Original research••

Correction of omega-3 fatty acid deficiency and improvement in disease activity in patients with systemic lupus erythematosus treated with krill oil concentrate: a multicentre, randomised, double-blind, placebo-controlled trial

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Abstract

Objective Omega-3 polyunsaturated fatty acids (PUFAs) play a critical role in regulating inflammation and lipid metabolism. This study sought to ascertain the frequency of omega-3 deficiency in patients with SLE and investigate whether supplementation with krill oil concentrate (KOC) could replenish omega-3 levels and decrease SLE disease activity.

Methods A multicentre, randomised, double-blind, placebo-controlled trial was conducted in adult patients with active SLE. Eligible patients were randomised to receive 4 g/day KOC or placebo (vegetable oil mixture) for the first 24 weeks, and thereafter patients could opt to enter an open-label extension. The primary end point was improvement of the red blood cell Omega-3 Index from baseline to week 24. Changes in clinical features, including SLE Disease Activity Index 2000 (SLEDAI-2K) disease activity scores, were also monitored.

Results Seventy-eight patients met eligibility criteria and were randomised to a treatment group (n=39 per group). The baseline Omega-3 Index in the total SLE cohort was a mean 4.43% (±SD 1.04%). After 4 weeks of KOC treatment, the Omega-3 Index rapidly increased to 7.17%±1.48% (n=38) and after 24 weeks to 8.05%±1.79% (n=25) (each p<0.001 vs baseline), whereas no significant change from baseline was noted in patients receiving placebo. Increases in the Omega-3 Index in KOC-treated patients persisted through week 48. After patients switched from placebo to KOC at 24 weeks, the mean Omega-3 Index showed a rapid and significant increase (from 4.63%±1.39% at week 24 (n=26) to 7.50%±1.75% at week 48 (n=12); p<0.001). Although there were no changes in disease activity in the study population overall, SLEDAI-2K scores decreased significantly in the KOC group during the 24-week randomised period among those who had high disease activity at baseline (SLEDAI-2K ≥9) (p=0.04, p=0.02 and p=0.01 vs placebo at 4, 8 and 16 weeks, respectively; n=9 per group). KOC was well-tolerated, with no significant safety concerns.

Conclusion KOC corrected omega-3 deficiency in patients with SLE. Supplementation with KOC was safe and decreased disease activity in those with more active disease. These findings warrant further evaluation of omega-3 fatty acid supplementation with KOC in the management of SLE.

Trial registration number NCT03626311.

What is already known on this topic

Krill oil is a source of omega-3 polyunsaturated fatty acids (PUFAs), but it is currently unknown whether supplementation with krill oil could effectively replenish omega-3 PUFAs in patients with SLE.

What this study adds

The baseline Omega-3 Index, a measure of red blood cell membrane omega-3 PUFA concentration, was suboptimal in patients with SLE, and was rapidly corrected within 1 month of blinded treatment with krill oil concentrate compared with no change in the placebo group.
The effect of krill oil concentrate on the Omega-3 Index in patients with SLE persisted through 48 weeks during the open-label extension.
Krill oil concentrate transiently decreased disease activity in patients with SLE who had more active disease at baseline.

How this study might affect research, practice or policy

Omega-3 supplementation with krill oil concentrate was safe and well tolerated and might serve as a useful complement to the standard of care medications in SLE disease management.

Introduction

SLE is a chronic autoimmune disease with an unpredictable disease course alternating between periods of flares and remission. The disease is commonly treated with immunosuppressants, but there is no known cure and it can be fatal.1 The leading cause of death in SLE is from cardiovascular disease (CVD) related to accelerated atherosclerosis.2 3 Patients with SLE experience metabolic changes in their lipid profile, including reduced levels of essential long-chain polyunsaturated fatty acids (PUFAs)—both omega-3 and omega-6—relative to individuals without SLE.4–7 Omega-3 PUFAs can modulate inflammatory responses by suppressing production of inflammatory mediators. One study among patients with recent-onset rheumatoid arthritis (RA) showed that omega-3 PUFA supplementation, administered as an adjunct to treat-to-target disease-modifying therapies, led to an increased frequency of remissions and fewer subjects with RA requiring additional therapy.8

The Omega-3 Index is a critical measure of the risk of CVD and is known to be decreased in the US population.7 This index is based on the red blood cell (RBC) concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), two biologically important omega-3 PUFAs, and is calculated according to the percentage of EHA+DHA relative to total fatty acids in RBC membranes.9 Since integration of EPA and DHA into cell membranes is essential for their biological function, RBC membrane analysis is an effective method for assessing the tissue distribution of these omega-3 PUFAs. Importantly, the Omega-3 Index has been shown to have prognostic value, in that lower values (<4%) are associated with a higher risk of sudden cardiac death and increased risk of CVD, whereas the risk decreases with higher Omega-3 Index levels (4%–8% moderate risk, >8% low risk).9 Currently, maintaining an Omega-3 Index between 8% and 11% is recommended to mitigate CVD risk.10 11 This may be especially important in people with SLE, in whom the incidence of CVD is markedly elevated.12–15 Traditional risk factors, although contributory, fail to fully account for the excess risk of cardiovascular events in SLE. Previous studies have suggested that supplementation with omega-3 PUFAs in subjects with SLE may correct dyslipidaemia and alter the risk of atherosclerotic CVD.16–20

