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NEUROENDOCRINE IMMUNE MECHANISMS IN RHEUMATIC DISEASES
NEUROENDOCRINE MECHANISMS IN RHEUMATIC DISEASE
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NEUROENDOCRINE IMMUNE MECHANISMS IN RHEUMATIC DISEASES An Overview and Future Implications Alfonse T. Masi, MD, DRPH
Systemic rheumatic diseases are complex chronic disorders of variable severity classified according to their clinical and immunologic manifestation~:~Specific causes of these diseases have not yet been determined. Available data support a multifactorial threshold model of causation (i.e., an accumulation of genetic and environmental influences [and their interactions] that operate in the individual and permit the disease to become manifest) as proposed for rheumatoid arthritis For decades, hormona131and immunologicz4mechanisms have been incriminated in the causation and perpetuation of these diseases. Additionally, abnormalities in the microvascular system,25,% particularly altered endothelial cell reacti~ity,~~ have long been described in these diseases. This issue summarizes the current state of knowledge on the complex interactions of the neuroendocrine and immune systems (Fig. 1) and how such mechanisms might relate to multiple rheumatic diseases. This article also outlines implications for future research and patient management. The article by Chikanza and Grossman" reviews the bidirectional
This study was supported in part by an Arthritis Foundation Clinical Science grant, the Rheumatoid Arthritis Precursors Study (RAPS), and a MTM Foundation gift.
From the University of Illinois College of Medicine at Peoria, Peoria, Illinois
RHEUMATIC DISEASE CLINICS OF NORTH AMERICA VOLUME 26 * NUMBER 4 * NOVEMBER 2000
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regulation of hormonal and cytokine mechanisms in the neuroendocrine immune (NEI) loop during inflammation and other forms of stress. Integrity of the NEI loop is essential for effective modulation of immune and inflammatory responses and restoration of physiologic homeostasis.’O, I1 Defects or deficiencies in maintaining normal regulation of the NEI loop can contribute to chronic inflammatory or autoimmune diseases. Proinflammatory cytokines (e.g., interleukin (IL)-lp, IL-6, and tumor necrosis factor-a (TNFa) are released in the acute-phase response and act not only as local mediators but also stimulate the neuroendocrine response. In turn, those hormones, particularly glucocorticosteroids (GCSs), are irnmunomodulatory.ll The complex orchestration of cascades of acute and chronic immunomediators in inflammation provokes neuroendocrine responses, that are accompanied by manifold GCS anti-inflammatory mechanisms.l0. l1 The NEI loop constitutes essential integrated physiologic circuits for the maintenance of health and the regulation of inflammation. Dysregulation of the NEI loop has important l1 physiopathologic consequences in the systemic rheumatic diseases.lO, The article by Walker and Jacobson reviews the roles of prolactin (PRL)68and gonadotropin-releasing hormone (GnRH) in affecting the hypothalamic-pituitary axis and immune responses and gender differences in autoimmunity. PRL helps to maintain immunocompetence in health, is a lymphocyte growth factor, and may be considered to function as a cytokine.68Reports of hyperprolactinemia in systemic lupus erythematosus (SLE) and other rheumatic diseases in human beings are summarized in tabular format, and its association with progression of disease in the New Zealand black-New Zealand white mouse model of lupus is reviewed.68Suppressing PRL with bromocriptine can provide beneficial effects in animal models of autoimmune disease, and a recent prelimi-
Figure 1. Reciprocal regulations and modeling of the neuroendocrine and immune systems.The acute phase response of active inflammation, (i.e., macrophage-related, generates proinflammatory cytokines), (e.g., IL-1p, IL-6, and TNFci), which stimulate the hypothalamic-pituitary-adrenal(HPA) axis to produce increased cortisol. In turn, increased cortisol modulates inflammatory responsiveness by diverse mechanisms and favors a T helper 2 (Th2) humoral immune reactivity over a T helper 1 (Thl) cell mediated immune pattern. The major sex hormones, (i.e., estradiol (EZ)and testosterone (T)), also modulate immunological responsiveness and contribute to gender dimorphism. In physiological concentrations, E, tends to enhance humoral immunity and favors a Th2 cytokine pattern, whereas T tends to be immunosuppressive. Dehydroepiandrosterone (DHEA) may favor Thl immune responsiveness and progesterone (P) favors Th2 function, as does activation of the sympathetic nervous system (SNS). Placental CRH stimulates the HPA axis to produce increased cortisol and adrenal androgens (e.g., DHEA and DHEAS). In turn, hypothalamic CRH decreases due to cortisol-HPA negative feedback mechanisms. During pregnancy, adrenal cortical function and hormonal production increases, and the gland may hypertrophy. Postpartum, placental CRH is lost and the adrenal may become understimulated, while hypothalamic production of CRH is still decreased. Physiological variations in CRH and HPA axis function during pregnancy and postpartum may contribute to the notable changes in onset risks and clinical activity of RA in these respective periods. Solid arrow = stimulation, dashed arrow = inhibition.
nary clinical trial in human SLE showed improvements equivalent to those associated with hydroxychloroquine.a Excessive PRL is produced by synovial lymphocytes in RA.6sIn a recent trial, quinagolide, a dopamine agonist and pituitary (but perhaps not lymphocyte) PRL-lowering drug, did not produce significant clinical benefit in nine RA patients.26 Effects of GnRH on the immune system, particularly on the IL-2 receptor and proliferation of B and T cells, may contribute to gender dimorphism and sex differences in immunologic responsiveness. Gender-specific actions of GnRH on murine lupus and its effects on the expression of this disease model are reviewed, with implications for the human disease.6s The article by Herrmann et a132reviews stress and rheumatic diseases, with an emphasis on psychologic and personality factors. Published reports that indicate evidence for and against minor or major psychologic stresses being contributory factors to the onset and course of RA; juvenile chronic arthritis, SLE, and fibromyalgia syndrome (FMS) are summarized. At present, interactions of the psyche and neuroendocrine immune system are not well defined in the rheumatic diseases, but stress seems to have an impact on these disorders, particularly juvenile chronic arthritis. Social and family functional status can influence clinical and psychologic outcomes in this disease.32Future research promises to reveal how the complex interacting psychoneuroimmunologic mechanisms may contribute to the multifactorial causes of the different rheumatic diseases.32 The article by Pitzalis and Kocha reviews the vascular endothelial system (VES) in the pathogenesis of inflammation and systemic rheumatic diseases and how the neuroendocrine system influences these mechanisms. The VES has long been recognized to play a critical role in the pathogenesis of acute and chronic inflammatory processes.25Recent research has defined the detailed physiopathogenesis of these processes, particularly how the VES interacts with immune and inflammatory mediators and how it is modulated by the neuroendocrine ~ystem.4~~ 51,54* 55, 63 Estrogens, androgens, and glucocorticoids exert different effects on the VES in physiologic (i.e., resting endothelium) and pathologic conditions (i.e., activated endothelium in response to toxic products, inflammatory mediators, and cytokines).a The formation of new blood vessels, or angiogenesis, is an important phenomenon not only in cancer but 38 and is modulated by also in chronic inflammatory processes like RAZ7, hormonal factors?, Sex hormone effects on the VES may enhance gender dimorphism in the rheumatic diseases through a series of complex mechanism^.^^ Individual sex hormones may have dose-related biphasic effects and differential influences on resting versus activated tissues (including the VES). Furthermore, hormones physiologically operate in combination rather than in i ~ o l a t i o nFinally, . ~ ~ hormones act at multiple levels of gene expression and cellular biology.63Hormones may have dualistic effects
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on the VES, protective and damaging, depending on various complex constellations of factors. Considerable research is needed to unravel the precise mechanisms by which the neuroendocrine system interacts with the VES and contributes to the diverse dysfunctions associated with the rheumatic diseases. The VES along with the neuroendocrine and immunologic systems may be considered to be core components in the physiopathogenesis of RA and other systemic rheumatic 51, 55, 63 Early results indicate that angiogenesis or cell migration is a useful target in the treatment of these conditions. The article by M a ~ presents i ~ ~ an integrative physiopathogenetic perspective of hormonal and immunologic risk factors in RA. The multifactorial threshold model of RAZ9is expanded to include a multiyear preclinical pha~e.4~ During a long interval of symptomatically silent disease incubation, multiple genetic, nongenomic somatic, behavioral, and environmental risk factors are proposed to perturb the normal physiologic homeostasis of the core systems (i.e., the neuroendocrine, immunologic, and microvascular compartments). The physiologic functions of steroids and other neuroendocrine hormones in modulating or remodeling the immunologic and endothelial-microvascularsystems are 47, 63 largely unexplored and not well under~tood.'~, When physiologic homeostasis is sufficiently disturbed, inflammatory and clinical manifestations may appear or progress. Conversely, regulatory mechanisms controlling the homeostasis of perturbed core systems may also become normalized to a point that would favor clinical improvements. Such amelioration of disease activity may occur in persons with less strong genetic loading predisposing to disease,3o,57 fewer 48 favorable effects of pregaccumulated nongenomic risk 51, 6o or effective suppressive therapy.21, 47, 54, 55 nan~y,~" The proposed physiopathogenetic concept of RA47,55 further presumes individualized variability in the onset risks and diverse severity of outcomes in RA.57Such a multifactorial integrative concepP7,55 is an alternative model for understanding RA compared with the more basic and specific proposed mechanisms of arthritogenic peptides interacting with selective T-cell receptor epitopes and having an essential role in disease causation.6,23 Long-term risk factors for subgroups of RA patients have been identified (i.e., for subsets of women with premenopausal onset and for men) and more general risk factors for men and women combined.47, 5z, 55 Further documentation of such predictive relations and successful research in establishing reliable risk factors (or markers) for RA promise 55 to lead to future prevention strategies.47* The article by Kanik and Wilder35reviews hormonal alterations in RA, including the effects of pregnancy. Differences in the incidence of RA and the notable changes in its clinical activity during the pregnant and postpartum periods are reviewed. Hormonal changes during these periods are suggested to influence either the susceptibility to disease or its manifestation^.^^ Increases in circulating corticosteroids, estrogens, st
