Abstract
Purpose:
Autologous serum tears (AST) contain growth factors and vitamins similar to those in healthy tears and are an effective treatment option for ocular surface disease. This study determined the differences in composition of AST in patients with systemic diseases versus patients with localized ocular surface diseases and the effects on ocular surface symptom improvement.
Method:
An observational study was performed on 53 patients with either systemic diseases (Group I) or localized ocular surface diseases (Group II) who were prescribed AST. Concentrations of epidermal growth factor (EGF), interleukin 8 (IL-8), fibronectin, vitamin A, and tumor necrosis factor-α (TNF-α) were determined through ELISA assays from patients in both groups. The Ocular Surface Disease Index (OSDI) scores were calculated prior to and 6 weeks after initiation of treatment with AST for new patients.
Results:
The average concentration of EGF in Group I (29.39 pg/ml ± 52.85 pg/ml) was significantly lower than in Group II (88.04 pg/ml± 113.75 pg/ml) (p < 0.05). Levels of fibronectin, IL-8, and vitamin A were similar in both groups. There was a 24% reduction in OSDI score 6 weeks after initiation in Group I compared to a 36% reduction reported in Group II (p = 0.065). The OSDI score was reduced significantly after the treatment in all subjects (p = 0.002).
Conclusion:
Serum tears are a promising therapy for management of ocular surface disease and associated symptoms. The differences between levels of EGF in patients with localized ocular surface disease and systemic inflammatory disease may account for differences in therapeutic outcome.
Keywords: Autologous serum tears, Ocular surface disease, Systemic inflammatory disorders, Epidermal growth factor, Ocular surface symptoms
1. Introduction
The tear film is a complex product of the main and accessory lacrimal glands, goblet cells located on the ocular surface, and the meibomian glands of the eyelids. The tear film plays a critical role in maintaining a healthy ocular surface environment by providing growth factors, vitamins, electrolytes, and neuropeptides that support the growth and migration of epithelial cells [1]. A myriad of systemic diseases that affect the ocular surface and local ocular surface diseases can negatively impact the tear film and its composition. These include mucoaqueous deficiency such as Sjögren’s syndrome and goblet cell destruction, as well as ocular adnexal abnormalities such as lagophthalmos or meibomian gland dysfunction [2]. Tear film instability can lead to a variety of ocular symptoms including dryness, irritation, light sensitivity, foreign body sensation, red eyes, and vision loss.
While the symptoms of ocular surface disease do not necessarily correlate with disease severity, there are various treatments to alleviate them. The current first line therapy for the management of ocular surface disease is the use of lubricating artificial tears. Artificial tears, however, are not the ideal substitute for natural tears as they lack the complex composition of water, salts, hydrocarbons, proteins, and lipids of natural tears [3,4]. Other FDA approved treatment options for inflammatory causes of decreased tear production and dry eye include cyclosporine (Restasis® and Cequa®) and Lifitegrast, (Xiidra®), respectively. Blood derived products such as autologous serum tears (AST) were developed because they have similar biochemical properties to those of human tears [5]. AST contain similar growth factors, cytokines, vitamins, and nutrients found in natural tears. These include epidermal growth factor (EGF), fibronectin, and vitamin A, all of which support epithelial cell growth and migration [6]. Transforming growth factor- β (TGF- β) is another important component which has been shown to have a multifaceted role on the ocular surface, with normal levels of TGF- β suppressing autoimmune reactions by supporting generation of CD4+ T cells. Stressed settings, however, cause TGF- β to support IL-17 producing effector cells, increasing the inflammatory response [7].
