CLINICAL SCIENCE
Long-term Use of Autologous Serum 50% Eye Drops for the Treatment of Dry Eye Disease Munira Hussain, MS, CCRP, Roni M. Shtein, MD, MS, Alan Sugar, MD, H. Kaz Soong, MD, Maria A. Woodward, MD, Karen DeLoss, OD, and Shahzad I. Mian, MD
Purpose: The aim of this study was to describe the outcomes of 50% autologous serum (AS) eye drops after long-term use in a large cohort of patients with dry eyes.
Methods: A retrospective cohort study was conducted on all patients treated with 50% AS eye drops at our institution between June 2008 and January 2013. Records were reviewed for clinical history, systemic risk factors, dry eye etiology, patients’ symptoms, and adverse events. Ocular surface evaluation included Schirmer testing with topical anesthesia, fluorescein staining, and ocular surface disease index. Data were reviewed at initial visit, 1 month, and every 3 to 6 months during treatment with AS. Paired t tests were performed to compare the progression of signs and symptoms of dry eye disease. Results: A total of 123 eyes of 63 patients were evaluated with a mean follow-up of 12 months (range, 3–48 months). Corneal fluorescein staining (mean baseline, 1.77 6 1.1) improved at the 3- to ,6month, 6- to ,12-month, and final follow-up (mean: 1.2 6 1.0, 1.3 6 1.0, and 1.1 6 1.1; P = 0.003, 0.017, and 0.0003, respectively). Schirmer scores (mean baseline, 6.6 6 6.5 mm) improved at the 12- to 24-month follow-up (mean = 10.7 6 11.4, P = 0.03), whereas ocular surface disease index scores (mean baseline, 54.1 6 22.3) improved at the 3- to ,6- and 6- to ,12-month follow-up (mean: 49.5 6 8.2 and 39.3 6 21.4, P = 0.029 and 0.003, respectively). No complications were noted. Conclusions: Fifty percent AS eye drops seem to be a safe and effective long-term treatment for dry eye disease, especially in patients with severe disease who have exhausted all other conventional forms of treatment. Key Words: autologous serum eye drop, dry eye syndrome, graftversus-host disease (GVHD), PROSE, Sjögren syndrome (Cornea 2014;33:1245–1251)
D
ry eye disease is a common disorder that is caused by decreased tear production, excessive tear evaporation,
Received for publication February 24, 2014; revision received August 7, 2014; accepted August 13, 2014. Published online ahead of print October 8, 2014. From the Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI. The authors have no funding or conflicts of interest to disclose. Reprints: Shahzad I. Mian, MD, Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, 1000 Wall St, Ann Arbor, MI 48105 (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
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and/or a tear film mucin deficiency. Dry eye disease impacts nearly 5 million Americans who are 50 years and older,1 of all races, and is more common in women. Standard treatments for dry eye disease include the use of artificial tears and lubricating ointments, topical cyclosporine 0.05%, topical corticosteroids, and punctal occlusion.2 However, none of these treatments supply epithelium-promoting growth factors or other essential components present in natural tears.3 Similar to tears, human serum contains immunoglobulins, vitamin A, fibronectin, and growth factors that promote epithelial health.2,4–6 Therefore, serum can serve as an excellent surrogate for tears. The use of autologous serum (AS) eye drops was first reported as early as 1975 by Ralph et al7 and later described by Fox et al8 for the treatment of severely dry eyes. Since then, many studies have reported the beneficial effects of autologous tears for the treatment of dry eyes,3,9–18 persistent epithelial defects,19–22 superior limbic keratoconjunctivitis,23 and neurotrophic keratopathy.24 The purpose of this study was to describe the outcomes after long-term use of 50% AS eye drops in a large cohort of patients with dry eyes.
METHODS A retrospective cohort study was conducted at the University of Michigan Health System on the patients who used AS eye drops. After institutional review board approval, data on all patients using AS eye drops between June 2008 and January 2013 were included. Patients who had used AS for ,3 months were excluded. We reviewed the clinical records for relevant clinical history, systemic risk factors, dry eye etiology, subjective symptoms, and adverse events. We reviewed ocular surface evaluations including Schirmer testing with topical anesthesia, fluorescein staining, and ocular surface disease index (OSDI) questionnaire. Schirmer test was performed by adding 1 drop of proparacaine hydrochloride ophthalmic solution 0.5% (Bausch + Lomb, Rochester, NY) and placing a standard filter paper strip inside the margin of the lower eyelid. The level of strip wetting, in millimeters, was measured after 5 minutes. Corneal staining was assessed using the Oxford grading scheme.25 The corneal surface was stained using a fluorescein strip, examined with a slit-lamp microscope, and graded 0 to 4 in the order of increasing severity. The OSDI is a 12-item questionnaire that assesses dry eye symptoms and their impact on vision-related functioning. The items were graded on a scale of 0 to 4. The final score www.corneajrnl.com |
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was calculated by multiplying the sum of the scores by 25 and then dividing the total by the number of questions answered. Scores range from 0 to 100, with higher scores indicating more severe symptoms.26 All data were reviewed at baseline, 3- to 6-month (AS use of at least 3 but ,6 months), 6- to 12-month (AS use of at least 6 but ,12 months), and 12- to 24-month intervals (AS use between 12 and 24 months). Paired t tests were performed to compare the progression of signs and symptoms of ocular surface disease with respect to baseline values. Student t tests were used to compare the outcomes between groups. A P value of ,0.05 was considered statistically significant. Mixed linear regression analysis with a random effect for subject was used to model outcome variables of interest (Schirmer, fluorescein staining, and OSDI scores) while adjusting for the correlation between measures of the same subject. SAS v9.3 (SAS Institute, Cary, NC) was used to perform this analysis.
Preparation of AS Eye Drops AS eye drops were prepared as follows: a total of 60 mL of blood was collected by venipuncture using 5-mL BD Vacutainer serum separator tubes (Becton Dickinson, NJ). The blood was allowed to clot for 15 minutes at room temperature after which it was spun at 14,000 revolutions per minute for 15 minutes. The serum was compounded at a local pharmacy into eye drops in an International Standards Organization class 5 environment using proper aseptic technique and diluted to 50% with sterile 0.9% sodium chloride. The solution was sterilized by filtering through a 0.22-mm filter (Attentus Medical Sales, Inc, Houston, TX) and aliquoted into sterile 3-mL dropper vials. Patients were instructed to store unopened vials in a freezer (220°C) for up to 3 months and opened vials in a refrigerator (4°C) for up to 1 week. We chose to use a 50% concentration because of limited clinical efficacy noted with 20% AS eye drops in our practice before 2008.