and progesterone during ~regnancy'~ may play a role in modulating the expression of RA. Possible mechanisms include the regulation of cytokine production such as TNFa, IL-12, and IL-10.13,35, 39, 59, 69 The postpartum period is characterized by adrenal and gonadal defi~iencies,'~ which may predispose to the development or increased activity of RA.35,6o Evidence for functional abnormalities of the adrenal cortex in RA patients is also reviewed,35particularly the findings of GCS and dehydroepiandrosterone or dehydroepiandrosterone sulfate (DHEAS) dysreg50, 53 Adrenal cortical dysfunction has been demulation or disso~iation.'~, onstrated before the development of RA53and within the first year of disease activity.19,35 Some specific hormonal abnormalities seem to be restricted by sex and premenopausal state.35,53 Such complex relations may be the reason for the contradictory results noted in some studies that do not analyze population subsets ~eparately.~~ The identification of particular hormonal abnormalities within specific patient populations at risk for RA is important. New hormonal therapeutic approaches that are more effective in addressing these factors and less toxic than current regimens may be developed in selected patients.35 The article by Cutolo and WilderI7 reviews differing roles of androgens and estrogens in susceptibility to autoimmune and rheumatic diseases from basic biologic and clinical perspectives. The effects of these hormones on B lymphocytes, T lymphocytes, monocytes and macrophages, and bone cells are reviewed.17 Aggregate data indicate that androgens tend to suppress cellular and humoral immunity. Depending on dosage levels, estrogens may enhance humoral immunity but may also decrease cellular immunity. Functional androgen and estrogen receptors were demonstrated on synovial macrophages, monocytes, and lymphocytes. Accordingly, sex hormones may have immunomodulatory effects in RA synovitis. Cyclosporin A increases androgenicity, (i.e., increases conversion of testosterone to dihydrotestosterone) and may inhibit synovial macrophages by such a metabolic pathway.20Some data indicate that environmental estrogens may increase susceptibility to autoimmunity and that use of oral contraceptives exacerbates the activity of SLE.17,41 Inflammatory mediators (i.e., cytokines) may alter the peripheral metabolism of sex hormones and further complicate interpretation of such hormonal effects on susceptibility relations in the rheumatic diseases.I7 The article by Baerwald et a13 reviews disturbances in interactions between the autonomic nervous system (ANS) and the hypothalamicpituitary-adrenal (HPA) axis in chronic rheumatic diseases and the effects of their respective products on inflammation and the immune response. These central nervous system pathways allow multiple channels of communication with behavioral, emotional, psychosocial, and stressful experiences. The ANS, HPA axis, and other neurobiologic processes influence the immune system by various pathways in addition to noradrenergic and peptidergic innervations of the ANS of lymphoid organ^.^ In turn, inflammatory cytokines can interact with central neurons and modulate their activity and downregulate P,-adrenoceptor
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density on peripheral blood mononuclear cells? Basic research is reviewed to support the hypothesis that disturbed interactions between the ANS and immune system contribute to the pathogenesis of human rheumatic diseases: including RA,3 and to animal models of arthriti~.~ Catecholamines could modulate the immune response by direct actions on immune cells and by effects of ANS neuropeptides on various tissues such as endothelium, connective tissue, and smooth muscle^.^ The resultant effects are modulation of lymphocyte proliferation, differentiation, cell adhesion, and migration." 3, 43 To further confound the complex relations, the time point at which catecholamines are applied during the course of an immune reaction is essential for the net effect of the catecholamine actions? The article by Da Silva and Bij1smaz1reviews new insights into genomic and nongenomic mechanisms of GCSs in RA, and guidelines are provided for optimizing discretionary therapy. Glucocorticoids can regulate transcription of a large variety of target genes by alternative mechanisms (e.g., either by direct binding of GCSs to glucocorticoid response elements [i.e., transactivation] or by indirect inhibitory interactions on transcription [i.e., transrepression])." 21 Glucocorticoids exert potent inhibitory effects on the transcription and actions of a large variety of proinflammatory and T helper 1 type cytokines of pivotal importance in the pathogenesis of RA, including IL-lp, IL-2, IL-6, and TNFa. Conversely, the production of T helper 2 type cytokines such as IL-4, IL-10, and IL-13 is either stimulated or not effected by GCSS.~~ In addition, GCSs potently inhibit the production of metalloproteinases, especially collagenase and stromelysin, which are the main effectors of cartilage degradation induced by IL-1 and TNFa.21Furthermore, GCSs control trafficking of inflammatory cells by reducing the expression of adhesion molecules such as intercellular adhesion molecule-1 and E-selectin through inhibition of proinflammatory cytokines and by direct inhibitory effects on the expression of adhesion molec u l e ~Glucocorticoids .~~ inhibit chemotactic cytokines and the cytokineinducible form of nitric oxide synthase, thereby suppressing the amplification of inflammatory responses by these mediators.2I Studies that support the emerging evidence that normal endogenous GCS levels have clinically significant influences on RA activity and that low-dosage glucocorticoid therapy may retard erosive joint damage are reviewed.21Also, dysfunctions in GCS response to inflammationlo,l1 may predispose to the development or progression of RA.21Further research is needed, however, to clearly establish such relations.47,55 The effectiveness of low-dosage GCSs as opposed to higher dosages in treating RA is reviewed and their major side effects.21Guidelines are provided to optimize GCS therapy in RA, considering the dosage, timing of administration, and management of side effects.2l The article by Cutolo16reviews the modulating effects of sex hormones on tissue-specific immune responses and their adjuvant effects in therapy of RA. In a small-scale open study of male RA patients, oral 5r
testosterone undecanoate administered daily for 6 months showed favorable clinical and immunologic changes without notable side effects.I8A double-blind placebo-controlled study of testosterone as adjuvant therapy for RA in 57 postmenopausal patients showed an expected anabolic effect and slight disease modification, although not statistically significant.9Interestingly, the immunosuppressive agent cyclosporin A induces a dose-dependent side effect of hypertrichosis in both sexes and an increase in peripheral androgen metabolism.20Such findings suggest that this agent has indirect androgen-mediated immunosuppressive activity.'" 2o The article by Bijlsma and Jacobs8reviews the multifactorial mechanisms of bone loss in RA and the effects of androgens and estrogens on bone preservation. Male and female RA patients show decreases in bone mineral density that are more evident at the hip and radius than at the spine. Such bone losses in RA patients cause an estimated doubling of their fracture risk even without GCS treatment.8 When RA patients are treated with GCSs, the fracture risk is estimated to again d ~ u b l e . ~ Proinflammatory cytokines and other inflammatory mediators (e.g., prostaglandin E2) are believed to increase bone resorption in RA by stimulating osteoclasts.8 Also, mechanical and other bone-preserving factors are often decreased in patients with active RA. Guidelines for bone preservation and treatment of glucocorticoidinduced osteoporosis in RA include the avoidance of or use of the lowest possible dosage of GCSs, reduction of underlying disease activity, and increase in physical activity. Also recommended are maintenance of an adequate calcium intake, preferably 1500 mg daily in patients using GCSs plus at least 400 IU of vitamin D supplements daily! Estrogen replacement therapy could be considered for postmenopausal women with osteoporosis.8Also, in patients treated with GCSs who have bone mineral density measurements indicating osteopenia or osteoporosis, treatment with bisphosphonates is recommended8in agreement with the findings in a recent detailed review.' The article by Chikanza et all2reviews neuroendocrine profiles and influences of the hormonal system in pediatric rheumatic diseases. Their role in the inflammatory rheumatic diseases of children requires further study. Some data suggest that juvenile rheumatoid arthritis (JRA) patients, particularly those with positive antinuclear antibody, have higher serum levels of PRL and IL-6 than comparison patients.I2 In a recent study, pubertal JRA patients had significantly lower mean serum DHEAS and testosterone values than normal control^.^' These JRA patients also had lower than expected DHEAS and testosterone levels in synovial f l ~ i d . 3Qualifications ~ of this reporP are that inflammatory disease controls were not studied and that the normal comparison subjects had higher than expected serum DHEAS levels.6l Adrenal androgens in pubertal JRA and the question of whether hormones could make a difference in treatment were recently reviewed.36 Whether or not hormonal alterations might influence immunoreactivity or microvascular or endothelial responsiveness warrants further
