Systemic lupus erythematosus (SLE) is a syndrome characterized by dysregulation of the immune system and widespread inﬂammation that can involve multiple organs and body systems. Skin and joints are most frequently affected. SLE afﬂicts women up to nine times more frequently than men and usually manifests during the childbearing years. SLE is identiﬁed serologically by autoantibodies to DNA, RNA, other nuclear antigens, and cytoplasmic/cell surface molecules. Numerous studies (human and animal models) provide evidence for bi-directional communication between the immune and endocrine systems and disruptions in communication that contribute to susceptibility and severity of disease. This article will discuss the impact of hormones and hormone-related factors in SLE from the perspectives of researchers in basic science, clinical science, and clinical practice.
Clinical Practitioner Perspective
By Ida Dzifa Dey, M.B. Ch.B., M.W.A.C.P. and David A. Isenberg, M.D., F.R.C.P., F.A.M.S.
Dey is a clinical research fellow and Isenberg is a professor at the Centre for Rheumatology, Department of Medicine, University College London Hospitals, London.
Systemic lupus erythematosus (SLE) is a highly variable multisystem autoimmune rheumatic disease (ARD). It is clearly not a homogenous disease entity but a variable syndrome with some patients manifesting mild clinical signs (e.g., skin rash), whereas others present with potentially fatal disease (e.g., nephritis, cerebral involvement).
Classification and Diagnosis
In 1971, the American College of Rheumatology published preliminary criteria for the classiﬁcation of SLE for clinical trials and studies and revised these criteria in 1982 and 1997. These classiﬁcation criteria are often used as the basis for diagnosis, although strictly speaking, they have not been formally validated for that purpose. They consist of four cutaneous, four systemic, and three laboratory components.1 These criteria show about 90 percent sensitivity and speciﬁcity but have weaknesses (e.g., patients with cutaneous lupus can be diagnosed as having SLE without any systemic features). The Systemic Lupus International Collaborating Clinics (SLICC) group has recently re-examined the criteria—incorporating new knowledge of autoantibodies, neuropsychiatric lupus, and advances in imaging—recognizing the importance of low complement and the need for biopsy-proven lupus nephritis to be a “stand alone” criterion. At least four of these criteria need to have been present at some time, not necessarily simultaneously, for lupus to be diagnosed.2 The diagnosis should be based on clinical signs and symptoms in general, and supported by laboratory evidence.
Lupus is the third most common ARD. Its incidence rates vary with a worldwide annual incidence from 1.8 to 7.6 cases per 100,000. Current studies suggest the incidence may be increasing.
Differences in prevalence rates occur among people of the same race in different geographical locations. African Americans/African Caribbean women have a higher rate of SLE, followed by Asians, then Caucasians.3 One in 10,000 white males, one in 1,000 white females, and one in 250 African American females have SLE in the United States. Previous studies reported low rates of SLE in Africa,4 but paradoxically high rates among black women in the Americas, the Caribbean, and Europe, suggesting the importance of environmental inﬂuences. However that may not necessarily be the case and the apparent lower rate in Africa may be due to under-reporting.
Ninety percent of persons with SLE are female. The disease frequently starts in women of childbearing age. The use of exogenous hormones has been associated with lupus onset and ﬂares, suggesting a role for hormonal factors in the pathogenesis of the disease.5 The female-to-male ratio varies from 4.3 to 13.6:1 during the childbearing years, but the pre-puberty and post-menopause sex ratios are almost identical between females and males (2.3:1 and 2.2:1), implicating a correlation of maximal female sex hormone production with the onset of SLE.6 Of interest, SLE seems to be common in men with Klinefelter syndrome (genotype XXY) [see story, page 24], also suggesting a strong hormonal inﬂuence.
Clinical Features – How Lupus Affects the Body
There is a wide spectrum of clinical features and patients are highly variable in their disease manifestations. Almost every organ in the body can be affected, from the skin to the central nervous system. It is important to recognize differences between active ongoing disease activity and organ damage. Approximately one-third of patients develop other autoimmune diseases, notably autoimmune thyroid disease, Sjögren’s syndrome [see story, page 24], and antiphospholipid syndrome.
Management Systemic Lupus Erthematosus (SLE)
The social and psychological effects of both the chronic disease and its therapy, combined with its effects on fertility and pregnancy, must be recognized and dealt with by physicians and patients. Some general advice needs to be given to patients, such as appropriate rest and avoiding excess stress. Avoidance of ultraviolet light exposure is recommended, because this may cause disease ﬂares and a photosensitive rash. A diet low in saturated fats and high in ﬁsh oils and avoidance of both smoking and estrogen-containing contraceptive pills are advised. Because fatigue is common, a careful exploration of causes of fatigue (including anemia, hypothyroidism, and ﬁbromyalgia) by the physician is important. Vitamin D supplementation may have beneﬁts in the treatment of patients who are deﬁcient.
