Menoufia Medical Journal

ORIGINAL ARTICLE
Year
: 2017  |  Volume : 30  |  Issue : 2  |  Page : 525--531

Comparative study using cyclosporine A 0.05% eye drops, autologous serum 20% eye drops, and combined use of cyclosporine A 0.05% eye drops and autologous serum 20% eye drops in the treatment of moderate to severe dry eye


Mohammad A Al-Sayed Ahmad Kasper, Hassan G Farahat, Osama A Al-Morsy, Ahmad A Alhagaa 
 Department of Ophthalmology, Faculty of Medicine, Menoufia University, Shebeen Al-Koom, Menoufia, Egypt

Correspondence Address:
Mohammad A Al-Sayed Ahmad Kasper
3 Sheraton Al-Matar, Area 4, Al-Nozha, Cairo, 11843
Egypt

Abstract

Objectives A comparative study was carried out between the cyclosporine A 0.05%, the autologous serum, and combined therapy of both in the treatment of moderate to severe dry eye. Background Dry eye disease is a common and often underdiagnosed condition. Patients and methods A prospective interventional case study was carried out on 30 patients attending the ophthalmology outpatient clinic of Menoufia University; these patients were subdivided as follows: group A received topical autologous serum 20% four times daily for 2 months, group B received cyclosporine A emulsion 0.05% twice daily for 2 months, and group C received topical cyclosporine A emulsion 0.05% two times daily and topical autologous serum 20% four times daily for 2 months. The three groups received nonpreserved tears up to five times daily, to be followed 1 month after stoppage of treatment, except for nonpreserved tears (Refresh Plus). All patients were subjected to a full assessment of history, slit-lamp examination, lissamine green staining of the ocular surface, the tear break-up time test, Schirmer's test, and conjunctival impression cytology before treatment, at 1 and 2 months after treatment, and then 1 month after stoppage of treatment. The results obtained were subjected to a statistical analysis. Results In our study, we found that autologous serum eye drops had a more delayed onset of action, but more sustained action; topical cyclosporine A had a rapid onset of action, but regression occurred soon after stoppage of treatment. Both autologous serum and cyclosporine 0.05% had additive effects with a rapid sustained action. Conclusion Combined topical cyclosporine A emulsion 0.05% and autologous serum eye drops 20% are effective in the treatment of dry eye cases through their combined anti-inflammatory and epitheliotropic effects. Therefore, we recommend the use of combined autologous serum 20% and cyclosporine 0.05% in the treatment of severe dry eye.



How to cite this article:
Al-Sayed Ahmad Kasper MA, Farahat HG, Al-Morsy OA, Alhagaa AA. Comparative study using cyclosporine A 0.05% eye drops, autologous serum 20% eye drops, and combined use of cyclosporine A 0.05% eye drops and autologous serum 20% eye drops in the treatment of moderate to severe dry eye.Menoufia Med J 2017;30:525-531


How to cite this URL:
Al-Sayed Ahmad Kasper MA, Farahat HG, Al-Morsy OA, Alhagaa AA. Comparative study using cyclosporine A 0.05% eye drops, autologous serum 20% eye drops, and combined use of cyclosporine A 0.05% eye drops and autologous serum 20% eye drops in the treatment of moderate to severe dry eye. Menoufia Med J [serial online] 2017 [cited 2019 Sep 21 ];30:525-531
Available from: http://www.mmj.eg.net/text.asp?2017/30/2/525/215461


Full Text

 Introduction



Dry eye syndrome is a common disorder of the tear film that is characterized by a deficiency in the quantity and/or the quality of tears, an unstable tear film, ocular surface damage, and bothersome symptoms such as ocular irritation, dryness, fatigue, and fluctuating visual disturbances [1],[2],[3].

Dry eye disease (DED), also known as keratoconjunctivitis sicca, is a multifactorial disorder of the tears and ocular surface. Risk factors for the development of DED include advanced age, female sex, hormonal imbalance, autoimmune disease, abnormal corneal innervations, vitamin deficiency, environmental stress, contact lens use, infection, medication use, and ophthalmic surgery. The pathogenesis of DED is not fully understood; however, it is recognized that inflammation plays a prominent role in the development and amplification of the signs and symptoms of DED [4],[5],[6].

DED, a chronic inflammatory condition that may be mediated by activated T-cell lymphocytes, affects the ocular surface and lacrimal glands. The damage caused by DED may be irreversible and despite the availability of various tear substitutes, many patients with dry eye syndrome can experience corneal pathology, with a subsequent reduction in vision [7],[8],[9],[10],[11],[12],[13].

