primary outcome:
Omega‐3 and omega‐6 polyunsaturated fatty acids for dry eye disease
The prespecified primary outcome was subjective improvement in dry eye symptoms (eg, dryness, scratchiness, foreign body sensation, burning), as quantified by patient questionnaires, physician‐chosen scales, or assessments as reported in each included study. Outcomes were reported as mean changes in scores or symptoms from baseline and/or the proportion of participants who had improvement in subjective symptoms. The primary outcome time point was one‐month follow‐up, but we reported outcomes measured beyond one month when reported in the included studies.All eight studies included in the analysis evaluated subjective symptoms of dry eye and reported this parameter as final mean score, mean change from baseline, or number of participants with improved symptoms of dry eye.In four studies (Asbell 2018; Deinema 2017; Goyal 2017; Kangari 2013), researchers evaluated subjective symptoms of dry eye using Ocular Disease Surface Index (OSDI) scores. Meta‐analysis (Analysis 1.1, Figure 4), based upon the availability of quantitative data, was performed by combining data from four studies, reported as mean change from baseline (Asbell 2018; Deinema 2017; Goyal 2017) or mean score at study endpoint (Kangari 2013). The summary estimate for these studies indicated little to no reduction in dry eye symptoms with long‐chain PUFA supplementation relative to placebo (four studies, 677 participants; mean difference (MD) ‐2.47, 95% confidence interval (CI) ‐5.14 to 0.19 OSDI units); however this result should be viewed with caution due to moderate statistical heterogeneity (I² = 48%) and wide confidence intervals (low certainty evidence).Three trials led by the same study investigator adopted the Dry Eye Questionnaire and Scoring System (DESS) (Bhargava 2015a; Bhargava 2016a; Bhargava 2016b). Researchers evaluated five symptoms (ie, itching or burning, sandy or gritty sensation, redness, blurring of vision, ocular fatigue, and excessive blinking) on a scale ranging from 0 (absent) to 4 (always). Each of the three trials reported mean DESS scores at the study endpoint, and reported a significant difference in mean score at the end of the follow‐up period, in favor of the omega‐3 intervention. However, the summary estimate was not presented because of substantial statistical heterogeneity across studies (I² = 88%) (Analysis 1.2).Symptom score data were reported only as P values or in a non‐numeric form in two studies (Kawakita 2013; Pinazo‐Durán 2013), or included non‐dry eye participants (as in Kawashima 2016).We used the GRADE classification to judge the certainty of the body of evidence for this outcome, and we downgraded the findings by two levels to low, as results were inconsistent between studies, and two of the four studies included for the OSDI parameter had received industry support (ie, judged to have high risk of "other bias").Data were not combinable for the primary outcome measure related to dry eye symptoms, as the number of participants analyzed was not explicitly reported in Pinheiro 2007. This study reported that the mean reduction in dry eye symptoms was greater in both of the flaxseed oil groups compared with the placebo group. In the other trial, the mean OSDI score improved from baseline at 12 months in the flaxseed oil group (P = 0.02) but not in the placebo (olive oil) group (P = 0.17) (Macsai 2008). However, the mean change in OSDI score was not different between these groups (MD ‐4.05, 95% CI ‐13.12 to 4.12 OSDI units) (Macsai 2008). We graded the certainty of evidence as low after downgrading for imprecision and risk of bias.Aside from one trial (Oxholm 1986), all of the studies in this category measured dry eye symptoms.In Aragona 2005, participants who received omega‐6 PUFA supplements had a greater improvement (reduction) in dry eye symptoms (measured via a custom grading scale, with scores ranging from 0 to 18) compared with those in the placebo group (MD ‐3.1, 95% CI ‐3.76 to ‐2.44). Barabino 2003 reported that there was no significant difference in mean symptom score (measured via the Rolando scoring system) between intervention groups after 45 days of treatment (MD ‐4.6, 95% CI ‐9.91 to 0.71). We could not combine data from these two studies due to the use of different grading scales. The remaining four trials reported results in non‐numeric formats or only with P values (Kokke 2008; Manthorpe 1984; Oxholm 1986; Theander 2002). In Kokke 2008, which involved the evaluation of contact lens wearers, no significant changes were evident for overall contact lens comfort over the trial duration in the placebo group. For the omega‐6 intervention group, results showed a reduction (relative to baseline) in the specific symptom of "dryness" at three and six months of follow‐up (P < 0.01), as measured on a 10‐point visual analogue scale. Manthorpe 1984,Oxholm 1986, and Theander 2002 all reported no significant change in subjective ocular dryness/ocular symptoms over the course of follow‐up. We graded the certainty of evidence as low after downgrading for imprecision and risk of bias.All four studies in this category quantified dry eye symptoms, using a range of different rating scales. A meta‐analysis could not be performed due to lack of quantitative data or differences in the rating scales used.Investigators in Oral sea buckthorn oil study 2010 examined eight dry eye symptoms (ie, soreness, foreign body sensation, dryness, grittiness, burning, redness, watery eyes, and blurry vision) using a 4‐point severity scale ranging from 0 (none) to 3 (severe). These study authors reported