Table 1.

Description of the included studies.

Lp.	Author Year	Study Design	Study Group	Intervention	Results
1	Lindqvist HM et al., 2019 [17]	RCT	39 RA women aged 25–65 years	CG: habitual diet (n = 19). IG: replacement of one meal per day, with a meal containing 75 g blue mussels or 75 g meat (n = 20). Duration 11 weeks, change between groups after 8 weeks of elimination.	GI patients differed in erythrocyte fatty acid profile compared to CG, with changes in the increase of omega-3 fatty acids: EPA and DHA at the group level. The fatty acid profile in plasma phospholipids and serum 1H NMR metabolites was not significantly different between diets. The change in the pattern of fatty acids in erythrocytes may be associated with a reduction in disease activity, although it cannot be excluded that factors other than omega-3 fatty acids potentiate this effect.
2	Lindqvist HM et al., 2018 [18]	RCT	39 RA women aged 25–65 years	CG: habitual diet (n = 19). IG: replacement of one meal per day, with a meal containing 75 g blue mussels or 75 g meat (n = 20). Duration 11 weeks, change between groups after 8 weeks of elimination.	A reduction in DAS28-CRP (p = 0.048) but not DAS28 was observed in the IG group. Blue mussel consumption was associated with moderate to good response to EULAR criteria and a reduction in RA symptoms. Blood lipid levels were unchanged.
3	Dawczynski C et al., 2018 [19]	RCT	38 RA patients aged 59.5 ± 12.4 years	IG: (n = 19) enriched with oil from the microalgae Schizochytrium sp. (2.1 g DHA/d) CG: (n = 19) with sunflower oil (placebo) Time: 10 weeks	In IG, daily DHA consumption led to a decrease in the sum of tender and swollen joints from 13.9 ± 7.4 to 9.9 ± 7.0 and the total DAS28 score from 4.3 ± 1.0 to 3.9 ± 1.2 in contrast to CG. An increase in LA and AA content in erythrocyte lipids was observed in the placebo group. In contrast, in the IG group the amount of DHA was doubled in EL, and the ratio of AA/EPA and AA/DHA decreased significantly.
4	Proudman SM et al., 2015 [20]	RCT	IG: 86 RA patients aged 56.1 ± 15.9 CG: 56 RA patients aged 55.5 ± 14.1	IG: 5.5 g/d omega-3 FAs + EPA + DHA CG: 0.4 g/d omega-3 FAs + EPA + DHA	IG patients had lower DMARD triple therapy failure rate (HR = 0.28) (95% CI 0.12–0.63; p = 0.002), higher ACR first remission rate (HRs = 2.17) (95% CI 1.07–4.42; p = 0.03) compared to CG. No differences in DAS28 and mHAQ or adverse events between IG and CG.
5	Fu Y et al., 2015 [21]	RCT	50 RA patients aged 28–75 years	IG: lipid extract from hard-shelled mussel (Mytilus coruscus) (HMLE) CG: Placebo Time: 6 months	The HMLE group showed significant improvement in DAS-28 disease activity score, clinical disease activity index (CDAI), decrease in TNF-α (tumour necrosis factor α), interleukin (IL)-1β and PGE2 (prostaglandin E2) after 6-month intervention. IL-10 was increased in both groups, significantly more in the HMLE group.
6	Park Y et al., 2013 [22]	RCT	IG: 41 RA patients aged 49.24 ± 10.46 CG: 40 RA patients aged 47.63 ± 8.78	IG: 2.09 g EPA and 1.165 g DHA CG: sunflower oil with high oleic acid content. Time: 16 weeks	The IG group showed a significant increase in erythrocyte levels of omega-3 FAs and EPAs and a decrease in omega-6 FAs, 18: 2n6, 20: 4n6 and 18: 1n9 compared with the placebo group. Supplementation with n-3 PUFAs had no significant effect on the need for non-steroidal anti-inflammatory drugs (NSAIDs), clinical symptoms of RA, or levels of cytokines, eicosanoids and bone turnover markers. In contrast, n-3 PUFA supplementation significantly reduced NSAID requirements and leukotriene B4 levels in patients who weighed more than 55 kg.
7	Dawczynski C et al., 2011 [23]	RCT	54 RA patients and 6 patients with psoriatic arthritis in mean age 56 ± 13 years	I: 3.0 g omega-3 FAs/d; II: 3.2 g GLA/d III: 1.6 g omega-3 FAs + 1.8 g GLA/d; IV: 3.0 g olive oil Time: 12 weeks.	In group I, the AA/EPA ratio decreased from 6.5 ± 3.7 to 2.7 ± 2.1 in plasma lipids and from 25.1 ± 10.1 to 7.2 ± 4.7 in erythrocyte membranes (p ≤ 0.001). A strong increase in GLA and dihomo-γ-linolenic acid was observed in plasma lipids, cholesterol esters and erythrocyte membranes in groups II and III.
8	Bahadori B et al., 2010 [24]	RCT	23 patients with moderate to severe RA	IG: 0.2 g fish oil emulsion/kg intravenously for 14 days, then 0.05 g fish oil/kg CG: 0.9% saline (placebo) intravenously for 14 days, then paraffin (placebo) taken orally as capsules.	The number of swollen joints was significantly lower in the omega-3 FA group compared with the placebo group after 1 week of infusion (p = 0.002) as well as after 2 weeks of infusion (p = 0.046). The number of tender joints also tended to be lower in the omega-3 FA group, although this did not reach statistical significance. Both the number of swollen and tender joints were significantly lower in the omega-3 FA group compared with the placebo group during and at the end of oral treatment.
