|Year : 2017 | Volume
| Issue : 4 | Page : 213-220
Serum components and clinical efficacies of autologous serum eye drops in dry eye patients with active and inactive Sjogren syndrome
I-Hsin Ma1, Lily Wei Chen1, Wen-Hui Tu1, Chia-Ju Lu1, Chien-Jung Huang1, Wei-Li Chen2
1 Department of Ophthalmology, National Taiwan University Hospital, Taipei, Taiwan
2 Department of Ophthalmology, National Taiwan University Hospital; Center of Corneal Tissue Engineering and Stem Cell Biology, National Taiwan University Hospital, Taipei, Taiwan
|Date of Submission||15-Oct-2017|
|Date of Acceptance||24-Oct-2017|
|Date of Web Publication||5-Dec-2017|
Department of Ophthalmology, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei
Source of Support: None, Conflict of Interest: None
PURPOSE: Autologous serum eye drops are considered safe and efficient for the treatment of various ocular surface disorders, including dry eye diseases (DED) caused by the primary and secondary Sjogren syndrome (SS). However, the serum components in patients of SS may be different from those of normal patients and can thus lead to unpredictable therapeutic effects. This study divided the SS patients into active and inactive types based on the erythrocyte sedimentation rate and the presence or absence of active rheumatoid arthritis.
METHODS: We compared the serum components of these two groups with standard and multiplex enzyme linked immunosorbent assay arrays and predicted the therapeutic effects of topical autologous serum for the treatment of DED with ocular surface disease index (OSDI) and Oxford Schema scale (OSS).
RESULTS: Hyaluronic acid and transforming growth factor b1 levels were significantly higher in the active SS group compared to the inactive SS group (P < 0.01), whereas epidermal growth factors, insulin growth factor 1, and fibroblast growth factor b had no significant differences between these two groups. Active SS group had significantly higher expressions of interleukin (IL) 1 beta, IL 6, and tumor necrosis factor alpha compared to inactive SS patients (P < 0.05). There were no statistical differences in therapeutic effects between these two groups, as measured with the OSDI or OSS.
CONCLUSION: Dividing the Sjogren dry eye patients into active and inactive groups may appear as a reasonable method to predict the quality of autologous serum eye drops, but there seems to be no significant predictability to the therapeutic effects.
Keywords: Autologous serum, cytokine, dry eye, growth factor, Sjogren syndrome
|How to cite this article:|
Ma IH, Chen LW, Tu WH, Lu CJ, Huang CJ, Chen WL. Serum components and clinical efficacies of autologous serum eye drops in dry eye patients with active and inactive Sjogren syndrome. Taiwan J Ophthalmol 2017;7:213-20
|How to cite this URL:|
Ma IH, Chen LW, Tu WH, Lu CJ, Huang CJ, Chen WL. Serum components and clinical efficacies of autologous serum eye drops in dry eye patients with active and inactive Sjogren syndrome. Taiwan J Ophthalmol [serial online] 2017 [cited 2020 Jul 9];7:213-20. Available from: http://www.e-tjo.org/text.asp?2017/7/4/213/218990
| Introduction|| |
Dry eye disease (DED) is common and has prevalence rates of 7.4%–33.7% among the general population based on different populations and time periods., The Beaver Dam population-based study found the DED prevalence rate to be 14% in adults 48–91 years of age, and the Shipai study in the elderly population in Taiwan reported a prevalence of 33.7% with significantly more women than men.
