The disparity between the dry eye “DREAM” study results and real world clinical experience: Is the gut microbiome the missing link ?

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The disparity between the dry eye “DREAM” study results and real world clinical experience: Is the gut microbiome the missing link ?

Dr. Fishman’s comments on latest DREAM study publication:

Why is there is a huge disparity between the clinical experience of most well-known dry eye and corneal specialists and the results that are emerging from the DREAM study? To cut to the chase, the study lumped together all of the many different subtypes of dry eye disease, and they failed to consider the impact of the baseline differences in gut microbiome when enrolling the patients. Let’s unpack these ideas here.

Contrary to what the DREAM study investigators report that Omega-3 fatty acids supplementation is essentially ineffective for dry eye patients (including the newest installment), many patients with dry eye disease who start on supplementation with Omega-3 FA as a primary therapy have remarkable improvements in their symptoms. These “real world” clinical experiences have been confirmed by numerous publications that show quantitative improvement in signs of ocular surface disease (for e.g, osmolarity, tear breakup time, OSDI, MMP-9 levels). More importantly, precise analytical chemistry measurements (for e.g., LC / mass spectrometry) show improvements in the meibum and ocular surface conditions in patients with dry eye disease. This has been my overwhelming experience over the past 15 years as well. Just last week, I had three patients who remarked that primary therapy of Omega-3 supplements completely resolved their dry eye symptoms and “changed their life.” Ironically, it was the same day that this latest DREAM study paper was released ahead-of-print.

Much has been written on the short comings of the DREAM study including poor control (olive oil), huge heterogeneity of the causes/etiology of dry eye patients (lumping dry eye patients together), flawed inclusion/exclusion criteria, the type of omega-3 FA used in the study (i.e, GLA based) and the dose amount. Moreover in the NEJM publication, while both groups improved, the study group authors in lectures and interviews argue that Omega-3 FA are ineffective for dry eye patients.

So what is the missing link ? I think that one of the most obvious disconnects is that the investigators lumped together all the subtypes of dry eye disease. It would be equivalent of running a clinical trial on “cancer” and failing to identify the myriad of cancer subtypes and concluding that a single therapy failed because it did not collectively cure lung, colon, skin cancer etc. When you think of the many etiologies of dry eye (similar to the many subtypes of cancer), how could one ever believe that a single intervention would show any statistical significance with such heterogeneity in etiology.

Secondly, just as the DREAM study lumped together all subtypes of dry eye disease, they lumped together the gut microbiome of every patient. Why is this another disconnect? One of my (many) theories as to why Omega-3 FAs help a significant subset of dry eye patients (and not all), is that certain dry eye subtypes have a gut microbiome dysbiosis that is helped with the “pre-biotic” effects of the Omega-3 FAs. This effect could very well have a long lasting impact on the microbial community in the gut and may not be altered simply by withdrawing Omega-3FA for the time period studied in this latest DREAM study report. Failing to take this into account could very much wash out the results.

Interestingly, the dramatic clinical improvement that I often see and the many published works finding the same seem an unlikely effect from just the Omega-3 FAs alone. Instead, I hypothesize that there is an amplification effect via the hundreds of millions of bacterial species that makeup the microbiome of the gut. It goes without saying, that my writing these theories down here are just that… theories. We need to test these hypotheses with well-controlled double-blinded clinical studies. At FishmanVision, we have already published on the gut microbiome and dry eye disease, and this is an active area of clinical and research interest for us. Click here for our ARVO poster.

 

I enjoy lecturing on the gut -eye connection , and you can click here for short snippet of a lecture on the impact of the microbiome and dry eye disease that I gave at an annual Alldocs meeting.

 

 

 

Associations Between Systemic Omega-3 Fatty Acid Levels With Moderate-to-Severe Dry Eye Disease Signs and Symptoms at Baseline in the Dry Eye Assessment and Management Study”

Authors: Kuklinski, Eric J. BA; Hom, Milton M. O.D., F.A.A.O.; Ying, Gui-Shuang Ph.D.; Lin, Meng C. O.D., Ph.D.; Chapkin, Robert S. Ph.D.; Jones, Richard Ph.D.; Moser, Ann B.A.; Kim, Ka Yeun BS; Maguire, Maureen G. Ph.D.; Asbell, Penny A. M.D., M.B.A., F.A.C.S. the DREAM Study Research Group

Eye & Contact Lens: Science & Clinical Practice: February 24, 2020 – Volume Publish Ahead of Print – Issue – doi: 10.1097/ICL.0000000000000687

Abstract

Purpose: 

Omega-3 (n-3) fatty acid supplementation is used to treat systemic inflammatory diseases, but the role of n-3 in the pathophysiology and therapy of dry eye disease (DED) is not definitive. We evaluated the relationship of systemic n-3 levels with signs and symptoms at baseline in the Dry Eye Assessment and Management (DREAM) Study.

Methods: 

Blood samples from participants at baseline were analyzed for n-3 and n-6, measured as relative percentage by weight among all fatty acids in erythrocytes. Symptoms were evaluated using the Ocular Surface Disease Index. Signs including conjunctival staining, corneal staining, tear breakup time (TBUT), and Schirmer’s test with anesthesia were also evaluated.

Results: 

There was no correlation between the systemic n-3 levels and DED symptoms. When the associations with signs of DED were assessed, lower DHA levels were associated with higher conjunctival staining, with mean scores of 3.31, 2.96, and 2.82 for low, medium, and high levels of DHA, respectively (linear trend P=0.007). None of the other signs were associated with DHA or the other measures of n-3.

Conclusion: 

Previous studies have found varying results on the role of n-3 supplementation with the signs and symptoms of DED. Among patients with DED enrolled in the DREAM Study, lower systemic n-3 levels were not associated with worse symptoms and most signs of DED.

 

 

 

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