9	Kolahi S et al., 2010 [25]	RCT	I: 40 RA female patients aged 50 (18–74) II: 43 RA female patients aged 50 (19–74)	I: fish oil 1 g/d II: no fish oil, conventional drugs Time: 3 months	In the fish oil supplementation group, osteoprotegerin levels increased, while sRANKL, TNF-alpha and the sRANKL/osteoprotegerin ratio decreased and there was a significant positive correlation between the sRANKL/osteoprotegerin ratio and TNF-alpha levels (r = 0.327, p = 0.040).
10	Dawczynski C et al., 2009 [26]	RCT	39 RA patients aged 57.9 ± 10.8 years	IG: 40 g fat in the form of 200 g yogurt with 3–8% fat, 30 g cheese with about 50% fat in dry matter, and 20–30 g butter daily; 1.1 g a-linolenic acid, 0–7 g EPA, 0.1 g DPA and 0.4 g DHA. 50 mg/d AA CG: dairy products with comparable fat content, 70 mg/d AA Time: 12 weeks and an 8-week elimination phase in between.	In the IG group, we found that omega-3 FAs inhibited the immune response by significantly reducing the number of lymphocytes and monocytes. N-3 LC-PUFAs did not increase oxidative stress biomarkers, such as 8-iso-PGF(2alpha) and 15-keto-dihydro PGF(2alpha), and DNA damage, such as 7,8-dihydro-8-oxo-2′-deoxyguanosine.
11	Aryaeian N et al., 2009 [27]	RCT	Gr. P: 22 RA patients aged 47.95 ± 11.14 Gr. C: 22 RA patients aged 46.23 ± 13.07 Gr. E: 21 RA patients aged 49.33 ± 11.89 Gr. CE: 22 RA patients aged 43.77 ± 12.75	C: CLAs 2.5 g equivalent to 2 g of a 50/50 mixture of cis 9-trans11 and trans 10-cis12 CLAs E: vitamin E 400 mg CE: CLAs and vitamin E at the above doses P: placebo. Time: 3 months	DAS28, pain and morning stiffness were significantly decreased in the Ci CE group compared with the P group (p < 0.05). Compared with baseline, ESR levels decreased significantly in groups C (p < or =0.05), E (p < or =0.05) and CE (p < or =0.001). The CE group had significantly lower ESR levels than the P group (p < 0.05) and a significantly lower white blood cell count compared with the other groups (p < 0.05).
12	Bae SC. et al., 2009 [28]	RCT	20 RA patients with the mean age of 52.1 ± 10.3 years	I: quercetin + vitamin C (166 mg + 133 mg/capsule) II: alpha-lipoic acid (300 mg/capsule) III: placebo for 4 weeks (3 capsules/day). Time: 4 weeks with a 2-week break before starting the next supplementation.	There were no significant differences in serum levels of proinflammatory cytokines and CRP between the study groups. Disease severity scale scores were not significantly different between study groups, although quercetin supplementation tended to reduce the VAS.
13	Aryaeian N et al., 2008 [29]	RCT	Gr. P: 22 RA patients aged 47.95 ± 11.14 Gr. C: 22 RA patients aged 46.23 ± 13.07 Gr. E: 21 RA patients aged 49.33 ± 11.89 Gr. CE: 22 RA patients aged 43.77 ± 12.75	C: CLAs 2.5 g equivalent to 2 g of a 50/50 mixture of cis 9-trans11 and trans 10-cis12 CLAs E: vitamin E 400 mg CE: CLAs and vitamin E at the above doses P: placebo. Time: 3 months	After supplementation, SBP levels decreased significantly in group C compared with groups E and P, and mean arterial pressure decreased significantly in groups C and CE. There were no significant differences in PGE2, triglycerides, cholesterol, LDL-C, HDL-C, LDL/HDL, cholesterol/HDL, fasting blood sugar, CRP, arylesterase activity, and platelet count between groups. Erythrocyte sedimentation rate decreased in C, E and CE groups.
14	Galarraga B et al., 2008 [30]	RCT	IG: 49 RA patients in median age 58 years CG: 48 RA patients in median age 61 years	IG: 10 g cod liver oil containing 2.2 g omega-3 Fas CG: air-filled placebo capsules. Time: 9 months	Of the 49 patients, 19 (39%) in the cod liver oil group and 5 (10%) in the placebo group were able to reduce daily NSAID requirements by >30%. There were no differences between the groups in clinical parameters of RA disease activity or in observed side effects.
15	Berbert AA et al., 2005 [31]	RCT	43 RA patients in mean age 49 ± 19 years	CG: soybean oil (placebo) IG1: 3 g/d omega-3 FAs from fish oil IG2: 3 g/d omega-3 FAs from fish oil + 9.6 mL olive oil. Time: 24 weeks	There was statistically significant improvement (p < 0.05) in IG1 and IG2 groups relative to CG in joint pain intensity, right and left hand grip strength at 12 and 24 w, duration of morning stiffness, onset of fatigue, Ritchie joint index for painful joints at 24 w, ability to bend to pick up clothing from the floor, and getting in and out of a car at 24 w. IG2 vs. CG showed additional improvement for duration of morning stiffness after 12 w, global patient assessment at 12 and 24 w, and from rheumatoid factor at 24 w. In addition, IG2 showed significant improvement in global patient assessment relative to IG1 at 12 w.