The etiologies and pathogenesis of DED have been long studied and are believed to be multifactorial.,,,, Various treatment options were proposed, targeting different classifications and severities of the disease. These include lubrication for aqueous deficiency; lid cleansing, expression, and hot compression for meibomitis; tetracycline, steroids, cyclosporine, and other anti-inflammatory agents for halting the inflammation propagation on the ocular surface.,,,, It has also been verified in tear component studies that inflammatory cytokines and chemokines were elevated in the DED group., In particular, T-cell recruitment plays an important role on the ocular surface condition in DED.,,, This finding provides evidence for treating DED patients with anti-inflammatory eye drops.,
In addition to the abovementioned treatment strategies, autologous serum has been used to treat patients with severe DED.,,,, The effect of autologous serum lies in its content: Abundant epitheliotrophic growth factors including epithelial growth factor (EGF) and transforming growth factor (TGF); vitamin A and extracellular matrix molecules such as hyaluronic acid (HA). All these components were reported to facilitate the growth of epithelium.,,, Serum also contains bactericidal components that have been shown to prevent infectious processes,,, as well as inhibitors of inflammatory cytokines.,,, Another advantage of autologous serum lies in its biomechanical properties. With pH level and osmolarity similar to those of natural tears, autologous serum eye drops serve as a good tear substitute. Finally, the autologous serum is devoid of additives such as stabilizers or preservatives. The positive effects of autologous serum on ocular surface disorders could be demonstrated at a cellular level, and included goblet cell regeneration, decreased dysmorphic ocular surface epithelium, and the inhibition of apoptosis on the ocular surface cells during stress.,,
In spite of wide clinical usage, topical autologous serum was recently found to produce variable treatment responses in patients with different etiologies of DED., Serum of patients with secondary Sjogren syndrome (SS) was reported to have elevated pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-a), interleukin-1beta (IL-1b), IL-6, and IL-8. Accordingly, the secondary SS patients were suspected to respond poorly to autologous serum for the treatment of DED when compared with patients with primary SS.,, Bradley et al., however, found no significant difference between serum growth factor levels in dry eye syndrome patients versus controls.
In the clinic, not all DED patients have the same clinical response after using topical autologous serum for treatment. We thus believed that the quality and efficacy of autologous serum might not be the same for patients with different etiologies and severities of DEDs. To the best of our knowledge, no prior study has analyzed the serum components and the treatment effects of autologous serum for active and inactive SS. We thus classified our SS patients into active and inactive groups, analyzed their serum components and correlated their serum condition with the treatment outcome. Through this study, we aimed to provide a simple screening method to individualize therapy and determine the DED patients with SS who would likely benefit from topical autologous serum.
| Materials and Methods|| |
Patient enrollment and group sorting
From June 2015 to February 2016, the study enrolled 21 patients with primary or secondary SS diagnosed according to European Classification Criteria for Primary and Secondary SS. All enrolled patients had severe DED that was intractable with topical lubricants. All patients continuously used autologous serum eye drops for at least 6 months. Twenty percent autologous serum drop was prescribed every 2 h during waking hours. This study was conducted under the guidance of Declaration of Helsinki and acquired written consent from each patient.
Enrolled patients were divided into active or inactive SS by the level of erythrocyte sediment rate (ESR). All patients, regardless of the underlying etiology of SS, were allocated to the active group for ESR higher than age plus ten, divided by two in women; and higher than age divided by two in men. Patients who had rheumatoid arthritis with active inflammatory arthritis confirmed in a rheumatologist's clinic were also sorted into the active SS group. Those patients who did not qualify for the active group were sorted into the inactive group
Measurement of dry eye severity
All patients took the questionnaire for ocular surface disease index (OSDI) to derive a subjective symptomatic score and answered the preferred dry eye treatment modality questions according to their previous treatment experience in our hospital. The objective ocular surface condition was measured by Oxford Scheme Scale (OSS). The measurement result used for analysis was the average of both eyes.
Blood draw was performed on patients by venipuncture after at least 8 h of fasting. Twenty milliliters of full blood were acquired from each patient. The samples were set to settle in room temperature (20°C –25°C) for 2 h, then centrifuged at 3000 g for 15 min. The serum was then processed with sterile technique and stored at −80°C before further analysis.
Quantification of serum elements
IL-1b, IL-2, IL-4, IL-6, CXCL8 (IL-8), IL-17, tumor necrosis factor-a (TNF-a), EGF, and TGF-b1 were measured by a customized membrane array (Quantibody ® custom array, RayBiotech) and signal scanned with GenePix ® 4000B Microarray Scanner. HA, insulin growth factor-1 (IGF-1), and fibroblast growth factor-basic (FGF-b) were quantified with standard enzyme-linked immunosorbent assay (ELISA), according to individual manufacturer's instructions (Biotech Trading Partner ®, R and D Systems, Inc., and BioLegend, Inc., respectively).
