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Autoimmune Disease and the Female Patient
Oral Maxillofacial Surg Clin N Am 19 (2007) 153–162
Autoimmune Disease and the Female Patient Andrea Schreiber, DMD Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, 345 East 24th Street, New York, NY 10010, USA
Any discussion of autoimmune disease requires a basic understanding of the function of the normal immune system, which, simply stated, is to fight infection and heal wounds. The components of that system are cellular and humoral. Immunity is frequently categorized as natural (nonspecific or innate) and acquired (specific). The primary cellular components of the nonspecific immune system are leukocytes (macrophages, eosinophils, basophils), which act by phagocytosis, whereas the primary cellular components of the specific immune system are lymphocytes, which can be further subcategorized into B cells and T cells. The function of the specific or acquired immune system is to distinguish between self and nonself. When confronted with an antigen or foreign ‘‘invader,’’ B cells produce an antibody (immunoglobulin) specific to the foreign antigen. The B cell, once stimulated by an antigen, is programmed to ‘‘remember’’ that antigen in case it is detected again and mobilize the immune system if it does. T cells have antigen receptors on their cell surfaces and are even further subcategorized into helper and killer cells. There are two forms of T-cell receptors: those responsible for major histocompatibility complex restricted antigen recognitiondthe ab receptorsd and those that are nonrestricteddthe gd receptors. Cytotoxic or killer T cells (gd) attack antigens directly, whereas helper T cells (ab) produce cytokines and stimulate B cells and leukocytes to attack antigens. Cytokines, such as interferon and interleukins, are immune factors involved in the inflammatory process. Helper T cells are implicated in autoimmune diseases because they mistake the body’s
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own cells (self) as antigen and then trigger responses to destroy it. Specific autoantibodies have been identified for several autoimmune diseases. The complement system, a cadre of more than 30 identified proteins, is also involved in regulating the immune response. The main function of complement is to clear immune complexes, which are essentially the cellular debris left after immune activity has occurred. A failure of the complement system can contribute to autoimmune disease manifestation by failure to regulate cellular apoptosis and the deposition of immune complexes, which leads to organ system damage. Autoimmune diseases are a group of disorders that involves the recognition of ‘‘self’’ as a foreign antigen and the production of autoantibodies that attack native cells as foreign. There are disagreements within the immunology community as to which entities satisfy the definition of autoimmunitydthe range is from 20 to more than 70 disease entities (the commonly recognized diseases are listed in Box 1). Autoimmune disease affects 5% to 8% of the population of the United Statesd or more than 8 million people. Almost 80% of these individuals are women [1,2]. Because 5% of the female population of the United States is afflicted with some form of autoimmune disease and because it has been found to be one of the ten leading causes of death in young to middleaged women in this country, early diagnosis and proper treatment of autoimmune diseases are important issues in women’s health [3]. This article focuses on the pathogenesis of the gender gap of autoimmune disease. Specifically, the discussion focuses on the role of sex hormones in the immune response and the clinical manifestations of common diseases (ie, systemic lupus erythematosus [SLE], antiphospholipid syndrome [APS], and multiple sclerosis [MS]. Therapeutic
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Box 1. Common autoimmune diseases Systemic lupus erythematosus Multiple sclerosis Anti-phospholipid syndrome Rheumatoid arthritis Grave’s disease Rheumatic fever and heart disease Dermatomyositis Myasthenia gravis Systemic sclerosis Pemphigus vulgaris Goodpasture syndrome Sjo¨gren’s syndrome
modalities for these diseases are suggested to allow oral and maxillofacial surgeons to treat this unique population of patients in their everyday practice. Role of sex hormones in the immune response The prevalence of autoimmune disease in women is widely recognized, but the reason for the observed difference in the incidence of these diseases between men and women is less well understood. There are several proposed mechanisms for the female gender prevalence of immune disorders, including hormonal, genetic, environmental, cytokine, metabolic, and apoptotic [1–4]. One of the most investigated theories involves the apparent influence of sex hormones on the immune system. Sexual dimorphism in immune response between men and women is evidenced in women producing more profound cellular and humoral immune reactions and being more susceptible to autoimmune diseases. Disease expression is further affected by the reproductive stage of a woman and possibly the use of oral contraceptives and hormone replacement therapy [4]. Patients with certain immune-based diseasess such as SLE and MS, may have exacerbations during pregnancy or menses [5]. In a study of the effects of age, sex, and menopausal state on the course of early rheumatoid arthritis, Kuiper and colleagues [5] found that the Disease Activity Score was higher for women than men of similar age. Radiographic evidence of joint destruction was greater in female patients versus male patients and in postmenopausal versus premenopausal women. Physical disability was similarly found to be the worst for
postmenopausal women [5]. These effects likely represent the duration of the disease process. Systemic sclerosis is another debilitating autoimmune disease with female prevalence (most frequently postmenopausal) that manifests with fibrosis and vascular damage to the skin and viscera. Lekakis and colleagues [6] demonstrated that the administration of short-term estrogen therapy improved abnormal endothelial function in women with Raynaud’s phenomenon and systemic sclerosis [6]. Investigation into the role of sex hormones in the human immune response has focused on differences in number and function of B cells and T cells. A comparison of the number and subsets of T cells in men versus women reveals a similar number of lymphocytes in each group, but the percentage of T cells is lower in men, which may be caused by increased testosterone concentrations [4]. The differences in immune response between men and women and among women in different reproductive stages may be caused by the direct effects of sex hormones on cytokine production. This theory still remains to be proven, however. No available data indicate differences in B-cell counts between men and women, and there does not seem to be a great variation in B-cell count for women in menses, women taking oral contraceptives, or women taking hormone replacement therapy. Estrogen may have an effect on B-cell subsets in that they seem to enhance the survival of autoreactive B cells and may play a role in the higher incidence of autoimmune diseases in women. Women also demonstrate higher levels of IgG and IgM than their male counterparts, which may be caused by a stimulating effect of female sex hormones or an inhibiting effect of testosterone. Estrogen increases antibody production, whereas testosterone decreases it [4]. Because differences in sex hormone levels occur at various stages of a woman’s life, information about the effect of sex hormones on the immune response can be gleaned by investigation into the effect of pregnancy, menses, menopause, and use of oral contraceptives and hormone replacement therapy on the incidence and severity of various autoimmune diseases. An increase in granulocyte number is noted in pregnancy and the luteal phase of the normal ovarian cycle. Girls and women between puberty and menopause have higher immunoglobulin levels and more immunoglobulin response to infection or immunization than men. Hypogonadal men have similar immunoglobulin levels to normal women, but when treated with
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androgen therapy, the levels mirror those of normal men [7]. Research also has shown that progesterone enhances and estrogen decreases the chemotactic activity of neutrophils. The acquired immune system of women is different from men in that estrogens stimulate Thelper cells and B cells and androgens enhance killer T-cell activity. Estrogens, androgens, and their receptors play a role in immunoregulation and autoreactivity. Estrogens seem to have an effect on lymphocyte development by increasing B cells that express recognition of self-DNA as antigen [7]. No difference in natural killer cells is demonstrated between the sexes. Natural killer cells are capable of killing tumor cells and virusinfected cells in the absence of prior immunization. It has been suggested that the ability of natural killer cells to lyse other cells is suppressed by progesterone because higher activity is noted in men and postmenopausal women compared to women of child-bearing age and women taking oral contraceptives. Women are three times more likely to develop MS and rheumatoid arthritis and account for 75% of patients who have myasthenia gravis. Women produce a more vigorous response to infection called the TH-1 response, which generates a more proinflammatory mix of cytokines, whereas men produce a TH-2 response in which antibody production predominates and there is a milder cytokine response. It is thought that women shift to a TH-2 response in pregnancy, which may explain why symptoms of MS and rheumatoid arthritis improve during pregnancy [2]. SLE is the most female dominant autoimmune disease, with a reported 9:1 ratio. Also noted is an increased incidence of disease after puberty and a decline after menopause. Levels of sex steroids can affect cytokine levels, which are important in the generation of an immune response. The levels of androgen seem to be important in the pathogenesis of SLE, as evidenced by the fact that androgens are preferentially oxidized by women with the disease and by the fact that men with low levels of androgens have an increased propensity for the disease. Male and female patients who have SLE also seem to have altered estrogen metabolism, with urinary metabolites demonstrating skewing toward the more feminizing estrogen metabolites. The relationship of sex hormones, cytokines, and lymphocytes is complex and involves B-cell differentiation, T-cell subset selection, T-cell maturation, and apoptosis [8].