16	Remans PH et al., 2004 [32]	RCT	IG: 26 RA patients aged 52.97 ± 11.2 CG: 29 RA patients aged 59.57 ± 11.0	IG: 1.4 g EPA, 0.211 g DHA, 0.5 g-GLA and micronutrients CG: placebo Time: 4 months	There was no significant change in the number of tender joints or other clinical parameters in any of the study groups compared with baseline. In patients receiving nutrient supplementation but not placebo, there was a significant increase in plasma levels of vitamin E (p = 0.015) and EPA, DHA, and docosapentaenoic acid with a decrease in AA levels (p = 0.01).
17	Sundrarjun T et al., 2004 [33]	RCT	I: 23 RA patients aged 46.2 ± 0.5 II: 23 RA patients aged 46.0 ± 0.5 III: 14 RA patients aged 48.6 ± 0.7	I: low omega-6 FA diet + omega-3 FA supplement (fish oil), II: low omega-6 FA diet (placebo group) III: no special diet or intervention (control group).	At week 18, group I had significant decreases in linoleic acid, CRP, and sTNF-R p55 and significant increases in EPA and DHA compared with group III. There were no significant differences in clinical variables among the three groups. At week 24, there was a significant reduction in interleukin-6 and TNF-alpha in groups I and III.
18	Volker D et al., 2000 [34]	RCT	50 RA patients	IG: fish oil containing 60% omega-3 FAs supplemented at 40 mg/kg body weight/d. CG: diet naturally low in omega-6 FAs Time: 15 weeks	Dietary supplementation resulted in a significant increase in plasma EPA and monocyte lipid levels and clinical improvement in IG.
19	Sarzi-Puttini P et al., 2000 [35]	RCT	I: 25 RA patients aged 49.56 (32–64) II: 25 RA patients aged 50.28 (29–70)	IG: A diet high in unsaturated fats and low in saturated fats with hypoallergenic foods CG: control diet, well balanced Time: 24 weeks	Significant reductions in Ritchie index, number of tender and swollen joints, and ESR were obtained in IG.
20	Zurier RB et al., 1996 [36]	RCT	56 RA patients	IG: 2.8 gm/d GLA CG: placebo (sunflower oil capsules) Time: 6 months This was followed by a 6-month single-blind study during which all patients received GLA.	There was a statistically and clinically significant reduction in signs and symptoms of disease activity in RA patients in the IG group. During the second 6 months, improvements in disease activity were observed in both groups.
21	Leventhal LJ et al., 1994 [37]	RCT	RA patients	Black currant seed oil (BCSO) administered for 24 weeks	BCSO treatment reduced signs and symptoms of disease activity (p < 0.05). The overall clinical response was not better in the treatment group than in the placebo group.
22	Geusens P et al., 1994 [38]	RCT	I: 20 RA patients aged 56.2 ± 2 years II: 21 RA patients aged 57.2 ± 2 years III: 19 RA patients aged 59.2 ± 2 years	I: 6 capsules containing 1 g each of olive oil (placebo), II: 3 capsules each containing 1 g fish oil (1.3 g/d omega-3 FAs) plus 3 placebo capsules, III: 6 capsules containing 1 g each of fish oil (2.6 g/d omega-3 FAs) Time: 12 months	Patients taking 2.6 g/d of omega-3 FAs had significant improvements in patient global assessment, pain, and reduction in antirheumatic medication.
23	Lau CS et al., 1993 [39]	RCT	64 RA patients	I: 10 capsules of Maxepa (171 mg EPA+ 114 mg DHA) II: placebo Duration: 12 months, then 3 months placebo.	Patients taking Maxepa consumed significantly less NSAIDs compared with placebo from month 3 [71.1 (55.9–86.2)% and 89.7 (73.7–105.7)%]. This effect reached a maximum at month 12 and persisted until month 15. No change in clinical or laboratory parameters of RA activity was observed in association with reduced NSAID consumption.
24	Leventhal LJ et al., 1993 [40]	RCT	IG: 19 RA patients aged 58 ± 13 CG: 18 RA patients aged 50 ± 16	IG: 1.4 g/d GLA in borage seed oil CG: cottonseed oils (placebo).	Signs and symptoms of disease activity in patients with rheumatoid arthritis decreased significantly in the IG group (p < 0.05). The overall clinical response (significant change in four measurements) was also better in the treatment group (p < 0.05).
25	Kjeldsen-Kragh J et al., 1992 [41]	RCT	67 RA patients	I: corn oil (placebo), 7 g/day for 16 weeks, and naproxen, 750 mg/day for 10 weeks, followed by a gradual dose reduction to 0 mg/day over the next 3 weeks; II: 3.8 g EPA + 2.0 g DHA and naproxen, 750 mg/day for 16 weeks III: 3.8 g EPA + 2.0 g DHA and naproxen 750 mg/day for 10 weeks	Group II showed improvement in the duration of morning stiffness and global health score. In group III, for the duration of morning stiffness, the deterioration was significantly less compared to group I.