Scores of OSDI, grades of OSS, and the concentrations of IL-1b, IL-2, IL-4, IL-6, CXCL8 (IL-8), IL-17, TNF-a, EGF, HA, IGF-1, and FGF-b were compared between active and inactive SS using Wilcoxon rank test. Statistical significance was considered to be a P < 0.05.
| Results|| |
Among 21 Sjogren dry eye patients under autologous serum treatment in this study, fifteen were sorted into the inactive SS group and six were sorted into the active SS group. All patients in the active disease group were secondary SS patients, whereas only 6 among 15 patients in the inactive SS group had secondary SS. The demographic data and clinical manifestations of these 21 patients are shown in [Table 1], which reveals a predominance of female and middle-aged patients in the study cohort.
|Table 1: Demographics and disease activity in patients with Sjogren dry eye|
Click here to view
[Table 2] provides a comparison of the epitheliotrophic factor levels that were found in the serum of these two groups. HA and TGF-b1 levels were significantly higher in the active SS group compared to the inactive SS group (P = of 0.02 and 0.01, respectively). In comparison, there were no significant differences for EGF, IGF-1, and FGF-b between these two groups (P > 0.05).
|Table 2: Concentrations of epitheliotrophic factors and extracellular matrix components in patients with active and inactive Sjogren dry eyes|
Click here to view
[Table 3] provides a comparison of the pro-inflammatory cytokines in the serum of these two groups. Active SS group had significantly higher expressions of IL-1b, IL-6, and TNF-alpha compared to the inactive SS group (P < 0.05). For other proinflammatory cytokines, there was also a trend toward higher expressions in the active SS group, but the results did not meet statistical significance (P = 0.058, P= 0.099 and P= 0.092, respectively).
|Table 3: Concentrations of pro-inflammatory cytokines in patients with active and inactive Sjogren dry eyes|
Click here to view
In [Table 2] and [Table 3], we show the median expression levels of each component. The results are also expressed by means ± standard deviations [Figure 1] and [Figure 2] are boxplots for epitheliotrophic factors and pro-inflammatory cytokines. The active SS group tended to have wider spread of data for most growth factors and cytokines examined in this study. The expression levels of HA, TGF-b1, IL-1b, IL-6, and TNF-a were significantly higher in the active SS group. [Figure 3] is the boxplot for the treatment outcomes that were assessed using OSDI and OSS. There seems to be no statistical differences between the two groups of SS patients.
|Figure 1: Boxplots for epitheliotrophic factors in serum of active and inactive SS. SS: Sjogren syndrome, IGF-1: Insulin Growth factor-1, HA: Hyaluronic acid, FGF-b: Fibroblast growth factor-beta, EGF: Epidermal growth factor, TGFb1: Transforming growth factor|
Click here to view
|Figure 2: Boxplots for pro-inflammatory factors in serum of active and inactive SS. IL: Interleukin, TNFa: Tumor necrosis factor-alpha|
Click here to view
|Figure 3: Boxplots for treatment outcomes using serum of active and inactive Sjogren syndrome|
Click here to view
| Discussion|| |
Topical autologous serum was first used to treat ocular chemical burns back in the 1970s. Soon after, the therapeutic indications broadened to cover persistent or recurrent epithelial defects,,,, neurotrophic keratopathy, superior limbic keratoconjunctivitis, and various etiologies of DED.,,, The advantages of topical autologous serum in treating ocular surface diseases can be explained by the abundant corneal epitheliotrophic factors that facilitate epithelium growth,,,,, its similar biomechanical and biochemical properties to those of tears,, and its absence of stabilizers and preservatives that are associated with corneal toxicity.