a trend toward improved (reduced) ocular redness (P = 0.04) and burning (P = 0.05) in the sea buckthorn supplement group, relative to placebo, after three months of treatment. Creuzot 2006 also assessed eight dry eye symptoms and reported that the number of participants who had specific symptoms ameliorated was significantly greater in the PUFA supplement group than in the placebo group for conjunctival hyperemia (P = 0.045), reflex lacrimation (P = 0.047), sensations of dryness (P = 0.059), and discomfort (P = 0.091). Creuzot‐Garcher 2011 measured ocular symptoms as related to sensations of eye fatigue, burning, prickling, sand/dust, light sensitivity, and reflex tearing and reported that the PUFA supplement group showed greater improvement than the placebo group in subjective symptoms of dry eye, but the difference between groups did not reach statistical significance, except in one sub‐domain (sensation of eye fatigue; P = 0.044). Brignole‐Baudouin 2011 used a four‐step rating scale to assess the symptoms of ocular burning, dryness, foreign body sensation, photophobia, and stinging, which were also used to derive a "global subjective dry eye score." Neither the global dry eye score nor the analysis of each individual symptom showed a significant difference between groups at the three‐month study endpoint.We downgraded the certainty of evidence for this outcome, which we assessed using the GRADE approach, by two levels ‐ from high to low for risk of bias (one level) and inconsistency (one level).Both studies reported data related to dry eye symptoms.In Korb 2015, dry eye symptoms were a secondary outcome and were quantified using both the OSDI and SPEED questionnaires. This study reported that although both omega‐3 plus conventional therapy and conventional therapy intervention arms were significantly improved from baseline, researchers found no significant intergroup differences at three months of follow‐up (SPEED: MD ‐2.9, 95% CI ‐5.97 to 0.17 units; OSDI: MD ‐3.5, 95% CI ‐15.03 to 8.03 units). In Mohammadpour 2017, the OSDI score significantly improved (reduced) over the one‐month treatment duration in both omega‐3 plus conventional therapy (P < 0.001) and conventional therapy (P = 0.003) groups. In addition, the study authors reported that the "OSDI improvement was significantly higher in the (omega‐3) treatment group in comparison to the control group (p=0.026)."Combining data from these two studies (Analysis 3.1; Figure 10), which had negligible heterogeneity (I² = 0%) revealed a significantly improved (lower) OSDI score at the study endpoint with omega‐3 supplementation with conventional therapy relative to conventional therapy alone (two studies, 70 participants; MD ‐7.16, 95% CI ‐13.97 to ‐0.34).We used GRADE to judge the certainty of the body of evidence for this outcome; we downgraded the findings by two levels to low due to imprecision (ie, small sample size for each trial), and we determined that both trials had high risk of bias in one of the blinding domains.All five studies evaluated subjective symptoms of dry eye and reported this parameter as the final mean score, mean change from baseline, or number of participants with improved symptoms of dry eye.In three studies (Epitropoulos 2016; NCT01107964; Oleñik 2013), the researchers evaluated subjective symptoms of dry eye using the OSDI questionnaire. Meta‐analysis, based upon the availability of quantitative data, was performed by combining data from two studies, reported as mean change from baseline (Epitropoulos 2016; NCT01107964) (Analysis 4.1, Figure 11). The summary estimate for these studies indicated a significant reduction in dry eye symptoms with long‐chain omega‐3 PUFA supplementation relative to an omega‐6 PUFA intervention (two studies, 130 participants; MD ‐11.88, 95% CI ‐18.85 to ‐4.92 OSDI units). The level of heterogeneity between these two studies was negligible (I² = 0%). Symptom score data were reported only as P values in one study (Oleñik 2013).Two trials led by the same study investigator adopted the DESS (Bhargava 2013; Bhargava 2015b). Bhargava 2013 reported data as change from baseline at the study endpoint (ie, at three months of follow‐up) and the other trial (Bhargava 2015b) reported mean DESS scores at the study endpoint. Both studies reported a difference in mean score at the end of the follow‐up period, in favor of the omega‐3 PUFA intervention. However the summary estimate was not presented because of substantial statistical heterogeneity between the studies (I² = 100%) (Analysis 4.2).Using GRADE to judge the certainty of the body of evidence, we downgraded the findings by one level to moderate, as one of the two studies included for the OSDI parameter had received industry support (ie, judged to have high risk of "other bias").Due to lack of quantitative data, a meta‐analysis could not be performed for this outcome. Two studies stated that a greater number of participants in the "active" (omega‐3 only) group than in the comparator group improved in terms of dry eye symptoms (Gilbard 2008; Wojtowicz 2011). In contrast, Papas 2007 reported no significant intergroup differences in symptoms of dry eye between the active (omega‐3 only) and comparator groups.Sheppard 2013 measured dry eye symptoms using the OSDI questionnaire. These trial authors reported a significant improvement from baseline in the combined omega‐3 and omega‐6 PUFA group (P = 0.004), which was significantly greater than the level of improvement in the omega‐6 PUFA group (P = 0.05).Reeder 2006 reported no significant intergroup differences in symptoms of dry eye between the two intervention arms.