- Email: [email protected]
Re: Woodward et al.: The association between sociodemographic factors, common systemic diseases, and keratoconus: an analysis of a nationwide heath care claims database (Ophthalmology 2016;123:457-65)
Correspondence Finally, the heteroplasmy rates of primary LHON mutations are not 100% in all patients. For clinical manifestations of LHON, however, a heteroplasmy rate of 60% is required. Overall, this interesting study could benefit from investigations of organs other than the eye, from genetic testing of first degree relatives, and from a long-term follow-up. Because of the multisystem nature of LHON, treatment of the eyes exclusively may not affect involvement of organs other than the eyes.
JOSEF FINSTERER, MD, PHD1 SINDA ZARROUK-MAHJOUB, PHD2 1 Krankenanstalt Rudolfstiftung, Vienna, Austria; 2Genomics Platform, Pasteur Institute of Tunis, Tunis, Tunisia
Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article. Correspondence: Josef Finsterer, MD, PhD, Krankenanstalt Rudolfstiftung, Neurolgocal, Postfach 20, Vienna 1180, Austria. E-mail: fi[email protected].
References 1. Feuer WJ, Schiffman JC, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy: initial results. Ophthalmology 2016;123:558–70. 2. Finsterer J, Stöllberger C, Prainer C, Hochwarter A. Lone noncompaction in Leber’s hereditary optic neuropathy. Acta Cardiol 2004;59:187–90. 3. Mulliez E, Blanckaert M, Blanckaert J. Acute manifestation of LHON and coincidental finding of a pituitary adenoma: a case report. Bull Soc Belge Ophthalmol 2000;277:35–42. 4. Phasukkijwatana N, Chuenkongkaew WL, Suphavilai R, et al. The unique characteristics of Thai Leber hereditary optic neuropathy: analysis of 30 G11778A pedigrees. J Hum Genet 2006;51:298–304. 5. Fruhman G, Landsverk ML, Lotze TE, et al. Atypical presentation of Leigh syndrome associated with a Leber hereditary optic neuropathy primary mitochondrial DNA mutation. Mol Genet Metab 2011;103:153–60. REPLY: We thank Drs Finsterer and Zarrouk-Mahjoub for their interest in our paper.1 We have not tested first-degree relatives because this was outside the scope of our study. All the patients with Leber’s Hereditary Optic Neuropathy who we enrolled and treated underwent an examination with blood work to exclude other mediconeurologic conditions at baseline. Visual loss was the only manifestation of their genetic mutation and we are carefully monitoring other organ systems of our patients as part of the safety assessment of the treatment. We too have previously noted spontaneous natural history improvement, especially in acute patients.2 We agree with the authors that care is needed in the interpretation of potential treatment efficacy, especially with the small number of patients and the short follow up in our published manuscript. Further, we hope that readers of our report will keep in mind that the tantalizing suggestion of possible efficacy is not the main focus of this phase I safety trial. To date, our data suggest that the gene therapy vector is safe.
JOHN GUY, MD Department of Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida Financial Disclosures: The author has no proprietary or commercial interest in any materials discussed in this article. Correspondence: John Guy, MD, Department of Ophthalmology, Bascom Palmer Eye Institute, 1638 NW 10th Avenue, Miami, FL 33136. E-mail: [email protected].
References 1. Feuer WJ, Schiffman JC, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy: initial results. Ophthalmology 2016;123:558–70. 2. Lam BL, Feuer WJ, Schiffman JC, et al. Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy: preparation for gene therapy clinical trial. JAMA Ophthalmol 2014;132:428–36.
