Alternative Medicine Review 2001 (Jun); 6 (5): 460–471 ~ FULL TEXT
Tom Patavino, MS, DC (Cand.), David M. Brady, DC, CCN, ND (Cand.)
Introduction
Systemic lupus erythematosus (SLE) is an autoimmune disease that imposes
multiple complications on an affected individual, the family, and the healthcare
provider who tries to control its manifestations. The etiology of this
disease is unknown and its course often differs from patient to patient.
To complicate matters further, SLE is often misdiagnosed or overlooked
by healthcare providers.
The diagnosis of SLE is presently based on criteria promulgated by the
American College of Rheumatology (ACR). The ACR defines the presence of
Lupus in patients presenting with four of the eleven signs or symptoms
outlined in Table 1.
There are several classifications of lupus. Discoid lupus erythematosus
is described as usually being limited to the skin and may, or may not,
present with a positive anti-nuclear antibody (ANA) test. It is a cutaneous
form of the disease; its symptoms include mucosal ulcerations of the nose,
mouth and vagina, butterfly rash, loss of hair, thick scarring discoid
lesions, skin pigmentation changes, hives and welts, and Raynaud's phenomena
(color changes in the fingertips ? red, white, or blue ? as a response
to stress and temperature change). [ 1 ]
Drug induced lupus is a condition characterized by lupus-like symptoms
that are a result of an adverse reaction to a prescription drug. In most
cases the symptoms disappear with discontinuation of the drug. Anticonvulsant
drugs, such as carbamazepine, have been particularly found to induce lupus-like
symptoms in patients. [ 2 ]
When the disease progresses and begins to involve one or multiple systems
of the body, it achieves the diagnosis of systemic lupus erythematosus.
SLE itself is divided into subtypes based on the severity of the disease.
The non-organ-threatening type of the disease presents with symptoms of
severe fatigue, dyspnea, fever, swollen glands and joints, muscle and joint
pain, and rashes or other skin conditions. The organ-threatening form of
the disease presents with the above symptoms, as well as involvement of
the heart, lungs, liver, and kidneys. The prognosis is less favorable than
the non-organ-threatening form of SLE and it is often these complications
that become terminal. [ 1 ]
Although SLE occurs in every age group and gender, the target population
is women between the ages of 15 and 45. It is estimated that in the United
States 80-92 percent of the lupus population is female. Drug-induced lupus
appears to be the only non-gender biased form of the disease, with men
being as equally susceptible as women. In addition, certain ethnic groups
? American Indians, African Americans, and Asians ? have a higher incidence
of the disease compared to other nationalities, with Hispanics and Caucasians
following. These prevalence trends also seem to exhibit variability based
on geographic location. For example, China and the Philippines show a greater
incidence than Japan. The incidence is nearly ten times greater in the
American Sioux tribes compared to other American Indian tribes. Although
these trends are inconsequential by themselves, when analyzing the global
incidence it is apparent the disease is on the rise and controlling it
is proving extremely difficult. [ 1 ]
SLE poses a major obstacle to the healthcare community because the etiology
and progression of the disease are so poorly understood. Conventional medicine,
with variable success, approaches the disease with various forms of drug
therapy. Corticosteroids, such as prednisone, are a staple in the treatment
protocol, with prednisone being used to both suppress the aggressive autoimmune
response and stabilize the resultant inflammation. Nonsteroidal anti-inflammatory
drugs (NSAIDS) are readily prescribed to aid the corticosteroids. Antimalarials,
such as hydroxychloroquine, are frequently used to subdue manifestations
of the disease. Finally, cytotoxic drugs like methotrexate, azathioprine,
and cyclophosphamide are used with the objective of reducing steroid dosage. [ 3-5 ]
Variable results are obtained from these conventional approaches and
side effects often must be weighed against the actual manifestation of
the disease. Prednisone has been found to cause a variety of side effects,
such as musculoskeletal complications like avascular necrosis and Cushinoid
symptoms. [ 6 ] The gastrointestinal damage
caused by the excessive use of NSAIDS is well documented. The cytotoxic
drugs often fail to achieve remission and cause side effects such as cytopenia,
hepatitis, nausea, vomiting, stomatitis, and central nervous system (CNS)
disturbance. [ 3,5 ]
With conventional medicine failing to make any significant breakthroughs,
it is both appropriate and rational to determine if alternative medicine
can make contributions to fill the void. At the present time, the use of
vitamins, minerals, dietary fatty acids, and the elimination of symptom-inducing
foods show great promise as possible treatment options for SLE. In addition,
the use of DHEA and Chinese medicine already appear to exhibit therapeutic
effects on SLE activity.
