We read with great interest the article entitled "Smoking was associated with poor response to intravenous steroids therapy in Graves' ophthalmopathy" by Xing et al [1]. Cigarette smoking is known to be the most important risk factor for the development or deterioration of GO, and it is associated with poor response to treatment for GO. However, the exact mechanisms which prove deleterious effect of cigarette smoking on GO rem...
We read with great interest the article entitled "Smoking was associated with poor response to intravenous steroids therapy in Graves' ophthalmopathy" by Xing et al [1]. Cigarette smoking is known to be the most important risk factor for the development or deterioration of GO, and it is associated with poor response to treatment for GO. However, the exact mechanisms which prove deleterious effect of cigarette smoking on GO remain poorly understood.
It has been suggested that smoke-induced generation of reactive oxygen species (ROS) may play a role in the pathogenesis of GO, either through direct contact with the paranasal sinuses, or indirectly through the bloodstream [2]. Previously, we had revealed that smokers had significant higher urinary 8-OHdG (product of oxidative DNA damage) than never smokers in GO patients [3]. Recently , we observed that cigarette smoke extract (CSE)-induced more cytotoxicity and ROS accumulation in a dose-dependent manner in the GO orbital fibroblasts as compared to those of normal controls. The increased generation of ROS, especially the superoxide anions and hydrogen peroxide, can stimulate orbital fibroblasts proliferation and induce the production of pro-inflammatory cytokines, being key pathological features of GO [4]. More importantly, we also noted that cigarette smoke-mediated oxidative stress could induce fibrotic-related genes expression, including apolipoprotein J, fibronectin, and connective tissue growth factor (CTGF) in the GO orbital fibroblasts (169%, 180%, and 170%, respectively) , and these inductions could be inhibited by pretreatment with antioxidants.
Apolipoprotein J, fibronectin, and CTGF are all important fibrogenic factors. Especially, CTGF is critical for TGF-beta-mediated fibroblast-myofibroblast transdifferentiation and subsequent extracellular matrix deposition [5], which may contribute to the tissue remodeling and fibrosis process in GO. Besides, CSE has been reported to stimulate adipocyte differentiation in GO orbital fibroblasts either by synergizing with ROS or interleukin -1 [2,6]. Collectively, previous reports and our current findings may explain, in part, why smoking is associated with poor response to immunosuppressive therapy in GO.
References
1. Xing L, Ye L, Zhu W, Shen L, Huang F, Jiao Q, Zhou X, Wang S, Wang
W, Ning G. Smoking was associated with poor response to intravenous
steroids therapy in Graves' ophthalmopathy. Br J Ophthalmol. 2015;99:1686-
91.
2. Yoon JS, Lee HJ, Chae MK, Lee SY, Lee EJ. Cigarette smoke extract- induced adipogenesis in Graves' orbital fibroblasts is inhibited by quercetin via reduction in oxidative stress. J Endocrinol. 2013;216:145- 56.
3. Tsai CC, Cheng CY, Liu CY, Kao SC, Kau HC, Hsu WM, Wei YH. Oxidative stress in patients with Graves' Ophthalmopathy: Relationship between oxidative DNA damage and clinical evolution. Eye (Lond). 2009;23:1725-30.
4. Tsai CC, Cheng CY, Liu CY, Kao SC, Kau HC, Hsu WM, Wei YH.
Oxidative stress in patients with Graves' Ophthalmopathy: Relationship
between oxidative DNA damage and clinical evolution. Eye (Lond).
2009;23:1725-30.
6. Cawood TJ, Moriarty P, O'Farrelly C, O'Shea D. Smoking and thyroid -associated ophthalmopathy: a novel explanation of the biological link. Journal of Clinical Endocrinology and Metabolism. 2007;92:59-64.
We read with great interest the article entitled "Pathogenesis of
thyroid eye disease: review and update on molecular mechanisms" by Khong
et al [1]. We would like to contribute to the article with our novel
findings.
In our previous study, we first demonstrated the up-regulation of
mRNA and protein expression of fibrosis-related genes including
fibronectin, apolipoprotein J and connective tissue growth factor...