Treatment with omega-3 PUFAs has been studied in several murine lupus models, including lupus nephritis in female (NZB×NZW) F1 mice20 and other autoimmune-prone mice.21–24 In these models, the beneficial effects have included prolonged life span, delay in the onset of autoimmune disease activity and amelioration of nephritis. Studies in human subjects have demonstrated variable results, with some but not all showing positive outcomes with omega-3 PUFA-containing fish oils at various doses and dosing regimens.5 25–36 Results of several studies indicated modest alterations in disease activity, blood lipid levels, symptom severity and inflammatory biomarkers with the use of fish oil supplementation over limited periods of time. Evidence in one study showed that prolonged clinical remission of SLE was achieved in a small number of patients following oral supplementation with EPA and DHA,31 although this remains to be verified. Preliminary studies have similarly shown decreased SLE Disease Activity Index 2000 (SLEDAI-2K) scores37 in patients receiving omega-3 PUFAs as compared with those receiving placebo,38 and improved clinical symptoms, laboratory parameters and Systemic Lupus Activity Measure scores39 after correction of the omega-3 fatty acid deficiency in subjects with SLE.40 Moreover, in literature reviews of trials assessing the therapeutic properties of omega-3 fatty acids in patients with SLE, results suggested a trend towards an association between omega-3 fatty acid supplementation and improvements in disease activity and a variety of other disease complications.41 42 However, many of those studies were limited in that they had high dropout rates, short study durations, high variability in some laboratory values and minimal evaluation of adverse effects.

Krill oil, which is derived from small, shrimp-like crustaceans that primarily inhabit Antarctic oceans and is a rich source of EPA and DHA as well as choline, has been used in the management of multiple chronic diseases.43–45 Krill oil was selected for the study because of its unique composition of EPA and DHA bound to phospholipids—a feature not found in fish oil or algae oil.46 47 This unique feature of krill oil may enhance the bioavailability of these fatty acids. Despite its unique properties, there has been, to date, no study of the specific potential health benefits of krill oil in patients with SLE.

Although it has been proposed that omega-3 supplementation could be a useful adjunct to standard of care medications in SLE disease management,4 43 current evidence remains inconclusive with regard to whether the omega-3 PUFAs in krill oil could effectively replenish omega-3 fatty acids and measurably reduce disease activity in patients with SLE. This study, therefore, sought to investigate whether supplementation with a krill oil concentrate (KOC) could correct the omega-3 deficiency in patients with active SLE, as measured using the Omega-3 Index, and decrease clinical activity of the disease, as measured by changes in the SLEDAI-2K.

Methods

Study design and population

This was a multicentre, randomised, double-blind, placebo-controlled trial conducted in adult male and female patients with active SLE (SLEDAI-2K ≥6) across 20 US sites (NCT03626311). The study was carried out from 2018 to 2020. All subjects were required to have a clinical diagnosis meeting at least 4 of the 11 American College of Rheumatology revised classification criteria for SLE48 and had to be receiving a stable SLE treatment regimen for at least 30 days before administration of the first dose of study medication. In addition, subjects had to have a history of low intake of seafood and be willing to avoid fatty fish consumption while participating in the study. Subjects were excluded if, at the time of screening, they were taking omega-3 supplementation of any kind.

Among the 116 patients assessed for eligibility, 38 did not meet the screening criteria. Thus, a total of 78 patients were enrolled and randomised to a treatment group. All eligible patients provided their informed consent to participate.

For the first 24 weeks, patients were randomised 1:1 in a blinded manner to receive either SuperbaBoost KOC at 4 g/day or a comparable amount of placebo (both provided by Aker BioMarine Human Ingredients, Lysaker, Norway). Capsules were identical in size, shape and flavoured to minimise smell and taste differences. The electronic case report forms were used for random treatment allocation as each subject entered the study. All patients and site investigators remained blinded with regard to treatment assignments during the initial 24-week randomised period. Thereafter, all subjects were eligible to continue a 24-week open-label extension period in which patients taking placebo could opt to switch to KOC at the same dose, whereas those initially receiving KOC could continue to receive the same dose for the subsequent 24 weeks.

During treatment, patients were maintained on stable doses of background medications, except for glucocorticoids, for which decreased doses were encouraged during the first 20 weeks of each portion of the trial.

Primary end point

The ability of KOC to replenish the deficient omega-3 fatty acid levels in patients with active SLE was assessed over time by monitoring changes in the Omega-3 Index, which measures the percentage of EPA and DHA in RBC membranes.9 The Omega-3 Index is an established biomarker that reflects long-term intake of EPA and DHA and is less influenced by recent consumption of meals. To ascertain the total levels of EPA and DHA and calculate the RBC Omega-3 Index, patients with SLE performed self-administered finger stick tests (OmegaQuant) at home over several timepoints throughout the trial (at screening, baseline and monthly through 48 weeks); blood samples were directly sent to the OmegaQuant laboratory for analysis.

Secondary end points

The potential effect of KOC on disease activity was assessed using the SLEDAI-2K.37 In addition, serum chemistry and haematology panels, urinalysis and serum biomarkers of inflammation (C reactive protein (CRP), complement components C3 and C4 and anti-double-stranded DNA (anti-dsDNA)) were assessed. General disease activity was assessed using scores on the physician’s global assessment of health (PGA) and patient’s assessment of disease status, and health-related quality of life was evaluated with the patient’s global assessment of health (PtGA), the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score49 and the pain score on 10 mm visual analogue scale.

Safety

KOC supplementation was assessed for safety by monitoring the frequency and severity of adverse events (AEs) from the first day of initiation of the study medication to 30 days following the last dose.