26	Espersen GT et al., 1992 [42]	RCT	32 RA patients	I: dietary supplementation with omega-3 FAs (3.6 g/d) II: placebo Time: 12 weeks	Plasma Interleukin-1 beta levels were significantly reduced in the study group after 12 weeks (p < 0.03). The clinical status of the patients improved in the group receiving fish oil (p < 0.02). It was concluded that dietary supplementation with n-3 fatty acids leads to a significant reduction in plasma IL-1 beta levels in patients with rheumatoid arthritis.
27	Nielsen GL et al., 1992 [43]	RCT	57 RA patients aged 61 (33–78) years IG: 29 patients CG: 28 patients	IG: 6 capsules of omega-3 FAs (3.6 g) CG: 6 capsules with a fat composition like the average Danish diet.	Significant improvement in morning stiffness and joint tenderness in the study group.
28	Brzeski M et al., 1991 [44]	RCT	40 RA patients with upper gastrointestinal lesions due to use of non-steroidal anti-inflammatory drugs I: 19 RA patients II: 21 RA patients	I: 540 mg/d GLA (evening primrose oil 6 g/d), II: placebo (olive oil 6 g/d).	Three Patients in each group reduced their NSAID dose. The GLA treatment group had a significant reduction in morning stiffness after 3 months of supplementation, and the placebo group had a reduction in pain and joint index after 6 months.
29	van der Tempel H et al., 1990 [45]	RCT	16 RA patients in mean age 53 years	IG: fish oil CG: placebo (fractionated coconut oil) Duration: 12 weeks	Joint swelling index and duration of morning stiffness were lower in IG than in CG. The relative amounts of EPA and DHA in plasma cholesterol ester and neutrophil membrane phospholipid fractions increased in the IG group, mainly at the expense of omega-6 Fas, and the mean in vitro production of leukotriene B4 by neutrophils decreased after 12 weeks of supplementation. Production of leukotriene B5 increased to significant amounts during fish oil treatment.
30	Kremer JM et al., 1990 [46]	RCT	49 RA patients I: 20 RA patients aged 59 (32–81) II: 17 RA patients aged 58 (30–80 III: 12 RA patients aged 58 (22–81)	I: dietary supplement with omega-3 FA-s (27 mg/kg EPA and 18 mg/kg DHA) daily II: 54 mg/kg EPA and 36 mg/kg DHA daily III: olive oil capsules containing 6.8 gm of oleic acid daily. Time: 24 weeks	Significant improvement from baseline in the number of tender and swollen joints was observed in groups I and II. A total of 5 of 45 clinical measurements were significantly changed from baseline in group III, 8 of 45 in group I, and 21 of 45 in group II during the study. Leukotriene B4 production by neutrophils decreased by 19% in group I and 20% in group II, whereas interleukin-1 production by macrophages decreased significantly by 40.6% in group I (p = 0.06) and 54.7% in group II (p = 0.0005).
31	Tulleken JE et al., 1990 [47]	RCT	I: 14 RA patients aged 52 (29–66) years II: 14 RA patients aged 58 (43–68) years	I: fish oil II: coconut oil enriched with alpha-tocopherol (placebo) Time: 3 months	The results of the study provide evidence that the beneficial effects of fish oil supplementation cannot be attributed to the antioxidant properties of alpha-tocopherol per se.
32	Magaro M et al., 1988 [48]	RCT	I: 6 RA female patients aged 37 (20–55) years II: 6 RA female patients 36 (20–50) years	I: diet high in PUFA supplemented with EPA and DHA II: diet high in saturated fatty acids.	Fish oil consumption resulted in subjective relief of symptoms of active rheumatoid arthritis and decreased neutrophil chemiluminescence.
33	Kremer JM et al., 1985 [49]	RCT	IG: 17 RA patients in mean age 55.2 years CG: 20 RA patients in mean age 56.5 years	IG: diet high in polyunsaturated fat and low in saturated fat, with daily supplementation (1.8 g) of EPA. CG: diet with lower ratio of polyunsaturated to saturated fats and placebo supplementation. Time: 12 weeks	At week 12 of the study, a reduction in morning stiffness time and number of tender joints was observed in the IG group. After discontinuation of the diet, there was a significant deterioration in the experimental group’s global assessment of disease activity, pain score, and number of tender joints.
34	Leeb BF et al., 2006 [50]	Clinical Trial	34 RA patients aged 61 ± 4.2 years	2 mL/kg (0.1 to 0.2 g fish oil/kg) of fish oil emulsion intravenously for 7 consecutive days Time: 5 weeks	56% achieved a DAS28 reduction > 0.6 in V2 (mean 1.52); 27% > 1.2. In V3, 41% of patients showed a DAS28 reduction > 0.6 (mean 1.06) and 36% > 1.2.
