the patient and control groups (p = 0.93) (Table 1). All patients had at least one mutation in the MEFV gene, while some patients had multiple mutations (Table 1). Despite clinical remission, the patient group had statistically significantly higher amyloid, fibrinogen and C-reactive protein levels, and ESR and spot urine protein-to-creatinine ratio than the control group (p < 0.001) (Table 2). These findings were considered as an indicator of subclinical inflammation. The corrected intraocular pressure was 14.96 ± 2.61 mmHg in the FMF group and 14.61 ± 2.15 mmHg in the control group, with no significant difference between the groups (p = 0,476).

Table 1

Demographic and genetic characteristics of the patient and control groups

 

Patient (n = 51)

Control (n = 51)

p

Age (year)

12.00 ± 3.30

12.11 ± 3.16

0.867

Gender n (%)

Girl

Boy

31 (60.8)

20 (39.2)

31 (61.0)

20 (39.0)

0.937

ISSF Score (n)

≥ 6: 16

3–5: 15

< 3: 20

-

-

M694V

heterozygous

11 (21.6)

0 (0.0)

0.001

E148Q

heterozygous

7 (13.7)

0 (0.0)

0.014

R202Q

heterozygous

homozygous

28 (54.9)

9 (17.6)

0 (0.0)

0 (0.0)

< 0.001

A744S. E167D. F479L

heterozygous

2 (3.9)

0 (0.0)

0.497

L110P

heterozygous

1 (2.0)

0 (0.0)

0.999

R761H

heterozygous

3 (5.9)

0 (0.0)

0.245

V726A

heterozygous

3 (5.9)

0 (0.0)

0.245

P369S

heterozygous

3 (5.9)

0 (0.0)

0.245

R408Q

heterozygous

4 (7.8)

0 (0.0)

0.120

M680I

heterozygous

homozygous

2 (3.9)

1 (2.0)

0 (0.0)

0 (0.0)

0.497

ISSF: The international severity scoring system for familial mediterranean fever

Table 2

Laboratory parameters of the patient and control groups

 

Patient (n = 51)

Control (n = 51)

p

Amyloid (mg/dL)

2.37 (6.21) [0.02–177.00]

0.04 (0.04) [0.01–0.09]

< 0.001

Fibrinogen (mg/dL)

286.55 ± 46.02

223.87 ± 26.58

< 0.001

CRP (mg/dL)

0.09 (2.84) [0.01–16.95]

0.07 (0.03) [0.06–1.50]

< 0.001

ESR (mm/h)

16 (21) [1–82]

12 (6) [320]

< 0.001

Proteinuria

0.12 (0.10) [0.05–5.10]

0.09 (0.11) [0.01–0.21]

< 0.001

CRP: C-reactive protein. ESR: erythrocyte sedimentation rate

The SD-OCT measurements revealed that the temporal inferior RNFL was significantly thinner in the patient group than in the control group (p = 0.008). The RNFL thickness in other quadrants (temporal superior, nasal superior, nasal, nasal inferior and global) did not significantly differ between the two groups. Moreover, although the central macular thickness and submacular choroidal thickness were lesser in the patient group than in the control group, but the difference was statistically insignificant (p > 0.05). There was no statistically significant difference in AL between the groups (p = 0.222). On the other hand, the thickness at nasal (ediN500, ediN1000, ediN1500), temporal (ediT500, ediT1000 and ediT1500) were also lesser in the patient group than in the control group; however, the difference was statistically insignificant (p > 0.05). After grouping the patients according to ISSF scores, there was no significant difference in the results of SD-OCT measurements between the groups according to the disease score (p > 0.05) (Table 34).

