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Table 1 Results of clinical trials on n-3 PUFA and RA

From: Polyunsaturated fatty acids: any role in rheumatoid arthritis?

Author, Year Type of study N Intervention Results References
Kremer JM et al., 1985 Db-CT 17 exp. group
20 ctr
Exp group: diet high in PUFAs and low in saturated fat, with a daily supplement (1.8 g) of EPA.
CTR: diet with a lower PUFAs ratio and a placebo supplement.
At week 12:
Exp Group: improvement in morning stiffness and TJC.
2 months after stopping diet: deterioration in EGA, PGA, pain and TJC
Kremer JM et al., 1987 dd-CT with cross-over design 21 exp. group
19 ctr
14-week treatment periods and 4-week washout periods
Exp group: a daily dosage of 2.7 g of EPA and 1.8 g of docosahexenoic acid
CTR: identical-appearing placebos
At week 14:
Exp group: improvement of mean time to onset of fatigue and TJC
Persistent of effect after 4 weeks washout
Kremer JM et al., 1990 Db -RCT 20 Exp group A
17 Exp group B
12 Exp group C
24 week trial:
Exp Group A: 27 mg/kg EPA and 18 mg/kg DHA (low dose regimen)
Exp Group B: 54 mg/kg EPA and 36 mg/kg DHA (high dose regimen)
Exp group C: olive oil capsules containing 6.8 g of oleic acid
At week 24:
Improvement in TJC and SJC in group A and B (low and high dose group)
Improvement of SJC at week 12 only in group B.
Reduction of neutrophil LTB in both A and B group.
Reduction of macrophage IL1 only in group B.
Van der Tempel H et al., 1990 Db-RCT 16 RA patients 12 week trial with crossover design
Exp group: fractionated fish oil fatty acids
Control group: fractionated coconut oil
At week 12:
Improvement of SJC and duration of morning stiffness in Exp group.
Reduction of neutrophil LTB4 in Exp group.
Espersen JT et al., 1992 Db-RTC 32 active RA patients 12 week trial:
Exp group: dietary supplementation with n-3 fatty acids (3.6 g per day)
Control group: placebo
At week 12:
Reduction of IL1beta in Exp group
Improvement in Ritchie index in Exp group-
Magarò M et al., 1992 RCT 10 Exp group
10 control group
45 days trial
Exp group: dietary supplementation of 1.6 g of EPA and 1.1 g of DHA
Control group: continued usual diet.
At 45 days:
Reduction of neutrophils chemiluminescence in Exp group.
Reduction of Rithie index, morning stiffness and ESR in Exp group.
Nielsen GL et al., 1992 Db-RCT 51 RA patients 12 week trial:
Exp group: dietary supplementation of 3.6 g of n-3 PUFAs
Control group: supplementation with fat composition as the average
At week 12:
Improvement of morning stiffness and TJC in Exp group
Kjeldsen-Kragh J et al., 1992 Db-trial 67 active RA 29 weeks trial:
Placebo Group 1: corn oil 7 g/day for 16 weeks, and naproxen 750 mg/day for 10 weeks followed by a stepwise reduction to 0 mg/day during the following 3 weeks
Exp Group 2: 3.8 g of EPA + 2.0 g of DHA and naproxen 750 mg/day for 16 weeks
Exp Group 3: EPA + DHA as Group 2 and naproxen as Group 1.
At the end of the trial:
- Improvement of morning stiffness duration, PGA and EGA in Exp group 2.
Geusens P et al., 1994 Db-RCT 90 active RA:
19 Exp group A
21 Exp group B
20 Control group
52 weeks trial:
Exp group A: 2.6 g of n-3 PUFAs
Exp group B: 1.3 g ofn-3 PUFAs +3 g of olive oil,
Control group: 6 g of olive oil
Significant reduction in PGA after 3 months, maintained up to 12 months in Exp A group.
Higher proportion of patients in Exp group A with reduction in PGA, pain score and the assumption of NSAID and/or DMARDs.
Kremer JM et al., 1995 Db-trial Active RA taking diclofenac 75 mg/twid
37 Exp group
29 Control group
48 week trial:
- Diclofenac replaced with placebo at week 18 or 22
- fish oil replaced with corn oil at week 26 or 30
Exp group: 130 mg/kg/day of n-3 PUFAs until week 26. Than 9 capsules/day of corn oil
Placebo group: 9 capsules/day of corn oil
At the first visit while taking diclofenac placebo (week 22 or 26):
- Reduction of TJC, morning stiffness, PGA, EGA, pain index in Exp group
- Reduction of IL1beta levels in Exp group
8 weeks after discontinuation of diclofenac:
- Maintenance of TJC reduction in Exp group.
