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Autologous serum compared to artificial tear drops for dry eye disease

Suero autólogo comparado con lágrimas artificiales para ojo seco

Abstract

Introduction Dry eye is one of the most common ocular surface disorders. Although artificial tear drops therapy is the most widely used treatment, it has recently been suggested that autologous serum could be a beneficial alternative treatment for this disorder, but its use is controversial.

Methods We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE/PubMed, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach.

Results and conclusions We identified six systematic reviews, including seven primary studies overall, of which all were randomized trials. We concluded that autologous serum treatment might not lead to adverse effects compared to artificial teardrops, but the certainty of the evidence is low. On the other hand, we are uncertain whether autologous serum therapy improves the quality of life, severity of the pathology, pain or the corneal epitheliopathy grade compared to artificial tear drops as the certainty of the evidence has been assessed as very low.

Problem

Dry eye affects hundreds of millions of people worldwide. It is a chronic multifactorial disease of the ocular surface characterized by a loss of tear film homeostasis. Several factors play an etiological role in this condition. These factors are tear film instability and hyperosmolarity, ocular surface inflammation, damage and neurosensory abnormalities [1]. Common symptoms are irritation or burning sensation, foreign body sensation, visual disturbances, blurred vision, photophobia and pain.

Artificial tears are the most commonly used treatment. However, artificial tears differ in their components from physiological tears. For this reason, other alternatives have been proposed that consider pathophysiology elements in their composition. One alternative is autologous serum.

Autologous serum contains several growth factors involved in the epithelial migration process, necessary for ocular surface repair and maintenance of tear stability. These factors are not present in artificial tears. Some of these factors are epithelial growth factor, nerve growth factor, fibronectin and vitamin A. It has also been shown that the use of autologous serum would inhibit the release of inflammatory cytokines. This process would generate an environment that enables tear film stabilization, promoting epithelial migration and fibroblastic activation necessary for corneal repair [1]. However, its use is controversial.

Methods

We searched Epistemonikos, the largest database of systematic reviews in health, which is maintained by multiple sources of information. These sources include MEDLINE/PubMed, EMBASE, and Cochrane, among others. We extracted and analyzed data from the identified reviews and primary studies. We generated a structured summary called FRISBEE (Friendly Summaries of the Body of Evidence using Epistemonikos), following a pre-established format with this information. This format includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analyses of all studies when possible, a summary table of results using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) method, and a section on other decision-making considerations.

Key messages

  • The use of autologous serum may have no adverse effects (low certainty of the evidence).
  • It is not possible to establish whether the use of autologous serum improves the quality of life, severity of dry eye, pain, or degree of corneal epitheliopathy because the certainty of the existing evidence assessed is very low.

About the body of evidence for this question

What is the evidence.
See the evidence matrix in Epistemonikos below
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We found six systematic reviews [2],[3],[4],[5],[6],[7], which included seven primary studies reported in eight references [8],[9],[10],[11],[12],[13],[14],[15] of which, all are randomized trials.

What type of patients did the studies include? * 

All trials included patients with dry eye [8],[9],[10],[11],[12],[13],[14]. The patients average age included in the trials was 46 years.

Three trials [8],[9],[14] included patients with severe dry eye defined as Schirmer's test score less than five millimeters and tear film breakup time less than five seconds.

Two trials [8],[9] included patients with fluorescein staining scores greater than or equal to one on the Oxford scale. Only one trial included patients with dry eye due to Sjögren's syndrome [11]. One trial included only male patients with dry eye following surgery with the laser-assisted in situ keratomileusis technique [12]. Two trials did not define diagnostic criteria for dry eye [10],[13].

Regarding exclusion criteria, one trial excluded patients with uncontrolled cerebrovascular or cardiovascular disease, history of refractive surgery, lactating or pregnant women [8]. Two trials excluded patients with any other ocular pathology, severe anemia, previous use of autologous serum or use of drops for other indications [8],[9]. In addition, two trials excluded patients with a history of lacrimal occlusion or the use of contact lens [8],[14].