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Patients who have SLE demonstrate elevated estrogen/androgen ratios compared to healthy controls. Patients who have SLE metabolize estrogens differently than unaffected patients, with increasing fraction of high-potency estrogens being noted. These potent estrogens cause patients who have SLE to circulate more lymphocytes that are primed for autoreactivity by bypassing developmental deletion. Patients who have SLE also demonstrate decreased availability of testosterone and dehydroepiandosterone. Hypogonadal men (Klinefelter’s) demonstrate an increased incidence of autoimmune disease compared to healthy men [9]. In men with SLE, a significant prevalence of sex hormone abnormality, notably hypoandrogenism, was found compared to a disease-free control male population. SLE is characterized by increased activity of a subset of helper T cells and decreased activity of killer T cells. A defect in interferon production also has been reported. Patients who have SLE are immunoreactive to self because of circulating lymphocytes that are primed to react and are exposed to intracellular cell components as a result of a defect in apoptosis or programmed cell death. Apoptosis is part of the human body’s homeostatic mechanism for new cell proliferation and old cell death. Regulated cell death occurs by endonuclease activity. Apoptotic cells remain intact and are cleared by the complement system and phagocytes. If there is a defect in this process, the cell membrane dissolves and intracellular components become available for immunosurveillance. Patients who have SLE demonstrate errant apoptosis and apoptotic cell clearance [7]. The future may hold promise for pharmacologic hormone therapy aimed at normalizing the male/female sex hormone ratio in patients who have SLE as a future therapeutic or preventive modality. Another theory to consider in the comparison of incidence of autoimmune diseases in men versus women is the role of X inactivation and cellular mosaicism. Biologically speaking, women are not the weaker sex. Women are generally healthier and live longer than men. According to the US Census Bureau, in 2010 the life expectancy for women will be 81 years of age compared with 74 years of age for men. In 2002, it was four times more likely for a woman aged 65 or older to be widowed than her male counterpart. More male fetuses are lost in utero than female fetuses, and more males babies die in infancy. In looking at a genetic as opposed to hormonal explanation for these differences, some
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explanation for male vulnerability may be because men have only one X chromosome and women have two. Having only one X chromosome makes men more vulnerable to genetic mutations. A woman with a similar genetic defect on one allele may have partial protections from a second, normal allele. Women come equipped with ‘‘backup systems’’; men do not. Mosaicism for the X chromosome in a woman plays a role in the female expression of disease and often is advantageous and protective. Men frequently manifest more severe forms of X-linked mutation diseases, such as hemophilia and Duchenne muscular dystrophy. The X chromosome also encodes antibodies that protect against infection, which could make men more immunodeficient than women. It is reasonable to consider that X inactivation may play a role in the prevalence of autoimmune disease in women [10].
Common autoimmune diseases Systemic lupus erythematosus SLE is a chronic autoimmune disease that may affect multiple organ systems in the body and may manifest myriad symptoms. Common symptoms include fatigue, joint problems, skin rashes, fever, headache, abdominal discomfort, and dizziness. Vasculitis with impaired circulation, accelerated atherosclerosis, myocarditis, endocarditis, pericarditis, pleuritis, and nephritis also may occur. More than 70% of cases of SLE are characterized as widespread with periods of flares and remissions, with the remainder of cases being mild. The 10year survival rate of SLE with treatment is approximately 90%. SLE is more common in women of African, Hispanic, Asian, and Native American descent and is most frequent in women of child-bearing age (15–45). There are several subcategories of lupus, including discoid lupus erythematosus, drug-induced lupus erythematosus, neonatal lupus erythematosus, and neuropsychiatric lupus erythematosus. The American College of Rheumatology has identified 11 signs and symptoms to aid in the diagnosis of SLE (Box 2). A patient must demonstrate at least 4 of these symptoms for lupus to be suspected. Because symptoms may not all occur at once, an accurate medical history and comprehensive physical examination are necessary for diagnosis. Laboratory data that may aid in the diagnosis of SLE include complete blood count, erythrocyte sedimentation rate, urinanalysis,
Box 2. American College of Rheumatology criteria for the diagnosis of lupus Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis: nonerosive involving two or more peripheral joints, nonsymmetrical Serositis: pericarditis or pleuritis Renal disorder: proteinuria or cell casts Neurologic disorder: seizures or psychosis Hematologic disorder: hemolytic anemia, leucopenia, lymphopenia, thrombocytopenia Antinuclear antibody Immunologic disorder: + anti–double-stranded DNA, + antiphospholipid antibody or false + VDRL
echocardiograms, radiographs, brain imaging, and skin or renal biopsies to evaluate for organ system involvement. An antinuclear antibody panel is helpful to establish a diagnosis. The presence of certain autoantibodies may aid in the diagnosis of SLE, including ANA, anti-ds DNA, anti-Sm, anti-Ro (SSA), and anti-La (SSB). Although they may be frequently increased in patients who have SLE, not all patients who have SLE demonstrate elevated levels. Other conditions also may cause elevated levels of these autoantibodies. High levels of ANA are found in approximately 98% of patients who have SLE. ANA may be strongly positive in other autoimmune diseases and weakly positive in healthy women, however. High or low levels of ANA do not necessarily correlate with severity of disease, and ANA may be negative in a patient who has SLE. Anti-ds DNA antibodies are more frequently found in SLE than other autoimmune disorders. This finding usually indicates vascular injury and correlates well with renal involvement [11]. Given the range of organ system involvement and level of severity of disease, patients who have SLE may be managed by any or all of the following specialists: internists, rheumatologists, nephrologists, dermatologists, clinical immunologists, cardiologists, hematologists, or
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neurologists. Treatment plans are individualized depending on the nature of symptoms and severity of the disease. Treatment goals are to minimize flare-ups and prevent organ damage. Common therapeutic modalities include nonsteroidal antiinflammatory medications, antimalarial agents, corticosteroids, immunosuppressives, thalidomide, hormones, and various other agents. Nonsteroidal anti-inflammatory drugs may be used alone or in combination with other therapies to decrease inflammation and treat joint pain and fever. Antimalarial agents are used alone or in combination with other therapies to treat fatigue, joint pain, pleuritis, and skin rashes and prevent flares. Side effects of antimalarial agents include headache, change in skin color, hair loss, and reversible retinal damage. Corticosteroids are the mainstay of therapy for most patients who have SLE because of their rapid anti-inflammatory effect. Generally, the lowest possible doses for the shortest possible duration are administered to avoid side effects of weight gain, osteoporosis, hyperglycemia, hypertension, muscle wasting, fluid retention, glaucoma, and increased susceptibility to infections. Immunosuppressive medications that are usually reserved for patients with renal, vascular, or neurologic involvement work by blocking immune cells. Side effects of immunosuppressive therapy include nausea, vomiting, hair loss, increased susceptibility to infection, and infertility in female patients. Thalidomide inhibits cytokines and reduces disease progression by reducing new blood vessel formation. A major side effect of thalidomide is peripheral neuropathy. Treatment with mild male hormones, such as dehydroepiandosterone and danazol, has been shown to offer some benefit for patients who have mild SLE but not for patients who have severe SLE. Side effects of male hormone therapy include development of acne and excess facial hair. Additional experimental therapies include monoclonal antibodies, plasmapheresis, nucleoside analogs, and autologous stem cell transplantation coupled with immunosuppressive therapy. Patients who have SLE also present with specific cardiovascular, pulmonary, and renal disorders that require attention. Cardiovascular disease may be the result of disease or treatment (eg, steroids), which in turn increases the risk of myocardial infarction and stroke. These risks include hypertension secondary to renal disease, accelerated atherosclerosis, valvular pathology, congestive heart failure, thromboembolic