RESULTS Data on 123 eyes of 63 patients treated with AS eye drops were analyzed. All patients were treated with 50% AS eye drops 4 times per day for a minimum of 3 months. Demographic data of patients using AS eye drops are listed in Table 1. Three patients used the AS drops in only 1 eye, for persistent epithelial defect in 2 patients and for severe dry eye with complete permanent tarsorrhaphy in 1 patient. Twentyone (33%) patients concurrently used Prosthetic Replacement of Ocular Surface Ecosystem (PROSE) treatment, a customdesigned scleral contact lens (Boston Foundation for Sight, Needham, MA) for ancillary management of severe dry eyes. All patients were refractory to conventional treatments for dry eyes consisting of maximal lubrication, topical corticosteroids (loteprednol 0.3% and 0.5%, tobramycin 0.3%/dexamethasone 0.1%, fluorometholone 0.1%, prednisolone acetate 1%, neomycin 3.5 mg/polymyxin B/dexamethasone 0.1%, loteprednol 0.5%/tobramycin 0.3%), topical cyclosporine 0.05% (Restasis; Allergan, Irvine, CA), and/or punctal occlusion. Topical steroid use decreased from 21 patients (33%) at
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TABLE 1. Demographics of Patients Using AS Eye Drops No. patients Age (mean 6 SD) Gender, n (%) Male Female Indication, n (%) Severe idiopathic dry eye disease GVHD Sjögren syndrome Persistent epithelial defect Stevens–Johnson syndrome PROSE, n (%) Mean serum use (range), mos
63 61 6 11 11 (17.5) 52 (82.5) 38 11 11 2 1 21 11.8
(60) (17.5) (17.5) (3) (2) (33) (3–48)
baseline to 6 of 41 patients (15%) at 6 months, to 4 of 21 patients (19%) at 12 months, and to 2 of 12 patients (17%) at 24 months. Because of the small sample size at follow-up, simple descriptive statistics were used to report on steroid use while the patients were on serum eye drops. Five (8%) patients discontinued serum tear use after a mean of 3 months because of transient benefit or lack of subjective improvement. Four (6%) patients discontinued AS eye drops because of high cost after an average of 8 (range, 3–20) months. Figure 1 shows the dry eye disease parameters with the use of AS drops. The mean Schirmer score improved from 6.6 6 6.5 to 10.7 6 11.4 mm at the 12- to 24-month follow-up visit (P = 0.03) (Fig. 1A). OSDI scores improved at the 3- to 6- (mean, 43.5 6 8.2; P = 0.03) and 6- to 12month follow-up (mean, 39.3 6 21.4; P = 0.003) compared with baseline (mean, 54.1 6 22.3) examination (Fig. 1B). There was an improvement in fluorescein staining from baseline (mean, 1.7 6 1.0) to the last follow-up visit (mean, 1.1 6 1.1; P = 0.0003). Fluorescein staining was also significantly improved at the 3- to 6-month (mean, 1.2 6 1.0; P = 0.003) and 6- to 12-month (mean, 1.3 6 1.0; P = 0.017) follow-up compared with baseline (Fig. 1C). No adverse events were associated with the use of serum tears. Linear mixed regression model results (Table 2) showed that the best predictor of follow-up status was baseline status. Specifically, for every 1 unit increase in baseline Schirmer score, there was a 0.5 unit increase in the follow-up Schirmer score (P , 0.0001); for every unit increase in baseline fluorescein staining score, there was a 0.3 unit increase in the follow-up fluorescein staining score (P = 0.0027); for every unit increase in the baseline OSDI score, there was a 0.7 unit increase in the follow-up OSDI score (P = 0.0007).
Graft-Versus-Host Disease Eleven (17.5%) patients with dry eye disease associated with graft-versus-host disease (GVHD) used serum tears for an average of 19 (range, 3–48) months. Patients with GVHD had lower Schirmer scores (P = 0.001) and higher fluorescein staining scores (P = 0.014) at baseline compared with those without GVHD (Table 3). Schirmer scores were improved at the last follow-up visit (P = 0.017) in patients with GVHD Ó 2014 Lippincott Williams & Wilkins
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FIGURE 1. Dry eye disease parameters with the use of AS drops: Schirmer with anesthesia (A), OSDI score (B), and corneal fluorescein staining score (C).
compared with baseline values but not in patients without GVHD. There was a trend toward improved fluorescein staining at the last follow-up visit (P = 0.062) compared with Ó 2014 Lippincott Williams & Wilkins
baseline in patients with GVHD. Fluorescein scores were significantly improved at the last follow-up (P = 0.009) in patients without GVHD compared with baseline values. There www.corneajrnl.com |
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TABLE 2. Linear Mixed Regression Model Results P
Dependent Variable Independent Variables Estimate (SE) Schirmer score Fluorescein staining OSDI
Time Baseline Schirmer Time Baseline fluorescein Time Baseline OSDI
0.11 0.45 20.01 0.31 0.28 0.69
(0.04) (0.10) (0.01) (0.10) (0.39) (0.15)
0.0040 ,0.0001 0.2029 0.0027 0.4799 0.0007
The model for fluorescein staining was adjusted for Sjögren syndrome.
was no significant improvement in the OSDI scores at the last follow-up visit compared with baseline values in patients with or without GVHD (Table 3). Schirmer, fluorescein, and OSDI scores did not differ significantly at the last follow-up visit between patients with GVHD when compared with patients using serum tears for the other underlying conditions.
¨ gren Syndrome Sjo Eleven (17.5%) patients with Sjögren syndrome were treated with serum drops for a mean of 11.5 (range, 3–33) months. Fluorescein staining improved at the last follow-up visit (P = 0.029) compared with baseline (Table 3). Schirmer and OSDI scores did not differ significantly between the baseline values and the last follow-up visit in patients with or without SS. Patients with SS had significantly lower baseline OSDI scores (P = 0.018) than did other patients with dry eyes (Table 3).
Prosthetic Replacement of Ocular Surface Ecosystem Twenty-one (33%) patients concurrently used PROSE for the management of severe dry eye after a mean of 7 (range, 0–30) months from starting serum eye drops. Of these, 9 patients were diagnosed with idiopathic dry eye, 6 patients with GVHD, 4 with Sjögren syndrome, and 1 patient each was diagnosed with Stevens Johnson syndrome and chemical burn. Figure 2 shows the dry eye disease parameters in patients using PROSE. Fluorescein staining improved in patients who used AS before starting PROSE and at the last follow-up after initiation of PROSE when compared with baseline (mean, 1.4 6 1.2; P = 0.05 and mean, 0.9 6 1; P = 0.0002, respectively) (Fig. 2A). OSDI scores
improved in patients after they started serum drops and before they started PROSE (mean, 30.5 6 21.8; P = 0.0004) as compared with baseline (mean, 61.2 6 24.3). OSDI scores increased significantly (mean, 54.7 6 24.7; P = 0.005) at the last follow-up visit after starting concurrent PROSE when compared with baseline values (Fig. 2B). Although not statistically significant, the mean Schirmer score improved after the serum eye drops were started (Fig. 2C). There was also a trend toward improved Schirmer scores in patients after concurrent use of PROSE (mean, 8 6 7.9 mm; P = 0.07) when compared with baseline (mean, 4.6 6 3.7). No adverse events were associated with the concurrent use of PROSE and serum tears.
