Lupus: Systemic Lupus Erythematosus (SLE)
CONVENTIONAL MEDICINE’S APPROACH TO LUPUS TREATMENT
Since lupus potentially targets multiple organ systems, the type of treatment should be tailored for each individual person. Doctors may prescribe one, two, or more medicines at a time to maximize treatment response. An effective overall treatment strategy includes maintaining a healthy lifestyle – which may include conventional medicine, complementary medicine, exercise, good nutrition, and avoiding smoking and excessive sunlight – in order to reduce the frequency and severity of lupus flares. It is important to consider both the positive and detrimental effects of any treatment type before commencing a treatment plan.
Several categories of conventional medications are available that reduce inflammation, which is the chief cause of symptoms in lupus. Many of these medicines are often quite effective at reducing symptoms and preventing severe flare-ups. Unfortunately, these medicines are commonly associated with significant adverse long-term side effects.
Corticosteroids (glucocorticoids) are one type of steroid with powerful, anti-inflammatory effects. Synthetic corticosteroids mimic the effects of natural corticosteroids produced in the body and effectively reduce inflammation in people with lupus.
The most common corticosteroid medicine prescribed to treat lupus is prednisone. It may be taken orally in pill form, or injected into the skin to treat rashes, or intramuscularly (IM) to treat muscle inflammation. Other corticosteroids include hydrocortisone, dexamethasone, and methylprednisolone.
The possible side effects of corticosteroids include easy bruising; fat redistribution leading to an increase in fat around the abdomen; weight-gain and insulin resistance; and psychological changes ranging from irritability and depression to euphoria. They may also lead to increased risk of complications from diabetes, high blood pressure, glaucoma, and may cause elevated triglyceride and cholesterol levels. If taken over the long term, corticosteroids cause bone loss and therefore leads to an elevated risk of bone fracture. Due to effects on triglyceride and cholesterol, long-term corticosteroid use could also contribute to an increased risk for atherosclerosis (Doria 2003).
Due to these potentially severe side effects, the lowest dose of corticosteroids that provides symptom relief is prescribed. Injected corticosteroids are usually only used to treat very severe disease flares; once symptoms come under control, oral administration is resumed (Doria 2003; Cameron 1999).
Like corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) also suppress inflammation. However, NSAIDs are less effective for individuals with severe lupus than corticosteroids. NSAIDs, of which there are more than 20 types available, are both anti-inflammatory and analgesic, meaning they provide pain relief as well as reduce inflammation. Examples of NSAIDs include ibuprofen and naproxen. Although adverse effects are possible, and these risks are elevated in people with lupus, administration of NSAIDS with close monitoring by physicians can be helpful (Horizon 2004).
NSAIDs operate by inhibiting the secretion of leukotrienes and prostaglandins that cause inflammation and pain. Possible side effects include stomach upset, nausea, and even gastrointestinal bleeding; fluid retention; kidney damage, and increases in blood pressure and heart attack risk (Bjarnason 1993).
Aspirin may be particularly helpful in individuals who have anti-phosopholipid antibodies, which can make blood particularly "sticky" and prone to clotting. In the case of patients who are discovered to have anti-phospholipid antibodies without any known thrombotic problems, the question of preventative (prophylactic) treatment is unresolved. Currently, aspirin is the general recommendation (Bruce 2005).
Due to aspirin’s blood thinning, anti-inflammatory, and analgesic effects, doctors may recommend taking low-dose aspirin to reduce the risk of heart disease in people with lupus and relieve the pain of aching joints (Verheugt 2011).
Although the original purpose was to treat the parasitic disease malaria, it was discovered more than 50 years ago that anti-malarial drugs were also effective in treating the symptoms of lupus through minor immune suppression. In people with lupus, these drugs have been shown to reduce inflammation in the lining of the lung (pleurisy) and heart (pericarditis), improve joint and muscle pain, and reduce fever and fatigue. Examples of anti-malarials include chloroquine, hydroxychloroquine, and quinacrine (Ben-Zvi 2011; Chang 2011; Yildirim-Toruner 2011).
Possible side effects include gastrointestinal symptoms like nausea, vomiting, diarrhea, stomach cramps; headache, dizziness, and irritability; and the skin may darken in color and become very dry (Yildirim-Toruner 2011).
Immune System Modulators
Immune system modulators treat lupus by altering the number or function of immune cells. As lupus is an immune-mediated disease, this approach is often effective.