Table 3

Ophthalmic findings of patients according to The International Severity Scoring System for Familial Mediterranean Fever (ISSF)

 

ISSF score ≥ 6

(Severe) (n = 16)

ISSF score : 3–5

(Intermediate) (n = 15)

ISSF score ≤ 2

(Mild) (n = 20)

p

AL (mm)

23.11 ± 0.83

23.90 ± 0.79

23.19 ± 0.77

0.451

RNFL-T (µm)

70.88 ± 11.10

71.83 ± 11.91

73.16 ± 11.54

0.731

RNFL-TS (µm)

142.55 ± 21.02

142.66 ± 20.88

144.32 ± 118.68

0.598

NS (µm)

116.38 ± 24.16

117.22 ± 24.32

115.66 ± 19.62

0.236

N (µm)

78.79 ± 11.11

79.19 ± 11.02

77.19 ± 10.11

0.563

Ni (µm)

117.26 ± 24.42

118.16 ± 23.54

116.44 ± 22.46

0.632

Ti (µm)

142.17 ± 18.17

142.77 ± 17.79

143.20 ± 17.97

0.229

G (µm)

102.16 ± 11.71

101.45 ± 10.07

101.29 ± 8.25

0.611

CMK (µm)

213.73 ± 13.74

214.66 ± 14.09

213.61 ± 13.97

0.348

ediM (µm)

336.48 ± 81.71

339.62 ± 80.33

338.38 ± 84.66

0.189

ediN500 (µm)

309.21 ± 76.14

308.60 ± 76.11

311.41 ± 76.64

0.975

ediN1000 (µm)

295.61 ± 72.43

291.66 ± 73.33

293.43 ± 74.23

0.532

ediN1500 (µm)

259.61 ± 72.11

262.60 ± 71.55

261.12 ± 70.33

0.870

ediT500 (µm)

336.72 ± 79.28

340.53 ± 79.99

343.82 ± 66.14

0.176

ediT1000 (µm)

335.65 ± 78.07

336.83 ± 76.80

338.51 ± 78.76

0.634

ediT1500 (µm)

324.08 ± 79.36

328.44 ± 78.19

326.91 ± 79.11

0.443

AL: axial length, RNFL: Peripapiller retinal nerve fiber layer thikness (G: global, T: temporal, Ts: temporal superior, Ti: temporal inferior, N: nazal, Ns: nazal superior, Ni: nazal inferior), CMK: central macular thickness, ediM: Enhanced depth imaging choroidal thickness under the macula

Table 4

Ophthalmic findings of the patient and control groups

 

Patient (n = 51)

Control (n = 51)

p

AL (mm)

23.21 ± 0.81

23.00 ± 0.88

0.222

RNFL-T (µm)

70.82 ± 11.01

74.11 ± 10.08

0.132

RNFL-TS (µm)

142.45 ± 21.11

145.13 ± 17.57

0.504

NS (µm)

117.33 ± 24.25

112.60 ± 19.36

0.298

N (µm)

79.80 ± 11.35

77.07 ± 10.78

0.230

Ni (µm)

119.24 ± 24.38

114.47 ± 19.74

0.299

Ti (µm)

142.16 ± 18.90

152.20 ± 17.12

0.008

G (µm)

102.80 ± 11.05

103.27 ± 8.89

0.823

CMK (µm)

213.53 ± 14.79

217.64 ± 13.76

0.163

ediM (µm)

336.39 ± 81.28

353.38 ± 84.43

0.318

ediN500 (µm)

308.61 ± 76.75

331.44 ± 79.93

0.157

ediN1000 (µm)

285.69 ± 73.55

301.87 ± 80.71

0.307

ediN1500 (µm)

259.67 ± 71.92

268.47 ± 80.70

0.573

ediT500 (µm)

336.53 ± 79.28

353.80 ± 86.10

0.309

ediT1000 (µm)

335.84 ± 78.83

341.56 ± 79.41

0.725

ediT1500 (µm)

326.02 ± 79.06

336.42 ± 79.91

0.524

AL: axial length, RNFL: Peripapiller retinal nerve fiber layer thickness (G: global, T: temporal, Ts: temporal superior, Ti: temporal inferior, N: nazal, Ns: nazal superior, Ni: nazal inferior), CMK: central macular thickness, ediM: Enhanced depth imaging choroidal thickness under the macula

Correlations between SAA, CRP, proteinuria and fibrinogen levels, and ocular findings were analyzed in the patient group. While proteinuria and AL were positively correlated in the patient group, ediN1500 and fibrinogen level were negatively correlated (Table 5).