The effectiveness of AST has been reported in multiple studies for the management of systemic and local diseases that affect the ocular surface. This list includes the following: Sjögren’s syndrome, secondary Sjögren’s syndrome, ocular graft versus host disease, Stevens Johnson syndrome, mucus membrane pemphigoid, post LASIK dry eye, and severe dry eye [8–16]. Interestingly, the results from multiple studies have failed to show significant improvement in objective clinical findings such as tear break up time, Schirmer testing, or ocular surface staining [8–13]. However, many studies have demonstrated an improvement in subjective symptomatic measures of dry eye, including one by Ali et al. that showed both objective and subjective improvement in patients with systemic autoimmune disease [8–13,17]. There are a few studies that compare the outcomes of ASTs between two different subgroups, one comparing primary and secondary Sjögren’s and another comparing chronic Stevens-Johnson disease and non-autoimmune dry eye [18,19]. Existing studies, including the ones mentioned above, either investigated a specific indication or they grouped all indications together without comparing efficacy between the different indications.
AST have been shown to have minimal side effects overall, however the possible side effect of limbitis in the treatment of patients with underlying immunologic systemic diseases should be considered, as originally reported by Welder et al. [20]. Contamination of ASTs with various bacteria and ocular infections because of the use of AST have been reported in previous studies, but is very rare [21].
Prior studies on serum only, the source of AST, have shown that cytokines, growth factors, and other mitogens are quite variable in serum concentration between healthy controls and those with systemic conditions like SJS [22]. Serum from patients with systemic conditions have higher levels of inflammatory mediators, which could be present in their serum and affect both the composition and the efficacy of the AST. Additionally, it is unknown how the levels of growth factors, nutrients, and vitamins in AST vary between different conditions. There are currently no studies that have compared the composition of AST and the improvement in symptomology based on a patient’s underlying condition.
The purpose of this study was to determine if there is a difference in the composition of AST between patients with systemic diseases with dysregulation of the immune system and/or inflammation, and those with local ocular surface diseases. Moreover, we aim to find the effect of AST on the ocular surface symptom improvement.
2. Methods
2.1. Patient recruitment
A prospective, observational cohort study involving 53 patients with ocular surface diseases requiring AST as part of their treatment was carried out in Chicago, Illinois, USA between November 2017 and November 2018. The tenets of the Declaration of Helsinki were followed and written informed consent was obtained from the subjects after explanation of the nature and possible consequences of the study. Institutional Review Board (IRB) approval was obtained from the University of Illinois at Chicago (Chicago, IL, USA #2017–0765) and Loyola University Chicago Health Sciences Division (Maywood, IL, USA #209824). Patients were recruited at the Illinois Eye and Ear Infirmary, University of Illinois at Chicago (Chicago, Illinois, USA).
2.2. Sample collection and processing
The AST were compounded at the Illinois Eye and Ear Infirmary per their established protocol. A total of 53 patients with ocular surface diseases requiring AST as part of their treatment were recruited over the stated time period. Written informed consent was obtained at the time of recruitment. The diagnoses of the specific ocular surface disease and the indication for prescribing of AST were provided by the referring cornea specialists. Information collected included age, sex, and past medical history of systemic immune mediated disorders such as Sjögren’s Syndrome (primary and secondary), ocular graft versus host disease (oGVHD), Stevens Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), lupus, rheumatoid arthritis (RA), uveitis, chemical burn, and herpes keratitis. The patient’s blood was drawn at the Illinois Eye and Ear Infirmary, and a 2-mL aliquot of 20% AST was obtained from each patient at the time of compounding. The aliquot was placed in a sterile 5 cc vial and transported on wet ice to Loyola in an insulated container.
2.3. ELISA testing
The samples were stored at −40 °C in the Ophthalmology Research Laboratory in the Center for Translational Research and Education (CTRE) at Loyola where all ELISA testing was performed. ELISA assays were run for vitamin A (LSBio LS-F25655–1 Seattle, WA), fibronectin (Thermo Fischer BMS2028 Waltham, MA), epidermal growth factor (EGF) (Thermo Fischer KHG0062 Waltham, MA), tumor necrosis factorα (TNFα) (Thermo Fischer 88–7346-88 Waltham, MA), interleukin-8 (IL-8) (Thermo Fischer 88–8086-88 Waltham, MA), interferon γ (IFNγ) (Thermo Fischer 88–7316-88 Waltham, MA), and interleukin 17 (IL-17) (Thermo Fischer KAC1591 Waltham, MA) using the manufacturer’s protocol.