Since then, significant advances have been made in the treatment of many facets of dry eye including preservative-free artificial tear preparations, steroids, cyclosporine ophthalmic emulsion, oral pilocarpine, biotears oral formulation, supplementation with omega 3 essential fatty acids, punctal plugs, and iodide iontophoresis. Autologous serum and umbilical cord serum eye drops have been found in clinical trials to be beneficial in patients who have persistent symptoms and signs. In cases refractory to medical treatment, surgery may be necessary [14],[15],[16],[17],[18],[19],[20],[21],[22].

Despite the presence of all these advances in the treatment of dry eye, it remains a disorder of long term maintenance rather than permanent cure.

 Patients and Methods



Our study included 30 patients with dry eye, who were subdivided into three groups from among patients attending the outpatient ophthalmology clinic, Menoufia University Hospital. The research protocol adhered to the tenets of the Helsinki Declaration and was approved by the Local Ethics Committee (Ethics Committee at the Faculty of Medicine, Menoufia University, Shebeen Al-Koom, Egypt).

Exclusion criteria

Patients with a history or evidence of ocular surgery or ocular trauma within the previous 6 months, pregnancy, or lactation were excluded. Also, patients with proved blood diseases, especially hepatitis B or hepatitis C, were excluded.

Inclusion criteria

Patients with chronic moderate to severe aqueous tear-deficient type dry eye with one or more dry eye-related symptoms including burning, blurred vision, foreign body sensation, dryness, photophobia, itching, and pain, patients with dry eye-related punctate epithelial keratopathy defined as corneal punctate fluorescein staining, Schirmer's test of less than 10 mm/5 min, and tear break-up time (TBUT) of less than 10 s were included.

Examination technique

All patients were subjected to the following:

Pretreatment assessment

Assessment of full medical and ophthalmic history (using Ocular Surface Disease Index), slit-lamp examination, lissamine green staining of ocular surface (according to the van Bjiesterveld scale [23–25]), TBUT test, Schirmer's test with and without topical anesthesia [26], and conjunctival impression cytology [27] (according to Nelson's classification for squamous metaplasia [28],[29]).

Treatment data

The first group (A) received topical autologous serum 20% four times daily for 2 months, the second group (B) received cyclosporine A emulsion 0.05% two times daily for 2 months, and the last group (C) received topical cyclosporine A emulsion 0.05% two times daily and topical autologous serum 20% four times daily for 2 months. The three groups received nonpreserved tears (Refresh Plus; Allergan Australia Pty Ltd., Pacific Highway, Gordo) up to five times daily up to 1 month after stoppage of treatment, except for nonpreserved tears (Refresh Plus; Allergan).

Post-treatment assessment

Assessment of full medical and ophthalmic history (Ocular Surface Disease Index) with a special focus on symptomatic improvement, slit-lamp examination, lissamine green staining of the ocular surface (according to van Bjiesterveld scale), TBUT test, Schirmer's test with and without topical anesthesia and conjunctival impression cytology (according to Nelson's classification for squamous metaplasia were performed at 1, 2, and 3 months after treatment).

 Results



Demographic data of the studied group

Sex

In the first group, there were six (60%) women and four (40%) men, in the second group, there were six (60%) women and four (40%) men, and in the third group there were three (30%) women and seven (70%) men as shown in [Table 1] and [Figure 1].{Table 1}{Figure 1}

Age

The age of the patients in group (A) ranged from 28 to 75 years, with a mean of 51.1 years, with an SD of 16.37 years, whereas in group (B), the age of the patients ranged from 32 to 73 years, with a mean of 52.9 years with an SD of 13.5, and in group (C), the age of the patients ranged from 45 to 79 years, with a mean of 62.5 years with an SD of 10.17 as shown in [Table 1].

Comparison between three groups of clinical assessment

In our study, we found that there was a statistically nonsignificant (NS) difference between the three groups in the effect of treatment on symptoms at 1, 2, and 3 months as shown in [Table 2],[Table 3],[Table 4].{Table 2}{Table 3}{Table 4}

TBUT, Schirmer's test values, and squamous metaplasia grading 1 and 2 months after treatment showed a statistically significant (SS) difference between groups B and A and a highly significant (HS) difference 3 months after treatment as shown in [Figure 2] and [Figure 3]; there was NS difference in 1-month and 2-month post-treatment ocular staining grading and an SS difference at 3 months after treatment as shown in [Figure 4].{Figure 2}{Figure 3}{Figure 4}

There was NS difference between groups B and C in TBUT values, Schirmer test values, and lissamine green staining 1 month after treatment, with a HS difference 3 months after treatment as shown in [Figure 5]. Also, there was an SS difference in squamous metaplasia grading 1 and 3 months after treatment.{Figure 5}

There was NS difference between groups A and C in the TBUT values, Schirmer test values, and squamous metaplasia grading 2 and 3 months after treatment. There was an SS difference 1 month after treatment.

