Predictive and potentially predictive factors in early arthritis: a multidisciplinary approach

P. Härle, T. Bongartz, J. Schölmerich, U. Müller-Ladner and R. H. Straub

Laboratory of Neuroendocrinoimmunology, Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.

Correspondence to: R. H. Straub, Department of Internal Medicine I, University Hospital, 93042 Regensburg, Germany. E-mail: rainer.straub{at}klinik.uni-r.de


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Objectives. Rheumatoid arthritis (RA) is characterized by variable degrees of joint inflammation, joint destruction, progressive disability and premature death. Destruction of joint cartilage and bone may occur early during disease, as was shown in longitudinal studies of RA, and there is increasing consent among rheumatologists that early diagnosis and early initiation of therapy with disease-modifying anti-rheumatic drugs (DMARDs) can limit the severity of RA. Unfortunately, the currently used diagnostic and predictive indicators (clinical, laboratory and radiological) are of limited value for making an early diagnosis and prognosis of the disease course at the individual level, thus reducing optimal benefit from present and emerging therapies. Therefore, this review focuses on the multidisciplinary aspects of neuroendocrine–immune changes in RA.

Methods. A Medline search was performed using the search terms ‘androgens’, ‘estrogens’, ‘sympathetic nervous system’, ‘sensory nervous system’, ‘prognosis’, ‘early rheumatoid arthritis’, ‘arthritis’ and ‘studies’ in various combinations. For the tabular overview, we only listed clinical studies focusing on endocrine and neuronal aspects.

Results. In addition to the currently used predictive indicators, there is an abundant body of literature describing changes of the neuronal, endocrine and immune parameters during inflammatory diseases. Unfortunately, no longitudinal studies concerning neuroendocrine aspects have been done up to now.

Conclusion. Parameters of the neuroendocrine system should be included in anticipated longitudinal clinical studies to find their true predictive value in early RA.

KEY WORDS: Immune system, Endocrine system, Nervous system, Prognosis, Early rheumatoid arthritis


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 Introduction
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In patients with early inflammatory arthritis, there is often uncertainty whether a patient has rheumatoid arthritis (RA) or another rheumatic disease. At present, the diagnosis of RA is defined according to the 1987 revised criteria of the American College of Rheumatology (ACR) [1]. Unfortunately, these classification criteria have low sensitivity in the very early diagnosis of RA. However, more important than the correct diagnosis is the ability to predict the severity of the disease course, and the ACR criteria have low ability to discriminate between persistent, disabling or erosive disease [2]. In RA, the magnitude of joint, cartilage and bone destruction exhibits considerable heterogeneity and may occur early during disease, as was shown in longitudinal studies of RA [3]. There is increasing consent among rheumatologists that early diagnosis and early initiation of therapy with disease-modifying anti-rheumatic drugs (DMARDs) can limit the severity of RA [4–6]. Furthermore, DMARDs appear to be most effective when given very early in disease [7] but optimal benefit from present and emerging therapies is limited by our suboptimal predictive abilities during this early period. In contrast to an aggressive disease course, numerous patients presenting with inflammatory arthritis follow a benign or even self-limiting course. In this case, the therapeutic benefit of potentially harmful DMARDs clearly outweighs the risks of side-effects in these patients [8]. In addition, there are economic aspects that make it necessary to develop markers to facilitate early diagnosis and prognosis. The relatively expensive treatment with biologicals could be done more cost-effectively by using them selectively for cases with a predictable severe disease course very early in the disease. This could prevent considerable secondary costs resulting from subsequent debilitation. Therefore, early and reliable parameters for assessing the prognosis of the disease process are needed. The currently used predictive indicators are only moderately successful and lack sensitivity [8–10]. They include sociodemographic factors (e.g. age, sex), clinical scores (health assessment questionnaire, HAQ), the disease activity score (e.g. DAS28), laboratory parameters (C-reactive protein, erythrocyte sedimentation rate, high rheumatoid factor titre, probably antibodies against citrullinated antigens), inherited factors (subtypes of HLA-DR1, -3 and -4) and radiographic indicators (osteoporosis, bone erosions). Nevertheless, clinical judgement keeps a central role.