Some immune system modulating drugs globally suppress the immune system, and are thus called immunosupressives. While the self-reactive immune cells are suppressed, the cells that fight against infections are also inhibited, which can lead to increased susceptibility to infections. Potentially severe side effect may occur with all immunosuppressive drugs. Examples of commonly prescribed immunosuppressive drugs include the following:
Cyclophosphamidehas been used for several decades and is quite effective in treating lupus-related kidney disease. However, the side effects of cyclophosphamide can be severe and include nausea, vomiting, infertility, and hair loss. One study indicates that low-dose cyclophosphamide is still effective in treating individuals with lupus nephritis (Mitwalli 2011).
This medicine is newer, more effective, and causes fewer side effects than cyclophosphamide. Due to these positive characteristics, mycophenolate mofetil has replaced cyclophosphamide as the first-line drug for the treatment of lupus (Walsh 2007; Shum 2011; Hahn 2011).
Azathioprine is an immunosuppressive drug that also has fewer severe side effects than cyclophosphamide, and overall, data suggests that it is similar in effectiveness (Houssiau 2010) .
When an antibody "sticks" to the surface of a cell, it either blocks its function and/or tags the cell for removal from the body. Scientists have taken advantage of this quality of antibodies to design ones that stick to and induce the clearance of many different cell types, including B and T cells.
Monoclonal antibodies are created through a complex process involving culturing specialized immune cells with disease-specific stimuli (antigens) and purifying the antibodies that are produced as a result.
Monoclonal antibodies represent one of the greatest advancements in lupus treatment in recent history. The advent of monoclonal antibodies targeted towards receptors on the surface of B-cells allows physicians to turn the immune system against itself, in a sense, and eradicate self-reactive B-cells that underlie lupus pathology.
The Food and Drug Administration (FDA) has approved a few of these drugs to treat some diseases, especially certain types of cancer. Monoclonal antibodies also show promise as drugs to treat lupus.
One monoclonal antibody drug recently approved by the FDA to treat lupus is belimumab, which targets B-cell activating factor (BAFF), a protein involved in activation, differentiation, and proliferation of B-cells (Thanou-Stavraki 2011; fda.gov 2011; Sabahi 2006). The FDA’s approval of belimumab for the treatment of lupus is a groundbreaking achievement, as this is the first new drug developed specifically for lupus that has been approved for the last 50 years (Thanou-Stavraki 2011). Belimumab is co-marketed by Human Genome Sciences and GlaxoSmithKline under the name Benlysta®, with cost estimates exceeding $30,000 annually. However, insurance should cover this therapy in most cases, as few new therapeutic options for lupus exist (Pollack 2010).
Rituximab is also a monoclonal antibody drug that targets a receptor on B-cell surfaces called CD20, thereby causing the immune system to destroy B-cells. It was originally approved to treat lymphoma, and may be effective in other diseases characterized by too many or malfunctional B-cells, including lupus. Currently, studies are mixed as to whether this drug is effective in treating lupus (Haubitz 2010). Rituximab is not approved to treat lupus, but is often used off-label for this purpose by many physicians.
Other monoclonal antibody drugs that may be effective in treating lupus and are still being studied include epratuzumab, abetimus, ocrelizumab, and atacicept, all of which target B cells (Haubitz 2010). Additional drugs are being developed and tested with targets such as T cells and pro-inflammatory proteins.
Currently, monoclonal antibody drugs face several challenges and may cause adverse reactions in some patients. However, scientists are quickly elucidating the role of particular proteins and receptors in the molecular physiology of lupus and it is very likely that monoclonal antibody therapy will become much more efficacious in the near future.
A Novel Approach: Stem Cells
A stem cell is unique in that it is a nonspecific cell type and has the potential to develop into many different types of specialized cells. These cells can divide and produce another stem cell to replenish itself or grow into a specialized cell, such as a nerve cell, brain cell, or a B cell.
Stem cell transplantation has the potential to revolutionize the treatment of several types of diseases. In this procedure, stem cells are taken from a person, grown in the laboratory into specialized cells, and then transplanted back into the individuals to replace diseased cells. To treat lupus, one approach is to take blood stem cells from a person with lupus and grow them in the laboratory into healthy new B and T cells that do not attack self-tissues. The next step is to replace the autoimmune B and T cells in an individual with the individual’s own new, healthy B and T cells.
This general approach is called autologous hematopoietic stem cell transplantation. The word "autologous" refers to the fact that the transplanted blood cells are derived from the person’s own stem cells; "hematopoietic" refers to the fact that the type of stem cell used is the precursor of blood cells like B and T cells. As of 2011, approximately 200 stem cell transplantations for the treatment of lupus have taken place (Illei 2011).
Data regarding the safety and efficacy of autologous stem cell transplantation is not yet plentiful, but some studies suggest that this treatment approach may be promising.