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phenomena, and elevated homocysteine levels, which have been implicated in the development of strokes and myocardial infarctions. More than 60% of patients who have SLE develop pulmonary problems, including pleuritis, lupus pneumonitis, and pulmonary hypertension. Approximately 50% of patients who have SLE develop lupus nephritis as a result of damage and scarring of renal tissues; approximately 30% of these patients progress to end-stage renal failure. Cardiac manifestations of SLE include pericarditis, myocarditis, and endocarditis. There is a reported prevalence of pericarditis in 60% of patients [12]. Cerebrovascular disease in patients who have SLE is reported in approximately 50% of patients studied by Roldan and colleagues [13], whereas significant valvular disease was found in almost 70% of patients. Valvular pathology occurred two to three times more frequently with than without cerebrovascular disease. Valvular heart disease seems to be associated with embolic ischemic brain injury and cerebrovascular disease in patients who have SLE [13]. Valvular pathology is the most common form of cardiac involvement found in patients who have SLE, with a reported incidence of up to 77%. Transesophageal echocardiography is the most sensitive test for valve pathology. The condition frequently takes the form of valve thickening, vegetations of immunoglobulin and complement (Libman-Sacks vegetations), and valvular regurgitation. Most patients are asymptomatic until the regurgitation becomes severe. Autopsy evidence of Libman-Sacks endocarditis is reported at between 13% and 74%. There is no clear correlation between the existence of Libman-Sacks vegetations and clinical finding of murmurs. The mechanism of valvular damage in SLE is thought to be complement activation and immune complex deposition. The prevalence of infective endocarditis in patients who have SLE has been reported to be comparable to that of patients with prosthetic heart valves. Because of poor prognosis of patients who have SLE and infective endocarditis, this needs to be ruled out and differentiated from pseudoinfective endocarditis or Libman-Sacks endocarditis by repeated blood cultures. In view of this risk, it is suggested that all patients who have SLE receive antibiotic prophylaxis before procedures with a risk of bacteremia [14,15]. The significance of valvular heart disease in patients who have lupus is underscored by Roldan’s [16] finding that the combined incidence of
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stroke, infective endocarditis, need for valve replacement, peripheral embolism, and heart failure was 22% in patients who have lupus with valvular disease confirmed on echocardiography but only 8% in patients who have lupus without it. Many complications experienced by patients who have lupus, such as ischemic strokes, peripheral emboli, and infective endocarditis, were associated with valvular disease. The nature of the valvular pathology may change over time. New abnormalities may develop, and temporal relation to other clinical sequelae of lupus has yet to be established [16,17]. Drug-induced lupus erythematosus may share symptoms and laboratory findings characteristic with SLE. The first reported case was linked to use of sulfadiazine. More than 80 drugs have since been associated with development of drug-induced lupus. Patients are generally older than typical patients who have SLE, and the female preponderance is less obvious. Recognition of this entity is important because symptoms often resolve shortly after stopping the drug. Antiphospholipid syndrome APS is an autoimmune disorder of unknown origin. APS may occur primarily without associated disease (primary APS) or in conjunction with other autoimmune entities (secondary APS), most notably SLE, rheumatoid arthritis, and Sjo¨gren’s disease. It is frequently discussed in conjunction with SLE because up to 50% of patients who have lupus demonstrate antiphospholipid (APL) antibodies. A female preponderance is reported in the child-bearing years, similar to that of SLE. Antiphospholipid antibodies are also found in a small percentage of healthy patients. APS is characterized by recurrent vascular thrombosis (arterial or venous), thrombocytopenia, and miscarriage [18–20]. The mechanism for the thrombosis is unclear but it is theorized that a defect in apoptosis may expose membrane phospholipids to coagulation proteins, which become targets of autoantibodies and result in a hypercoagulable state. The clinical manifestations are related to the site of injury and may present as local, systemic, or neurologic problems. Retinal, renal, pulmonary, and dermal manifestations are common. Neurologic consequences include reversible or fixed focal deficits from strokes or transient ischemic attacks. APS should be considered in the differential diagnosis of new strokes in younger patients (!50 years). Concern about the association of APS with SLE
involves the triad of valvular abnormalities, Libman-Sacks endocarditis, and emboli resulting in increased risk of strokes, myocardial infarctions, and need for valve replacement [21]. APS involves a range of antiphospholipid plasma antibodies, including anticardiolipin antibodies, anti-beta 2 glycoprotein I antibodies, and lupus anticoagulant. These are antibodies to a phospholipids-protein complex. Anticardiolipin antibodies have been subdivided into isotypes that may help explain the heterogeneity of the disease. The IgG isotype is associated with thrombosis and pregnancy loss, and the IgM isotype is associated with hemolytic anemia. A higher titer of the IgG isotype seems to correlate well with increased risk of miscarriage and thrombosis. Management of APS is directed toward the prevention of recurrent thrombosis, which is a frequent occurrence in these patients. Prolonged anticoagulant therapy for patients after venous thrombosis is advised. The target International Normalized Ratio (INR) has been reported to be between 2.5 and 3.5 [17,18]. In patients who suffer an arterial thrombosis or stroke, combinations of aspirin, clopidrel, and warfarin have been used. Pregnant patients may be managed on aspirin and subcutaneous heparin injections and should be monitored closely [19,20]. Echocardiography has shown the incidence of valvular pathology to be approximately 33% in patients who have APS and more than 70% in patients who have SLE and APS. The incidence of valvular pathology in patients who have SLE is highest among individuals who have APS. Valvular lesions usually present as thickening of the leaflets and frequently result in a regurgitant valve. Clinical valvular disease is not common. The presence of APLs increases the risk of thromboembolic eventsdmost often cerebrovascular in nature. The risk of development of bacterial or pseudoinfective endocarditis also exists. Treatment is usually aimed at preventing thrombus formation with antiplatelet or anticoagulant therapy [21]. SLE and APS demonstrate accelerated atherosclerotic disease. The mechanism seems to be an aberration in the metabolism of lipoproteins that leads to formation of proinflammatory cytokines and activation of the innate and acquired immune response. The identification of protective antibodies may offer immunomodulation treatment strategies for SLE, APS, and atherosclerosis [22]. Other mechanisms have been suggested for the accelerated rate of development of atherosclerosis, including cytokines, estrogen deficiency immune
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complexes, and errant apoptosis. The failure of hormone replacement therapy to be cardioprotective in postmenopausal women raises questions as to the role of estrogens in this disease process. Attention is turned to the role of estrogen metabolites in increasing inflammatory immune response [23]. The role of atherosclerosis in autoimmune disease is complicated by the fact that patients may present with a combination of traditional risk factors, such as hypertension, diabetes, hyperlipidemia, and the enhanced risk factors of autoimmune disease, including antiphospholipid antibodies and inflammation. It is proposed that antiphospholipid antibodies and inflammation may cause atherosclerotic plaques in patients with autoimmune disease to rupture more readily than plaques in patients without autoimmune disease. Patients with autoimmune disease, specifically SLE and APS, must be evaluated and treated for cardiovascular disease (CVD) based on traditional risk factors and disease-related risk factors [24]. Multiple sclerosis MS is an autoimmune disease of the central nervous system that affects approximately 400,000 Americans and millions of people worldwide [25]. The disease is most common in young adults between the ages of 20 and 50, and women are afflicted two to three times more frequently than men. The age and sex distribution of the MS patient population is consistent with other autoimmune diseases that are thought to be modulated by sex hormone levels. This theory is further supported by the observation that the frequency of relapses decreases in each trimester of pregnancy but increases in the postpartum period. The lowering of the helper-suppressor T-cell ratio in pregnancy and its observed effect on mediating the course of MS is likely caused by estriol, a hormone that is produced by the fetal placental unit. More specifically, a shift from T-helper 1 (proinflammatory) to T-helper 2 (anti-inflammatory) response is noted in pregnancy. In the postpartum period, a 70% increase in relapse rate is noted [26]. Lasting protective effects against the development of MS from the exogenous administration of estrogens (in the form of oral contraceptives) have not been demonstrated. Apparently, the protection afforded by estrogens in pregnancy and with oral contraceptive use is not demonstrable in the postpartum period or when the use of the oral
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contraceptives is terminated [27]. Whites are the most commonly affected ethnic group. The clinical characteristics of MS are secondary to loss of the myelin sheath surrounding nerve fibers, which results in disruption of the conduction of electrical impulses. The trigger for this response remains unknown, but genetic and environmental factors have been implicated. Although no specific MS gene has been identified, a first-degree relative of a patient who has MS is 20 times more likely to contract MS than a nonrelative. Environmental triggers, including viruses and toxic substances, have been implicated in the generation of MS. The most commonly implicated, but not proven, infectious triggers seem to be herpes simplex 6 and chlamydial pneumonia [28]. It has been noted that relapses in patients who have MS frequently follow respiratory or gastrointestinal illnesses. Of particular interest is geographic clustering of MS cases in the northern latitudes of the northern and southern hemispheres. There are four distinct disease patterns of MS: relapsing-remitting, primary-progressive, secondary-progressive, and progressive-relapsing [28]. The relapsing-remitting pattern is the most common form of the disease identified at the time of diagnosis. This pattern is characterized by exacerbations of symptoms followed by partial or complete recovery and periods of remission. The primary-progressive pattern displays a chronic and continuous worsening of symptoms with no exacerbations or periods of remission. The secondary-progressive form starts as a pattern of relapsing-remitting MS and is followed by a course of slowly progressive deterioration with few, if any, remissions observed. Approximately half of the patients initially diagnosed with the relapsing-remitting form of the disease progress to this pattern within 10 years of diagnosis. The progressive-relapsing form is the rarest pattern of the disease, which is characterized by progressive worsening with periodic acute exacerbations. A small percentage of individuals who have MS never demonstrate significant functional deficit, whereas another small percentage of patients becomes severely disabled in a short period of time. The most common symptoms of MS include changes in cognitive function (including problems with memory and attention), depression, fatigue, gait disturbances, paresthesias, visual disturbances, dizziness, pain, and bowel, bladder, and sexual dysfunction. Because patients may experience some, but not all, of these symptoms and may experience