2.4. Symptom analysis
In addition, 20 patients who were evaluated and received serum tears for the first time were enrolled in a prospective study to evaluate the changes in ocular symptoms associated with the use of the AST. Patients completed a standard validated ocular surface disease index (OSDI) questionnaire both prior to and 6 weeks following the initiation of treatment with AST [23]. Results of OSDI questionnaires in addition to information including age, sex, and past medical history were collected and evaluated.
2.5. Statistical analysis
The data is presented as mean ± standard deviation and/or percentage. The statistical analyses were performed using SPSS software version 24. Mean differences between groups were analyzed using ttest, Mann-Whitney U, Chi-Square tests, and one-way ANOVA. P-values less than 0.05 were considered to be statistically significant.
3. Results
3.1. Study composition
A total of 53 patients were enrolled in the study, of which 52 (104 eyes) were included for analysis. One patient was omitted because the patient had a lacrimal gland lymphoma, which was difficult to classify as systemic or non-systemic at the time of diagnosis. Of those included for analysis, 33 were females (63%) and 19 were males (37%). Of the total participants, 31 were in the systemic disease group (Group I), while 21 were in the localized ocular surface disease group (Group II). The diseases included in Group I are noted in the methods section above (Fig. 1). There was no significant difference in terms of gender between the groups (p value = 0.42).
Fig. 1.
Indications for AST
The average age of the patients in the studied population was 53.13 ± 12.82. The average age in Group I and Group II was (53.65 ± 12.85) and (52.38 ± 13.04), respectively. There was no statistically significant difference in terms of age between the two groups (p value = 0.73). The average age of patients with rheumatoid arthritis (RA) (N = 7) was 55.43 ± 12.27; dry eye (N = 18) was 49.00 ± 9.46; graft-versus-host-disease (GVHD) (N = 15) was 54.20 ± 7.74; Stevens-Johnson disease (SJS) (N = 3) was 29.67 ± 10.21 and uveitis, alkali-burn, herpes simplex keratitis and systemic lupus erythematous (SLE), toxic epidermal necrolysis (TEN) (N = 5) was 72.00 ± 10.63. When comparing the diseases individually, there was a statistically significant difference in the age for patients (p value= < 0.0001).
There were 20 patients who participated in the OSDI survey before and six weeks after the initiation of serum tears. In this group, there were 12 females and 8 males. The average age was 47.4 ± 9.28. There were 12 in Group I and 8 in Group II. Of those in Group I, 7 had GVHD. The average age for Group I was 47.83 ± 9.78 and the average age for Group II was 46.75 ± 9.10. There was no statistically significant difference in terms of age between the two groups (p value = 0.806).
3.2. ELISA results
There was a statistically significant difference (p value = 0.015) in the level of EGF between Group I (29.39 pg/ml ± 52.85 pg/ml) and Group II (88.04 pg/ml ± 113.75 pg/ml) (Table 1). The level of IL-8, fibronectin and vitamin A in Group I was 128.41 ± 122.45, 106.01 ± 108.48, 1.97 ± 0.92 and in Group II was 111.3 ± 108.61, 159.12 ± 166.25, 2.35 ± 0.99, respectively. There were no statistically significant differences in the levels of IL-8, fibronectin, and vitamin A (p value = 0.607, p value = 0.169, p value = 0.289) (Fig. 2). There were no significant differences between the subgroups of systemic diseases and localized dry eye in levels of IL-8, fibronectin, EGF and vitamin A (Table 2 and Fig. 3). In terms of TNF-α levels, 9 out of 31 patients in Group I and 2 out of 21 patients in Group II had detectable levels of TNF-α (χ2 = 1.533, p value = 0.216).
Table 1.
