Keratoconus International Consortium (KIC)- advancing keratoconus research

Keratoconus is a progressive disorder characterised by abnormal corneal elevation, thickness distribution and corneal thinning [1]. It typically has an onset in the second decade of life and may progress until the fifth decade. It is a significant cause of visual impairment, especially in young adults. While diagnosis is unequivocal when clinical signs of corneal thinning and steepening are observed directly through biomicroscopy or corneal tomography, detection of early keratoconus remains challenging as there is currently no standard diagnostic or grading system for keratoconus. Further, there is no accepted definition of progression, and no ability to predict the prognosis and outcomes of treatment for individual patients [1‐6].

The incidence of the disease is historically reported as 1 in 2000, based on longitudinal data collection from 1936 to 1982 from a single county in Minnesota, USA [7]. However, the limitations of this study, together with advances in imaging with corneal topography and tomography have suggested a higher incidence, including 1 in 375 being reported in the Netherlands based on national health insurance data [8]. Variations in prevalence across different populations are also apparent, with a prevalence of 1 in 42 reported from a college student population in Jerusalem, with a prevalence of 1.43% reported from a university student population in Syria [9] and a prevalence of 1 in 139 reported from a population-based study in Shahroud, Iran [10]. Evidence suggests a higher prevalence of keratoconus amongst Black and Hispanic communities in the USA and amongst Maori and Polynesian populations in New Zealand compared to Caucasian populations [11, 12]. Data from the United Kingdom has also shown Asian patients present at a younger age and with more advanced disease [13, 14].

The aetiology of keratoconus remains unknown, although it appears to be a complex, heterogeneous disorder with multiple causative factors that can be broadly classified as environmental, biomechanical, biochemical and genetic [1, 15‐20]. The most likely mode of inheritance has been suggested as autosomal dominant although recessive genes may also exist [21‐24]. An association with environmental and biomechanical factors is often described, with mechanical trauma from eye-rubbing, stimulation through contact lens wear or kerato-refractive laser surgery reported as contributing factors in the progression of keratoconus [25, 26]. The possible role of biochemical factors has also been implicated in the aetiology of this disease with elevated levels of matrix metalloproteinases and inflammatory cytokines found in keratoconus [27]. However, it is unclear if this is reflective of a cause or effect.

One of the main limitations of existing studies on keratoconus has been the relatively small number of patients that have been studied and reported, leading to underpowered analyses and false positive findings that limit generalisability of the results. Furthermore, differences in study design, patient populations, sampling methods, diagnostic methodology, outcome measurements, and length of follow-up have precluded the development of an overall predictive model for keratoconus. Diagnosis at the early stages of the disease is critical as corneal cross linking (CXL) can be performed to slow the progression of the condition to maintain vision and corneal regularity [28]. Differences in treatment outcomes have also been recorded with a higher risk of treatment failure from CXL or corneal transplantation in the paediatric population compared to adults indicating important gaps in the current understanding [29‐32].

KIC will be a first worldwide study in KC that will allow us to undertake a unified analysis to enable better diagnosis of individuals at early risk of disease, explore a therapeutic algorithm specific to the pediatric KC, coming up with a revised classification system of KC useful for clinical decision making, identification of biomarkers to be targeted for future therapy, and finally drawing together of multiple sites for when there is a treatment ready for trialing and potentially avoiding graft surgery. The main aims of KIC are:

The preliminary findings of the KIC identified that 15.3% of patients had a reported family history of keratoconus which represents an increase over historical findings of 6–10% [21]. Although it may represent an increase in incidence, this value likely reflects both a growing understanding of the disease and clinician diagnostic capabilities. Over half (57.7%) of the KC patients reported some degree of eye-rubbing. Literature suggests rates between 44–100% of patients reporting eye-rubbing with a recent meta-analysis indicating a threefold odds ratio of developing KC in eye rubbers compared to non-eye rubbers [44, 45]. Although eye-rubbing represents a significant risk factor, the variance within the literature and available populations, suggests that an incomplete understanding of the impact of eye rubbing on aspects such as disease progression. Combined, these outcomes therefore suggest a role for developing a larger international, longitudinal database to help further define clinical and demographic variables that may contribute to disease diagnosis and progression. Although clinical evaluation continues to be variable across cohorts, the presence of a single, standardised, large dataset should help refine data collection and provide an increasingly relevant platform to allow for more accurate and robust determination of risk factors for the disease, with the added provision of offering the ability to validate findings with other groups within the consortium. Furthermore, longitudinal data will allow analysis of risk factors for disease progression and assessment of treatment efficacy.

