Proceedings of the Nutrition Society
The 3rd International Immunonutrition Workshop was held at Platja D’Aro, Girona, Spain on 21–24 October
3rd International Immunonutrition Workshop
Session 3: Fatty acids and the immune system
Fish oil and rheumatoid arthritis: past, present and future
Michael James*, Susanna Proudman and Les Cleland
Rheumatology Unit, Royal Adelaide Hospital, Adelaide, South Australia, Australia
Meta- and mega-analysis of randomised controlled trials indicate reduction in tender joint
counts and decreased use of non-steroidal anti-inflammatory drugs with fish-oil supplemen-
tation in long-standing rheumatoid arthritis (RA). Since non-steroidal anti-inflammatory drugs
confer cardiovascular risk and there is increased cardiovascular mortality in RA, an additional
benefit of fish oil in RA may be reduced cardiovascular risk via direct mechanisms and
decreased non-steroidal anti-inflammatory drug use. Potential mechanisms for anti-inflammatory
effects of fish oil include inhibition of inflammatory mediators (eicosanoids and cytokines), and
provision of substrates for synthesis of lipid suppressors of inflammation (resolvins). Future
studies need progress in clinical trial design and need to shift from long-standing disease to
examination of recent-onset RA. We are addressing these issues in a current randomised con-
trolled trial of fish oil in recent-onset RA, where the aim is to intervene before joint damage has
occurred. Unlike previous studies, the trial occurs on a background of drug regimens deter-
mined by an algorithm that is responsive to disease activity and drug intolerance. This allows
drug use to be an outcome measure whereas in previous trial designs, clinical need to alter drug
use was a ‘problem’. Despite evidence for efficacy and plausible biological mechanisms, the
limited clinical use of fish oil indicates there are barriers to its use. These probably include the
pharmaceutical dominance of RA therapies and the perception that fish oil has relatively
modest effects. However, when collateral benefits of fish oil are included within efficacy, the
argument for its adjunctive use in RA is strong.
Rheumatoid arthritis: Fish oil: Pain: Non-steroidal anti-inflammatory drugs
Efficacy: different outcome measures and the evidence
The main reason that patients with rheumatoid arthritis
(RA) seek medical treatment is for alleviation of pain and
discomfort. Meta- and mega-analysis of ten double-blind,
placebo-controlled trials showed that fish oil supplying
2.9– >6g long-chain n-3 fatty acids daily for 3 months
was associated with decreased number of tender joints and
duration of morning stiffness in patients with RA of 10–11
years’ duration(1,2). It was concluded that there was little
difference in the magnitude of effect between 2.9 and
7.1g/d long-chain n-3 fats(3).
Another symptomatic outcome measure is overall pain
experience, which is measured most commonly in clinical
trials by use of a visual linear analogue scale or categorical
scales. A meta-analysis of fish oil trials that measured
inflammatory joint pain, mainly with RA patients, reported
a beneficial effect of fish oil on patient-reported joint pain
intensity, number of painful or tender joints, duration of
morning stiffness and non-steroidal anti-inflammatory
drug (NSAID) use(4). However, another meta-analysis that
examined the effect of fish oil on pain scores in RA
reported that ‘There were no significant effects in twelve
studies’(5). However, this latter meta-analysis did not take
Abbreviations: AA, arachidonic acid; COX, cyclooxygenase; DMARD, disease-modifying anti-rheumatic drugs; LOX, lipoxygenase; LTB, leukotriene B;
NSAID, non-steroidal anti-inflammatory drugs; RA, rheumatoid arthritis; RCT, randomised controlled trials.
*Corresponding author: Dr Michael James, fax 61-8-82224139, email firstname.lastname@example.org
Proceedings of the Nutrition Society (2010), 69, 316–323
gThe Authors 2010 First published online 28 May 2010
Proceedings of the Nutrition Society
account of the influence and management of NSAID or
disease-modifying anti-rheumatic drugs (DMARD) in nine
of those trials (Table 1).
The meta-analysis that concluded that fish oil had no
effect on pain did not consider that the extent of patient-
determined NSAID use can be considered a measure of
pain(5). It is clear that fish oil had an NSAID sparing effect
in the four trials designed to examine that issue(3,6–8). In
another trial where need to change drug use was a with-
drawal criterion, there were ‡6 times the number of trial
participants withdrawn in the placebo group compared
with the fish-oil groups, an indication of lesser pain/
discomfort in the fish oil groups(9). Of the remainder of the
12 studies cited, one did not measure pain(10), one did not
use fish oil(11)and the other did show a decrease in pain
There was no effect of fish oil on disease activity as
measured by erythrocyte sedimentation rate(5).
Efficacy of fish oil in RA includes collateral benefits that
extend beyond symptomatic effects. RA is associated with
an approximate 2-fold increased standardised mortality
ratio and the excess mortality is due mainly to cardio-
vascular deaths(13). Acute and unrecognised myocardial
infarction are 3–6-fold increased in RA and sudden cardiac
death is approximately 2-fold increased(14). The increased
cardiovascular risk is not explained by traditional (i.e.
