Diet and Rheumatoid
Arthritis: A Review of the Literature
Lisa K. Stamp, FRACP, PhD*, Michael J. James, PhD†and Leslie G. Cleland, FRACP, MD‡
INTRODUCTION Rheumatoid arthritis is a common inflammatory condition. A large number of
patients seek alternative or complementary therapies of which diet is an important com-
ponent. This article reviews the evidence for diet in rheumatoid arthritis along with the
associated concept of oral tolerization.
METHODS References were taken from Medline from 1966 to September 2004. The keywords,
rheumatoid arthritis, diet, n-3 fatty acids, vitamins, and oral tolerization, were used.
RESULTS Randomized controlled trials (RCTs) indicate that dietary supplementation with n-3
fatty acids provides modest symptomatic benefit in groups of patients with rheumatoid
arthritis. Epidemiological studies and RCTs show cardiovascular benefits in the broader
population and patients with ischemic heart disease. A number of mechanisms through
which n-3 fats may reduce inflammation have been identified. In a small number of patients
with rheumatoid arthritis, other dietary manipulation such as fasting, vegan, and elimination
diets may have some benefit. However, many of these diets are impractical or difficult to
sustain long term.
CONCLUSIONS Dietary manipulation provides a means by which patients can a regain a sense
of control over their disease. Dietary n-3 supplementation is practical and can be easily
achieved with encapsulated or, less expensively, bottled fish oil.
Semin Arthritis Rheum 35:77-94 © 2005 Elsevier Inc. All rights reserved.
KEYWORDS rheumatoid arthritis, diet, n-3 fatty acids, oral tolerization
erally applied. Since, once acquired the disease generally
requires lifelong treatment, it is not surprising that pa-
tients frequently request information regarding alternative
and/or complementary therapies for management of their
disease. It has been reported that 33 to 75% of RA patients
believe food plays an important role in their symptom
severity and 20 to 50% will have tried dietary manipula-
tion in an attempt to relieve their suffering (1,2). While
adjustment of diet, with or without pharmacotherapy, is
considered routine clinical practice in the management of
many common medical conditions such as ischemic heart
heumatoid arthritis (RA) is a common, chronic dis-
ease, for which multiple pharmacotherapies are gen-
disease and diabetes, it is less accepted by physicians in
the management of RA. In an age when alternative and
complementary medicine is a multi-billion-dollar indus-
try, patients are often faced with difficult choices and
many obtain inadequate advice from their medical practi-
tioners. The evidence regarding dietary change in RA will
be considered in this review. The related issue known as
oral tolerization will also be discussed.
This review is based on a Medline literature search from 1966 to
fatty acids,” “vitamins,” and “oral tolerization,” were used. Articles
Diet and the Control of Inflammation
Dietary Fatty Acids
There are three major classes of fatty acids: namely, saturated
fatty acids (no double bonds); monounsaturated fatty acids
*Department of Medicine, Christchurch School of Medicine and Health
Sciences, University of Otago, New Zealand.
†Associate Professor, Rheumatology Unit, Royal Adelaide Hospital, Ad-
‡Professor, Rheumatology Unit, Royal Adelaide Hospital, Adelaide, Australia.
Reprints will not be available from the author.
Address correspondence to: Dr Lisa Stamp, Department of Medicine and
Health Sciences, Christchurch School of Medicine, P.O. Box 4345,
Christchurch, New Zealand. E-mail: firstname.lastname@example.org
0049-0172/05/$-see front matter © 2005 Elsevier Inc. All rights reserved.
(1 double bond); and polyunsaturated fatty acids (PUFAs)
(?2 double bonds). The PUFAs can be further classified
according to the site of the double bond proximal to the
methyl terminus, as n-6 or n-3. The enzymes required to
introduce double bonds in the n-3 and n-6 positions are not
present in mammals. These fatty acids must therefore be
obtained from the diet and accordingly they are known as
essential fatty acids.
In the typical Western diet, far more n-6 fat is consumed
than n-3 fat (3). This is mainly due to the abundance of
linoleic acid (LA; 18:2n-6) in soybean, safflower, sunflower,
and are present in many processed foods. The n-3 homo-
logue of LA, ?-linolenic acid (ALA; 18:3n-3), is present in
flaxseed oil but this is not a significant dietary component.
ALA is present in lesser amounts in rapeseed and canola oils.
Once ingested, LA and ALA may be used in energy metabo-
lism or be converted to the C20 fatty acids arachidonic acid
(AA) and eicosapentaenoic acid (EPA), respectively (Table 1)
or are further elongated and desaturated to their correspond-
ing C22 fatty acids. All of these fatty acids are incorporated
into cell membranes and tissues.
Effect of Dietary Fatty
Acids on Mediators of Inflammation
Eicosanoids—Prostaglandins and Leukotrienes. AA is me-
tabolized via cyclooxygenase (COX) and 5-lipoxygenase to
n-6 prostaglandins (PGs) and leukotrienes (LTs), respec-
tively. These C20 oxy-lipids are known collectively as eico-
is a competitive substrate for metabolism by the PG and LT
synthetic pathways and it is converted to the n-3 LTs. How-
ever, EPA is a poor COX substrate and, while n-3 PGs are not
tion of n-6 PGs. In some cases, the respective activities of the
AA-derived and EPA-derived leukotrienes differ, with some,
but not all, n-3 eicosanoids having lesser activity than their
are pro-inflammatory. For example, PGE2causes vasodilata-
tion and increased vascular permeability and hyperalgesia
and LTB4attracts neutrophils and induces their degranula-
tion (4). TXA2promotes synthesis by mononuclear phago-
cytes of the inflammatory cytokines, interleukin (IL)-1?, and
tumor necrosis factor (TNF)-? (5). The net result is pain,
warmth, redness, swelling, and loss of function. These com-
prise the cardinal clinical signs and symptoms of the inflam-
matory joint disease RA. The n-3 eicosanoids are entirely
homologous with the n-6 eicosanoids except for the addi-
tional double bond in the n-3 position. The n-3 eicosanoids
accordingly have a one unit higher subscript number since
this refers to the number of double bonds after oxidation.
While PGE3is edematogenic, very little appears to be pro-
duced (6,7). Although conversion of EPA to LTB5is quite
efficient, LTB5is 10 to 30 times less potent than LTB4as a
neutrophil chemotaxin (8,9). The reduction in LTB4and in-
crease in LTB5production that occurs in the presence of EPA
results in decreased neutrophil chemotaxis and adhesion
(10). TXA3has little activity as an aggregator of platelets, one
of the hallmark activities of TXA2. The activity of TXA3as a
promoter of IL-1? and TNF-? synthesis by phagocytes is not
been implicated in the tissue destruction seen in RA (11-13).