Nordstrom DC et al., 1995 Clinical Trial 22 Active RA 3 months trial:
Exp group: alpha-LNA
Control group: placebo
At the end of the trial:
- No change in clinical and laboratory parameters
- No change in EPA, DHA and A levels
Belch JJ et al., 1998 Db-CT 16 Exp group A
15 Exp group B
18 CTR
12 months of treatment followed by 3 months of placebo
Exp goup A: 540 mg GLA/day (EPO),
Exp group B: 15 patients 240 mg EPA and 450 mg GLA/day (EPO/fish oil)
CTR inert oil (placebo).
At 12 months: subjective improvement of symptoms and reduction of NSAID in group A and B.
After additional 3 month on placebo: relapse of symptoms in group A and B.
Volker D et al., 2000 Db-RCT 50 RA patients with n-6 PUFAs intake in background diet <10 g/day 15 weeks trial:
Exp group: fish oil with 60% of n-3 PUFAs at dosage of 40 mg/Kg body weight
Control group: placebo
At the end of the trial:
Significant improvement in clinical variable in Exp group.
Increase of EPA in plasma and monocyte lipids in Exp group
Remans PH et al., 2004 Db-RCT 66 RA patients 4 months trial:
Exp group: dietary supplementation containing 1.4 g of EPA, 0.211 g of DHA, 0.5 g of gamma-LNA and micronutrients
Control group: placebo
At the end of the trial:
No change in clinical varable
Increase in plasma EPA, DHA, vitamin E and decrease in AA in Exp group
Leeb BF et al., 2006 Open pilot study (one group design) 34 active RA (DAS28 > 4) 5 week study:
2 mL/kg (= 0.1–0.2 g fish oil/kg) fish oil emulsion intravenously on 7 consecutive days. Background therapy unchanged.
At the end of the study:
- No safety issues
- Overall reduction of DAS28 from baseline
- Reduction of DAS28 > 0.6 in 41% of patients
Galarraga B et al., 2008 Db-RCT 97 RA 9 months trial.
At 12 weeks, patients were instructed to gradually reduce, and if possible, stop their NSAID intake
Exp group: 10 g of cod liver oil containing 2.2 g of n-3 PUFAs
Control group: air-filled identical placebo capsules
At the end of the study:
39% of patients in the Exp group and 10% in the control group were able to reduce their daily NSAID requirement by >30%.
Dawczynski C et al., 2009 Db-RCT with cross over design 45 RA patients 2 investigation periods of 3 and an 2 months washout phase between the 2 periods.
Verum: daily diet containing 40 g of fat (200 g of yogurt, 30 g of cheese, 20–30 g of butter). The milk fat was partially exchanged with special oil with high concentration of EPA and alpha-LNA. Overall n-3 PUFAs: alpha-LNA 1.1 g, EPA 0.7 g, DPA 1.1 g, DHA 0.4 g.
Placebo: commercial dairy products with comparable fat contents
At the end of the 3 months treatment period:
- improvement of lipid profile (increase of HDL and reduction of LpA)
- Decrease in lipopolysaccharide-stimulated cylo-oxygenase-2 expression
- Decrease of lymphocytes and monocytes blood count.
At the end of the overall follow-up:
- Reduce diastolic blood pressure
Bahadori B et al., 2010 Db-RCT 23 active RA patients 22 weeks trial:
Exp group: 0.2 g of fish oil emulsion/kg infusion IV for 14 consecutive days followed by 20 weeks of 0.05 g of fish oil/kg capsule.
Control group: 0.9% saline infusion IV for 14 consecutive days, followed by 20 weeks of paraffin wax capsule.
After 1 and to weeks of IV infusion:
- reduction of SJC in the Exp group.
At the end of the study:
- reduction of SJC and TJC in the Exp group.
Proudman SM et al., 2015 RCT Active Early RA: disease duration <12 months, DMARDs naïve
86 Fish oil group
53 controls
52 weeks trial:
DMARD combination of MTX, sulphasalazine, hydroxychloroquine and leflunomide according to a predetermined algorithm based on disease activity and toxicity
Fish oil group: 5.5 g/day of n-3 PUFAs (EPA + DHA)
Control group: 0.4 g/day of n-3 PUFAs
At week 52:
- Failure of triple DMARD therapy was lower in the fish oil group adjusted HR = 0.24 (adjusted for smoking history, shared epitope and baseline anti-cyclic citrullinated peptide)
- The rate of first ACR remission was significantly greater in the fish oil group adjusted HR = 2.09.
Rajaei E et al., 2015 Db-RCT 60 active RA 12 weeks trial
Exp group: 2 capsules/day of n-3 PUFAs (1.8 g of EPA + 2.1 g of DHA).
Control group: placebo
At the end of the trial:
- Improvement of EGA and PGA in the Exp group
- Reduction of NSAID assumption in the Exp group
  1. EPO evening primrose oil, EPA Eicosapentaenoic acid, DHA docosahexaenoic acid, alpha-LNA alpha-linoleic acid, gamma-LNA gamma-linoleic acid, AA arachidonic acid