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investigation,12particularly in view of a recent report of increased circulating levels of vascular endothelial growth factor in polyarticular and systemic JRA patients." Patients with JRA have been reported to have alteration of ANS function.12The manifestations include increased vasoconstriction and an increased central noradrenergic outflow, resulting in a decreased response to an orthostatic stressor.l2,40* Catecholamines are proposed to enhance proinflammatory mediators in JRA as opposed to downregulation in Neuroendocrine changes in juvenile SLE and ankylosing spondylitis (AS) are also reviewed.I2 The article by Johnson et a133reviews the functional integrity of the major neuroendocrine axes (i.e., the HPA, hypothalamic-pituitarygonadal, and hypothalamic-pituitary-thyroidal) and psychologic profiles of Sjogren's syndrome (SS) patients. This disease is characterized by a strong female preponderance, widespread involvement of epithelial tissues showing increased rates of apoptosis, infiltration by activated CD4 T cells in the lesions, generalized B-cell hyperactivity, and a genetic predisposition (i.e., an autoimmune epithelialitis). In a detailed study of psychiatric dysfunction, most patients showed psychologic abnormalities that were primarily affective di~turbances.4~ Such findings were interpreted as atypical Evening ovine corticotropin-releasing hormone (CRH) stimulation of the HPA axis of SS patients showed lower basal serum corticotropin and cortisol levels than normal 34 Also, the stimulated increments in serum corticotropin were somewhat blunted at the 60-minute postinjection sampling. The stimulated increments of serum cortisol levels from baseline were comparable in the SS and normal study subjects, however.33 The findings in female SS patients suggested subtle central deficiencies in the three neuroendocrine axes studied (i.e., HPA, HPG, HPT) as well as elevated basal PRL concentrations. The findings do not indicate whether any one specific neuroendocrine system plays a primary role over the others in affecting the immune function of SS patients or in the expression of their disease.33Synergistic and antagonistic effects of multiple hormones may contribute to this disease, making the specific effects of individual hormones difficult to discern.33The potential therapeutic usefulness of hormonal immunomodulation in this condition is disc~ssed.~~
The article by Lahita4I reviews basic mechanisms whereby sex hormones may contribute to the development of SLE and to the gender dimorphism of the HPA axis and the immune system. A number of neuroendocrine perturbations involving androgens and estrogens have been described in SLE, and these may contribute to the disease processes. *A question raised by this guest editor (A.T.M.) is whether or not decreased serum albumin levels and lower oncotic pressure or increased capillary permeability in active JRA may have contributed to decreased intravascular volume of the patients and to their observed ANS changes."
Gender plays a major role in SLE expression, and sex steroid metabolism is altered in this disease. Sex hormones are not likely to be the underlying cause of this disease but rather modulators, possibly through their immunomodulatory effects.4I The SLE patient with Klinefelter's syndrome has the estrogen and androgen metabolism of a woman with SLE.42When SLE does occur in young patients with Klinefelter's syndrome, it can be treated with synthetic androgens such as methyltestosterone tablets or an androgen patch. Symptoms of the disease can be alleviated by such therapy, and the serologic features may even be normalized, as reported in one patient.58Use of another androgen, dehydroepiandrosterone, in female SLE patients resulted in favorable clinical and immunologic effects.22,41* 67 Thus, hormonal manipulation could have ameliorating effects on the disease activity of SLE.*I The article by Gooren et a P reviews adrenal and gonadal sex steroid relations to AS and the immunologic system. The greater frequency and severity of AS in men than in women suggests that sex hormones may interact with genetic and immunologic factors to play a role in this disease. Previous studies reported somewhat elevated ratios of serum androgen to estrogen in male AS patients compared with controls as previously summarized.& More recent better designed studies have found that serum testosterone, 17P-estradiol, and androstenedione levels Interestdid not differ significantly between AS patients and ingly, somewhat elevated serum DHEAS levels were found in 50 male AS patients compared with age-matched controls.28 The onset of AS was related to pregnancy in about 20% of more than 500 female patients studied; half of these new patients developed onset during pregnancy and the remainder within 6 months after delivery. No clear effect of pregnancy on the activity of the disease was observed. The article by Neeck and C r ~ f f o r dreviews ~~ neuroendocrine perturbations in fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS). These disorders have overlapping symptomatology and clinical manifestations but are suspected to have subtle differences in neuroendocrine profiles. Authors infer that a hyperactivity of the HPA axis is present in FMS, whereas a hypofunction of the HPA axis is typical in CFS.56 In FMS, a hyperactivity of CRH neurons is suspected to be driven by stress of chronic musculoskeletal pain or central nervous system mechanisms resulting from enhanced n o c i c e p t i ~ nOther . ~ ~ hormonal perturbations are also believed to result from the elevated CRH a~tivity.~" Reduced plasma cortisol levels were reported in CFS patients compared with controls and altered circadian variation in capillary resistance.@In a subset of CFS patients selected for subnormal response to corticotropin stimulation, adrenal size by computed tomography was Deficient serotonergic activity has been suggested in CFS and is reviewed?" Decreased activity of hypothalamic neurons producing CRH or arginine vasopressin in this syndrome is ~ o n s i d e r e d The .~~
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suggestion of chronically low arginine vasopressin function with increased vasopressinergic responsivity of the anterior pituitary in CFS is also discussed.s6 FUTUREPROSPECTS Within the past decade, new and broader concepts of causation of the systemic rheumatic diseases have evolved and promise to reveal valuable insights into their evolution. Bidirectional regulatory mechanisms between the neuroendocrine and immune systems are now recognized'", l1 and their reciprocal interactions with endothelium of the microvascular system in inflammation and systemic rheumatic disease^.^" 5s, 63 These new concepts and related scientific developments are also expected to be translated into clinically relevant therapeutic applications. Some of these benefits are evident at present,16,21 but further advances may be expected in the future. Neuroendocrine mechanisms are an important component of the complex interactive determinants of the systemic rheumatic diseases. These processes are more likely to be modulatory rather than causal per se, even considering their essential interactions and influences on the immunologic10,11, 13, 35, 39, 41,59,60, 68, 69 and microvascular54,55. 63 systems. The neuroendocrine system may also modulate effects of other important host mechanisms that operate in the rheumatic diseases (e.g., genetic 57 and acquired risk factors in RA (e.g., heavy or long sus~eptibilities)~~, duration of cigarette smoking) and their effects on the VES.47,48 Neuroendocrine mechanisms emphasize the relevance of the individualized physiologic dysfunctions or perturbations that may precede the clinical onset or progression of these diseases'", 11, 47, ss, 69 or suppress the activity of RA as is well documented during ~regnancy.~', 35, sl, 6o RA and related rheumatic diseases may begin as perturbations of complex interacting physiologic processes during an extended preclinical phase. Subsequently, such dysfunctions may progress over further time into inflammatory or pathologic sequelae (i.e., physiopathogenetic evolution). Such a new paradigm is an extension of the multifactorial threshold model of RAz9and further implies that RA or related diseases evolve gradually from a preclinical phase and may not necessarily require specific etiologic or triggering events for their clinical expression. Such physiopathogenetic evolution would be analogous to the insidious development of congestive heart failure in persons predisposed to cardiac disease and would be an alternative to the theory of the onset of RA being triggered by specific factors (e.g., either arthritogenic peptide& 23 or infectious agent antigensz5).In either congestive heart failure or RA, severe insults could precipitate or accelerate disease onset but would be considered as superimposed factors on the basic underlying physiopathogenetic processes. Without a significant precipitating event in RA, transition from an earlier subclinical phase of physiologic dysfunctions or perturbations to
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later clinical and pathologic manifestations likely occurs when the core systems (i.e., the neuroendocrine, immunologic, and microvascular components) become sufficiently decompensated. At such later stages, inflammation and tissue lesions are promoted rather than repaired during 55 earlier periods of homeo~tasis.~~, * Elucidation of neuroendocrine contributions to these diseases can help to clarify their long-term evolution among predisposed persons. The ultimate objective is to recognize susceptible persons during their preclinical phases and to develop strategies for primary prevention and 35, 41, 47, 55 more effective and less toxic therapies.33, SUMMARY A new physiopathogenetic paradigm may be proposed for RA and possibly its related systemic rheumatic diseases (i.e., mechanisms whereby multiple risk factors initially perturb the homeostasis of core physiologic components over an extended premorbid phase, which may progress to clinical disease in later decompensated stages).47,55 These complex interactive processes are likely to be individualized according to genetic, nongenomic somatic, developmental, behavioral, and envi47, 48, 55, 57 Future research promises to further ronmental elucidate the roles of neuroendocrine mechanisms in the rheumatic diseases and offers promise for enhanced therapies and possible avenues for disease modification if not eventual prevention. ACKNOWLEDGMENTS Sincere gratitude is expressed to Rachelle Lynn for her dedicated and outstanding contributions in the preparation of this manuscript, and to Doug Goessman for his expert graphics and photography services. Vanessa M. Weiss is also thanked for her helpful editorial suggestions.