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different symptoms at different times, the diagnosis of MS may be elusive initially. The prognosis for patients seems to be better if their symptoms are visual or sensory rather than motor in nature. Diagnosis of MS requires documentation of at least two distinct episodes of relapses and involvement of more than one area of the nervous system [29]. In addition to a comprehensive history and clinical examination, an MRI, evoked potentials, and evaluation of the cerebrospinal fluid are useful in confirming the diagnosis, but no specific laboratory test for MS exists. Characteristically, reduced velocity of evoked potentials is found in patients who have MS. The demyelination process is thought to explain several clinical characteristics of the disease, including exacerbation induced by elevated temperature, electrical sensation in the extremities, paroxysmal symptoms of trigeminal neuralgia, and ataxia (thought to be caused by ‘‘cross talk’’ between demyelinated neighbor axons) [28]. Evaluation of the cerebrospinal fluid of patients who have MS demonstrates oligoclonal IgG bands in more than 90% of cases, which seems to confirm an underlying inflammatory cause of the disease. Although the cause of MS is unknown, the histologic presentation has been well documented. MS plaques are lesions that classically present with demyelination and perivascular inflammation. Although it has not yet been determined if the perivascular inflammation is the cause or result of the demyelination process, it seems likely that the demyelination is a result of an acute inflammatory process. The result of the plaque formation is a slowing of nerve conduction in affected areas. Plaque formation is thought to be the result of a failure to regulate autoreactive myelin T cells, which leads to the release of inflammatory mediators and cytokines [28]. The goal of treatment of MS is to limit the frequency of relapses, limit the effects of relapses, prevent permanent disability from disease progression, and promote tissue repair, if possible. The most commonly used agents in the treatment of relapsing-remitting MS are the beta interferons (beta 1-a and beta 1-b), which were initially used because of the observation that relapses frequently followed viral infections. The efficacy of the interferons is more likely related to their antagonistic effect on proinflammatory cytokines. Other agents that are commonly used in an effort to reduce the frequency of flare-ups and associated disabilities are glatiramer acetate (which seems to inhibit binding to T-cell receptors),
azathioprine (an immunosuppressive agent that inhibits lymphocyte infiltration), and mitoxantrone (an antineoplastic agent that inhibits DNA synthesis and suppresses T-cell, B-cell, and macrophage activity), which is limited in use only for patients with severe progressive disease. Corticosteroids, a mainstay of treatment for many autoimmune diseases, are used for treatment of acute relapses because of their anti-inflammatory effects. Corticosteroids may be administered intravenously or orally and are used to reduce the consequences of the relapses, not to prevent them [28]. Management of the female oral surgical patient who has autoimmune disease The surgical management of patients who have autoimmune disease is the same, regardless of gender. The first principle of treatment is for oral and maxillofacial surgeons to be familiar with their patients and the course and nature of the patient’s disease. If information gathered from a patient is insufficient to determine the impact of the disease or treatment regimen on proposed surgical care, consultation with treating physicians is definitely indicated. Formulas and gross generalizations on patient management should be avoided because, as noted in this article’s brief discussion of three (of a possible R70) diseases categorized as autoimmune, the clinical characteristics, nature and severity, and organ system involvement vary greatly from disease to disease and within a specific disease entity from patient to patient. A common finding in the treatment of many autoimmune diseases is the intermittent and possibly chronic administration of corticosteroids and immunosuppressive and antineoplastic agents. Before embarking on any surgical/anesthetic treatment course, oral and maxillofacial surgeons must be aware of the dosage, duration, and frequency of use of these medications. Elective surgery may need to be timed to ensure adequate healing potential, and antibiotics and stress steroid dosing may need to be considered for certain patients. Many postmenopausal female patients with autoimmune diseases may have been placed on bisphosphonate therapy, especially if they have a history of chronic steroid use in the past. Consideration in the management of these patients for required and elective surgery must include a discussion of the risk, however marginal, of osteonecrosis.
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Because many autoimmune diseases demonstrate multiorgan system involvement, including pulmonary, cardiac, and renal disorders, oral and maxillofacial surgeons must be aware of specific risks that patients may encounter before embarking on a surgical/anesthetic course of treatment. In SLE, for example, consideration of altered renal status and the risk of endocarditis secondary to valvular involvement is indicated. The risk/ benefit of changing anticoagulation and antiplatelet medication protocols in patients with APS also must be considered carefully.
Summary Although the pathogenesis of autoimmune disease and the cause of female prevalence of these entities remain to be clearly elucidated, the principles of treatment for all patients with autoimmune disease hinge on the surgeon’s appreciation of the diversity of symptomatology and organ system involvement. Such an approach results in better treatment outcomes with respect to surgical intervention in this population of patients.
References [1] Fairweather D, Rose NR. Women and autoimmune diseases. Emerging Infect Dis 2004;10(11):2005–11. [2] McCarthy M. The ‘‘gender gap’’ in autoimmune disease. Lancet 2000;356(9235):1088. [3] Walsh SJ, Rau LM. Autoimmune diseases: a leading cause of death among young and middle-aged women in the United States. Am J Public Health 2000;90(9):1463–6. [4] Bouman A, Heineman MJ, Faas MM. Sex hormones and the immune response in humans. Hum Reprod Update 2005;11(4):411–23. [5] Kuiper S, van Gestel AM, Swinkels HL, et al. Influence of sex, age, and menopausal state on the course of early rheumatoid arthritis. J Rheumatol 2001; 28(8):1809–16. [6] Lekakis J, Mavrikakis M, Papamichael C, et al. Short-term estrogen administration improves abnormal endothelial function in women with systemic sclerosis and Raynaud’s phenomenon. Am Heart J 1998;136(5):905–12. [7] Ackerman L. Sex hormones and the genesis of autoimmunity. Arch Dermatol 2006;142:371–6. [8] Lahita RG. Emerging concepts for sexual predilection in the disease systemic lupus erythematosus. Ann N Y Acad Sci 1999;(876):64–70.
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[9] Sequeira JF, Keser G, Greenstein B, et al. Systemic lupus erythematosus: sex hormones in male patients. Lupus 1993;2(5):315–7. [10] Migeon BR. The role of x inactivation and cellular mosaicism in women’s health and sex-specific diseases. JAMA 2006;295(12):1428–33. [11] Available at: www.lupus.org. [12] Bijl M, Brouwer J, Kallenberg GG. Cardiac abnormalities in SLE: pancarditis. Lupus 2000;9(4): 236–40. [13] Roldan CA, Gelgand EA, Qualis CR, et al. Valvular heart disease as a cause of cerebrovascular disease in patients with systemic lupus erythematosus. Am J Cardiol 2005;95(12):1441–7. [14] Fluture A, Chaudhari S, Frishman W. Valvular heart disease and systemic lupus erythematosus: therapeutic implications. Heart Dis 2003;5(5):349–53. [15] Miller CS, Egan RM, Falace DA, et al. Prevalence of infective endocarditis in patients with systemic lupus erythematosus. J Am Dent Assoc 1999;130(3): 387–92. [16] Roldan CA, Shively BK, Crawford MH. An echocardiographic study of valvular heart disease associated with systemic lupus erythematosus. N Engl J Med 1996;335(19):1424–30. [17] Ruiz-Irastorza G, Khamashta MA, Castellino G, et al. Systemic lupus erythematosus. Lancet 2001; 357(9261):1027–32. [18] Ng HJ, Crowther MA. Anticoagulation therapy in the antiphospholipid syndrome: recent advances. Curr Opin Pulm Med 2005;11(5):368–72. [19] Asherson RA, Iaccarino C, Khamashta L, et al. The antiphospholipid antibody syndrome: diagnosis, skin manifestations and current therapy. Clin Exp Rheumatol 2006;24(1 Suppl 40):S46–51. [20] DeMarco P, Singh I, Weinstein A. Management of the antiphospholipid syndrome. Curr Rheumatol Rep 2006;8(2):114–20. [21] Hojnik M, George J, Ziporen L, et al. Heart valve involvement (Libman-Sacks endocarditis) in the antiphopholipid syndrome. Circulation 1996;93(8): 1579–87. [22] Jara LJ, Medina G, Vera-Lastra O, et al. Accelerated atherosclerosis, immune response and autoimmune rheumatic diseases. Autoimmun Rev 2006; 5(3):195–201. [23] Cutolo M, Sulli A, Seriolo B. Estrogens, autoimmunity and the heart. Lupus 2005;14(9):675–8. [24] Frostegard J. Atherosclerosis in patients with autoimmune disorders. Arterioscler Thromb Vasc Biol 2005;25(9):1776–85. [25] Rodriguez M. Multiple sclerosis: insights into molecular pathogenesis and therapy. Mayo Clin Proc 1997;72(7):663–4. [26] Bennett KA. Pregnancy and multiple sclerosis. Clin Obstet Gynecol 2005;48(1):38–47. [27] Hernan M, Hohol MJ, Olek MJ, et al. Oral contraceptives and the incidence of multiple sclerosis. Neurology 2000;55(6):848–53.