Natural Approaches to Lupus Treatment
Alternatives to conventional therapy treatments are becoming more popular
due to the inability to find a cure for SLE and a growing desire for a
treatment plan carrying a lower risk of adverse side effects.
DHEA
One alternative therapy gaining acceptance is the use of dehydroepiandrosterone
(DHEA). DHEA is a steroid molecule manufactured by the cholesterol-pregnenolone
pathway, and is an intermediate to androstenediol and androstenedione,
which have the potential to become either estrone or testosterone. The
physiological role of DHEA is not fully understood, but certain findings
suggest it may play an instrumental role in the pathogenesis of SLE. As
noted previously, this predominantly female-based disease is marked by
abnormally high levels of estrogen metabolites and the inactivation of
already low levels of testosterone. This suggests androgens may have an
effect on controlling these hormone abnormalities. [ 12,13 ]
DHEA levels are also low in the serum of SLE patients, implying that steroids
have a stronger link to the disease than anticipated. [ 14 ]
With that in mind, the role of the hormone and its various properties has
been explored in multiple studies.
DHEA was found to have various immunoregulatory effects, such as enhancing
IL-2 production and the subsequent proliferation of T-helper 1 cells, and
a decrease in anti-DNA antibodies in mouse models. [ 15 ]
A shift toward T-helper 1 dominance results in a decrease in pro-inflammatory
cytokines.
DHEA supplementation was also shown to be beneficial in a double-blind,
placebo-controlled study conducted by van Vollenhoven et al. DHEA, administered
at a dose of 200 mg/day for three months to 28 females with SLE, resulted
in a reduction in prednisone dosage, a lower occurrence of flare-ups, and
a decrease in activity of the disease based on the SLE disease activity
index. The same findings were not present with the placebo group, with
the condition of the patients either staying the same or deteriorating.
The exact mechanisms were not understood, but were believed to be related
to testosterone levels and IL-2 production. DHEA may have regulated the
abnormally low levels of these in the study group. The treatment was well
tolerated with a low toxicity profile; however, side effects of acne and
mild hirsutism occurred in a number of patients. Topical steroid treatment
was beneficial in most cases and no patient dropped out of the study due
to side effects. [ 16 ]
In another study, van Vollenhoven et al explored the effects of DHEA
in a double-blind, placebo-controlled clinical trial. SLE patients were
randomly divided into a DHEA or placebo group for six months. All patients
continued their prior adjunctive therapy of corticosteroids and immunosuppressives.
Exact dosages of medications were not revealed in the study, but it is
implied that differences among study participants were negligible. The
researchers found that the placebo group demonstrated significant loss
of bone density of the lumbosacral spine, probably due to the effects of
corticosteroid therapy. The test group received 200 mg/day of DHEA for
six months and maintained bone density throughout the course of the study.
This suggests DHEA may have an antiresorptive effect that may counteract
bone damage caused by corticosteroids. [ 17 ]
Bone mineral density levels were also found to have a direct correlation
to DHEA levels in a study conducted on 150 premenopausal SLE patients.
Patients with adequate serum levels of DHEA had significantly higher bone
mineral density levels compared to patients with low DHEA levels. Density
mass was determined by measuring the femoral necks and the lumbar spine.