Framingham) risk factors, and it has been postulated that
chronic systemic inflammation is a contributor, perhaps via
altered endothelial function(13). The magnitude of this issue
had led to management of cardiovascular risk being
recommended as an integral component of RA treat-
ment(15). Additional to the disease-associated increased
cardiovascular risk is that further added by NSAID use. A
comprehensive review suggests slightly increased cardio-
vascular risk with non-selective NSAID, with possibly
naproxen being the safest and diclofenac conferring in-
creased risk similar to that of the cyclooxygenase (COX)-2
selective drug, celecoxib(16). It is well established that fish
oil decreases cardiovascular risk due to the protective
effect of fish and fish oil on coronary mortality(17),
includingsudden cardiac death(18,19). Thelatter is
concordant with the anti-arrhythmic effects of n-3 fatty
acids, including fish oil(20–24). A protective effect seems
evident at doses of long-chain n-3 fats >250mg(17), much
lower than those needed for symptomatic effects in RA.
Fish oil may reduce cardiovascular mortality in RA via
direct myocardial actions and possibly via anti-thrombotic
actions, evidence for which has been reported in an RA
clinic setting with fish oil(25). In addition, there is a further
possible protective effect due to the NSAID sparing effect
of fish oil in RA(6–8). The potential for this latter effect is
underlined by comparison of the use of NSAID by 77% of
patients with established RA in a large US and Canada
database with 22% NSAID use in our early arthritis
patients taking fish oil(25,26). The latter also had an
improved blood lipid profile(25).
Consideration of what constitutes ‘efficacy’ of fish oil
should be sufficiently broad to encompass all that will
benefit an RA patient. This extends beyond symptomatic
Potential mechanisms for anti-inflammatory effects
of fish oil
B(LTB)4, are products of the n-6 PUFA, arachidonic acid
(AA). This is prevalent in cell membranes, in part due to
the high intake of n-6 relative to n-3 fats. AA is released
from membrane phospholipids in response to inflammatory
stimuli, whereupon the free AA is a substrate for COX
and 5-lipoxygenase (5-LOX) with the production of PGE2
and LTB4, respectively. PGE2synthesised peripherally by
COX-1 and COX-2 results in swelling(27), and PGE2pro-
duced in the central nervous system by constitutive/
inducible COX-2 and inducible PGE synthase results in
hyperalgesia(28–30). LTB4 is a chemoattractant and acti-
vator of neutrophils, which are essential for inflammatory
arthritis expression in animal models(31)and which are the
most prominent leucocyte type in rheumatoid synovial
Fish oil contains the n-3 fatty acids EPA and DHA.
These are homologues of AA (Fig. 1). AA has 20 C and
Table 1. Influence of non-steroidal anti-inflammatory drugs (NSAID) on outcomes in studies with fish oil in patients with rheumatoid
References Design issues Outcomes/comments
Skoldstam et al.(6),
Belch et al.(7)and
Lau et al.(8)
Kremer et al.(3)
Participants were instructed to titrate
NSAID use according to the pain level
NSAID sparing effect of fish oil
The trial included an NSAID cessation
period as provocation
Change of NSAID or DMARD was a
NSAID sparing effect of fish oil
Kremer et al.(9)
% Withdrawn due to need to change drugs:
olive oil, 26%; fish oil in low dose, 4%;
fish oil in high dose, 0%. (P = 0.008 for olive v. fish oil),
i.e. fish oil decreased clinical need for drug changes
NSAID use expected to make pain measures insensitive,
i.e. the conditions are not suited to examination of
fish oil and pain
Kremer et al.(47),
Tulleken et al.(48),
van der Tempel et al.(49)
and Volker et al.(50)
All or most trial participants were taking
NSAID at baseline and either were instructed
not to change them during the study or there
is no information on NSAID management
during the study
DMARD, disease-modifying anti-rheumatic drugs.
Fish oil and rheumatoid arthritis 317
Proceedings of the Nutrition Society
four double bonds with the double bond proximal to the
methyl terminus being in the n-6 position. This is desig-
nated 20:4n-6. EPA is 20:5n-3 and DHA is 22:6n-3.
EPA and DHA are effective competitive inhibitors of AA
metabolism by COX, having Kivalues of approximately
2mM, which is similar to that of ibuprofen(32)(Fig. 2). EPA
could be potentially metabolised by COX to the n-3 eico-
sanoid, PGE3. However, EPA is a poor COX substrate and
little, if any PGE3, is formed by leucocytes(33). EPA is a
good substrate for 5-LOX and both LTB5and LTB4are
synthesised in relation to the amounts of EPA/AA sub-
strates(34). However, LTB5 has little pro-inflammatory
activity on neutrophils relative to LTB4(35). Thus, the
overall effect of EPA is production of a less inflammatory
mix of eicosanoids compared with those derived from AA.
