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

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

[61]

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

[62]

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.

[65]

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.

[67]

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-

[69]

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.

[70]

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

[71]

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.

[72]

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.

[66]

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.

[73]

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

[76]

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.

[63]

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

[68]

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

[64]

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

[78]

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%.

[74]

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

[108]

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.

[79]

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.

[77]

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

[75]