April 2016
Volume 57, Issue 4
Open Access
Letters to the Editor  |   April 2016
Author Response: Causal Management of Keratoconus: Controlling Inflammation
Author Affiliations & Notes
  • Arkasubhra Ghosh
    GROW Research Laboratory Narayana Nethralaya Foundation, Bangalore, India;
    Singapore Eye Research Institute, Singapore;
  • Rohit Shetty
    GROW Research Laboratory Narayana Nethralaya Foundation, Bangalore, India;
    Cornea Department, Narayana Nethralaya, Bangalore, India; and the
  • Shyam S. Chaurasia
    Ocular Immunology and Angiogenesis Lab, Department of Veterinary Medicine and Surgery, University of Missouri, Columbia, Missouri, United States.
Investigative Ophthalmology & Visual Science April 2016, Vol.57, 2165. doi:10.1167/iovs.16-19532
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      Arkasubhra Ghosh, Rohit Shetty, Shyam S. Chaurasia; Author Response: Causal Management of Keratoconus: Controlling Inflammation. Invest. Ophthalmol. Vis. Sci. 2016;57(4):2165. doi: 10.1167/iovs.16-19532.

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      © ARVO (1962-2015); The Authors (2016-present)

  • Supplements
We are glad to receive comments from Galvis et al.1 on our study published in IOVS.2 We agree with their suggestions and appreciate the fact that inflammation is now considered one of the major components of keratoconus (KC) pathophysiology. As they rightly point out, our study in fact comes at the heels of an increasing number of reports indicating that the molecular drivers of KC may be inflammation-dependent factors causing matrix degradation.37 Furthermore, the inflammation observed in KC is somewhat skewed, resembling chronic inflammation associated with systemic diseases rather than acute inflammation.8 This is evidenced by the fact that acute inflammation proteins such as TNFα are not overly expressed in KC, but chronic inflammation-associated target genes such as matrix metalloproteinase (MMP) 9 are significantly high. In fact, MMP9 is known to reduce barrier functions,9 providing a chronic low-grade stimulation for the sustained inflammatory milieu. The KC disease pathology shows a similar phenomenon in not being associated with red eyes but evidently correlated with atopy, eye rubbing, and mechanical damage, which may be due to low-level irritation caused by an underlying subclinical, chronic inflammation. This is supported by the fact that ectasia progresses at variable rates in keratoconic patients. Rehany and Rumelt10 have reported an association of vernal keratoconjunctivitis (VKC) and early occurrence of corneal hydrops in KC, suggesting a role of inflammation in disease pathophysiology. In our previous clinical study, we noticed a higher incidence (55.5%) of progressive KC in patients with VKC. In the same study, we also observed a higher failure rate (17.6%) after corneal collagen cross-linking in patients with chronic ocular allergy.11 In addition, we demonstrated the secondary effects of cyclosporin A (CsA) in reducing MMP9 and inhibiting inflammation to halt progression of KC,2 supporting our hypothesis that inflammation is a key driver. A previous study has suggested that MMP9−/− mice have reduced severity of colitis, rheumatoid arthritis, and several autoimmune inflammatory diseases.12 This also suggests that specific MMP9 inhibitors in trials such as apratastat and PCK314512 may present novel treatment options for KC. 
Corneal biomechanical strength is an another important factor to be considered in KC.13 It is known that inflammation can actually lead to a transcriptional deregulation of the collagen genes14 essential for maintaining tissue architecture. This might be an important contributor to the structural weakness observed in KC patient corneas.15 However, one wonders whether patients with inflammatory-driven dry eye disease or ocular allergies are predisposed to KC. In addition, can we restore corneal structural strength by controlling inflammation? These questions remain to be solved and thereby open new avenues to investigate mechanisms involved in KC. Most importantly, we feel that management of inflammation can be an important first step in the management and progression of KC. 
Galvis V, Tello A, Carreñno NI, Berrospi RD, Niño CA. Causal management of keratoconus: controlling inflammation. Invest Ophthalmol Vis Sci. 2016; 57: 2164.
Shetty R, Ghosh A, Lim RR, et al. Elevated expression of matrix metalloproteinase-9 and inflammatory cytokines in keratoconus patients is inhibited by cyclosporine A. Invest Ophthalmol Vis Sci. 2015; 56: 738–750.
Lema I, Sobrino T, Duran JA, Brea D, Diez-Feijoo E. Subclinical keratoconus and inflammatory molecules from tears. Br J Ophthalmol. 2009; 93: 820–824.
Lema I, Duran JA, Ruiz C, Diez-Feijoo E, Acera A, Merayo J. Inflammatory response to contact lenses in patients with keratoconus compared with myopic subjects. Cornea. 2008; 27: 758–763.
Lema I, Duran JA. Inflammatory molecules in the tears of patients with keratoconus. Ophthalmology. 2005; 112: 654–659.
Jun AS, Cope L, Speck C, et al. Subnormal cytokine profile in the tear fluid of keratoconus patients. PLoS One. 2011; 6: e16437.
Balasubramanian SA, Mohan S, Pye DC, Willcox MD. Proteases proteolysis and inflammatory molecules in the tears of people with keratoconus. Acta Ophthalmol. 2012; 90: e303–e309.
Feghali CA, Wright TM. Cytokines in acute and chronic inflammation. Front Biosci. 1997; 2: d12–d26.
Pflugfelder SC, Farley W, Luo L, et al. Matrix metalloproteinase-9 knockout confers resistance to corneal epithelial barrier disruption in experimental dry eye. Am J Pathol. 2005; 166: 61–71.
Rehany U, Rumelt S. Corneal hydrops associated with vernal conjunctivitis as a presenting sign of keratoconus in children. Ophthalmology. 1995; 102: 2046–2049.
Shetty R, Nagaraja H, Jayadev C, Pahuja NK, Kurian Kummelil M, Nuijts RM. Accelerated corneal collagen cross-linking in pediatric patients: two-year follow-up results. Biomed Res Int. 2014; 2014: 894095.
Hu J, Van den Steen PE, Sang QX, Opdenakker G. Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov. 2007; 6: 480–498.
Shetty R, Nuijts RM, Srivatsa P, et al. Understanding the correlation between tomographic and biomechanical severity of keratoconic corneas. Biomed Res Int. 2015; 2015: 294197.
Greenwel P, Tanaka S, Penkov D, et al. Tumor necrosis factor alpha inhibits type I collagen synthesis through repressive CCAAT/enhancer-binding proteins. Mol Cell Biol. 2000; 20: 912–918.
Shetty R, Sathyanarayanamoorthy A, Ramachandra RA, et al. Attenuation of lysyl oxidase and collagen gene expression in keratoconus patient corneal epithelium corresponds to disease severity. Mol Vis. 2015; 21: 12–25.

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