Investigational product

Krill oil, extracted from Antarctic krill (Euphausia superba), is the only ingredient that was used in the investigational product. The oil contains EPA and DHA fatty acids that are primarily bound to phospholipids, while a minor fraction of fatty acids is also bound to triglycerides. The oil also contains astaxanthin, a naturally occurring antioxidant (concentration typically ranging from 100 μg/g to 450 μg/g) that enhances the stability of the oil.50

Patients were randomised to receive either KOC or identical equivalent placebo at a dosage of 4 g/day, divided into four capsules of 1 g each—two taken in the morning and two in the evening. Each capsule contained either 1000 mg of SuperbaBoost KOC or a placebo control that was identical in look and taste (both provided by Aker BioMarine Antarctic, Lysaker, Norway). For the KOC capsules, the content was as follows: 601 mg of phospholipids (including 558 mg of phosphatidylcholine) and 322 mg of total omega-3 fatty acids (193 mg EPA and 96 mg DHA). This dosage delivers a total of 1288 mg of omega-3 fatty acids per day, including 772 mg of EPA and 384 mg of DHA. The content of the placebo capsules comprised a mixture of olive oil (extra virgin, cold pressed), maize oil (refined), palm kernel oil (refined) and medium chain triglycerides, in a ratio of 4:4:3:2, resembling the fatty acid ratio of a typical Western diet.

SuperbaBoost KOC was produced under Good Manufacturing Practice food regulations and has been designated as Generally Recognised as Safe for use in humans.

Power calculation

To date, the effect of omega-3 phospholipid supplementation on the Omega-3 Index has not been addressed in patients with SLE, but studies in healthy subjects have shown an effect size in the range of 0.45–2.75 with an SD of 0.46–0.74, depending on the dose. In the present study, we assumed that the effect of the difference in Omega-3 Index between the two groups would be 0.5 with an SD of 0.6. Therefore, the effect size was calculated to be 0.8, which was used to determine the sample size. Under these assumptions and with a 1:1 treatment group allocation, an estimated sample size of 34 patients would be needed in each group to reach 90% power to detect a statistically significant difference between groups. Accounting for an anticipated 10% dropout rate, a target sample size of 76 subjects (38 per group) was considered sufficient.

Statistical methods

Continuous variables are expressed as the mean±SD, and categorical variables are expressed as the number (percentage). Between-group differences in the distribution of continuous variables were determined by Student’s t-test. For categorical variables, differences were determined by either Fisher’s exact test or χ² test.

In assessing trends in the Omega-3 Index (mean±SEM values), the change from baseline to each follow-up visit was expressed as both the absolute mean difference and the relative per cent change relative to baseline in each group. For comparison of the Omega-3 Index between the KOC and placebo groups at each follow-up visit, the absolute mean difference was calculated by Student’s t-test.

Change from baseline in SLEDAI-2K disease activity scores was assessed using an analysis of covariance model in which both the baseline SLEDAI-2K score and the treatment group were included as independent variables and the SLEDAI-2K score at 24 weeks was included as the dependent variable. Differences in the SLEDAI-2K scores between the treatment groups were expressed as the mean with 95% CIs. In addition, treatment efficacy among the subset of patients with more severe disease, defined as a baseline SLEDAI-2K score of ≥9, was explored and compared between the two treatment groups.

Measures of immune function, general health and patient-reported quality of life were compared between groups by Student’s t-test.

P values <0.05 were considered statistically significant. All statistical analyses were performed using R statistical software (V.4.2.2, R Core Team; https://www.R-project.org/).

Results

Patients

The study enrolled 78 adult patients with active SLE who were randomised 1:1 to a treatment group, of whom 97% were women. Among them, 53% reported being of European ancestry and 36% of African ancestry. The baseline demographic and clinical characteristics of the randomised subjects are shown in table 1.

Table 1

Baseline demographic and clinical characteristics of the 78 patients with SLE randomised to receive krill oil concentrate or placebo in the 48-week ORKIDS trial*

Of note, the trial was affected by the COVID-19 pandemic in 2020, which led to difficulties in patient retention and protocol adherence, resulting in a higher than expected dropout rate. Thus, the excess number of patients exiting the trial could be attributed to the effects of the pandemic on the healthcare system, not to persistent disease. With the dropouts, the final sample size of the KOC group was 30 patients, and the placebo group had 34 patients. Patient disposition is shown in figure 1.

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Figure 1

Distribution of the study patients with SLE randomised to receive 4 g/day krill oil concentrate from day 1 to week 48 compared with patients with SLE randomised to receive 4 g/day placebo over the first 24 weeks and then switched to krill oil concentrate for the subsequent 24 weeks.

Effects of KOC on Omega-3 Index

In accordance with the study protocol, the Omega-3 Index was assessed monthly by participants using home kits, with samples subsequently mailed to the laboratory for assessment of the Omega-3 Index. Patients continued to self-test their omega-3 levels even when they were unable to have in-person visits because of the COVID-19 pandemic.

At baseline, 69 patients (88.5%) had low or intermediate Omega-3 Index levels (<6%), including 37 from the placebo group and 32 from the KOC group. Among them, the Omega-3 Index was <4.0% in 12 patients receiving KOC and 18 receiving placebo, comprising 38.0% of the study population. The mean Omega-3 Index at baseline was 4.43% (±SD 1.04%). After 4 weeks of treatment with KOC, a significant increase in the Omega-3 Index was observed, increasing from 4.57%±1.11% at baseline (n=36) to 7.17%±1.48% at week 4 (n=38) (p<0.001), and to 8.05%±1.75% at week 24 (n=25) (p<0.001). Notably, after 24 weeks of KOC treatment, only 3 patients had an Omega-3 Index <6% and no patient had an Omega-3 Index <4.0%. In contrast, in the placebo group there was no significant change from baseline in the Omega-3 Index at any time point up to week 24 (table 2).