Treatment with anti-TNF-? monoclonal antibodies (inflix-
imab) and a TNF-? receptor fusion protein (etanercept) has
been shown to reduce disease activity and joint damage (eg,
erosions, joint space narrowing) in RA (14-16). IL-1 receptor
antagonists may also reduce tissue damage (17). Some but
not all studies have shown that both IL-1? and TNF-? are
reduced by dietary n-3 fatty acid supplementation in healthy
subjects and those with RA (summarized in Table 2). At least
American Rheumatology Association
Disease activity score
disease modifying antirheumatic drugs
early morning stiffness
erythrocyte sedimentation rate
health assessment questionnaire
intercellular adhesion molecule
leukocyte function associated antigen
mucosa associated lymphoid tissue
major histocompatibility complex
physician global assessment
patient global assessment
polyunsaturated fatty acids
Ritchie articular index
randomised controlled trial
swollen joint count
transforming growth factor ?
tumor necrosis factor
78L.K. Stamp, M.J. James, and L.G. Cleland
part of the explanation for these differing findings may lie in
inflammatory cytokine synthesis (18).
The mechanisms resulting in inhibition of cytokine produc-
produced may play a role. More direct effects of fatty acids on
effects of fatty acids on cell signaling and transcription of other
proteins have been demonstrated (19-21).
Recent evidence suggests that nonsteroidal antiinflamma-
tory drugs (NSAIDs) and COX-2 inhibitors may alter the
balance of TXA2/PGE2production in favor of TXA2, which
may in turn increase the production of IL-1? and TNF-?,
which are known to be associated with tissue damage in RA
(22). The ability of n-3 fatty acids to reduce NSAID require-
ment could therefore be beneficial in terms of preventing or
reducing tissue damage. This effect via NSAID-sparing could
be additive with the inhibitory effect of dietary n-3 fats on
IL-1? and TNF-? shown in volunteer studies. This question
has not been addressed formally but warrants investigation.
Effect of n-3 Fatty Acids in the Presence of Aspirin/NSAIDs
on Novel Inflammatory Mediators. Recent studies have
shown that mice treated with n-3 fatty acids and aspirin/
NSAIDs produce novel inflammatory mediators, which in-
hibit human polymorphonuclear leukocyte transendothelial
migration (23). Furthermore, mice treated with aspirin and
active lipids known as resolvins (24). This name was derived
from their antiinflammatory properties and tendency toward
resolution of the inflammatory state. While NSAIDs may
have unwanted effects on TNF-? and IL-?, the data with
n-3 fatty acids may be beneficial in the inflammatory process
even in the presence of NSAIDs.
Effect of n-3 Fatty Acids on MHC Class II Expression and
Antigen Presentation. Major histocompatibility complex
(MHC) molecules are expressed strongly by professional an-
tigen-presenting cells (dendritic cells) and also by macro-
phages and B-cells. Their function is to present processed
peptides, which typically arise from antigens outside the an-
tigen-presenting cell (APC), but which are not necessarily
nonself. Antigen presentation within the context of MHC
class II (in the case of humans either HLA-DQ, -DR, or -DP)
are recognized by cognate CD4?T-cells. The repertoire of
peptides that can be presented efficiently is determined by
the amino acids that line the peptide-binding groove, which
is the site of considerable genetic polymorphism. Given the
capacity of APCs to present both self and nonself antigens
with varying efficiency, according to genetically determined
configurations within the groove, it is not surprising that
both susceptibilities to auto-immune diseases and defense
against invasive infections are influenced by MHC class II
polymorphisms. Examples of the former include susceptibil-
ity to systemic lupus erythematosus (HLA-DR3) and, of the
latter, association of the tuberculoid response pattern in lep-
rosy with HLA-DR4 (25). The strong association between RA
and certain HLA-DR alleles (DR1 and certain DR4 subtypes)
disease. Notably the rheumatoid susceptibility alleles encode
for an electropositive pocket at position 4 in the peptide-
binding groove, suggesting preference for presentation of
peptides that bear a negative charge that can be accommo-
dated in this pocket (25).
The number of MHC molecules expressed on APCs and
the concentration of antigen are also are important factors in
T-cell responses to antigen (26). It has been shown that pa-
tients with RA have high levels of MHC class II expression on
T-cells and synovial lining cells (27). Reduction in MHC
expression and antigen presentation function by n-3 fatty
acids may reduce pathogenic T-cell activation in RA.
function (28). In human monocytes in vitro incubation with
EPA and/or DHA followed by stimulation with interferon
(IFN)-?, a potent stimulus for MHC class II expression, re-
Table 1 Metabolism of n-6 and n-3 Fatty Acids
Fatty Acid Family
18 carbon fatty acid
Linoleic acid (LA; 18:2n-6)
Sunflower, corn, and safflower oil
Large intake (7–8% dietary
Arachidonic acid (AA; 20:4n-6)
Mainly synthesized from ingested
leukotrienes (TXA2, PGE2, LTB4)
?-Linolenic acid (ALA; 18:3n-3)
Flaxseed, canola, and rapeseed oil
Minor intake (0.3-1.0% dietary energy)a
20 carbon fatty acids
Eicosapentaenoic acid (EPA; 20:5n-3)
Mainly from ingested EPA (fish, fish oil)
Metabolites of C20 fatty acid
relevant to inflammation
Competitive inhibitors of n-6
prostaglandin and leukotriene
Suppression IL-1? and TNF-?
Effect on inflammatory
aIn the last 10 years, LA intake will have decreased and ALA intake will have increased in some countries where canola oil use has displaced
sunflower, safflower, or corn oil use.
Diet and rheumatoid arthritis79
sulted in reduction of the proportion of monocytes express-
ing HLA-DR and HLA-DP. In addition, their mean intensity
of expression of HLA-DR and HLA-DP, as assessed by flow
cytometry, was reduced compared with control IFN-?-
treated monocytes (29, 30). Dietary n-3 supplementation
with fish oil capsules containing 0.93 g EPA and 0.63 g DHA
reduced expression of HLA-DR and HLA-DP on human
monocytes ex vivo (31). Hughes and Pinder have shown that
human monocytes display a reduced ability to present anti-
gen after culture with exogenous EPA and DHA (30).