Table 5

Correlation between laboratory and spectral-domain optical coherence tomography analysis results of the patients.

Patients (n = 51)

 
   

Amyloid (mg/dL)

CRP (mg/dL)

proteinuria

 

Fibrinogen (mg/dL)

ESR (mm/h)

AL (mm)

rs

-0.139

-0.010

0.282

r

-0.147

-0.150

 

p

0.332

0.943

0.045

p

0.303

0.293

ACD (mm)

rs

-0.056

0.220

0.126

r

-0.101

-0.046

 

p

0.699

0.120

0.378

p

0.483

0.747

RNFL-T (µm)

rs

0.355

0.050

-0.079

r

0.216

0.029

 

p

0.011

0.728

0.580

p

0.127

0.841

RNFL-TS (µm)

rs

0.199

0.332

-0.049

r

0.161

0.159

 

p

0.162

0.017

0.730

p

0.259

0.266

NS (µm)

rs

-0.040

0.087

0.140

r

-0.159

-0.075

 

p

0.782

0.546

0.325

p

0.265

0.601

N (µm)

rs

0.108

-0.035

0.190

r

0.129

0.035

 

p

0.449

0.806

0.183

p

0.367

0.808

Ni (µm)

rs

0.076

0.008

-0.140

r

-0.094

0.038

 

p

0.594

0.956

0.327

p

0.512

0.790

Ti (µm)

rs

0.106

0.195

0.055

r

-0.036

0.073

 

p

0.458

0.170

0.701

p

0.800

0.609

G (µm)

rs

0.214

0.207

0.023

r

0.041

0.061

 

p

0.132

0.145

0.871

p

0.775

0.671

CMK (µm)

rs

-0.185

-0.151

0.275

r

-0.194

-0.139

 

p

0.194

0.291

0.050

p

0.172

0.332

ediM (µm)

rs

0.092

-0.260

-0.149

r

-0.188

-0.064

 

p

0.522

0.066

0.297

p

0.186

0.653

ediN500(µm)

rs

0.051

-0.146

-0.057

r

-0.232

0.044

 

p

0.723

0.305

0.691

p

0.101

0.761

ediN1000(µm)

rs

0.012

-0.208

-0.110

r

-0.265

0.026

 

p

0.933

0.144

0.442

p

0.060

0.859

ediN1500(µm)

rs

0.047

-0.159

-0.062

r

-0.285

-0.017

 

p

0.746

0.265

0.668

p

0.043

0.903

ediT500(µm)

rs

-0.001

-0.155

-0.073

r

-0.212

-0.120

 

p

0.993

0.277

0.610

p

0.135

0.401

ediT1000(µm)

rs

0.011

-0.158

-0.053

r

-0.208

-0.190

 

p

0.938

0.267

0.714

p

0.142

0.183

ediT1500(µm)

rs

0.029

-0.141

-0.061

r

-0.239

-0.224

 

p

0.841

0.324

0.669

p

0.091

0.114

CRP: C-reactive protein, ESR: erythrocyte sedimentation rate, AL: axial length, RNFL: Peripapiller retinal nerve fiber layer thikness (G: global, T: temporal, Ts: temporal superior, Ti: temporal inferior, N: nazal, Ns: nazal superior, Ni: nazal inferior), CMK: central macular thickness, ediM: Enhanced depth imaging choroidal thickness under the macula

Discussion

This study aimed to investigate the ocular effects of chronic subclinical inflammation in patients with FMF and found that the peripapillary RNFL assessed by SD-OCT was thinner in the temporal inferior area in the patient group. In addition, a statistically significant thinning was identified in the RNFL in the temporal region with increasing serum levels of amyloid. As well, the choroidal thickness was shown to be lesser in the patient group than in the control group, although the difference was statistically insignificant.