ELISA composition differences between systemic and localized disease.
| Systemic Inflammatory Diseases (N = 31) | Localized Diseases (N = 21) | P-Value | |
|---|---|---|---|
| Age (y) | 53.65 ± 12.85 | 52.38 ± 13.04 | 0.731 |
| IL-8 (pg/ml) | 128.41 ± 122.45 | 111.3 ± 108.61 | 0.607 |
| Fibronectin (ug/ml) | 106.01 ± 108.48 | 159.12 ± 166.25 | 0.169 |
| Vitamin A (mg/ml) | 1.97 ± 0.92 | 2.35 ± 0.99 | 0.289 |
| EGF (pg/ml) | 29.39 ± 52.85 | 88.04 ± 113.75 | 0.015 |
Fig. 2.
Concentration of ELISA composition of EGF, IL-8, fibronectin and vitamin A, between Inflammatory disease group were 29.39 pg/ ml±52.85 pg/ml, 128.41 ± 122.45, 106.01 ± 108.48, 1.97 ± 0.92 and in Non-Inflammatory disease group were 88.04 pg/ ml±113.75 pg/ml, 111.3 ± 108.61, 159.12 ± 166.25, 2.35 ± 0.99, respectively. There was only a statistically significant difference in the level of EGF between two group (*, p value = 0.015). There were no statistically significant differences in the levels of IL-8, fibronectin, and vitamin A (p value = 0.607, p value = 0.169, p value = 0.289, respectively).
Table 2.
ELISA composition differences between diagnoses.
| RA (N = 7) | Dry Eye (N = 18) | GVHD (N = 15) | SJS (N = 3) | SS (N = 4) | Othera (N = 5) | p-Value | |
|---|---|---|---|---|---|---|---|
| IL-8 (pg/ml) | 131.49 ± 109.17 | 104.54 ± 99.53 | 107.71 ± 105.65 | 284.83 ± 225.74 | 119.01 ± 96.53 | 113.93 ± 136.39 | 0.255 |
| Fibronectin (ug/ml) | 101.49 ± 87.79 | 178.19 ± 172.16 | 107.43 ± 94.29 | 59.01 ± 49.27 | 65.78 ± 45.31 | 131.68 ± 205.67 | 0.47 |
| Vitamin A (mg/ml) | 1.6 ± 0.72 | 2.45 ± 1.04 | 1.52 ± 0.53 | 3.68 | 2.01 ± 0.22 | 2.51 ± 1.02 | 0.122 |
| EGF (pg/ml) | 4.91 ± 12.99 | 89.04 ± 122.81 | 43.37 ± 58.65 | 7.24 ± 12.55 | 51.13 ± 85.84 | 49.21 ± 50.80 | 0.286 |
Uveitis, alkali-burn, herpes simplex keratitis, systemic lupus erythematous (SLE) and toxic epidermal necrolysis (TEN).
Fig. 3.
Concentration of ELISA composition of EGF, IL-8, fibronectin and vitamin A between disease subtypes.
3.3. OSDI results
The average initial OSDI in the localized ocular surface disease group was 41.041 ± 10.05 and the average initial OSDI in the systemic disease group was 66.81 ± 9.45. After six weeks, the average in the localized ocular and systemic disease group was 25.47 ± 7.96 and 50.22 ± 9.58 respectively. There was a 36% reduction in OSDI scores in patients with localized ocular surface disease compared to a 24% reduction in OSDI scores in patients with systemic disease (p value = 0.065) which was not statistically significant. Both groups showed an overall reduction in ODSI six weeks post treatment (p value = 0.002). (Table 3).
Table 3.
OSDI in differences between localized and systemic disease.