Recent advances regarding joint tissue composition and pathophysiology have defined a number of biological marker candidates, which need to be validated in studies to assess their predictive potency. There is an abundant body of literature that describes changes in the neuronal, endocrine and immune systems during inflammatory disease [11, 12]. Therefore, a multidisciplinary approach is needed to analyse and correlate current and novel immune and neuroendocrine variables during early disease and to uncover early predictive factors for a chronic and aggressive inflammatory disease course. In addition, new pathophysiological insights from studies that investigate neuroendocrine as well as immunological factors might unravel novel diagnostic and therapeutic options. Unfortunately, the data available at the moment are based on cross-sectional studies and data from longitudinal studies are needed to show the pathophysiological impact of neuroendocrine changes in early RA. However, markers of the neuroendocrine system may prove to be clinically useful and will give new insights into pathogenic processes, to facilitate the establishment of novel therapeutic approaches. To give a brief overview of the physiological interplay of the neuroendocrine–immune network, we would like to refer to Figs 1 and 2 (local vs systemic neuroendocrine–immune pathways) and the explanatory legend.



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FIG. 1. Inflammatory and anti-inflammatory feedback pathways during systemic inflammation. The humoral hypothalamic–pituitary–adrenal axis, which regulates adrenal hormones, is shown on the left (separated by the dashed line). The neuronal hypothalamic–autonomic nervous system axis, which influences local neurotransmitter release, is shown on the right. The small box at the bottom of the figure leads to local hormonal pathways shown in Fig. 2. Cytokines released in the periphery signal to the central nervous system directly via the bloodstream or via receptors on sensory nerves. This causes activation of humoral and neuronal sympathetic anti-inflammatory feedback pathways in order to dampen inflammation in the periphery. In addition, cytokines enhance the release of leptin, which suppresses glucocorticoid synthesis in the adrenal glands. Black lines symbolize the immune system, red lines the endocrine system and purple/blue lines the neuronal system. ACTH, adrenocorticotropin-releasing hormone.

 


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FIG. 2. Cytokines released in the periphery influence steroid metabolism in peripheral tissue. The stimulation of aromatase activity by inflammatory cytokines enhances conversion of androgen into oestrogens, which leads to an inflammatory stimulus in the synovial tissue. IL-6 has been found to mediate an increase in reductive 17ß-hydroxysteroid dehydrogenase (17ß-HSD) activity, which converts oestrone to the biologically more active 17ß-oestradiol. Summarizing, in the chronic inflammatory situation anti-inflammatory hormonal (DHEA/DHEAS and cortisol) and neuronal sympathetic pathways seem to be defective and inflammatory pathways seem to be up-regulated (oestrogens), leading to an overall inflammatory situation. Black lines symbolize the immune system, red lines symbolize the endocrine system. 17ß-HSD, 17ß-hydroxy-steroid dehydrogenase; ST, sulphatase.

 

    Potentially predictive parameters of the endocrine system
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Although pathogenic factors of the endocrine system are known, there are no predictive factors established yet. Nevertheless, immune, endocrine and neuronal factors interact with one another during inflammatory disease [13]. Therefore, we give an overview of endocrine and neuronal pathogenic factors in the next two paragraphs and a tabular overview in Tables 1 and 2, which might, in the future, prove useful in predicting the course of early arthritis.


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TABLE 1. Potentially predictive factors of the endocrine system

 

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TABLE 2. Potentially predictive factors of the nervous system