References 1. Adachi JD, Olszynski WP, Hanley DA, et al: Management of corticosteroid-induced osteoporosis. Semin Arthritis Rheum 29:228, 2000 2. Baerwald CG, Panayi GS: Neurohumoral mechanisms in rheumatoid arthritis. Scand J Rheumatol 26:1, 1997 3. Baerwald CGO, Burmester G-R, Krause A Interactions of autonomic nervous, neuroendocrine and immune systems in rheumatoid arthritis. Rheum Dis Clin North Am 26~841-858,2000 4. Barnes PJ: Anti-inflammatory actions of glucocorticoids: Molecular mechanisms. Clin Sci 94:557, 1998 5. Beato M, Herrlich P, Schutz G: Steroid hormone receptors: Many actors in search of a plot. Cell 835351, 1995 6. Bhayani HR, Hedrick SM: The role of polymorphic amino acids of the MHC molecule in the selection of the T cell repertoire. J Immunol 1461093, 1991 7. Bijlsma JWJ: Long-term glucocorticoid treatment of rheumatoid arthritis: Risk or benefit? Rheumatology in Europe 27:67, 1998
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8. Bijlsma JWJ, Jacobs JWG: Hormonal preservation of bone in rheumatoid arthritis. Rheum Dis Clin North Am 26:897-910, 2000 9. Booji A, Biewenga-Booji CM, Huber-Brunning 0, et al: Androgens as adjuvant treatment in postmenopausal patients with rheumatoid arthritis. Ann Rheum Dis 55:811, 1996 10. Chikanza IC, Grossman A: Neuroendocrine immune response to inflammation: Concept of neuroendocrine immune loop (NEI). Bailleres Clin Rheumatol 10:199, 1996 11. Chikanza IC, Grossman A: Reciprocal interactions between the neuroendocrine and immune systems during inflammation. Rheum Dis Clin North Am 26:693-712, 2000 12. Chikanza IC, Kuis W, Heijnen CJ: The influence of the hormonal system on pediatric rheumatoid diseases. Rheum Dis Clin North Am 26:911-926, 2000 13. Chrousos GP, Torpy TJ, Gold PW: Interactions between the hypothalamic-pituitaryadrenal axis and the female reproductive system: Clinical implications. Ann Intern Med 129:229, 1998 14. Clevenger CV, Flanagan-Cato LM: Neuroendocrine immunology. In Conn PM, Freeman ME (eds): Neuroendocrinology in Physiology and Medicine. Totowa, NJ, Humana Press, 2000, p 509 15. Cronstein BN, Kimmel SC, Levin RI, et al: A mechanism for the antiinflammatory effects of corticosteroids: The glucocorticoid receptor regulates leukocyte adhesion to endothelial cells and expression of endothelial-leukocyte adhesion molecule 1 and intercellular adhesion molecule 1. Proc Natl Acad Sci USA 89:9991, 1992 16. Cutolo M: Sex hormone adjuvant therapy in rheumatoid arthritis. Rheum Dis Clin North Am 26881-896, 2000 17. Cutolo M, Wilder RL: Different roles for androgens and estrogens in the susceptibility to autoimmune rheumatic diseases. Rheum Dis Clin North Am 26:825-839, 2000 18. Cutolo M, Balleari E, Giusti M, et al: Androgen replacement therapy in male patients with rheumatoid arthritis. Arthritis Rheum 34:1, 1991 19. Cutolo M, Foppiani L, Prete C, et al: Hypothalamic-pituitary-adrenocortical axis function in premenopausal women with rheumatoid arthritis not treated with glucocorticoids. J Rheumatol 26:282, 1999 20. Cutolo M, Giusti M, Villaggio B, et al: Testosterone metabolism and cyclosporin A treatment in rheumatoid arthritis. Br J Rheumatol 4433, 1997 21. Da Silva JAP, Bijlsma JWJ: Optimizing glucocorticoid therapy in rheumatoid arthritis. Rheum Dis Clin North Am 26:859-880, 2000 22. Derksen RH: Dehydroepiandrosterone (DHEA) and systemic lupus erythematosus. Semin Arthritis Rheum 27335, 1998 23. Dizier MH, Eliaou JF, Babron MC, et al: Investigation of the HLA component involved in rheumatoid arthritis (RA) by using the marker association-segregation chi-square (MASC) method: Rejection of the unifying-shared-epitope hypothesis. Am J Hum Genet 53:715, 1993 24. Dumonde DC: Infection and Immunology in the Rheumatic Diseases. Oxford, Blackwell Scientific Publications, 1976 25. Dumonde DC, Kelly RH, Morley J: Lymphoid and microvascular dysfunction in experimental models of rheumatoid inflammation. In Dumonde DC (ed): Infection and Immunology in the Rheumatic Diseases. Oxford, Blackwell Scientific Publications, 1976, p 375 26. Eijsbouts A, van den Hoogen F, Laan RFJM, et al: Treatment of rheumatoid arthritis with the dopamine agonist quinagolide [letter]. J Rheumatol 262284, 1999 27. Folkman J: Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med 127, 1995 28. Gooren LJG, Giltay EJ, van Schaardenburg D, et al: Gonadal and adrenal sex steroids in ankylosing spondylitis. Rheum Dis Clin North Am, in press 29. Harris ED, Jr: Rheumatoid Arthritis. Philadelphia, WB Saunders, 1997 30. Hasstedt SJ, Clegg DO, Ingles L, et al: HLA-linked rheumatoid arthritis. Am J Hum Genet 55:738, 1994 31. Hench PS: The ameliorating effect of pregnancy on chronic atrophic (infectious rheumatoid) arthritis, fibrositis, and intermittent hydrarthrosis. Proc Mayo Clin 13:161, 1938 32. Herrmann M, Scholmerich J, Straub RH: Stress and rheumatic diseases: A review of
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studies in patients with rheumatoid arthritis, juvenile chronic arthritis, systemic lupus erythematosus, and fibromyalgia syndrome. Rheum Dis Clin North Am 26:737-764, 2000 33. Johnson EO, Skopouli FN, Moutsopoulos HM: Neuroendocrine manifestations in Sjogren’s syndrome. Rheum Dis Clin North Am, in press 34. Johnson EO, Vlachoyiannopoulos PG, Skopouli FN, et al: Hypofunction of the stress axis in Sjogren’s syndrome. J Rheumatol 25:1508, 1998 35. Kanik KS, Wilder RL: Hormonal alterations in rheumatoid arthritis, including effects of pregnancy. Rheum Dis Clin North Am 262305-824, 2000 36. Khalkhali-Ellis 2, Moore TL, Hendrix MJ: Could hormones make a difference in the treatment of juvenile rheumatoid arthritis? BioDrugs 13:77, 2000 37. Khalkhali-Ellis Z , Moore TL, Hendrix MJ: Reduced levels of testosterone and dehydroepiandrosterone sulphate in the serum and synovial fluid of juvenile rheumatoid arthritis patients correlates with disease severity. Clin Exp Rheumatol 16:753, 1998 38. Koch AE: Angiogenesis: Implications for rheumatoid arthritis. Arthritis Rheum 41:951, 1998 39. Kovacs WJ, Olsen NJ: Sex hormones and immune responses. In Volpe R (ed): Contemporary Endocrinology: Autoimmune Endocrinopathies. Totowa, NJ, Humana Press, 1999, p 163 40. Kuis W, de Jong-de Vos van Steenwijk C, Sinnema G, et al: The autonomic nervous system and the immune system in juvenile rheumatoid arthritis. Brain Behav Immun 10:387, 1996 41. Lahita