Cystic fibrosis (CF) is an autosomal recessive disorder caused by defects in the CFTR (cystic fibrosis transmembrane conductance regulator) protein. It is characterized by recurrent lung infections and pancreatic insufficiency, leading to shortened lifespan.
Ivacaftor is a CFTR modulator that increases the open probability of the CFTR channel, enhancing chloride ion transport. It was initially developed for CF patients with gating mutations such as G551D. It is now used in combination with other modulators such as lumacaftor, elexacaftor, and tezacaftor.
Trikafta (tezacaftor/ivacaftor/elexacaftor) has been shown to restore CFTR function in patients with the F508del mutation, which is present in 90% of CF patients, and the majority of CF patients may take it in the future.
A notable side effect of ivacaftor is the formation of non-congenital cataracts in children. A similar risk has not been clearly demonstrated in adults.
Reported cataracts have not been considered to affect visual function. However, additional studies are ongoing, and the full extent of future risk has not yet been defined.
In many cases, symptoms are mild or unnoticed.
Cortical Cataract
Age of onset: Mainly in children aged 2 to 6 years.
Incidence: In a Vertex study, 1/24 (4.17%) developed cataracts within 84 weeks of starting ivacaftor.
Features: Opacities occur in the cortex. The impact on visual function is considered minimal.
Subcapsular Cataract
Age of onset: Mainly in older children and adolescents aged 12 years and older.
Incidence: With lumacaftor + ivacaftor combination, 1/176 (0.57%) developed within 96 weeks.
Features: Reported as posterior subcapsular opacities.
In cases aged 6–11 years, 1/58 (1.72%) developed cataracts within 24 weeks of starting lumacaftor and ivacaftor combination (type of cataract not specified).
Differences in the type and incidence of cataracts by age group have been suggested. Younger patients may be at higher risk, but the detailed risk levels of both groups have not yet been fully defined.
The exact pathophysiology of ivacaftor-associated cataracts is unknown. Cataract formation has been confirmed in preclinical studies using rats, but there are known differences in eye development between rats and humans.
Studying the association between drugs and cataracts is generally difficult because it is challenging to separate the effects of the drug itself from the effects of the disease being treated1).
Long-term use of inhaled or oral steroids is a known risk factor for drug-induced cataracts in general1). The mechanism of cataract formation due to ivacaftor is thought to be different, but the details have not been elucidated.
The influence of additional comorbidities on the development of ivacaftor-related cataracts cannot be ruled out.
Not everyone develops cataracts. Reported incidence rates are approximately 4% in children aged 2–6 years and about 0.5–1.7% in those aged 12 years and older. While recognizing the risk of cataracts, it is important to detect them early through regular eye examinations.
The diagnosis of ivacaftor-related cataracts is made by slit-lamp examination under dilated pupils. The following examination process is recommended.
Vertex Pharmaceuticals recommends baseline and follow-up ophthalmic examinations at the start of ivacaftor treatment. Other sources also recommend regular ophthalmic screening for children under 12 years of age taking ivacaftor.
There is no uniform recommendation for specific examination intervals. Baseline examination before starting treatment is essential, and regular follow-up visits should be scheduled according to the physician’s judgment.
No specific treatment for ivacaftor-related cataracts has been established. The mainstay of management is regular ophthalmic monitoring.
In vitro studies have confirmed that ivacaftor increases the open probability of CFTR channels and enhances chloride ion transport. However, the mechanism by which this causes cataracts remains unknown.
Several hypotheses have been proposed, but none have been proven.
Additional studies are currently underway to evaluate the risk of cataract formation in pediatric patients taking ivacaftor. In particular, clarifying differences in risk levels by age group is a key challenge.
In the future, the majority of cystic fibrosis patients are expected to take Trikafta (a triple combination therapy including ivacaftor). Accordingly, the need for large-scale epidemiological studies to evaluate the long-term effects of ivacaftor-related cataracts has been highlighted.
Research is also being conducted on whether rapamycin and statins may have complementary effects in improving cystic fibrosis-related symptoms, but their impact on ophthalmic complications is unknown.