The remaining trials reported no exclusion criteria [10],[11],[12],[13].

What type of interventions did the studies include? * 

All trials compared the use of autologous serum versus artificial tears [8],[9],[10],[11],[12],[13],[14]. 

Regarding differences in autologous serum concentration, five trials used 20% autologous serum [8],[9],[10],[12],[14], one trial used 50% autologous serum [11] and one trial used 40% autologous serum [13].

Regarding the frequency of autologous serum administration, two trials used autologous serum four times daily [8],[9]. Two trials used autologous serum five times daily [11],[12]. One trial used autologous serum six times daily [10]. The remaining trials did not report the frequency of autologous serum use [13],[14].

What type of outcomes did they measure 

The trials reported multiple outcomes, which were grouped by the systematic reviews as follows:

  • Pain, measured through a visual analog scale.

  • Corneal epitheliopathy, measured through fluorescein staining.

  • Quality of life, measured using the ocular surface disease index questionnaire.

  • The severity of the pathology, measured through Schirmer's test and tear film breakup time test. 

  • Adverse reactions.

The average follow-up of the trials was three months, with a range between two weeks and 12 months.

*Information on primary studies is extracted from the identified systematic reviews, not directly from the studies unless otherwise specified.

Summary of results

Information on the effects of using autologous serum compared with artificial tears for dry eye is based on seven randomized trials [8],[9],[10],[11],[12],[13],[14] involving 271 patients.

Four trials measured quality-of-life (160 eyes) [8],[9],[11],[13]. All trials measured dry eye severity by tear film breakup time test (481 eyes) [8],[9],[10],[11],[12],[13],[14]. Six trials assessed dry eye severity using the Schirmer test (456 eyes) [8],[9],[10],[11],[12],[13],[14]. Four trials measured corneal epitheliopathy (360 eyes) [8],[10],[12],[14], and only one trial assessed pain (20 eyes) [14].

All trials evaluated adverse effects associated with the use of autologous serum [8],[9],[10],[11],[12],[13],[14]. However, no review allowed the extraction of data in a way that could be incorporated into a meta-analysis. Thus, the information on this outcome is presented as a narrative synthesis.

The summary of the results is as follows:

  • It is not possible to establish whether autologous serum improves the quality of life because the certainty of the existing evidence has been assessed as very low.
  • It is not possible to establish whether autologous serum decreases the severity of the condition because the certainty of the existing evidence has been assessed as very low.
  • It is not possible to establish whether the use of autologous serum decreases pain because the certainty of the existing evidence has been assessed as very low.
  • It is not possible to establish whether autologous serum improves the degree of corneal epitheliopathy because the certainty of the existing evidence has been assessed as very low.

The use of autologous serum may have no adverse effects associated with its use (low certainty in evidence).

Follow the link to access the interactive version of this table (Interactive Summary of Findings - iSoF)

Other considerations for decision-making

To whom this evidence applies and to whom it does not apply.

  • The evidence presented in this summary applies to adult patients with dry eye and patients with a fluorescein staining result greater than or equal to one. 
  • The patients included in these trials are adults, so the results should be extrapolated with caution to the pediatric population in the absence of direct evidence.
  • The presented evidence does not apply to patients with a history of severe anemia, previous use of autologous serum or patients with previous ocular or eyelid pathology other than dry eye that required topical use of medications.

About the outcomes included in this summary

  • The authors of this summary consider that the outcomes selected are critical for decision-making. They are also in line with the outcomes reported by the identified systematic reviews. 
  • Corneal epitheliopathy, quality of life and severity of dry eye outcomes are necessary for visual prognosis and associated long-term repercussions. 
  • Pain and adverse effects are necessary to know the symptomatology, intervention efficacy and complications during treatment.

