LUPUS ERYTHEMATOSUS AND NUTRITION: A REVIEW OF THE LITERATURE

LUPUS ERYTHEMATOSUS AND NUTRITION:

A REVIEW OF THE LITERATURE













Author:

© 2004 Amy C. Brown, PhD, RD

Department of Human Nutrition, Food, & Animal Sciences

University of Hawaii @ Manoa

1955 East-West Road, Rm 216

Honolulu, HI 96822


808/956-3846 ♦ 808/956-4883 (fax)

amybrown@hawaii.edu

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Lupus Erythematosus and Nutrition: A Review of the Literature
Amy C. Brown, PhD, RD*


The purpose of this paper was to search the scientific literature for dietary
compounds that alleviate or exacerbate symptoms of lupus erythematosus (LE) in both
animal and human models. A detailed literature review was undertaken to find articles
showing a relationship between LE and nutrition by using MEDLINE/INDEX MEDICUS
(1950 - March 2000) for English-language articles, followed by cross-referencing.
Aggravating substances appear to include excess calories, excess protein, high fat
(especially saturated and omega-6 polyunsaturated fatty acids), zinc, iron, and L-
canavanine found in alfalfa tablets. Possible beneficial dietary compounds include vitamin
E, vitamin A (beta-carotene), selenium, fish oils (omega-3 polyunsaturated fatty acids),
evening primrose oil, flaxseed, a plant herb (Tripterygium wilfordii), DHEA
(dehydroepiandrosterone), and calcium plus vitamin D (if taking corticosteroids). Some
people with systemic LE placed on food allergy elimination diets reported improvement in
their LE symptoms, however, this may be related to a decrease of other substances in the
diet. Also, although no direct evidence was reported on the beneficial effects of either
bromelain or a vegetarian diet (possibly allowing fish), it is suggested that they might be
beneficial. Limitations to this research are that the findings are based on relatively few
studies, many of which were without control groups or extrapolated from animal models.
No large-scale studies have been done with LE patients to substantiate the benefit, if any,
of these individual dietary interventions, and if they were conducted, the remission and
exacerbation pattern of LE may interfere with elucidating their effectiveness. Also, dietary
changes should not be attempted without a physician's approval/monitoring.

* Department of Human Nutrition, Food, & Animal Sciences, University of Hawaii at Manoa, Honolulu, HI.
Address reprint requests to Amy C. Brown, PhD, RD, Department of Human Nutrition, Food, & Animal Sciences, University of
Hawaii @ Manoa, Honolulu, HI 96822. Email: amybrown@hawaii.edu, 808/956-3846.

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Lupus Erythematosus and Nutrition: A Review of the Literature



The relationship between nutrition and lupus erythematosus (LE) remains elusive
especially since most autoimmune diseases are multifactorial in origin with genetic,
environmental, hormonal, viral, and psychoneurological influences all playing a role.1,2 It is
known that no specific diet for the treatment of LE exists; however, a review of the literature
investigating the influence of nutrition in both animals and humans suggests that certain
substances in the diet may aggravate or alleviate LE symptoms (Tables 1 & 2).

This article elaborates on many of the studies behind the various dietary
compounds listed in Tables 1 & 2 that may aggravate or alleviate LE symptoms. Although,
much of the research presented in this review article is based on animal studies, those
involving human experiments are also discussed. Human subjects are designated as
having discoid or systemic lupus erythematosus when specified in the literature, or "LE" if
no such designation was provided.