For example, in one small clinical study conducted in China, the disease status of almost 65% of patients did not get any worse over 7 years (Song 2011). A comprehensive review of several studies that investigated autologous hematopoietic stem cell transplantation revealed that, in total, 81% of those that survived at least 3 years beyond the procedure showed some positive response to treatment (Gratwohl 2005). However, it is important to note that this analysis also found that an average of 11% of people who participated in these types of studies ultimately died because of transplant-related causes.
Stem cell transplantation is currently reserved for individuals with very severe disease who have not responded to conventional lupus treatments. In this population specifically, a remarkable 50% probability of 5-year disease free survival was achieved in the two largest studies to date exploring stem cell transplantation as a therapeutic option for lupus (Illei 2011).
THE INFLUENCE OF LIFESTYLE ON DISEASE ACTIVITY
Lifestyle, including diet, physical activity, and stress levels, can have a potent effect on many different chronic diseases, including lupus. A healthy lifestyle is an important factor in preventing flares, reducing disease severity, and improving overall quality-of-life.
The level of stress an individual with lupus experiences can significantly affect disease. Whether this stress comes from work, finances, relationships, or from managing this chronic disease, it can trigger flares or worsen lupus severity. A recent study found that the people with lupus who had a greater ability to cope with stress reported a greater quality-of-life (Hyphantis 2011). Additional data suggests that people who participate in a short stress-management program may have less pain (Greco 2004).
Ultra-violet (UV) light from the sun can cause or exacerbate the skin lesions often associated with lupus, and therefore avoiding or reducing exposure to the sun may be necessary for some people to avoid triggering these symptoms. One study found that photosensitivity was tightly linked with lupus disease, irrespective of the type of lupus, the level of serum autoantibodies, and use of anti-inflammatory medications (Sanders 2003). Fortunately, avoiding sun exposure or applying sunscreen is quite effective in preventing the damaging effects of UV light (Kuhn 2011). Ironically, the need to avoid exposure to sunlight may exacerbate the widespread vitamin D deficiency in lupus patients.
Exercising regularly is important for everyone’s health, but is especially important for individuals with lupus. Exercise helps prevent inflamed joints from becoming excessively stiff and keeps muscles, bones, and cartilage strong (Chilibeck 1995). Physical activity has also been shown to improve physical fitness in individuals with lupus, but can also help improve feelings of depression and overall quality-of-life (Carvalho 2005). Exercise can be daunting to those who are already feeling ill because of lupus, but remaining active is an important part of remaining as healthy as possible, even during flares. Those feeling too ill for more vigorous exercise can participate in gentle range-of-motion exercises so that muscles and joints can remain as flexible as possible.
One small pilot study with individuals with lupus confirmed that both aerobic exercise and the more gentle range-of-motion exercises are safe for people with lupus and did not worsen signs or symptoms (Ramsey-Goldman 2000).
NUTRITION AND LUPUS DISEASE ACTIVITY
Vitamin D is an essential nutrient, and the precursor to the active form is produced in the skin after absorbing ultra-violet light. Other sources of vitamin D include fatty fish like salmon and mackerel; fortified foods like margarine, milk, and breakfast cereals; and vitamin D supplements (Berdanier 2008).
Studies have shown that vitamin D may be important in reducing the risk of lupus (Cantorna 2004). It has been shown that higher blood levels of vitamin d are associated with less severe lupus disease activity (Amital 2010).
Two observational studies found that women with systemic lupus erythematosus have significantly lower levels of 25-hydroxy vitamin D (Toloza 2010; Borba 2009). Another study found that, while 22% of healthy control women had a deficiency in vitamin D, 69% of women with lupus exhibited a deficiency in this vitamin (Ritterhouse 2011).
Reduced levels of vitamin D in people with lupus may be due to one or both of two possible scenarios:
- The deficiency is related to the disease itself; or
- The deficiency is caused/exacerbated by avoiding sun exposure due to increased photosensitivity of individuals with lupus.
As discussed above, lupus and some of its treatments can cause bone loss and lead to osteoporosis. Healthy levels of vitamin D are necessary to help the body absorb calcium and keep bones as strong as possible and this is especially important in individuals with lupus.
Life Extension suggests that 25-hydroxyvitamin D levels be kept between 50 and 80 ng/ml for optimal health. This usually necessitates supplementation with 5,000 – 8,000 IU vitamin D daily for most individuals. However, supplemental doses should always be determined based upon blood test results.
The oil from fatty fish, such as mackerel, tuna, salmon, and halibut, is especially rich in omega-3 fatty acids (Kris-Etherton 2000). Fish oil is rich in two types of omega-3 fatty acids: docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA).
