Reigniting Hope: Managing Systemic Lupus Erythematosus with Integrative Orthomolecular Medicine

By Richard Z. Cheng, M.D., Ph.D.

OMNS (Nov 16, 2024) A recent story from Shanghai highlights the difficult journey of SLE patients. A woman named Shabai, after two decades battling this autoimmune disease and suffering kidney failure requiring dialysis, sought relief through assisted death in Switzerland. In her final social media post on October 24, 2024, she expressed gratitude for a ‘wonderful life,’ offering a heartfelt farewell with her father. Shabai’s story has ignited public empathy, underscoring the profound impact of SLE on physical and emotional well-being.

Having been asked to write about SLE, I aim to explore how integrative orthomolecular medicine can offer effective management strategies for this complex condition. Through a holistic approach that addresses root causes, nutrient support, and lifestyle factors, integrative orthomolecular medicine opens new avenues for reducing symptoms and enhancing quality of life. Patients with SLE should not give up hope; there are promising strategies that can empower them to live healthier, fuller lives despite their diagnosis.

Introduction: Systemic Lupus Erythematosus (SLE) is a complex autoimmune disease characterized by the production of autoantibodies and immune complex formation, affecting multiple organ systems.

While the exact etiology remains unclear, an integrative orthomolecular approach can provide insights into the root causes and intermediary mechanisms involved in SLE development and progression.

Root Causes Contributing to SLE:

1. Unhealthy Diet: High consumption of carbohydrates, omega-6 polyunsaturated fatty acids (PUFAs), and ultra-processed foods may contribute to inflammation and immune dysregulation in SLE (1).
   • A high-carbohydrate diet is associated with increased SLE risk (2). Specifically, women in the highest quintile of carbohydrate consumption had a nearly twofold increased risk compared to those in the lowest quintile (2). This suggests that diets high in carbohydrates may contribute to the development of SLE in this population.
   • Overconsumption of omega-6 seed oil: Research suggests that an imbalanced omega-6 to omega-3 ratio, a global trend, may contribute to autoimmune diseases like systemic lupus erythematosus (SLE) (3). Omega-3 fatty acids have anti-inflammatory properties and may benefit autoimmune conditions (4-6). Research on mice demonstrated that omega-3-rich diets could reduce autoantibody production and kidney damage in SLE models (7). The complex relationship between dietary fats and autoimmunity is further highlighted by findings that both excessive omega-6 intake and reduced omega-3 consumption may exacerbate autoimmune diseases (8).
   • Ultra-processed foods: Recent studies suggest a link between ultra-processed food (UPF) intake and increased risk of systemic lupus erythematosus (SLE), particularly in women. Higher UPF consumption was associated with a >50% increased SLE risk and doubled risk for anti-dsDNA+ SLE (9).
   • Dietary toxins in plant-based foods: Lectins, found in many plant-based foods, have been identified as potential contributors to autoimmune diseases, including systemic lupus erythematosus (SLE). These carbohydrate-binding proteins can resist digestion, enter the bloodstream, and trigger immune responses (10,11). Lectins may disrupt intestinal barrier integrity, leading to various autoimmunities (11). While some researchers caution against labeling plant compounds as “anti-nutrients” (12), others emphasize the potential risks of lectins, oxalates, and other plant-based toxins (13,14). Natural plant metabolites have been explored as potential remedies for SLE due to their immunomodulatory properties (15). Environmental factors, including toxic chemicals, are believed to contribute significantly to autoimmune diseases (16). Oxidative stress, arising from both endogenous and exogenous sources, has been identified as a unifying theme in the pathogenesis of SLE and other autoimmune conditions (17).
2. Environmental Toxins: Exposure to chemicals, pesticides, and heavy metals may trigger autoimmune responses. Occupational exposure to crystalline silica has been studied as a possible trigger for SLE (18).
   • Environmental toxins and chemicals have been implicated in the development and exacerbation of systemic lupus erythematosus (SLE) and other autoimmune conditions. Various studies have linked exposure to silica, solvents, pesticides, heavy metals, and endocrine disruptors like bisphenol A (BPA) and bisphenol F (BPF) to increased SLE risk (19-21). These toxins can trigger autoimmunity through multiple mechanisms, including epigenetic alterations, immune dysregulation, antioxidant depletion, and barrier degradation in genetically susceptible individuals (22). Cigarette smoking, oral contraceptives, and postmenopausal hormone therapy have also been associated with SLE incidence, while alcohol consumption may decrease risk (23). Environmental exposures can lead to chronic inflammation, tissue damage, and the release of self-antigens, potentially contributing to the development of autoimmunity (24). Further research is needed to fully elucidate the complex interactions between environmental factors and genetic susceptibility in SLE pathogenesis (25).
   • Heavy metals exposure has been linked to autoimmune diseases, including SLE (20,26). Metals such as mercury, cadmium, and lead can disrupt immune responses, potentially exacerbating immune tolerance issues and chronic inflammation (27-29). These metals can affect both innate and adaptive immunity, leading to chronic inflammation and disrupted immune tolerance (30,31). This exposure triggers immune dysregulation through pathways like oxidative stress, genetic predisposition, and epigenetic alterations (26,31,32).
3. Infections: Infections play a crucial role in the etiopathogenesis and exacerbation of systemic lupus erythematosus (SLE) (33,34). Various pathogens, particularly viruses like Epstein-Barr virus, can trigger autoimmunity through molecular mimicry and immune dysregulation (35,36). SLE patients are more susceptible to infections due to genetic factors and immunosuppressive treatments (37). Bacterial infections, including periodontal disease, may contribute to SLE pathogenesis by exposing nuclear autoantigens and stimulating Toll-like receptors (TLRs) 2 and 4 (38,39). Periodontal disease is associated with increased inflammatory markers and may be a risk factor for cardiovascular disease in SLE patients (40). Preventive measures, such as screening for chronic infections before immunosuppressive therapy, are crucial in managing SLE patients (35,37).
4. Nutrient Deficiencies: Insufficient intake of vitamins and micronutrients, especially B vitamins, vitamins C, D3, and K2, as well as magnesium and selenium, may contribute to immune dysfunction in SLE (1). Vitamin D deficiency, in particular, has been linked to increased SLE activity (1). Vitamin D deficiency is prevalent in systemic lupus erythematosus (SLE) patients and associated with increased disease activity (41). Low vitamin D levels correlate with higher autoantibody production, B cell hyperactivity, and interferon-α activity in SLE patients (42). Vitamin D plays a crucial role in immune regulation and may contribute to autoimmune disease pathogenesis (43). Supplementation with vitamin D has shown potential in reducing inflammatory markers and disease activity in SLE patients (44). Factors such as photosensitivity, photoprotection, and postmenopausal status are associated with vitamin D deficiency in SLE patients (41,45). Hydroxychloroquine use may help prevent vitamin D deficiency (45). While the relationship between vitamin D and SLE is complex, addressing vitamin D deficiency may have benefits beyond bone health for SLE patients (46,47).
5. Mental Health and Stress: Emotional or physical stress can trigger SLE flares (18). Chronic stress may contribute to immune system dysregulation.
6. Genetics: SLE has a strong genetic component, with multiple genetic variants associated with increased susceptibility (18).
7. Hormonal Imbalance: SLE often manifests or worsens during periods of hormonal fluctuations, such as puberty, pregnancy, or menopause (18). Hormonal imbalances play a significant role in the pathogenesis of autoimmune diseases, particularly systemic lupus erythematosus (SLE). The higher prevalence of SLE in women, especially during reproductive years, suggests a strong influence of sex hormones (48,49). Studies have shown that SLE patients exhibit abnormal hormone levels, including elevated estrogen and prolactin, and decreased androgens (50,51). These hormonal alterations affect both innate and adaptive immune responses, contributing to disease development and progression (52). Estrogen, in particular, can exert pro-inflammatory effects through genomic and non-genomic pathways, influencing B cell maturation and selection (53,54). Additionally, environmental factors such as estrogenic endocrine disruptors may trigger or alter autoimmune disease onset (53). The complex interplay between sex hormones, cytokines, and the immune system highlights the importance of hormonal balance in SLE pathogenesis (55). Notably, dehydroepiandrosterone (DHEA) has shown promise as a potential treatment for SLE. Multiple studies have demonstrated that DHEA supplementation (200 mg/day) can reduce disease activity, decrease corticosteroid requirements, and improve health-related quality of life in SLE patients (56-59). DHEA has also been found to have a protective effect against corticosteroid-induced osteopenia (58).
8. Ultraviolet Radiation: Sunlight, particularly UVB rays, is a well-established trigger for SLE flares (18).
9. Lifestyle Factors: Smoking is both a potential flare trigger and a risk factor for SLE, increasing the risk of skin and kidney problems (18).