Possible Harmful Substances
Excess Energy. Most animal studies suggest that energy restriction ameliorates
autoimmune disease3,4 and increases longevity in New Zealand black or white mice
(NZB/NZW) which spontaneously develop an autoimmune disease resembling systemic
LE.5-8 The disease in these mice is manifested by synthesized antibodies to double
stranded DNA, high levels of circulating immune complexes (a marker of SLE clinical
activity), and deposition of the later in the renal glomerulus. As a result, glomerulonephritis
is the major cause of death with mortality rates averaging 50 percent by about 8.5 months.9

Caloric restriction delays the onset of glomerulonephritis in these mice, however,
this dietary manipulation is severe and initiated early - parameters that cannot be
duplicated in the human model since caloric restrictions would be equivalent to 25-35
percent or more of total intake prior to adolescence. The degree of energy restriction in
one mice study was even higher at 60 percent (at 2 months of age) versus the control
group allowed to feed ad libitum. At 14 months, the percentage of these mice still living
that had not died due to renal disease was 100 and 0 percent respectively.10 Although

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there are no studies showing the effect of caloric restriction in humans, Kipen reported that
SLE disease activity was associated with an increase in body mass index (BMI) over a
three year period in pre-menopausal women (n=55).11

In terms of animal models, the exact mechanisms by which energy restriction
benefits autoimmune conditions are still being explored. Safai-Kutti reported a reduction in
circulating immune complexes, occurring in mice eating an energy-restricted diet,12 while
Chandraseker observed a decrease in pro-inflammatory cytokines.13 Mizutani reported
that reducing calories to 32 percent or less than controls in autoimmune-prone mice
resulted in decreased immunoprecipitates, less coronary vascular lesions, and fewer
glomerular lesions.14 Restricting calories in mice was reported by Meydani to also reduce
prostaglandin E2 (PGE2) synthesis, another compound known for its proinflammatory
effects.15 One study restricting calories in mice and comparing them to a control group
reported a delay or inhibition of Sjogren's syndrome abnormalities, increased
immunosuppressive transforming growth hormone beta-1, and decreased cytokines.12

Excess Protein. Low-protein diets are also known to improve survival rates in
autoimmune mice.6 Mice fed a moderately restricted protein diet experienced longer
lasting immunologic functions and delayed development of autoimmunity when compared
to mice fed a normal protein diet.16

These results are not surprising since high protein intakes have been commonly
associated with acceleration of kidney damage in both autoimmune-prone humans and
experimental animals.17 Protein restriction has long been the standard treatment for renal
failure.18

After establishing that the amount of dietary protein influenced the outcome of
autoimmune-prone mice, researchers focused on specific types of protein. One study
indicated that limiting proteins containing high levels of phenylalanine and tyrosine, such as
those found in beef and dairy products, is beneficial to mice with a systemic LE-type
condition.4 Carr and others reported that 12 of 15 mice fed a casein-free diet were still
alive at 10 months, compared to only 1 in 10 mice on the control diet, and that casein-free
mice had less anti-DNA antibody and immunoreactants in the glomeruli.19 Another amino

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acid in question is tryptophan because elevated urinary excretion levels of tryptophan
metabolites were reported in 11 discoid lupus patients.20 Researchers have also
suggested that tryptophan breakdown products may lead to autoantibody production,21
and a research study investigating this possibility determined that a tryptophan-deficient
diet fed to lupus animals resulted in longer survival times.22

The average American ingests about 100 grams of protein a day, an amount that
can be reduced by almost half in healthy people without jeopardizing their protein
requirements. The Recommended Daily Allowances (RDA - 1989) for protein are 50
grams for women and 63 grams for men in the 25-50 years age group. Vegetarian diets
often automatically reduce dietary protein, and there was a case study reported of a patient
with SLE that went on a vegetarian diet (zero percent animal protein). Her antibody titers
returned to normal, urinary protein excretion decreased, and serum albumin rose. Although
protein dropped from 97 to 32 grams, so did calories (2295 to 1216) and grams of fat (70
to 50).23 The caloric reduction along with the fact that this is a single-case study and that
the possibility of remission exists does not warrant any dietary recommendation, however,
further study in this area is suggested.