Even if there is no evident clinical involvement in chronic inflammatory diseases, changes occur in many organs and tissues. This may vary depending on the severity and duration of the disease and other accompanying factors. In FMF, the persistence of subclinical inflammation between the attacks, apart from the inflammation occurring during the attack, facilitates the emergence of adverse effects of the disease on other organs and tissues. Such damage may occur by several mechanisms described, and it may also be related to the increased risk of endothelial dysfunction and atherosclerosis due to chronic subclinical inflammation, even in the remission period [9, 10, 18]. One of the target organs is the eye in FMF. The most common ocular findings in these patients include ocular surface and tear film abnormalities, optic nerve edema, uveitis, episcleritis, optic neuritis, and amaurosis fugax, which often occur in the acute attack period [7, 1924]. Apart from these findings, revealing potential changes in retinal and choroidal microvascular structures related to subclinical inflammation that persists in remission would also contribute to enlightening the pathophysiology of the disease.

There were reports on elevated TNF-α and serum levels of other cytokines in some chronic disorders with ocular involvement [25]. A study by Tuzcu et al. showed especially temporal RNFL thickness to be susceptible to inflammation and inflammatory cytokines. The researchers found that the disease activity score and the RNFL thickness in the temporal quadrant were negatively correlated in patients with ankylosing spondylitis. Their study findings indicated that the RNFL thickness decreased due to the inflammatory effects of other cytokines, especially TNF-alpha, on the eye in ankylosing spondylitis, which is an inflammatory disease [26]. FMF is also a chronic inflammatory disease. In FMF, inflammation is known to persist not only during acute attacks but also in the remission period. Supporting this, elevated serum levels of IL-1β and TNF-α were demonstrated during the remission period compared to the normal population [27, 28]. The decreased RNFL thickness shown in the present study is a finding suggestive of persisting inflammation even during the remission period. The retina is one of the target organs due to its complex neurovascular tissue. The photoreceptors on the retinal pigment epithelium form the outer layer, while the RNFL forms the innermost layer [29]. This layer is one of the ocular areas most affected by the impaired supply associated with inflammation. Therefore, microvascular damage associated with inflammation may lead to the atrophy of these cells, reducing RNFL thickness. The present study also evaluated the measurements according to the disease score and established no difference in RNFL thickness between those with severe, intermediate and mild disease scores. The lack of significance in the RNFL thickness variation by the disease severity score suggests that the effect of subclinical inflammation may be more determinant of chronic damage, rather than the changes associated with acute attacks. Especially considering that the remission period is longer than the attack period, the persisting subclinical inflammation in the remission period may be a more significant factor for the development of damage.

Previous studies on choroidal thickness changes in FMF patients report different results. A study by Alim et al. established no difference in choroidal thickness between patients with FMF in remission and healthy controls [30]. Gündoğan et al., on the other hand, showed increased choroidal thickness during an attack in patients with FMF compared to the control group. The authors attributed this finding to choroidal edema associated with increased inflammation. They concluded that the systemic inflammatory and vasculopathic nature of FMF might cause increased vascular permeability, exudation, and dilated choroidal vessels and thus an increase in choroidal thickness during acute attacks. However, the study could not determine whether it was permanent damage since choroidal thickness was not assessed during the remission period in the same patient group [31]. Another study by Biçer et al. found the nasal quadrant choroidal thickness to be significantly lesser in adult FMF patients compared to the control group [32]. In the present study, the choroidal thickness was lesser in the patient group compared to the control group; however, the difference was statistically insignificant. The thinner choroid in the study by Biçer et al. might be due to the adult patient population of the study and the prolonged exposure of the patients to chronic subclinical inflammation. The aforementioned study reported that the choroidal thinning in adults might be related to atrophy. Chronic inflammation can reduce the vascular support and function of the choroid. Ultimately, vascular support and function of the retinal layers may also be impaired due to atrophy that develops with age. However, the researchers suggested that because the patient and control groups were matched for age and gender, age-related effects were excluded and these changes were associated with the disease. The choroid is an organ with a rich vascular structure, and thus thinning of the choroid is likely to completely reflect microvascular damage and tissue loss. In addition, arteriosclerosis, another sign of chronic inflammation, may contribute to thinning of the choroid with a longer duration of disease. The absence of choroidal thinning in the present study can be explained by the shorter duration of the disease compared to adults, since the patients were in the pediatric age group. However, the choroidal thickness can also be expected to decrease in pediatric patients, regardless of the attacks, with a longer duration of disease. The lack of any difference between the groups according to the disease score may also be related to the relatively short duration of the disease. With a longer duration of disease, it is believed that ocular findings may accompany the changes that may occur in all organs of patients with high scores.