Table 2

Change in Omega-3 Index from baseline to week 48 in patients with SLE randomised to receive krill oil concentrate or placebo

Significant differences in the Omega-3 Index between the KOC and placebo groups were seen at weeks 4, 8, 12, 16, 20 and 24 (each p<0.001) (table 2 and figure 2). The difference between the two groups continued throughout the 48-week trial, but the gap clearly narrowed after week 24 during the open-label extension. Among patients who switched to taking KOC during this open-label extension period, the Omega-3 Index significantly rose from 4.63%±1.39% at week 24 to 7.50%±1.75% at week 48 (p=0.001). Moreover, among patients who had started taking KOC from day 1 onwards through week 48, the significant increase from baseline in the Omega-3 Index persisted (table 2 and figure 2).

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Figure 2

Trends in the Omega-3 Index over 48 weeks among patients with SLE in each randomisation group (n=39 per group). Values are the mean±SEM, as measured by OmegaQuant finger stick test at each time point. The crossover from the blinded randomised period to the open-label extension period occurred after week 24.

Effects of KOC on disease activity

Using the SLEDAI-2K score, disease activity at baseline and changes in disease activity over time were evaluated directly at each study site. Among the full population of patients assessed for disease activity at baseline (day 1), the SLEDAI-2K scores were comparable between the two groups (mean±SD 7.74±2.22 in the KOC group vs 7.62±2.55 in the placebo group; each n=39). SLEDAI-2K scores did not differ significantly between the KOC-treated and placebo-treated groups during the initial 24-week randomised period (table 3). However, among the subset of patients with SLE who had more severe disease at baseline (SLEDAI-2K≥9; n=9 per group), a significant decrease from baseline in the SLEDAI-2K score was observed during the first 16 weeks of KOC treatment (p=0.04, p=0.02 and p=0.01 vs placebo at weeks 4, 8 and 16, respectively). However, this difference between groups was not sustained through week 24 (p=0.54) (table 3). Changes in the Omega-3 Index and SLEDAI-2K scores in individual patients in the group with high baseline disease activity are shown in online supplemental appendix 1. These findings indicate that after taking KOC supplementation, several patients experienced a sustained improvement in disease activity in parallel with an improved Omega-3 Index.

Table 3

Change in disease activity scores over the first 24 weeks in patients receiving krill oil concentrate compared with placebo, by total population and by the subset of patients with SLE with high baseline disease activity*

Effects of KOC on serological manifestations of SLE and health-related quality of life

KOC treatment had no significant effect on anti-dsDNA status and levels of complement components C3 and C4. Similarly, CRP values were not significantly different between the two groups over 24 weeks (online supplemental appendix 2). Finally, KOC supplementation had no significant effect on general health status according to the PGA scores or various patient-reported health-related quality of life outcomes (FACIT-F, VAS pain and PtGA scores) (online supplemental appendix 3).

Adverse events

Among the 78 randomised subjects, 67 reported experiencing at least one AE over the 48-week trial. It is notable that patients receiving KOC exhibited a lower incidence of AEs compared with the placebo group, with 186 AEs observed in the KOC group and 342 in the placebo group. Most AEs were mild or moderate in severity (table 4). Very few AEs were thought to be related to the study treatment. There was no notable difference in the frequency of severe AEs between the KOC and placebo groups (online supplemental appendix 4).

Table 4

Frequency of AEs over 48 weeks reported by patients with SLE randomised to receive krill oil concentrate or placebo*

Discussion

This study yielded a number of new findings that could contribute to more effective management of patients with SLE. First, the Omega-3 Index, a measurement of the incorporation of the omega-3 PUFAs DHA and EPA into cell membranes, was consistently low in patients with active SLE. Of the patients studied, 38% had baseline values that would put them at high risk of CVD and nearly all at moderate risk. Second, treatment with KOC corrected this abnormality within 1 month in nearly all patients. Finally, there was apparent improvement in disease activity in patients with more active disease. These results suggest that monitoring the Omega-Index in patients with lupus and considering replenishment of omega-3 PUFAs in those with documented deficiency could improve disease activity and also potentially contribute to CVD risk mitigation.

An initial question is whether the low Omega-3 Index in this cohort of patients with lupus relates to an action of SLE on lipid metabolism or rather is reflective of the generally low Omega-3 Indices found in adults in the USA.7 Although this was not directly studied in this trial, the mean baseline Omega-3 Index in the current lupus cohort (4.43%±1.04%) was not different from that reported for normal healthy adults in a coastal town and five inland cities in the USA (mean±SD 5.13%±1.34% in the coastal population and 4.48%±1.08% in the five inland city populations).51 This suggests that the North American diet rather than the disease process was the main factor contributing to the low Omega-3 Index found in patients with SLE in this study. Dietary deficiency of omega-3 PUFAs could, however, contribute both to the risk of CVD and to disease activity in patients with lupus.

In our cohort, rather than directly measuring plasma DHA and EPA levels, we chose to use the Omega-3 Index for a number of reasons.52 First, the Omega-3 Index specifically measures the proportion of long-chain omega-3 fatty acids EPA and DHA in erythrocyte membranes, reflecting their biological availability within the body. Second, the erythrocyte membrane composition is a more stable and representative marker of long-term dietary intake of omega-3s compared with plasma levels, which can fluctuate more rapidly and are influenced by nutritional intakes. Finally, large-scale epidemiological studies provide evidence that the Omega-3 Index is a significant predictor of coronary heart disease and all-cause mortality, especially sudden cardiac death.53–56 Its strong correlation with heart health outcomes makes the Omega-3 Index a valuable tool for assessing cardiovascular risk associated with cell membrane levels of omega-3 PUFAs.