High Fat (especially saturated fat and omega-6 polyunsaturated fatty acids). Diets
high in overall fat were associated with more severe autoimmune disease and decreased
life span in mice compared to a control group, whereas low fat diets were reported to
retard the development of disease.24,25

The type of dietary fat also dramatically affects the onset of autoimmune disease in
mice particularly if it consists of saturated or omega-6 polyunsaturated fatty acids.
Alexander reported that by 10 months of age, the percentage of mice still alive was; 94
percent of the fish oil (omega-3 polyunsaturated fatty acids) group, 35 percent of the mice
fed corn oil (omega-6 polyunsaturated fatty acids), and zero percent of the group fed
saturated fat in the form of lard (n-9 fatty acids).26 Fernandes supported these results with
a study showing that omega-3 fatty acids lowered the severity of autoimmune disease in
mice, while both saturated (n-9) and polyunsaturated (n-6) dietary lipids exacerbated the
disease.27

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Autoimmune-prone mice fed saturated fats experience more severe nephritis and
glomerular pathology.28,29 Several researchers have reported that mice fed saturated fat
diets produced higher levels of autoantibodies than those on low fat or high unsaturated fat
diets.28,30,31 High fat diets in mice have also been reported to increase proteinuria,24,32
prostaglandin (PGE2) production, cytokine levels (interleukin 6),33 and macrophage
function.24 These types of results have led some researchers to suggest that dietary fat,
especially saturated fat, restriction may be an effective therapeutic approach to murine
lupus nephritis.29

Several studies suggest that limiting essential omega-6 fatty acids and/or zinc may
suppress immune response, and therefore flare-ups. Hurd and Gilliam postulated that
some of the prostaglandins or related products of arachidonic acid (prostacyclin,
thromboxane, or lipoxgenase pathway products) may be necessary for the full expression
of autoimmunity.35 Essential fatty acid deficiency in mice resulted in an increased survival
time, delay in antibody production, and less severe renal disease.34-36 However,
researchers of another study reported that the survival of mice (MRL/l) was not affected by
polyunsaturated fatty acid deficiency.37 In studies that do show positive results, limiting
essential fatty acids may be beneficial because less are then available for the synthesis of
specific prostaglandins responsible for inflammation.

Thorner conducted one of the few human studies in which SLE patients reduced
their omega-6 polyunsaturated fatty acid intake. After one year, the number of patients with
active SLE dropped from 11 to 3. Spontaneous improvement, placebo effects, and lack of
a control group must be considered as possible influences in this and other studies
investigating the role of diet on LE symptoms. However, the researchers suggested the
possibility of reducing the intake of omega-6 polyunsaturated fatty acids as a non-
pharmacological approach to the treatment of patients with SLE.38 Foods high in omega-6
fatty acids are listed in Table 4.

Zinc. Zinc is important for enhancing the immune response, and MRL/1 mice on zinc-
deficient diets were reported to have increased survival times. Researchers observed a
decrease in lymphoproliferation,39 and a delayed expression of autoantibodies.40 It has

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been suggested that zinc deprivation results in increased serum corticosteroids which may
contribute to the decreased number of autoimmune disease symptoms.39

Iron. Only one animal study suggests that high iron intakes, seven times the requirement,
in mice resulted in high proteinuria, renal histopathology, and mortality. The researchers
theorized that excess iron may enhance the Haber-Weiss reaction causing free radical
damage of the tissues. During an inflammatory response, neutrophils and macrophages
release superoxide (O2 ) and hydrogen peroxide (H2O2), and the reaction of these
compounds with iron produces a highly toxic hydroxyl radical (OH ).41 A source of excess
iron for humans is ingestion of pre-natal vitamin/mineral supplements that often contain 30-
60 mg (Recommended Dietary Allowance (RDA) for women = 15 mg/day).

