Systemic Lupus Erythematosus (SLE) is a rheumatic autoimmune disease. Heal your body. Learn the best tests, genetic information, natural treatments, lifestyle factors and supplements. Systemic Lupus Erythematosus or SLE is a potentially life threatening, rheumatic autoimmune disease. This article serves as a resource for individuals who would like to understand the most important testing, genetic risk factors, therapies and treatments to better manage this complex health condition.
What Are the Signs & Symptoms of Lupus?
- Painful and/or swollen joints
- Muscle pain, “all over body pain”
- Persistent FeverCharacteristic butterfly-like facial rash
- Pain that flares with or without cyclical patterns
- Difficulty breathing, or painful breathing
- Hair loss
- What Complications Can Be Caused by Lupus?
What Complications Can Be Caused by Lupus?
The inflammation caused by Lupus can lead to involvement with organs and tissues. Some of these include:
- Muscular symptoms: myalgia, myositis, muscle weakness
- Bone and joint symptoms: osteoarthritis, Jaccoud arthropathy, joint pain in the hands and fingers
- Cardiovascular complications: pericarditis, edema, fluid accumulation, damage or inflammation to cardiac valves
- Gastrointestinal symptoms: pancreatitis, IBS, liver complications, bowel and duct obstructions
- Kidney disease: nephritis, sclerotic nephritis
What Lab Tests Help to Diagnose Lupus?
SLE is diagnosed on the basis of a number of criteria, tests and symptoms. Because many autoimmune diseases can overlap in symptoms, diagnosing Lupus can present challenges. There is no single diagnostic test for Lupus. Your doctor can diagnose Lupus based upon a variety of factors. Some of these include:
Positive ANA blood test (anti-nuclear antibody) – While a positive ANA can be seen with other autoimmune diseases, ANA with reflex is a go-to test for Lupus diagnosis, especially when the immunofluorescence staining part of the test can identify a Lupus-specific pattern. A very high percentage of Lupus patients (98%) will show a positive ANA (8) . This can include a positive ANA with the following immunofluorescence staining criteria:
- Outline pattern (peripheral) – Very strongly correlative with Lupus. If this pattern appears, there is a high probability of Lupus (8)
- Homogenous pattern – may also be seen in mixed connective tissue disease
- Speckled pattern – can also be seen in: scleroderma, mixed connective tissue disease, Sjogren’s, Rheumatoid arthritis, polymyositis
Many drugs can cause a false positive ANA. Your doctor should be informed before running the ANA test if you’re taking any of these medications: Acetazolamide, hydralazine, procainamide, phenytoin, penicillin, tetracyclines, sulfonamides, aminosalicylic acids, chlorprothixene, griseofulvin, streptomycin (9).
ESR (erythrocyte sedimentation rate) – The ESR is another inflammatory test, and some consider it to be very relevant for Lupus. ESR is not specific for Lupus, but is used to evaluate disease activity and progression.
Other Lab Test Markers Which May be Relevant For Lupus
(That Your Doctor May Not Know About)
- CH50/CH100 – This is a blood test that look at potential deficiencies of complement immune proteins. The CH50/CH100 test is not specific for which of the complement proteins are low, but it identifies if your classical pathway (which involves complement proteins: C1-C9) is deficient.
- Complement C4 – 75% of Lupus patients have shown to be deficient in Total C4 (1). Complement C4 is integral to the complement immune system, and can influence the function of the entire complement immune response, which can also work with IgG and IgM antibodies.
- Complement C1q – 93% of patients with Lupus have shown to be deficient in Complement C1q (1)
- C1q is part of the Classical pathway of the complement immune system.
- C1S/C1R – Deficiencies of C1q/Cr occur roughly 51-57% of the time in Lupus (1). These are complement immune proteins that are activated by the Classical pathway of the complement immune system.
- FOXP3 CD39+ TREGs – T-regulatory cells (TREGs) are a type of immune cell that play a critical role in “self tolerance”, and in the inhibition of autoimmunity. Lupus patients have consistently shown low TREGs activity in numerous studies (10, 11). Interestingly, complement C4 appears to modulate the differentiation of TREGs cells, as well as influence the concentration of TGFß (an important anti-inflammatory cytokine) (11).
- TGFß-1 – Transforming growth factor ß-1 is an immune signaling cytokine and growth factor. TGFß-1 plays an important role in Lupus because it is immunosuppressant, it inhibits inflammation. TGFß-1 can work with TREGs cells to generate what’s known as “self tolerance”. In Lupus, TGFß-1 levels have shown to be lower (16).