Recently, different expression levels of tear cytokines were found and compared among the normal population, non-Sjogren dry eye patients and Sjogren dry eye patients.,,, Accordingly, the serum levels of cytokines in different patients could be different and the measurements could be used to guide the usage of autologous serum eye drops to prevent possible side effects. It has been reported that the levels of IL-1b, IL-2, IL-4, IL-6, IL-17A, TNF-a, and TNF-b were elevated in patients with SS.,,, Both IL-1b secreting and TNF-a secreting circulating lymphocytes significantly increased in Sjogren dry eye patients. Moreover, the amount of IL-1b secreting lymphocytes in the peripheral blood correlated with the SS disease status. Recently, Hwang et al. looked into the differences between primary and secondary SS. They noticed the elevation of tumor necrosis factor a, IL-1b, IL-6, and IL-8 in the serum of patients with secondary SS. However, many Sjogren dry eye patients may have received treatments for their autoimmune disease before visiting the eye clinic. The disease activity, in addition to the classification of SS, should be noted before the use of autologous serum eye drops for DED.
In this study, we collected all DED patients with primary and secondary SS and simply divided them into active and inactive groups according to the levels of ESR. We used the ESR elevation criteria  and the clinical observation of active arthritis by rheumatologists as the definition of active SS. This classifying method is convenient for ophthalmologists since they do not review the complex systemic and medication histories of these patients before prescribing topical autologous serum for the treatment of their DED. In this study, we evaluated several important epitheliotrophic growth factors and extracellular matrix components by membrane array and ELISA. The results showed no significant differences in the expression of EGF, FGF, and IGF between active and inactive SS, whereas the level of HA and TGF-b were significantly higher in the active SS group.
The expression of EGF, FGF, and IGF has been associated with epithelial proliferation and migration.,, HA is an extracellular matrix component as well as an indicator of connective tissue turnover. Although the serum level of HA was not elevated in the primary SS patients presented with dry mouth, it was well-documented to be elevated in rheumatoid arthritis, chronic liver and lung diseases.,, TGF-b1 regulates the epithelial and stromal repair  and limits self-immunity by decreasing the self-reactive T-cells.,, It may also regulate IL-17, which leads to excessive metalloproteinase production and can cause ocular surface disruption.,,, The upregulation of HA and TGF-b1 may thus theoretically influence the therapeutic effects of topical autologous serum.
Clinical observation of the poorer response to autologous serum in patients with secondary SS compared to those with primary SS has been reported, and the elevated levels of proinflammatory cytokines were thought to play a key role.,,,, It has been demonstrated that patients receiving anti-inflammatory treatments may have decreased inflammatory cytokines in tears. In our study, we demonstrated the elevation of IL-1b, IL-6, TNF-alpha, IL-2, IL-4, and IL-8 in serum of active SS (with the first three factors achieving statistical significance). The elevation of these cytokines in active SS may damage the corneal surface and lead to harming effects from the use of autologous serum eye drops. To the best of our knowledge, no prior study had assessed the different levels of pro-inflammatory cytokines in the autologous serum of active and inactive SS patients. This study results suggest that classifying SS patients according to their disease activity may provide a good method to predict the quality of topical autologous serum eye drops.
In this study, we not only measured the serum components in patients with active and inactive SS but also correlated the serum quality to the treatment results. Our results indicated no significant differences in OSDI and OSS between the active and inactive SS groups. Several reasons may explain this discrepancy between the serum components and the therapeutic results. First, the small sample size of the study could have led to poor statistical power. Second, the wide distribution of the measured data for serum components, especially in the active SS group, could have masked the real effects. Third, the systemic autoimmune medications could have accumulated in the serum and affected the ocular surface condition after it was used as topical eye drops. Finally, SS is a complex disease entity and patients' lifestyles and habits of drug usage could all affect the study outcomes.
| Conclusion|| |
We devised a simple way of classifying patients with SS into active and inactive groups according to their ESR and the presence or absence of active rheumatoid arthritis. The two groups were found to have different levels of serum components, with the inactive group exhibiting better corneal epitheliotrophic abilities and lesser harmful effects. However, the differences in serum quality did not seem to lead to different therapeutic effects. Further large-scaled studies are needed to confirm our study results.
Financial support and sponsorship
Supported, in part, by the National Taiwan University Hospital(NTUH) Plan Asia One, the Department of Medical Research at NTUH and NTUH grant 106-S3519.
Conflicts of interest
The authors declare that there are no conflicts of interests of this paper.
| References|| |
Lin PY, Tsai SY, Cheng CY, Liu JH, Chou P, Hsu WM, et al.