Fish oil also has been shown capable of inhibiting the
peptide mediators of inflammation, TNFa and IL-1b
(Fig. 2). Fish oil suppressed ex vivo monocyte TNFa
and IL-1b production in healthy volunteers at 2.4 to 4.7g/d
long-chain n-3 fats(36–38)and in patients with RA at
2.9–5.9g/d long-chain n-3 fats(9). However, a review of
studies of this phenomenon shows considerable variation
in outcome(39). Some of this variation may be due to
genetic factors because the extent of suppression of TNFa
appears to be a function of the basal level of synthesis and
a polymorphism in the TNFa gene(40). It is possible that
other variability in the effect of dietary fish oil on cytokine
synthesis is due to the large inter-individual variation in
blood levels of EPA arising from a fixed oral dose of EPA
(Fig. 3). This source of variation is rarely considered and
may be larger in the community than that shown in Fig. 3
where healthy trial participants received intensive dietary
advice and were provided with monounsaturated cooking
oil, spread and salad dressing, all with the aim of achieving
a uniform dietary background(41).
In addition to suppression of lipid and peptide inflam-
matory mediator production, EPA and DHA are substrates
for a class of anti-inflammatory lipids which are proposed
as being promoters of inflammation resolution (Fig. 2). The
discovery and elucidation of these compounds has led
to the suggestion that chronic inflammation is a failure
of resolution(42). DHA can be metabolised by 15-LOX
or aspirin-treated COX-2 to 17(S)- and 17(R)-hydroxy
derivatives, respectively, and these are metabolised by
5-LOX to resolvin D1 and aspirin-triggered resolvin
D1, respectively(43). Likewise, EPA can be metabolised
to a tri-hydroxy derivative, resolvin E1, via 5-LOX
and aspirin-treated COX-2 or perhaps cytochrome P450
enzymes(42,44,45). These resolvins suppress dermal inflam-
mation, murine peritonitis and colitis, and a receptor that
mediates resolvin E1 activity has been identified(43,45,46). It
is proposed that the cellular interactions that occur between
neutrophils and endothelium or cells within an inflamma-
tory focus with the development of an inflammatory reac-
tion serve to up-regulate 15-LOX which, combined with
neutrophil 5-LOX, generate resolvins that lead to resol-
ution of inflammation(42). The production of lipids with
pro-resolution properties is not limited to EPA and DHA.
AA is a substrate for the production of tri-hydroxy deri-
vatives known as lipoxins or aspirin-triggered lipoxins via
5-LOX and 15-LOX or aspirin-treated COX-2(42). The
lipoxins and resolvins have overlapping activities and it is
not clear whether there are distinct roles, e.g. produced in
different tissues or different leucocyte targets or act at
different times after the initiation of inflammation, or
whether there is simple redundancy.
Clinical trial design for rheumatoid arthritis studies:
past and future
Clinical trials of fish oil in RA have been conduc-
ted asdouble-blind, randomised,
trials(3,6,8,9,12,47–54). This is a standard design for examina-
tion of the effects of agents, mainly drugs, in clinical
medicine. In these trials, fish-oil was examined as an
addition to other medications already being taken by the
patients at baseline. The medications were a combination
of NSAID and DMARD that were mainly methotrexate,
hydroxychloroquine, D-penicillamine and gold. In general,
the need to change DMARD dose during the trials due to
disease activity or drug toxicity was a trial withdrawal
criterion(6,9,12,48–50,53). The need for this is understandable
within that type of design, which could not evaluate the
effects of fish oil against a changing drug background.
Thus, the medical need to change medications during the
trial was seen as a problem. However, the need for drug
changes can be informative. In one of the studies where
DMARD change or need for steroids was a withdrawal
criterion, the number withdrawn for this reason was
reported and analysed with significantly more withdrawals
in the placebo group compared with the fish-oil group(9).
In one study where patients with longstanding RA took
fish oil supplying 2.6g/d long-chain n-3 fats, medication
adjustment was allowed and was reported as an outcome
measure; 47% of those in the fish oil group had their
medication decreased compared with 15% in the placebo
group, a statistically significant difference(54). In the
remaining studies, it was stated that DMARD and NSAID
were continued, presumably without change but with no
further information given(47,51,52).
(AA; 20 : 4n-6)
EPA (20 : 5n-3)
DHA (22 : 6n-3)
n-6 double bond
n-3 double bond
n-6 double bond
Fig. 1. Basis for n-3 and n-6 fatty acid designation.