Omega-3 fatty acids, also sometimes referred to as polyunsaturated fatty acids (PUFAs), promote health in a number of ways. EPA and DHA are of particular interest in autoimmune diseases, including lupus.
Similar to vitamins, the body needs EPA and DHA, but can only produce them in very limited quantities. Therefore, these fatty acids must be included in the diet in adequate amounts (Connor 2000).
Recent evidence has revealed a critical role for EPA and DHA in establishing balanced immunity in autoimmune disease. Experimental studies found that EPA was able to induce immune cells into a regulatory phenotype, thus countering the action of aggressive effector immune cells (Iwami 2011).
Two clinical studies found that taking fish oil reduced lupus severity (Duffy 2004; Walton 1991). Another study found that taking fish oil reduced the level of serum lipids in people with lupus (Clark 1993), which may be useful as they are at a greater risk of developing heart disease.
The ratio between inflammatory omega-6 fatty acids and anti-inflammatory omega-3 fatty acids in the blood is of critical importance in autoimmune diseases. If the ratio is too high, disease activity may increase (Simopoulos 2008). Life Extension recommends that everyone strive to maintain an omega-6 to omega-3 ratio of 4:1 or lower. Readers can learn more about the importance of the omega-6 to omega-3 ratio and how to test it in the Life Extension Magazine article entitled "Optimize Your Omega-3 Status."
Minerals and Vitamins
There are several forms of vitamin E, 4 tocopherols and 4 tocotrienols, each of which has different levels of activity in the human body. Vitamin E has been shown to reduce several different markers of inflammation in the body, including inflammatory cytokines (Singh 2005). Since inflammation is responsible for the widespread tissue damage in lupus, antioxidant vitamins may aid in prevention or delay of the disease.
Vitamin E helps stabilize membranes of lysosomes, or immune cells that contain destructive enzymes used to fight intruders. When membranes are unstable, these enzymes cause damage to surrounding healthy tissue. Vitamin E can help prevent the onset of autoimmune attacks by stabilizing membranes of lysosomes (Ayres 1978). The symptoms of mice with lupus that were treated with vitamin E greatly improved. The mice lived longer, immune cell activity was normalized, anti-DNA antibodies were reduced, and kidney function improved (Weimann 1999).
One study indicates that vitamin E can reduce the level of autoantibodies in lupus patients (Maeshima 2007), but further studies are needed to confirm these effects. A case report of two patients indicates that a topical formula containing vitamin E improves the health of skin in people with discoid lupus erythematosus (Yildirim-Toruner 2011).
The active form of vitamin A, called retinol, is important for healthy skin, bones, and soft tissues (Coates 2010), and supports healthy immune function (Harbige 1996). Since people with lupus have an abnormally functioning immune system and a higher risk of osteoporosis, healthy vitamin A levels are especially important for this population. Interestingly, one study showed that people with lupus consumed less vitamin A in their diets than age-matched healthy controls, which may contribute to a vitamin A deficiency (Bae 2002).
Consumption of beta-carotene, a vitamin A precursor, is an ideal way to ensure that vitamin A levels are sufficient while simultaneously avoiding vitamin A toxicity. The body will convert beta-carotene into active vitamin A as necessary and excrete any excess.
Plants and Herbs
Curcumin, a bioactive derivative of the spice turmeric, has been tested over the last several years for its antioxidant, anti-cancer, and anti-inflammatory clinical properties. Curcumin decreases the ability of lupus autoantibodies to bind their specific antigens an average of 52% (Kurien 2010). The damaging inflammation of lupus-mediated injury is facilitated by the binding of autoantibodies to protein and nucleic acid antigens. Therefore, successful blocking of antigen/autoantibody binding suppresses inflammation before it even begins.
Experimental studies have revealed a considerable role for curcumin in modulating inflammatory cross-talk between cells of the immune system by suppressing cytokines such as IL-1beta, IL-6, IL-12 and TNFα (Bright 2007). Moreover, a recent animal model of an autoimmune disease identified NFkβ suppression as a key mechanism behind curcumin’s anti-inflammatory action.
A clinical trial tested the effects of curcumin in 24 patients with the lupus-associated kidney disease lupus nephritis. One group of patients took 500 mg of turmeric daily over a 3-month period, which is equivalent to a daily curcumin dose of 22.1 mg. Compared to the placebo control group, the turmeric group exhibited significant improvement in proteinuria (Khajehdehi 2011).
Although some clinical studies have been conducted showing some signs and symptoms are reduced in some autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, clinical studies have not yet been conducted to determine if curcumin has a similar effect with lupus (Bright 2007). However, these results are promising and suggest potential beneficial effects of curcumin in people with lupus.