Prevalence of dry eye among an elderly Chinese population in Taiwan: The Shihpai eye study. Ophthalmology 2003;110:1096-101.
McCarty CA, Bansal AK, Livingston PM, Stanislavsky YL, Taylor HR. The epidemiology of dry eye in Melbourne, Australia. Ophthalmology 1998;105:1114-9.
Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye syndrome. Arch Ophthalmol 2000;118:1264-8.
Perry HD, Donnenfeld ED. Dry eye diagnosis and management in 2004. Curr Opin Ophthalmol 2004;15:299-304.
Isreb MA, Greiner JV, Korb DR, Glonek T, Mody SS, Finnemore VM, et al.
Correlation of lipid layer thickness measurements with fluorescein tear film break-up time and Schirmer's test. Eye (Lond) 2003;17:79-83.
Stern ME, Beuerman RW, Fox RI, Gao J, Mircheff AK, Pflugfelder SC, et al.
A unified theory of the role of the ocular surface in dry eye. Adv Exp Med Biol 1998;438:643-51.
Herrero-Vanrell R, Peral A. International dry eye workshop (DEWS). Update of the disease. Arch Soc Esp Oftalmol 2007;82:733-4.
Bron AJ, de Paiva CS, Chauhan SK, Bonini S, Gabison EE, Jain S, et al.
TFOS DEWS II pathophysiology report. Ocul Surf 2017;15:438-510.
Solomon A, Dursun D, Liu Z, Xie Y, Macri A, Pflugfelder SC, et al.
Pro- And anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis Sci 2001;42:2283-92.
Lee JH, Min K, Kim SK, Kim EK, Kim TI. Inflammatory cytokine and osmolarity changes in the tears of dry eye patients treated with topical 1% methylprednisolone. Yonsei Med J 2014;55:203-8.
Wei Y, Asbell PA. The core mechanism of dry eye disease is inflammation. Eye Contact Lens 2014;40:248-56.
de Paiva CS, Pflugfelder SC. Rationale for anti-inflammatory therapy in dry eye syndrome. Arq Bras Oftalmol 2008;71:89-95.
Pflugfelder SC. Antiinflammatory therapy for dry eye. Am J Ophthalmol 2004;137:337-42.
Pflugfelder SC, Jones D, Ji Z, Afonso A, Monroy D. Altered cytokine balance in the tear fluid and conjunctiva of patients with Sjögren's syndrome keratoconjunctivitis sicca. Curr Eye Res 1999;19:201-11.
Tong L, Lee SY, Petznick A. Clinical considerations in proinflammatory cytokine profiling of tears from patients with dry eye by means of antibody microarrays. Invest Ophthalmol Vis Sci 2011;52:9610.
Moriyama M, Hayashida JN, Toyoshima T, Ohyama Y, Shinozaki S, Tanaka A, et al.
Cytokine/chemokine profiles contribute to understanding the pathogenesis and diagnosis of primary Sjögren's syndrome. Clin Exp Immunol 2012;169:17-26.
Stevenson W, Chauhan SK, Dana R. Dry eye disease: An immune-mediated ocular surface disorder. Arch Ophthalmol 2012;130:90-100.
Pflugfelder SC, Corrales RM, de Paiva CS. T helper cytokines in dry eye disease. Exp Eye Res 2013;117:118-25.
El Annan J, Chauhan SK, Ecoiffier T, Zhang Q, Saban DR, Dana R, et al.
Characterization of effector T cells in dry eye disease. Invest Ophthalmol Vis Sci 2009;50:3802-7.
Poon AC, Geerling G, Dart JK, Fraenkel GE, Daniels JT. Autologous serum eyedrops for dry eyes and epithelial defects: Clinical and in vitro
toxicity studies. Br J Ophthalmol 2001;85:1188-97.
Kojima T, Ishida R, Dogru M, Goto E, Matsumoto Y, Kaido M, et al.
The effect of autologous serum eyedrops in the treatment of severe dry eye disease: A prospective randomized case-control study. Am J Ophthalmol 2005;139:242-6.
Takamura E, Shinozaki K, Hata H, Yukari J, Hori S. Efficacy of autologous serum treatment in patients with severe dry eye. Adv Exp Med Biol 2002;506:1247-50.
