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Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are common and often debilitating diseases. The prevalence and incidence of autoimmune diseases is increasing, thus pressing the integrative medical community to understand the etiology more deeply in order to improve treatment approaches. The annual incidence of RA is about 40 per 100,000 and the prevalence among women is 9.8 per 1000 and 4.1 per 1000 for men.1 Women are affected 2 to 3 times more often than men. The prevalence of SLE is 20 to 150 cases per 100,000, again with a strong female predominance of 10:1. SLE prevalence is more common in African American women, with rates of 406/100,000 compared with 164/100,000 in Caucasians.2 The incidence of SLE does appear to be increasing: rates tripled between a 1950–1979 cohort and a 1980–1992 cohort, although this is complicated by better detection of mild disease.3
Conventional treatments often fall short in both these diseases. Biologic medications used in the treatment of RA produce clinically relevant improvement 50% of the time.4 Mortality in conventionally treated SLE patients shows a threefold increase when compared with the general population.5 Clinical remission with conventional treatment is rare, and morbidity from treatments is significant. Integrative physicians can formulate effective adjunct treatments for patients with RA and SLE by understanding and therapeutically addressing hormonal aberrations associated with these diseases.
RA onset is highly variable and ranges from insidious, sudden, migratory, and intermittent to unrelenting. It is most often characterized by symmetric swelling, pain, and stiffness in the hands. The most common joints affected are the metacarpal phalangeal joints (MCPs), proximal interphalangeal joints (PIPs), wrists, elbows, knees, midfoot and the metatarsal phalangeal joints (MTPs), although this disease can affect any joint in the body except the sacroiliac joints, thoracic spine, and lumbar spine. Patients often experience global morning stiffness that lasts >1 hour. In 2010, the American College of Rheumatology updated the diagnostic criteria (Table 1). The new criteria allow for earlier diagnosis, thus allowing physicians to institute disease modifying antirheumatic medications (DMARDS) more quickly.
Table 1: American College of Rheumatology Rheumatoid Arthritis Diagnostic Criteria
6 of 10 points
- CCP and RF (0–3)
- # and size of involved joints (0–5)
- >6 weeks' duration1
- ESR and CRP1
The diagnosis of SLE is more complex and can be quite insidious compared with RA, making age of onset difficult to determine, but generally it affects women of childbearing age. SLE is a multisystem, autoimmune inflammatory condition characterized by a fluctuating, chronic course from mild and long-term to rapidly fatal. The hallmark lab finding in SLE is the anti-nuclear antibody (ANA) and anti-dsDNA antibody. Given that the immune system has mounted a response to the very core of the body, it makes sense that many systems can be affected and the symptoms picture is highly variable (Table 2). The American College of Rheumatology Criteria are shown in Table 3.
Table 2: SLE Systems Affected
Table 3: American College of Rheumatology Systemic Lupus Erythematosus Diagnostic Criteria
Must Have 4 of 11 Criteria
- Photosensitivity (rash)
- Nonerosive arthritis
- Pleurisies or pericarditis
- Discoid rash
- Oral/nasopharyngeal ulcers
- Malar rash
- Neurologic disorder – psychosis or seizures
- Hematologic disorder: hemolytic anemia, leukopenia (<4000/mL), lymphopenia (<1500/mL), thrombocytopenia (<100,000/mL)
- Renal disorder: proteinuria (>3+ dipstick or >0.5 g/d) or cylindruria (cellular casts)
- Positive antinuclear antibody (95%–100%) in the absence of drugs known to cause positive ANA
- Immunologic disorder (antibodies to DNA, Smith,cardiolipin, lupus anti-coagulant, or false positive serological test for syphilis)
The etiologies of RA and SLE are a complex interplay between infectious organisms, microbiome/gut immune changes, psychoneuroimmunology factors, environmental toxicity, nutritional deficiencies, dietary factors, genetic and epigenetic changes, and hormones. The focus of this review will be on assessment and treatment of adrenal, gonadal, and adipose hormone aberrations that drive the autoimmune process and inflammation.
Adrenal and Gonadal Hormones
Untangling the complexity of hypothalamic-pituitary-adrenal axis (HPA) and hypothalamic-pituitary-gonadal axis (HPG) alternations is challenging. Patterns change from the onset of disease and are highly influenced by inflammatory cytokines and glucocorticoid treatment. There are some basic patterns in the HPA axis that predispose an individual to RA and SLE and drive disease activity. Patients often have low serum DHEA-S and low serum, urinary, or salivary cortisol.6-8 Of these hormones, low DHEA-S is the most strongly correlated with disease activity in RA.9
To make matters worse, patients with RA and SLE likely have elevated aromatase activity due to inflammatory cytokine signaling. What little adrenal androgens they manage to make are converted to estrogens. Then, in turn, patients with SLE and RA tend to overly metabolize estrogens into 4- or 16- hydroxyestrones. One study found that urinary concentrations of the 2-hydroxylated estrogens were 10 times lower in patients with RA and SLE than in healthy controls and that the ratio of 16-hydroxyestrone/2-hydroxyestrogens was 20 times higher in RA and SLE patients than in controls. B and T cells both have estrogen receptors (ER) on their membranes and respond to E2 by increasing IgG and IgM production. 16-hydroxyestrone also appears to exacerbate a TH2 response.10,11 4- and 16-hydroxyestrones increase B cell proliferation in autoimmune diseases, and patients with higher levels of these metabolites have increased disease activity scores.12 To date, there have been no clinical studies on the effect of addressing estrogen metabolism on clinical outcomes.
Exogenous hormones also play a role in risk and disease severity, especially in SLE. The use of estrogen-containing contraceptive agents is associated with a 50% increase in risk of developing SLE.13 Environmental estrogens present in pesticides, plastics, and detergents also contribute to risk of RA and SLE and increase disease flares.14,15
The role of progesterone in RA and SLE is not fully understood and may have positive or negative effects. It has been observed that patients with RA often have symptom improvement during luteal phase and during pregnancy when progesterone levels are very elevated.16 This may be due to progesterone's immunomodulatory effect: it appears to decrease Th1 and Th17 cytokines.17
Elevated prolactin is associated with many autoimmune diseases such as RA, SLE, MS, Hashimoto's thyroiditis, and Sjögren's syndrome. It appears that prolactin increases TNFa secretion from monocytes in RA patients and interferes specifically with B cell tolerance induction.18,19 The role of prolactin in RA and SLE pathogenesis is not well understood, and more study is needed to prove that elevated prolactin increases disease activity.
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