The increased bone mineral density suggests DHEA acts as a protective mechanism
against early bone loss and subsequent onset of osteoporosis. This study
also showed serum DHEA levels had an inverse relationship with corticosteroid
therapy. The patients receiving higher doses of prednisone appeared to
have lower DHEA levels and decreased bone mineral densities compared to
the control group. The same findings were not apparent with testosterone
levels, bone mineral density, and steroid dosage, suggesting it was indeed
DHEA possessing these properties and not another hormone along the pathway. [ 18 ]
The relationship between DHEA and SLE was further explored in a one-year
study conducted on 50 SLE patients. [ 19 ] Thirty-seven
premenopausal and 13 postmenopausal women were given 200 mg DHEA once daily
and monitored throughout the course of the study. Thirty-four patients
were treated for six months, with 21 patients completing the full 12 months
of the study. Patients showed an increase in serum levels of DHEA, DHEA
sulfate, and testosterone in the first three months of therapy, and maintained
these levels throughout the study with continued supplementation. More
importantly, DHEA supplementation resulted in a decrease in SLE activity,
based on measurements using the SLE disease activity scores, and a reduction
in prednisone doses. Although benefits were apparent, DHEA therapy was
not without drawbacks. Sixty-two percent of the premenopausal woman in
the study suffered acne as a side effect, and a smaller group had mild
cases of hirsutism, consistent with the findings of van Vollenhoven. The
postmenopausal women suffered acne at a lower frequency, but had a greater
rate of breast tenderness, alopecia, and oily hair and skin compared to
the premenopausal group. Acne, the most common side effect, was controlled
in most of the woman by topical steroid treatments.
The role of DHEA was also explored to determine if it possesses antioxidant
properties. Considering the amount of free radical destruction that takes
place in SLE, any additional antioxidant protection would be beneficial.
A study was conducted using rats that were fed either a vitamin E deficient
diet supplemented with DHEA or a diet adequate in vitamin E with DHEA supplementation.
The study found DHEA did possess the antioxidant property of decreasing
iron-induced lipid peroxidation in the vitamin E deficient rats. This was
not the case in the rats fed adequate vitamin E diets. It was believed
antioxidant properties existed, but were masked by vitamin E, suggesting
the antioxidant effect may not be evidenced unless there is a vitamin E
deficiency. Although the vitamin E deficient rats showed some antioxidant
activity, they also had an increase in weight loss and the presence of
fatty enlarged kidneys, liver, and adrenal glands. DHEA may have the potential
to scavenge free radicals, especially in conditions of inadequate vitamin
E, but does not appear to spare vitamin E and prevent signs of a deficiency. [ 20 ]
The Role of Essential Fatty Acids
Diet plays a key role in response to many diseases, including SLE. The
role of essential fatty acids and dietary oils has been extensively examined
using both mice and human models. A study examined the effects of a mouse
diet with varying amounts of calories and the addition of fish oils (omega-3
fatty acids) and corn oil (omega-6 fatty acids), and their effects on an
induced antibody response. The mice were injected with sheep cells that
induced an overactive immune response, the formation of plaque-forming
cells, abnormal IL-1 and IL-2 activity, proteinuria, and subsequent death.
Mice fed a diet containing fish oil had lower levels of proteinuria, decreased
abnormal cytokine and interleukin activity, and better survival rates than
mice fed corn oil diets. These findings may be linked to omega-3 fish oil's
ability to inhibit the abnormal auto-immune activity of the B- and T-Lymphocytes
and abnormal interleukin expression. [ 21 ]
The omega-3 fatty acids eicosapentanoic acid (EPA) at 180 mg and docosahexanoic
acid (DHA) at 120 mg were administered to 12 SLE patients. Six g/day omega-3
fatty acids resulted in a decrease in arachidonic acid and its resultant
inflammation, which is usually high in SLE. Higher doses ? 18 g/day ? demonstrated
an additional positive effect on cholesterol. Beneficial HDL levels were
raised, while triglyceride and VLDL levels were lowered in the study group.