Geerling G, Maclennan S, Hartwig D. Autologous serum eye drops for ocular surface disorders. Br J Ophthalmol 2004;88:1467-74.
Jirsova K, Brejchova K, Krabcova I, Filipec M, Al Fakih A, Palos M, et al.
The application of autologous serum eye drops in severe dry eye patients; subjective and objective parameters before and after treatment. Curr Eye Res 2014;39:21-30.
Tsubota K, Goto E, Fujita H, Ono M, Inoue H, Saito I, et al.
Treatment of dry eye by autologous serum application in Sjögren's syndrome. Br J Ophthalmol 1999;83:390-5.
Tsubota K, Goto E, Shimmura S, Shimazaki J. Treatment of persistent corneal epithelial defect by autologous serum application. Ophthalmology 1999;106:1984-9.
Liu L, Hartwig D, Harloff S, Herminghaus P, Wedel T, Kasper K, et al.
Corneal epitheliotrophic capacity of three different blood-derived preparations. Invest Ophthalmol Vis Sci 2006;47:2438-44.
Quinto GG, Campos M, Behrens A. Autologous serum for ocular surface diseases. Arq Bras Oftalmol 2008;71:47-54.
Soni NG, Jeng BH. Blood-derived topical therapy for ocular surface diseases. Br J Ophthalmol 2016;100:22-7.
Dalmon CA, Chandra NS, Jeng BH. Use of autologous serum eyedrops for the treatment of ocular surface disease:First US experience in a large population as an insurance-covered benefit. Arch Ophthalmol 2012;130:1612-3.
Noble BA, Loh RS, MacLennan S, Pesudovs K, Reynolds A, Bridges LR, et al.
Comparison of autologous serum eye drops with conventional therapy in a randomised controlled crossover trial for ocular surface disease. Br J Ophthalmol 2004;88:647-52.
Hwang J, Chung SH, Jeon S, Kwok SK, Park SH, Kim MS, et al.
Comparison of clinical efficacies of autologous serum eye drops in patients with primary and secondary Sjögren syndrome. Cornea 2014;33:663-7.
Chen DY, Hsieh TY, Chen YM, Hsieh CW, Lan JL, Lin FJ, et al.
Proinflammatory cytokine profiles of patients with elderly-onset rheumatoid arthritis: A comparison with younger-onset disease. Gerontology 2009;55:250-8.
Chen Y, Deng F, Zheng J, Yin J, Huang R, Liu W, et al.
High circulating level of interleukin-18 in patients with primary Sjögren's syndrome is associated with disease activity. Mod Rheumatol 2016;26:156-8.
Bradley JC, Bradley RH, McCartney DL, Mannis MJ. Serum growth factor analysis in dry eye syndrome. Clin Exp Ophthalmol 2008;36:717-20.
Miller A, Green M, Robinson D. Simple rule for calculating normal erythrocyte sedimentation rate. Br Med J (Clin Res Ed) 1983;286:266.
Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi T, Michaud K, et al.
Rheumatoid arthritis disease activity measures: American college of rheumatology recommendations for use in clinical practice. Arthritis Care Res (Hoboken) 2012;64:640-7.
Schiffman RM, Christianson MD, Jacobsen G, Hirsch JD, Reis BL. Reliability and validity of the ocular surface disease index. Arch Ophthalmol 2000;118:615-21.
Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea 2003;22:640-50.
Ralph RA, Doane MG, Dohlman CH. Clinical experience with a mobile ocular perfusion pump. Arch Ophthalmol 1975;93:1039-43.
Mukerji N, Sinha R, Vajpayee RB. Role of autologous serum in persistent epithelial defects. Br J Ophthalmol 2002;86:832.
Schrader S, Wedel T, Moll R, Geerling G. Combination of serum eye drops with hydrogel bandage contact lenses in the treatment of persistent epithelial defects. Graefes Arch Clin Exp Ophthalmol 2006;244:1345-9.
Chiang CC, Chen WL, Lin JM, Tsai YY. Allogeneic serum eye drops for the treatment of persistent corneal epithelial defect. Eye (Lond) 2009;23:290-3.