Intermediary Mechanisms in SLE

1. Leaky Gut: Increased intestinal permeability, or “leaky gut,” is a common underlying cause of autoimmunity (60). In SLE, this can lead to undigested food particles entering the bloodstream, triggering immune responses and potentially causing molecular mimicry.
2. Elevated Oxidative Stress: SLE patients exhibit high levels of oxidative stress, which can damage cellular components and contribute to inflammation (61). This may be exacerbated by nutrient deficiencies and environmental toxins.
3. Impaired Mitochondrial Function: Mitochondrial dysfunction has been implicated in various autoimmune diseases and may play a role in SLE pathogenesis (62).
4. Insulin Resistance in SLE: Insulin resistance (IR) is more prevalent in systemic lupus erythematosus (SLE) patients compared to healthy controls, increasing the risk of cardiovascular disease and type 2 diabetes mellitus (63). SLE patients exhibit higher C-peptide levels and elevated HOMA2-IR-C-peptide index, independent of traditional cardiovascular risk factors (64). IR in SLE is associated with disease activity, inflammation markers, and damage over time (64,65). Oxidative stress, indicated by increased malondialdehyde levels, correlates with IR in SLE patients (66). Type B insulin resistance syndrome, characterized by autoantibodies to insulin receptors, can occur in SLE patients and may respond to immunosuppressive treatment (67,68). Cyclophosphamide and mycophenolate mofetil have been successfully used to treat SLE-associated type B insulin resistance (69). Understanding these mechanisms can lead to better treatment strategies for SLE patients with IR.
5. Immune System Dysregulation: SLE is characterized by an imbalance of T-helper cell subsets (Th1/Th2/Th17) and regulatory T-cells (Tregs), contributing to tissue damage and increased proinflammatory responses (1).
6. Autoantibody Production: The hallmark of SLE is the production of autoantibodies, particularly antinuclear antibodies (ANA), which target the body’s own tissues (18).
7. Complement Activation: Intravascular activation and conversion of complement contribute to increased capillary permeability and tissue damage in SLE (61).
8. Cytokine Imbalance: SLE patients exhibit elevated levels of proinflammatory cytokines, including IFN-γ, TNF, IL-4, IL-6, IL-10, IL-12, IL-17, and IL-18, while IL-2 levels are typically lower compared to healthy controls (1).

Integrative Intervention:

1. Healthy diet: A 2022 study found that low carbohydrate intake, improved self-reported symptoms in SLE patients (70). While not specific to SLE, a 2023 case report on a very low calorie ketogenic diet (VLCKD) for rheumatic disorders found: “VLCKD allowed the patient to achieve weight goal, better management of joint pain, headache episodes and normalization of inflammatory indices (71). A review on diet and SLE management stated: “Currently, a diet rich in vitamin- and mineral-rich foods and MUFA/PUFA with moderate energy consumption is recommended to control the inflammatory findings of the disease and the complications and co-morbidities resulting from SLE therapy” (1).
2. Nutritional supplements: Supplementation of vitamins, micronutrients, antioxidants and mitochondrial nutrients, often at high doses, has shown various effectiveness on autoimmune diseases, including SLE.
   1. High dose vitamin B1 (thiamine): High-dose thiamine has shown benefits for autoimmune diseases like rheumatoid arthritis, lupus, and Hashimoto’s thyroiditis. These findings suggest potential broader applications for autoimmune skin conditions (72-79).
   2. High dose vitamin B2 (riboflavin): High-dose vitamin B2 (riboflavin) has shown potential benefits in managing autoimmune diseases, primarily due to its role in reducing oxidative stress, supporting mitochondrial function, and modulating immune responses (80-82).
   3. High dose vitamin B3 (niacin/nicotinamide): Vitamin B3 (niacin/nicotinamide) shows promise in treating various autoimmune and inflammatory conditions. High doses of nicotinamide can reduce regulatory T cells and alter immune tolerance (83). In dermatology, it has been used to treat autoimmune skin diseases in dogs (84) and shows potential for treating acne, rosacea, and photoaging in humans (85,86). Nicotinamide has also been investigated for preventing type 1 diabetes (87) and as a cytoprotectant in immune system disorders (88). Recent studies demonstrate its ability to suppress T cell activation and pro-inflammatory cytokine production in juvenile idiopathic arthritis (89). Additionally, niacin has shown potential in enhancing remyelination in aging central nervous systems by rejuvenating macrophage/microglia function (90). These findings suggest that vitamin B3 may have therapeutic applications across various autoimmune and inflammatory conditions.
   4. High dose vitamin B5 (pantothenic acid): Recent research suggests a potential role for vitamin B5 and vitamin D in autoimmune diseases, including systemic lupus erythematosus (SLE). Vitamin B5 has been shown to inhibit Th17 cell differentiation and related autoimmune diseases by impeding PKM2 nuclear translocation (91). It may also have paradoxical effects on inflammatory and anti-inflammatory cytokines (29). Vitamin B5 deficiency can have significant health consequences (92).
   5. High dose vitamin B6 (pyridoxine): Research suggests that vitamin B6 supplementation may have beneficial effects for autoimmune conditions like systemic lupus erythematosus (SLE). Higher intake of vitamin B6 was associated with a reduced risk of active disease in SLE patients (93). High-dose vitamin B6 demonstrated strong anti-inflammatory properties in monocytes by downregulating key inflammatory mediators (94). It also prevented excessive inflammation by reducing sphingosine-1-phosphate accumulation (95). In critically ill patients, vitamin B6 supplementation increased immune responses (96). Vitamin B6 deficiency is associated with inflammation, and supplementation may improve immune function (97). However, very high doses of vitamin B6 can cause peripheral neuropathy, so appropriate dosing is crucial (98).
   6. High dose vitamin B7 (biotin): Recent research suggests potential benefits of vitamin B7 supplementation for autoimmune disorders. High-dose biotin (vitamin B7) has shown promise in treating progressive multiple sclerosis by promoting remyelination and enhancing energy production (99), although studies of biotin on SLE are limited.
   7. High dose vitamin C (ascorbic acid): Recent studies suggest that vitamin C supplementation may have beneficial effects in treating autoimmune diseases like Systemic Lupus Erythematosus (SLE) and rheumatoid arthritis by regulating cytokines, modulating immune responses, and reducing oxidative stress (100). High-dose vitamin C treatment has been shown to increase glucocorticoid activity and potentially control autoimmune diseases (101). In SLE patients, combined vitamin C and E supplementation decreased lipid peroxidation but did not affect endothelial function (102). Vitamin C intake was inversely associated with SLE disease activity in a 4-year prospective study (103).
   8. High dose vitamin D: Recent research suggests a potential role for vitamin D in autoimmune diseases, including systemic lupus erythematosus (SLE). Vitamin D deficiency has been associated with autoimmune disorders, including SLE (104). Up to 69% of SLE patients were found to be vitamin D deficient in one study, compared to only 22% of healthy controls without antinuclear antibodies (ANA) (42). While a randomized trial found no significant effect of high-dose vitamin D on SLE disease activity, it did demonstrate a corticosteroid-sparing effect (105). Some SLE patients develop anti-vitamin D antibodies, which are associated with anti-dsDNA antibodies (106). The concept of acquired vitamin D resistance may explain the need for high-dose vitamin D therapy in autoimmune diseases (107,108). Vitamin D supplementation is increasingly recommended for SLE patients (109).
   9. The recent trials of CAM treatments for SLE indicate that supplements such as vitamin D, omega 3 fatty acids, N-acetyl cysteine and turmeric show some promise for reducing SLE disease activity (80).
3. PBMT (Photobiomodulation therapy): PBMT shows promise in treating autoimmune diseases like multiple sclerosis (MS) and systemic lupus erythematosus (SLE). Studies demonstrate that PBMT, particularly using wavelengths of 670nm and 830nm, can modulate immune responses by increasing anti-inflammatory cytokines like IL-10 and decreasing pro-inflammatory cytokines such as IFN-γ (110,111). PBMT also reduces nitric oxide production, potentially alleviating nitrosative stress in MS patients (111). In experimental autoimmune encephalomyelitis, a mouse model of MS, 670nm light treatment reduced disease severity and modulated cytokine production (112). For SLE, both extracorporeal photochemotherapy and ultraviolet-A1 irradiation therapy have shown clinical improvements (113). Additionally, photodynamic therapy with 5-aminolevulinic acid successfully treated skin ulcers in an SLE patient (114). These findings suggest that various forms of light therapy could be valuable in managing autoimmune diseases.
4. Methyelene Blue: Recent research suggests that methylene blue and metabolic modulators may have therapeutic potential for systemic lupus erythematosus (SLE) and other autoimmune diseases. Methylene blue has shown promise in reducing symptoms of experimental autoimmune encephalomyelitis by modulating immune responses and activating the AMPK/SIRT1 pathway (115). Metabolic disturbances, including oxidative stress and altered lipid profiles, have been observed in SLE patients (53). Normalizing T cell metabolism through inhibition of glycolysis and mitochondrial metabolism has demonstrated efficacy in treating lupus in animal models and human cells (116). Other potential therapeutic approaches include methimazole, which prevents experimental SLE in mice (117), and histone deacetylase inhibitors, which may reverse epigenetic dysregulation in SLE (118). DNA methylation patterns have also emerged as important biomarkers and potential therapeutic targets in SLE (119).
5. Stem cell therapy for SLE: Stem cell therapy, particularly using mesenchymal stem cells (MSCs), has shown promise in treating systemic lupus erythematosus (SLE) (120), a chronic autoimmune disease affecting multiple organs. MSCs demonstrate immunomodulatory effects, inhibiting inflammatory factors and pathways while promoting regulatory T cells (121-123). Clinical trials have indicated that MSC therapy is generally safe and can improve disease activity, reduce autoantibodies, and ameliorate organ dysfunction in SLE patients (123,124). However, challenges remain, including potential complications and variable efficacy (123,124). Further research is needed to optimize stem cell therapy for SLE, including investigating MSC modification methods to enhance their immunosuppressive effects (121,125).