In the present study, the mean Omega-3 Index was increased into the optimal range (>8%) within the first 24 weeks of treatment with KOC and often within the first 4 weeks. This rapid and persistent improvement in the levels of omega-3 fatty acids was sustained to the end of the study. Thus, our findings along with those of several previous studies25–36 suggest that there could be potential benefits to this alternative treatment in patients with SLE, particularly in terms of conferring possible long-term protection from CVD. Further studies in larger cohorts will be needed to determine whether KOC treatment can sustain these effects and could attenuate the risk of CVD and sudden cardiac death among patients with SLE.

A transient effect of KOC treatment on disease activity was noted, but only in subjects with a higher level of disease activity. This was not associated with changes in serological markers of lupus nor with changes in patient-reported outcomes. The subtle effect of KOC treatment on lupus disease activity is consonant with previous reports showing inconsistent effects on lupus disease activity.25 38 40 Whether higher doses of KOC would provide more consistent clinical benefit is unknown, but previous results showing that higher Omega-3 Indices are associated with a greater anti-inflammatory effect4 10 11 16 17 support this possibility.

Notably, AEs were modest in patients receiving KOC and even fewer in number than in those receiving placebo. These results are consistent with the designation of KOC as generally regarded as safe.

A number of previous studies have examined the effects of various omega-3 PUFA-containing fish oils on lupus. Some have measured changes in lipid metabolites, but none has examined the impact on the Omega-3 Index, a measure of the incorporation of omega-3 PUFAs into lipid membranes that is a risk factor for CVD and all-cause mortality.55 57–59 KOC may be a more reliable means to restore Omega-3 levels. The key feature of krill oil is that Omega-3 PUFAs are incorporated into easily digested phospholipids, and this enriched composition has been suggested to achieve more effective tissue integration compared with the triglyceride-rich form found in most traditional fish oils.60

It has been postulated that a diet rich in the plant-based nutrient α-linolenic acid (ALA), such as that derived from consumption of walnuts, could have a confounding effect on RBC and plasma levels of omega-3 fatty acids EPA and DHA. However, previous findings have indicated that consumption of ALA is not sufficient to substantially raise the DHA and EPA levels among persons on a Western diet.61 62 Therefore, it is unlikely that this had an impact on omega-3 PUFA levels in the present study cohort.

There are some limitations of the study. First, only one dose level of KOC (4 g/day) was employed. Although this dosage of KOC effectively increased the Omega-3 Index, it is not known whether a higher daily dose might have additional clinical benefit. Furthermore, the patient cohort was relatively small, as it was powered on correction of the Omega-3 Index. Although the primary outcome was achieved, the cohort may not have been of sufficient size to capture clinical benefit. A signal for clinical benefit was noted, but this would require a larger trial to confirm.

Unfortunately, the trial was affected by the COVID-19 pandemic which resulted in a higher than expected dropout rate. However, it is unlikely that this had a major effect on the results. Because of the somewhat larger number of subjects exiting the trial owing to COVID-19 restrictions, we carried out a post hoc power calculation. With the dropouts, the final sample size of one group was 30 and of the second 34. With an effect size of 0.8 and given the same groups of 30 participants in the KOC group and 34 in the placebo group and using an alpha of 0.05 for a two-sided test, the calculated power of the study was ~88.2%, slightly lower than what we had planned to achieve to avoid type II error (90% power, and therefore 10% type II error), but still lower than the conventional 20% type II error).

A final limitation of the study is that a much larger trial would be required to determine whether KOC supplementation has an effect on CVD risk in patients with SLE.

In summary, KOC supplementation was found to reverse the omega-3 PUFA deficiency in patients with SLE detected by measuring the Omega-3 Index. KOC treatment increased the Omega-3 Index from a range predictive of high or moderate risk of CVD to values indicative of lower risk. Finally, KOC treatment decreased lupus disease activity in those with increased activity at baseline. These results suggest that KOC might be beneficial in the management of persons living with SLE.

Contributors: All authors were involved in drafting the article or revising it critically for important intellectual content. All authors approved the final version to be published. PEL had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design: JS, P-AH, LJ, PEL. Acquisition of data: DJW, VR. Analysis and interpretation of data: JS, AC, CD, BW, YD, LJ, PEL. YD is responsible for the overall content as guarantor.
Funding: This work was supported by Aker BioMarine Human Ingredients AS, which sponsored the trial and was the manufacturer and supplier of the investigational KOC product.
Competing interests: YD and LJ are current employees of Aker, and P-AH was an employee of Aker at the time of the study. These authors collaborated with JS, DJW, VR and PEL and AMPEL research staff to design and conduct the study and were involved in the analysis and interpretation of the study results. All authors critically reviewed the manuscript for important intellectual content, approved the final draft and agreed to its submission.
Patient and public involvement: Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the 'Methods' section for further details.
Provenance and peer review: Not commissioned; externally peer reviewed.
Supplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.

Ethics statements

Patient consent for publication:

Ethics approval:

The study received Institutional Review Board/Ethics Committee approvals from all participating sites (approval #20181076) and was conducted in compliance with the US Code of Federal Regulations clinical research guidelines and International Council for Harmonisation Good Clinical Practice Guidelines, and carried out in accordance with the principles of the Declaration of Helsinki. Patient input was sought during the development of the protocol.