Matsumoto Y, Dogru M, Goto E, Ohashi Y, Kojima T, Ishida R, et al.
Autologous serum application in the treatment of neurotrophic keratopathy. Ophthalmology 2004;111:1115-20.
Goto E, Shimmura S, Shimazaki J, Tsubota K. Treatment of superior limbic keratoconjunctivitis by application of autologous serum. Cornea 2001;20:807-10.
Carreño E, Enríquez-de-Salamanca A, Tesón M, García-Vázquez C, Stern ME, Whitcup SM, et al.
Cytokine and chemokine levels in tears from healthy subjects. Acta Ophthalmol 2010;88:e250-8.
Lee SY, Han SJ, Nam SM, Yoon SC, Ahn JM, Kim TI, et al.
Analysis of tear cytokines and clinical correlations in Sjögren syndrome dry eye patients and non-Sjögren syndrome dry eye patients. Am J Ophthalmol 2013;156:247-530.
Jee D, Park SH, Kim MS, Kim EC. Antioxidant and inflammatory cytokine in tears of patients with dry eye syndrome treated with preservative-free versus preserved eye drops. Invest Ophthalmol Vis Sci 2014;55:5081-9.
Stenwall PA, Bergström M, Seiron P, Sellberg F, Olsson T, Knutson F, et al.
Improving the anti-inflammatory effect of serum eye drops using allogeneic serum permissive for regulatory T cell induction. Acta Ophthalmol 2015;93:654-7.
Roescher N, Tak PP, Illei GG. Cytokines in Sjögren's syndrome. Oral Dis 2009;15:519-26.
Willeke P, Schotte H, Schlüter B, Erren M, Becker H, Dyong A, et al.
Interleukin 1beta and tumour necrosis factor alpha secreting cells are increased in the peripheral blood of patients with primary Sjögren's syndrome. Ann Rheum Dis 2003;62:359-62.
Willeke P, Schlüter B, Schotte H, Domschke W, Gaubitz M, Becker H, et al.
Interferon-gamma is increased in patients with primary Sjogren's syndrome and Raynaud's phenomenon. Semin Arthritis Rheum 2009;39:197-202.
Wilson SE, Chen L, Mohan RR, Liang Q, Liu J. Expression of HGF, KGF, EGF and receptor messenger RNAs following corneal epithelial wounding. Exp Eye Res 1999;68:377-97.
Nishida T, Nakamura M, Ofuji K, Reid TW, Mannis MJ, Murphy CJ, et al.
Synergistic effects of substance P
with insulin-like growth factor-1 on epithelial migration of the cornea. J Cell Physiol 1996;169:159-66.
Ofuji K, Nakamura M, Nishida T. Signaling regulation for synergistic effects of substance P
and insulin-like growth factor-1 or epidermal growth factor on corneal epithelial migration. Jpn J Ophthalmol 2000;44:1-8.
Tishler M, Yaron I, Shirazi I, Yaron M. Salivary and serum hyaluronic acid concentrations in patients with Sjögren's syndrome. Ann Rheum Dis 1998;57:506-8.
Emlen W, Niebur J, Flanders G, Rutledge J. Measurement of serum hyaluronic acid in patients with rheumatoid arthritis: Correlation with disease activity. J Rheumatol 1996;23:974-8.
Nyberg A, Engström-Laurent A, Lööf L. Serum hyaluronate in primary biliary cirrhosis – A biochemical marker for progressive liver damage. Hepatology 1988;8:142-6.
Kokawa N, Sotozono C, Nishida K, Kinoshita S. High total TGF-beta 2 levels in normal human tears. Curr Eye Res 1996;15:341-3.
Prud'homme GJ, Piccirillo CA. The inhibitory effects of transforming growth factor-beta-1 (TGF-beta1) in autoimmune diseases. J Autoimmun 2000;14:23-42.
Ogawa N, Dang H, Lazaridis K, McGuff HS, Aufdemorte TB, Talal N, et al.
Analysis of transforming growth factor beta and other cytokines in autoimmune exocrinopathy (Sjögren's syndrome). J Interferon Cytokine Res 1995;15:759-67.