Summary of Key Benefits:

1. Healthy Diets Low in Carbohydrates, Omega-6 PUFAs, Plant-Based Toxins, and Ultra-Processed Foods: A diet focused on low carbohydrates, reduced omega-6 polyunsaturated fatty acids (PUFAs), minimal plant-based toxins (like lectins and oxalates), and limited ultra-processed foods can help lower inflammation, support metabolic health, and improve immune regulation. This dietary approach may alleviate symptoms, reduce flare-ups, and promote overall well-being for individuals with SLE and other autoimmune conditions by addressing key dietary triggers of inflammation and immune dysregulation.
2. Vitamin B1: Potential for reducing autoimmune symptoms.
3. Vitamin B2: Supports oxidative stress reduction and immune modulation.
4. Vitamin B3: Shows promise for treating inflammatory conditions.
5. Vitamin B5: May inhibit inflammatory pathways.
6. Vitamin B6: Anti-inflammatory effects with improved immune function.
7. Vitamin B7: Promotes energy and remyelination in certain cases.
8. Vitamin C: Reduces oxidative stress and supports immune modulation.
9. Vitamin D: Associated with reduced disease activity and immune regulation benefits.
10. PBMT (Photobiomodulation Therapy): Modulates immune response by increasing anti-inflammatory cytokines (like IL-10) and reducing pro-inflammatory cytokines. PBMT also supports cellular energy production and reduces oxidative stress, making it beneficial for managing inflammation and symptoms in SLE and other autoimmune conditions.
11. Methylene Blue: Enhances mitochondrial function, reduces oxidative stress, and modulates immune responses. Methylene blue’s impact on the AMPK/SIRT1 pathway may support energy production and reduce inflammation, which could benefit autoimmune diseases, including SLE.
12. Hormonal Balance: Hormonal balance helps regulate immune responses, reduces autoimmune disease activity, decreases corticosteroid needs, and improves quality of life, especially in conditions like SLE.
13. Detox of Heavy Metals: Reduces the toxic load that may exacerbate autoimmune conditions. By eliminating metals like mercury, cadmium, and lead, patients can improve immune tolerance, decrease chronic inflammation, and support overall immune system health.

Conclusion: Addressing root causes and intermediary mechanisms in SLE through integrative methods offers promise for improved outcomes. By combining nutritional, environmental, and lifestyle modifications with targeted interventions for immune regulation and oxidative stress, SLE patients may experience relief and enhanced quality of life. Integrative orthomolecular medicine presents a holistic, patient-centered approach to nurturing resilience and optimism in the face of chronic autoimmune challenges.

Through this integrative orthomolecular approach, we have observed significant improvements in our patients’ quality of life (126,127). In many cases, these methods have even contributed to reversing symptoms of various autoimmune diseases. This experience reinforces the potential of integrative medicine to provide renewed hope and health to those facing the challenges of autoimmune conditions.

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