 
Endocrine factors in the pathogenesis of RA
The incidence of RA in women increases steadily from menarche to a maximum around the menopause. In men, RA is uncommon before the age of 45 but thereafter the incidence increases rapidly and becomes similar to that seen in women [14]. This epidemiological phenomenon strongly suggests that sex hormones—androgens and oestrogens—play an important role in RA. There is intriguing evidence in the literature that patients with RA and other inflammatory diseases have low levels of adrenal [dehydroepiandrostenedione (DHEA)/DHEA sulphate (DHEAS) and androstenedione (ASD)] and gonadal (testosterone, dihydrotestosterone) androgens [11, 15–17]. This observation was also made in a study with HLA-identical but RA-discordant sibling pairs, in which the RA sibling showed lower DHEAS serum levels [18]. Furthermore, there is evidence that low levels of DHEA and a dissociation of cortisol and DHEA are present in young premenopausal women even before the clinical manifestation of RA [19]. It is a matter of debate whether the subtle adrenal cortical dysfunction may either predispose to younger-onset RA or whether this dysfunction may serve as a long-term marker in a minority of women. However, hypoandrogenism appears to be a common feature in many inflammatory diseases, such as SLE, Crohn's disease, psoriasis, systemic sclerosis, atopic dermatitis, African trypanosomiasis and others [11]. DHEA is the major androgen in women, production peaking between the second and third decades and then declining steadily [20]. In addition, DHEAS serves as the major precursor of sex hormones (Fig. 2) [21]. DHEAS is metabolized into ASD and testosterone, which are further converted into oestrogens via the aromatase in peripheral tissue, mainly in adipose tissue. Aromatase expression is up-regulated by inflammatory cytokines such as TNF, IL-1 and IL-6 [22], leading to locally high levels of oestrogens [23] (Fig. 2). Oestrogens are known to facilitate the humoral immune response but tend to suppress T-cell-dependent activity, at least at high concentrations [24]. Androgens, especially testosterone, suppress both T- and B-cell immunity and therefore counteract the oestrogen effect [15, 25, 26]. The intensive peripheral conversion of androgens into oestrogens might be the reason why the substitution of testosterone may cause a flare of disease activity [27].

But not only hormones of the HPA/HPG axis seem to play an immune-modulatory role in inflammatory disease. Leptin, a hormone mainly produced by adipose tissue seems to add to the adrenal hypoandrogenism (Fig. 1); this was shown by a negative correlation of serum leptin and ASD in patients with RA and SLE [28]. In addition, inflammatory cytokines such as TNF were able to increase the synthesis of leptin [29]. In addition to the unbalanced levels of androgens, oestrogens and leptin, inadequate levels of cortisol in relation to the inflammatory activity, as measured by serum IL-6 or TNF levels, were observed [30]. There is evidence that the adrenal glands show a decreased response to ACTH [31], the major stimulator for synthesis of cortisol and adrenal androgens. Another study presented data contradictory to this observation [32]: it showed a normal cortisol response in the ACTH test but systemic levels were still low in relation to the inflammatory activity. At the cytokine level, elevated concentrations of circulating TNF, IL-1 and IL-6 as parameters of high inflammatory activity were detected in RA patients [33]. These cytokines are known, in addition to their inflammatory properties, as potent modulators of the hypothalamus–pituitary–adrenal axis [20]. Therefore, they serve as linkers between the immune and the endocrine systems. In chronic inflammatory diseases, high levels of especially IL-6 (long half-life) correlate with a desensitization of the HPA axis with low cortisol and androgen serum levels in relation to the inflammatory activity [30, 34]. As was shown in a recent publication, long-term treatment with anti-TNF blocking agents leads again to sensitization of the HPA axis and elevated adrenal androgens [35]. This might enable the organism to produce anti-inflammatory androgens and cortisol adequately, thus helping to down-regulate inflammation.