We read with great interest the article entitled "Pathogenesis of
thyroid eye disease: review and update on molecular mechanisms" by Khong
et al [1]. We would like to contribute to the article with our novel
findings.
In our previous study, we first demonstrated the up-regulation of
mRNA and protein expression of fibrosis-related genes including
fibronectin, apolipoprotein J and connective tissue growth factor (CTGF),
in the orbital fibroblasts from patients with TED, as compared with those
of normal controls [2]. In addition, the expression of CTGF in orbital
fibroblasts can be modulated by oxidative stress. Recently, we further
revealed that the enhanced expression of CTGF in TED orbital fibroblasts
correlated with the clinical activity score and ophthalmopathy index,
suggesting that increased levels of CTGF are pathologically significant
[unpublished data].
CTGF, a cysteine-rich matricellular protein of the CCN family, has
been implicated in mediating various cellular processes, including
adhesion, proliferation, differentiation, and migration, and extracellular
matrix production, all of which are common features of tissue remodelling
and fibrosis. Evidence has been increased suggesting that over-expression
of CTGF has been noted in numerous fibrotic disorders, including
pulmonary, renal, hepatic, skin, cardiac, and ocular fibrosis.
Inflammation often dominates the early course of TED, followed by
remodeling of orbital connective tissue, including accumulation of
extracellular matrix and fibrosis. Fibrosis process represents a relative
quiescent stage in the disease course of TED; however, it may cause much
of the substantial morbidity of the patients including severe lid
retraction, restrictive strabismus, proptosis, exposure keratopathy, and
compressive optic neuropathy. Current knowledge about the inflammatory
process of TED has been rapidly expanding, however, only limited studies
have addressed the fibrosis process of this disease. Elucidation of the
molecular mechanisms that initiate and regulate the process of fibrosis,
especially the role of CTGF in TED, is crucial for the development of
novel treatments.
References
1. Khong JJ, McNab AA, Ebeling PR, Craig JE, Selva D. Pathogenesis of
thyroid eye disease: review and update on molecular mechanisms. Br J
Ophthalmol 2016;100:142-50.
2. Tsai CC, Wu SB, Chang PC, Wei YH. Alteration of Connective Tissue
Growth Factor (CTGF) Expression in Orbital Fibroblasts from Patients with
Graves' Ophthalmopathy. PLoS One 2015;10:e0143514.
Optic disc edema in astronauts following long-duration space flight
We commend Morgan and colleagues for their discussion of optic disc
changes during and after long-duration space flight (LDSF). 1 They note
that astronauts after LDSF have developed clinical features (disc edema,
globe flattening) similar to those of idiopathic intracranial hypertension
(IIH) that may persist for many months post flight and sugg...
Optic disc edema in astronauts following long-duration space flight
We commend Morgan and colleagues for their discussion of optic disc
changes during and after long-duration space flight (LDSF). 1 They note
that astronauts after LDSF have developed clinical features (disc edema,
globe flattening) similar to those of idiopathic intracranial hypertension
(IIH) that may persist for many months post flight and suggest that these
changes result from increased intracranial pressure (ICP) "which persists
for months and years after their return to Earth."1
Cephalad microgravity fluid shifts may increase head and neck venous
pressure, thus inhibiting cerebrospinal fluid (CSF) drainage into the
venous system, increasing CSF pressure and leading to changes similar to
those seen in patients with IIH. However, lumbar puncture opening pressure
(LPOP) has been only moderately elevated (21 to 28.5 cm H20) in the 4
astronauts examined from 12 to 60 days post-mission.2 Although LPOP may
have been higher during the mission, we doubt these post-flight pressures
are sufficiently high to sustain disc edema for months post-mission.