DISCUSSION In this study, we investigated the safety and effectiveness of the long-term use of AS eye drops in a large cohort of patients with dry eye disease who were refractory to conventional treatments. Schirmer scores and fluorescein staining improved in our population of patients, especially during the first year, and all patients reported subjective improvement with the use of AS. Using linear mixed regression models, Schirmer scores showed a significant trend of improvement over time. Dry eye disease has a known inflammatory component, and the growth factors in serum tears can reduce inflammation.27,28 Because Schirmer scores increase with antiinflammatory treatments, this is consistent in this study with the use of serum eye drops. There were no significant effects of either dry eye indication or PROSE treatment in any of the models. Longitudinal analyses also showed that the most important predictor for improvement was baseline measurement, which would mean that starting treatment with serum tears earlier in the dry eye disease course might be beneficial. Previous studies have shown variable effectiveness of AS for the treatment of dry eyes. Tananuvat et al11 treated 12 patients with severe dry eyes with 20% AS drops in 1 eye and artificial tears in the fellow eye for 2 months and reported no statistical difference between the 2 treatments. Noble et al3 reported improved impression cytology after 3 months with 50% AS treatment in 16 patients. When the treatment was reversed to conventional therapy, the cytological improvements were reversed. Another crossover study,29 comparing a 2-week treatment with 20% AS with conventional artificial tears in
TABLE 3. Dry Eye Disease Parameters in Patients With GVHD and Sjo¨gren Syndrome Treated With 50% AS at Baseline and Last Follow-up Mean Schirmer Score (6SD) GVHD Non-GVHD P Sjögren Non-Sjögren P
Mean OSDI Score (6SD)
Mean Fluorescein Score (6SD)
Baseline
Last Follow-up
P
Baseline
Last Follow-up
P
Baseline
Last Follow-up
P
2.7 (63.1) 7.7 (66.8) 0.001 7.3 (68.5) 7.6 (611.9) 0.936
6.2 (64.9) 8.5 (68.2) 0.354 7.4 (69.6) 9.7 (610.8) 0.435
0.017 0.534
51.7 (626.9) 55 (620.6) 0.57 39.1 (630.5) 56.7 (620.1) 0.018
42.4 (623.6) 48.2 (627.2) 0.432 48.6 (618.1) 48.8 (626.5) 0.987
0.269 0.153
2.2 (61.2) 1.6 (60.9) 0.014 1.5 (61.1) 3 (610.2) 0.564
1.3 (61.2) 1.1 (61.1) 0.715 0.8 (61) 2.5 (610.1) 0.437
0.062 0.009
0.981 0.088
0.447 0.071
0.029 0.005
Bold indicates significant P values.
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FIGURE 2. Dry eye disease parameters in patients using PROSE: fluorescein staining in patients with concurrent PROSE use (A), OSDI in patients with concurrent PROSE use (B), and Schirmer scores in patients with concurrent PROSE use (C).
12 patients with severe dry eye syndrome found that the patients treated with AS showed a significant improvement in OSDI scores. There were no significant changes in Oxford Ó 2014 Lippincott Williams & Wilkins
staining scores and tear breakup time between the 2 groups. Most recently, Celebi et al17 observed improved tear breakup time and OSDI scores in the AS treatment group when www.corneajrnl.com |
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compared with the preservative-free artificial tear arm after 1 month of treatment. They did not observe any significant difference in Schirmer test and conjunctival and corneal staining scores between the 2 treatment groups after 1 month of treatment and after the crossover. The variable effectiveness of AS in published studies may be because of the variation in the duration of treatment and in the concentration of serum eye drops, which ranged from 20% to 100%. AS concentration of 20% is often used to dilute tumor growth factor in the serum to physiologic tear levels, because it is thought to be inhibitory for some epithelial processes. Because of the previous limited efficacy observed with 20% AS at our institution (M Hussain, RM Shtein, A Sugar, H Kaz Soong, MA Woodward, K DeLoss, SI Mian, unpublished results), the standard practice has been to use 50% serum tear drops. There were no adverse effects noted with this concentration. Although there have been a few complications reported in the literature, such as immunoglobulin deposits,30,31 presence of corneal infiltrates,20 conjunctivitis,10,11 and decreased corneal sensitivity12 in patients using serum tears, the rate of complications occurring is small. There were no complications in this study population. In this study, patients with GVHD treated with serum drops showed a significant improvement in Schirmer and corneal staining scores. Although there was no significant improvement in OSDI scores, most patients reported subjective relief of symptoms with serum drops. In one of the first case reports with 2 patients with GVHD with severely dry eyes refractory to conventional treatment, AS tears were felt to be safe and beneficial.10 Ogawa et al12 used serum eye drops to treat 14 patients with severe dry eye associated with GVHD for a mean of 19 months and observed a significant improvement in corneal staining scores and tear film breakup time. Autoimmune conditions associated with dry eye disease may affect serum cytokines and growth factors and result in different epitheliotropic properties when used as serum eye drops.32 Previous studies suggest that epitheliotropic properties of AS from autoimmune patients should be comparable with those from nonautoimmune patients with dry eyes.33,34 In this study, the 11 patients with SS treated with serum drops showed a significant improvement in fluorescein staining compared with baseline, but there was no significant improvement in Schirmer and OSDI scores. This is consistent with the findings of a study conducted by Tsubota et al9 in which the authors reported a significant improvement in rose bengal and fluorescein staining scores after 4 weeks of AS treatment in 12 patients with SS. The authors did not report any significant improvement in the Schirmer test or tear film breakup time. In this study, 21 (33%) patients used AS drops in conjunction with PROSE by applying the AS drops over the PROSE device and not within the tear reservoir. Although not statistically significant, our patients showed a trend toward improved fluorescein staining and Schirmer scores after starting PROSE along with the serum eye drops. OSDI scores increased significantly after the concurrent use of PROSE. This may be because of the initial adjustment to the PROSE. To our knowledge, there are no previous reports of concurrent use of PROSE and AS in the literature. Despite the benefits, there are potential barriers to the widespread use of AS eye drops.
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Risk of Infection Because serum eye drops are preservative-free to avoid toxicity, this treatment may have a potential risk of causing infection. The composition of serum tears that helps encourage ocular surface healing may be potentially conducive to microbial growth, and because these patients have a compromised ocular surface, they are at a higher risk of developing infection.35–37 However, there were no infections reported in this study, caused by serum tear usage.
Storage A recent study has shown that the epitheliotropic properties of AS remain stable after storage for 6 months at 220°C.38 The serum eye drops in this study were used within 3 months, but in some cases, the patients stored them at 220° C for up to 6 months. There were no adverse events related to the storage of serum eye drops for up to 6 months in this study.
Blood Draw Frequent blood draws are inconvenient and are a drawback of serum eye drop therapy, especially in patients who need prolonged treatment. Chiang et al39 have shown that in patients who need serum tear treatment but whose AS is unavailable or unsuitable for use, allogeneic serum can offer an alternative. However, allogeneic blood poses the risks of transmitting blood-borne diseases and hypersensitivity reactions. Further, ethical and legal issues with allogeneic serum must be taken into account.
Cost AS eye drops are expensive, and most insurance carriers in the United States do not cover this treatment. The local compounding pharmacy that the majority of our patients used charged $175 to $250 for 8 to 10 vials of AS eye drops, which, if used 4 times every day in both eyes, would equal to about a 2-month supply. Four (6%) patients in this study discontinued the use of AS eye drops because of the accumulating high costs after a mean of 8 (range, 3–20) months. This study does not include the patients who were recommended serum tears but did not try it because of high cost. This militates for a need to have AS eye drops become a covered insurance benefit. Dalmon et al40 have recently reported the use of AS as an insurance-covered benefit in California. A well-designed prospective study to test the safety, efficacy, and cost of AS eye drops at varying concentrations may be important in developing therapeutic guidelines and evidence-based design of a standardized and cost-effective protocol for producing AS eye drops. This study is one of the first to evaluate the efficacy of AS tears in a large population of patients with a long duration of follow-up. Because this study is retrospective, clinical data were often not available at specified follow-up time points. It was not possible to specifically assess the effect of AS drops per se because of the wide variety of previous or current Ó 2014 Lippincott Williams & Wilkins
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treatments being used at the start of serum eye drops and the lack of a control group. In summary, we conclude that 50% AS eye drops seem to be safe and effective for long-term treatment of dry eye disease. They are a valuable option in patients with severe dry disease who have exhausted conventional forms of treatment.