Alfalfa (L-Canavanine). Researchers studying the cholesterol-lowering effect of alfalfa
seeds observed signs of SLE-like symptoms in both laboratory animals and a few human
case studies.42-44 Two human patients were reported to experience symptoms of malaise,
lethargy, depression, and arthralgias after ingesting 8-15 alfalfa tablets daily.45 In vitro
experiments suggest that L-canavanine, an amino acid in alfalfa products, acts on
suppressor-inducer T cells to regulate antibody synthesis and lymphocyte proliferation.46
Feeding L-canavanine to autoimmune mice resulted in increased antibody production and
higher renal histology scores.47 However, the alfalfa tablets of one manufacturer tested
negative for canavanine (with a detection limit of 5 ppm), and alanine, an amino acid, has
previously been mistaken for canavanine.48



Possible Beneficial Substances
Vitamin E. Although animal studies on MRL/lpr mice show that vitamin E treatment delays
the onset of autoimmunity and extends mean survival time,49 treating LE patients with
vitamin E continues to be controversial. Vitamin E studies related to LE first started to
appear in the late 1940s, and a historical overview of the literature reveals that large
vitamin E doses may be beneficial in some cases, while dosages below 300 IU may not be

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sufficient.50 For example, four discoid LE patients in one study, receiving 900-1600 IU of
vitamin E daily, showed partial or complete clearing of rashes, while two patients receiving
only 300 IU daily had no benefit.51 Other human studies reporting either positive 5,52-57
or negative 58-61 results of vitamin E on discoid LE lesions are listed in Table 3.

Investigators warn that "while the effect of mixed tocopherols in LE is apparently
profound, often rapid and at times almost specific, the fact remains that recurrences are
not uncommon."62 Also, Vitamin E is a fat soluble vitamin that acts as an anticoagulant at
the high dosages used in these studies, much higher than the Reference Daily Intake (RDI)
of 30 IU (9 mg) alpha-TE. Dietary sources of vitamin E are listed in Table 4.

Vitamin A. Vitamin A-deficient LE animals were reported to experience more severe
lupus-like symptoms. Researchers attributed this observation to increased hyper-
gammaglobulinemia and an earlier onset of autoantibodies, both naturally occurring
thymocytoxic autoantibodies and IgM anti-erythrocyte antibodies.63 Three patients whose
skin lesions flared with sun exposure were given 50 mg of beta-carotene three times daily,
and experienced a clearing of all lesions starting within one week of treatment.64 Other
researchers reported that very high levels of vitamin A (100,000 U daily for 2 weeks) in
SLE patients resulted in an enhancement of antibody-dependent cell-mediated cytotoxicity,
natural killer cell activity and blastogenic response to mitogens.65
However patients should be cautious with extremely high levels of vitamin A unless they are
water-soluble, because ingesting excess vitamin A from animal sources may result in one
or more of the following symptoms: anemia, headache, dry skin, hair loss, nausea, lack of
appetite, bone pain, stunted growth in infants/children, pseudohydrocephalus, and death.
Table 4 lists vegetable sources high in vitamin A (beta-carotene). Although excess beta-
carotene from plant sources does not result in the symptoms elicited from animal sources,
it can produce hypercarotenemia turning the skin slightly orange.

Selenium (Se). Anti-inflammatory properties have been attributed to selenium, a natural
antioxidant.66 Supplementing the diets of auto-immune mice with selenium increases their
survival time, and although the mechanism by which selenium exerted this effect is unclear,

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there is a significantly higher level of natural killer cell activity in the selenium-supplemented
mice.67 It was also observed that low levels of blood glutathione-peroxidase (GSH-Px)
exist in some patients with systemic LE, and that GSH-Px activity increased slowly after
administering tablets containing 0.2 mg selenium (Na2SeO3) and 10 mg tocopherol
succinate for 6-8 weeks. Some researchers have suggested that physicians could check
GSH-Px activity and consider selenium and vitamin E supplementation in people with LE
or other conditions such as severe psoriasis, eczema, dermatitis herpetiforms, and liver
disease.60 Again, warnings against high intakes of selenium should be given to patients
since toxicity results in symptoms of diarrhea, vomiting, hair and nail loss, and lesions of
the nervous system and skin. Dietary sources of selenium are listed in Table 4.