Acknowledgements

The support of Lupus Therapeutics and the LuCIN investigators is gratefully acknowledged, including the following investigators: Elena Massarotti (Brigham and Women’s Hospital), Meggan Mackay (Feinstein Institute for Medical Research), Christian Pineau (McGill University Health Centre, Montreal General Hospital), Mark Matsos (McMaster University Medical Center), Chaim Putterman (Albert Einstein College of Medicine), Sonali Narain (Northwell Health), Paul Fortin (University of Laval), Meenakshi Jolly (Rush Medical Center), Kyriakos Kirou (Hospital for Special Surgery), Walter Winn Chatham (University of Alabama at Birmingham), Sheetal Desai (University of California Irvine Health), Maria F Carpintero (University of Miami), W Joseph McCune (University of Michigan Health System), Jennifer Anolik (University of Rochester Medical Center), Francis Luk (Wake Forest Baptist Health), Uma Thanarajasingam (Mayo Clinic), Jonathan Kay (UMass Memorial Medical Center), Narender Annapureddy (Vanderbilt Clinical Research Center) and Christine Peschken (Shared Health operating the Health Sciences Centre, Winnipeg). AMPEL provided writing and editorial assistance (performed by Medical Writer Lesley Welch Allen).

Bernatsky S, Boivin J-F, Joseph L, et al. Mortality in systemic lupus erythematosus. Arthritis Rheum 2006; 54:2550–7.
doi:10.1002/art.21955•Google Scholar
Moghaddam B, Marozoff S, Li L, et al. All-cause and cause-specific mortality in systemic lupus erythematosus: a population-based study. Rheumatol (Oxford) 2021; 61:367–76.
doi:10.1093/rheumatology/keab362•Google Scholar
Ansari A, Larson PH, Bates HD, et al. Cardiovascular manifestations of systemic lupus erythematosus: current perspective. Prog Cardiovasc Dis 1985; 27:421–34.
doi:10.1016/0033-0620(85)90003-9•Google Scholar
Klack K, Bonfa E, Borba Neto EF, et al. Diet and nutritional aspects in systemic lupus erythematosus. Rev Bras Reumatol 2012; 52:384–408.
Google Scholar
Mohan IK, Das UN. Oxidant stress, anti-oxidants and essential fatty acids in systemic lupus erythematosus. Prostaglandins Leukot Essent Fatty Acids 1997; 56:193–8.
doi:10.1016/s0952-3278(97)90533-0•Google Scholar
Wu T, Xie C, Han J, et al. Metabolic disturbances associated with systemic lupus erythematosus. PLoS ONE 2012; 7.
doi:10.1371/journal.pone.0037210•Google Scholar
Stark KD, Van Elswyk ME, Higgins MR, et al. Global survey of the Omega-3 fatty acids, Docosahexaenoic acid and Eicosapentaenoic acid in the blood stream of healthy adults. Prog Lipid Res 2016; 63:132–52.
doi:10.1016/j.plipres.2016.05.001•Google Scholar
Proudman SM, James MJ, Spargo LD, et al. Fish oil in recent onset rheumatoid arthritis: a randomised, double-blind controlled trial within algorithm-based drug use. Ann Rheum Dis 2015; 74:89–95.
doi:10.1136/annrheumdis-2013-204145•Google Scholar
Harris WS, Von Schacky C. The Omega-3 index: a new risk factor for death from coronary heart disease? Prev Med 2004; 39:212–20.
doi:10.1016/j.ypmed.2004.02.030•Google Scholar
von Schacky C. The Omega-3 index as a risk factor for cardiovascular diseases. Prostaglandins & Other Lipid Mediators 2011; 96:94–8.
doi:10.1016/j.prostaglandins.2011.06.008•Google Scholar
Harris WS, Del Gobbo NL, Tintle NL, et al. The Omega-3 index and relative risk for coronary heart disease mortality: estimation from 10 cohort studies. Atherosclerosis 2017; 262:51–4.
doi:10.1016/j.atherosclerosis.2017.05.007•Google Scholar
Ajeganova S, Hafström I, Frostegård J, et al. Patients with SLE have higher risk of cardiovascular events and mortality in comparison with controls with the same levels of traditional risk factors and intima-media measures, which is related to accumulated disease damage and antiphospholipid syndrome: a case–control study over 10 years. Lupus Sci Med 2021; 8.
doi:10.1136/lupus-2020-000454•Google Scholar
Magder LS, Petri M. Incidence of and risk factors for adverse cardiovascular events among patients with systemic lupus erythematosus. Am J Epidemiol 2012; 176:708–19.
doi:10.1093/aje/kws130•Google Scholar
Levinson DJ, Abugroun A, Daoud H, et al. Coronary artery disease (CAD) risk factor analysis in an age-stratified hospital population with systemic lupus erythematosus (SLE). Int J Cardiol Hypertens 2020; 7.
doi:10.1016/j.ijchy.2020.100056•Google Scholar
Petri MA, Barr E, Magder LS, et al. Development of a systemic lupus erythematosus cardiovascular risk equation. Lupus Sci Med 2019; 6.
doi:10.1136/lupus-2019-000346•Google Scholar
Xin W, Wei W, Li X, et al. Effect of fish oil supplementation on fasting vascular endothelial function in humans: a meta-analysis of randomized controlled trials. PLoS One 2012; 7.
doi:10.1371/journal.pone.0046028•Google Scholar
Brown AC. Lupus erythematosus and nutrition: a review of the literature. J Ren Nutr 2000; 10:170–83.
doi:10.1053/jren.2000.16323•Google Scholar
Berge K, Musa-Veloso K, Harwood M, et al. Krill oil supplementation LOWERS serum triglycerides without increasing low-density lipoprotein cholesterol in adults with borderline high or high Triglyceride levels. Nutr Res 2014; 34:126–33.