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[28] Compston A, Coles A. Multiple sclerosis. Lancet 2002;359(9313):1221–31. [29] Available at: www.nationalmssociety.org.
Further readings Chockalingham A, Prabhakar D, Gnanavelu G, et al. Pancarditis as initial presentation of systemic lupus erythematosus. Int J Cardiol 2003;87(1):111–4.
Cutolo M, Sulii A, Capellino S, et al. Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus 2004;13(9):635–8. Lahita RG. Sex hormones and systemic lupus erythematosus. Rheum Dis Clin North Am 2000;26(4): 951–68. Merrill JT. The antiphospholipid syndrome and atherosclerosis: clue to pathogenesis. Curr Rheumatol Rep 2003;5(5):401–6.
Autoimmune Disease and the Female Patient Andrea Schreiber, DMD Department of Oral and Maxillofacial Surgery, New York University College of Dentistry, 345 East 24th Street, New York, NY 10010, USA
Any discussion of autoimmune disease requires a basic understanding of the function of the normal immune system, which, simply stated, is to fight infection and heal wounds. The components of that system are cellular and humoral. Immunity is frequently categorized as natural (nonspecific or innate) and acquired (specific). The primary cellular components of the nonspecific immune system are leukocytes (macrophages, eosinophils, basophils), which act by phagocytosis, whereas the primary cellular components of the specific immune system are lymphocytes, which can be further subcategorized into B cells and T cells. The function of the specific or acquired immune system is to distinguish between self and nonself. When confronted with an antigen or foreign ‘‘invader,’’ B cells produce an antibody (immunoglobulin) specific to the foreign antigen. The B cell, once stimulated by an antigen, is programmed to ‘‘remember’’ that antigen in case it is detected again and mobilize the immune system if it does. T cells have antigen receptors on their cell surfaces and are even further subcategorized into helper and killer cells. There are two forms of T-cell receptors: those responsible for major histocompatibility complex restricted antigen recognitiondthe ab receptorsd and those that are nonrestricteddthe gd receptors. Cytotoxic or killer T cells (gd) attack antigens directly, whereas helper T cells (ab) produce cytokines and stimulate B cells and leukocytes to attack antigens. Cytokines, such as interferon and interleukins, are immune factors involved in the inflammatory process. Helper T cells are implicated in autoimmune diseases because they mistake the body’s
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own cells (self) as antigen and then trigger responses to destroy it. Specific autoantibodies have been identified for several autoimmune diseases. The complement system, a cadre of more than 30 identified proteins, is also involved in regulating the immune response. The main function of complement is to clear immune complexes, which are essentially the cellular debris left after immune activity has occurred. A failure of the complement system can contribute to autoimmune disease manifestation by failure to regulate cellular apoptosis and the deposition of immune complexes, which leads to organ system damage. Autoimmune diseases are a group of disorders that involves the recognition of ‘‘self’’ as a foreign antigen and the production of autoantibodies that attack native cells as foreign. There are disagreements within the immunology community as to which entities satisfy the definition of autoimmunitydthe range is from 20 to more than 70 disease entities (the commonly recognized diseases are listed in Box 1). Autoimmune disease affects 5% to 8% of the population of the United Statesd or more than 8 million people. Almost 80% of these individuals are women [1,2]. Because 5% of the female population of the United States is afflicted with some form of autoimmune disease and because it has been found to be one of the ten leading causes of death in young to middleaged women in this country, early diagnosis and proper treatment of autoimmune diseases are important issues in women’s health [3]. This article focuses on the pathogenesis of the gender gap of autoimmune disease. Specifically, the discussion focuses on the role of sex hormones in the immune response and the clinical manifestations of common diseases (ie, systemic lupus erythematosus [SLE], antiphospholipid syndrome [APS], and multiple sclerosis [MS]. Therapeutic
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Box 1. Common autoimmune diseases Systemic lupus erythematosus Multiple sclerosis Anti-phospholipid syndrome Rheumatoid arthritis Grave’s disease Rheumatic fever and heart disease Dermatomyositis Myasthenia gravis Systemic sclerosis Pemphigus vulgaris Goodpasture syndrome Sjo¨gren’s syndrome
modalities for these diseases are suggested to allow oral and maxillofacial surgeons to treat this unique population of patients in their everyday practice. Role of sex hormones in the immune response The prevalence of autoimmune disease in women is widely recognized, but the reason for the observed difference in the incidence of these diseases between men and women is less well understood. There are several proposed mechanisms for the female gender prevalence of immune disorders, including hormonal, genetic, environmental, cytokine, metabolic, and apoptotic [1–4]. One of the most investigated theories involves the apparent influence of sex hormones on the immune system. Sexual dimorphism in immune response between men and women is evidenced in women producing more profound cellular and humoral immune reactions and being more susceptible to autoimmune diseases. Disease expression is further affected by the reproductive stage of a woman and possibly the use of oral contraceptives and hormone replacement therapy [4]. Patients with certain immune-based diseasess such as SLE and MS, may have exacerbations during pregnancy or menses [5]. In a study of the effects of age, sex, and menopausal state on the course of early rheumatoid arthritis, Kuiper and colleagues [5] found that the Disease Activity Score was higher for women than men of similar age. Radiographic evidence of joint destruction was greater in female patients versus male patients and in postmenopausal versus premenopausal women. Physical disability was similarly found to be the worst for
postmenopausal women [5]. These effects likely represent the duration of the disease process. Systemic sclerosis is another debilitating autoimmune disease with female prevalence (most frequently postmenopausal) that manifests with fibrosis and vascular damage to the skin and viscera. Lekakis and colleagues [6] demonstrated that the administration of short-term estrogen therapy improved abnormal endothelial function in women with Raynaud’s phenomenon and systemic sclerosis [6]. Investigation into the role of sex hormones in the human immune response has focused on differences in number and function of B cells and T cells. A comparison of the number and subsets of T cells in men versus women reveals a similar number of lymphocytes in each group, but the percentage of T cells is lower in men, which may be caused by increased testosterone concentrations [4]. The differences in immune response between men and women and among women in different reproductive stages may be caused by the direct effects of sex hormones on cytokine production. This theory still remains to be proven, however. No available data indicate differences in B-cell counts between men and women, and there does not seem to be a great variation in B-cell count for women in menses, women taking oral contraceptives, or women taking hormone replacement therapy. Estrogen may have an effect on B-cell subsets in that they seem to enhance the survival of autoreactive B cells and may play a role in the higher incidence of autoimmune diseases in women. Women also demonstrate higher levels of IgG and IgM than their male counterparts, which may be caused by a stimulating effect of female sex hormones or an inhibiting effect of testosterone. Estrogen increases antibody production, whereas testosterone decreases it [4]. Because differences in sex hormone levels occur at various stages of a woman’s life, information about the effect of sex hormones on the immune response can be gleaned by investigation into the effect of pregnancy, menses, menopause, and use of oral contraceptives and hormone replacement therapy on the incidence and severity of various autoimmune diseases. An increase in granulocyte number is noted in pregnancy and the luteal phase of the normal ovarian cycle. Girls and women between puberty and menopause have higher immunoglobulin levels and more immunoglobulin response to infection or immunization than men. Hypogonadal men have similar immunoglobulin levels to normal women, but when treated with
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androgen therapy, the levels mirror those of normal men [7]. Research also has shown that progesterone enhances and estrogen decreases the chemotactic activity of neutrophils. The acquired immune system of women is different from men in that estrogens stimulate Thelper cells and B cells and androgens enhance killer T-cell activity. Estrogens, androgens, and their receptors play a role in immunoregulation and autoreactivity. Estrogens seem to have an effect on lymphocyte development by increasing B cells that express recognition of self-DNA as antigen [7]. No difference in natural killer cells is demonstrated between the sexes. Natural killer cells are capable of killing tumor cells and virusinfected cells in the absence of prior immunization. It has been suggested that the ability of natural killer cells to lyse other cells is suppressed by progesterone because higher activity is noted in men and postmenopausal women compared to women of child-bearing age and women taking oral contraceptives. Women are three times more likely to develop MS and rheumatoid arthritis and account for 75% of patients who have myasthenia gravis. Women produce a more vigorous response to infection called the TH-1 response, which generates a more proinflammatory mix of cytokines, whereas men produce a TH-2 response in which antibody production predominates and there is a milder cytokine response. It is thought that women shift to a TH-2 response in pregnancy, which may explain why symptoms of MS and rheumatoid arthritis improve during pregnancy [2]. SLE is the most female dominant autoimmune disease, with a reported 9:1 ratio. Also noted is an increased incidence of disease after puberty and a decline after menopause. Levels of sex steroids can affect cytokine levels, which are important in the generation of an immune response. The levels of androgen seem to be important in the pathogenesis of SLE, as evidenced by the fact that androgens are preferentially oxidized by women with the disease and by the fact that men with low levels of androgens have an increased propensity for the disease. Male and female patients who have SLE also seem to have altered estrogen metabolism, with urinary metabolites demonstrating skewing toward the more feminizing estrogen metabolites. The relationship of sex hormones, cytokines, and lymphocytes is complex and involves B-cell differentiation, T-cell subset selection, T-cell maturation, and apoptosis [8].