318 M. James et al.
Proceedings of the Nutrition Society
These trials mainly spanned the period 1985–1995
with one being conducted in 2000. Modern rheumatology
practice has changed since that era, which generally con-
centrated only on relief of symptoms. While that is criti-
cally important for each patient, it tended to ignore the
underlying disease process that determines long-term
patient outcomes. Serial monotherapy with DMARD was
common and this gave a remission rate of <20%(55). It is
now recognised that combination DMARD therapy can
achieve greater disease suppression and this may delay the
progression of joint damage(56,57). It is also accepted that
outcomes are better if there is intervention during a
‘window of opportunity’ in early disease when joint
damage is still absent or minimal(58). This knowledge has
framed modern RA treatment, which has implications for
future clinical trial design.
With the aim for remission rather than ‘merely’ symp-
tom relief, there is a frequent need to change medication in
response to disease activity or drug intolerance or toxicity.
While a changing medication background against which
fish oil is tested makes analysis difficult, not allowing
medication changes is a distortion that dissociates the trial
results from applicability to standard rheumatology prac-
tice. While this was a feature of previous fish oil in RA
trials, it is not unique to them. It is also a condition for
trials with ‘biological agent’ therapies(59–61)and we have
pointed out the ethical problem of avoiding the drug
complexities by deliberately under-treating trial partici-
pants in RA(62). These citations provide examples of ran-
domised controlled trials (RCT) in RA where the conduct
does not reflect ‘real life’ clinical practice because treat-
ments should be adjusted in response to disease activity.
To address this deficiency, we have established a struc-
tured approach to the treatment of early RA that uses triple
DMARD therapy from the outset, but with rules-based
dose adjustments of DMARD and additions of leflunomide
and anti-TNF agents if needed. The rules are responsive to
signs of disease activity and drug intolerance or toxicity.
The approach is directed by an explicit set of algorithms
that we have published(63)and this results in a systematised
series of allowable drug changes (Fig. 4).
We are conducting an RCT of fish oil in early RA in this
treatment framework. Patients will have different drug
trajectories toward remission or disease control. However,
because the drug regimen is systematised and involves a
(AA; 20 : 4n-6)
(COX-1 or COX-2)
(neutrophil activator and
DHA (22 : 6n-3)
EPA (20 : 5n-3)
(relatively little activity
compared with LTB4)
Resolvin D1 (RvD1) and
Cyt P450 or aspirin-
treated COX-2 and 5-LOX
Resolvin E1 (RvE1) and
Lipoxin A4 (LxA4) and
15-LOX or aspirin-treated
COX-2 and 5-LOX
15-LOX or aspirin-treated
COX-2 and 5-LOX
Fig. 2. Possible metabolic pathways for anti-inflammatory effects of the long-chain n-3 fatty acids, EPA and
DHA. Cyt P450, cytochrome P450; LTB4, leukotriene B4; LOX, lipoxygenase; COX, cyclooxygenase.
Plasma phospholipid EPA
(% total fatty acids)
0.75 g EPA /d 1.5 g EPA/d
Fig. 3. Change in plasma phospholipid EPA arising from the in-
gestion of purified EPA at doses of 0.75g/d for 0–3 weeks and
1.5g/d for 3–6 weeks in healthy volunteers. Each line represents
one subject. Mean data were reported previously(41).
Fish oil and rheumatoid arthritis319
Proceedings of the Nutrition Society
pre-determined hierarchy of responses to persistent disease
activity and drug intolerance or toxicity, variations in drug
use can be employed as measures of disease activity, as
modified by tolerance/toxicity considerations, rather than
being discarded due to withdrawal.
The drug-based outcome measures that will be used
for analysis of the effects of fish oil will include (a) the
proportion of participants progressing from triple DMARD
therapy to leflunomide at 12 months and (b) the number
of DMARD ‘step-ups’ and ‘step-downs’ as well as an
‘area under the curve’ for individual drugs ingested. The
progression to leflunomide is a salient event because it
represents a failure of triple DMARD therapy at the max-
imum allowable or tolerable doses, and it is a transition
from treatments costing AUD100–200 to approximately
AUD3000 per patient per year, after which are biological
agents costing >AUD20000 per patient per year. The
number of step-ups and step-downs may detect a suppress-
ive effect of fish oil on disease activity or an effect on
tolerance to DMARD. An area under the curve for drugs
ingested, while not equivalent to area under the curve of
blood levels, is a reflection of total exposure to each drug
over a certain period.
Our RCT of fish oil in early RA is still in a 3-year
follow-up phase and results are not available. However,
because our early RA clinic recommends use of fish oil
and because regular plasma and erythrocyte EPA and DHA
are measured, it is possible to undertake observational
studies with patients from this clinic. As an example,
patients were classified as fish oil users or not according to
plasma phospholipid EPA levels over a period of 3 years.
At 3 years, NSAID use was significantly lower (approxi-
mately half), and remission rate was significantly higher in
fish oil users(25). The OR for remission if in the fish oil
user group was 2.14 (95% CI 1.01, 4.5)(25).