As Morgan et al. note, microgravity exposure may disrupt flow within
the orbital optic nerve subarachnoid space (ONSAS), causing accumulation
of toxic metabolites and creating a ball-valve like effect that allows CSF
to enter the ONSAS but inhibits outflow, thus increasing pressure within
that compartment.3 In theory, either one or both ON sheaths may be
affected in a given astronaut, with or without increased ICP. Of seven
astronauts with disc edema, four have displayed disc asymmetry. One of
these had unilateral disc edema associated with an LPOP of 18 cmH20 1 week
after space flight.4 We also have observed persistent asymmetric disc
edema 6 months following LDSF in an astronaut with LPOP's of 22 and 16 cm
H20 performed 7 days and 1 year post mission respectively, again
suggesting ON sheath compartmentalization (manuscript in preparation). We
thus believe that increased ICP may not be the sole, or even primary,
cause of persistent optic disc changes post LDSF.
Thomas H. Mader MD
C. Robert Gibson OD
Andrew G. Lee MD
Prem S. Subramanian, MD, PhD
Neil R. Miller MD
References
1. Morgan WH, Balaratnasingam C, Lind CRP, Colley S, Kang MH, House
PH, Yu D. Cerebrospinal fluid pressure and the eye. Br J Ophthalmol
2015; 0:1-7.
2. Mader TH, Gibson CR, Pass AF, et al. Optic disc edema, globe
flattening, choroidal folds, and hyperopic shifts observed in astronauts
after long-duration space flight. Ophthalmology 2011;118:2058-69.
We thank Cheng and Tham for their interest in our systematic review
of global variations and time trends in primary open angle glaucoma
(POAG).[1] The comments raise some important issues relating to the
assimilation of evidence from observational studies, particularly in
summarising estimates of chronic disease prevalence.
Cheng and Tham have questioned our inclusive approach, which resu...
We thank Cheng and Tham for their interest in our systematic review
of global variations and time trends in primary open angle glaucoma
(POAG).[1] The comments raise some important issues relating to the
assimilation of evidence from observational studies, particularly in
summarising estimates of chronic disease prevalence.
Cheng and Tham have questioned our inclusive approach, which resulted
in us having a greater number of studies, number of POAG cases and
population denominator, and led to more precise estimates of POAG
prevalence compared to their earlier review.[2] The purpose of our more
complex approach was to explicitly model and quantify the heterogeneity
between population surveys, which used different survey methods and case
definitions of POAG. By quantifying these differences we are able to
provide estimates of POAG prevalence standardised to studies which use
optimal methods, i.e., that did not rely on intraocular pressure and
routinely performed visual field assessments on all participants, while
allowing studies with suboptimal methods to contribute to overall
estimates by accounting for the differences in study methods. This is
particularly important when attempting to appreciate time trends in POAG,
given changes in study methods over time. Moreover it allows greater
global representation of studies, allowing more recent studies,
particularly from less developed countries often with suboptimal methods,
to contribute. This would not have been the case if a more exclusive
approach had been adopted.
Cheng and Tham also raise the issue of examining response rates.
However, we examined differences in response rates in our earlier
review,[3] and found that these had little effect on our prevalence
estimates. We acknowledge in the paper the difficulty of extracting
response rates, as these are not routinely reported, and sometimes
confused with participation rates, i.e., the number who took part and
completed an examination out of those who agreed to take part. In general,
our experience is that assessment of study quality of observational
studies is complex, compared to established methods in experimental
studies. Attempts were made to judge the quality of studies on criteria
such as response rates and methods used. However, it is difficult to
extract measures of study quality in a meaningful way; for example well-
designed studies may have low response rates. Our experience suggests that
subjective assessments of study quality can sometimes be arbitrary and may
not capture characteristics which may influence the outcome of interest.
Hence, we have chosen an approach which seeks to understand variability by
explicitly modelling differences in study methods. We believe that this
makes for a fuller assessment, providing evidence based guidance for the
conduct of future studies. For instance, our work suggests that a recent
shift away from routine visual field testing, perhaps as an inadvertent
consequence of recent ISGEO guidelines,[4] may have artefactually
influenced prevalence estimates; such an effect would not have been
identified and quantified by a more exclusive approach.
Cheng and Tham also question whether our more inclusive strategy may
have led to lower global estimates of POAG prevalence; 2.2% (95% CrI 1.8%
to 2.8%) in our study [1] versus 3.1% (1.7% to 5.3%) in their earlier
review.[2] However, we would like to point out that these estimates are
not dissimilar, with our more precise estimate being encapsulated within
the much wider confidence interval of their earlier estimate.[2] That our
estimate is marginally lower may in part be attributable to our different
ethnic/regional categorization of studies, particularly amongst Asians.