ACKNOWLEDGMENTS The authors thank Dr David Musch and Leslie Niziol for statistical data analyses. REFERENCES 1. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:93–107. 2. Tsubota K. Tear dynamics and dry eye. Prog Retin Eye Res. 1998;17: 565–596. 3. Noble BA, Loh RS, MacLennan S, 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: 647–652. 4. Ohashi Y, Motokura M, Kinoshita Y, et al. Presence of epidermal growth factors in human tears. Invest Ophthalmol Vis Sci. 1989;30:1879–1882. 5. Nelson JD, Gordon JF. Topical fibronectin in the treatment of keratoconjunctivitis sicca. Chiron Keratoconjunctivitis Sicca Study Group. Am J Ophthalmol. 1992;114:441–447. 6. Joh T, Itoh M, Katsumi K, et al. Physiological concentrations of human epidermal growth-factor in biological fluids: use of a sensitive enzymeimmunoassay. Clin Chim Acta. 1986;158:81–90. 7. Ralph RA, Doane MG, Dohlman CH. Clinical experience with a mobile ocular perfusion pump. Arch Ophthalmol. 1975;93:1039–1043. 8. Fox RI, Chan R, Michelson JB, et al. Beneficial effect of artificial tears made with autologous serum in patients with keratoconjunctivitis sicca. Arthritis Rheum. 1984;27:459–461. 9. Tsubota K, Goto E, Fujita H, et al. Treatment of dry eye by autologous serum application in Sjogren’s syndrome. Br J Ophthalmol. 1999;83: 390–395. 10. Rocha EM, Pelegrino FS, de Paiva CS, et al. GVHD dry eyes treated with autologous serum tears. Bone Marrow Transplant. 2000;25: 1101–1103. 11. Tananuvat N, Daniell M, Sullivan LJ, et al. Controlled study of the use of autologous serum in dry eye patients. Cornea. 2001;20:802–806. 12. Ogawa Y, Okamoto S, Mori T, et al. Autologous serum eye drops for the treatment of severe dry eye in patients with chronic graft-versus-host disease. Bone Marrow Transplant. 2003;31:579–583. 13. Geerling G, Maclennan S, Hartwig D. Autologous serum eye drops for ocular surface disorders. Br J Ophthalmol. 2004;88:1467–1474. 14. Kojima T, Ishida R, Dogru 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;139:242–246. 15. Lee GA, Chen SX. Autologous serum in the management of recalcitrant dry eye syndrome. Clin Experiment Ophthalmol. 2008;36:119–122. 16. Pan Q, Angelina A, Zambrano A, et al. Autologous serum eye drops for dry eye (review). Cochrane Database Syst Rev. 2013;8:1–47. 17. Celebi AR, Ulusoy C, Mirza GE. The efficacy of autologous serum eye drops for severe dry eye syndrome: a randomized double-blind crossover study. Graefes Arch Clin Exp Ophthalmol. 2014;252:619–626. 18. Jeng BH. Use of autologous serum in the treatment of ocular surface disorders. Arch Ophthalmol. 2011;129:1610–1612.
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19. Tsubota K, Goto E, Shimmura S, et al. Treatment of persistent corneal epithelial defect by autologous serum application. Ophthalmology. 1999; 106:1984–1989. 20. Poon AC, Geerling G, Dart JK, et al. Autologous serum eyedrops for dry eyes and epithelial defects: clinical and in vitro toxicity studies. Br J Ophthalmol. 2001;85:1188–1197. 21. Young AL, Cheng AC, Ng HK, et al. The use of autologous serum tears in persistent corneal epithelial defects. Eye (Lond). 2004;18:609–614. 22. Jeng BH, Dupps WJ Jr. Autologous serum 50% eyedrops in the treatment of persistent corneal epithelial defects. Cornea. 2009;28:1104–1108. 23. Goto E, Shimmura S, Shimazaki J, et al. Treatment of superior limbic keratoconjunctivitis by application of autologous serum. Cornea. 2001; 20:807–810. 24. Matsumoto Y, Dogru M, Goto E, et al. Autologous serum application in the treatment of neurotrophic keratopathy. Ophthalmology. 2004;111: 1115–1120. 25. Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea. 2003;22:640–650. 26. Schiffman RM, Christianson MD, Jacobsen G. Reliability and validity of the ocular surface disease index. Arch Ophthalmol. 2000;118:615–621. 27. Lisi S, Sisto M, D’Amore M, et al. Emerging avenues linking inflammation, angiogenesis and Sjögren’s syndrome. Cytokine. 2013;61: 693–703. 28. Stern ME, Schaumburg CS, Pflugfelder SC. Dry eye as a mucosal autoimmune disease. Int Rev Immunol. 2013;32:19–41. 29. Urzua CA, Vasquez DH, Huidobro A, et al. Randomized double-blind clinical trial of autologous serum versus artificial tears in dry eye syndrome. Curr Eye Res. 2012;37:684–688. 30. McDonnell PJ, Schanzlin DJ, Rao NA. Immunoglobulin deposition in the cornea after application of autologous serum. Arch Ophthalmol. 1988;106:1423–1425. 31. Schrader S, Wedel T, Moll R, et al. Combination of serum eye drops with hydrogel bandage contact lenses in the treatment of persistent epithelial defects. Graefes Arch Clin Exp Ophthalmol. 2006;244:1345–1349. 32. Harloff S, Hartwig D, Kasper K, et al. Epitheliotrophic capacity of serum eye drops from healthy donors versus serum from immunosuppressed patients with rheumatoid arthritis (article in German). Klin Monbl Augenheilkd. 2008;225:200–206. 33. Bradley JC, Bradley RH, McCartney DL, et al. Serum growth factor analysis in dry eye syndrome. Clin Experiment Ophthalmol. 2008;36: 717–720. 34. Phasukkijwatana N, Lertrit P, Liammongkolkul S, et al. Stability of epitheliotrophic factors in autologous serum eye drops from chronic Stevens–Johnson syndrome dry eye compared to non-autoimmune dry eye. Curr Eye Res. 2011;36:775–781. 35. Leite SC, de Castro RS, Alves M, et al. Risk factors and characteristics of ocular complications, and efficacy of autologous serum tears after haematopoietic progenitor cell transplantation. Bone Marrow Transplant. 2006;38:223–227. 36. Sauer R, Blüthner K, Seitz B. Sterility of non-preserved autologous serum drops for treatment of persistent corneal epithelial defects (article in German). Ophthalmologe. 2004;101:705–709. 37. Thanathanee O, Phanphruk W, Anutarapongpan O, et al. Contamination risk of 100% autologous serum eye drops in management of ocular surface diseases. Cornea. 2013;32:1116–1119. 38. Fischer KR, Opitz A, Böeck M, et al. Stability of serum eye drops after storage of 6 months. Cornea. 2012;31:1313–1318. 39. Chiang CC, Chen WL, Lin JM, et al. Allogeneic serum eye drops for the treatment of persistent corneal epithelial defect. Eye (Lond). 2009;23: 290–293. 40. 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: 1612–1613.