De Paiva CS, Chotikavanich S, Pangelinan SB, Pitcher JD 3rd
, Fang B, Zheng X, et al.
IL-17 disrupts corneal barrier following desiccating stress. Mucosal Immunol 2009;2:243-53.
De Paiva CS, Volpe EA, Gandhi NB, Zhang X, Zheng X, Pitcher JD 3rd
, et al.
Disruption of TGF-β signaling improves ocular surface epithelial disease in experimental autoimmune keratoconjunctivitis sicca. PLoS One 2011;6:e29017.
Mieliauskaite D, Venalis P, Dumalakiene I, Venalis A, Distler J. Relationship between serum levels of TGF-beta1 and clinical parameters in patients with rheumatoid arthritis and Sjögren's syndrome secondary to rheumatoid arthritis. Autoimmunity 2009;42:356-8.
Kim HS, Shang T, Chen Z, Pflugfelder SC, Li DQ. TGF-beta1 stimulates production of gelatinase (MMP-9), collagenases (MMP-1, -13) and stromelysins (MMP-3, -10, -11) by human corneal epithelial cells. Exp Eye Res 2004;79:263-74.
Postal M, Peliçari KO, Sinicato NA, Marini R, Costallat LT, Appenzeller S, et al.
Th1/Th2 cytokine profile in childhood-onset systemic lupus erythematosus. Cytokine 2013;61:785-91.
Wen CL, Wang CR, Chuang CY, Chen CY. Increased production of interleukin-6 and autoantibodies in patients with Sjögren's syndrome. Zhonghua Min Guo Wei Sheng Wu Ji Mian Yi Xue Za Zhi 1992;25:189-95.
Wei Y, Gadaria-Rathod N, Epstein S, Asbell P. Tear cytokine profile as a noninvasive biomarker of inflammation for ocular surface diseases: Standard operating procedures. Invest Ophthalmol Vis Sci 2013;54:8327-36.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]
|This article has been cited by|
||In-Depth Thinking About the Diagnostic Methods and Treatment Strategies for the Corneal Nerves in Ocular Surface Disorders
| ||Hsiao-Sang Chu,Sheng-Lung Huang,Wei-Li Chen |
| ||Current Ophthalmology Reports. 2020; |
|[Pubmed] | [DOI]|
||The Role of Multisystem Disease in Composition of Autologous Serum Tears and Ocular Surface Symptom Improvement
| ||Madeline Ripa,Sayena Jabbehdari,Ghasem Yazdanpanah,Emoke Lukacs,Brandon Karcher,Omer Iqbal,Charles Bouchard |
| ||The Ocular Surface. 2020; |
|[Pubmed] | [DOI]|
||Umbilical Cord Blood and Serum for the Treatment of Ocular Diseases: A Comprehensive Review
| ||Giuseppe Giannaccare,Adriano Carnevali,Carlotta Senni,Laura Logozzo,Vincenzo Scorcia |
| ||Ophthalmology and Therapy. 2020; |
|[Pubmed] | [DOI]|
||A retrospective analysis of characteristic features of responder patients to autologous serum eye drops in routine care
| ||Natanael Levy,Gaelle Ho Wang Yin,Roxane Noharet,Rkia Ghazouane,Fanny Grimaud,Houssein Aboudou,Albert Darque,Nicolas Delmotte,Julie Veran,Louis Hoffart,Daniele Denis,Florence Sabatier,Jeremy Magalon |
| ||The Ocular Surface. 2019; |
|[Pubmed] | [DOI]|
||Application of Novel Drugs for Corneal Cell Regeneration
| ||Sang Beom Han,Yu-Chi Liu,Karim Mohamed-Noriega,Jodhbir S. Mehta |
| ||Journal of Ophthalmology. 2018; 2018: 1 |
|[Pubmed] | [DOI]|
||Contribution of HIV Infection, AIDS, and Antiretroviral Therapy to Exocrine Pathogenesis in Salivary and Lacrimal Glands
| ||Imran Nizamuddin,Peter Koulen,Carole McArthur |
| ||International Journal of Molecular Sciences. 2018; 19(9): 2747 |
|[Pubmed] | [DOI]|