Effect of n-3 Fatty Acids on Adhesion Molecules. Cognate
adhesion molecules that are expressed by endothelial cells
and leukocytes mediate movement of leukocytes from the
circulation into tissues. The cognate pair intercellular adhe-
sion molecule (ICAM)-1 and leukocyte function associated
antigen (LFA)-1 have been implicated in migration of leuko-
cytes into inflamed synovium in small laboratory rodents
(32) and ICAM-1 blockade reduces disease activity in RA
of ICAM-1 and LFA-1 on human monocytes (29-31).
Effect of n-3 Fatty Acids on Catabolic Enzymes. Chronic
joint inflammation involves cartilage degradation, which
leads ultimately to joint failure. These catabolic events are
up-regulated by cytokines and involve matrix metallopro-
teinases (MMPs) as the ultimate effector molecules. n-3 fatty
acids added in vitro suppress MMP expression, reduce pro-
teoglycan degradation, and inhibit the expression of COX-2
in IL-1-stimulated bovine chondrocytes (21). Supplementa-
tion of human osteoarthritic cartilage explants with n-3, but
not n-6 fatty acids, resulted in reduction of collagenase and
aggrecanase proteolytic activity. In addition, expression of
mRNA for MMP-13 and MMP-3 was abolished with n-3 fatty
acid supplementation (34). These observations provide evi-
dence for a regulator effect of n-3 fatty acids on gene
Effects of Dietary n-3 Fats on the Clinical
Manifestations of RA
There have been 14 published randomized controlled trials
of fish oil in RA (summarized in Table 3). All but the more
They have all shown a modest benefit when n-3 supplemen-
tation is used in combination with standard pharmacother-
apy for RA. Deterioration in symptoms after discontinuation
of the fish oil has been reported (38). The total n-3 fatty acid
Table 2 Effects of n-3 Fatty Acids on TNF-? and IL-1?
Number and Type
9 healthy males
n-3 Fatty Acids
EPA ? DHA 1.23
Endres et al (170)
17 patients with RANot measured54 Kremer et al (42)
25 healthy subjects00 Moliva et al (171)
12 healthy women58-7048-90 Meydani et al (172)
22 healthy subjects
7-35 25-40Meydani et al (173)
EPA ? DHA 0.27
Six 1 g capsules/day
(EPA ? DHA 86%)
20 multiple sclerosis
patients and 15
15 healthy males
Gallai et al (174)
n-3 fatty acid 0.65
DHA 6 g/day
EPA ? DHA 1.83
Caughey et al (48)
32 healthy subjects
58 healthy males
Schmidt et al (175)
Blok et al (176)
11 healthy males
15 healthy males
Kelley et al (177)
Caughey et al (48)
15 healthy males
20 Mantzioris (50)
Yaqoob et al (178)0
*Based on 65-kg subject.
80L.K. Stamp, M.J. James, and L.G. Cleland
with a modified lactovegetarian diet low in AA resulted in
greater improvement than either dietary modification alone
low in n-6 fatty acids, a dietary adjustment that is known to
increase EPA incorporation into tissue (41).
In all of the studies, the benefits of fish oil were observed
NSAIDs and/or disease-modifying antirheumatic agents
(DMARDs). Collectively, the studies have established that
fish oil supplements that deliver 2.6 g or more per day of the
long-chain n-3 fatty acids EPA plus DHA reduce symptoms
in RA after a latent period of about 12 weeks. The latency is
reduced with higher doses of fish oil (42). The required dose
of 9 to 20 standard fish oil capsules per day is relatively
expensive and it can be taken more conveniently and less
expensively using bottled fish oil in juice as discussed below
Effect of Fish Oil on NSAID Use in RA
Whether fish oil supplements can reduce requirement for
NSAID has been addressed in several studies. Kremer and
coworkers treated patients with diclofenac and fish oil for 18
or 22 weeks before discontinuing only the diclofenac. The
the remaining 8 weeks of the study (44). Kjeldsen-Kragh and
coworkers reduced and stopped NSAID 16 weeks after start-
ing fish or corn oil, a change that was better tolerated by the
fish oil group (45). Two other studies have shown patients
taking fish oil were able to reduce their NSAID without de-
terioration in clinical or laboratory indices of disease activity
(46, 47). With regard to analgesic action, taking fish oil in
antiinflammatory doses reduces production, by monocytes
stimulated in vitro, of nocioceptive PGE2(48), which occurs
through COX-2 (49). Dietary supplementation with fish oil
in antiinflammatory doses inhibits PGE2synthesis by stimu-
lated peripheral blood monocytes (50). This provides a
mechanistic basis for the reduction in NSAID requirements
in RA patients taking antiinflammatory doses of fish oil long
It should be noted that all of the clinical trials to date have
been in patients with long-standing RA. The influence of fish
oil supplements or other strategies for dietary n-3 fat enrich-
ment in the management of early RA has not been reported.
of combination therapies gaining favor. The assessment of
long-term outcomes of n-3 fatty acid supplementation in a
setting where multiple medications are used and there are
frequent medication changes will be difficult. Biochemical
changes due to n-3 fatty acid enhancement may be easier to
establish than any correlation with clinical outcomes.
Cardiovascular Disease, RA, and n-3 Fatty Acids
The ability of n-3 fatty acids to provide additional health
benefits, over and above symptom relief, in patients with RA
must not be overlooked. Patients with RA have a reduced life
expectancy and increased mortality from cardiovascular dis-
ease (51, 52) and it has been suggested that prevention of
cardiovascular disease should be an aim in the management
of RA (53).
Medications used in the management of RA may contrib-
ute to increased cardiovascular risk. Patients with RA have
risk factor for ischemic heart disease (54). Methotrexate
(MTX) has been independently associated with increased
cardiovascular mortality in patients with RA (55), and espe-
cially in combination with sulfasalazine, has been shown to
increase plasma homocysteine levels (56). Cyclosporin A can
cause hypertension and nephrotoxicity. Dietary fish oil has
been shown to reduce these unwanted effects of cyclosporin
A in rodents (57, 58) and humans (59, 60).
cular risk. Low-dose aspirin can reduce cardiovascular risk
through functionally selective inhibition of platelet COX-1,
by irreversible disablement of this enzyme, in a setting where
reconstitution cannot occur within the life span of the cell
By contrast, in the vascular compartment, COX-2 inhibitors
selectively inhibit endothelial COX-2, the activity of which
leads to production of prostacyclin, a mediator which pro-
motes vascular patency. It is not surprising therefore that
highly selective COX-2 inhibitors have been associated with
substantially increased vascular risk (62-64). Indeed, the
highly selective COX-2 inhibitor rofecoxib was withdrawn
worldwide in September 2004 on the basis of increased car-
diovascular events with rofecoxib as compared with placebo
(65, 66). It has been argued that the respective risks of stan-
dard NSAIDs (serious upper gastrointestinal events) and
COX-2 selective NSAIDs (serious cardiovascular and upper
gastrointestinal events) need to be weighed against their use-
term relief from arthritis pain, while reducing cardiovascular
risk without increasing serious upper gastrointestinal events.