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Long-term Use of Autologous Serum 50% Eye Drops for the Treatment of Dry Eye Disease Munira Hussain, MS, CCRP, Roni M. Shtein, MD, MS, Alan Sugar, MD, H. Kaz Soong, MD, Maria A. Woodward, MD, Karen DeLoss, OD, and Shahzad I. Mian, MD
Purpose: The aim of this study was to describe the outcomes of 50% autologous serum (AS) eye drops after long-term use in a large cohort of patients with dry eyes.
Methods: A retrospective cohort study was conducted on all patients treated with 50% AS eye drops at our institution between June 2008 and January 2013. Records were reviewed for clinical history, systemic risk factors, dry eye etiology, patients’ symptoms, and adverse events. Ocular surface evaluation included Schirmer testing with topical anesthesia, fluorescein staining, and ocular surface disease index. Data were reviewed at initial visit, 1 month, and every 3 to 6 months during treatment with AS. Paired t tests were performed to compare the progression of signs and symptoms of dry eye disease. Results: A total of 123 eyes of 63 patients were evaluated with a mean follow-up of 12 months (range, 3–48 months). Corneal fluorescein staining (mean baseline, 1.77 6 1.1) improved at the 3- to ,6month, 6- to ,12-month, and final follow-up (mean: 1.2 6 1.0, 1.3 6 1.0, and 1.1 6 1.1; P = 0.003, 0.017, and 0.0003, respectively). Schirmer scores (mean baseline, 6.6 6 6.5 mm) improved at the 12- to 24-month follow-up (mean = 10.7 6 11.4, P = 0.03), whereas ocular surface disease index scores (mean baseline, 54.1 6 22.3) improved at the 3- to ,6- and 6- to ,12-month follow-up (mean: 49.5 6 8.2 and 39.3 6 21.4, P = 0.029 and 0.003, respectively). No complications were noted. Conclusions: Fifty percent AS eye drops seem to be a safe and effective long-term treatment for dry eye disease, especially in patients with severe disease who have exhausted all other conventional forms of treatment. Key Words: autologous serum eye drop, dry eye syndrome, graftversus-host disease (GVHD), PROSE, Sjögren syndrome (Cornea 2014;33:1245–1251)
D
ry eye disease is a common disorder that is caused by decreased tear production, excessive tear evaporation,
Received for publication February 24, 2014; revision received August 7, 2014; accepted August 13, 2014. Published online ahead of print October 8, 2014. From the Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan Medical School, Ann Arbor, MI. The authors have no funding or conflicts of interest to disclose. Reprints: Shahzad I. Mian, MD, Department of Ophthalmology and Visual Sciences, W.K. Kellogg Eye Center, University of Michigan, 1000 Wall St, Ann Arbor, MI 48105 (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins
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and/or a tear film mucin deficiency. Dry eye disease impacts nearly 5 million Americans who are 50 years and older,1 of all races, and is more common in women. Standard treatments for dry eye disease include the use of artificial tears and lubricating ointments, topical cyclosporine 0.05%, topical corticosteroids, and punctal occlusion.2 However, none of these treatments supply epithelium-promoting growth factors or other essential components present in natural tears.3 Similar to tears, human serum contains immunoglobulins, vitamin A, fibronectin, and growth factors that promote epithelial health.2,4–6 Therefore, serum can serve as an excellent surrogate for tears. The use of autologous serum (AS) eye drops was first reported as early as 1975 by Ralph et al7 and later described by Fox et al8 for the treatment of severely dry eyes. Since then, many studies have reported the beneficial effects of autologous tears for the treatment of dry eyes,3,9–18 persistent epithelial defects,19–22 superior limbic keratoconjunctivitis,23 and neurotrophic keratopathy.24 The purpose of this study was to describe the outcomes after long-term use of 50% AS eye drops in a large cohort of patients with dry eyes.
METHODS A retrospective cohort study was conducted at the University of Michigan Health System on the patients who used AS eye drops. After institutional review board approval, data on all patients using AS eye drops between June 2008 and January 2013 were included. Patients who had used AS for ,3 months were excluded. We reviewed the clinical records for relevant clinical history, systemic risk factors, dry eye etiology, subjective symptoms, and adverse events. We reviewed ocular surface evaluations including Schirmer testing with topical anesthesia, fluorescein staining, and ocular surface disease index (OSDI) questionnaire. Schirmer test was performed by adding 1 drop of proparacaine hydrochloride ophthalmic solution 0.5% (Bausch + Lomb, Rochester, NY) and placing a standard filter paper strip inside the margin of the lower eyelid. The level of strip wetting, in millimeters, was measured after 5 minutes. Corneal staining was assessed using the Oxford grading scheme.25 The corneal surface was stained using a fluorescein strip, examined with a slit-lamp microscope, and graded 0 to 4 in the order of increasing severity. The OSDI is a 12-item questionnaire that assesses dry eye symptoms and their impact on vision-related functioning. The items were graded on a scale of 0 to 4. The final score www.corneajrnl.com |
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was calculated by multiplying the sum of the scores by 25 and then dividing the total by the number of questions answered. Scores range from 0 to 100, with higher scores indicating more severe symptoms.26 All data were reviewed at baseline, 3- to 6-month (AS use of at least 3 but ,6 months), 6- to 12-month (AS use of at least 6 but ,12 months), and 12- to 24-month intervals (AS use between 12 and 24 months). Paired t tests were performed to compare the progression of signs and symptoms of ocular surface disease with respect to baseline values. Student t tests were used to compare the outcomes between groups. A P value of ,0.05 was considered statistically significant. Mixed linear regression analysis with a random effect for subject was used to model outcome variables of interest (Schirmer, fluorescein staining, and OSDI scores) while adjusting for the correlation between measures of the same subject. SAS v9.3 (SAS Institute, Cary, NC) was used to perform this analysis.
Preparation of AS Eye Drops AS eye drops were prepared as follows: a total of 60 mL of blood was collected by venipuncture using 5-mL BD Vacutainer serum separator tubes (Becton Dickinson, NJ). The blood was allowed to clot for 15 minutes at room temperature after which it was spun at 14,000 revolutions per minute for 15 minutes. The serum was compounded at a local pharmacy into eye drops in an International Standards Organization class 5 environment using proper aseptic technique and diluted to 50% with sterile 0.9% sodium chloride. The solution was sterilized by filtering through a 0.22-mm filter (Attentus Medical Sales, Inc, Houston, TX) and aliquoted into sterile 3-mL dropper vials. Patients were instructed to store unopened vials in a freezer (220°C) for up to 3 months and opened vials in a refrigerator (4°C) for up to 1 week. We chose to use a 50% concentration because of limited clinical efficacy noted with 20% AS eye drops in our practice before 2008.
