This study aimed to investigate the ocular effects of chronic subclinical inflammation in patients with FMF and found that the peripapillary RNFL, as measured by SD-OCT, was thinner in the temporal inferior quadrant in the patient group. Furthermore, an inverse correlation was observed between serum amyloid levels and temporal RNFL thickness. Similarly, choroidal thickness was found to be lower in the patient group compared to the control group.

Even if there is no evident clinical involvement in chronic inflammatory diseases, changes occur in many organs and tissues. In FMF, the persistence of subclinical inflammation between attacks, in addition to the inflammation occurring during the attacks, contributes to the development of adverse effects on other organs and tissues. Such damage may occur through several described mechanisms and may also be associated with an increased risk of endothelial dysfunction and atherosclerosis resulting from chronic subclinical inflammation, even during remission.1

Elevated serum levels of TNF-α and other cytokines have been reported in certain chronic ocular disorders.19 A study by Tuzcu et al. demonstrated that temporal RNFL thickness is particularly vulnerable to inflammation and inflammatory cytokines. The researchers found a negative correlation between disease activity scores and temporal quadrant RNFL thickness in patients with ankylosing spondylitis. Their findings suggested that RNFL thickness was reduced due to the inflammatory effects of cytokines—particularly TNF-α—on the eye in ankylosing spondylitis, a chronic inflammatory disorder.20 In FMF, inflammation is known to persist not only during acute attacks but also throughout remission. In support of this, elevated serum levels of IL-1β and TNF-α were observed during remission compared to those in the healthy population.21 The decreased RNFL thickness observed in the present study suggests the presence of persistent inflammation, even during remission. The retina is one of the target organs due to its complex neurovascular structure. Photoreceptors located on the retinal pigment epithelium constitute the outermost layer, while the RNFL comprises the innermost layer.22 This layer is among the ocular structures most vulnerable to impaired supply resulting from inflammation. Therefore, microvascular damage induced by inflammation may result in the atrophy of these cells, leading to a reduction in RNFL thickness. The present study also evaluated RNFL measurements in relation to disease severity and found no significant difference in RNFL thickness among patients with mild, moderate, or severe scores. The absence of a statistically significant correlation between the change in RNFL thickness and the disease severity score suggests that the effect of subclinical inflammation may be more predictive of chronic damage than changes associated with acute attacks.

Previous studies investigating changes in choroidal thickness in FMF patients have reported inconsistent findings. A study by Alim et al. found no significant difference in choroidal thickness between FMF patients in remission and healthy controls.23 Gündoğan et al., on the other hand, demonstrated increased choroidal thickness in FMF patients during an attack compared to healthy controls. The authors attributed this observation to choroidal edema resulting from increased inflammation. They concluded that the systemic inflammatory and vasculopathic nature of FMF may lead to increased vascular permeability, exudation, and dilation of choroidal vessels, thereby contributing to increased choroidal thickness during acute attacks. However, the study was unable to ascertain whether the damage was permanent, as choroidal thickness was not evaluated during the remission period in the same patient group.24 Another study by Biçer et al. found that the choroidal thickness in the nasal quadrant was significantly lower in adult FMF patients than in the control group.25 In the present study, the choroidal thickness was lower in the patient group than in the control group. The thinner choroid observed in the study by Biçer et al. might be attributable to the adult study population and their prolonged exposure to chronic subclinical inflammation. The aforementioned study suggested that choroidal thinning in adults may be associated with atrophy. Chronic inflammation may impair the vascular integrity and function of the choroid. Ultimately, age-related atrophy may also impair the vascular integrity and function of the retinal layers. However, the researchers suggested that, since the patient and control groups were matched for age and sex, age-related influences were ruled out, and the observed changes were attributed to the disease. The choroid, with its rich vascular structure, is likely to reflect microvascular damage and tissue loss through its thinning. In addition, arteriosclerosis, a sign of chronic inflammation, may contribute to choroidal thinning as the disease duration increases. The absence of choroidal thinning in the present study may be attributed to the shorter disease duration in comparison to adults. However, choroidal thickness is also expected to decrease in pediatric patients with longer disease duration, irrespective of attacks. The absence of a difference in disease scores between the groups may also be attributed to the relatively short duration of the disease. With prolonged disease duration, it is believed that ocular findings may accompany systemic changes in patients with high disease activity scores.

All patients included in the study were receiving regular colchicine treatment. Colchicine, while effectively controlling FMF symptoms, has been associated with ocular toxicity, including retinal changes and corneal deposits. These effects should be considered when interpreting ophthalmic findings. Experimental studies suggest that colchicine can interfere with or delay the repair of nerve structures after injury. Dybowski et al. reported that administering colchicine intraocularly inhibits the regeneration of retinal nerve fibers. They proposed that the formation of new microtubules is essential for nerve growth and that colchicine exerts its effect by selectively binding to the β-tubulin unit of the α/β-tubulin heterodimer, thereby preventing the incorporation of additional heterodimers into the microtubule structure. They noted that this effect occurs shortly after intraocular colchicine injection, and that any unbound colchicine is subsequently cleared and inactivated via systemic circulation. Considering that patients in the study group received colchicine at therapeutic doses and exhibited no signs of toxicity, we believe that systemic clearance of unbound colchicine likely limits its impact on nervous tissue.26