In this regard, fish oil supplements might be regarded as the
achieved. With regard to mechanism, EPA does not simply
act as an inhibitor of AA metabolism by COX, but also pro-
vides an alternate substrate for COX, and thereby yields
in prostacyclin activity in the vascular space (67, 68). The
result is a shift in eicosanoid balance that is likely to contrib-
ute to the reduced cardiovascular risk seen with n-3 fatty
acids as discussed below.
With regard to the cardiovascular preventive effects of
n-3 fatty acids that are found in fish and fish oil, Albert and
coworkers showed a reduction in sudden cardiac death in
patients with no previous history of ischemic heart disease
or cerebrovascular disease who consumed at least 1 fish
meal per week (69). Furthermore in a prospective, nested
case-controlled study of healthy male physicians without
evidence of cardiovascular disease at enrollment, baseline
n-3 fatty acid blood levels were correlated inversely with
Diet and rheumatoid arthritis81
the subsequent risk of sudden cardiac death (70). Second-
ary prevention studies have shown that increased dietary
n-3 fatty acid intake, as fish or fish oil, lowers myocardial
re-infarction rates (for review see (71)). The DART trial
showed a 29% reduction in overall mortality in the 2 years
after myocardial infarction in the fish/fish oil group (72)
and the GISSI trial showed a 20% reduction in total mor-
tality and 45% reduction in sudden cardiac death 3.5 years
after myocardial infarction in the fish oil group (73). In
addition, the GISSI trial demonstrated that dietary supple-
mentation with fish oil resulted in significant reduction in
mortality by 3 months (74).
The reduction in sudden cardiac death is attributed to
electrical stabilization of cardiomyocytes by n-3 fatty acids
and thus lower rates of fatal cardiac arrhythmia (for review,
see (75)). This has been further demonstrated in preliminary
human cardiac electrophysiological studies. Intravenous in-
fusion of n-3 fatty acids followed by immediate electrophys-
iological testing showed a reduction in sustained ventricular
tachycardia (76). In addition, oral dietary supplementation
with 900 mg/day of n-3 fatty acids for 40 ? 11 days sup-
pressed inducible ventricular tachycardia at electrophysio-
logical testing (77).
Practicalities of Fish Oil Supplementation
perspective with regard to fish oil supplements. For antiin-
2.7 to 4 g of EPA ? DHA per day, coupled with advice to
avoid n-6 rich foods and increase n-3 fats in the background
diet. Our current practice is to recommend a 10 to 15 mL
supplement as it is generally easier to take and can be sup-
month for 15 mL/day of a commercial bottled fish body oil
product compared with A$45 to A$120 per month for cap-
sules that deliver the equivalent daily amounts of the same or
similar fish oil).
Table 3 Summary of Clinical Trials of n-3 Fatty Acid Supplementation in Rheumatoid Arthritis
Study and Design
Number of Patients for Analysis
and Duration of Study
n ? 62, 8 months
Western diet vs AA <90
Reduce n-6 fatty acid
Adam et al (39) Double blind (DB), placebo
controlled (PC), cross-over (CO)
Volker et al, 2000 (40) DB, PCn ? 50, 15 weeks
Kremer et al, 1995 (44) DB, PC, COn ? 49, 30 weeksNil
Geusens et al, 1994 (179) DB, PC, Pn ? 60, 52 weeksMaintain usual fat intake
Lau et al, 1993 (46) DB, PCn ? 64, 52 weeks initially
? further 12 weeks follow-up
n ? 67, 16 weeks
Kjeldsen-Kragh et al, 1992 (45) DB, PC, PNil
Nielsen et al, 1992 (180) DB, PC, Pn ? 51, 12 weeksNil
Skoldstam et al, 1992 (47) DB, PC, Pn ? 43, 24 weeksNil
Van der Tempel, 1990 (181) DB, PC, COn ? 16, 12 weeks Maintain usual fat intake
Kremer et al, 1990 (42) DB, PC, parallel (P)n ? 49, 24 weeksNil
Tulleken et al, 1990 (182) DB, PC, P
Cleland et al, 1988 (80) DB, PC, P
Kremer et al, 1987 (183) DB, PC, CO
n ? 27, 12 weeks
n ? 46, 12 weeks
n ? 33, 14 weeks
Kremer et al, 1985 (38) DB, PC, Pn ? 38 (6 patients excluded
as noncompliers), 12 weeks
Ratio PUFA to saturated
fatty acid 1.4:1
*Based on 65-kg subject.
82 L.K. Stamp, M.J. James, and L.G. Cleland
One potential obstacle to fish oil therapy is apprehen-
sion about its taste. The fishy taste can be minimized by
adding the fish oil to the surface of fruit or vegetable juice
in a small glass without stirring, then swallowing the con-
tents of the glass. This is followed immediately by more
juice from a second glass to remove any oil that may cause
an unpleasant aftertaste. We recommend taking the dose
immediately before a solid meal to facilitate passage of the
oil. One can also facilitate passage of oil by lying on one’s
left side for 15 minutes after the dose. This position favors
distribution of the oil to the passage from the stomach to
the small intestine (78). In the RA trials to date, capsules
have been used but a large number are required. In our
own Early Arthritis Clinic, about 80% of patients contin-
ued some form of fish oil supplementation in the long term
as found on follow-up of more than 3 years. About two-
thirds of these latter patients take un-encapsulated fish oil,
which is offered as the first-line supplementation strategy
(unpublished data). Importantly, no toxicities have been
associated with fish oil supplements.
Strategies for long-term n-3 fatty acid ingestion, which
involve practical, palatable, and inexpensive food options,
are also needed. We have demonstrated that novel n-3 fat-
enriched foods and fish can easily provide 1 g EPA ? DHA
with little or no change to dietary habits (50, 79). This
amount should provide a cardioprotective effect (cf, GISSI
study (73)). Where an antiinflammatory effect is sought,
these foods could be used in combination with a supplemen-
tary dose of fish oil.
As with DMARDs, the onset of action of fish oil is delayed
with effects being evident at 12 weeks but not at 4 or 8 weeks
after commencement (38, 80). In addition, there is no direct
dose-by-dose effect as with the analgesic action of NSAIDs.