These results showed that autologous serum eye drops had more delayed onset of action, but a more sustained action; topical cyclosporine A had a rapid onset of action, but regression occurred soon after stoppage of treatment. Both autologous serum and cyclosporine 0.05% exerted additive effects as a rapid sustained action.

Also, we found that autologous serum eye drops led to a greater improvement in the degree of keratinization than topical cyclosporine A 0.05% and this can be attributed to the fact that the drops included growth factors, fibronectin, and vitamins.

 Discussion



Dry eye is a multifactorial disease of the tears and the ocular surface that results in symptoms of discomfort, visual disturbances, and tear film instability, with potential damage to the ocular surface.

Group A included 10 patients treated with topical autologous serum 20% and preservative-free artificial tears for 2 months. Patients were on preservative-free artificial tears only for 1 month during the follow-up period.

The age distribution of the patients in our study ranged from 28 to 75 years, whereas in Noble et al.'s [22] study, the age of the patientsranged from 30 to 40 years, and in Ogawa et al.'s [18] study, the age of the patientsranged from 22 to 43 years. This difference in age distribution may be correlated to earlier presentation of patients in studies carried out abroad.

In terms of symptoms, there was a HS difference before treatment and 3 months after treatment, with an 80% improvement from severe and disabling (grade 3) to mild or no symptoms (grade 0). The P- value was 0.007.

In Noble et al.'s [22] study: 32 eyes were assessed; there was 100% significant improvement in symptoms within 1 month of treatment.

InOgawa et al.'s [18] study, 14 patients were assessed; 93% of the patients reported a significant improvement in their symptoms at the end of the treatment.

This difference from other studies may be related to variations in the severity of the conditions studied, being more severe in our study, and thus a significant improvement started to appear 3 months after treatment.

In terms of TBUT and Schirmer's values, there was a SS difference between pretreatment and post-treatment TBUT and a HS difference in Schirmer's values 1 month after treatment. A highly SS difference was detected between pretreatment and post-treatment TBUT values and Schirmer's values 2 and 3 months after treatment.

In the Noble et al.'s [22] study, 32 eyes were assessed; there was a significant improvement in TBUT and Schirmer's test scores within 1 month of treatment in all patients.

InOgawa et al.'s [18] study, 14 patients were assessed; 95% of the patients experienced a significant improvement in TBUT scores: from 2.8 to 5.8 s, with P  less than 0.05. Schirmer's test was not evaluated.

This difference from other studies may be related to variations in the severity of the conditions studied, being more severe in our study, and thus a significant improvement occurred 3 months after treatment.

The improvement in ocular surface staining scores in our study started gradually 1 month after treatment and continued to improve during 2 and 3 months after treatment. This is also in agreement with other studies such as Noble et al. [22], Ogawa et al. [18], in which the improvement in ocular surface staining scores occurred more rapidly 1 month after treatment.

No significant difference was detected between the results of our study and other studies such asNoble et al.'s [22] studyandOgawa et al.'s [18] study in the pretreatment results of conjunctival impression cytology.

The squamous metaplasia and distribution of goblet cells showed marked improvement 3 months after treatment.

There was a significant difference between groups B and A in the effect of treatment on the degree of keratinization 1 and 3 months after treatment and no significant difference between the three groups 2 months after treatment.

This was not in agreement with other studies, and this difference may be related to the severity of the conditions studied, being more severe in group B.

In our study, no significant complications were reported with the use of serum drops, except eczema in a single case, which was treated with topical corticosteroid. A major complication that we encountered was the requirement of repeated blood donation and the need for refrigeration of the autologous serum drops as shown in [Table 5].{Table 5}

Group B included 10 patients treated with topical cyclosporine A emulsion 0.05% and preservative-free artificial tears for 2 months. Patients were on preservative-free artificial tears only for 1 month during the follow-up period.

In our study, the mean age distribution was 52.9 ± 13.5 years.

In Brown et al.'s [17] study, the mean age distribution was 45.05 years and in Perry et al.'s [21] study, the mean age distribution was 43.17 years. The lower age incidence in our study may be attributed to the earlier development of dry eye, which might be linked to increased previous ocular surface infections (trachoma).