The kidney and eye are quite similar in developmental, structural and pathogenic pathways. Given the structural and functional similarities between renal podocytes and retinal pericytes, the pathological processes affecting these organs may also overlap.27 Renal microvascular alterations play a key role in the pathophysiology of kidney injury and are among the primary contributors to proteinuria in kidney disease.28 A study by Balmforth et al. demonstrated an association between glomerular inflammatory damage and choroidal thinning.22 The authors interpreted choroidal thinning as a marker of systemic inflammation with renal involvement, reporting a strong correlation between increased proteinuria levels and reduced choroidal thickness. These findings indicate that retinal and choroidal changes observed in CKD may reflect widespread systemic microvascular damage. The present study revealed a significantly higher incidence of proteinuria in the patient group compared to controls, despite values remaining within normal limits. This suggests that in FMF, increased protein excretion—and consequently, early renal involvement—may occur even in the absence of amyloidosis. However, no significant association was found between proteinuria and RNFL thickness. A previous study reported that retinal thinning in patients with chronic inflammation predominantly affects the outer retinal layers.22 This finding also implies choroidal involvement, as the outer one-third of the retina is nourished by the choroid, while the inner two-thirds are supplied by the central retinal artery. Although choroidal damage may impact retinal structure, the absence of a significant association between proteinuria and RNFL thickness suggests that alternative, non-vascular mechanisms may be involved. Inflammation leads to direct tissue damage in the eye prior to vascular involvement, meaning that vascular damage, which contributes to increased proteinuria, may not influence RT. Consistent with this, elevated fibrinogen levels—an important inflammatory marker—and the negative correlation between fibrinogen and choroidal thickness further suggest that inflammation plays a key role in inducing significant choroidal alterations.

On the other hand, it has been shown that AL levels increase in parallel with protein excretion in FMF. The simultaneous involvement of both the kidney and the eye suggests that inflammation may affect these organs via shared pathological pathways. The NLRP3 inflammasome (NACHT, LRR, and PYD domain-containing protein 3) is a macromolecular cytoplasmic complex that regulates the innate immune system’s early inflammatory response through the production of IL-1β and IL-18. Activation of NLRP3 is a key factor in the kidney injury process, including the development of proteinuria.29 Additionally, NLRP3 has been implicated in the inflammatory processes of other organs. Studies have shown that inhibiting NLRP3 in certain inflammatory conditions, including retinal injury and involvement of other ocular layers, can restore several ocular findings, particularly retinal neovascularization, by blocking the IL-1β/IL-18 activation pathway.30 An experimental study demonstrated significantly elevated IL-1β levels in MEFV gene-positive mice, even in the absence of active disease.31 Similarly, elevated IL-18 levels have been reported in both the acute attack and remission phases of FMF patients.32

Given these findings, it is plausible that shared inflammatory mechanisms—particularly those mediated by NLRP3 activation—may contribute to both renal and ocular alterations in FMF. Although we observed a positive correlation between proteinuria and AL, no significant associations were found between proteinuria and RNFL or choroidal thickness. This correlation may reflect shared microvascular injury mechanisms affecting both renal and ocular tissues in the early stages of FMF.

This study has several limitations. The patients were evaluated only during remission, which limits our understanding of inflammation-related ocular changes during acute attacks. A subgroup analysis based on remission duration was not feasible due to the small sample size, though most patients were in prolonged remission under regular colchicine treatment. While colchicine itself may affect ocular tissues, including untreated patients for comparison was not ethically possible. Future studies with larger cohorts are needed to investigate the cumulative effects of subclinical inflammation and to explore colchicine-related ocular changes more effectively. Although our study did not focus on the effects of specific MEFV mutations, future research into genotype–phenotype correlations may provide insights into FMF-related ocular involvement. Additionally, analyzing inflammatory markers and inflammasome activity during both remission and attack phases, as well as accounting for confounding factors like diet, medications, and environmental influences, could enhance our understanding of disease mechanisms. Long-term, multi-center studies following patients into adulthood are also warranted to better clarify FMF pathogenesis and potential therapeutic targets. Although this was a prospective study, the relatively short follow-up period may limit the ability to observe the long-term cumulative effects of subclinical inflammation. Therefore, future longitudinal studies with extended follow-up are warranted to better understand the progression of ocular changes in FMF.

The results of this study indicate that chronic inflammation can lead to thinning of the RNFL and choroid, even in childhood, when the duration of disease exposure is relatively short. Moreover, these findings suggest that the ocular manifestations of this chronic disease may be more diverse and long-lasting than previously anticipated. The observation that ocular changes in the patient group were present during the remission period and were not influenced by disease activity may be attributed to elevated levels of certain inflammatory markers, which persist even in remission. However, it is important to note that other inflammatory factors, which increase during active disease and return to normal during remission, also play an important role in the pathogenesis of FMF. These inflammatory markers, although elevated during active periods, may not have contributed to permanent damage due to the relatively short disease duration in the study participants. However, in a longer disease course, however, these inflammation-related factors could potentially lead to irreversible damage.