Potential endocrine factors as predictive parameters
The data on the above-mentioned endocrine changes do not yet give conclusive cut-off values and therefore cannot be used as established diagnostic and predictive parameters for individual patients. However, changes at the endocrine level, locally and systemically, might play an important role in the subclinical phase of the disease and in the process of chronification or perpetuation of an acute inflammatory process (Table 1). In early arthritis, there might be some distinct hormonal inflammatory and anti-inflammatory constellations defining the inflammatory predisposition of the individual. In one report, DHEA levels were already low 4–20 yr before the onset of RA [19], which suggests that subtle adrenal cortical dysfunction may predispose to RA onset below the age of 50 yr. New ideas from studies comparing different arthritic entities might be obtained from the ratio between androgen and oestrogen metabolites in the synovial fluid (SF). In SF of RA patients compared with SF of patients with traumatic knee injury or osteoarthritis, inflammatory oestrogen levels were significantly elevated relative to anti-inflammatory androgen levels [23]. The cells that convert androgens (DHEA) into oestrogens were demonstrated to be macrophages [36]. In addition to the peripheral mechanisms of hypoandrogenism, there is a central alteration of hormonal regulatory systems. For example, high levels of IL-6 in chronic inflammatory diseases correlate with desensitization of the HPA axis with reduced cortisol and androgen serum levels in relation to the inflammatory activity [30]. To test the integrity of the HPA axis in chronic inflammatory diseases the standard insulin–hypoglycaemia or Corticotropin-releasing hormone (CRH) test can be used. There is a need for ongoing studies to establish cut-off values or ratios between different parameters of the endocrine system in these tests in order to come up with a prediction model for the course of early RA for the individual patient. It is necessary to study local and systemic effects of components of the endocrine system to make possible a more precise prediction of chronification or self-limitation of early inflammatory disease, and, if a chronic disease course is predicted, to make a more precise prognosis. This might lead to the initiation of aggressive therapy very early after the diagnosis of RA, with a combination of available DMARDs/biologicals and a combination of androgenizing agents (e.g. DHEAS, aromatase inhibitor) to lower the immune response and perhaps even reconstitute the endocrine balance in patients with chronic inflammatory disease. The regained sensitivity of the HPA axis observed during anti-TNF therapy supports this optimistic attitude to such theories [35]. The importance of reconstituting the endocrine balance is emphasized by the beneficial therapeutic effects of DHEA in patients with SLE and Crohn's disease [37, 38].

However, there is a third component in addition to the immune and endocrine system controlling chronic inflammatory disease that needs to be included in a multidisciplinary diagnostic approach, as outlined in the next section.


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Neuronal factors in the pathogenesis of RA
It has been suggested for many years that alterations of nervous system function play a significant role in rheumatoid arthritis (Table 2) [11, 39]. RA usually manifests bilaterally, whereas paralysed patients developing RA do not show arthritis in the paralysed limb (summarized in [40]). Furthermore, joints that are predominantly affected in RA show high-density innervation with sensory nerve fibres, according to the large cerebral representation of the small joints of the hands and feet in the sensory homunculus. Sensory neurons release inflammatory peptides such as substance P (SP). The release of SP causes local sensitization, which can lead via afferent pathways to central and contralateral sensitization, subsequently contributing to the bilateral phenotype in RA and the continuous imprinting of pain pathways [41]. Moreover, central memory of pain can cause chronic and persistent pain with continuous inflammatory neuropeptide release in the periphery [42]. SP also exerts trophic effects during repair of tissue damage. Therefore, SP has a dual role in the modulation of inflammatory and repair processes. Unfortunately, measurement of SP levels in synovial fluid is difficult to achieve due to its rapid degradation after cellular release. Nevertheless, the interplay between neurotransmitters of the sensory, sympathetic and parasympathetic nervous systems might play a role in the balance of inflammation in the arthritic joint. Immunohistochemical studies in human and murine synovial tissue have shown that tyrosine hydroxylase-positive nerve fibres (sympathetic) are strongly reduced in combination with a higher number of sensory fibres (SP) in chronic inflammatory arthritis [43]. The sympathetic neurotransmitter norepinephrine inhibits TNF via the ß2-receptor on immune cells (up-regulation of intracellular cAMP) [44], which is one of the pathways of sympathetic feedback inhibition of inflammation (Fig. 1) [20].