35	Cleland LG et al., 2006 [51]	Clinical Trial	I: 13 RA patients aged 51.1 ± 15.9 II: 18 RA patients 61.8 ± 9.9	I: no fish oil II: fish oil to provide 4–4.5 g EPA plus DHA daily or equivalent fish oil capsule dose (7 × 1 g capsules twice daily). Time: 3 years	After 3 years, AA was 30% lower in platelets and 40% lower in peripheral blood mononuclear cells in those taking fish oil. Serum thromboxane B2 was 35% lower and PGE2 in whole blood stimulated by lipopolysaccharide was 41% lower with fish oil consumption compared with no fish oil. NSAID use was reduced by 75% from baseline with fish oil intake (p < 0.05) and by 37% without fish oil (NS). Remission at 3 years was more common with fish oil use (72%) compared to no fish oil (31%).
36	Adam O et al., 2003 [52]	Clinical Trial	68 RA patients CG: west diet (n = 34) IG: anti-inflammatory diet with a daily intake of AA < 90 mg/d (n = 34)	CG: placebo IG: fish oil capsules (30 mg/kg body weight) Time: 3 months, followed by a 2-month break between treatments.	Among patients on anti-inflammatory diets, the number of tender and swollen joints decreased by 14% during placebo treatment, whereas during fish oil capsules, there were significant reductions in the number of tender (28% vs. 11%) and swollen (34% vs. 22%) joints (p < 0.01) and greater EPA enrichment in erythrocyte lipids (244% vs. 217%) and less formation of leukotriene B(4) (34% vs. 8%, p > 0.01), 11-dehydro-thromboxane B(2) (15% vs. 10%, p < 0.05), and prostaglandin metabolites (21% vs. 16%, p < 0.003). A low-AA diet alleviates clinical signs of inflammation in RA patients and potentiates the beneficial effect of fish oil supplementation.
37	Kremer JM et al., 1995 [53]	Clinical Trial	IG: 23 RA patients in mean age 58 years CG: 26 RA patients in mean age 57 years	IG: 130 mg/kg/d omega-3 FAs CG: 9 capsules/d of corn oil Diclofenac placebo was replaced at week 18 or 22, and fish oil supplementation continued for 8 weeks (until week 26 or 30).	In the group taking fish oil, there was a significant reduction in the number of tender joints duration of morning stiffness, global arthritis activity and pain. In patients taking corn oil, none of the clinical parameters improved from baseline. The reduction in the number of tender joints remained significant 8 weeks after discontinuation of diclofenac in patients taking fish oil. IL-1 beta decreased significantly from baseline through weeks 18 and 22 in patients consuming fish oil (−7.7 +/−3.1; p = 0.026).
38	Haugen MA et al., 1994 [54]	Clinical Trial	IG: 27 RA patients in mean age 51 years CG: 26 RA patients aged 55 years	IG: 7–10 days of fasting, then a gluten-free vegan diet. For another 3–5 months. After 3.5 months a lacto-vegetarian diet. CG: continuation of normal diet.	Concentrations of 20: 3n-6 and 20: 4n-6 fatty acids were significantly reduced after 3.5 months on a vegan diet (p < 0.0001 and p < 0.01, respectively), but concentrations increased to baseline values on a lactovegetarian diet. The 20: 5n-3 concentration was significantly reduced after the vegan (p < 0.0001) and lactovegetarian (p < 0.01) diets. No correlation between changes in fatty acid profiles and clinical improvement.
39	Pullman-Mooar S et al., 1990 [55]	Clinical Trial	7 RA patients in age range of 26–45 years and 7 normal controls	Borage seed oil (9 capsules/d = 1.1 gm/d GLA) Time: 12 weeks	GLA administration increased DGLA ratio, DGLA to AA ratio and DGLA to stearic acid ratio in circulating mononuclear cells. After 12 weeks of GLA supplementation, a significant reduction in the production of PGE2, leukotriene B4 and leukotriene C4 by stimulated monocytes was observed.
40	Jäntti J et al., 1989 [56]	Clinical Trial	I: 10 RA patients in mean age 50 years II: 10 RA patients in mean age 38 years	I: 20 mL evening primrose oil with 9% GLA II: olive oil Time: 12 weeks	Group I showed a decrease in serum levels of oleic acid, EPA, and apolipoprotein B and an increase in serum levels of linoleic acid, GLA, dihomo-gamma-linolenic acid, and AA. Serum EPA concentrations decreased in group II. The decrease in serum EPA and increase in serum AA levels induced by evening primrose oil may not be beneficial in patients with rheumatoid arthritis in light of the role of these FAs as eicosanoid precursors.
41	Cleland LG et al., 1988 [57]	Clinical Trial	RA patients	I: dietary supplementation with fish oil (18 g/d) II: olive oil supplementation Time: 12 weeks	After 12 weeks, the fish oil-treated group showed improvements in tender joint scores and grip strength, a reduction in the mean duration of morning stiffness, a reduction in pain, and a 30% reduction in leukotriene B4 production by isolated neutrophils stimulated in vitro.
42	Belch JJF et al., 1988 [58]	Clinical Trial	I: 16 RA patients aged 48 (30–74) years II: 15 RA patients aged 46 (35–68) years III: 18 RA patients aged 53 (28–73) years	I: 540 mg GLA/day (EPO) II: 240 mg EPA and 450 mg GLA/day (EPO/fish oil), III: oil (placebo). After a 12-month treatment period, a 3-month placebo period was used in all groups.	After 12 months, there was a significant improvement and reduction in NSAID use in the EPO and EPO with fish oil groups. After 3 months of placebo, relapse occurred in those receiving active treatment.