In terms of symptoms, there was a SS difference before treatment and 1 and 2 months after treatment, with a 90% improvement from severe and disabling symptoms (grade 3) to mild or no symptoms (grade 0), with a P- value of 0.0008. Symptoms worsened in 40% of patients 3 months after treatment.

In Brown et al.'s [17] study, 14 patients were assessed; of these, 93% of patients showed a significant improvement in symptoms at the end of the treatment.

In Perry et al.'s [21] study, 20 patients were assessed; all patients reported a significant improvement in symptoms.

This difference from other studies may be related to variations in the severity of the conditions studied, being more severe in our study, and thus a significant improvement started to appear 3 months after treatment.

In our study, there was a statistically HS difference between pretreatment and post-treatment TBUT and Schirmer I test values 1, 2, and 3 months after treatment.

There was a SS difference between pretreatment and 1-month and 3-month post-treatment TBUT values in Brown et al.'s [17] study and Perry et al.'s [21] study.

In Brown et al.'s [17] study, there was a SS difference between pretreatment and post-treatment Schirmer's scores (mean ± SD = 7.55 ± 1.44, P = 0.033) and the same result was obtained in Perry et al.'s [21] study, in which mean ± SD = 7.64 ± 1.12, P = 0.012. This is also in agreement with our results.

In our study, there was a SS improvement in staining grade; this effect started gradually 1 month after treatment and continued over 2 and 3 months after treatment. Other studies such as Brown et al.'s [17] study and Perry et al.'s [21] study obtained results similar to ours in terms of the effect of treatment on lissamine green staining of the ocular surface.

No significant difference was detected between our study and other studies such as Brown et al.'s [17] study and Perry et al.'s [21] study in terms of pretreatment results of conjunctival impression cytology.

The most commonly reported side-effect with topical cyclosporine therapy in other studies was mild ocular burning and stinging upon instillation and this occurred in 70% of our patients; the remaining 50% of our patients complained of foreign body sensation, ocular pain, and conjunctival hyperemia as shown in [Table 6].{Table 6}

Group C included 10 patients treated with combined topical autologous serum 20%, topical cyclosporine 0.05% and preservative-free artificial tears for 2 months. Follow-up on preservative-free artificial tears was performed only for 1 month.

In our study, the age distribution ranged from 45 to 79 years.

In our study, there was a HS difference between pretreatment and 3-month post-treatment symptoms, with an 80% improvement from severe and disabling symptoms (grade 3) to mild or no symptoms (grade 0), with a P- value of 0.007, which is similar to group A.

In terms of TBUT and Schirmer's test scores, there was a statistically HS improvement that started 1 month after treatment and continued to show improvement over 2 and 3 months.

In our study, a HS improvement in ocular surface staining started 1 month after treatment and reached its maximum 3 months after treatment.

There was a SS improvement in the degree of squamous metaplasia and a SS improvement in goblet cell density as shown in [Table 7].{Table 7}

Summary and recommendations

On the basis of the findings of the present study, we can conclude that combined topical cyclosporine A emulsion 0.05% and autologous serum eye drops 20% are effective in the treatment of dry eye cases through their combined anti-inflammatory and epitheliotropic effects. Also, we found that autologous serum eye drops led to greater improvement in the degree of keratinization than topical cyclosporine A 0.05% and this can be attributed to the fact that the drops included growth factors, fibronectin, and vitamins.