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Patients who have SLE demonstrate elevated estrogen/androgen ratios compared to healthy controls. Patients who have SLE metabolize estrogens differently than unaffected patients, with increasing fraction of high-potency estrogens being noted. These potent estrogens cause patients who have SLE to circulate more lymphocytes that are primed for autoreactivity by bypassing developmental deletion. Patients who have SLE also demonstrate decreased availability of testosterone and dehydroepiandosterone. Hypogonadal men (Klinefelter’s) demonstrate an increased incidence of autoimmune disease compared to healthy men [9]. In men with SLE, a significant prevalence of sex hormone abnormality, notably hypoandrogenism, was found compared to a disease-free control male population. SLE is characterized by increased activity of a subset of helper T cells and decreased activity of killer T cells. A defect in interferon production also has been reported. Patients who have SLE are immunoreactive to self because of circulating lymphocytes that are primed to react and are exposed to intracellular cell components as a result of a defect in apoptosis or programmed cell death. Apoptosis is part of the human body’s homeostatic mechanism for new cell proliferation and old cell death. Regulated cell death occurs by endonuclease activity. Apoptotic cells remain intact and are cleared by the complement system and phagocytes. If there is a defect in this process, the cell membrane dissolves and intracellular components become available for immunosurveillance. Patients who have SLE demonstrate errant apoptosis and apoptotic cell clearance [7]. The future may hold promise for pharmacologic hormone therapy aimed at normalizing the male/female sex hormone ratio in patients who have SLE as a future therapeutic or preventive modality. Another theory to consider in the comparison of incidence of autoimmune diseases in men versus women is the role of X inactivation and cellular mosaicism. Biologically speaking, women are not the weaker sex. Women are generally healthier and live longer than men. According to the US Census Bureau, in 2010 the life expectancy for women will be 81 years of age compared with 74 years of age for men. In 2002, it was four times more likely for a woman aged 65 or older to be widowed than her male counterpart. More male fetuses are lost in utero than female fetuses, and more males babies die in infancy. In looking at a genetic as opposed to hormonal explanation for these differences, some
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explanation for male vulnerability may be because men have only one X chromosome and women have two. Having only one X chromosome makes men more vulnerable to genetic mutations. A woman with a similar genetic defect on one allele may have partial protections from a second, normal allele. Women come equipped with ‘‘backup systems’’; men do not. Mosaicism for the X chromosome in a woman plays a role in the female expression of disease and often is advantageous and protective. Men frequently manifest more severe forms of X-linked mutation diseases, such as hemophilia and Duchenne muscular dystrophy. The X chromosome also encodes antibodies that protect against infection, which could make men more immunodeficient than women. It is reasonable to consider that X inactivation may play a role in the prevalence of autoimmune disease in women [10].
Common autoimmune diseases Systemic lupus erythematosus SLE is a chronic autoimmune disease that may affect multiple organ systems in the body and may manifest myriad symptoms. Common symptoms include fatigue, joint problems, skin rashes, fever, headache, abdominal discomfort, and dizziness. Vasculitis with impaired circulation, accelerated atherosclerosis, myocarditis, endocarditis, pericarditis, pleuritis, and nephritis also may occur. More than 70% of cases of SLE are characterized as widespread with periods of flares and remissions, with the remainder of cases being mild. The 10year survival rate of SLE with treatment is approximately 90%. SLE is more common in women of African, Hispanic, Asian, and Native American descent and is most frequent in women of child-bearing age (15–45). There are several subcategories of lupus, including discoid lupus erythematosus, drug-induced lupus erythematosus, neonatal lupus erythematosus, and neuropsychiatric lupus erythematosus. The American College of Rheumatology has identified 11 signs and symptoms to aid in the diagnosis of SLE (Box 2). A patient must demonstrate at least 4 of these symptoms for lupus to be suspected. Because symptoms may not all occur at once, an accurate medical history and comprehensive physical examination are necessary for diagnosis. Laboratory data that may aid in the diagnosis of SLE include complete blood count, erythrocyte sedimentation rate, urinanalysis,
Box 2. American College of Rheumatology criteria for the diagnosis of lupus Malar rash Discoid rash Photosensitivity Oral ulcers Arthritis: nonerosive involving two or more peripheral joints, nonsymmetrical Serositis: pericarditis or pleuritis Renal disorder: proteinuria or cell casts Neurologic disorder: seizures or psychosis Hematologic disorder: hemolytic anemia, leucopenia, lymphopenia, thrombocytopenia Antinuclear antibody Immunologic disorder: + anti–double-stranded DNA, + antiphospholipid antibody or false + VDRL
echocardiograms, radiographs, brain imaging, and skin or renal biopsies to evaluate for organ system involvement. An antinuclear antibody panel is helpful to establish a diagnosis. The presence of certain autoantibodies may aid in the diagnosis of SLE, including ANA, anti-ds DNA, anti-Sm, anti-Ro (SSA), and anti-La (SSB). Although they may be frequently increased in patients who have SLE, not all patients who have SLE demonstrate elevated levels. Other conditions also may cause elevated levels of these autoantibodies. High levels of ANA are found in approximately 98% of patients who have SLE. ANA may be strongly positive in other autoimmune diseases and weakly positive in healthy women, however. High or low levels of ANA do not necessarily correlate with severity of disease, and ANA may be negative in a patient who has SLE. Anti-ds DNA antibodies are more frequently found in SLE than other autoimmune disorders. This finding usually indicates vascular injury and correlates well with renal involvement [11]. Given the range of organ system involvement and level of severity of disease, patients who have SLE may be managed by any or all of the following specialists: internists, rheumatologists, nephrologists, dermatologists, clinical immunologists, cardiologists, hematologists, or
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neurologists. Treatment plans are individualized depending on the nature of symptoms and severity of the disease. Treatment goals are to minimize flare-ups and prevent organ damage. Common therapeutic modalities include nonsteroidal antiinflammatory medications, antimalarial agents, corticosteroids, immunosuppressives, thalidomide, hormones, and various other agents. Nonsteroidal anti-inflammatory drugs may be used alone or in combination with other therapies to decrease inflammation and treat joint pain and fever. Antimalarial agents are used alone or in combination with other therapies to treat fatigue, joint pain, pleuritis, and skin rashes and prevent flares. Side effects of antimalarial agents include headache, change in skin color, hair loss, and reversible retinal damage. Corticosteroids are the mainstay of therapy for most patients who have SLE because of their rapid anti-inflammatory effect. Generally, the lowest possible doses for the shortest possible duration are administered to avoid side effects of weight gain, osteoporosis, hyperglycemia, hypertension, muscle wasting, fluid retention, glaucoma, and increased susceptibility to infections. Immunosuppressive medications that are usually reserved for patients with renal, vascular, or neurologic involvement work by blocking immune cells. Side effects of immunosuppressive therapy include nausea, vomiting, hair loss, increased susceptibility to infection, and infertility in female patients. Thalidomide inhibits cytokines and reduces disease progression by reducing new blood vessel formation. A major side effect of thalidomide is peripheral neuropathy. Treatment with mild male hormones, such as dehydroepiandosterone and danazol, has been shown to offer some benefit for patients who have mild SLE but not for patients who have severe SLE. Side effects of male hormone therapy include development of acne and excess facial hair. Additional experimental therapies include monoclonal antibodies, plasmapheresis, nucleoside analogs, and autologous stem cell transplantation coupled with immunosuppressive therapy. Patients who have SLE also present with specific cardiovascular, pulmonary, and renal disorders that require attention. Cardiovascular disease may be the result of disease or treatment (eg, steroids), which in turn increases the risk of myocardial infarction and stroke. These risks include hypertension secondary to renal disease, accelerated atherosclerosis, valvular pathology, congestive heart failure, thromboembolic