- Anti-cardiolipin antibodies – Cardiolipin is a mitochondrial membrane lipid. 36% of Lupus patients have shown antibodies to cardiolipin (13). Antibodies against cardiolipin are associated with pregnancy loss and autoimmunity in general. This antibody is found more in women than men.
- CD4-CD8 – (double negative T-cells): This class of double negative T-cells has been found to increase production of the cytokines IL-4, IL-17, and lead to organ damage in SLE, and formation of anti-DNA antibodies (24, 25, 26, 27)
- TLR7 & TLR9 – toll like receptors 7 and 9 are centrally involved in rheumatic autoimmune diseases. Activation of TLR7 and TLR9 are associated with anti-extractable clear antigens and anti dsDNA (53)
- CD38 – CD38 is a protein that is expressed in numerous tissues, which can also function as a receptor. It acts to increase calcium channel signaling, via the effect on the NAD+ pathway. The elevations in CD38 in SLE patients correlates with increased expression of cytokines from Th2 (IL-4, IL-10, IL-13) and Th1 (IL-1b, IL-12 , IFN- c, TNF- a). This correlation was shown to be more consistent among SLE patients with active disease, compared to SLE patients with less active disease. Interestingly, CD38 autoantibodies are hypothesized to dampen the immune activation of CD38+ T-cells (40).
- Sm/RNP histone antibody – This is a type of antibody produced as a result of impaired clearance of cellular antigens
- Ro antibody – These are a type of antibody produced as a result of impaired clearance of cellular antigens
- dsDNA antibody – Anti-double stranded DNA antibody produced as a result of impaired clearance of cellular antigens
- LL37 antibody – LL-37 is a cathelicidin antimicrobial peptide stored and released by neutrophils, macrophages and epithelial cells. LL-37 can be released following activation by bacteria, viruses, fungi, or by 1,25 dihydroxVitaminD (calcitriol). It has been proposed that LL-37 activation induces the Type-1 interferon system (57). One studyl showed that anti-LL37 and HNP antibodies induce neutrophilic extracellular traps (NET’s) (58).
Once you have your blood work The Functional Blood Chemistry Analyzer (FBCA) can aid in your health journey by interpreting results. Functional Blood Chemistry Analyzer (see below). Inputting your regular blood work in this report can help save a lot of time and guess work in functional ranges and areas to focus in on.
What Are the Causes of Lupus?
Like with other autoimmune diseases, Lupus involves a combination of genetic factors, combined with various environmental triggers.
Knowing your genetic susceptibilities for autoimmunity can lead to a better understanding of what testing and therapies may be useful in order to support your physiology. This is a field of study referred to as genomics.
Strong genetic associations exist for Lupus (SLE). Many of the major genetic risk factors for Lupus reside located on chromosome 6, within the HLA region (also known as the MHC or “major histocompatibility complex”) (6). This is a series of genes that play important roles in immune function and signaling.
It has also been identified that more than 50% of Lupus-susceptibility genes can be traced back to direct or indirect functions of IFN-1 (interferon-1) activities (64).
What Genes Can Trigger Lupus?
Genetic polymorphisms are well known to influence Lupus susceptibility. This information may be useful not only to establish the potential risk of Lupus, but also to identify specific molecular pathways which may be involved for each person. The identification of molecular pathways introduces a more detailed and nuanced roadmap for personalized medicine treatment. Some of the major Lupus-related genes include:
- Complement C4 – Complement C4 is an important part of the innate immune system pathways, known as the complement cascades. C4 blood protein deficiency has been found in 75% of Lupus patients (1). Low blood C4 levels can be caused by variations of the RCCX gene cluster, associated with a low C4 genetic copy number (3).
- ITGAM – This is an integrin receptor of immune cells. It can work with complement protein C3b, and it also is involved in the migration of neutrophils. Mutations of the ITGAM gene are linked to Lupus (15).
- C1q – 93% of patients with Lupus have been found to have deficiencies of C1q (1), caused by gene variations of the C1q gene (2). C1q is another complement-related immune protein.
- Complement C2 – Is a complement gene located within the HLA region. C2 and C4 both participate in the Lectin pathway of the complement immune cascade. An SNP within the C2 gene has been shown to be associated with lupus, as well as increased frequency of photosensitivity, hair loss and anti-cardiolipin antibodies (12).
- TNFAIP3 – Tumor necrosis factor alpha inducible protein-3 is a gene located on chromosome 6 in the HLA region. This gene is a promoter of an inflammatory immune-signaling cytokine known as TNF-a. SNPs of this gene are strongly linked to Lupus (14).