Therefore, we recommend the use of combined autologous serum 20% and cyclosporine 0.05% drops in the treatment of severe dry eye for their combined rapid and sustained effects. Also, further researches are required to determine the effect of topical cyclosporine and topical autologous serum after 3 months to ensure either dryness is cured or there is incidence of recurrence.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Novic BM, Dana R, Sullivan DA, Schaumberg D. Impact of dry eye syndrome on vision – related quality of life. Am J Ophthalmol 2007; 143:409–415.
2Liesegang TJ, Hoskins Jr HD, Albert DM, O'Day DM, Spivey BE, Sadun AA, et al. Ophthalmic education: where have we come from, and where are we going?. American J Ophthalmology 2003; 136:114.
3Anthony J. Methodologies to diagnose and monitor dry eye disease: report of the diagnostic methodology subcommittee of the international dry eye workshop. Ocul Surf 2007; 5:105–152.
4Chen Y, Chauhan SK, Saban DR, Sadrai Z, Okanobo A, Dana R. Interferon-γ-secreting NK cells promote induction of dry eye disease. J Leukoc Biol 2011; 89:965–972.
5[No authors listed]. Research in dry eye: report of the Research Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007; 5:179–193.
6Behrens A, Doyle J, Stern L. Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea 2006; 25:900–907.
7Enríquez-de-Salamanca A, Castellanos E, Stern ME, Fernández I, Carreño E, García-Vázquez C, et al. Tear cytokine and chemokine analysis and clinical correlations in evaporative-type dry eye disease. Mol Vis 2010; 16:862–873.
8Pflugfelder SC, Jones D, Ji Z, Afonso A, Monroy D. Altered cytokine balance in the tear fluid and conjunctiva of patients with Sjogren's syndrome keratoconjunctivitis sicca. Curr Eye Res 1999; 19:201–211.
9Pflugfelder SC. Anti-inflammatory therapy for dry eye. Am J Ophthalmol 2004; 137:337–342.
10Chen YT, Nikulina K, Lazarev S, Bahrami AF, Noble LB, Gallup M, et al. Interleukin-1 as a phenotypic immune modulator in keratinizing squamous metaplasia of the ocular surface in Sjögren's syndrome. Am J Pathol 2010; 177:1333–1343.
11El Annan J, Goyal S, Zhang Q, Freeman GJ, Sharpe AH, Dana R. Regulation of T-cell chemotaxis by programmed death-ligand 1 (PD-L1) in dry eye–associated corneal inflammation. Invest Ophthalmol Vis Sci 2010; 51:3418–3423.
12Baudouin C, Aragona P, Messmer EM, Tomlinson A, Calonge M, Boboridis KG, et al. role of hyperosmolarity in the pathogenesis & management of dry eye disease. Ocul Surf 2013; 11:246–258.
13Luo L, Li DQ, Pflugfelder SC. Hyperosmolarity-induced apoptosis in human corneal epithelial cells is mediated by cytochrome-c and MAPK pathways. Cornea 2007; 26:452–460.
14Schechter BA. Efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. J Ocul Pharmacol 2006; 22:150–154.
15Geerling G, Maclennan S, Hartwig D. Controlled study of the use of autologous serum in dry eye patients. Br J Ophthalmol 2004; 88:1467–1474.
16Moon JW, Lee HJ, Shin KC, Wee WR, Lee JH, Kim MK. Short term effect of topical cyclosporine and visco-elastic on the ocular surface in patients with dry eye. Korean J Ophthalmol 2007; 21:189–194.
17Brown MM, Brown GC, Brown HC, Peet J, Roth Z. Value-based medicine comparative effectiveness and cost- effectiveness analysis of topical cyclosporine for the treatment of dry eye syndrome. Arch Ophthalmol 2009; 127:146–152.
18Ogawa Y, Okamoto S, Mori T. 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.
19Chiang CC, Lin JM, Chen WL, Tsai YY. Allogenic serum eye drops for the treatment of severe dry eye in patients with chronic graft-versus-host disease. Cornea 2007; 26:861–863.
20Dastjerdi MH, Hamrah P, Dana R. High-frequency topical cyclosporine 0.05% in the treatment of severe dry eye refractory to twice-daily regimen. Cornea 2009; 28:1091–1096.
21Perry HD, Solomon R, Donnenfeld ED, Perry AR, Wittpenn JR, Greenman HE, et al. Evaluation of topical cyclosporine for the treatment of dry eye disease. Arch Ophthalmol 2008; 126:1046–1050.
22Noble BA, Loh RS, MacLennan S, Pesudovs K, Reynolds A, Bridges LR, et al. Comparison of autologous serum eye drops with conventional therapy in a randomized controlled cross over trial for ocular surface disease. Br J Ophthalmol 2004; 88:647–652.
23Bron A, Evans V, Smith J. Grading of corneal and conjunctival staining in the context of other dry eye tests. Cornea 2003; 22:640–650.
24Bijsterveld V. Diagnostic tests in the sicca syndrome. Arch Ophthalmol 1969; 8210–14.
25Kim J, Foulks GN. Evaluation of the effect of lissamine green and rose Bengal on human corneal epithelial cells. Cornea 1999; 183:328–332.
26Macri A, Pflugfelder SC. Correlation of the Schirmer I and fluorescein clearance tests with the severity of corneal epithelial and eyelid disease. Arch Ophthalmol 2000; 118:1632–1638.
27Divani SN, Margari C, Zikos GA, Zikos A, Papavassiliou GB. Diagnostic impression cytology: a simple technique for the diagnosis of external eye diseases. Cytopathology 1997; 8:373–380.
28Lin H, Li W, Dong N, Chen W, Liu J, Chen L, et al. Changes in corneal epithelial layer inflammatory cells in aqueous tear-deficient dry eye. Invest Ophthalmol Vis Sci 2010; 51:122–128.
29Nelson DJ. Impression cytology. Cornea 1988; 7:71–81.