Re: Woodward et al.: The association between sociodemographic factors, common systemic diseases, and keratoconus: an analysis of a nationwide heath care claims database (Ophthalmology 2016;123:457-65) TO THE EDITORS: We read with interest the article by Woodward et al.1 The authors claimed that patients with sleep apnea, asthma, and Down syndrome are more likely to develop keratoconus (KC). We recently performed a study evaluating the association between KC and familial Mediterranean fever (FMF).2 We found that FMF was a predisposing factor for KC development (odds ratio, 18.1; 95% confidence interval [CI], 11.9-27.5), especially in patients with homozygous mutation (odds ratio, 43.4; 95% CI, 28.6-65.7). We concluded that inflammation may precipitate KC in patients with FMF. We hypothesized that MEFV gene mutations leading to interleukin (IL)-1B activation may be a predisposing factor for KC development by increasing keratocyte apoptosis3 and IL-1B may play a key role in the pathogenesis of both FMF and KC. Woodward et al1 also concluded that patients with diabetes mellitus had lower odds of KC. We have recently examined the association between KC and diabetes and concluded that there may be a positive association between type 2 diabetes mellitus and the presence and severity of KC in contrast to the literature.4 There are 2 types of advanced glycation end products (AGEs)d those that form intermolecular crosslinks and those that remain nonecrosslinked. Crosslinks formed between collagen molecules prevent collagen degradation by reducing their elasticity. It usually takes weeks or months for cross-linking AGEs to come into existence; therefore, only molecules that are exposed to high glucose levels for longer periods of time are influenced by this mechanism of glycation. However, nonecross-linking AGEs form within days.5 We hypothesize that the difference between our results and those of previous publications may be explained by the concept that nonecross-linking AGEs change the equilibrium distribution to render collagen more vulnerable to collagenolysis.
e45
Ophthalmology Volume 123, Number 7, July 2016 Relatively brief periods of hyperglycemia may make collagen more prone to collagenolysis, which is quite the opposite of protracted periods of glucose exposure. It might be useful to perform a prospective study in an animal model that would compare the effects of different exposure times (brief [days] and long [weeks/ months]) to different glucose concentrations in diabetic patients to further understand the exact effect of exposure time to hyperglycemia on KC.
MUSTAFA KOSKER, MD CANAN GURDAL, MD Diskapi Yildirim Beyazit Training and Research Hospital, Department of Ophthalmology, Ankara, Turkey Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article. Correspondence: Mustafa Kosker, MD, Department of Ophthalmology, Diskapi Yildirim Beyazit Training and Research Hospital, 6450 Turkey. E-mail: [email protected].
References 1. Woodward MA, Blachley TS, Stein JD. The association between sociodemographic factors, common systemic diseases, and keratoconus: an analysis of a nationwide heath care claims database. Ophthalmology 2016;123:457–65. 2. Kosker M, Arslan N, Alp MY, et al. Association between keratoconus and familial Mediterranean fever in Turkey. Cornea 2016;35:77–80. 3. Chae JJ, Wood G, Masters SL, et al. The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1b production. Proc Natl Acad Sci U S A 2006;103:9982–7. 4. Kosker M, Suri K, Hammersmith KM, et al. Another look at the association between diabetes and keratoconus. Cornea 2014;33: 774–9. 5. Aronson D, Rayfield EJ. How hyperglycemia promotes atherosclerosis: molecular mechanisms. Cardiovasc Diabetol 2002;1:1. REPLY: We thank Dr Kosker for his comments on our article about the relationship of keratoconus to common systemic diseases and appreciate his sharing with journal readers and us the interesting work that he and his group have been performing in this research area. Including our publication, now 3 studies, each using a different study design and different patient population, all support the notion that persons with diabetes mellitus are less likely to have keratoconus than those without diabetes.1e3 Kosker contends the reason their study4 found the opposite result with ours and others in the literature may be due to differences in the proportion of patients with cross-linked advanced glycosyl-
e46
ation end products (AGEs) and nonecross-linked AGEs among the various studies. None of the existing studies including his and ours collected data on AGEs, so it is impossible to know with any certainty whether differences in the types of AGEs among the groups are contributing to the differences in findings among the studies. That said, there is no reason for us to believe that the severity or duration of diabetes was so dramatically different among the study populations that the types of AGEs would be so different among the enrollees in the various studies. A more likely explanation for the difference in results between their study and ours is differences in the study population, study design, eligibility criteria, and the extent by which the studies accounted for selection bias. We acknowledge that all 4 of these studies are retrospective and agree with Kosker that the best way to study the relationship between diabetes and keratoconus would be to perform a prospective study with a large cohort of patients who are followed for many years with serial measurements of clinical and laboratory data, including AGEs. We hope that the findings of our analyses and theirs help to motivate others to perform such a prospective analysis to more fully delineate the relationship between these 2 conditions.