Pharmacological therapy is directed at organand non– organ-threatening disease, organ-speciﬁc measures, and adjuvant therapies (e.g., bone and renal protection). Patients with SLE are treated with four main groups of drugs, often in combination: non-steroidal anti-inﬂammatory drugs (NSAIDs), antimalarials, corticosteroids, and cytotoxic drugs.
Complications of therapy include osteoporosis, hypertension, and metabolic syndrome.
Biological therapies directed at immune processes implicated in the pathogenesis of the disease are being developed and show promise for the future.
Morbidity and mortality have improved but the advent and development of newer targeted therapies offer further potential for increased survival. However challenges such as the increased risk of atherosclerosis and possibly malignancy remain.
Clinical Researcher Perspective
By Robert G. Lahita, M.D., Ph.D.
Chairman of Medicine, Newark Beth Israel Medical Center; Professor of Medicine, University of Medicine and Dentistry of New Jersey, Newark.
Systemic Lupus Erythematosus is the prototypic autoimmune disease. The disease is associated with many T cell and B cell abnormalities and the hallmark of the disease is the synthesis of autoantibodies which are directed at self antigens. There is no genetic basis for this illness, other than association with immune response genes on chromosome 6. There are facets of the disease that are clearly endocrine in nature including the signiﬁcant effect that sex steroid hormones have on the illness, and the role of prolactin.
An extensive body of work has been done with murine models of lupus, some of which have signiﬁcant endocrine aspects to the presentation of the murine disease.1 The NZB/ NZW F1 hybrid mouse that develops SLE because of genetic inﬂuence predominates in the females of the strain, as with the human illness. Males who are gonadectomized have worse disease whereas females who are ovariectomized have quiescent disease, revealing the importance of estradiol in the exacerbation of the illness and the protective nature of androgens.2 There is also a strain of mouse, the BXSB, with SLE that is not mediated by hormones, wherein males succumb to the disease rather than females.
Estrogen and SLE
Studies in humans have examined the metabolism of estrogen in both females and males with SLE. Hydroxylation of estrone toward feminizing 16 hydroxy metabolites was the predominant route in patients with SLE (male and female). Catechol estrogens were depleted in patients with SLE.
The Connection Between Androgens and SLE
In the absence of corticosteroids that decrease levels of free testosterone, oxidation of testosterone at C-19 was increased in female patients with SLE.4 Males did not show this metabolic aberration. For many years, the occasional observation of autoimmune disease in hypogonadal males with Klinefelter syndrome or acquired hypogonadism has reinforced the putative link between the absence of androgens and worsened disease in humans. The observation that hormones such as dehydroepiandrosterone (DHEA) could ameliorate the murine illness suggested that this might be useful as a therapy in humans.5 Unfortunately, this was not the case. DHEA therapy of SLE patients did not meet end points in early studies and was abandoned. Use of 19-nortestosterone to treat the disease and avoid aromatization of estrogens was also unsuccessful. Curiously, males who were treated with this steroid had worsened disease, possibly because of feedback inhibition of endogenous testosterone.
Males with Klinefelter Syndrome also get SLE and other autoimmune diseases, suggesting that the epigenetic effects of one X chromosome might ultimately be behind the manifestations of the illness. Hypogonadotrophic Klinefelter patients show no increase of the disease. Autoimmune disease in Klinefelter males is the same as in the general male population.6 It may be either the higher levels of estrogen or the lower levels of androgen that further the illness in the Klinefelter male.
Hyperprolactinemia from a microor a macro-adenoma of the pituitary can be associated with SLE.7 In such cases, the disease is clinically identical to the typical idiopathic form. The disease remits when bromocriptine analogs are given or the adenoma is removed. Lupus ﬂares during pregnancy are well known, but patients are likely to have a ﬂare of the disease any time postpartum. Nevertheless, the relationship of the hyperprolactinemia of pregnancy to ﬂares of lupus is not known.
Use of Sex Steroids to Control SLE
Use of sex steroids like DHEA and 19-nortestosterone to treat lupus have not been successful due to their many side effects and overall lack of efﬁcacy.
Oral Contraceptives and Hormone Therapy
For many years, oral contraceptives were incriminated as a cause of heightened lupus activity. These observations might relate to the total amounts of ethinyl estradiol in early preparations. Further research has indicated, however, that oral contraceptives can be used safely in patients with lupus.9 The same was true of hormonal replacement therapy in postmenopausal women with the disease. However, a secondary manifestation of procoagulant activity, antiphospholipid syndrome, may coexist with systemic lupus in certain patients and is a deﬁnite contraindication to any estrogen use, preor postmenopausal.
SLE in Pregnancy
Fetal wastage occurs in 50 percent of all pregnancies in lupus patients, and still births, miscarriage, and prematurity are common.10 Hypertension, antiphospholipid antibodies, and hypocomplementemia may be at the root of most of these problems. These fetal problems might be related to local vasculitis, anti-trophoblastic antibodies, or the procoagulant state resulting from antiphospholipid antibodies. The health of the mother is also at issue, and it is unclear whether women with quiescent SLE worsen during pregnancy or whether disease activity is worse when the mother’s disease is serologically and clinically active during conception. The immunosuppression or immunomodulating effects of various steroids like estriol and progesterone during pregnancy are unknown, but must play a role. This entire subject is appropriate for further investigation in lupus and other rheumatic diseases.