LDL levels were not altered significantly, but the omega-3 fatty acids
did show the potential to make an impact in controlling atherosclerotic
plaquing, a problem not only for SLE patients, but the general population
as well. [ 22 ]
Kelley found that fish oil had an effect on suppressing macrophage activity
and the production of cyclooxygenase metabolites that contribute to renal
damage in a mouse lupus model. Life span was significantly longer in mice
supplemented with fish oil, and symptoms of renal damage and lymphoproliferation
were delayed compared to the control group. It should be noted that fish
oil delayed the onset of the lupus symptoms, but the mice eventually succumbed
to the same kidney problems and eventual death as the control group, although
at a slower rate. [ 23 ]
Another animal study also found fish oil supplementation offered an
increased life span and renal protection; however, this study demonstrated
a finding that was not recognized in the earlier studies. There was a significant
difference in levels of the renal antioxidant enzymes catalase, glutathione
peroxidase, and superoxide dismutase in the mice fed corn oil versus those
fed fish oil. Fish oil-fed mice had higher renal levels of antioxidants,
which suggests omega-3 fatty acids may protect the kidneys from free radical
damage that manifest throughout the course of the disease. The corn oil-fed
mice did not demonstrate this effect. [ 24 ]
T-lymphocytes decline with age in mouse models, and this is believed
to be universal in the presentation of SLE in both mice and humans. Researchers
found no significant differences between T-lymphocyte activity in fish
oil- and corn oil-fed mice. However, when the oils were combined with a
calorie-restricted diet, the differences became apparent. The age-related
decline in T-lymphocyte numbers was greatly reduced in the mice fed fish
oil and the calorie-restricted diet. This was not the case with the corn
oil group. This study supports the finding of other researchers that the
onset of fatal kidney damage could be postponed by modulating the T-helper
1 and T-helper 2 ratios. [ 25 ]
The antioxidant effects of omega-3 and omega-6 fatty acids were the
focus of several studies by Venkatraman. In an initial study using a mouse-SLE
model, mice fed a diet of vitamin E and fish oil showed greater antioxidant
capacity compared to mice fed a vitamin E and corn oil diet. [ 26 ]
A further study focused on the combination of vitamin E and omega-3 fatty
acids to determine optimum dosage levels in experimentally-induced SLE
mice. The SLE mice had elevated serum levels of anti-DNA antibodies, IL-4,
IL-6, IL-10, IL-12, and TNF-a. (IL-4, IL-6 and IL-10 are involved in the
humoral immunity response and IL-12 is involved in cell-mediated immunity.)
Mice fed the fish oil diet and 75 IU of vitamin E demonstrated lower inflammatory
cytokines, prostaglandin E2 (PGE2), leukotriene B4 (LTB4), and thromboxane
B2 (TXB2). Mice fed a diet of fish oil and a higher dosage of 500 IU vitamin
E demonstrated these same findings, as well as the additional benefits
of lowering IL-6, IL-10, IL-12, and TNF-a. This study demonstrated that
the combination of fish oil and vitamin E has an impact on many of the
key mediators of SLE. [ 27 ]
Flaxseed oil, comprised of 70-percent omega-3 fatty acids, has been
shown to have a direct effect on the antibody profile of SLE patients.
Anti-cardiolipin and anti-DNA antibodies are elevated in SLE patients and
are used as diagnostic markers of the disease. It was found that mice fed
diets supplemented with flaxseed oil had reductions in both antibodies.
These findings were not noted in mice fed diets supplemented with other
oil sources, including safflower, Juniperus virginiana, fish, corn, or
soybean oils. Surprisingly, a high level of omega-3 fatty acid in the fish
oil did not show the same result, suggesting the effects were directly
related to another aspect of flaxseed oil besides the omega-3 content. [ 28 ]
Flaxseed oil was shown to be effective in lupus patients with nephritis.
Serum 1evels of creatinine were reduced and creatinine clearance rates
were improved with supplementation of flaxseed oil in quantities of 15-45
g/day. Thirty g/day seemed to be the most beneficial dosage, as 45 g/day
was thought to raise protein levels in the urine. Thirty g/day also demonstrated
the ability to lower total cholesterol by 11 percent and LDL cholesterol
by 12 percent. Higher dosages showed similar effects, but less significant
reductions. Blood viscosity was also reduced, which may improve proteinuria
by decreasing glomerular capillary permeability. [ 29 ]
Lupus nephritis patients have also demonstrated higher levels of platelet-activating
factor (PAF), which is linked to renal damage and consequential proteinuria.
Hall et al conducted a study on mice with laboratory-induced SLE, exploring
the effect of flaxseed oil. Mice fed a control diet consisting of mouse
chow and no additional supplementation experienced irreversible platelet
damage and premature death. The mice supplemented with flaxseed oil demonstrated
platelet aggregation inhibition and subsequently had longer life spans.