Fish Oils. Fish oils retard, but do not entirely prevent, lupus-like disorders found in
autoimmune-prone mice. These mice eventually develop the illness, but at a slower rate
than controls. Fish oil supplementation appears to have an anti-inflammatory effect,68 and
prolongs the life of autoimmune-prone mice.7,69-76 The increased life span might be due to
delayed onset of renal disease since mice introduced to a fish oil diet as weanlings had an
almost total protection against renal disease. One possible mechanism related to the
beneficial effect of fish oil in autoimmune-prone mice may be related to its high omega-3
fatty acid content - eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

Omega-3 fatty acids inhibit the production of eicosanoids (pro-inflammatory
compounds such as prostaglandin E2 (PGE2) and leukotriene B4 (LTB4)), while fatty acids
from the omega-6 series have the opposite effect.77-80 Arachidonic acid, an omega-6 fatty
acid, is metabolized into pro-inflammatory eicosanoids.81-84 Omega-3 fatty acids can
displace arachidonic acid in the cell membranes,70,74 resulting in less PGE2 formation,
and compete with arachidonic acid for cyclooxygenase and lipoxygenase enzymes.69 This
competition shifts production to the non-inflammatory series-3 prostaglandins and series-5
leukotrienes that have been suggested to directly suppress immunologic and or
inflammatory mediators of murine lupus.69,70,80 Specifically, there is a reduced synthesis of
endogenous dienoic cyclooxygenase metabolites and leukotriene 4 (LT4), while increased
synthesis of trienoic PG and leukotriene 5 (LT5).69 Another factor is that omega-3 fatty

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acids are poor substrates for cyclooxygenase which is the rate-limiting step in the
synthesis of prostaglandins, particularly PGE2.78

Omega-3 fatty acids may also inhibit the inflammatory response by decreasing T-
cell activity and cytokine (stimulate prostaglandin production) concentration.85-87 Normally,
inflammation activates T cells and cytokines at the site of tissue injury and in the
circulation.82 Certain types of cytokines are also involved in peroxidation which is a
common final pathway in much of the tissue damage seen in intense inflammation.
Cytokines (IL -1 and TNF-alpha) generate H
-
2O2 and O2 in mesangial cells and
macrophages, and these can result in free radical damage to the tissues. Reactive oxygen
intermediates (ROI), implicated in immune-complex mediated glomerulonephritis, affect
glomerular filtration rate, impair sieving, and inhibit renal function. ROIs may react with
polyunsaturated fatty acids in cell membranes resulting in derivatives that attract
inflammatory cells that can further secrete inflammatory cytokines and growth factors.
Peroxidation of lipid membranes also leads to altered fluidity, and may change ion
transport and enzyme activities in target tissues such as renal cells.82 To help protect
vessels and organs from the damage of excess inflammation, some researchers have
suggested the administration of antioxidants such as vitamin E and selenium.81

The majority of animals studies show omega-3 fatty acids alleviating the severity of
autoimmune disease, but Table x shows only modest anti-inflammatory effects have been
reported in humans with LE.88-90 However, omega-3 fatty acids have been reported to
improve blood lipid values which is of benefit to patients with SLE who have a higher rate
of premature atherosclerosis than the general population.89,91,92 Despite the controversy
over whether or not omega-3 fatty acids benefit humans with autoimmune conditions,
Kinsella stated that hospital nutritional support, such as enteral and parenteral formulas in
addition to intravenous emulsions, may need to be modified for use in patients with
inflammatory reactions such as lupus erythematosus, rheumatoid arthritis, and multiple
sclerosis.93 Dietary sources of omega-3 fatty acids (EPA/DHA) are listed in Table 4.

Bromelain. Although no animal or human studies have been conducted on bromelain
related to LE, this complex of proteases from the pineapple plant has been known to act as

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