Clinical benefits have been observed to last up to 6 weeks
after discontinuing therapy (42). These points need to be
explained to patients commencing fish oil therapy for antiin-
Daily n-3 Fatty Acid
30 mg n-3 fatty acids
per kg body weight
2.3 g/day n-3
Outcome Measure that Improved
Significantly in Fish Oil Group
TJC, SJC 2CRP in those on MTX
Able to be reduced in
those that improved
Overall improvement SJC, early
morning stiffness (EMS), HAQ, pain
score, patient global (PtG),
physician global (PhyG)
TJC, EMS, PtG, PhysG, physician
PtG and pain score as assessed by
physician in high dose group 47%
high-dose group able to reduce
DMARD and/or NSAID
Reduced requirement for NSAID with
no deterioration in clinical variables
RAI and EMS, Improvements lost
once NSAID stopped
EPA 4.6 DHA 2.5 Continued Continued diclofenac
until week 18 or 22
Able to be reduced in
Low-dose EPA 0.8 and
DHA 0.2, High-dose
EPA 1.7 and DHA
EPA 1.7 DHA 1.1
Varied as required
during study period
No patient on
Required NSAID used as
Continued in 1 group and
weaned off in 2 groups
after week 10
EPA 3.8 DHA 2.0
EPA 2.0 DHA 1.2EMS, TJC, CRP Continued any
EPA 1.8 DHA 1.2 50% patients able to reduce NSAID
TJC, RAI, improved grip strength,
Able to be reduced in
those that improved
EPA 2.0 DHA 1.3ContinuedContinued
Low-dose EPA 1.7
DHA 1.2* High-dose
EPA 3.5 DHA 2.4*
EPA 2.0 DHA 1.3
EPA 3.2 DHA 2.0
EPA 2.7 DHA 1.8
TJC, SJC, and mean grip strength in
low- and high-dose groups EMS
and PhysG in high-dose group only
SJC, RAI, joint pain index
ARA class, TJC, PhysG, time to
EPA 1.8 DHA 1.2ContinuedContinued
Diet and rheumatoid arthritis83
n-3 Fats and Risk of Developing RA
Dietary n-3 fats may favorably influence risk for developing
RA. A case-controlled study has shown a reduced risk for
developing RA in subjects consuming 2 or more fish meals
0.93) compared with subjects consuming less than 1 fish
meal per week (81). The Japanese, who have a high average
consumption of long-chain n-3 fats compared with Western
norms, have approximately one-third the incidence of RA
(82), despite a high prevalence of the HLA-DR alleles con-
taining the peptide binding groove configuration that is as-
sociated with susceptibility for RA (83, 84)
Long-chain n-3 fats, especially DHA, are an important
constituent of neural tissue. During pregnancy, n-3 fats are
transferred from the mother to the fetus. This can result in a
negative n-3 balance in the mother, which could contribute
to the propensity for RA to emerge or flare in the postpartum
inant contributor. Presumably to support optimally the con-
tinued rapid neural development that occurs in the infant,
breast milk is rich in n-3 fats (85). Continued maternal de-
pletion of n-3 fats associated with breastfeeding may thus
women who are breastfeeding (86). However, since the fetus
and infant appear to be especially vulnerable to the toxic
effects of excess fat-soluble vitamins, cod liver oil should not
be used in antiinflammatory doses during pregnancy. These
fat-soluble vitamins are present at acceptably low levels in
fish body oils.
Antioxidants, Vitamins, and RA
provide evidence for production of oxygen free radicals
within rheumatoid joints. These highly reactive oxygen spe-
cies are likely to be involved in joint damage in RA (89, 90).
Antioxidants have a protective role against tissue damage
caused by oxygen free radicals. In addition, TNF-? induces
the expression of IL-8 and collagenase through a mechanism
cells. This effect was at least partially inhibited by an antiox-
in RA (91). Despite this, there is little evidence that supple-
mentation with antioxidants (such as vitamin E, C, and sele-
nium) either alone (see below) or in combination (92) has a
significant clinical benefit in patients with RA.
Vitamin E (?-Tocopherol)
that involve free-radical intermediates in the reaction, their
activities can be influenced by antioxidants such as vitamin E
Vitamin E inhibits IL-1? production in resting and acti-
vated monocytes through inhibition of the 5-lipoxygenase
pathway (95, 96). In a transgenic mouse model of RA, vita-
min E supplementation inhibited IL-1? but not TNF-? pro-
duction. While there was no improvement in the intensity of
tion (97). In comparison, Venkatraman and Chu reported a
IL-1? in mice fed on a high vitamin E diet as compared with
mice fed a low vitamin E diet (98). In addition, using a mac-
rophage cell line, lipopolysaccharide-induced PGE2produc-
tion and COX-2 expression were inhibited by aspirin and
vitamin E (99).
Serum concentrations of vitamin E are similar in patients
with RA and controls and are negatively correlated with C-
reactive protein (CRP) (100). Human studies have reported
variable effects with vitamin E supplementation. A 12-week
study in 42 patients with RA reported a significant reduction
in pain, but no change in Ritchie Articular Index (RAI), du-
ration of morning stiffness, swollen joint count (SJC), or lab-
oratory parameters with vitamin E supplementation com-
pared with placebo (101). In a shorter 3-week study, there
was no difference between vitamin E supplementation and
diclofenac in 85 hospitalized RA patients (102).
Vitamin C (Ascorbic Acid)
Vitamin C is both an intracellular and an extracellular scav-
enger of free radicals. In rat adjuvant arthritis, supplementa-
tion with ascorbic acid leads to a reduction in paw volume,
arthritis score (103), and polymorphonuclear infiltration as
well as increased pain tolerance (104). Despite this, dietary
supplementation with vitamin C has not shown any clinical
benefit in patients with RA (105).
Selenium forms an important part of glutathione peroxidase,
of effects on the immune system via this pathway (for review,
see Peretz and coworkers (106)).
reduced compared with healthy controls (107-109). This
may, in part, be due to inadequate dietary intake of selenium
(110). Serum selenium levels appear to be lowest in patients
with longstanding active disease and a correlation between
serum selenium levels and the number of active joints has
been reported (111). Despite this, the effect of dietary sup-
plementation with selenium in patients with RA has been
variable. Several studies have reported no improvement in
and red blood cell selenium concentrations with dietary sup-
ers reported improvement in swollen and tender joint counts
and morning stiffness along with reduction in CRP with se-
lenium supplementation compared with placebo. However,
centrations did not return to normal levels (109). Thus the
and red cell concentrations of selenium respond to dietary
supplementation, levels in polymorphonuclear leukocytes
do not. This may at least in part explain the lack of clinical
benefit in response to selenium supplementation (115).