In addition to the neuronal peripheral and local regulatory mechanisms, there is evidence that central alterations of the autonomic nervous system might occur in chronic inflammatory disease. One of the modulatory factors could be CRH, which increased plasma epinephrine and norepinephrine upon intracerebroventricular administration in animals [45]. Furthermore, in humans, it was shown that autonomic nervous system functions, including respiratory sinus arrhythmia and the latency time of pupillary light reflex tests, were altered in various chronic inflammatory diseases (Crohn's disease, ulcerative colitis and SLE) [46, 47]. In addition, chronic application of IL-6 resulted in a tachyphylactic reduction in HPA responsiveness [48]. These observations could imply that the response of hypothalamic CRH secretion and sympathetic nervous system activation is probably dependent on the type of systemic inflammation and the pattern of circulating cytokines.

Recent experiments examining vagus nerve function in acute rat LPS models showed a significant inhibition of TNF release from macrophages upon electrical vagus stimulation, thus attenuating systemic inflammatory response [49, 50]. Enhanced central parasympathetic tone could mediate, via release of the parasympathetic neurotransmitter acetylcholine (ACh), a reduction in inflammatory cytokine release. The TNF-suppressive effect of ACh was shown to be mediated by the nicotinic ACh receptor {alpha}7 subunit on macrophages [51]. It is a matter of debate whether there is a dysfunction of the nicotinic {alpha}7 subunit on macrophages or a central dysfunction of the vagus nerve in RA patients leading to enhanced TNF release. The role of the parasympathetic nervous system needs further evaluation and might lead to new pathophysiological insights into chronic inflammatory diseases.

Potential neuronal factors as predictive parameters
There seems to be an alteration in neuronal reflex patterns in chronic inflammatory diseases. Therefore, tests examining the function of the sympathetic and parasympathetic nervous system, such as the insulin–hypoglycaemia test, the CRH test and standard tests like the respiratory heart rate variation, pupillometry latency tests in conjunction with the ocular application of drugs, which selectively interfere with the function of any branch of the peripheral nervous system, might be useful in detecting alterations within the nervous system (Table 2) [46]. The test results might give estimates of dysfunction of the peripheral nervous system and inflammatory predisposition in any phase of the disease. Furthermore, in healthy subjects there is a positive coupling of the activity of the HPA axis and the sympathetic nervous system, conferring strong cooperative anti-inflammatory potential [52]. In contrast, in chronic inflammatory disease an uncoupling of the HPA axis and the sympathetic nervous system has been observed [53]. The inverse interrelation between serum cortisol and plasma neuropeptide Y (NPY) as a marker of the activity of the sympathetic nervous system might prove useful in detecting early alterations in the anti-inflammatory response systems [53]. Therefore, the measurement of plasma NPY during functional tests might be an important adjunct in the assessment of sympathetic function.

The authors have declared no conflicts of interest.