43	Kremer JM et al., 1987 [59]	Clinical Trial	IG: 21 RA patients CG: 19 RA patients	IG: 2.7 g EPA + 1.8 g DHA in 15 MAX-EPA capsules (R.P. Scherer, Clearwater, FL, USA) CG: placebo capsules Timing: 14-week treatment periods and 4-week washout periods.	In the IG group, the mean time to onset of fatigue improved by 156 min and the number of tender joints decreased by 3.5. Production of leukotriene B4 by neutrophils was correlated with a decrease in the number of tender joints (r = 0.53; p < 0.05).
44	Beyer K et al., 2021 [60]	Observational study	78 RA patients aged 57.0 ± 12.0 years with varying degrees of periodontitis	No	Elevated phospholipid levels with concomitant decreased choline levels, increased medium-chain acylcarnitines (MC-AC), and decreased MC-AC to long-chain (LC)-AC ratio were associated with prednisolone intake. Higher concentrations of total FA and total cholesterol were found in active RA.
45	Mustonem AM et al., 2019 [61]	Observational study	I: 10 RA patients after total knee replacement II: 10 OA patients after total knee replacement III: 6 atroscopy patients not suffering from RA or OA	No	After treatment, the proportion of omega-6 FAs significantly decreased in the OA and RA groups. The proportion of MUFAs increased in both RA and OA patients. RA patients had a lower proportion of 20: 4n-6, total omega-6 and 22: 6n-3, and a lower omega-3 product/precursor ratio compared with OA patients. Mean FA chain length in synovial fluid decreased in both diagnoses.
46	Nasriati F et al., 2018 [62]	Observational study	35 RA patients with an average age of 45.29 years	No	There was no significant correlation between TNF-α levels and VCAM-1 levels (p = 0.677; r = +0.073) or between TNF-α levels and FFA levels (p = 0.227; r = −0.21). There was a weak negative correlation of FFA with sVCAM-1.
47	de Pablo P et al., 2018 [63]	Observational study	I: 96 pre-RA subjects II: 258 matched controls	No	The erythrocytic level of omega-6 FA was inversely associated with RA risk, whereas no association was observed with other omega-6 or omega-3 FAs.
48	Beyer K et al., 2018 [64]	Observational study	78 RA patients aged 57 ± 12	No	Patients with omega-3 > 8 index had lower VAS pain severity score and lower periodontal probing depth.
49	Bärebring L et al., 2018 [65]	Observational study	66 RA patients aged 59.9 ± 12.2	No	An omega-3 rich diet with animal fat restriction was not associated with DAS28 (B = −0.02, p = 0.787), but high diet quality was significantly negatively associated with hs-CRP (B = −0.6, p = 0.044) and ESR (B = −2.4, p = 0.002).
50	Gan RW et al., 2017 [66]	Observational study	136 RA patients: I. Anti-CCP2(+) (n = 40, aged 43.7 ± 15.4) II. High titre RF(+) (n = 27, aged 48.1 ± 13.2) III. RF(−) and anti-CCP2(−) (n = 69, aged 46.5 ± 13.9 )	No	Increased omega-3 FA% in RBCs was inversely associated with RF in SE-positive participants and anti-CCP positivity in SE-positive participants, but not in SE-negative participants. In the SERA cohort, use of omega-3 FA supplements was associated with a lower incidence of RF.
51	Jeffery L et al., 2017 [67]	Observational study	22 RA patients aged 53.0 ± 12.5	No	Higher plasma EPA concentrations were associated with greater reduction in DAS28. Plasma EPA PC was positively associated with response to treatment according to EULAR criteria. An increase in Th17 cells after therapy was associated with a lack of response to anti-TNF. ETN increased Th17 frequency in vitro. EPA status was associated with clinical improvement on anti-TNF therapy in vivo and prevented the effects of ETN on Th17 cells in vitro.
52	Gan RW et al., 2016 [68]	Observational study	I: Anti-CCP2 (+) (n = 30, aged 45.6 ± 16.5 ) II: Control (Ab−) (n = 47, aged 48.6 ± 14.4)	No	The probability of anti-CCP2 was inversely proportional to the total FA omega-3 content in RBCs (0.47; 95% CI 0.24–0.92).
53	Rodríguez-Carrio J et al., 2016 [69]	Observational study	124 RA patients aged 52.47 ± 12.76	No	RA patients showed reduced levels of palmitic (p < 0.0001), palmitoleic (p = 0.002), oleic (p = 0.010), arachidonic (p = 0.027), EPA (p < 0.0001) and DHA (p < 0.0001) acids and an overrepresentation of the NEFA profile compared to HC (p = 0.002). FA imbalance may underlie IFNγ production by CD4+ T cells. Changes in NEFA levels were associated with clinical response to TNF-α blockade.
54	Kosinska MK et al., 2015 [70]	Observational study	I: 16 post-mortem donors II: 20 RA patients aged 56 (49–72) III: 26 eOA patients aged 38 (26–56) IV: 22 lOA patients aged 69 (53–74)	No	Significant changes were noted between groups in the relative distribution of PLs and the degree of FA saturation and chain length of FAs. Compared with the control group, more FA-saturated LPC species were reported in the synovial fluid of eOA (63.5% (59.0–70.7%)), lOA (68.8% (65.3–70.6%)) and RA (72.4% (70.2–75.4%)) patients.