MARIA A. WOODWARD, MD TAYLOR S. BLACHLEY, MS JOSHUA D. STEIN, MD, MS University of Michigan, Ann Arbor, Michigan Financial Disclosures: The authors made the following disclosures: M.A.W.: National Eye Institute, National Institutes of Health, Bethesda, Maryland (K23 Mentored Clinical Scientist Award no. K23EY02359601); Advisory Board e Intelligent Retinal Imaging Systems J.D.S.: Research to Prevent Blindness, Inc., New York, New York Correspondence: Maria A. Woodward, MD, Department of Ophthalmology and Visual Sciences, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105. E-mail: [email protected].
References 1. Woodward MA, Blachley TS, Stein JD. The association between sociodemographic factors, common systemic diseases, and keratoconus: an analysis of a nationwide heath care claims database. Ophthalmology 2016;123:457–65. 2. Seiler T, Huhle S, Spoerl E, Kunath H. Manifest diabetes and keratoconus: a retrospective case-control study. Graefes Arch Clin Exp Ophthalmol 2000;238:822–5. 3. Kuo IC, Broman A, Pirouzmanesh A, Melia M. Is there an association between diabetes and keratoconus? Ophthalmology 2006;113:184–90. 4. Kosker M, Suri K, Hammersmith KM, et al. Another look at the association between diabetes and keratoconus. Cornea 2014;33: 774–9.
JOSEF FINSTERER, MD, PHD1 SINDA ZARROUK-MAHJOUB, PHD2 1 Krankenanstalt Rudolfstiftung, Vienna, Austria; 2Genomics Platform, Pasteur Institute of Tunis, Tunis, Tunisia
Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article. Correspondence: Josef Finsterer, MD, PhD, Krankenanstalt Rudolfstiftung, Neurolgocal, Postfach 20, Vienna 1180, Austria. E-mail: fi[email protected].
References 1. Feuer WJ, Schiffman JC, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy: initial results. Ophthalmology 2016;123:558–70. 2. Finsterer J, Stöllberger C, Prainer C, Hochwarter A. Lone noncompaction in Leber’s hereditary optic neuropathy. Acta Cardiol 2004;59:187–90. 3. Mulliez E, Blanckaert M, Blanckaert J. Acute manifestation of LHON and coincidental finding of a pituitary adenoma: a case report. Bull Soc Belge Ophthalmol 2000;277:35–42. 4. Phasukkijwatana N, Chuenkongkaew WL, Suphavilai R, et al. The unique characteristics of Thai Leber hereditary optic neuropathy: analysis of 30 G11778A pedigrees. J Hum Genet 2006;51:298–304. 5. Fruhman G, Landsverk ML, Lotze TE, et al. Atypical presentation of Leigh syndrome associated with a Leber hereditary optic neuropathy primary mitochondrial DNA mutation. Mol Genet Metab 2011;103:153–60. REPLY: We thank Drs Finsterer and Zarrouk-Mahjoub for their interest in our paper.1 We have not tested first-degree relatives because this was outside the scope of our study. All the patients with Leber’s Hereditary Optic Neuropathy who we enrolled and treated underwent an examination with blood work to exclude other mediconeurologic conditions at baseline. Visual loss was the only manifestation of their genetic mutation and we are carefully monitoring other organ systems of our patients as part of the safety assessment of the treatment. We too have previously noted spontaneous natural history improvement, especially in acute patients.2 We agree with the authors that care is needed in the interpretation of potential treatment efficacy, especially with the small number of patients and the short follow up in our published manuscript. Further, we hope that readers of our report will keep in mind that the tantalizing suggestion of possible efficacy is not the main focus of this phase I safety trial. To date, our data suggest that the gene therapy vector is safe.