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phenomena, and elevated homocysteine levels, which have been implicated in the development of strokes and myocardial infarctions. More than 60% of patients who have SLE develop pulmonary problems, including pleuritis, lupus pneumonitis, and pulmonary hypertension. Approximately 50% of patients who have SLE develop lupus nephritis as a result of damage and scarring of renal tissues; approximately 30% of these patients progress to end-stage renal failure. Cardiac manifestations of SLE include pericarditis, myocarditis, and endocarditis. There is a reported prevalence of pericarditis in 60% of patients [12]. Cerebrovascular disease in patients who have SLE is reported in approximately 50% of patients studied by Roldan and colleagues [13], whereas significant valvular disease was found in almost 70% of patients. Valvular pathology occurred two to three times more frequently with than without cerebrovascular disease. Valvular heart disease seems to be associated with embolic ischemic brain injury and cerebrovascular disease in patients who have SLE [13]. Valvular pathology is the most common form of cardiac involvement found in patients who have SLE, with a reported incidence of up to 77%. Transesophageal echocardiography is the most sensitive test for valve pathology. The condition frequently takes the form of valve thickening, vegetations of immunoglobulin and complement (Libman-Sacks vegetations), and valvular regurgitation. Most patients are asymptomatic until the regurgitation becomes severe. Autopsy evidence of Libman-Sacks endocarditis is reported at between 13% and 74%. There is no clear correlation between the existence of Libman-Sacks vegetations and clinical finding of murmurs. The mechanism of valvular damage in SLE is thought to be complement activation and immune complex deposition. The prevalence of infective endocarditis in patients who have SLE has been reported to be comparable to that of patients with prosthetic heart valves. Because of poor prognosis of patients who have SLE and infective endocarditis, this needs to be ruled out and differentiated from pseudoinfective endocarditis or Libman-Sacks endocarditis by repeated blood cultures. In view of this risk, it is suggested that all patients who have SLE receive antibiotic prophylaxis before procedures with a risk of bacteremia [14,15]. The significance of valvular heart disease in patients who have lupus is underscored by Roldan’s [16] finding that the combined incidence of
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stroke, infective endocarditis, need for valve replacement, peripheral embolism, and heart failure was 22% in patients who have lupus with valvular disease confirmed on echocardiography but only 8% in patients who have lupus without it. Many complications experienced by patients who have lupus, such as ischemic strokes, peripheral emboli, and infective endocarditis, were associated with valvular disease. The nature of the valvular pathology may change over time. New abnormalities may develop, and temporal relation to other clinical sequelae of lupus has yet to be established [16,17]. Drug-induced lupus erythematosus may share symptoms and laboratory findings characteristic with SLE. The first reported case was linked to use of sulfadiazine. More than 80 drugs have since been associated with development of drug-induced lupus. Patients are generally older than typical patients who have SLE, and the female preponderance is less obvious. Recognition of this entity is important because symptoms often resolve shortly after stopping the drug. Antiphospholipid syndrome APS is an autoimmune disorder of unknown origin. APS may occur primarily without associated disease (primary APS) or in conjunction with other autoimmune entities (secondary APS), most notably SLE, rheumatoid arthritis, and Sjo¨gren’s disease. It is frequently discussed in conjunction with SLE because up to 50% of patients who have lupus demonstrate antiphospholipid (APL) antibodies. A female preponderance is reported in the child-bearing years, similar to that of SLE. Antiphospholipid antibodies are also found in a small percentage of healthy patients. APS is characterized by recurrent vascular thrombosis (arterial or venous), thrombocytopenia, and miscarriage [18–20]. The mechanism for the thrombosis is unclear but it is theorized that a defect in apoptosis may expose membrane phospholipids to coagulation proteins, which become targets of autoantibodies and result in a hypercoagulable state. The clinical manifestations are related to the site of injury and may present as local, systemic, or neurologic problems. Retinal, renal, pulmonary, and dermal manifestations are common. Neurologic consequences include reversible or fixed focal deficits from strokes or transient ischemic attacks. APS should be considered in the differential diagnosis of new strokes in younger patients (!50 years). Concern about the association of APS with SLE
involves the triad of valvular abnormalities, Libman-Sacks endocarditis, and emboli resulting in increased risk of strokes, myocardial infarctions, and need for valve replacement [21]. APS involves a range of antiphospholipid plasma antibodies, including anticardiolipin antibodies, anti-beta 2 glycoprotein I antibodies, and lupus anticoagulant. These are antibodies to a phospholipids-protein complex. Anticardiolipin antibodies have been subdivided into isotypes that may help explain the heterogeneity of the disease. The IgG isotype is associated with thrombosis and pregnancy loss, and the IgM isotype is associated with hemolytic anemia. A higher titer of the IgG isotype seems to correlate well with increased risk of miscarriage and thrombosis. Management of APS is directed toward the prevention of recurrent thrombosis, which is a frequent occurrence in these patients. Prolonged anticoagulant therapy for patients after venous thrombosis is advised. The target International Normalized Ratio (INR) has been reported to be between 2.5 and 3.5 [17,18]. In patients who suffer an arterial thrombosis or stroke, combinations of aspirin, clopidrel, and warfarin have been used. Pregnant patients may be managed on aspirin and subcutaneous heparin injections and should be monitored closely [19,20]. Echocardiography has shown the incidence of valvular pathology to be approximately 33% in patients who have APS and more than 70% in patients who have SLE and APS. The incidence of valvular pathology in patients who have SLE is highest among individuals who have APS. Valvular lesions usually present as thickening of the leaflets and frequently result in a regurgitant valve. Clinical valvular disease is not common. The presence of APLs increases the risk of thromboembolic eventsdmost often cerebrovascular in nature. The risk of development of bacterial or pseudoinfective endocarditis also exists. Treatment is usually aimed at preventing thrombus formation with antiplatelet or anticoagulant therapy [21]. SLE and APS demonstrate accelerated atherosclerotic disease. The mechanism seems to be an aberration in the metabolism of lipoproteins that leads to formation of proinflammatory cytokines and activation of the innate and acquired immune response. The identification of protective antibodies may offer immunomodulation treatment strategies for SLE, APS, and atherosclerosis [22]. Other mechanisms have been suggested for the accelerated rate of development of atherosclerosis, including cytokines, estrogen deficiency immune
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complexes, and errant apoptosis. The failure of hormone replacement therapy to be cardioprotective in postmenopausal women raises questions as to the role of estrogens in this disease process. Attention is turned to the role of estrogen metabolites in increasing inflammatory immune response [23]. The role of atherosclerosis in autoimmune disease is complicated by the fact that patients may present with a combination of traditional risk factors, such as hypertension, diabetes, hyperlipidemia, and the enhanced risk factors of autoimmune disease, including antiphospholipid antibodies and inflammation. It is proposed that antiphospholipid antibodies and inflammation may cause atherosclerotic plaques in patients with autoimmune disease to rupture more readily than plaques in patients without autoimmune disease. Patients with autoimmune disease, specifically SLE and APS, must be evaluated and treated for cardiovascular disease (CVD) based on traditional risk factors and disease-related risk factors [24]. Multiple sclerosis MS is an autoimmune disease of the central nervous system that affects approximately 400,000 Americans and millions of people worldwide [25]. The disease is most common in young adults between the ages of 20 and 50, and women are afflicted two to three times more frequently than men. The age and sex distribution of the MS patient population is consistent with other autoimmune diseases that are thought to be modulated by sex hormone levels. This theory is further supported by the observation that the frequency of relapses decreases in each trimester of pregnancy but increases in the postpartum period. The lowering of the helper-suppressor T-cell ratio in pregnancy and its observed effect on mediating the course of MS is likely caused by estriol, a hormone that is produced by the fetal placental unit. More specifically, a shift from T-helper 1 (proinflammatory) to T-helper 2 (anti-inflammatory) response is noted in pregnancy. In the postpartum period, a 70% increase in relapse rate is noted [26]. Lasting protective effects against the development of MS from the exogenous administration of estrogens (in the form of oral contraceptives) have not been demonstrated. Apparently, the protection afforded by estrogens in pregnancy and with oral contraceptive use is not demonstrable in the postpartum period or when the use of the oral