RG: Sex hormones and systemic lupus erythematosus. Rheum Dis Clin North Am 26:957-968, 2000 42. Lahita RG, Bradlow HL: Klinefelter’s syndrome: Hormone metabolism in hypogonadal males with systemic lupus erythematosus. J Rheumatol 14 (Suppl 13):154, 1987 43. Madden KS, Felten DL: Experimental basis for neural-immune interactions. Physiol Rev 75:77, 1995 44. Maeno N, Takei S, Imanaka H, et al: Increased circulating vascular endothelial growth factor is correlated with disease activity in polyarticular juvenile rheumatoid arthritis. J Rheumatol 26:2244, 1999 45. Malinow KL, Molina R, Gordon B, et al: Neuropsychiatric dysfunction in primary Sjogren’s syndrome. Ann Intern Med 103:344, 1985 46. Masi AT Do sex hormones play a role in ankylosing spondylitis? Rheum Dis Clin North Am 18:153, 1992 47. Masi AT Hormonal and immunologic risk factors for the development of rheumatoid arthritis: An integrative physiopathogenetic perspective. Rheum Dis Clin North Am 26:775-804, 2000 48. Masi AT, Chang HJ: Cigarette smoking and other acquired risk factors for rheumatoid arthritis. In Kaufman LD, Varga J (eds): Rheumatic Diseases and the Environment. New York, Chapman & Hall, 1999, p 111 49. Masi AT, Medsger TA, Jr: Epidemiology of the rheumatic diseases. In McCarty DJ (ed): Arthritis and Allied Conditions, ed 11. Philadelphia, Lea & Febiger, 1989, p 16 50. Masi AT, Chrousos GP, Bornstein SR Enigmas of adrenal androgen and glucocorticoid dissociation in premenopausal onset rheumatoid arthritis. J Rheumatol 26247, 1999 51. Masi AT, Feigenbaum SL, Chatterton RT Hormonal and pregnancy relationships to rheumatoid arthritis: Convergent effects with immunologic and microvascular systems. Semin Arthritis Rheum 25:1, 1995 52. Masi AT, Aldag JC, Chatterton RT, et al: Adrenal androgen and glucocorticoid dissociation in premenopausal rheumatoid arthritis: A significant correlate or precursor to onset? Z Rheumatol 58:300, 1999 53. Masi AT, Chatterton RT, Fecht T, et al: Dissociation of serum dehydroepiandrosterone sulfate (DHEAS) and cortisol levels in younger premenopausal women prior to onset of rheumatoid arthritis (RA) before age 5 0 Results of a prospective, controlled study. Arthritis Rheum 41 (Suppl):S126, 1998 54. Masi AT, Feigenbaum SL, Chatterton RT, et al: Integrated hormonal-immunologicalvascular (H-I-V triad) systems interactions in the rheumatic diseases. Clin Exp Rheumatol 13:203, 1995
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55. Masi AT, Bijlsma JW, Chikanza IC, et al: Neuroendocrine, immunologic, and microvascular systems interactions in rheumatoid arthritis: Physiopathogenetic and therapeutic perspectives. Semin Arthritis Rheum 29:65, 1999 56. Neeck G, Crofford LJ: Neuroendocrine perturbations in fibromyalgia and chronic fatigue syndrome. Rheum Dis Clin North Am 26:989-1002, 2000 57. Ollier W, Winchester R: The germline and somatic genetic basis for rheumatoid arthritis. Current Directions in Autoimmunity 1:166, 1999 58. Olsen NJ, Kovacs WJ: Case report testosterone treatment of systemic lupus erythematosus in a patient with Klinefelter’s syndrome. Am J Med Sci 310:158, 1995 59. Olsen NJ, Kovacs WJ: Gonadal steroids and immunity. Endocr Rev 17369, 1996 60. Olsen NJ, Kovacs WJ: Hormones, pregnancy and rheumatoid arthritis. J GenderSpecific Medicine, in press 61. Orentreich N, Brind JL, Rizer RL, et al: Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrino1 Metab 59:551, 1984 62. Ostensen M, Ostensen H: Ankylosing spondylitis-the female aspect. J Rheumatol 25:120, 1998 63. Pitzalis C, Koch A: The vascular endothelial system (VES) in the pathogenesis of inflammation and systemic rheumatic diseases: Relationship to the neuroendocrine system. Rheum Dis Clin North Am 26:765-774, 2000 64. Poteliakhoff A: Adrenocortical activity and some clinical findings in acute and chronic fatigue. J Psychosom Res 25:91, 1981 65. Scott LV, Teh J, Reznek R, et al: Small adrenal glands in chronic fatigue syndrome: A preliminary computer tomography study. Psychoneuroendocrinology 24:759, 1999 66. Sokoloff L, Bunim JJ: Vascular lesions in rheumatoid arthritis. Journal of Chronic Disease 5:668, 1957 67. van Vollenhoven RF, Morabito LM, Engleman EG, et al: Treatment of systemic lupus erythematosus with dehydroepiandrosterone: 50 patients treated up to 12 months. J Rheumatol 25:285, 1998 68. Walker SE, Jacobson JD: Roles of prolactin-and gonadotropin-releasing hormone in rheumatic diseases. Rheum Dis Clin North Am 26:713-726, 2000 69. Wilder RL, Elenkov IJ: Hormonal regulation of tumor necrosis factor-alpha, interleukin12 and interleukin-10 production by activated macrophages. A disease-modifying mechanism in rheumatoid arthritis and systemic lupus erythematosus? Ann NY Acad Sci 876:14, 1999
Address reprint requests to Alfonse T. Masi, MD., DRPH, Department of Medicine, University of Illinois College of Medicine at Peoria, One Illini Drive, Box 1649, Peoria IL 61656-1649
0889457X/OO $15.00
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NEUROENDOCRINE IMMUNE MECHANISMS IN RHEUMATIC DISEASES An Overview and Future Implications Alfonse T. Masi, MD, DRPH
Systemic rheumatic diseases are complex chronic disorders of variable severity classified according to their clinical and immunologic manifestation~:~Specific causes of these diseases have not yet been determined. Available data support a multifactorial threshold model of causation (i.e., an accumulation of genetic and environmental influences [and their interactions] that operate in the individual and permit the disease to become manifest) as proposed for rheumatoid arthritis For decades, hormona131and immunologicz4mechanisms have been incriminated in the causation and perpetuation of these diseases. Additionally, abnormalities in the microvascular system,25,% particularly altered endothelial cell reacti~ity,~~ have long been described in these diseases. This issue summarizes the current state of knowledge on the complex interactions of the neuroendocrine and immune systems (Fig. 1) and how such mechanisms might relate to multiple rheumatic diseases. This article also outlines implications for future research and patient management. The article by Chikanza and Grossman" reviews the bidirectional
This study was supported in part by an Arthritis Foundation Clinical Science grant, the Rheumatoid Arthritis Precursors Study (RAPS), and a MTM Foundation gift.