Examination of early or recent-onset RA and use of
innovative study design provides both challenges and
opportunities for determining the place of fish oil as
adjunctive treatment in modern treatment regimens. To this
end, we have developed a computer-based patient man-
agement system with a decision support engine that
incorporates the algorithm described above (Fig. 4). This is
suited to routine management as well as testing of new
treatments against a background of best practice combi-
nation therapy in early RA.
Fish oil compared with anti-cytokine therapy
An important consideration for rheumatologists consider-
ing fish oil for their patients may be the perception that the
effects of fish oil are modest, especially compared with the
biological anti-cytokine agents. The primary end-point
measure used to demonstrate efficacy of the anti-cytokine
agents etanercept, infliximab, anakinra and adalimumab for
US Food and Drug Administration registration was the
ACR20(64–67). This is a composite score, endorsed by the
American College of Rheumatology, that requires a 20%
improvement in tender or swollen joint counts as well as
20% improvement in three of five other criteria. Unfortu-
nately, insufficient data are available from the fish oil RCT
to calculate ACR20 values for comparison with the anti-
cytokine agents. The meta-analysis by Goldberg and Katz
reported the significant effects of fish oil as standardised
mean differences, which is the difference between means
divided by the pooled standard deviation(4). It is possible to
calculate standardised mean differences of some of the
same parameters from an RCT with the anti-TNF mono-
clonal antibody, adalimumab(68). While the effects of fish
oil are numerically less, they are comparable (Table 2). In
addition, there are collateral cardiovascular benefits with
the use of fish oil, as discussed earlier.
Summary and conclusions
Meta-analysis provides high-level evidence for sympto-
matic benefits of fish oil in RA. In addition, there is
0 6 12 18
Fig. 4. Allowed drug changes that result from the treatment algo-
rithm described(63). Allowed dosing escalations can be made
every 3–6 weeks according to disease activity and toxicity. Disease-
modifying anti-rheumatic drug (DMARD): HCQ, hydroxychloroquine;
SSZ, sulfasalazine; MTX, methotrexate; LEF, leflunomide; Anti-
TNF, anti-TNF biological agent therapy; CsA, cyclosporine A; Azt,
azathioprine. —— If active disease, drug doses escalated as
shown. ---- If remission/low disease activity, drug doses main-
tained.aOral MTX is used unless intolerable gastro-intestinal side
effects, in which case subcutaneous (sc) MTX is used. If the max
oral dose (25 mg) is reached, 25 mg sc MTX is used if dose
adjustment is still needed.bIf there is still active disease after the
DMARD HCQ, SSZ, MTX have reached their max allowed doses,
leflunomide (LEF) is added. If active disease is still present, then an
anti-TNF agent (usually adalimumab) is added. N.B. Addition of LEF
at 30 weeks and anti-TNF at 36 weeks is illustrative only. The
requirement and timing are determined by disease activity.
Table 2. Comparison of fish oil with adalimumab (Values are the
standardised mean difference*)
Tender or swollen
- 0.52 to - 0.69‡
*Hedges’ g was used to calculate the standardised mean difference, which is
the difference between means divided by the pooled standard deviation.
†Goldberg and Katz(4).
‡Calculated from data in FDA(67).
320M. James et al.
Proceedings of the Nutrition Society
biological plausibility for the effects of fish oil. However,
the uptake of fish oil in clinical management of RA is
limited. While there may be perceptions of relatively
modest benefits compared with the expensive biological
agents, some benefits may be comparable. It is probable
that the main barrier to clinician acceptance is the pro-
motion of pharmaceutical use as the dominant treatment
modality by the pharmaceutical industry sales force that
attends to the ‘detailing’ of doctors. In the absence of an
equivalent marketing effort for fish oil, rheumatologists are
not inclined to consider, or even be aware of fish oil as a
potential component of routine therapy for RA patients,
despite the efficacy for symptom relief, the NSAID sparing
and the benefits for cardiovascular health, which is compro-
mised in RA patients due to their disease. Future trials
need to examine recent-onset RA and use designs that
allow ‘real-world’ drug use in order to enhance the exter-
nal validity of the findings for modern rheumatology
There are no conflicts of interest for any author. The main
body of this work received no specific grant from any
funding agency in the public, commercial or not-for-profit
sectors. The data represented in Fig. 3 are from a study
supported by Monsanto Company and published previously
as stated in the legend. All authors contributed sub-
stantially to the writing and editing of the manuscript.
1. Fortin PR, Lew RA, Liang MH et al. (1995) Validation of a
meta-analysis: the effects of fish oil in rheumatoid arthritis.
J Clin Epidemiol 48, 1379–1390.