| With Inflammatory Disease (N = 12)a | Without Inflammatory Disease (N = 8)a | Total (N = 20) | P-value | |||||
|---|---|---|---|---|---|---|---|---|
| GvHD (N = 7) | Sjogren (N = 3) | RA (N = 2) | Total (N = 12) | |||||
| Age | 47.57 ± 8.4 | 45.0 ± 13.8 | 53.0 ± 12.7 | 47.83 ± 9.8 | 46.75 ± 9.1 | 47.4 ± 9.28 | 0.806b | |
| Gender | Male | 5 (62.5) | 1 (12.5) | 1 (12.5) | 7 (87.5) | 1 (12.5) | 8 (40) | 0.136c |
| Female | 2 (16.7) | 2 (16.7) | 1 (8.3) | 5 (41.7) | 7 (58.3) | 12 (60) | ||
| OSDI before AST | 69.21 ± 10.2 | 58.33 ± 5.2 | 71.1 ± 3.32 | 66.81 ± 9.4 | 41.04 ± 10.1 | 56.5 ± 16.1 | < 0.0001b | |
| OSDI after AST | 50.97 ± 7.8 | 41.67 ± 5.7 | 60.42 ± 11.7 | 50.22 ± 9.6 | 25.47 ± 7.9 | 40.32 ± 15.2 | < 0.0001b | |
The reduction in OSDI score after using AST in both groups was statistically significant (paired T-Test, p < 0.0001) indicating ocular surface symptom improvement.
Independent T-Test.
Chi-Square.
4. Discussion
Autologous serum tears are an important adjunct therapy for the treatment of dry eye disease in patients with localized ocular surface disease and in patients with systemic diseases that affect the ocular surface. Although there have been reports regarding the variable effectiveness of AST in patients with systemic diseases as opposed to those without, there remain no dedicated studies which investigate the differences in efficacy and ocular surface symptom improvement between the two groups. Our current study reveals that there is a significantly lower epidermal growth factor level and a trend to lower reduction in OSDI scores in patients with systemic autoimmune disease compared to those with localized ocular surface disease (p value = 0.015 and p value = 0.065, respectively). Despite these differences, both groups showed an overall reduction in ODSI scores six weeks post treatment (p value = 0.002) similar to the results of a recent study which has shown OSDI reduction and significant clinical improvement after the administration of AST [24]. There was no significant difference in the levels of IL-8, IL-17, fibronectin, or vitamin A between the two groups. The proportion of patients with detectable levels TNF-α were also not different between the two groups (χ2 = 1.533, p value = 0.216).
Our study is the first to show a difference in EGF between patients with systemic disease and those with localized ocular disease and the role of AST in ocular surface symptom improvement. Previous studies on serum have shown that cytokines, such as INF-γ, TNF-α, and IL-8, are quite variable in serum concentration between healthy controls and those with inflammatory conditions like SJS [22]. However, other studies have shown no difference in AST composition between controls and patients with SJS [18]. Other studies have compared the components of AST in patients with Sjögren’s syndrome specifically and have shown an increased level of hyaluronic acid and transforming growth factor b1 in those with active disease [25].
Epidermal growth factor, a 6 KdA polypeptide mitogen first described by Cohen et al., plays an important role in wound healing by promoting keratinocyte migration and re-epithelialization [26,27]. It does so by binding to EGFR, a tyrosine kinase transmembrane protein found in the basal layer of epithelium. With acute injury, there is a rise of free ligands for EGFR, including EGF [27]. Binding of EGF ligand to EGFR elicits a signaling transduction cascade that ultimately leads to the migration of keratinocytes and rapid re-epithelialization [28]. EGF plays a similar role in corneal epithelium by promoting epithelial migration and proliferation to improve the wound healing process [29]. In addition to promoting proliferation of corneal epithelium, EGF plays a vital role in preventing apoptosis [6]. Finally, EGF also increases goblet cell number and muc-1 expression, which is a membrane tethered mucin that contributes to tear film stability [30]. The relatively lower levels of EGF in patients with systemic diseases shown in our study are consistent with the previously noted findings that decreased EGF levels are implicated in the pathophysiology of both Sjögren syndrome and chronic GVHD. Azuma et al. showed that salivary EGF levels are decreased in Sjögren’s syndrome and decreased levels of EGF correlate with the severity of oral symptoms [31]. The same group showed that tears in patients with Sjögren’s syndrome have significantly less EGF than healthy controls [32]. EGF has also been shown to be significantly reduced in patients with chronic GVHD [33]. The exact mechanism for lower levels of serum EGF in patients with systemic conditions remains unknown. These findings could occur due to the higher level of systemic inflammation causing upregulation of EGF receptors (EGFR) and a resulting decrease of free EGF in serum. Other possibilities include the presence of a milieu that leads to increased breakdown of EGF or its increased endocytosis following binding to EGFR. Regardless, both changes would then be reflected in the levels of EGF in AST. While the serum levels of EGF in rheumatoid arthritis have been reported to be high in reported literature, in our patient population we interestingly found low levels of EGF in AST [34–37]. This could be secondary to the small sample size. However, this could also be attributed to systemic disease modifying drugs or biologic agents that our patients might be taking as systemic levels of EGF are predictive of disease severity in RA and decline with treatment [38]. Future studies with a larger sample size could help to elucidate possible subgroup differences. Recently, significantly higher level of EGF among nonresponding patients treating with AST has been reported compared with responders [24].