55	Di Giuseppe D et al., 2014 [71]	Observational study	32,232 women in whom 205 cases of RA were diagnosed during a 7.5-year follow-up	No	Consumption of omega-3 FAs greater than 0.21 g/day was associated with a 35% reduced risk of developing RA (RR 0.65; 95% CI 0.48–0.90), and consumption of >0.21 g/day was associated with a 52% reduced risk of developing RA. Long-term consumption of ≥1 serving of fish per week compared with <1 serving was associated with a 29% reduced risk (RR 0.71; 95% CI 0.48–1.04).
56	Lee AL. & Park Y, 2013 [72]	Observational study	CG: 100 healthy women aged 50.04 ± 8.00 IG: 100 RA female patients aged 48.39 ± 9.69	no	In RA patients, the levels of ALA, EPA and omega-3 index [EPA + DHA] in erythrocytes were significantly lower than those in the CG. Regression analysis showed that ALA, EPA levels and EPA to AA ratio were negatively associated with RA risk. PGE2 concentration was significantly decreased with increased DHA concentration in erythrocytes of RA patients.
57	Hayashi H et al., 2012 [73]	Observational study	37 RA patients aged 65 ± 9.8 years I: Low disease activity, DAS28 < 3.2 (n = 18) II: High disease activity, DAS28 ≥ 3.2 (n = 19)	no	Serum leptin and albumin levels were significantly lower, while inflammatory markers were elevated, in the high disease activity group. Dietary assessment showed lower fish oil intake and lower MUFA intake ratio in the high disease activity group. There was a negative correlation between DAS28 and dietary intake in terms of MUFA/FAs intake ratio. Serum oxidative stress marker (reactive oxygen metabolites) showed a positive correlation with DAS28.
58	Ormseth MJ et al., 2011 [74]	Observational study	166 RA patients aged 54.0 (45.0–62.8) and 92 control subjects aged 53.0 (44.8–59.2)	no	Serum FFAs levels were not significantly different in RA patients and controls (0.56 mmol/L (0.38–0.75) and 0.56 mmol/L (0.45–0.70), respectively, p = 0.75). In multivariate regression analysis, serum FFAs levels were associated with HOMA-IR (p = 0.011), CRP (p = 0.01), triglycerides (p = 0.005) and Framingham risk score (p = 0.048) in RA but not with IL-6 (p = 0.48).
59	Elkan AC et al., 2009 [75]	Observational study	80 RA patients in mean age 61.4 ± 12 years	no	A total of 18% of women and 26% of men suffered from rheumatoid cachexia. These patients reported high dietary saturated fat intake, which partially correlated with fatty acid composition in adipose tissue and significantly with disease activity. However, patients with and without cachexia did not differ in their dietary fat intake or in their adherence to the Mediterranean diet.
60	Rosell M et al., 2009 [76]	Observational study	I: 1889 RA patients II: 2145 controls	no	Fatty fish consumption was associated with a moderately reduced risk of developing rheumatoid arthritis (OR 0.8 (95% confidence interval = 0.6–1.0)).
61	Das Gupta AB et al., 2009 [77]	Observational study	I: 50 patients aged 49.9 ± 8.2 years II: 50 patients aged 44.7 ± 7.7 years	I: indomethacin (75 mg/d) II: indomethacin (75 mg/d) and omega-3 FAs (3 g/d) over 12 weeks.	Both groups showed moderate improvement in disease activity after 12 weeks of treatment. Physical functioning, physical role, body pain, general health, vitality, social functioning, grip strength and duration of morning stiffness improved significantly better in the combination group compared with the indomethacin-only treatment group.
62	Pedersen M et al., 2005 [78]	Observational study	57,053 individuals from the Danish National Registry. Sixty-nine individuals developed RA.	no	Increased intake of 30 g/d of fatty fish (≥8 g fat/100 g fish) was associated with a 49% reduction in RA risk (p = 0.06), whereas intake of medium-fat fish (3–7 g fat/100 g fish) was associated with a significantly increased RA risk.
63	Gruenwald J et al., 2004 [79]	Observational study	50 RA patients aged between 29 and 73 years	Take 1 capsule of Sanhelios Mussel Lyprinol Lipid Complex (458 mg of fish oil concentrate (50% EPA; 50% DHA) and 35 mg of Lyprinol) twice daily (morning and evening), then from day 3, 2 capsules twice daily. Duration: 12 weeks	A reduction in morning stiffness time, painful and swollen joints was observed at 6 and 12 weeks post-study. Pain was reduced by an average of 60%.
64	Furse RK et al., 2001 [80]	Observational study	healthy volunteers and patients with RA	no	Administration of GLA, an unsaturated fatty acid, reduces joint inflammation in patients with rheumatoid arthritis by inhibiting IL-1 beta release from LPS-stimulated human monocytes. GLA induces a protein that reduces the stability of pro-IL-1 beta mRNA. IL-1 beta is important for host defence, but the enhancement mechanism may be excessive in genetically predisposed patients. Reduction of IL-1 beta autoinduction may therefore be protective in some patients with endotoxic shock and diseases characterised by chronic inflammation.