JOHN GUY, MD Department of Ophthalmology, Bascom Palmer Eye Institute, Miami, Florida Financial Disclosures: The author has no proprietary or commercial interest in any materials discussed in this article. Correspondence: John Guy, MD, Department of Ophthalmology, Bascom Palmer Eye Institute, 1638 NW 10th Avenue, Miami, FL 33136. E-mail: [email protected].
References 1. Feuer WJ, Schiffman JC, Davis JL, et al. Gene therapy for Leber hereditary optic neuropathy: initial results. Ophthalmology 2016;123:558–70. 2. Lam BL, Feuer WJ, Schiffman JC, et al. Trial end points and natural history in patients with G11778A Leber hereditary optic neuropathy: preparation for gene therapy clinical trial. JAMA Ophthalmol 2014;132:428–36.
Re: Woodward et al.: The association between sociodemographic factors, common systemic diseases, and keratoconus: an analysis of a nationwide heath care claims database (Ophthalmology 2016;123:457-65) TO THE EDITORS: We read with interest the article by Woodward et al.1 The authors claimed that patients with sleep apnea, asthma, and Down syndrome are more likely to develop keratoconus (KC). We recently performed a study evaluating the association between KC and familial Mediterranean fever (FMF).2 We found that FMF was a predisposing factor for KC development (odds ratio, 18.1; 95% confidence interval [CI], 11.9-27.5), especially in patients with homozygous mutation (odds ratio, 43.4; 95% CI, 28.6-65.7). We concluded that inflammation may precipitate KC in patients with FMF. We hypothesized that MEFV gene mutations leading to interleukin (IL)-1B activation may be a predisposing factor for KC development by increasing keratocyte apoptosis3 and IL-1B may play a key role in the pathogenesis of both FMF and KC. Woodward et al1 also concluded that patients with diabetes mellitus had lower odds of KC. We have recently examined the association between KC and diabetes and concluded that there may be a positive association between type 2 diabetes mellitus and the presence and severity of KC in contrast to the literature.4 There are 2 types of advanced glycation end products (AGEs)d those that form intermolecular crosslinks and those that remain nonecrosslinked. Crosslinks formed between collagen molecules prevent collagen degradation by reducing their elasticity. It usually takes weeks or months for cross-linking AGEs to come into existence; therefore, only molecules that are exposed to high glucose levels for longer periods of time are influenced by this mechanism of glycation. However, nonecross-linking AGEs form within days.5 We hypothesize that the difference between our results and those of previous publications may be explained by the concept that nonecross-linking AGEs change the equilibrium distribution to render collagen more vulnerable to collagenolysis.
e45
Ophthalmology Volume 123, Number 7, July 2016 Relatively brief periods of hyperglycemia may make collagen more prone to collagenolysis, which is quite the opposite of protracted periods of glucose exposure. It might be useful to perform a prospective study in an animal model that would compare the effects of different exposure times (brief [days] and long [weeks/ months]) to different glucose concentrations in diabetic patients to further understand the exact effect of exposure time to hyperglycemia on KC.
MUSTAFA KOSKER, MD CANAN GURDAL, MD Diskapi Yildirim Beyazit Training and Research Hospital, Department of Ophthalmology, Ankara, Turkey Financial Disclosures: The authors have no proprietary or commercial interest in any materials discussed in this article. Correspondence: Mustafa Kosker, MD, Department of Ophthalmology, Diskapi Yildirim Beyazit Training and Research Hospital, 6450 Turkey. E-mail: [email protected].