Additionally, our study found that TNF-α and INF-γ were not detectable in every sample.
While nine patients with systemic disease had detectable levels of TNF-α and three with localized ocular surface disease had detectable levels of TNF-α, this was not a statistically significant difference. None of the patients had detectable levels of INF-γ in their autologous serum tears. This could be due to either low levels of both factors in serum, secondary to processing during the production of AST, or stability of these ligands during storage.
Moreover, this is also the first study to compare differences in treatment efficacy in ocular surface symptom improvement with AST in patients with localized ocular surface disease to those with systemic diseases. Existing randomized controlled studies either investigated a specific indication or grouped all indications together without comparing efficacy between the different indications [8–13]. Currently, Hwang et al. compared primary to secondary Sjögren’s syndrome and showed subjective improvement in those with primary Sjögren’s [18].
While not statistically significant, our study showed a clear trend toward more improvement of OSDI scores in those with localized dry eye disease compared to those with systemic autoimmune disease 6 weeks post treatment with AST. This could partly be due to the higher levels of EGF in the autologous serum tears of patients with no systemic disease that ultimately promotes better healing. However, further determination as to whether there is a clinical significance to this trend requires more investigation. Our study reaffirms that AST provides ocular surface symptom improvement for both patients with localized ocular surface disease and systemic disease. Previous studies have looked at OSDI scores after use of AST and found AST to lead to subjective improvement in symptoms for dry eye patients [8–13]. This is also consistent with a recent study which showed 85.1% of patients with systemic autoimmune diseases reported a significant decrease in ocular symptoms [17].
The results of this study may help to guide the treatment algorithms for patients with systemic diseases and dry eye symptoms. As there seems to be a greater decrease in symptoms for those patients with localized ocular surface disease who have higher levels of EGF in their autologous serum, EGF could be investigated as a potential therapeutic target in the future.
We acknowledge several limitations to this study. All of the study subjects who were willing to donate serum tears were long-term users of autologous serum tears, and this might introduce a bias as those who benefited were more likely to be compliant with therapy. As a result, we were also unable to correlate the improvement in ODSI with EGF levels as most first-time patients were unwilling to donate AST but were willing to take the surveys. In the current study, availability of samples limited the number of components of autologous serum tears we were able to measure, and we used only those factors with well-validated ELISA protocols. Additionally, our results may have been affected by immune-modulating drugs in the systemic disease group. We evaluated OSDI data as a reliable and valid test for quantifying the subjective improvement of the ocular surface diseases. Objective exam data was not included in this study; however, the role of AST on the improvement of ocular surface diseases have been attributed to the symptoms’ improvement [17,24].
Lower levels of EGF might explain the differences in ODSI in patients with systemic disease associated ocular surface disorders when compared to those with localized ocular surface disease. While there is a difference, both groups seem to benefit from AST and this should not limit the prescription of AST to those with systemic disease associated ocular surface disorders.
Supplementary Material
Acknowledgements
Perritt Charitable Foundation.
Funding
Grant sponsorship: Illinois Society for the Prevention of Blindness-No role in study design, collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Footnotes
Declaration of competing interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
Appendix A. Supplementary data
Supplementary data to this article can be found online at https://doi.org/10.1016/j.jtos.2020.02.011.
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