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  1. Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24.[ISI][Medline]
  2. Harrison BJ, Symmons DP, Barrett EM, Silman AJ. The performance of the 1987 ARA classification criteria for rheumatoid arthritis in a population based cohort of patients with early inflammatory polyarthritis. American Rheumatism Association. J Rheumatol 1998; 25:2324–30.[ISI][Medline]
  3. Machold KP, Stamm TA, Eberl GJ et al. Very recent onset arthritis—clinical, laboratory, and radiological findings during the first year of disease. J Rheumatol 2002;29:2278–87.[ISI][Medline]
  4. Hochberg MC. Early aggressive DMARD therapy: the key to slowing disease progression in rheumatoid arthritis. Scand J Rheumatol Suppl 1999;112:3–7.[Medline]
  5. Emery P. Evidence supporting the benefit of early intervention in rheumatoid arthritis. J Rheumatol Suppl 2002;66:3–8.[Medline]
  6. Quinn MA, Conaghan PG, Emery P. The therapeutic approach of early intervention for rheumatoid arthritis: what is the evidence? Rheumatology 2001;40:1211–20.[Abstract/Free Full Text]
  7. Dougados M, Smolen JS. Pharmacological management of early rheumatoid arthritis—does combination therapy improve outcomes? J Rheumatol Suppl 2002;66:20–6.[Medline]
  8. Kirwan JR, Quilty B. Prognostic criteria in rheumatoid arthritis: can we predict which patients will require specific anti-rheumatoid treatment? Clin Exp Rheumatol 1997;15:S15–25.[ISI][Medline]
  9. Williamson AA, McColl GJ. Early rheumatoid arthritis: can we predict its outcome? Intern Med J 2001;31:168–80.[CrossRef][ISI][Medline]
  10. Vittecoq O, Pouplin S, Krzanowska K et al. Rheumatoid factor is the strongest predictor of radiological progression of rheumatoid arthritis in a three-year prospective study in community-recruited patients. Rheumatology 2003;42:939–46.[Abstract/Free Full Text]
  11. Straub RH, Cutolo M. Involvement of the hypothalamic– pituitary–adrenal/gonadal axis and the peripheral nervous system in rheumatoid arthritis: viewpoint based on a systemic pathogenetic role. Arthritis Rheum 2001;44:493–507.[CrossRef][ISI][Medline]
  12. Masi AT. Neuroendocrine immune mechanisms in rheumatic diseases. An overview and future implications. Rheum Dis Clin North Am 2000;26:1003–17.[ISI][Medline]
  13. Härle P, Cutolo M, Schölmerich J, Straub RH. Rheumatoid arthritis—pathogenetic role of neuroendocrine axes and the peripheral nervous system. Med Klin 2002;97:720–9.[CrossRef][ISI][Medline]
  14. Wilder RL. Adrenal and gonadal steroid hormone deficiency in the pathogenesis of rheumatoid arthritis. J Rheumatol Suppl 1996; 44:10–2.[Medline]
  15. Cutolo M, Seriolo B, Villaggio B, Pizzorni C, Craviotto C, Sulli A. Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis. Ann N Y Acad Sci 2002;966:131–42.[Abstract/Free Full Text]
  16. Masi AT, Chatterton RT, Aldag JC, Malamet RL. Perspectives on the relationship of adrenal steroids to rheumatoid arthritis. Ann N Y Acad Sci 2002;966:1–12.[Abstract/Free Full Text]
  17. Tengstrand B, Carlstrom K, Hafstrom I. Bioavailable testosterone in men with rheumatoid arthritis-high frequency of hypogonadism. Rheumatology 2002;41:285–9.[Abstract/Free Full Text]
  18. Deighton CM, Watson MJ, Walker DJ. Sex hormones in postmenopausal HLA-identical rheumatoid arthritis discordant sibling pairs. J Rheumatol 1992;19:1663–7.[ISI][Medline]
  19. Masi AT, Chatterton RT, Aldag JC. Perturbations of hypothalamic-pituitary-gonadal axis and adrenal androgen functions in rheumatoid arthritis: an odyssey of hormonal relationships to the disease. Ann N Y Acad Sci 1999;876:53–62.[Abstract/Free Full Text]
  20. Straub RH, Konecna L, Hrach S et al. Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence. J Clin Endocrinol Metab 1998;83:2012–7.[Abstract/Free Full Text]
  21. DHEA. Monograph. Altern Med Rev 2001;6:314–8.[Medline]