2. James MJ & Cleland LG (1997) Dietary n-3 fatty acids and
therapy for rheumatoid arthritis. Semin Arthritis Rheum 27,
3. Kremer JM, Lawrence DA, Petrillo GF et al. (1995) Effects
of high-dose fish oil on rheumatoid arthritis after stopping
nonsteroidal antiinflammatory drugs. Arthritis Rheum 38,
4. Goldberg RJ & Katz J (2007) A meta-analysis of the
analgesic effects of omega-3 polyunsaturated fatty acid sup-
plementation for inflammatory joint pain. Pain 129, 210–223.
5. MacLean CH, Mojica WA, Morton SC et al. (2004) Effects
of Omega-3 Fatty Acids on Lipids and Glycemic Control in
Type II Diabetes and the Metabolic Syndrome and on
Inflammatory Bowel Disease, Rheumatoid Arthritis, Renal
Disease, Systemic Lupus Erythematosus, and Osteoporosis.
Evidence Report/Technology Assessment. No. 89. Publi-
cation No. 04-E012-2. Rockville, MD: Agency for Health-
care Research and Quality.
6. Skoldstam L, Borjesson O, Kjallman A et al. (1992) Effect of
six months of fish oil supplementation in stable rheumatoid
arthritis. A double blind, controlled study. Scand J Rheuma-
tol 21, 178–185.
7. Belch JJF, Ansell D, Madhok R et al. (1988) Effects of
altering dietary essential fatty acids on requirements for non-
steroidal anti-inflammatory drugs in patients with rheumatoid
arthritis: a double blind controlled study. Ann Rheum Dis 47,
8. Lau CS, Morley KD & Belch JJ (1993) Effects of fish oil
supplementation on non-steroidal anti-inflammatory drug
requirement in patients with mild rheumatoid arthritis – a
double blind placebo controlled study. Br J Rheumatol 32,
9. Kremer JM, Lawrence DA, Jubiz W et al. (1990) Dietary fish
oil and olive oil supplementation in patients with rheumatoid
arthritis. Arthritis Rheum 33, 810–820.
10. Lau CS, McLaren M & Belch JJ (1995) Effects of fish oil on
plasma fibrinolysis in patients with mild rheumatoid arthritis.
Clin Exp Rheumatol 13, 87–90.
11. Nordstrom DC, Honkanen VE, Nasu Y et al. (1995) Alpha-
linolenic acid in the treatment of rheumatoid arthritis. A
double-blind, placebo-controlled and randomized study:
flaxseed vs. safflower seed. Rheumatol Int 14, 231–234.
12. Nielsen GL, Faarvang KL, Thomsen BS et al. (1992)
The effects of dietary supplementation with n-3 poly-
unsaturated fatty acids in patients with rheumatoid arthritis:
a randomized double blind trial. Eur J Clin Invest 22,
13. Van Doornum S, McColl G & Wicks IP (2002) Accelerated
atherosclerosis: an extraarticular feature of rheumatoid
arthritis? Arthritis Rheum 46, 862–873.
14. Maradit-Kremers H, Crowson CS, Nicola PJ et al. (2005)
Increased unrecognized coronary heart disease and sudden
deaths in rheumatoid arthritis: a population-based cohort
study. Arthritis Rheum 52, 402–411.
15. John H, Kitas G, Toms T et al. (2009) Cardiovascular co-
morbidity in early rheumatoid arthritis. Best Pract Res Clin
Rheumatol 23, 71–82.
16. Farkouh ME & Greenberg BP (2009) An evidence-based
review of the cardiovascular risks of nonsteroidal anti-
inflammatory drugs. Am J Cardiol 103, 1227–1237.
17. Mozaffarian D (2008) Fish and n-3 fatty acids for the pre-
vention of fatal coronary heart disease and sudden cardiac
death. Am J Clin Nutr 87, 1991S–1996S.
18. Albert CM, Campos H, Stampfer MJ et al. (2002) Blood
levels of long-chain n-3 fatty acids and the risk of sudden
death. N Engl J Med 346, 1113–1118.
19. GISSI Prevenzione Investigators (1999) Dietary supple-
mentation with n-3 polyunsaturated fatty acids and vitamin E
after myocardial infarction: results of the GISSI-Prevenzione
trial. Lancet 354, 447–455.
20. McLennan PL, Bridle TM, Abeywardena MY et al.
(1992) Dietary lipid modulation of ventricular fibrillation
threshold in the marmoset monkey. Am Heart J 123,
21. McLennan PL (2001) Myocardial membrane fatty acids and
the antiarrhythmic actions of dietary fish oil in animal mod-
els. Lipids 36, S111–S114.
22. Billman GE, Kang JX & Leaf A (1999) Prevention of sudden
cardiac death by dietary pure n-3 polyunsaturated fatty acids
in dogs. Circulation 99, 2452–2457.
23. Metcalf RG, Sanders P, James MJ et al. (2008) Effect of
dietary n-3 polyunsaturated fatty acids on the inducibility of
ventricular tachycardia in patients with ischemic cardiomyo-
pathy. Am J Cardiol 101, 758–761.