- C1r, C1s – These immune protein complements have shown to be deficient in 50-57% of Lupus patients (1). Mutations of these genes have been identified in Lupus (7).
- TGFß-1 – This gene makes a cytokine, transforming growth factor ß-1, which functions to inhibit inflammation and is important for self tolerance. Variations of the TGFß-1 gene are linked to Lupus (17).
- SKIV2L – This gene is located near the RCCX gene region. Variants and SNPs from the SKIV2L gene have been found in some populations to have very strong associations to SLE Lupus (4). The SKIV2L gene regulates levels of interferon gamma. This is a cytokine with inflammatory activities, that can help control infections such as viruses.
- HLA region I variant, rs3131379 is a SNP shown in strong association with SLE (65). The HLA genes encode for cell surface antigen processing. Many HLA variants are associated with a wide variety of autoimmune diseases, including SLE.
- HLA region II variant rs1270942 is a SNP shown in strong association with SLE. The combined interactions between genotypes of rs1270942 and rs3131379, increase the probability of also carrying IRF5 (interferon regulatory factor-5) in SLE (65)
- SPP1 – This is a gene known as osteopontin. It is involved in calcium metabolism, osteoporosis and the formation of calcium-oxalate stones. A few studies have found associations between variants of SPP1 and Lupus (82)
- HRH4 – Histamine receptor-4. Polymorphisms have been shown to be associated with SLE. Histamine is an immune molecule that recruits inflammatory immune cells. This may be relevant, especially if mast cell activation syndrome (MCAS) is associated with SLE (83)
- BCL-2 – B-cell lymphoma-2 gene is essential as a regulator of the mitochondrial membrane, and is critical in apoptosis of cells (cell programmed death). BCL-2 variations are associated with SLE. Variations of combined BCL-2 and IL-10 genetics are associated with a 40-fold increased risk of SLE (84)
- IRF5 – several variants of interferon regulatory factor-5 are strongly associated to Lupus. IRF5 interacts with HLA class 1 and 2 molecules, modulates the expression of type 1 interferons, as well as influences toll-like receptor (TLR) signaling (66). A haplogroup consisting of 3 IRF5 SNP’s are strongly linked to elevated levels of IFN-a, as well as to levels of anti-dsDNA antibodies or anti-RBP antibodies (67)
- IL-10 – Interleukin-10 is a type 2 cytokine that is regarded as important for the formation of antibodies and the anti-inflammatory response. Variations of combined BCL-2 and IL-10 genetics are associated with a 40-fold increased risk of SLE (84)
- TLR9 – Is a cell signaling receptor. TLR (toll like receptors) act in antigen communication between various cell types of the immune system. TLR9 variant rs352140 is associated with Lupus and Lupus nephritis rs352140 (85)
- TYK2 Tyrosine Kinase 2 (86)
- MTNR1β (Melatonin receptor 1ß gene) The risk allele was shown to be significantly associated with SLE patients. SLE patients exhibit lower melatonin levels, compared to controls (87)
- IL-6 – While interleukin-6 isn’t necessarily associated with the development of SLE, gene status of one of the main promoter SNP’s is associated with treatment effects of certain drugs. For example, for patients with SLE, GG genotypes of rs1800795 had a higher response rate to the drug Rituximab than either GC heterozygotes or CC ancestral allele carriers. The CC genotypes were lower responders to Rituximab. The GG genotype confers higher levels of IL-6, whereas CC has lowest levels of IL-6 (71)
Understanding your genetic profile is key. The Metabolic Healing Nutrigenomics Report analyzes hundreds of genetic testing markers, based on your 23andme or Ancestry DNA raw data. (see below)
Does Epigenetics Influence Lupus?
Up until recently it has been believed that your genes rule your health destiny. More recent research reveals that it isn’t that simple. Epigenomics, or the study of gene expression shows us that our genes are greatly influenced by environmental factors (like toxins and infections) as well as food, stress, exercise, sleep, and even light and circadian rhythms.
The field of epigenomics is enabling a better understanding of how we can use therapeutic interventions in order to support the function of certain genes, which may be more vulnerable to autoimmune disease.
To illustrate the importance of epigenome research in Lupus, consider a monozygotic twins study. Monozygotic twins share identical DNA. However epigenetic differences identified through epigenomics and transcriptomics reveal significant influences on gene expression. In this case, an identical twin is diagnosed with Lupus, but not her sister. The affected twin showed increased gene expression in a number of interferon response genes, compared to her unaffected sister who did not (49). These differences in epigenomics illustrate that one identical twin developed Lupus, but the other did not.