The kidney and eye are quite similar in developmental, structural and pathogenic pathways. Since the renal podocytes and retinal pericytes are similar in function and structure, the diseases of these organs may also be similar [33]. Renal microvascular changes have an important place in the pathophysiology of kidney injury. These changes are one of the main causes of proteinuria in kidney disease [34]. A study by Balmforth et al. showed that glomerular inflammatory damage was associated with choroidal thinning [29]. The researchers considered the thinning of the choroid as an indicator of systemic inflammation also with an effect on the kidney and reported a strong correlation between the increase in proteinuria level and the thinning of the choroid. These findings suggest that the retinal and choroidal changes in CKD may be suggestive of a generalized systemic microvascular damage. The present study showed a significantly increased incidence of proteinuria in the patient group compared to the control group, even though it was within the normal limits. This finding shows that even if amyloidosis has not developed in FMF, the increase in protein excretion and thus kidney damage starts from the early period. Moreover, proteinuria was increased in patients with low ISSF compared to the control group, which also supports the persistence of subclinical inflammation in FMF. On the other hand, the present study could not demonstrate any significant relationship between proteinuria and RNFL thickness. A previous study reported that the decrease in retinal thickness in patients exposed to chronic inflammation occurs mostly in the outer retinal layers [29]. This also indicates choroidal damage. Because the outer one-third of the retina is supplied by the choroid and the inner two-thirds by the central retinal artery. While the choroidal damage affects the retina, the lack of any relationship between proteinuria and RNFL thickness suggests that the process may have occurred by mechanisms other than vascular damage. Inflammation causes direct tissue damage in the eye before vascular damage develops, and therefore vascular damage that increases proteinuria may not affect retinal thickness. Supporting this finding, the elevation in fibrinogen, an important inflammatory marker, and the negative correlation between fibrinogen and choroidal thickness suggest that inflammation causes significant changes in the choroid.