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contraceptives is terminated [27]. Whites are the most commonly affected ethnic group. The clinical characteristics of MS are secondary to loss of the myelin sheath surrounding nerve fibers, which results in disruption of the conduction of electrical impulses. The trigger for this response remains unknown, but genetic and environmental factors have been implicated. Although no specific MS gene has been identified, a first-degree relative of a patient who has MS is 20 times more likely to contract MS than a nonrelative. Environmental triggers, including viruses and toxic substances, have been implicated in the generation of MS. The most commonly implicated, but not proven, infectious triggers seem to be herpes simplex 6 and chlamydial pneumonia [28]. It has been noted that relapses in patients who have MS frequently follow respiratory or gastrointestinal illnesses. Of particular interest is geographic clustering of MS cases in the northern latitudes of the northern and southern hemispheres. There are four distinct disease patterns of MS: relapsing-remitting, primary-progressive, secondary-progressive, and progressive-relapsing [28]. The relapsing-remitting pattern is the most common form of the disease identified at the time of diagnosis. This pattern is characterized by exacerbations of symptoms followed by partial or complete recovery and periods of remission. The primary-progressive pattern displays a chronic and continuous worsening of symptoms with no exacerbations or periods of remission. The secondary-progressive form starts as a pattern of relapsing-remitting MS and is followed by a course of slowly progressive deterioration with few, if any, remissions observed. Approximately half of the patients initially diagnosed with the relapsing-remitting form of the disease progress to this pattern within 10 years of diagnosis. The progressive-relapsing form is the rarest pattern of the disease, which is characterized by progressive worsening with periodic acute exacerbations. A small percentage of individuals who have MS never demonstrate significant functional deficit, whereas another small percentage of patients becomes severely disabled in a short period of time. The most common symptoms of MS include changes in cognitive function (including problems with memory and attention), depression, fatigue, gait disturbances, paresthesias, visual disturbances, dizziness, pain, and bowel, bladder, and sexual dysfunction. Because patients may experience some, but not all, of these symptoms and may experience
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different symptoms at different times, the diagnosis of MS may be elusive initially. The prognosis for patients seems to be better if their symptoms are visual or sensory rather than motor in nature. Diagnosis of MS requires documentation of at least two distinct episodes of relapses and involvement of more than one area of the nervous system [29]. In addition to a comprehensive history and clinical examination, an MRI, evoked potentials, and evaluation of the cerebrospinal fluid are useful in confirming the diagnosis, but no specific laboratory test for MS exists. Characteristically, reduced velocity of evoked potentials is found in patients who have MS. The demyelination process is thought to explain several clinical characteristics of the disease, including exacerbation induced by elevated temperature, electrical sensation in the extremities, paroxysmal symptoms of trigeminal neuralgia, and ataxia (thought to be caused by ‘‘cross talk’’ between demyelinated neighbor axons) [28]. Evaluation of the cerebrospinal fluid of patients who have MS demonstrates oligoclonal IgG bands in more than 90% of cases, which seems to confirm an underlying inflammatory cause of the disease. Although the cause of MS is unknown, the histologic presentation has been well documented. MS plaques are lesions that classically present with demyelination and perivascular inflammation. Although it has not yet been determined if the perivascular inflammation is the cause or result of the demyelination process, it seems likely that the demyelination is a result of an acute inflammatory process. The result of the plaque formation is a slowing of nerve conduction in affected areas. Plaque formation is thought to be the result of a failure to regulate autoreactive myelin T cells, which leads to the release of inflammatory mediators and cytokines [28]. The goal of treatment of MS is to limit the frequency of relapses, limit the effects of relapses, prevent permanent disability from disease progression, and promote tissue repair, if possible. The most commonly used agents in the treatment of relapsing-remitting MS are the beta interferons (beta 1-a and beta 1-b), which were initially used because of the observation that relapses frequently followed viral infections. The efficacy of the interferons is more likely related to their antagonistic effect on proinflammatory cytokines. Other agents that are commonly used in an effort to reduce the frequency of flare-ups and associated disabilities are glatiramer acetate (which seems to inhibit binding to T-cell receptors),
azathioprine (an immunosuppressive agent that inhibits lymphocyte infiltration), and mitoxantrone (an antineoplastic agent that inhibits DNA synthesis and suppresses T-cell, B-cell, and macrophage activity), which is limited in use only for patients with severe progressive disease. Corticosteroids, a mainstay of treatment for many autoimmune diseases, are used for treatment of acute relapses because of their anti-inflammatory effects. Corticosteroids may be administered intravenously or orally and are used to reduce the consequences of the relapses, not to prevent them [28]. Management of the female oral surgical patient who has autoimmune disease The surgical management of patients who have autoimmune disease is the same, regardless of gender. The first principle of treatment is for oral and maxillofacial surgeons to be familiar with their patients and the course and nature of the patient’s disease. If information gathered from a patient is insufficient to determine the impact of the disease or treatment regimen on proposed surgical care, consultation with treating physicians is definitely indicated. Formulas and gross generalizations on patient management should be avoided because, as noted in this article’s brief discussion of three (of a possible R70) diseases categorized as autoimmune, the clinical characteristics, nature and severity, and organ system involvement vary greatly from disease to disease and within a specific disease entity from patient to patient. A common finding in the treatment of many autoimmune diseases is the intermittent and possibly chronic administration of corticosteroids and immunosuppressive and antineoplastic agents. Before embarking on any surgical/anesthetic treatment course, oral and maxillofacial surgeons must be aware of the dosage, duration, and frequency of use of these medications. Elective surgery may need to be timed to ensure adequate healing potential, and antibiotics and stress steroid dosing may need to be considered for certain patients. Many postmenopausal female patients with autoimmune diseases may have been placed on bisphosphonate therapy, especially if they have a history of chronic steroid use in the past. Consideration in the management of these patients for required and elective surgery must include a discussion of the risk, however marginal, of osteonecrosis.
AUTOIMMUNE DISEASE AND THE FEMALE PATIENT
Because many autoimmune diseases demonstrate multiorgan system involvement, including pulmonary, cardiac, and renal disorders, oral and maxillofacial surgeons must be aware of specific risks that patients may encounter before embarking on a surgical/anesthetic course of treatment. In SLE, for example, consideration of altered renal status and the risk of endocarditis secondary to valvular involvement is indicated. The risk/ benefit of changing anticoagulation and antiplatelet medication protocols in patients with APS also must be considered carefully.
Summary Although the pathogenesis of autoimmune disease and the cause of female prevalence of these entities remain to be clearly elucidated, the principles of treatment for all patients with autoimmune disease hinge on the surgeon’s appreciation of the diversity of symptomatology and organ system involvement. Such an approach results in better treatment outcomes with respect to surgical intervention in this population of patients.
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[28] Compston A, Coles A. Multiple sclerosis. Lancet 2002;359(9313):1221–31. [29] Available at: www.nationalmssociety.org.
Further readings Chockalingham A, Prabhakar D, Gnanavelu G, et al. Pancarditis as initial presentation of systemic lupus erythematosus. Int J Cardiol 2003;87(1):111–4.
Cutolo M, Sulii A, Capellino S, et al. Sex hormones influence on the immune system: basic and clinical aspects in autoimmunity. Lupus 2004;13(9):635–8. Lahita RG. Sex hormones and systemic lupus erythematosus. Rheum Dis Clin North Am 2000;26(4): 951–68. Merrill JT. The antiphospholipid syndrome and atherosclerosis: clue to pathogenesis. Curr Rheumatol Rep 2003;5(5):401–6.