  22. Herrmann M, Schölmerich J, Straub RH. Influence of cytokines and growth factors on distinct steroidogenic enzymes in vitro: a short tabular data collection. Ann N Y Acad Sci 2002;966:166–86.[Abstract/Free Full Text]
  23. Castagnetta LA, Carruba G, Granata O et al. Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with rheumatoid arthritis. J Rheumatol 2003;30:2597–605.[ISI][Medline]
  24. Cutolo M, Wilder RL. Different roles for androgens and estrogens in the susceptibility to autoimmune rheumatic diseases. Rheum Dis Clin North Am 2000;26:825–39.[ISI][Medline]
  25. Cutolo M, Bijlsma JW, Lahita RG, Masi AT, Straub RH, Bradlow HL. Altered neuroendocrine immune (NEI) networks in rheumatology. Ann N Y Acad Sci 2002;966:xiii–xviii.[ISI]
  26. Wilder RL. Hormones and autoimmunity: animal models of arthritis. Baillieres Clin Rheumatol 1996;10:259–71.[ISI][Medline]
  27. Hall GM, Larbre JP, Spector TD, Perry LA, Da Silva JA. A randomized trial of testosterone therapy in males with rheumatoid arthritis. Br J Rheumatol 1996;35:568–73.[ISI][Medline]
  28. Härle P, Pongratz G, Weidler C, Büttner R, Schölmerich J, Straub RH. The role of leptin in hypoandrogenicity in patients with systemic lupus erythematodes and rheumatoid arthritis. Ann Rheum Dis 2004;63:809–16.[Abstract/Free Full Text]
  29. Finck BN, Johnson RW. Anti-inflammatory agents inhibit the induction of leptin by tumor necrosis factor-alpha. Am J Physiol Regul Integr Comp Physiol 2002;282:R1429–35.[Abstract/Free Full Text]
  30. Straub RH, Paimela L, Peltomaa R, Schölmerich J, Leirisalo-Repo M. Inadequately low serum levels of steroid hormones in relation to interleukin-6 and tumor necrosis factor in untreated patients with early rheumatoid arthritis and reactive arthritis. Arthritis Rheum 2002;46:654–62.[CrossRef][ISI][Medline]
  31. Kanik KS, Chrousos GP, Schumacher HR, Crane ML, Yarboro CH, Wilder RL. Adrenocorticotropin, glucocorticoid, and androgen secretion in patients with new onset synovitis/rheumatoid arthritis: relations with indices of inflammation. J Clin Endocrinol Metab 2000; 85:1461–6.[Abstract/Free Full Text]
  32. Foppiani L, Cutolo M, Sessarego P et al. Desmopressin and low-dose ACTH test in rheumatoid arthritis. Eur J Endocrinol 1998; 138:294–301.[Abstract/Free Full Text]
  33. Straub RH, Schölmerich J, Cutolo M. The multiple facets of premature aging in rheumatoid arthritis. Arthritis Rheum 2003;48:2713–21.[CrossRef][ISI][Medline]
  34. Mastorakos G, Ilias I. Relationship between interleukin-6 (IL-6) and hypothalamic–pituitary–adrenal axis hormones in rheumatoid arthritis. Z Rheumatol 2000;59:II/75–9.[CrossRef]
  35. Straub RH, Pongratz G, Schölmerich J et al. Long-term anti-tumor necrosis factor antibody therapy in rheumatoid arthritis patients sensitizes the pituitary gland and favors adrenal androgen secretion. Arthritis Rheum 2003;48:1504–12.[CrossRef][ISI][Medline]
  36. Schmidt M, Kreutz M, Löffler G, Schölmerich J, Straub RH. Conversion of dehydroepiandrosterone to downstream steroid hormones in macrophages. J Endocrinol 2000;164:161–9.[Abstract/Free Full Text]
  37. Van Vollenhoven RF, McGuire JL. Studies of dehydroepiandrosterone (DHEA) as a therapeutic agent in systemic lupus erythematosus. Ann Med Interne (Paris) 1996;147:290–6.[ISI][Medline]
  38. Andus T, Klebl F, Rogler G, Bregenzer N, Schölmerich J, Straub RH. Patients with refractory Crohn's disease or ulcerative colitis respond to dehydroepiandrosterone: a pilot study. Aliment Pharmacol Ther 2003;17:409–14.[CrossRef][ISI][Medline]
  39. Konttinen YT, Kemppinen P, Segerberg M et al. Peripheral and spinal neural mechanisms in arthritis, with particular reference to treatment of inflammation and pain. Arthritis Rheum 1994;37:965–82.[ISI][Medline]