RESULTS Data on 123 eyes of 63 patients treated with AS eye drops were analyzed. All patients were treated with 50% AS eye drops 4 times per day for a minimum of 3 months. Demographic data of patients using AS eye drops are listed in Table 1. Three patients used the AS drops in only 1 eye, for persistent epithelial defect in 2 patients and for severe dry eye with complete permanent tarsorrhaphy in 1 patient. Twentyone (33%) patients concurrently used Prosthetic Replacement of Ocular Surface Ecosystem (PROSE) treatment, a customdesigned scleral contact lens (Boston Foundation for Sight, Needham, MA) for ancillary management of severe dry eyes. All patients were refractory to conventional treatments for dry eyes consisting of maximal lubrication, topical corticosteroids (loteprednol 0.3% and 0.5%, tobramycin 0.3%/dexamethasone 0.1%, fluorometholone 0.1%, prednisolone acetate 1%, neomycin 3.5 mg/polymyxin B/dexamethasone 0.1%, loteprednol 0.5%/tobramycin 0.3%), topical cyclosporine 0.05% (Restasis; Allergan, Irvine, CA), and/or punctal occlusion. Topical steroid use decreased from 21 patients (33%) at
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TABLE 1. Demographics of Patients Using AS Eye Drops No. patients Age (mean 6 SD) Gender, n (%) Male Female Indication, n (%) Severe idiopathic dry eye disease GVHD Sjögren syndrome Persistent epithelial defect Stevens–Johnson syndrome PROSE, n (%) Mean serum use (range), mos
63 61 6 11 11 (17.5) 52 (82.5) 38 11 11 2 1 21 11.8
(60) (17.5) (17.5) (3) (2) (33) (3–48)
baseline to 6 of 41 patients (15%) at 6 months, to 4 of 21 patients (19%) at 12 months, and to 2 of 12 patients (17%) at 24 months. Because of the small sample size at follow-up, simple descriptive statistics were used to report on steroid use while the patients were on serum eye drops. Five (8%) patients discontinued serum tear use after a mean of 3 months because of transient benefit or lack of subjective improvement. Four (6%) patients discontinued AS eye drops because of high cost after an average of 8 (range, 3–20) months. Figure 1 shows the dry eye disease parameters with the use of AS drops. The mean Schirmer score improved from 6.6 6 6.5 to 10.7 6 11.4 mm at the 12- to 24-month follow-up visit (P = 0.03) (Fig. 1A). OSDI scores improved at the 3- to 6- (mean, 43.5 6 8.2; P = 0.03) and 6- to 12month follow-up (mean, 39.3 6 21.4; P = 0.003) compared with baseline (mean, 54.1 6 22.3) examination (Fig. 1B). There was an improvement in fluorescein staining from baseline (mean, 1.7 6 1.0) to the last follow-up visit (mean, 1.1 6 1.1; P = 0.0003). Fluorescein staining was also significantly improved at the 3- to 6-month (mean, 1.2 6 1.0; P = 0.003) and 6- to 12-month (mean, 1.3 6 1.0; P = 0.017) follow-up compared with baseline (Fig. 1C). No adverse events were associated with the use of serum tears. Linear mixed regression model results (Table 2) showed that the best predictor of follow-up status was baseline status. Specifically, for every 1 unit increase in baseline Schirmer score, there was a 0.5 unit increase in the follow-up Schirmer score (P , 0.0001); for every unit increase in baseline fluorescein staining score, there was a 0.3 unit increase in the follow-up fluorescein staining score (P = 0.0027); for every unit increase in the baseline OSDI score, there was a 0.7 unit increase in the follow-up OSDI score (P = 0.0007).
Graft-Versus-Host Disease Eleven (17.5%) patients with dry eye disease associated with graft-versus-host disease (GVHD) used serum tears for an average of 19 (range, 3–48) months. Patients with GVHD had lower Schirmer scores (P = 0.001) and higher fluorescein staining scores (P = 0.014) at baseline compared with those without GVHD (Table 3). Schirmer scores were improved at the last follow-up visit (P = 0.017) in patients with GVHD Ó 2014 Lippincott Williams & Wilkins
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FIGURE 1. Dry eye disease parameters with the use of AS drops: Schirmer with anesthesia (A), OSDI score (B), and corneal fluorescein staining score (C).
compared with baseline values but not in patients without GVHD. There was a trend toward improved fluorescein staining at the last follow-up visit (P = 0.062) compared with Ó 2014 Lippincott Williams & Wilkins
baseline in patients with GVHD. Fluorescein scores were significantly improved at the last follow-up (P = 0.009) in patients without GVHD compared with baseline values. There www.corneajrnl.com |
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TABLE 2. Linear Mixed Regression Model Results P
Dependent Variable Independent Variables Estimate (SE) Schirmer score Fluorescein staining OSDI
Time Baseline Schirmer Time Baseline fluorescein Time Baseline OSDI
0.11 0.45 20.01 0.31 0.28 0.69
(0.04) (0.10) (0.01) (0.10) (0.39) (0.15)
0.0040 ,0.0001 0.2029 0.0027 0.4799 0.0007
The model for fluorescein staining was adjusted for Sjögren syndrome.
was no significant improvement in the OSDI scores at the last follow-up visit compared with baseline values in patients with or without GVHD (Table 3). Schirmer, fluorescein, and OSDI scores did not differ significantly at the last follow-up visit between patients with GVHD when compared with patients using serum tears for the other underlying conditions.
¨ gren Syndrome Sjo Eleven (17.5%) patients with Sjögren syndrome were treated with serum drops for a mean of 11.5 (range, 3–33) months. Fluorescein staining improved at the last follow-up visit (P = 0.029) compared with baseline (Table 3). Schirmer and OSDI scores did not differ significantly between the baseline values and the last follow-up visit in patients with or without SS. Patients with SS had significantly lower baseline OSDI scores (P = 0.018) than did other patients with dry eyes (Table 3).
Prosthetic Replacement of Ocular Surface Ecosystem Twenty-one (33%) patients concurrently used PROSE for the management of severe dry eye after a mean of 7 (range, 0–30) months from starting serum eye drops. Of these, 9 patients were diagnosed with idiopathic dry eye, 6 patients with GVHD, 4 with Sjögren syndrome, and 1 patient each was diagnosed with Stevens Johnson syndrome and chemical burn. Figure 2 shows the dry eye disease parameters in patients using PROSE. Fluorescein staining improved in patients who used AS before starting PROSE and at the last follow-up after initiation of PROSE when compared with baseline (mean, 1.4 6 1.2; P = 0.05 and mean, 0.9 6 1; P = 0.0002, respectively) (Fig. 2A). OSDI scores
improved in patients after they started serum drops and before they started PROSE (mean, 30.5 6 21.8; P = 0.0004) as compared with baseline (mean, 61.2 6 24.3). OSDI scores increased significantly (mean, 54.7 6 24.7; P = 0.005) at the last follow-up visit after starting concurrent PROSE when compared with baseline values (Fig. 2B). Although not statistically significant, the mean Schirmer score improved after the serum eye drops were started (Fig. 2C). There was also a trend toward improved Schirmer scores in patients after concurrent use of PROSE (mean, 8 6 7.9 mm; P = 0.07) when compared with baseline (mean, 4.6 6 3.7). No adverse events were associated with the concurrent use of PROSE and serum tears.