Proteinuria was also delayed by as much as four weeks compared to the control
group. This study suggests that, although flaxseed may not prevent the
inevitable manifestations of the disease, it prolonged the onset of damage
from PAF and increased the life span of the study group mice. [ 30 ]
Nutritional Status of Vitamins A and D
Supplementation with fat-soluble vitamins A and D may be indicated for
patients with SLE. One study examined serum levels of active vitamin D
(1,25(OH)2D3) in SLE, rheumatoid arthritis (RA), and osteoarthritis (OA)
patients. Levels of 1,25(OH)2D3 were normal in RA and OA patients, but
decreased in SLE patients. The best indicator of vitamin D status is believed
to be 1,25(OH)2D3, which is known to play a key role in calcium homeostasis
and immunoregulation by inhibition of lymphocyte activation and cytokine
release. No correlation was found with corticosteroid use and 1,25(OH)2D3
levels, so the low serum levels were believed to be due to the disease
itself. A possible explanation for the decreased vitamin D levels may be
linked to the lack of sunlight exposure in most SLE patients due to their
increased photosensitivity. The presence of deficiency suggests vitamin
D supplementation may be indicated in this population. [ 31 ]
Supplementation of vitamin A at 100,000 IU daily for two weeks showed
some beneficial immune responses in 10 women who participated in a study
conducted by Vien et al. This high dose of vitamin A demonstrated no significant
side effects and appeared to be tolerated by the participants. The supplementation
resulted in an increase in antibody-dependent cell-mediated cytotoxicity,
natural killer cell activity, and IL-2 response. The long-term effects
of vitamin A therapy and its impact on SLE have yet to be determined. [ 32 ]
Antioxidants
Free radical damage plays a significant role in the pathogenesis of
SLE. Several studies suggest antioxidant supplementation may improve the
disease status of SLE patients. High levels of lipid peroxidases were found
in SLE patients compared to healthy control patients [ 33 ]
and low levels of antioxidants were found in the serum of SLE patients. [ 34 ]
Comstock found that the antioxidants alpha-tocopherol, beta carotene, and
retinol were lower in patients with SLE, as well as RA, suggesting free
radical damage is an important component of the inflammatory disease process.
This also suggests RA and SLE patients may require additional supplementation
of antioxidants, such as vitamins A and E, and beta carotene. [ 34 ]
The effects of antioxidants on mice and rats also have been studied.
Rodents with MRL/ LPR (a lymphoproliferative disorder similar to SLE) were
supplemented five times weekly with a mixture of 40 mcg beta carotene,
200 mcg alpha-tocopheryl acetate, 400 mcg vitamin C, and 0.132 mcg selenium
in oil and compared to a control group of vitamin E-deficient rats. The
study group showed a decrease in anti-double stranded DNA(anti-dsDNA) titers
as well as a decrease in lymphoproliferation. This suggests antioxidants
may be beneficial in the treatment of SLE. [ 32 ]
An additional study on mice found that selenium supplementation at four
parts per million in drinking water improved natural killer cell activity
and survival rates of mice with lupus. Those mice supplemented with lower
or no selenium did not demonstrate this effect and consequently had shorter
life spans. [ 35 ]
Dietary Considerations
Diet may play a significant role in the course of SLE. An interest in
the use of non-sprouted alfalfa seeds as an anti-atherosclerotic and cholesterol-lowering
agent prompted several studies in the past few decades. Clinical observations
including pancytopenia and antinuclear antibody production in both primates
and humans led researchers to believe alfalfa may be linked to SLE. In
a study conducted by Bardana et al, 10 macaque monkeys were subjected to
diets that selectively included the addition or absence of alfalfa seeds.
It was found that the animals that ingested the alfalfa seeds developed
a variety of health problems. The most mild of these was the slight presence
of anti-dsDNA antibodies in the serum with no other clinical signs or symptoms.