Understanding the epigenetic nature of lupus opens the door for natural therapeutic treatments.
Lupus Natural Therapeutics
Exercise is fundamental to health. Exercise is known to improve parameters of inflammation, insulin resistance and reduce risk factors of heart disease.
Aerobic exercise, Lupus & Insulin Resistance – SLE patients are at a higher risk of developing insulin resistance. In a randomized controlled trial, SLE patients who performed 12-weeks of aerobic exercise exhibited significant reductions in fasting insulin levels (-39 vs +14), reduction in insulin secretion for meal test (-23 vs.+21), and significant increases in muscle AMPK activity (79).
Aerobic Exercise, Lupus, Fatigue and Vitality – A 2017 meta analysis study found that a minimum of 20-minutes of moderate intensity aerobic exercise 3 times weekly could improve fatigue and vitality in lupus patients (80).
5 Potential Supplements for Lupus
NAC (N-acetyl cysteine) – NAC is the precursor to the antioxidant glutathione. NAC is one therapeutic supplement with a lot of positive potential in Lupus. A recent study has identified that NAC may act by modulating one of the key biochemical targets in lupus, known as the kynurenine pathway (81). The use of NAC at a dosage of 2.4g-4.8g daily was shown to positively affect a number of immune markers in Lupus patients, including:
- Markedly increase NADPH production
- Modulation of orotate levels
- Increase of succinate, cytidine, hypoxanthine, methylmalonic acid, acetyl coenzyme A, CDP-choline
- Inhibition of Kynurenine activation of mTOR
- Inhibition of mTOR in CD4-CD8- (double negative T-cells)
- Modulation of CD4+ FOXP3 Regulatory T-cells by way of mTOR inhibition (21)
Curcumin is an anti-inflammatory compound derived from the botanical Turmeric. A cohort of 24 patients with Lupus Nephritis took 500mg of Turmeric daily, which contained 22mg of Curcumin. Compared to the placebo group, the Turmeric supplemented group showed reductions in proteinuria, blood pressure, and hematuria (75).
Fish Oil – To date there have been roughly 8 studies related to SLE patients using fish oil. Among the largest of these studies involved 64 SLE patients supplementing with 300mg Fish oil daily for 24 weeks. Notable improvements were observed in SLAM-R (Systemic Lupus Activity Measure), BILAG (British Isles Lupus Assessment Group index of disease activity for systemic lupus erythematosus), FMD (endothelial function using flow-mediated dilation of the brachial artery), as well as reduction in oxidative stress as reported by reduction in 8-isoprostanes from blood platelets (56).
Melatonin – Human studies involving melatonin and Lupus are lacking, but a chain of evidence shows probable therapeutic benefit. An Egyptian hospital study found significant associations between a melatonin receptor polymorphism, and reduced melatonin levels, compared with controls. Mouse studies have clearly demonstrated melatonin to have beneficial antioxidant effects in a model of Lupus nephritis by way of modulating the NLRP3 inflammasome (62). Additionally, a 2020 mouse study demonstrated that melatonin prevented endothelial dysfunction in SLE by way of activating the retinoic acid orphan receptor, ROR-a (63).
Vitamin D – A meta analysis reviewed 6 RCT studies on the effect of Vitamin D supplementation and Lupus. Vitamin D at varying dosages significantly reduced the SLEDAI score. In addition, Vitamin D supplementation was associated with improving fatigue and also increasing Complement C3 (78).
How to Use The Functional Blood Chemistry Analyzer (FBCA) is an excellent tool in Your Health Journey
Inputting your regular blood work in this report can help save a lot of time and guess work in functional ranges and areas to focus in on.
The Metabolic Healing Functional Blood Chemistry Analyzer (FBCA) is a software that can analyze your blood test and help you identify:
- Nutrient needs: B-12, Folate, B-6, Zinc, Copper
- Optimal Homocysteine levels
- Dietary needs
- Immune function markers
- Liver function status
- Kidney function status
- Blood sugar handling
- Electrolyte and hydration status
How to Use the Nutrigenomics Genetic Report
Knowing certain key genetic markers helps you to understand what how foods, nutrients and drugs interact within your body.
The Metabolic Healing Nutrigenomics Report analyzes hundreds of genetic testing markers, based on your 23andme or Ancestry DNA raw data. This includes important genes and SNP’s related to:
- Brain neurotransmitters (such as dopamine and serotonin)
- Immune function
- Blood clotting
- Iron metabolism
- Vitamins A, D, B-12, Folate
- Cardiovascular function
- Gut health
- Fatty Acid & Lipids
And so much more…