Basic Researcher Perspective
By Cherie Butts, Ph.D.
Associate director of immunology research at Biogen Idec, Inc., in Cambridge, Massachusetts.
Impact of Steroid Hormones on Immunity
The immune system provides a strong defense against internal and external threats. However, factors produced in the microenvironment can either enhance or limit its activity and lead to immunopathology. Steroid hormones alter both innate and adaptive immune processes and steroid hormone receptors (e.g., glucocorticoid receptor [GR], estrogen receptor [ER], and progesterone receptor [PR]) are expressed by a variety of immune cell populations, including granulocytes, natural killer (NK) cells, monocytes, dendritic cells (DCs), and B and T lymphocytes, which can affect disease outcome.1 Many autoimmune/inﬂammatory conditions, such as systemic lupus erythematosus (SLE), exhibit gender differences in incidence. This suggests a role for sex hormones in disease development.2 Numerous studies (human and animal model) provide evidence for bi-directional communication between the immune and endocrine systems and disruptions in communication that contribute to susceptibility and severity of disease.
Glucocorticoids (both endogenous-cortisol [or corticosterone in rodents] and synthetic dexamethasone) modulate immunity, and their overall effects depend on dose—pharmacologic or physiologic—and temporal sequence of release in relation to antigenic or pro-inﬂammatory challenges.3 Stress levels of glucocorticoids result in rapid involution of the thymus and lymphocyte apoptosis. Glucocorticoids also orchestrate redistribution of circulating white blood cells with neutrophilic leukocytosis, eosinopenia, monocyteopenia, and altered ratios of T-lymphocyte subtypes, resulting in decreased peripheral blood CD4+ and increased CD8+ cells and decreased inﬁltration of neutrophils and monocytes into tissues.
The relatively greater sensitivity to glucocorticoid suppression of components of cellular versus humoral immunity tends to shift immune responses from a cellular to a humoral pattern, which is important in SLE.4 Physiological glucocorticoids can also activate the mineralocorticoid receptor (MR). The primary receptor in immune cells is GR, which is consistent with the physiologic role of glucocorticoid regulation of the immune system by stress levels of these hormones. Recent studies have shown a role for the MR, acting as a receptor for cortisol/corticosterone, in the monocyte/macrophage lineage and potentially in other immune cells. In SLE, glucocorticoids can increase expression of the IL-6 receptor—supporting B cell growth. Because SLE is characterized by excessive or inappropriate antibody production, it is important to delineate whether glucocorticoids contribute to or exacerbate this shift. These ﬁndings indicate that in addition to their suppressive role, glucocorticoids can stimulate some aspects of the immune or inﬂammatory response to initiate or aggravate SLE.
Impaired glucocorticoid control of inﬂammation could result from a lack of responsiveness in cells and tissues that normally respond to circulating glucocorticoids due to impaired receptor function.5 The contribution of the glucocorticoid receptor to glucocorticoid resistance has been explored in studies examining binding number and afﬁnity characteristics of GR in SLE. Patients who exhibit hormone resistance had abnormally high levels of GRb (a dominant-negative isoform of the GR) or defective, mutated GR. A decrease in GR number in mononuclear cells was also identiﬁed in some lupus patients, and patients had a higher percentage of lymphocytes with high P-glycoprotein activity—a molecule responsible for transporting steroids outside the cell. In addition, patients with SLE often require large doses of glucocorticoids before a therapeutic effect is seen. Furthermore, a relatively recent study examining GR in SLE patients showed not only reduced GR expression in, but also lower binding afﬁnity for glucocorticoids.
In addition to glucocorticoids, sex hormones modulate immune responses. This has been especially demonstrated by studies examining immune function during pregnancy. Sex hormones can act indirectly on immunity by inducing epithelial and other cells to secrete factors that modify immune cell activity or directly by binding sex hormone receptors expressed by immune cells (Figure 1). They alter both innate and adaptive immune responses. Different isoforms of receptors for estrogen (ER) and progesterone (PR) are expressed by a variety of immune cell populations (e.g., dendritic cells, monocyte/macrophage populations, B lymphocytes, T lymphocytes) involved in SLE. Immune cells of the myeloid lineage express ERb, which is thought to uniquely facilitate binding to plant-derived and synthetic estrogens. In addition, PR-A:PR-B ratios change during an inﬂammatory response. This is due, in part, to the increase in PR-A gene expression initiated by NF-kB. Sex hormones indirectly alter immunity by modifying secretion of factors such as transforming growth factor b (TGF-b), interleukin 10 (IL-10), and prostaglandins, by epithelial, endothelial, and other cells.7 Low-to-moderate concentrations of estrogen have been shown to increase severity of a variety of autoimmune diseases driven by B and T cells and to increase antibody production by B cells. Therefore, estrogen has been implicated in improper regulation of B-cell development and aggravation of SLE and is thought to be a primary contributor to gender differences in incidence of disease.