24. Schrepf R, Limmert T, Claus Weber P et al. (2004)
Immediate effects of n-3 fatty acid infusion on the in-
duction of sustained ventricular tachycardia. Lancet 363,
25. Cleland LG, Caughey GE, James MJ et al. (2006) Re-
duction of cardiovascular risk factors with longterm fish oil
treatment in early rheumatoid arthritis. J Rheumatol 33,
26. Fries JF, Murtagh KN, Bennett M et al. (2004) The rise and
decline of nonsteroidal antiinflammatory drug-associated
Fish oil and rheumatoid arthritis 321
Proceedings of the Nutrition Society
gastropathy in rheumatoid arthritis. Arthritis Rheum 50,
27. Smith CJ, Zhang Y, Koboldt CM et al. (1998) Pharmacolo-
gical analysis of cyclooxygenase-1 in inflammation. Proc
Natl Acad Sci USA 95, 13313–13318.
28. Hori T, Oka T, Hosoi M et al. (1998) Pain modulatory
actions of cytokines and prostaglandin E2 in the brain. Ann
NY Acad Sci 840, 269–281.
29. Engblom D, Ek M, Saha S et al. (2002) Prostaglandins
as inflammatory messengers across the blood-brain barrier.
J Mol Med 80, 5–15.
30. Guay J, Bateman K, Gordon R et al. (2004) Carrageenan-
induced paw edema in rat elicits a predominant prostaglandin
E2 (PGE2) response in the central nervous system associated
with the induction of microsomal PGE2 synthase-1. J Biol
Chem 279, 24866–24872.
31. Chen M, Lam BK, Kanaoka Y et al. (2006) Neutrophil-
derived leukotriene B4 is required for inflammatory arthritis.
J Exp Med 203, 837–842.
32. Lands WE (1991) Biosynthesis of prostaglandins. Annu Rev
Nutr 11, 41–60.
33. Hawkes JS, James MJ & Cleland LG (1991) Separation
and quantification of PGE3 following derivatization with
panacyl bromide by high pressure liquid chromatography
with fluorometric detection. Prostaglandins 42, 355–368.
34. Cleland LG, James MJ, Gibson RA et al. (1990) Effect of
dietary oils on the production of n-3 and n-6 metabolites
of leukocyte 5-lipoxygenase in five rat strains. Biochim
Biophys Acta 1043, 253–258.
35. Goldman DW, Pickett WC & Goetzl EJ (1983) Human
neutrophil chemotactic and degranulating activities of leu-
kotriene B5 (LTB5) derived from eicosapentaenoic acid.
Biochem Biophys Res Commun 117, 282–288.
36. Meydani SN, Endres S, Woods MM et al. (1991) Oral (n-3)
fatty acid supplementation suppresses cytokine production
and lymphocyte proliferation: comparison between young
and older women. J Nutr 121, 547–555.
37. Endres S, Ghorbani R, Kelley VE et al. (1989) The effect of
dietary supplementation with n-3 polyunsaturated fatty acids
on the synthesis of interleukin-1 and tumor necrosis factor by
mononuclear cells. N Engl J Med 320, 265–271.
38. Caughey GE, Mantzioris E, Gibson RA et al. (1996) The
effect on human tumor necrosis factor a and interleukin-1b
production of diets enriched in n-3 fatty acids from vegetable
oil or fish oil. Am J Clin Nutr 63, 116–122.
39. Sijben JWC & Calder PC (2007) Differential immunomodu-
lation with long-chain n-3 PUFA in health and chronic dis-
ease. Proc Nutr Soc 66, 237–259.
40. Grimble RF, Howell WM, O’Reilly G et al. (2002) The
ability of fish oil to suppress tumor necrosis factor alpha
production by peripheral blood mononuclear cells in healthy
men is associated with polymorphisms in genes that influence
tumor necrosis factor alpha production. Am J Clin Nutr 76,
41. James MJ, Ursin VM & Cleland LG (2003) Metabolism
of stearidonic acid in human subjects: comparison with the
metabolism of other n-3 fatty acids. Am J Clin Nutr 77,
42. Serhan CN, Chiang N & Van Dyke TE (2008) Resolving
inflammation: dual anti-inflammatory and pro-resolution lipid
mediators. Nat Rev Immunol 8, 349–361.
43. Sun Y-P, Oh SF, Uddin J et al. (2007) Resolvin D1 and Its
Aspirin-triggered 17R Epimer: Stereochemical assignments,
anti-inflamamatory properties, and enzymic inactivation.
J Biol Chem 282, 9323–9334.
44. Serhan CN, Hong S, Gronert K et al. (2002) Resolvins:
a family of bioactive products of omega-3 fatty acid
transformation circuits initiated by aspirin treatment that
counter proinflammation signals. J Exp Med 196, 1025–1037.