References 1. Woodward MA, Blachley TS, Stein JD. The association between sociodemographic factors, common systemic diseases, and keratoconus: an analysis of a nationwide heath care claims database. Ophthalmology 2016;123:457–65. 2. Kosker M, Arslan N, Alp MY, et al. Association between keratoconus and familial Mediterranean fever in Turkey. Cornea 2016;35:77–80. 3. Chae JJ, Wood G, Masters SL, et al. The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1b production. Proc Natl Acad Sci U S A 2006;103:9982–7. 4. Kosker M, Suri K, Hammersmith KM, et al. Another look at the association between diabetes and keratoconus. Cornea 2014;33: 774–9. 5. Aronson D, Rayfield EJ. How hyperglycemia promotes atherosclerosis: molecular mechanisms. Cardiovasc Diabetol 2002;1:1. REPLY: We thank Dr Kosker for his comments on our article about the relationship of keratoconus to common systemic diseases and appreciate his sharing with journal readers and us the interesting work that he and his group have been performing in this research area. Including our publication, now 3 studies, each using a different study design and different patient population, all support the notion that persons with diabetes mellitus are less likely to have keratoconus than those without diabetes.1e3 Kosker contends the reason their study4 found the opposite result with ours and others in the literature may be due to differences in the proportion of patients with cross-linked advanced glycosyl-
e46
ation end products (AGEs) and nonecross-linked AGEs among the various studies. None of the existing studies including his and ours collected data on AGEs, so it is impossible to know with any certainty whether differences in the types of AGEs among the groups are contributing to the differences in findings among the studies. That said, there is no reason for us to believe that the severity or duration of diabetes was so dramatically different among the study populations that the types of AGEs would be so different among the enrollees in the various studies. A more likely explanation for the difference in results between their study and ours is differences in the study population, study design, eligibility criteria, and the extent by which the studies accounted for selection bias. We acknowledge that all 4 of these studies are retrospective and agree with Kosker that the best way to study the relationship between diabetes and keratoconus would be to perform a prospective study with a large cohort of patients who are followed for many years with serial measurements of clinical and laboratory data, including AGEs. We hope that the findings of our analyses and theirs help to motivate others to perform such a prospective analysis to more fully delineate the relationship between these 2 conditions.
MARIA A. WOODWARD, MD TAYLOR S. BLACHLEY, MS JOSHUA D. STEIN, MD, MS University of Michigan, Ann Arbor, Michigan Financial Disclosures: The authors made the following disclosures: M.A.W.: National Eye Institute, National Institutes of Health, Bethesda, Maryland (K23 Mentored Clinical Scientist Award no. K23EY02359601); Advisory Board e Intelligent Retinal Imaging Systems J.D.S.: Research to Prevent Blindness, Inc., New York, New York Correspondence: Maria A. Woodward, MD, Department of Ophthalmology and Visual Sciences, University of Michigan, 1000 Wall Street, Ann Arbor, MI 48105. E-mail: [email protected].
References 1. Woodward MA, Blachley TS, Stein JD. The association between sociodemographic factors, common systemic diseases, and keratoconus: an analysis of a nationwide heath care claims database. Ophthalmology 2016;123:457–65. 2. Seiler T, Huhle S, Spoerl E, Kunath H. Manifest diabetes and keratoconus: a retrospective case-control study. Graefes Arch Clin Exp Ophthalmol 2000;238:822–5. 3. Kuo IC, Broman A, Pirouzmanesh A, Melia M. Is there an association between diabetes and keratoconus? Ophthalmology 2006;113:184–90. 4. Kosker M, Suri K, Hammersmith KM, et al. Another look at the association between diabetes and keratoconus. Cornea 2014;33: 774–9.