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, 19–24]. 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 [35–37]. 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.