From the University of Illinois College of Medicine at Peoria, Peoria, Illinois
RHEUMATIC DISEASE CLINICS OF NORTH AMERICA VOLUME 26 * NUMBER 4 * NOVEMBER 2000
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regulation of hormonal and cytokine mechanisms in the neuroendocrine immune (NEI) loop during inflammation and other forms of stress. Integrity of the NEI loop is essential for effective modulation of immune and inflammatory responses and restoration of physiologic homeostasis.’O, I1 Defects or deficiencies in maintaining normal regulation of the NEI loop can contribute to chronic inflammatory or autoimmune diseases. Proinflammatory cytokines (e.g., interleukin (IL)-lp, IL-6, and tumor necrosis factor-a (TNFa) are released in the acute-phase response and act not only as local mediators but also stimulate the neuroendocrine response. In turn, those hormones, particularly glucocorticosteroids (GCSs), are irnmunomodulatory.ll The complex orchestration of cascades of acute and chronic immunomediators in inflammation provokes neuroendocrine responses, that are accompanied by manifold GCS anti-inflammatory mechanisms.l0. l1 The NEI loop constitutes essential integrated physiologic circuits for the maintenance of health and the regulation of inflammation. Dysregulation of the NEI loop has important l1 physiopathologic consequences in the systemic rheumatic diseases.lO, The article by Walker and Jacobson reviews the roles of prolactin (PRL)68and gonadotropin-releasing hormone (GnRH) in affecting the hypothalamic-pituitary axis and immune responses and gender differences in autoimmunity. PRL helps to maintain immunocompetence in health, is a lymphocyte growth factor, and may be considered to function as a cytokine.68Reports of hyperprolactinemia in systemic lupus erythematosus (SLE) and other rheumatic diseases in human beings are summarized in tabular format, and its association with progression of disease in the New Zealand black-New Zealand white mouse model of lupus is reviewed.68Suppressing PRL with bromocriptine can provide beneficial effects in animal models of autoimmune disease, and a recent prelimi-
Figure 1. Reciprocal regulations and modeling of the neuroendocrine and immune systems.The acute phase response of active inflammation, (i.e., macrophage-related, generates proinflammatory cytokines), (e.g., IL-1p, IL-6, and TNFci), which stimulate the hypothalamic-pituitary-adrenal(HPA) axis to produce increased cortisol. In turn, increased cortisol modulates inflammatory responsiveness by diverse mechanisms and favors a T helper 2 (Th2) humoral immune reactivity over a T helper 1 (Thl) cell mediated immune pattern. The major sex hormones, (i.e., estradiol (EZ)and testosterone (T)), also modulate immunological responsiveness and contribute to gender dimorphism. In physiological concentrations, E, tends to enhance humoral immunity and favors a Th2 cytokine pattern, whereas T tends to be immunosuppressive. Dehydroepiandrosterone (DHEA) may favor Thl immune responsiveness and progesterone (P) favors Th2 function, as does activation of the sympathetic nervous system (SNS). Placental CRH stimulates the HPA axis to produce increased cortisol and adrenal androgens (e.g., DHEA and DHEAS). In turn, hypothalamic CRH decreases due to cortisol-HPA negative feedback mechanisms. During pregnancy, adrenal cortical function and hormonal production increases, and the gland may hypertrophy. Postpartum, placental CRH is lost and the adrenal may become understimulated, while hypothalamic production of CRH is still decreased. Physiological variations in CRH and HPA axis function during pregnancy and postpartum may contribute to the notable changes in onset risks and clinical activity of RA in these respective periods. Solid arrow = stimulation, dashed arrow = inhibition.
nary clinical trial in human SLE showed improvements equivalent to those associated with hydroxychloroquine.a Excessive PRL is produced by synovial lymphocytes in RA.6sIn a recent trial, quinagolide, a dopamine agonist and pituitary (but perhaps not lymphocyte) PRL-lowering drug, did not produce significant clinical benefit in nine RA patients.26 Effects of GnRH on the immune system, particularly on the IL-2 receptor and proliferation of B and T cells, may contribute to gender dimorphism and sex differences in immunologic responsiveness. Gender-specific actions of GnRH on murine lupus and its effects on the expression of this disease model are reviewed, with implications for the human disease.6s The article by Herrmann et a132reviews stress and rheumatic diseases, with an emphasis on psychologic and personality factors. Published reports that indicate evidence for and against minor or major psychologic stresses being contributory factors to the onset and course of RA; juvenile chronic arthritis, SLE, and fibromyalgia syndrome (FMS) are summarized. At present, interactions of the psyche and neuroendocrine immune system are not well defined in the rheumatic diseases, but stress seems to have an impact on these disorders, particularly juvenile chronic arthritis. Social and family functional status can influence clinical and psychologic outcomes in this disease.32Future research promises to reveal how the complex interacting psychoneuroimmunologic mechanisms may contribute to the multifactorial causes of the different rheumatic diseases.32 The article by Pitzalis and Kocha reviews the vascular endothelial system (VES) in the pathogenesis of inflammation and systemic rheumatic diseases and how the neuroendocrine system influences these mechanisms. The VES has long been recognized to play a critical role in the pathogenesis of acute and chronic inflammatory processes.25Recent research has defined the detailed physiopathogenesis of these processes, particularly how the VES interacts with immune and inflammatory mediators and how it is modulated by the neuroendocrine ~ystem.4~~ 51,54* 55, 63 Estrogens, androgens, and glucocorticoids exert different effects on the VES in physiologic (i.e., resting endothelium) and pathologic conditions (i.e., activated endothelium in response to toxic products, inflammatory mediators, and cytokines).a The formation of new blood vessels, or angiogenesis, is an important phenomenon not only in cancer but 38 and is modulated by also in chronic inflammatory processes like RAZ7, hormonal factors?, Sex hormone effects on the VES may enhance gender dimorphism in the rheumatic diseases through a series of complex mechanism^.^^ Individual sex hormones may have dose-related biphasic effects and differential influences on resting versus activated tissues (including the VES). Furthermore, hormones physiologically operate in combination rather than in i ~ o l a t i o nFinally, . ~ ~ hormones act at multiple levels of gene expression and cellular biology.63Hormones may have dualistic effects
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on the VES, protective and damaging, depending on various complex constellations of factors. Considerable research is needed to unravel the precise mechanisms by which the neuroendocrine system interacts with the VES and contributes to the diverse dysfunctions associated with the rheumatic diseases. The VES along with the neuroendocrine and immunologic systems may be considered to be core components in the physiopathogenesis of RA and other systemic rheumatic 51, 55, 63 Early results indicate that angiogenesis or cell migration is a useful target in the treatment of these conditions. The article by M a ~ presents i ~ ~ an integrative physiopathogenetic perspective of hormonal and immunologic risk factors in RA. The multifactorial threshold model of RAZ9is expanded to include a multiyear preclinical pha~e.4~ During a long interval of symptomatically silent disease incubation, multiple genetic, nongenomic somatic, behavioral, and environmental risk factors are proposed to perturb the normal physiologic homeostasis of the core systems (i.e., the neuroendocrine, immunologic, and microvascular compartments). The physiologic functions of steroids and other neuroendocrine hormones in modulating or remodeling the immunologic and endothelial-microvascularsystems are 47, 63 largely unexplored and not well under~tood.'~, When physiologic homeostasis is sufficiently disturbed, inflammatory and clinical manifestations may appear or progress. Conversely, regulatory mechanisms controlling the homeostasis of perturbed core systems may also become normalized to a point that would favor clinical improvements. Such amelioration of disease activity may occur in persons with less strong genetic loading predisposing to disease,3o,57 fewer 48 favorable effects of pregaccumulated nongenomic risk 51, 6o or effective suppressive therapy.21, 47, 54, 55 nan~y,~" The proposed physiopathogenetic concept of RA47,55 further presumes individualized variability in the onset risks and diverse severity of outcomes in RA.57Such a multifactorial integrative concepP7,55 is an alternative model for understanding RA compared with the more basic and specific proposed mechanisms of arthritogenic peptides interacting with selective T-cell receptor epitopes and having an essential role in disease causation.6,23 Long-term risk factors for subgroups of RA patients have been identified (i.e., for subsets of women with premenopausal onset and for men) and more general risk factors for men and women combined.47, 5z, 55 Further documentation of such predictive relations and successful research in establishing reliable risk factors (or markers) for RA promise 55 to lead to future prevention strategies.47* The article by Kanik and Wilder35reviews hormonal alterations in RA, including the effects of pregnancy. Differences in the incidence of RA and the notable changes in its clinical activity during the pregnant and postpartum periods are reviewed. Hormonal changes during these periods are suggested to influence either the susceptibility to disease or its manifestation^.^^ Increases in circulating corticosteroids, estrogens, st