The biologically active form of vitamin B6is pyridoxal 5=-
phosphate (PLP). In patients with RA, plasma levels of vita-
L.K. Stamp, M.J. James, and L.G. Cleland
min B6are lower compared with healthy controls (116, 117).
increased catabolism of vitamin B6(118). Low plasma PLP
levels have been associated with higher TNF-? concentra-
tions (116), high CRP (117), and high erythrocyte sedimen-
tation rate (ESR) (118). Indices of disease severity, including
morning stiffness and degree of pain, have also been corre-
lated with plasma PLP levels (118). However, dietary supple-
mentation with vitamin B6does not result in clinical benefit
in patients with RA despite an increase in plasma PLP levels
Antioxidants and the Risk of Developing RA
In patients with RA, blood markers of antioxidant nutritional
status are lower than in normal controls (120). It has been
suggested that low antioxidant status is a risk factor for the
development of RA (121, 122). Furthermore, intake of cer-
tain antioxidant nutrients such as zinc and ?-cryptoxanthin
may protect against the development of RA (123).
Food Hypersensitivity and RA
Interest in food as a potential allergen has been raised by
anecdotal reports, which have a suggested a link between
certain foods and arthritis (124-126). Studies of dietary ma-
nipulation such as fasting, vegetarian diets, and elimination
diets have followed.
Elemental Diets and RA
Elemental diets aim to provide food in simpler components,
eg, protein as free amino acids, fat as medium-chain triglyc-
erides, and carbohydrates as small sugars. Such diets are
hypothesis that food allergy or intolerance is an important
factor in RA. General benefit has not been evident in several
clinical trials. Holst-Jensen and coworkers conducted a
6-month prospective, randomized controlled trial of 30 pa-
tients comparing an elemental diet and normal diet for 4
weeks (127). While there was a statistically significant im-
provement in average pain level and health assessment ques-
tionnaire (HAQ) score at the end of the 4-week period on the
elemental diet, this had disappeared by 3 months. None of
the objective parameters such as tender and swollen joint
counts or ESR improved and only 1 patient achieved com-
plete remission. Two other studies have shown similar small
improvements in some patients on elemental diets (128,
Vegetarian and Vegan Diets and RA
Vegetarian and vegan diets have been reported to improve
clinical symptoms in RA. Kjeldsen-Kragh and coworkers un-
dertook a 13-month trial in 27 patients starting with a 7- to
10-day subtotal fast. This was followed by gradual reintro-
duction of foods, with reelimination if they resulted in dete-
vegan diet for 3.5 months and then a lactovegetarian diet.
Twenty-six matched control patients consumed their normal
diet. In the treatment group, significant improvements were
noted in TJC, RAI, SJC, pain score, duration of morning
stiffness, grip strength, ESR, CRP, and HAQ score after 1
month. These benefits were sustained to the end of the 12-
month trial period (130). There was a 35% drop-out rate
during the trial with 22% due to disease flare (4/26 in the
treatment group and 7/26 in the control group). Other labo-
ratory variables such as platelet count, total IgG, IgM rheu-
matoid factor, C3, and C4 also decreased after 1 month on
the treatment protocol, although TNF-? levels remained un-
changed (131). Although 10 of the 27 patients on the dietary
protocol believed that food aggravated their arthritis symp-
in only 1 case (132).
Skoldstam and coworkers compared 16 patients with RA
on a 7- to 10-day fast followed by a 9-week lactovegetarian
diet with 10 patients with RA on their normal diet. They
found improvement in several clinical and biochemical pa-
rameters after the fasting in 5 of 15 patients, whereas only 1
patient had objective improvement after the lactovegetarian
diet (133). An uncooked vegan diet, rich in lactobacilli, re-
sulted in subjective improvement in arthritis symptoms but
no change in objective measures of disease activity. Compos-
ite disease activity indices (disease activity score (DAS) and
modified Paulus 20%) showed some improvement in the
treatment group (134). The diet was poorly tolerated with
half of the patients withdrawing due to adverse events
(mainly nausea and diarrhea). More recently, Hafstrom and
coworkers (135) examined the effects of a vegan diet free of
gluten with a well-balanced nonvegan diet for 1 year in 66
patients with active RA. Inclusion required RA for 2 to 10
years and patients were excluded if they had previously tried
dietary manipulation. Although the study was intended to
the control group completed at least 9 months of the study
diet. At 12 months, ACR20 response rates were 41% in the
vegan diet group versus 4% in the control group. However,
there was a similar degree of radiographic progression in
both groups. Interestingly, there was a significant mean re-
duction in serum IgG–antigliadin antibodies and IgG–?-lac-
toglobulin antibodies in the ACR responders on the vegan
positive clinical effects seen in the vegan diet group may
reflect a diminished immune response to food allergens
Four trials of fasting followed by vegetarian diets which
lasted at least 3 months have been subjected to systematic
review with the conclusion that there can be clinically signif-
icant beneficial long-term effect in RA with this dietary ma-
nipulation (136). However, as the diet required is strict and
there is no means currently to predict which patients will
respond, patient compliance may be problematic.
Mediterranean Diets and RA
effect of a Mediterranean diet versus the normal Western diet
in 56 patients with RA of at least 2 years duration (137). The
Mediterranean diet is high in consumption of cereals, vege-
tables, legumes, fruits, and olive oil. To improve compliance,
Diet and rheumatoid arthritis85
there was a significant reduction in the DAS28 and HAQ
scores and 2 measures of the Short Form (SF)36 (vitality and
requirement did not change.
Low-Fat Diets and RA
McDougall and coworkers postulated that the diet most
likely to be of benefit in RA contained no animal products
(vegan), as well as being low in all kinds of fats. In an uncon-
trolled study, 24 patients with RA were maintained on this
diet for 4 weeks. While pain, joint swelling, and joint tender-
of morning stiffness, ESR, or CRP (138). Clearly longer term
reached as to the benefit of this type of diet. Weight loss was
a feature of this and other dietary studies (138, 139) and may
is discussed in the section on weight loss below.
Fasting in RA
Total and subtotal fasting have been shown to reduce disease
activity in some patients with RA (130, 133, 140, 141). Clin-
ical and laboratory variables appear to improve within a few
days of commencing the fast and deteriorate on reintroduc-
tion of food. Despite its short-term positive effects, fasting is
no longer than 7 days and the positive effects are fleeting
compared with the chronic nature of RA. In addition, fasting
in patients with RA.