65	Linos A et al., 1999 [81]	Observational study	145 RA patients and 188 control subjects	no	In multiple regression analysis, consumption of olive oil or cooked vegetables significantly reduced the risk of developing RA (OR: 0.38 and 0.24, respectively).
66	Fraser DA et al., 1999 [82]	Observational study	9 RA patients after completion of 7-day fasting aged 51 (31–65) years	no	Both the concentration of the FFA mixture and the ratio of unsaturated and saturated fatty acids significantly affected lymphocyte proliferation in vitro (p < 0.0001).
67	Shapiro JA et al., 1996 [83]	Observational study	324 RA female patients and 1245 controls aged 15–64.	no	Consumption of cooked or baked fish but was associated with a reduced risk of rheumatoid arthritis. Adjusted odds ratios (OR) for 1- < 2 servings and > or =2 servings of cooked or baked fish per week, compared with <1 serving, were 0.78 (95% confidence interval (CI) = 0.53–1.14) and 0.57 (95% CI = 0.35–0.93).
68	Magarò M et al., 1992 [84]	Observational study	20 female RA patients aged between 25 and 45 years	IG: A diet enriched with fish oil (EPA and DHA) CG: current diet	Patients with IG had a significantly lower erythrocyte sedimentation rate and were observed to have improved clinical parameters compared to CG.
69	Jacobsson L et al., 1990 [85]	Observational study	IG1: 21 patients with recently diagnosed RA aged 57 (25–78) years IG2: 21 patients with RA of longer duration (mean 15 years, range 3–43) CG: 32 men and 25 women aged 57 years (range 50–70 years) and had no rheumatic symptoms at the time of the study.	no	The proportion of 18:2 serum phosphatidylcholine correlated inversely with such acute phase proteins as orosomucoid and CRP. It is proposed that decreases in essential FAs are associated with increased desaturase/elongation enzyme activity, increased eicosanoid production, or metabolic changes secondary to a cytokine-mediated inflammatory response. However, ascorbic acid levels were lower in RA and correlated inversely with haptoglobin, orosomucoid, and CRP levels, indicating an association between ascorbic acid levels and degree of inflammation.
70	Sperling RI et al., 1987 [86]	Observational study	12 RA patients	20 g/d of Max-EPA fish oil for 6 weeks	After fish oil supplementation, the AA:EPA ratio in neutrophil cell lipids decreased from 81:1 to 2.7:1, and mean leukotriene B4 production decreased by 33%. There was also a 37% decrease in platelet-activating factor production at week 6. Fish oil supplementation may have anti-inflammatory effects.
71	Klickstein LB et al., 1980 [87]	Observational study	Synovial fluid and synovial tissue sonication of patients with RA, SA and NIA	no	The concentration of 5(S),12(R)-dihydroxy-6,8,10-(trans/trans/cis)-14-cis-eicosatetraenoic acid (leukotriene B4) in synovial fluid was significantly elevated in patients with RA and rheumatoid factor present (p < 0.05, n = 14) and in patients with SA (p < 0.05, n = 10), compared with those with NIA (n = 9). The content of 5(S)-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE), but not leukotriene B4, was significantly elevated in the synovial tissue of seven RA patients compared with four NIA subjects (p < 0.05). A single intra-articular corticosteroid injection significantly decreased leukotriene B4 levels in synovial fluid of six RA patients. These data suggest the involvement of the potent chemotactic factors 5-HETE and leukotriene B4 in human inflammatory disease.

RA: Rheumatoid arthritis; DMARDs: disease modifying anti-rheumatic drugs; DAS 28: Disease Activity Score of 28 joints; VAS: Visual Analogue Scale; hs-CRP: high sensitivity-C-Reactive Protein; PUFA: polyunsaturated fatty acids; anti-CCP: Anti-cyclic citrullinated peptide; RF: Rheumatoid Factor; PGE2: prostaglandin E2; TNF: tumour necrosis factor; IL: interleukin; EPA: eicosapentaenoic acid; DHA: docosahexaenoic acid; RCT: randomised controlled trial; AA: arachidonic acid; LA: linoleic acid; FA: Fatty Acid; OA: osteoarthritis; ACR: American College of Rheumatology; RBC: red blood cell; The NEFA: non-esterified fatty acid; SE: shared epitope; SERA: The Scottish Early Rheumatoid Arthritis; ETN: etanercept; IG: intervention group; CG: control group; CI: confidential intervals; RR: risk ratio; HMLE: hard-shelled mussel; MUFA: Monounsaturated Fatty Acid; VCAM-1: vascular cell adhesion molecule 1; FFA: free fatty acids; EULAR: European Alliance of Associations for Rheumatology; mHAQ: Health Assessment Questionnaire; PLs: phospholipid species; eOA: early osteoarthritis; lOA: late osteoarthritis; IFN: interferon; PC: plasma phosphatidylcholine; MC-AC: medium-chain acylcarnitines; LPC: lysophosphatidylcholine; EL: erythrocyte lipids; NMR: Nuclear Magnetic Resonance; EPO: evening primrose oil; GLA: gamma-linolenic acid; CLAs: conjugated linoleic acids; HOMA-IR: homeostasis model assessment of insulin resistance; LDL-C: low-density lipoprotein cholesterol; HDL-C: high-density lipoprotein cholesterol; SA: spondyloarthropathy; NIA: noninflammatory arthropathy.