Changes of greater significance included extreme elevations in laboratory
values of anti-dsDNA and ANA antibodies, signs of lethargy, anorexia, and
a macular facial rash. The alfalfa seeds were withdrawn and most of the
hematological factors reverted to normal with the exception of ANA and
anti-dsDNA antibodies, thus suggesting the presence of SLE. The subjects
were then reintroduced to a diet containing alfalfa seeds and the condition
was immediately exacerbated. Lethargy, alopecia, edema, and atherosclerotic
changes appeared in the first 30 days after reintroduction of alfalfa. [ 37 ]
This prompted the researchers to further explore the relationship between
alfalfa seeds and SLE. They concluded that the amino acid L-canavanine
was the key constituent in alfalfa that causes the exacerbation of SLE
signs and symptoms. L-canavanine is found in many legumes including soybean,
alfalfa, and clover, as well as onions. However, cooking and autoclaving
apparently destroy the lupus-eliciting effects without decreasing the lipid-lowering
properties found in the foods. [ 38 ]
Food allergies and sensitivities have been shown to have an adverse
impact on rheumatoid arthritis, which is similar in many ways to SLE in
both treatment and flare-up activity. [ 39,40 ]
The discovery and elimination of possible food triggers may prove to be
beneficial in SLE as well.
Traditional Chinese Herbal Medicine
Traditional Chinese medicine has approached SLE by using herbal remedies
as a primary treatment option. Tripterygium wilfordii Hook F (TwHF), a
vine-like plant that grows in southern China, is one of the most studied
herbs in Chinese medicine for the treatment of SLE. TwHF has been found
to inhibit IL-2, interferon-1, and PGE2. More importantly, symptoms of
fatigue, arthralgia, fever, and abnormal lab findings were normalized.
Prednisone requirements were reduced by 50 percent by subjects taking TwHF. [ 41 ]
Although benefits were apparent with TwHF treatment, its usage was not
without side effects. Common side effects included stomach upset, diarrhea,
skin rash, and change in skin pigmentation. These effects were controllable
with dosage adjustment and many symptoms ceased without intervention. However,
other side effects of this herb were more serious and difficult to control,
including reversible infertility in men41 and amenorrhea in women. [ 42
] Toxicity
was also questionable with overdose being linked to myocardial and intestinal
damage and renal failure. Although TwHF has been shown to have beneficial
effects as a treatment for SLE, its dosage must be monitored closely to
avoid toxic outcomes. [ 42 ]
The effects of other herbs have been tested on mice with hopes of reducing
the necessity for steroids. Chen et al tested the effects of several popular
Chinese herbs, including Atractylodes ovata, Angelica sinensis, Cordyceps
sinensis, Ligustrum lucidum, and Codonopsis pilosula. Extracts were prepared
by decocting the dry herb with boiling water for 60 minutes and condensed
to a concentration of 1 g/mL. The extracts were then mixed with mouse chow
and results were recorded. Of the herbs tested, C. sinensis proved to be
one of the most effective at inhibiting anti-dsDNA antibodies and prolonging
the life span of the affected mice. Although the effects were apparent,
the actual mechanism causing these effects has yet to be determined. [ 43 ]
Conclusions
SLE has proven to be a difficult disease to manage because little is
known about its etiology. Finding an appropriate treatment has created
difficulty for the healthcare provider. What is known is that SLE can affect
any organ system in the body and every patient's response is unique. NSAIDS,
corticosteroids, antimalarials, and cytotoxic agents can be beneficial
to some patients and of little help to others. In addition, side effects
often outweigh benefits and create complications of their own. Chinese
medicine and DHEA may be viable alternatives as they have both demonstrated
the ability to reduce disease activity and decrease prednisone necessity.
However, long-term safety and appropriate dosage has not been established
to date. Additional clinical trials and appropriately designed studies
must be performed.
Antioxidant and omega-3 fatty acid supplementation have been shown to
reduce free radical damage and inflammation, improve immunoregulation,
and decrease cardiovascular and renal disease risk. Testing for food and
drug allergies may benefit a certain population of SLE patients. Despite
the inability to find a cure for SLE, research suggests alternative methods
may benefit those who fail to respond to conventional drug-based therapies
or who wish to offset the potential side effects of conventional medications.
It is up to the patient and their healthcare provider to explore all treatment
options, both conventional and alternative, in an attempt to most appropriately
control the manifestations of SLE in an individual patient.
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