Food Allergy and RA
reports (124-126, 142, 143). In 2 of these cases, serum IgE
antibodies against components of milk and cheese were de-
tected (126) and a high serum IgE with positive skin prick
test to cereals was seen in another (124). IgG antibodies
against shrimp (143) and milk (142) have been detected in
other cases. In all of these reports, the patients responded
favorably to elimination of the offending food from the diet.
Van der Laar and coworkers reported 2 RA patients with
raised serum IgE levels to several foods, which reduced after
imal small intestine after the elimination (144). The associa-
tions between food, allergy, and RA, as well as potential un-
derlying mechanisms, have been reviewed by Van Der Laar
and Van Der Korst (145).
Elimination Diets and RA
Elimination diets seek to remove foods that are putatively
allergenic from the diet. They generally have as their founda-
tion foods that are thought to be of low allergenic potential.
Putative allergenic foods are excluded and then sequentially
reintroduced. Foods are deemed to be “allergenic” (or, in a
descriptive sense, more correctly, “arthritogenic”) if their
elimination results in decreased RA disease activity and sub-
sequent ingestion results in increased disease activity. These
studies are usually single-blinded as patients are aware of
what food they eat. Several trials using this design have
shown some benefit. In the study by Darlington and cowork-
ers, all medications except 1 g paracetamol 4 times daily and
2 placebo capsules were stopped for 2 weeks. Patients then
had either 6 weeks of dietary modification or 6 weeks of
normal diet followed by 6 weeks of dietary modification.
During the first week of dietary modification, patients were
Other foods considered more likely to cause symptoms, such
5 weeks until the patient was on a normal diet. In both
groups there were significant improvements in pain and ten-
der joint counts, during the dietary modification phase of the
study that were not observed during the placebo period
(146). Beri and coworkers used a more formal dietary regi-
men consisting of 2 weeks of an isocaloric diet containing
fruit, vegetables, sugar, and refined oil. This was followed by
sequential reintroduction of pulses (legumes, eg, peas and
beans), wheat, rice, milk/milk products, and finally, nonveg-
etarian food items. Importantly, in this study only 52% of
participants completed the diet protocol. Of these, 71% had
significant clinical improvement on the isocaloric diet, with
subsequent deterioration in all patients at some point during
the food reintroduction phase of the study (147). Both these
studies demonstrated that a proportion of patients improve
with dietary manipulation, that there are marked individual
responses, and that compliance may be a major limiting fac-
In a 10-week double-blind, controlled trial in RA patients,
Panush and coworkers compared the “Dong Diet” (elimina-
tion of red meat, fruit, herbs, spices, dairy products, alcohol,
additives, and preservatives) with a “placebo” diet (elimina-
tion of certain foods from within each major food group).
They found no overall benefit, although 2 of 11 patients on
the experimental diet improved dramatically and deterio-
rated on returning to their normal diet. The authors con-
cluded that, although there was no proof of benefit on group
analysis, some patients may benefit from dietary change
Van Der Laar and coworkers conducted a 12-week trial
in 94 patients. Both diets were artificial food supplements
meeting all essential nutritional requirements. The “allergen-
free” diet was devoid of putatively allergenic compounds,
additives, and preservatives, while the “allergen-restricted”
diet contained milk proteins and yellow azo colorings. While
there were subjective improvements in both groups, there
allergen-restricted and 6 in the allergen-free groups had
Guidance for Use of Exclusion Diets in RA
As discussed above, exclusion diets may help a small minor-
ity of patients. Unfortunately there are no clear predictors as
to which patients will respond. If a patient suspects or be-
lieves their arthritis may be the result of hypersensitivity to a
86 L.K. Stamp, M.J. James, and L.G. Cleland
particular food item or group, it may be worthwhile to assess
response to withdrawal in an n ? 1 study. Objective clinical
and laboratory signs of disease activity should be docu-
mented after 1 or more cycles of withdrawal and reintroduc-
tion of the suspected food item. The findings can then be
used as a basis for deciding whether the food item should be
avoided in the longer term.
Potential Mechanisms of Elimination, Fasting, and
A number of potential mechanisms have been postulated for
the improvements seen with these diets.
Psychological/Placebo Effects. A placebo response or psy-
study by Kjeldsen-Kragh of fasting followed by vegetarian
diet, psychological characteristics were examined (130).
They found that patients who participated in the study had
shorter disease duration and used less steroid and DMARD
therapy, perhaps suggesting milder disease compared with a
nonparticipant comparison group. They were more likely to
report food allergy, and had a higher perceived ability to
control their own health, and a lower perception that chance
affected their health and response to treatment. In addition,
diet responders believed less in ordinary medical treatment
than the diet nonresponders (150). These data suggest a con-
tribution by placebo effect, although one would not expect
the improvement to last a year if this was the entire explana-
tion. Darlington and coworkers detected a placebo response
in their study of dietary elimination but felt this was unlikely
by Panush (148) using the “Dong diet,” 83% of participants
thought they were receiving the experimental diet, implying
that the patients were truly unaware of whether they were in
the experimental or placebo groups. Interestingly, no overall
improvement was observed in this study. The problems in-
herent in achieving adequate blinding in many dietary stud-
to separate entirely the effects of changes in diet from psy-
chological elements associated with change and assessment.
Weight Loss and Immunosuppression due to Reduced En-
and coworkers (148)), patients lost weight while on the diet
protocol. Restriction of energy intake and malnutrition are
known to cause immunosuppression, which can ameliorate
RA (151). No correlation, however, has been found between
weight loss and the variables that improved in the studies by
Kjeldsen-Kragh (130) or Darlington (146), although Ka-
vanagh and coworkers did find a significant correlation be-
tween weight loss and improved grip strength in their study
(128). It should be noted that patients with RA commonly
lose weight during periods of disease activity, a process
thought to be due to cytokine-driven hypermetabolism
(152). Elevated endogenous plasma cortisol levels exert an
antiinflammatory effect and a rise in plasma cortisol with
fasting has been seen in healthy individuals. However, Uden
and coworkers found no change in mean plasma cortisol
levels in fasting patients with RA (141).
Alteration of Fatty Acid Composition. The relative propor-
tions of AA and EPA were increased in serum, platelets, and
neutrophils and the release of LTB4from neutrophils was
reduced in RA patients after a 1 week total fast (140). The
latter effect suggests 1 mechanism by which fasting may have
Plasma phospholipid EPA levels were reduced after vegan
and lactovegetarian diets in patients with RA. However, no
significant difference between diet responders and nonre-
sponders was shown (153).