The earlier review simply treated Asians as one population.[2] However, we
found evidence suggesting that the age specific prevalence differed across
Asian populations,[1] which needs to be accounted for when deriving global
estimates, especially given the large population size of Asia. Moreover,
our review includes more recent studies from Asian populations, where POAG
numbers are high given the large population, but age-specific prevalence
is actually lower compared to other ethnic groups. We feel that our
modelling approach is justified and provides an important corrective to
earlier work. For example, the earlier review suggested urban-rural
differences in disease prevalence,[2] where we showed no effect as urban-
rural associations were inextricably linked to ethnicity and the ethnic
specific associations with age.[1]
We hope that these estimates provide greater certainty and
transparency so we understand how the global and regional estimates of
POAG prevalence are derived. Greater precision allows for more accurate
and appropriate planning of health care service needed to care for those
with the condition. We also believe that our work will assist with the
design of future population based studies, which seek to describe the
population prevalence of glaucoma.
Authors: Dr Alicja R Rudnicka,* Dr Venediktos V Kapetanakis,* Miss
Michelle P Y Chan,# Professor Paul J Foster,#** Professor Derek G Cook,*
Professor Christopher G Owen
*Population Health Research Institute, St George's, University of
London, Cranmer Terrace, London, SW17 0RE, UK
#Division of Genetics and Epidemiology, UCL Institute of
Ophthalmology, 11-43 Bath Street, London EC1V 9EL, UK
**NIHR Biomedical Research Centre Moorfields Eye Hospital NHS
Foundation Trust, 162 City Road, London EC1V 2PD, UK.
References:
1. Kapetanakis VV, Chan MP, Foster PJ, Cook DG, Owen CG, Rudnicka AR.
Global variations and time trends in the prevalence of primary open angle
glaucoma (POAG): a systematic review and meta-analysis. Br J Ophthalmol
2015.
2. Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global
prevalence of glaucoma and projections of glaucoma burden through 2040: a
systematic review and meta-analysis. Ophthalmology 2014; 121(11):2081-
2090.
3. Rudnicka AR, Mt-Isa S, Owen CG, Cook DG, Ashby D. Variations in
primary open-angle glaucoma prevalence by age, gender, and race: a
Bayesian meta-analysis. Invest Ophthalmol Vis Sci 2006; 47(10):4254-4261.
4. Foster PJ, Buhrmann R, Quigley HA, Johnson GJ. The definition and
classification of glaucoma in prevalence surveys. Br J Ophthalmol 2002;
86(2):238-242.
We read with great interest the article entitled "Smoking was associated with poor response to intravenous steroids therapy in Graves' ophthalmopathy" by Xing et al [1]. Cigarette smoking is known to be the most important risk factor for the development or deterioration of GO, and it is associated with poor response to treatment for GO. However, the exact mechanisms which prove deleterious effect of cigarette smoking on GO rem...
We read with great interest the article entitled "Pathogenesis of thyroid eye disease: review and update on molecular mechanisms" by Khong et al [1]. We would like to contribute to the article with our novel findings.
In our previous study, we first demonstrated the up-regulation of mRNA and protein expression of fibrosis-related genes including fibronectin, apolipoprotein J and connective tissue growth factor...
Optic disc edema in astronauts following long-duration space flight
We commend Morgan and colleagues for their discussion of optic disc changes during and after long-duration space flight (LDSF). 1 They note that astronauts after LDSF have developed clinical features (disc edema, globe flattening) similar to those of idiopathic intracranial hypertension (IIH) that may persist for many months post flight and sugg...
Dear Editor,
We thank Cheng and Tham for their interest in our systematic review of global variations and time trends in primary open angle glaucoma (POAG).[1] The comments raise some important issues relating to the assimilation of evidence from observational studies, particularly in summarising estimates of chronic disease prevalence.
Cheng and Tham have questioned our inclusive approach, which resu...
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