DISCUSSION In this study, we investigated the safety and effectiveness of the long-term use of AS eye drops in a large cohort of patients with dry eye disease who were refractory to conventional treatments. Schirmer scores and fluorescein staining improved in our population of patients, especially during the first year, and all patients reported subjective improvement with the use of AS. Using linear mixed regression models, Schirmer scores showed a significant trend of improvement over time. Dry eye disease has a known inflammatory component, and the growth factors in serum tears can reduce inflammation.27,28 Because Schirmer scores increase with antiinflammatory treatments, this is consistent in this study with the use of serum eye drops. There were no significant effects of either dry eye indication or PROSE treatment in any of the models. Longitudinal analyses also showed that the most important predictor for improvement was baseline measurement, which would mean that starting treatment with serum tears earlier in the dry eye disease course might be beneficial. Previous studies have shown variable effectiveness of AS for the treatment of dry eyes. Tananuvat et al11 treated 12 patients with severe dry eyes with 20% AS drops in 1 eye and artificial tears in the fellow eye for 2 months and reported no statistical difference between the 2 treatments. Noble et al3 reported improved impression cytology after 3 months with 50% AS treatment in 16 patients. When the treatment was reversed to conventional therapy, the cytological improvements were reversed. Another crossover study,29 comparing a 2-week treatment with 20% AS with conventional artificial tears in
TABLE 3. Dry Eye Disease Parameters in Patients With GVHD and Sjo¨gren Syndrome Treated With 50% AS at Baseline and Last Follow-up Mean Schirmer Score (6SD) GVHD Non-GVHD P Sjögren Non-Sjögren P
Mean OSDI Score (6SD)
Mean Fluorescein Score (6SD)
Baseline
Last Follow-up
P
Baseline
Last Follow-up
P
Baseline
Last Follow-up
P
2.7 (63.1) 7.7 (66.8) 0.001 7.3 (68.5) 7.6 (611.9) 0.936
6.2 (64.9) 8.5 (68.2) 0.354 7.4 (69.6) 9.7 (610.8) 0.435
0.017 0.534
51.7 (626.9) 55 (620.6) 0.57 39.1 (630.5) 56.7 (620.1) 0.018
42.4 (623.6) 48.2 (627.2) 0.432 48.6 (618.1) 48.8 (626.5) 0.987
0.269 0.153
2.2 (61.2) 1.6 (60.9) 0.014 1.5 (61.1) 3 (610.2) 0.564
1.3 (61.2) 1.1 (61.1) 0.715 0.8 (61) 2.5 (610.1) 0.437
0.062 0.009
0.981 0.088
0.447 0.071
0.029 0.005
Bold indicates significant P values.
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FIGURE 2. Dry eye disease parameters in patients using PROSE: fluorescein staining in patients with concurrent PROSE use (A), OSDI in patients with concurrent PROSE use (B), and Schirmer scores in patients with concurrent PROSE use (C).
12 patients with severe dry eye syndrome found that the patients treated with AS showed a significant improvement in OSDI scores. There were no significant changes in Oxford Ó 2014 Lippincott Williams & Wilkins
staining scores and tear breakup time between the 2 groups. Most recently, Celebi et al17 observed improved tear breakup time and OSDI scores in the AS treatment group when www.corneajrnl.com |
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compared with the preservative-free artificial tear arm after 1 month of treatment. They did not observe any significant difference in Schirmer test and conjunctival and corneal staining scores between the 2 treatment groups after 1 month of treatment and after the crossover. The variable effectiveness of AS in published studies may be because of the variation in the duration of treatment and in the concentration of serum eye drops, which ranged from 20% to 100%. AS concentration of 20% is often used to dilute tumor growth factor in the serum to physiologic tear levels, because it is thought to be inhibitory for some epithelial processes. Because of the previous limited efficacy observed with 20% AS at our institution (M Hussain, RM Shtein, A Sugar, H Kaz Soong, MA Woodward, K DeLoss, SI Mian, unpublished results), the standard practice has been to use 50% serum tear drops. There were no adverse effects noted with this concentration. Although there have been a few complications reported in the literature, such as immunoglobulin deposits,30,31 presence of corneal infiltrates,20 conjunctivitis,10,11 and decreased corneal sensitivity12 in patients using serum tears, the rate of complications occurring is small. There were no complications in this study population. In this study, patients with GVHD treated with serum drops showed a significant improvement in Schirmer and corneal staining scores. Although there was no significant improvement in OSDI scores, most patients reported subjective relief of symptoms with serum drops. In one of the first case reports with 2 patients with GVHD with severely dry eyes refractory to conventional treatment, AS tears were felt to be safe and beneficial.10 Ogawa et al12 used serum eye drops to treat 14 patients with severe dry eye associated with GVHD for a mean of 19 months and observed a significant improvement in corneal staining scores and tear film breakup time. Autoimmune conditions associated with dry eye disease may affect serum cytokines and growth factors and result in different epitheliotropic properties when used as serum eye drops.32 Previous studies suggest that epitheliotropic properties of AS from autoimmune patients should be comparable with those from nonautoimmune patients with dry eyes.33,34 In this study, the 11 patients with SS treated with serum drops showed a significant improvement in fluorescein staining compared with baseline, but there was no significant improvement in Schirmer and OSDI scores. This is consistent with the findings of a study conducted by Tsubota et al9 in which the authors reported a significant improvement in rose bengal and fluorescein staining scores after 4 weeks of AS treatment in 12 patients with SS. The authors did not report any significant improvement in the Schirmer test or tear film breakup time. In this study, 21 (33%) patients used AS drops in conjunction with PROSE by applying the AS drops over the PROSE device and not within the tear reservoir. Although not statistically significant, our patients showed a trend toward improved fluorescein staining and Schirmer scores after starting PROSE along with the serum eye drops. OSDI scores increased significantly after the concurrent use of PROSE. This may be because of the initial adjustment to the PROSE. To our knowledge, there are no previous reports of concurrent use of PROSE and AS in the literature. Despite the benefits, there are potential barriers to the widespread use of AS eye drops.
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Risk of Infection Because serum eye drops are preservative-free to avoid toxicity, this treatment may have a potential risk of causing infection. The composition of serum tears that helps encourage ocular surface healing may be potentially conducive to microbial growth, and because these patients have a compromised ocular surface, they are at a higher risk of developing infection.35–37 However, there were no infections reported in this study, caused by serum tear usage.
Storage A recent study has shown that the epitheliotropic properties of AS remain stable after storage for 6 months at 220°C.38 The serum eye drops in this study were used within 3 months, but in some cases, the patients stored them at 220° C for up to 6 months. There were no adverse events related to the storage of serum eye drops for up to 6 months in this study.
Blood Draw Frequent blood draws are inconvenient and are a drawback of serum eye drop therapy, especially in patients who need prolonged treatment. Chiang et al39 have shown that in patients who need serum tear treatment but whose AS is unavailable or unsuitable for use, allogeneic serum can offer an alternative. However, allogeneic blood poses the risks of transmitting blood-borne diseases and hypersensitivity reactions. Further, ethical and legal issues with allogeneic serum must be taken into account.
Cost AS eye drops are expensive, and most insurance carriers in the United States do not cover this treatment. The local compounding pharmacy that the majority of our patients used charged $175 to $250 for 8 to 10 vials of AS eye drops, which, if used 4 times every day in both eyes, would equal to about a 2-month supply. Four (6%) patients in this study discontinued the use of AS eye drops because of the accumulating high costs after a mean of 8 (range, 3–20) months. This study does not include the patients who were recommended serum tears but did not try it because of high cost. This militates for a need to have AS eye drops become a covered insurance benefit. Dalmon et al40 have recently reported the use of AS as an insurance-covered benefit in California. A well-designed prospective study to test the safety, efficacy, and cost of AS eye drops at varying concentrations may be important in developing therapeutic guidelines and evidence-based design of a standardized and cost-effective protocol for producing AS eye drops. This study is one of the first to evaluate the efficacy of AS tears in a large population of patients with a long duration of follow-up. Because this study is retrospective, clinical data were often not available at specified follow-up time points. It was not possible to specifically assess the effect of AS drops per se because of the wide variety of previous or current Ó 2014 Lippincott Williams & Wilkins
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treatments being used at the start of serum eye drops and the lack of a control group. In summary, we conclude that 50% AS eye drops seem to be safe and effective for long-term treatment of dry eye disease. They are a valuable option in patients with severe dry disease who have exhausted conventional forms of treatment.