There have previously been two main longitudinal studies investigating KC. The Collaborative Longitudinal Evaluation of Keratoconus (CLEK) study recorded a number of variables amongst 1209 patients including high and low contrast visual acuity, corneal curvature, biomicroscopy and quality of life [46]. Results from this study significantly expanded clinician’s understanding of the natural history of the disease, including the possible role of gender and family history in progression of the disease and its effect on quality of life [47‐52]. The Dundee University Scottish Keratoconus study (DUSKS) examined 200 patients at time of enrolment and after a mean of 1004 days. DUSKS provided valuable information regarding demographic and environmental associations with the disease including the role of contact lenses in KC, the role of eye rubbing and impact of scarring on disease progression [53, 54]. Significantly, DUSKS was the first longitudinal trial on KC to utilise corneal topography throughout the duration of the study.

The potential advantage of the KIC compared to CLEK and DUSKS is its international, multi-centre cohort design which allows examination of a wider range of KC parameters and the impact of ethnicity and differing environment factors on the disease. With ongoing recruitment of sites and patient data entry, the sample size has the potential to rapidly grow.

There are a number of published indices and grading systems used for KC based on visual acuity, biomicroscopic or topographic/tomographic signs [55‐59]. Numerous additional indices may be important, such as corneal aberrations, corneal volume, internal astigmatism and corneal biomechanics [2, 58, 60‐64]. More recently, epithelial thickness has been proposed as a diagnostic tool to diagnose and classify KC patients [65, 66]. The availability of numerous indices and the absence of standard criteria for the diagnosis and classification of KC indicates that we are no closer to differentiating the earliest stages of KC from normal corneas which represents an essential goal for identifying at risk patients for progression and further for those patients undertaking potential corneal laser refractive surgery [67, 68]. Significantly however, it also reflects the wide range of morphology within the disease. Of special interest to the KIC will be studies on risk factors and grades of disease for KC and in particular their association with prognosis and the outcomes of therapeutic treatments. In the future, targeted treatments, orchestrated across multiple trial sites will allow monitoring of treatment outcomes and provide information on the impact of different risk factors. The use of a large centralised, consistent database can provide researchers with an excellent platform to use developing technologies such as artificial intelligence to explore a variety of novel interactions within the data which may help resolve some of these knowledge gaps or help define future research directions.

The Sight Loss and Vision Priority Setting Partnership identified research priorities through consultation with patients, carers and clinicians [69]. Some of the top 11 priorities in corneal diseases can be addressed through the KIC projects: what is the cause of KC; how it can be prevented; what causes progression of KC; how can progression be prevented; development of new therapies such as genetic treatments for corneal disease; and how the outcomes of corneal transplantation can be improved.

The next phase of KIC is expanding the current database to include Optometrists, who are the primary eye care providers. As such some of the current Institutes do have Optometrists and Corneal Surgeons working together (example- L. V. Prasad Eye Institute, India), however we would like to expand to private practises where KC subjects will be separately monitored at majority of the disease stages. This includes at the beginning of the disease (for the diagnosis), in the middle of the disease for contact lens fitting and prescriptions of topical anti-inflammatories and antihistamine/mast-cell stabilizers, and at the end of the disease (often rehabilitating post graft corneas). Thus, recruitment continues to be ongoing and it is expected that follow up investigations from the KIC will bear the inclusion of optometrists appropriately. All investigators within the KIC are equally encouraged to present research ideas and opportunities.

We have recognised the need to expand KC research to a global level to overcome differences in study design, patient populations, sampling methods, outcome measurements and lengths of follow-up. Of note, the early members of the KIC represent a combination of ophthalmic and tertiary research institutions. This may provide a bias towards more significant, progressive cases. Given the increasing presence of topography and tomography diagnostic units in optometric practices, the KIC will expand to incorporate optometry practices to further explore the identification of early detection of KC and which features are associated with disease onset. Understanding the practice and clinical differences across allied health groups is likely to further increase understanding and awareness of KC protocols to the benefit of all patients. To assist the development of the KIC, revise the available data and understand future directions, it is intended for the KIC to meet at regular intervals. We believe this will limit concerns around data collection and further strengthen collaboration and developmental opportunities for all members.

The KIC is a powerful potential tool for groups to study many aspects of KC which will have important clinical implications when interpreting studies from different regions around the world. Its main strength is that it is led by its members, where all members have an equal opportunity to contribute not only to the data but lead individual projects of interest. An understanding of disease presentation and progression patterns among various ethnic groups is warranted and could be achieved through this global collaborative initiative. The KIC establishes a database with the aim of establishing the world’s leading consortium for this disease.

KIC, a multi-pronged, multi-ethnic and multi-centre approach that constitutes a large-scale, international collaboration to undertake unified data analysis to enable a better understanding of KC. Ultimately, this will optimise diagnostic and treatment interventions for our patients.