Harm/benefit balance and certainty in evidence

  • The use of autologous serum for dry eye may be safe compared to artificial tears, as the evidence shows little or no adverse effects. 
  • Additionally, there is uncertainty on the benefits autologous serum could have on the quality of life, disease severity, pain or development of epitheliopathy, given the existing evidence. 
  • Because of this, it is not possible to make an adequate balance between harms and benefits and other aspects such as costs. For this reason, patient and treating physician preference should be considered in decision-making.

Costs 

  • Three systematic reviews have indicated that the cost associated with the monthly use of autologous serum for dry eye can reach hundreds of dollars [3],[5],[6]. 
  • However, it is not appropriate to perform a cost-effectiveness analysis until there is a proven benefit of the intervention.

What do patients and their caregivers think 

  • In the face of the existing evidence, both patients and physicians should lean against the use of autologous serum as a first-line treatment for dry eye.
  • However, autologous serum could be a therapeutic alternative when initial treatment with environmental measures, artificial tears and pharmacological treatment has not worked.
  • The use of autologous serum could be reserved for a third stage in the stepwise treatment of dry eye.

Differences between this summary and other sources 

  • This summary's conclusions are consistent with the identified systematic reviews [2],[3],[4],[5],[6],[7]. While the intervention may have a role in dry eye treatment, the uncertainty of the existing evidence does not allow a clear conclusion of its benefits.
  • Although no clinical practice guidelines were found that make a direct comparison between the use of autologous saline and artificial tears, Tear film and Ocular surface Society and the American Academy of Ophthalmology guidelines [1],[17] mention the use of autologous serum in situations of conventional treatment failure or severe symptoms. Thus, it is not a first-line alternative for dry eye treatment. Guidelines indicate first-line treatment should be education, non-pharmacological treatment and use of ocular lubricants if deemed necessary. In addition, guidelines mention that both the high cost required for autologous serum production and the lack of international standards for its production are barriers to widespread use. These factors generate variations in doses and schedules administered to patients.

Could this information change in the future? 

  • Given the uncertainty of existing evidence, it is likely that this summary's findings will change.
  • No systematic reviews were identified in the international systematic review registry platform, PROSPERO (International prospective register of systematic reviews), which evaluated the use of autologous serum versus artificial tears for dry eye treatment.
  • One randomized trial was found in the International Clinical Trials Platform of the World Health Organization. However, this trial was terminated prematurely without reporting results or conclusions [18].

How we conducted this summary 

We collected all the relevant evidence for this question and presented it in an evidence matrix using automated and collaborative methods.

Follow the link to access the interactive versionAutologous serum compared to artificial tears for dry eye.

Notes

If new systematic reviews on this topic are published after the publication of this abstract, a "new evidence" notification will be displayed at the top of the matrix. While the project provides regular updates of these abstracts, users are invited to comment on the Medwave website or contact the authors by e-mail if they believe evidence warrants an earlier update.

After creating an Epistemonikos account, by saving the matrices, you will receive automatic notifications whenever there is new evidence that potentially answers this question.

This article is part of the Epistemonikos evidence synthesis project. It is elaborated with a pre-established methodology, following rigorous methodological standards and an internal peer review process. Each of these articles corresponds to a summary, called FRISBEE (Friendly Summary of Body of Evidence using Epistemonikos), whose main objective is to synthesize the body of evidence of a specific question, in a friendly manner for physicians. The main resources are based on the Epistemonikos evidence matrix and the analysis of the result is based on the GRADE methodology. Further details of this FRISBEE elaboration method are described here.

The Epistemonikos Foundation is an organization that seeks to bring information closer to health decision-makers through the use of technologies. Its main source is the Epistemonikos database (www.epistemonikos.org).

Authorship contributions
FMY: methodology, validation, formal analysis, research, resources, data processing, writing, visualization and fund acquisition. GO: conceptualization, methodology, validation, formal analysis, research, resources, data processing and writing. CA: conceptualization, research, resourcing, writing, oversight, administration and fund adquisition.

Competing interest
The authors declare no competing interest.

Ethics
This study did not have an ethics committee evaluation, given the use of secondary data sources.

Funding
There were no external sources of funding for this study.

Language of submission
Spanish