ACKNOWLEDGMENTS The authors thank Dr David Musch and Leslie Niziol for statistical data analyses. REFERENCES 1. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:93–107. 2. Tsubota K. Tear dynamics and dry eye. Prog Retin Eye Res. 1998;17: 565–596. 3. Noble BA, Loh RS, MacLennan S, 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: 647–652. 4. Ohashi Y, Motokura M, Kinoshita Y, et al. Presence of epidermal growth factors in human tears. Invest Ophthalmol Vis Sci. 1989;30:1879–1882. 5. Nelson JD, Gordon JF. Topical fibronectin in the treatment of keratoconjunctivitis sicca. Chiron Keratoconjunctivitis Sicca Study Group. Am J Ophthalmol. 1992;114:441–447. 6. Joh T, Itoh M, Katsumi K, et al. Physiological concentrations of human epidermal growth-factor in biological fluids: use of a sensitive enzymeimmunoassay. Clin Chim Acta. 1986;158:81–90. 7. Ralph RA, Doane MG, Dohlman CH. Clinical experience with a mobile ocular perfusion pump. Arch Ophthalmol. 1975;93:1039–1043. 8. Fox RI, Chan R, Michelson JB, et al. Beneficial effect of artificial tears made with autologous serum in patients with keratoconjunctivitis sicca. Arthritis Rheum. 1984;27:459–461. 9. Tsubota K, Goto E, Fujita H, et al. Treatment of dry eye by autologous serum application in Sjogren’s syndrome. Br J Ophthalmol. 1999;83: 390–395. 10. Rocha EM, Pelegrino FS, de Paiva CS, et al. GVHD dry eyes treated with autologous serum tears. Bone Marrow Transplant. 2000;25: 1101–1103. 11. Tananuvat N, Daniell M, Sullivan LJ, et al. Controlled study of the use of autologous serum in dry eye patients. Cornea. 2001;20:802–806. 12. Ogawa Y, Okamoto S, Mori T, et al. Autologous serum eye drops for the treatment of severe dry eye in patients with chronic graft-versus-host disease. Bone Marrow Transplant. 2003;31:579–583. 13. Geerling G, Maclennan S, Hartwig D. Autologous serum eye drops for ocular surface disorders. Br J Ophthalmol. 2004;88:1467–1474. 14. Kojima T, Ishida R, Dogru 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;139:242–246. 15. Lee GA, Chen SX. Autologous serum in the management of recalcitrant dry eye syndrome. Clin Experiment Ophthalmol. 2008;36:119–122. 16. Pan Q, Angelina A, Zambrano A, et al. Autologous serum eye drops for dry eye (review). Cochrane Database Syst Rev. 2013;8:1–47. 17. Celebi AR, Ulusoy C, Mirza GE. The efficacy of autologous serum eye drops for severe dry eye syndrome: a randomized double-blind crossover study. Graefes Arch Clin Exp Ophthalmol. 2014;252:619–626. 18. Jeng BH. Use of autologous serum in the treatment of ocular surface disorders. Arch Ophthalmol. 2011;129:1610–1612.
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19. Tsubota K, Goto E, Shimmura S, et al. Treatment of persistent corneal epithelial defect by autologous serum application. Ophthalmology. 1999; 106:1984–1989. 20. Poon AC, Geerling G, Dart JK, et al. Autologous serum eyedrops for dry eyes and epithelial defects: clinical and in vitro toxicity studies. Br J Ophthalmol. 2001;85:1188–1197. 21. Young AL, Cheng AC, Ng HK, et al. The use of autologous serum tears in persistent corneal epithelial defects. Eye (Lond). 2004;18:609–614. 22. Jeng BH, Dupps WJ Jr. Autologous serum 50% eyedrops in the treatment of persistent corneal epithelial defects. Cornea. 2009;28:1104–1108. 23. Goto E, Shimmura S, Shimazaki J, et al. Treatment of superior limbic keratoconjunctivitis by application of autologous serum. Cornea. 2001; 20:807–810. 24. Matsumoto Y, Dogru M, Goto E, et al. Autologous serum application in the treatment of neurotrophic keratopathy. Ophthalmology. 2004;111: 1115–1120. 25. Bron AJ, Evans VE, Smith JA. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea. 2003;22:640–650. 26. Schiffman RM, Christianson MD, Jacobsen G. Reliability and validity of the ocular surface disease index. Arch Ophthalmol. 2000;118:615–621. 27. Lisi S, Sisto M, D’Amore M, et al. Emerging avenues linking inflammation, angiogenesis and Sjögren’s syndrome. Cytokine. 2013;61: 693–703. 28. Stern ME, Schaumburg CS, Pflugfelder SC. Dry eye as a mucosal autoimmune disease. Int Rev Immunol. 2013;32:19–41. 29. Urzua CA, Vasquez DH, Huidobro A, et al. Randomized double-blind clinical trial of autologous serum versus artificial tears in dry eye syndrome. Curr Eye Res. 2012;37:684–688. 30. McDonnell PJ, Schanzlin DJ, Rao NA. Immunoglobulin deposition in the cornea after application of autologous serum. Arch Ophthalmol. 1988;106:1423–1425. 31. Schrader S, Wedel T, Moll R, et al. Combination of serum eye drops with hydrogel bandage contact lenses in the treatment of persistent epithelial defects. Graefes Arch Clin Exp Ophthalmol. 2006;244:1345–1349. 32. Harloff S, Hartwig D, Kasper K, et al. Epitheliotrophic capacity of serum eye drops from healthy donors versus serum from immunosuppressed patients with rheumatoid arthritis (article in German). Klin Monbl Augenheilkd. 2008;225:200–206. 33. Bradley JC, Bradley RH, McCartney DL, et al. Serum growth factor analysis in dry eye syndrome. Clin Experiment Ophthalmol. 2008;36: 717–720. 34. Phasukkijwatana N, Lertrit P, Liammongkolkul S, et al. Stability of epitheliotrophic factors in autologous serum eye drops from chronic Stevens–Johnson syndrome dry eye compared to non-autoimmune dry eye. Curr Eye Res. 2011;36:775–781. 35. Leite SC, de Castro RS, Alves M, et al. Risk factors and characteristics of ocular complications, and efficacy of autologous serum tears after haematopoietic progenitor cell transplantation. Bone Marrow Transplant. 2006;38:223–227. 36. Sauer R, Blüthner K, Seitz B. Sterility of non-preserved autologous serum drops for treatment of persistent corneal epithelial defects (article in German). Ophthalmologe. 2004;101:705–709. 37. Thanathanee O, Phanphruk W, Anutarapongpan O, et al. Contamination risk of 100% autologous serum eye drops in management of ocular surface diseases. Cornea. 2013;32:1116–1119. 38. Fischer KR, Opitz A, Böeck M, et al. Stability of serum eye drops after storage of 6 months. Cornea. 2012;31:1313–1318. 39. Chiang CC, Chen WL, Lin JM, et al. Allogeneic serum eye drops for the treatment of persistent corneal epithelial defect. Eye (Lond). 2009;23: 290–293. 40. 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: 1612–1613.
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