and progesterone during ~regnancy'~ may play a role in modulating the expression of RA. Possible mechanisms include the regulation of cytokine production such as TNFa, IL-12, and IL-10.13,35, 39, 59, 69 The postpartum period is characterized by adrenal and gonadal defi~iencies,'~ which may predispose to the development or increased activity of RA.35,6o Evidence for functional abnormalities of the adrenal cortex in RA patients is also reviewed,35particularly the findings of GCS and dehydroepiandrosterone or dehydroepiandrosterone sulfate (DHEAS) dysreg50, 53 Adrenal cortical dysfunction has been demulation or disso~iation.'~, onstrated before the development of RA53and within the first year of disease activity.19,35 Some specific hormonal abnormalities seem to be restricted by sex and premenopausal state.35,53 Such complex relations may be the reason for the contradictory results noted in some studies that do not analyze population subsets ~eparately.~~ The identification of particular hormonal abnormalities within specific patient populations at risk for RA is important. New hormonal therapeutic approaches that are more effective in addressing these factors and less toxic than current regimens may be developed in selected patients.35 The article by Cutolo and WilderI7 reviews differing roles of androgens and estrogens in susceptibility to autoimmune and rheumatic diseases from basic biologic and clinical perspectives. The effects of these hormones on B lymphocytes, T lymphocytes, monocytes and macrophages, and bone cells are reviewed.17 Aggregate data indicate that androgens tend to suppress cellular and humoral immunity. Depending on dosage levels, estrogens may enhance humoral immunity but may also decrease cellular immunity. Functional androgen and estrogen receptors were demonstrated on synovial macrophages, monocytes, and lymphocytes. Accordingly, sex hormones may have immunomodulatory effects in RA synovitis. Cyclosporin A increases androgenicity, (i.e., increases conversion of testosterone to dihydrotestosterone) and may inhibit synovial macrophages by such a metabolic pathway.20Some data indicate that environmental estrogens may increase susceptibility to autoimmunity and that use of oral contraceptives exacerbates the activity of SLE.17,41 Inflammatory mediators (i.e., cytokines) may alter the peripheral metabolism of sex hormones and further complicate interpretation of such hormonal effects on susceptibility relations in the rheumatic diseases.I7 The article by Baerwald et a13 reviews disturbances in interactions between the autonomic nervous system (ANS) and the hypothalamicpituitary-adrenal (HPA) axis in chronic rheumatic diseases and the effects of their respective products on inflammation and the immune response. These central nervous system pathways allow multiple channels of communication with behavioral, emotional, psychosocial, and stressful experiences. The ANS, HPA axis, and other neurobiologic processes influence the immune system by various pathways in addition to noradrenergic and peptidergic innervations of the ANS of lymphoid organ^.^ In turn, inflammatory cytokines can interact with central neurons and modulate their activity and downregulate P,-adrenoceptor
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density on peripheral blood mononuclear cells? Basic research is reviewed to support the hypothesis that disturbed interactions between the ANS and immune system contribute to the pathogenesis of human rheumatic diseases: including RA,3 and to animal models of arthriti~.~ Catecholamines could modulate the immune response by direct actions on immune cells and by effects of ANS neuropeptides on various tissues such as endothelium, connective tissue, and smooth muscle^.^ The resultant effects are modulation of lymphocyte proliferation, differentiation, cell adhesion, and migration." 3, 43 To further confound the complex relations, the time point at which catecholamines are applied during the course of an immune reaction is essential for the net effect of the catecholamine actions? The article by Da Silva and Bij1smaz1reviews new insights into genomic and nongenomic mechanisms of GCSs in RA, and guidelines are provided for optimizing discretionary therapy. Glucocorticoids can regulate transcription of a large variety of target genes by alternative mechanisms (e.g., either by direct binding of GCSs to glucocorticoid response elements [i.e., transactivation] or by indirect inhibitory interactions on transcription [i.e., transrepression])." 21 Glucocorticoids exert potent inhibitory effects on the transcription and actions of a large variety of proinflammatory and T helper 1 type cytokines of pivotal importance in the pathogenesis of RA, including IL-lp, IL-2, IL-6, and TNFa. Conversely, the production of T helper 2 type cytokines such as IL-4, IL-10, and IL-13 is either stimulated or not effected by GCSS.~~ In addition, GCSs potently inhibit the production of metalloproteinases, especially collagenase and stromelysin, which are the main effectors of cartilage degradation induced by IL-1 and TNFa.21Furthermore, GCSs control trafficking of inflammatory cells by reducing the expression of adhesion molecules such as intercellular adhesion molecule-1 and E-selectin through inhibition of proinflammatory cytokines and by direct inhibitory effects on the expression of adhesion molec u l e ~Glucocorticoids .~~ inhibit chemotactic cytokines and the cytokineinducible form of nitric oxide synthase, thereby suppressing the amplification of inflammatory responses by these mediators.2I Studies that support the emerging evidence that normal endogenous GCS levels have clinically significant influences on RA activity and that low-dosage glucocorticoid therapy may retard erosive joint damage are reviewed.21Also, dysfunctions in GCS response to inflammationlo,l1 may predispose to the development or progression of RA.21Further research is needed, however, to clearly establish such relations.47,55 The effectiveness of low-dosage GCSs as opposed to higher dosages in treating RA is reviewed and their major side effects.21Guidelines are provided to optimize GCS therapy in RA, considering the dosage, timing of administration, and management of side effects.2l The article by Cutolo16reviews the modulating effects of sex hormones on tissue-specific immune responses and their adjuvant effects in therapy of RA. In a small-scale open study of male RA patients, oral 5r
testosterone undecanoate administered daily for 6 months showed favorable clinical and immunologic changes without notable side effects.I8A double-blind placebo-controlled study of testosterone as adjuvant therapy for RA in 57 postmenopausal patients showed an expected anabolic effect and slight disease modification, although not statistically significant.9Interestingly, the immunosuppressive agent cyclosporin A induces a dose-dependent side effect of hypertrichosis in both sexes and an increase in peripheral androgen metabolism.20Such findings suggest that this agent has indirect androgen-mediated immunosuppressive activity.'" 2o The article by Bijlsma and Jacobs8reviews the multifactorial mechanisms of bone loss in RA and the effects of androgens and estrogens on bone preservation. Male and female RA patients show decreases in bone mineral density that are more evident at the hip and radius than at the spine. Such bone losses in RA patients cause an estimated doubling of their fracture risk even without GCS treatment.8 When RA patients are treated with GCSs, the fracture risk is estimated to again d ~ u b l e . ~ Proinflammatory cytokines and other inflammatory mediators (e.g., prostaglandin E2) are believed to increase bone resorption in RA by stimulating osteoclasts.8 Also, mechanical and other bone-preserving factors are often decreased in patients with active RA. Guidelines for bone preservation and treatment of glucocorticoidinduced osteoporosis in RA include the avoidance of or use of the lowest possible dosage of GCSs, reduction of underlying disease activity, and increase in physical activity. Also recommended are maintenance of an adequate calcium intake, preferably 1500 mg daily in patients using GCSs plus at least 400 IU of vitamin D supplements daily! Estrogen replacement therapy could be considered for postmenopausal women with osteoporosis.8Also, in patients treated with GCSs who have bone mineral density measurements indicating osteopenia or osteoporosis, treatment with bisphosphonates is recommended8in agreement with the findings in a recent detailed review.' The article by Chikanza et all2reviews neuroendocrine profiles and influences of the hormonal system in pediatric rheumatic diseases. Their role in the inflammatory rheumatic diseases of children requires further study. Some data suggest that juvenile rheumatoid arthritis (JRA) patients, particularly those with positive antinuclear antibody, have higher serum levels of PRL and IL-6 than comparison patients.I2 In a recent study, pubertal JRA patients had significantly lower mean serum DHEAS and testosterone values than normal control^.^' These JRA patients also had lower than expected DHEAS and testosterone levels in synovial f l ~ i d . 3Qualifications ~ of this reporP are that inflammatory disease controls were not studied and that the normal comparison subjects had higher than expected serum DHEAS levels.6l Adrenal androgens in pubertal JRA and the question of whether hormones could make a difference in treatment were recently reviewed.36 Whether or not hormonal alterations might influence immunoreactivity or microvascular or endothelial responsiveness warrants further
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investigation,12particularly in view of a recent report of increased circulating levels of vascular endothelial growth factor in polyarticular and systemic JRA patients." Patients with JRA have been reported to have alteration of ANS function.12The manifestations include increased vasoconstriction and an increased central noradrenergic outflow, resulting in a decreased response to an orthostatic stressor.l2,40* Catecholamines are proposed to enhance proinflammatory mediators in JRA as opposed to downregulation in Neuroendocrine changes in juvenile SLE and ankylosing spondylitis (AS) are also reviewed.I2 The article by Johnson et a133reviews the functional integrity of the major neuroendocrine axes (i.e., the HPA, hypothalamic-pituitarygonadal, and hypothalamic-pituitary-thyroidal) and psychologic profiles of Sjogren's syndrome (SS) patients. This disease is characterized by a strong female preponderance, widespread involvement of epithelial tissues showing increased rates of apoptosis, infiltration by activated CD4 T cells in the lesions, generalized B-cell hyperactivity, and a genetic predisposition (i.e., an autoimmune epithelialitis). In a detailed study of psychiatric dysfunction, most patients showed psychologic abnormalities that were primarily affective di~turbances.4~ Such findings were interpreted as atypical Evening ovine corticotropin-releasing hormone (CRH) stimulation of the HPA axis of SS patients showed lower basal serum corticotropin and cortisol levels than normal 34 Also, the stimulated increments in serum corticotropin were somewhat blunted at the 60-minute postinjection sampling. The stimulated increments of serum cortisol levels from baseline were comparable in the SS and normal study subjects, however.33 The findings in female SS patients suggested subtle central deficiencies in the three neuroendocrine axes studied (i.e., HPA, HPG, HPT) as well as elevated basal PRL concentrations. The findings do not indicate whether any one specific neuroendocrine system plays a primary role over the others in affecting the immune function of SS patients or in the expression of their disease.33Synergistic and antagonistic effects of multiple hormones may contribute to this disease, making the specific effects of individual hormones difficult to discern.33The potential therapeutic usefulness of hormonal immunomodulation in this condition is disc~ssed.~~
The article by Lahita4I reviews basic mechanisms whereby sex hormones may contribute to the development of SLE and to the gender dimorphism of the HPA axis and the immune system. A number of neuroendocrine perturbations involving androgens and estrogens have been described in SLE, and these may contribute to the disease processes. *A question raised by this guest editor (A.T.M.) is whether or not decreased serum albumin levels and lower oncotic pressure or increased capillary permeability in active JRA may have contributed to decreased intravascular volume of the patients and to their observed ANS changes."