doi:10.1016/j.nutres.2013.12.003•Google Scholar
von Schacky C, Angerer P, Kothny W, et al. The effect of dietary Omega-3 fatty acids on coronary atherosclerosis: a randomized, double-blind, placebo-controlled trial. Ann Intern Med 1999; 130:554–62.
doi:10.7326/0003-4819-130-7-199904060-00003•Google Scholar
Jolly CA, Muthukumar A, Reddy Avula CP, et al. Maintenance of NF-ΚB activation in T-lymphocytes and a naive T-cell population in autoimmune-prone (NZB/NZW)F(1) mice by feeding a food-restricted diet enriched with N-3 fatty acids. Cell Immunol 2001; 213:122–33.
doi:10.1006/cimm.2001.1866•Google Scholar
Venkatraman JT, Chandrasekar B, Kim JD, et al. Effects of N-3 and N-6 fatty acids on the activities and expression of hepatic antioxidant enzymes in autoimmune-prone NZB×NZW F1 mice. Lipids 1994; 29:561–8.
doi:10.1007/BF02536628•Google Scholar
Chandrasekar B, Troyer DA, Venkatraman JT, et al. Tissue specific regulation of transforming growth factor beta by Omega-3 lipid-rich Krill oil in autoimmune murine lupus. Nutrition Research 1996; 16:489–503.
doi:10.1016/0271-5317(96)00030-9•Google Scholar
Reddy Avula CP, Lawrence RA, Zaman K, et al. Inhibition of intracellular Peroxides and apoptosis of lymphocytes in lupus-prone B/W mice by dietary N-6 and N-3 lipids with calorie restriction. J Clin Immunol 2002; 22:206–19.
doi:10.1023/A:1016088708457•Google Scholar
Pestka JJ. N-3 polyunsaturated fatty acids and autoimmune-mediated glomerulonephritis. Prostaglandins Leukot Essent Fatty Acids 2010; 82:251–8.
doi:10.1016/j.plefa.2010.02.013•Google Scholar
Arriens C, Hynan LS, Lerman RH, et al. Placebo-controlled, randomized clinical trial of fish oil’s impact on fatigue, quality of life, and disease activity in systemic lupus erythematosus. Nutr J 2015; 14.
doi:10.1186/s12937-015-0068-2•Google Scholar
Clark WF, Parbtani A, Huff MW, et al. Omega-3 fatty acid dietary supplementation in systemic lupus erythematosus. Kidney Int 1989; 36:653–60.
doi:10.1038/ki.1989.242•Google Scholar
Westberg G, Tarkowski A. Effect of Maxepa in patients with SLE: a double-blind, crossover study. Scand J Rheumatol 1990; 19:137–43.
doi:10.3109/03009749009102117•Google Scholar
Walton AJ, Snaith ML, Locniskar M, et al. Dietary fish oil and the severity of symptoms in patients with systemic lupus erythematosus. Ann Rheum Dis 1991; 50:463–6.
doi:10.1136/ard.50.7.463•Google Scholar
Duffy EM, Meenagh GK, McMillan SA, et al. The clinical effect of dietary supplementation with Omega-3 fish oils and/or copper in systemic lupus erythematosus. J Rheumatol 2004; 31:1551–6.
Google Scholar
Clark WF, Parbtani A, Naylor CD, et al. Fish oil in lupus nephritis: clinical findings and methodological implications. Kidney Int 1993; 44:75–86.
doi:10.1038/ki.1993.215•Google Scholar
Das UN. Beneficial effect of Eicosapentaenoic and Docosahexanenoic acids in the management of systemic lupus erythematosus and its relationship to the cytokine network. Prostaglandins Leukot Essent Fatty Acids 1994; 51:207–13.
doi:10.1016/0952-3278(94)90136-8•Google Scholar
Wright SA, O’Prey FM, McHenry MT, et al. A randomized Interventional trial of Omega-3-polyunsaturated fatty acids on endothelial function and disease activity in systemic lupus erythematosus. Ann Rheum Dis 2008; 67:841–8.
doi:10.1136/ard.2007.077156•Google Scholar
Bello KJ, Fang H, Fazeli P, et al. Omega-3 in SLE: a double-blind, placebo-controlled randomized clinical trial of endothelial dysfunction and disease activity in systemic lupus erythematosus. Rheumatol Int 2013; 33:2789–96.
doi:10.1007/s00296-013-2811-3•Google Scholar
Lozovoy MAB, Simão ANC, Morimoto HK, et al. Fish oil N-3 fatty acids increase adiponectin and decrease Leptin levels in patients with systemic lupus erythematosus. Mar Drugs 2015; 13:1071–83.
doi:10.3390/md13021071•Google Scholar
Curado Borges M, de Miranda Moura dos Santos F, Weiss Telles R, et al. Omega-3 fatty acids, inflammatory status and biochemical markers of patients with systemic lupus erythematosus: a pilot study. Rev Bras Reumatol (Engl Ed) 2017; 57:526–34.
doi:10.1016/j.rbre.2016.09.014•Google Scholar
Simopoulos AP. Omega-3 fatty acids in inflammation and autoimmune diseases. J Am Coll Nutr 2002; 21:495–505.
doi:10.1080/07315724.2002.10719248•Google Scholar
Gladman DD, Ibañez D, Urowitz MB, et al. Systemic lupus erythematosus disease activity index 2000. J Rheumatol 2002; 29:288–91.
Google Scholar
Duarte-García A, Myasoedova E, Karmacharya P, et al. Effect of Omega-3 fatty acids on systemic lupus erythematosus disease activity: a systematic review and meta-analysis. Autoimmun Rev 2020; 19:102688.
doi:10.1016/j.autrev.2020.102688•Google Scholar
Bae SC, Koh HK, Chang DK, et al. Reliability and validity of systemic lupus activity measure-revised (SLAM-R) for measuring clinical disease activity in systemic lupus erythematosus. Lupus 2001; 10:405–9.
doi:10.1191/096120301678646146•Google Scholar