45. Arita M, Bianchini F, Aliberti J et al. (2005) Stereochemical
assignment, antiinflammatory properties, and receptor for
the omega-3 lipid mediator resolvin E1. J Exp Med 201,
46. Ishida T, Yoshida M, Arita M et al. (2009) Resolvin E1, an
endogenous lipid mediator derived from eicosapentaenoic
acid, prevents dextran sulfate
Inflamm Bowel Dis 1, 1.
47. Kremer JM, Bigauoette J, Michalek AV et al. (1985) Effects
of manipulation of dietary fatty acids on clinical manifes-
tations of rheumatoid arthritis. Lancet 1, 184–187.
48. Tulleken JE, Limburg PC, Muskiet FAJ et al. (1990) Vitamin
E status during dietary fish oil supplementation in rheumatoid
arthritis. Arthritis Rheum 33, 1416–1419.
49. van der Tempel H, Tulleken JE, Limburg PC et al. (1990)
Effects of fish oil supplementation in rheumatoid arthritis.
Ann Rheum Dis 49, 76–80.
50. Volker D, Fitzgerald P, Major G et al. (2000) Efficacy of
fish oil concentrate in the treatment of rheumatoid arthritis.
J Rheumatol 27, 2343–2346.
51. Kremer JM, Jubiz W, Michalek A et al. (1987) Fish-oil
fatty acid supplementation in active rheumatoid arthritis. Ann
Intern Med 106, 497–503.
52. Cleland LG, French JK, Betts WH et al. (1988) Clinical and
biochemical effects of dietary fish oil supplements in rheu-
matoid arthritis. J Rheumatol 15, 1471–1475.
53. Kjeldsen-Kragh J, Lund JA, Riise T et al. (1992) Dietary
omega-3 fatty acid supplementation and naproxen treat-
ment in patients with rheumatoid arthritis. J Rheumatol 19,
54. Geusens P, Wouters C, Nijs J et al. (1994) Long-term effect
of omega-3 fatty acid supplementation in active rheumatoid
arthritis. Arthritis Rheum 37, 824–829.
55. Wolfe F & Hawley DJ (1985) Remission in rheumatoid
arthritis. J Rheumatol 12, 245–252.
56. O’Dell JR, Leff R, Paulsen G et al. (2002) Treatment of
rheumatoid arthritis with methotrexate and hydroxychloro-
quine, methotrexate and sulfasalazine, or a combination of
the three medications: results of a two-year, randomized,
double-blind, placebo-controlled trial. Arthritis Rheum 46,
57. Egsmose C, Lund B, Borg G et al. (1995) Patients with
rheumatoid arthritis benefit from early 2nd line therapy:
5 year followup of a prospective double blind placebo con-
trolled study. J Rheumatol 22, 2208–2213.
58. Cush JJ (2007) Early rheumatoid arthritis – is there a window
of opportunity? J Rheumatol 80, 1–7.
59. Maini RN, Breedveld FC, Kalden JR et al. (2004) Sustained
improvement over two years in physical function, structural
damage, and signs and symptoms among patients with rheu-
matoid arthritis treated with infliximab and methotrexate.
Arthritis Rheum 50, 1051–1065.
60. Moreland LW, Schiff MH, Baumgartner SW et al. (1999)
Etanercept therapy in rheumatoid arthritis. A randomized,
controlled trial. Ann Intern Med 130, 478–486.
61. Weinblatt ME, Keystone EC, Furst DE et al. (2003) Adali-
mumab, a fully human anti-tumor necrosis factor alpha
monoclonal antibody, for the treatment of rheumatoid
arthritis in patients taking concomitant methotrexate: the
ARMADA trial. Arthritis Rheum 48, 35–45.
62. James M & Cleland L (2008) COMET results are not stellar.
Lancet 372, 1807–1808.
63. Proudman SM, Keen HI, Stamp LK et al. (2007) Response-
driven combination therapy with conventional disease-
modifying antirheumatic drugs can achieve high response
322 M. James et al.
Proceedings of the Nutrition Society Download full-text
rates in early rheumatoid arthritis with minimal glucocorti-
coid and nonsteroidal anti-inflammatory drug use. Semin
Arthritis Rheum 37, 99–111.
64. FDA (1998) Etanercept review. http://www.fda.gov/cder/
65. FDA (1999) Infliximab review. http://www.fda.gov/cder/
66. FDA (2001) Anakinra review. http://www.fda.gov/ohrms/
68. Keystone EC, Kavanaugh AF, Sharp JT et al. (2004) Radio-
graphic, clinical, and functional outcomes of treatment with
adalimumab (a human anti-tumor necrosis factor monoclonal
antibody) in patients with active rheumatoid arthritis receiving
concomitant methotrexate therapy: a randomized, placebo-
controlled, 52-week trial. Arthritis Rheum 50, 1400–1411.
(2002) Adalimumabreview. http://www.fda.gov/
Fish oil and rheumatoid arthritis323