Ginkgo biloba, or more simply "ginkgo", is an herb that has been used for thousands of years in traditional Chinese medicine. This nutrient is often prepared by making an extract from the dried leaves. These extracts contain high concentrations of molecules called flavonoids and terpenoids, which are antioxidants and improve blood flow, respectively (McKenna 2001).
A clinical study revealed that taking 120 mg of Ginkgo biloba extract three times per day for 10 weeks significantly reduced the number of Raynaud’s phenomenon attacks, a set of symptoms that often affect people with lupus (Muir 2002).
Pine bark extract
There is evidence that extract from the bark of the pine tree (Pinus pinaster) helps improve lupus inflammation, although more information is likely needed to make definite conclusions about this ingredient.
One study found that administration of pine bark extract reduced oxidative stress and improved lupus signs and symptoms in six patients that received the supplement in addition to prescription medications compared to a placebo group (Stefanescu 2001). Specifically, the patients who took pine bark extract exhibited a reduction in SLEDAI score, meaning that disease as a whole was decreased.
White peony extract
White peony (Paeonia lactiflora) root is a traditional Chinese medicinal herb that contains bioactive compounds called glucosides. A water and alcohol extract of the peony root, known as total glucosides of peony, has more than 15 identified compounds. The most active and abundant of these is paeoniflorin, which represents more than 90% of the total glucosides of peony (Feng 2016; He 2011). A number of studies have shown paeoniflorin and total glucosides of peony have immunomodulatory, anti-inflammatory, and pain-relieving properties, and provide supportive evidence for peony’s historical use in the treatment of autoimmune conditions, including lupus (He 2011; W Zhang 2012; Feng 2016).
One study that examined case histories of lupus patients treated with total glucosides of peony found that consistent treatment for five years or more was associated with lower medication dosages and lower disease activity compared with patients who had not used peony extract (Zhang 2011). In a mouse model of lupus, levels of lupus antibodies decreased significantly and disease-associated kidney damage was reduced after 15 and 30 days of treatment with total glucosides of peony (Ding 2011).
Laboratory and animal investigations indicate in conditions of immune over-activation, total glucosides of peony strengthen immune regulation and quiet immune over-activity (He 2011). Total glucosides of peony was found in a laboratory study to induce the differentiation of immune cells affected by lupus into regulatory cells capable of quieting immune over-activity (Zhao 2012). Paeoniflorin alone has also demonstrated immune-regulatory effects in immune cells (Zhang 2015; Zhai 2016).
Other Natural Therapies
DHEA is a hormone naturally produced by the adrenal gland and is converted into sex hormones. In addition to being produced in the body, DHEA can be derived from the Mexican yam (Coates 2010).
Low levels of DHEA-s, a plentiful metabolite of DHEA in humans, have been observed in patients with lupus and other inflammatory diseases (Sawalha 2008). DHEA and its various metabolites exert considerable influence over immune system activity by regulating production of multiple cytokines including IL-2, IL-1, IL-6 and TNFα (Sawalha 2008).
In a clinical trial, when individuals with lupus took 200 mg of DHEA daily for 24 weeks, the number of patients who experienced lupus flares was significantly reduced (Chang 2002). In another study, the same investigators showed that taking 200 mg of DHEA daily for 24 weeks reduced blood levels of the cytokine IL-10, which enhances antibody production (Chang 2004). This reduction in IL-10 may have contributed to the reduced incidence of lupus flares seen in the first study.
Another double-blind, randomized, controlled trial involving 41 women found that six months treatment with 20 – 30 mg DHEA daily improved mental and emotional well-being in lupus patients (Nordmark 2005). Also, at a dose of 200 mg daily, DHEA improved bone mineral density in postmenopausal women with lupus (Hartkamp 2004).
Life Extension suggests that DHEA-s blood levels be kept between 350 – 490 µg/dL for men and 275 – 400 µg/dL for women in order to achieve optimal immunomodulatory action.
Plants to Avoid
Tripterygium wilfordii (Thunder God Vine)
Several reports of severe toxicity and even death associated with the use of Thunder God Vine are available, and it appears that the dose required for clinical effectiveness is very close to that required to cause toxicity (Huang 2009; Wang 1989). Another report linked Thunder God Vine use with low bone mineral density in women (Huang 2000).
Life Extension does not suggest that use of Tripterygium wilfordii outside of a clinical setting. If a healthcare practitioner decides to use this therapy with patients, only a standardized extract of the skinned root should be used, as other parts of the plant are highly toxic (NCCAM 2011).