Axial length (AL) is a combination of anterior chamber depth, lens thickness, and vitreous chamber depth and is typically considered as the primary determinant of myopia [3537]. Several studies have proven the role of inflammation in susceptibility to myopia [38, 39]. The experimental study by Lin et al. showed a higher risk of myopia in inflammatory diseases such as Type 1 diabetes mellitus, systemic lupus erythematosus and uveitis [40]. The researchers stated that myopia was 1.5 times more common in Type 1 DM and 1.4 times more common in uveitis and SLE compared to the normal population and that these rates increased with a longer duration of disease. They indicated that the increased incidence of myopia in such chronic diseases was related to both acute and chronic inflammatory settings. The present study established no significant difference in AL between the patient group and the control group. This suggests that although FMF is an inflammatory disease, permanent ocular changes may be evident in more severe and long-lasting inflammatory diseases. A supporting finding was reported by Lin et al., stating that the increase in the incidence of myopia became evident with a longer duration of disease. Although the frequency and severity of attacks do not increase in older ages in patients with FMF, an increase in AL can be predicted as an effect of chronic inflammation. On the other hand, it was showed that AL increased as protein excretion increased due to FMF. The simultaneous involvement of the kidney and the eye suggests that inflammation affects both organs through some common pathways. The NLRP3 inflammasome (NACHT, LRR, and PYD domain-containing protein 3) is a macromolecular cytoplasmic complex that regulates the early inflammatory response of the innate immune system through the production of IL-1β and IL-18. The reactions that occur with the activation of NLRP3 are important factors of the kidney injury process, including proteinuria [41]. NLRP3 was also shown to be involved in the inflammatory process in other organs. Further reports indicate that the NLRP3 inhibition in some inflammatory processes, which include retinal injury and involvement of other ocular layers, restores many ocular findings, especially retinal neovascularization, by inhibiting the IL-1β/IL-18 activation pattern [42, 43]. The MEFV gene has an important role in the occurrence of inflammation in FMF. An experimental study showed that IL-1β levels were significantly increased in the MEFV gene-positive mice, even if the disease was inactive [44]. Similarly, IL-18 was reported to be high in both acute attack and remission periods in patients with FMF [45]. In conclusion, some inflammatory markers such as IL-1β and IL-18, which are active even in remission period, may cause both proteinuria and some permanent ocular changes via NLRP3. The finding that proteinuria does not reach serious levels can be explained by the shorter duration of the disease in children compared to adults. Even if amyloidosis does not develop in these patients, the level of proteinuria may increase with longer duration of disease.

This study has some limitations. Chronic FMF patients were assessed only when the disease was in remission. Evaluating the same patients during the attacks would better reveal the changes that can be caused by acute inflammation in the vascular and neural tissues of the eye. However, FMF was in remission in many patients for a long time, as they had been on regular medication. On the other hand, colchicine treatment has known adverse effects on the eye. In order to evaluate the changes related to colchicine, the patient group who did not use colchicine could also be included in the study. However, it would not be ethically appropriate to discontinue colchicine therapy in this patient group. Evaluating inflammatory markers and inflammasomes separately in attack and remission periods would allow a better understanding of what kind of effects the disease may have on ocular tissues. The pathogenesis of FMF and the treatment alternatives would be easier to reveal with the inclusion of a higher number of patients who have been followed for a longer period, including adulthood. Furthermore, it would be possible to assess the damage caused by genetic mutation due to the effect of mutation type on the severity of inflammation in studies to be conducted with a larger patient population.

Conclusion

The findings of this study show that chronic inflammation can cause thinning of the RNFL and choroid, even in childhood, when the duration of disease exposure is shorter. In addition, these findings suggest that the ocular manifestations of this chronic disease may be much more diverse and permanent. The finding that the ocular changes in the patient group were observed in the remission period and also not affected by the disease activity can be explained by the high levels of some of the inflammatory factors mentioned before, even in remission. Of course, the increase in some other inflammatory factors in the active period, the levels of which return to normal in remission, also plays an important role in the pathogenesis of the disease. However, these inflammatory factors, which increase during the active period, may not have affected the permanent damage process due to the short disease duration of the participants in the patient group. With a longer duration of disease in the following periods, it is possible that these attack-related inflammatory factors will cause permanent damage.

Declarations

Author contribution NMS, KT: designed the study; NMS, KT: were involved in patient care; NMS: collected the data; NMS, KT: analysis and interpretation of data; NMS, KT: drafting the manuscript; NMS, KT: design of the work, revising the work critically for important intellectual content. All authors approved the final version of manuscript.

Funding The authors did not receive support from any organization for the submitted work. The authors have no relevant financial or non-financial interests to disclose.

Data availability All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Declarations

Confict of interest The authors declare that they have no fnancial confict of interest related to this article.

Ethics approval This study was performed in line with the principles of the Declaration of Helsinki. The study protocol was approved by the Institutional Ethics Committee of Duzce University School of Medicine (approval number: 2020/230).

Consent for participate and publication The authors agree with the publication of this manuscript in International Ophthalmology and were fully involved in the study and preparation of the manuscript.

Informed consent Written informed consent was obtained from all individual participants and the parents included in the study

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