Gender plays a major role in SLE expression, and sex steroid metabolism is altered in this disease. Sex hormones are not likely to be the underlying cause of this disease but rather modulators, possibly through their immunomodulatory effects.4I The SLE patient with Klinefelter's syndrome has the estrogen and androgen metabolism of a woman with SLE.42When SLE does occur in young patients with Klinefelter's syndrome, it can be treated with synthetic androgens such as methyltestosterone tablets or an androgen patch. Symptoms of the disease can be alleviated by such therapy, and the serologic features may even be normalized, as reported in one patient.58Use of another androgen, dehydroepiandrosterone, in female SLE patients resulted in favorable clinical and immunologic effects.22,41* 67 Thus, hormonal manipulation could have ameliorating effects on the disease activity of SLE.*I The article by Gooren et a P reviews adrenal and gonadal sex steroid relations to AS and the immunologic system. The greater frequency and severity of AS in men than in women suggests that sex hormones may interact with genetic and immunologic factors to play a role in this disease. Previous studies reported somewhat elevated ratios of serum androgen to estrogen in male AS patients compared with controls as previously summarized.& More recent better designed studies have found that serum testosterone, 17P-estradiol, and androstenedione levels Interestdid not differ significantly between AS patients and ingly, somewhat elevated serum DHEAS levels were found in 50 male AS patients compared with age-matched controls.28 The onset of AS was related to pregnancy in about 20% of more than 500 female patients studied; half of these new patients developed onset during pregnancy and the remainder within 6 months after delivery. No clear effect of pregnancy on the activity of the disease was observed. The article by Neeck and C r ~ f f o r dreviews ~~ neuroendocrine perturbations in fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS). These disorders have overlapping symptomatology and clinical manifestations but are suspected to have subtle differences in neuroendocrine profiles. Authors infer that a hyperactivity of the HPA axis is present in FMS, whereas a hypofunction of the HPA axis is typical in CFS.56 In FMS, a hyperactivity of CRH neurons is suspected to be driven by stress of chronic musculoskeletal pain or central nervous system mechanisms resulting from enhanced n o c i c e p t i ~ nOther . ~ ~ hormonal perturbations are also believed to result from the elevated CRH a~tivity.~" Reduced plasma cortisol levels were reported in CFS patients compared with controls and altered circadian variation in capillary resistance.@In a subset of CFS patients selected for subnormal response to corticotropin stimulation, adrenal size by computed tomography was Deficient serotonergic activity has been suggested in CFS and is reviewed?" Decreased activity of hypothalamic neurons producing CRH or arginine vasopressin in this syndrome is ~ o n s i d e r e d The .~~
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suggestion of chronically low arginine vasopressin function with increased vasopressinergic responsivity of the anterior pituitary in CFS is also discussed.s6 FUTUREPROSPECTS Within the past decade, new and broader concepts of causation of the systemic rheumatic diseases have evolved and promise to reveal valuable insights into their evolution. Bidirectional regulatory mechanisms between the neuroendocrine and immune systems are now recognized'", l1 and their reciprocal interactions with endothelium of the microvascular system in inflammation and systemic rheumatic disease^.^" 5s, 63 These new concepts and related scientific developments are also expected to be translated into clinically relevant therapeutic applications. Some of these benefits are evident at present,16,21 but further advances may be expected in the future. Neuroendocrine mechanisms are an important component of the complex interactive determinants of the systemic rheumatic diseases. These processes are more likely to be modulatory rather than causal per se, even considering their essential interactions and influences on the immunologic10,11, 13, 35, 39, 41,59,60, 68, 69 and microvascular54,55. 63 systems. The neuroendocrine system may also modulate effects of other important host mechanisms that operate in the rheumatic diseases (e.g., genetic 57 and acquired risk factors in RA (e.g., heavy or long sus~eptibilities)~~, duration of cigarette smoking) and their effects on the VES.47,48 Neuroendocrine mechanisms emphasize the relevance of the individualized physiologic dysfunctions or perturbations that may precede the clinical onset or progression of these diseases'", 11, 47, ss, 69 or suppress the activity of RA as is well documented during ~regnancy.~', 35, sl, 6o RA and related rheumatic diseases may begin as perturbations of complex interacting physiologic processes during an extended preclinical phase. Subsequently, such dysfunctions may progress over further time into inflammatory or pathologic sequelae (i.e., physiopathogenetic evolution). Such a new paradigm is an extension of the multifactorial threshold model of RAz9and further implies that RA or related diseases evolve gradually from a preclinical phase and may not necessarily require specific etiologic or triggering events for their clinical expression. Such physiopathogenetic evolution would be analogous to the insidious development of congestive heart failure in persons predisposed to cardiac disease and would be an alternative to the theory of the onset of RA being triggered by specific factors (e.g., either arthritogenic peptide& 23 or infectious agent antigensz5).In either congestive heart failure or RA, severe insults could precipitate or accelerate disease onset but would be considered as superimposed factors on the basic underlying physiopathogenetic processes. Without a significant precipitating event in RA, transition from an earlier subclinical phase of physiologic dysfunctions or perturbations to
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later clinical and pathologic manifestations likely occurs when the core systems (i.e., the neuroendocrine, immunologic, and microvascular components) become sufficiently decompensated. At such later stages, inflammation and tissue lesions are promoted rather than repaired during 55 earlier periods of homeo~tasis.~~, * Elucidation of neuroendocrine contributions to these diseases can help to clarify their long-term evolution among predisposed persons. The ultimate objective is to recognize susceptible persons during their preclinical phases and to develop strategies for primary prevention and 35, 41, 47, 55 more effective and less toxic therapies.33, SUMMARY A new physiopathogenetic paradigm may be proposed for RA and possibly its related systemic rheumatic diseases (i.e., mechanisms whereby multiple risk factors initially perturb the homeostasis of core physiologic components over an extended premorbid phase, which may progress to clinical disease in later decompensated stages).47,55 These complex interactive processes are likely to be individualized according to genetic, nongenomic somatic, developmental, behavioral, and envi47, 48, 55, 57 Future research promises to further ronmental elucidate the roles of neuroendocrine mechanisms in the rheumatic diseases and offers promise for enhanced therapies and possible avenues for disease modification if not eventual prevention. ACKNOWLEDGMENTS Sincere gratitude is expressed to Rachelle Lynn for her dedicated and outstanding contributions in the preparation of this manuscript, and to Doug Goessman for his expert graphics and photography services. Vanessa M. Weiss is also thanked for her helpful editorial suggestions.
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