Alteration in Serum IL-6. A 7-day fast in 10 patients with
RA resulted in a significant reduction in serum IL-6 (35.5
pg/mL versus 22.5 pg/mL, P ? 0.05) (154). In the rheuma-
toid synovium, levels of IL-6 are high, and this cytokine has
a role in regulating the acute phase response, activation of
T-cells, and the proliferation of synovial fibroblasts. As ex-
pected, reduced IL-6 was associated with reduced CRP and
Altered Gut Flora. A change in gut flora, due to a different
diet, may alter the array of bacteria present. Patients with RA
have a high carriage rate of Clostridium perfringens (155). A
surface membrane protein of the normal bowel commensal,
Proteus mirabilis, has also been found to contain an amino
acid sequence that closely resembles the “common epitope”
known to be associated with RA. Patients with RA have a
higher titer of antibodies against this amino acid sequence
(156). Antiproteus antibodies also are higher in patients with
RA than in controls (157). This evidence has suggested a
potential role for P. mirabilis in RA. In RA patients treated
with fasting and a 1-year vegetarian diet, Kjeldsen-Kragh and
coworkers found a significant decrease in antibodies titers
against Proteus (but not Escherichia coli) in patients on the
experimental diet compared with controls (158). The de-
crease in antibody titer was greater in patients who re-
sponded to the experimental diet than those who did not
respond and correlated with reduction in disease activity.
Peltonen and coworkers have also shown an alteration in
fecal flora (although no attempt was made to identify indi-
vidual bacterial species) that correlated with reduced disease
activity in RA patients on an uncooked, vegan diet (159).
Dietary Lectins. Lectins, which are contained in a number of
dietary staples such as rice, potato, and wheat, bind complex
in the gut. This, combined with their potential to cause poly-
clonal T-cell activation, may influence specific and nonspecific
immune/inflammatory responses (160).
Mucosal Barrier and Immune Function. The gut mucosa is
far more than a mechanical barrier or filter as it allows selective
entry of desirable nutrients, while excluding from systemic cir-
culation substances that are potentially antigenic. The gut has a
Diet and rheumatoid arthritis87
mucosa-associated lymphoid tissue (MALT). MALT includes
the highly concentrated aggregates of lymphocyte and antigen-
presenting cells found in Peyer’s patches, as well as interstitial
mediated through IgA secretion at the mucosal surface. The
MALT deals with the myriad of environmental antigens that
present at the gut surface in such a way as to confer protective
Table 4 Studies of Oral Type II Collagen in Rheumatoid Arthritis
Trentham et al,
n ? 60, 12
0.1 mg/day for 4
0.5 mg/day for
in TJC, and
Trend in favor of
in both TJC
in 20 ?g/day
No change in
No difference in
after 6 months
to Lack of
Collagen 0 Placebo
13% (reason not
Sieper et al,
n ? 90, 12
1 mg/day or 10
Nil in previous 2
1 mg/day 13%, 10
Barnett et al,
n ? 228, 24
20, 100, 500, or
20 ?g/day 20% 100
?g/day 10% 500
?g/day 13% 2500
n ? 92, 12
stable on MTX
Collagen 52% MTX
McKown et al,
n ? 190, 24
0.1 mg/day for 4
0.5 mg/day for
88L.K. Stamp, M.J. James, and L.G. Cleland
avoiding inefficient responses to innocuous agents. Antigens
that induce pathogenic cell-mediated inflammatory responses
when given systemically may elicit an anergic response when
presented at the mucosal surface, especially when infrequently
presented in large amounts. Alternatively, active tolerization
mediated by transforming growth factor (TGF)-? producing
age” of food or commensal antigens, which elicit a systemic
inflammatory or allergic response, is central to the food allergy
also offer opportunities to moderate established systemic in-
that can induce a tolerization response. This is discussed in the
Oral Tolerization and RA
The term oral tolerization refers to the chronic ingestion of
low-dose antigen, which leads to alteration of the immune
response when the antigen is subsequently encountered. In
tion of oral antigen similar to that found in joints (eg, type II
cytokines (eg, TGF-?) when the homologous antigen is pre-
sented to T-cells with specificity for the tolerizing material.
Since the immunomodulatory cytokines are released in re-
sponse to presentation of self-components within joints, an
antiinflammatory effect may be seen when the tolerizing an-
tigen differs from the arthritogenic antigen. This is known as
using type II collagen in RA (summarized in Table 4). Oral
collagen has been used as sole agent (162-164) and in combi-
nation with DMARDs (165). It is important to note that in the
initial trial by Trentham and coworkers, in which a favorable
effect of oral tolerization with heterologous chicken type II col-
lagen was reported, patients on average had relatively mild dis-
ease and there was no DMARD washout period (162). Both of
type II collagen in patients whose RA was stable resulted in
deterioration of disease (166). Importantly, there have been no
significant adverse effects and no development of anticollagen
antibodies to suggest sensitization (162).
Unfortunately the data to date have not established the
efficacy of oral tolerization. While there has been a trend
toward improvement in individual clinical trials, no statisti-
cally significant improvements have been shown. It may be
that the most appropriate dose of antigen required for oral
used a variety of doses ranging from 20 ?g/day to 10 mg/day
the clinical trials, there have been small numbers of patients
who have responded well to oral collagen therapy. Several
groups have looked for patient factors that may help predict
those who will respond. No association between rheumatoid
factor status or HLA-DR type and response has been found
(162, 163). Barnett and coworkers reported that IgA or IgG
response to treatment with oral collagen (164). Based on
be recommended for routine clinical practice.
It is possible that an alternative route of antigen delivery
may improve tolerization and clinical benefit. In this regard,
there has been research into nasal administration of antigen
in animal models (167-169). There have been no clinical
studies in RA using this approach to date.
Dietary manipulation is a way for patients to assume some
control over their own health and management of their dis-
ease. Patients should be able to expect advice from their
doctors regarding dietary therapies for which there is a high
level of evidence. There is a strong scientific rationale for use
mation as well as consistent evidence of symptomatic im-
provement in randomized controlled trials in RA and certain
other inflammatory diseases. Antioxidant supplementation,
while having face value plausibility, lacks a comparable evi-
dence base. Fasting, elimination, and elemental diets cannot
be regarded as having an established place in treatment but
may help individual patients. Their use needs to be assessed
by sequential withdrawal and rechallenge with formal docu-
mentation of subjective and objective parameters. Finally,
finitive evidence and reliable protocols are yet to be estab-
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