Ramessar N, Borad A, Schlesinger N, et al. The effect of Omega-3 fatty acid supplementation in systemic lupus erythematosus patients: a systematic review. Lupus 2022; 31:287–96.
doi:10.1177/09612033211067985•Google Scholar
Salek M, Hosseini Hooshiar S, Salek M, et al. Omega-3 fatty acids: current insights into mechanisms of action in systemic lupus erythematosus. Lupus 2023; 32:7–22.
doi:10.1177/09612033221140724•Google Scholar
Jiao H, Acar G, Robinson GA, et al. Diet and systemic lupus erythematosus (SLE): from supplementation to intervention. Int J Environ Res Public Health 2022; 19.
doi:10.3390/ijerph191911895•Google Scholar
Gazi I, Liberopoulos EN, Saougos VG, et al. Beneficial effects of Omega-3 fatty acids: the current evidence. Hellenic J Cardiol 2006; 47:223–31.
Google Scholar
Cicero AFG, Colletti A. Krill oil: evidence of a new source of polyunsaturated fatty acids with high bioavailability. Clinical Lipidology 2015; 10:1–4.
doi:10.2217/clp.14.67•Google Scholar
Mödinger Y, Schön C, Wilhelm M, et al. Plasma Kinetics of choline and choline metabolites after a single dose of Superba boostTM Krill oil or choline Bitartrate in healthy volunteers. Nutrients 2019; 11.
doi:10.3390/nu11102548•Google Scholar
Burri L, Hoem N, Monakhova YB, et al. Fingerprinting Krill oil by 31P, 1H and 13C NMR Spectroscopies. J Am Oil Chemists' Soc 2016; 93:1037–49.
doi:10.1007/s11746-016-2836-3•Google Scholar
Winther B, Hoem N, Berge K, et al. Elucidation of Phosphatidylcholine composition in Krill oil extracted from Euphausia Superba. Lipids 2011; 46:25–36.
doi:10.1007/s11745-010-3472-6•Google Scholar
for the Diagnostic and Therapeutic Criteria Committee of the American College of Rheumatology. Updating the American college of rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 1997; 40.
doi:10.1002/art.1780400928•Google Scholar
Cella D, Yount S, Sorensen M, et al. Validation of the functional assessment of chronic illness therapy fatigue scale relative to other instrumentation in patients with rheumatoid arthritis. J Rheumatol 2005; 32:811–9.
Google Scholar
Bjørklund G, Gasmi A, Lenchyk L, et al. The role of Astaxanthin as a Nutraceutical in health and age-related conditions. Molecules 2022; 27.
doi:10.3390/molecules27217167•Google Scholar
Harris WS, Tintle NL, Cornish L, et al. The Omega-3 index is higher in people from a Coastal town versus 5 inland US cities: an observational study. Nutr Res 2022; 104:66–70.
doi:10.1016/j.nutres.2022.04.008•Google Scholar
OmegaQuant. Part 2—Omega-3 index series: 3 reasons to measure Omega-3 levels in red blood cells. 2020;
Available: here
Google Scholar
Abdelhamid AS, Brown TJ, Brainard JS, et al. Omega‐3 fatty acids for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev 2020; 3.
doi:10.1002/14651858.CD003177.pub5•Google Scholar
Harris WS. The Omega-3 index as a risk factor for coronary heart disease. Am J Clin Nutr 2008; 87:1997S–2002S.
doi:10.1093/ajcn/87.6.1997S•Google Scholar
Harris WS, Tintle NL, Etherton MR, et al. Erythrocyte long-chain Omega-3 fatty acid levels are inversely associated with mortality and with incident cardiovascular disease: the Framingham heart study. J Clin Lipidol 2018; 12:718–27.
doi:10.1016/j.jacl.2018.02.010•Google Scholar
McBurney MI, Tintle NL, Vasan RS, et al. Using an erythrocyte fatty acid fingerprint to predict risk of all-cause mortality: the Framingham offspring cohort. Am J Clin Nutr 2021; 114:1447–54.
doi:10.1093/ajcn/nqab195•Google Scholar
Del Gobbo LC, Imamura F, Aslibekyan S, et al. Omega-3 polyunsaturated fatty acid biomarkers and coronary heart disease: pooling project of 19 cohort studies. JAMA Intern Med 2016; 176:1155–66.
doi:10.1001/jamainternmed.2016.2925•Google Scholar
Harris WS, Luo J, Pottala JV, et al. Red blood cell polyunsaturated fatty acids and mortality in the women’s health initiative memory study. J Clin Lipidol 2017; 11:250–9.
doi:10.1016/j.jacl.2016.12.013•Google Scholar
Bernasconi AA, Wiest MM, Lavie CJ, et al. Effect of Omega-3 dosage on cardiovasulcar outcomes: an updated meta-analysis and meta-regression of Interventional trials. Mayo Clin Proc 2021; 96:304–13.
doi:10.1016/j.mayocp.2020.08.034•Google Scholar
Ramprasath VR, Eyal I, Zchut S, et al. Enhanced increase of Omega-3 index in healthy individuals with response to 4-week N-3 fatty acid supplementation from Krill oil versus fish oil. Lipids Health Dis 2013; 12.
doi:10.1186/1476-511X-12-178•Google Scholar
Greupner T, Kutzner L, Nolte F, et al. Effects of a 12-week high-Α-Linolenic acid intervention on EPA and DHA concentrations in red blood cells and plasma Oxylipin pattern in subjects with a low EPA and DHA status. Food Funct 2018; 9:1587–600.
doi:10.1039/c7fo01809f•Google Scholar
Greupner T, Kutzner L, Pagenkopf S, et al. Effects of a low and a high dietary LA/ALA ratio on long-chain PUFA concentrations in red blood cells. Food Funct 2018; 9:4742–54.
doi:10.1039/c8fo00735g•Google Scholar

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