  40. Miller LE, Wessinghage D, Muller-Ladner U et al. In vitro superfusion method to study nerve-immune cell interactions in human synovial membrane in long-standing rheumatoid arthritis or osteoarthritis. Ann N Y Acad Sci 1999;876:266–75.[Abstract/Free Full Text]
  41. Segond von Banchet GG, Petrow PK, Brauer R, Schaible HG. Monoarticular antigen-induced arthritis leads to pronounced bilateral upregulation of the expression of neurokinin 1 and bradykinin 2 receptors in dorsal root ganglion neurons of rats. Arthritis Res 2000;2:424–7.[CrossRef][ISI][Medline]
  42. Schaible HG, Ebersberger A, Von Banchet GS. Mechanisms of pain in arthritis. Ann N Y Acad Sci 2002;966:343–54.[Abstract/Free Full Text]
  43. Miller LE, Grifka J, Schölmerich J, Straub RH. Norepinephrine from synovial tyrosine hydroxylase positive cells is a strong indicator of synovial inflammation in rheumatoid arthritis. J Rheumatol 2002; 29:427–35.[ISI][Medline]
  44. Guirao X, Kumar A, Katz J et al. Catecholamines increase monocyte TNF receptors and inhibit TNF through beta 2-adrenoreceptor activation. Am J Physiol 1997;273:E1203–8.[ISI][Medline]
  45. Brown MR, Fisher LA, Spiess J, Rivier C, Rivier J, Vale W. Corticotropin-releasing factor: actions on the sympathetic nervous system and metabolism. Endocrinology 1982;111:928–31.[Abstract]
  46. Bertinotti L, Pietrini U, Del Rosso A et al. The use of pupillometry in joint and connective tissue diseases. Ann N Y Acad Sci 2002; 966:446–55.[Abstract/Free Full Text]
  47. Pongratz G, Zietz B, Glück T, Schölmerich J, Straub RH. Corticotropin-releasing factor modulates cardiovascular and pupillary autonomic reflexes in man: is there a link to inflammation-induced autonomic nervous hyperreflexia? Ann N Y Acad Sci 2002;966: 373–83.[Abstract/Free Full Text]
  48. Mastorakos G, Chrousos GP, Weber JS. Recombinant interleukin-6 activates the hypothalamic-pituitary-adrenal axis in humans. J Clin Endocrinol Metab 1993;77:1690–4.[Abstract]
  49. Bernik TR, Friedman SG, Ochani M et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J Exp Med 2002; 195:781–8.[Abstract/Free Full Text]
  50. Borovikova LV, Ivanova S, Zhang M et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000;405:458–62.[CrossRef][ISI][Medline]
  51. Wang H, Yu M, Ochani M et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003;421:384–8.[ISI][Medline]
  52. Straub RH, Günzler C, Miller LE, Cutolo M, Schölmerich J, Schill S. Anti-inflammatory cooperativity of corticosteroids and norepinephrine in rheumatoid arthritis synovial tissue in vivo and in vitro. FASEB J 2002;16:993–1000.[Abstract/Free Full Text]
  53. Straub RH, Herfarth H, Falk W, Andus T, Schölmerich J. Uncoupling of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis in inflammatory bowel disease? J Neuroimmunol 2002;126:116–25.[CrossRef][ISI][Medline]
  54. Harbuz MS, Korendowych E, Jessop DS, Crown AL, Li pdfan SL, Kirwan JR. Hypothalamo-pituitary-adrenal axis dysregulation in patients with rheumatoid arthritis after the dexamethasone/corticotrophin releasing factor test. J Endocrinol 2003;178:55–60.[Abstract/Free Full Text]
  55. Gonzalez-Gay MA, Hajeer AH, Garcia-Porrua C et al. Corticotropin-releasing hormone promoter polymorphisms in patients with rheumatoid arthritis from northwest Spain. J Rheumatol 2003;30:913–7.[ISI][Medline]
  56. Donn RP, Farhan A, Stevans A, Ramanan A, Ollier WE, Thomson W. Neuroendocrine gene polymorphisms and susceptibility to juvenile idiopathic arthritis. Rheumatology 2002;41:930–6.[Abstract/Free Full Text]
  57. Rovensky J, Bakosova J, Koska J, Ksinantova L, Jezova D, Vigas M. Somatotropic, lactotropic and adrenocortical responses to insulin-induced hypoglycemia in patients with rheumatoid arthritis. Ann N Y Acad Sci 2002;966:263–70.[Abstract/Free Full Text]
  58. Gutierrez MA, Garcia ME, Rodriguez JA, Mardonez G, Jacobelli S, Rivero S. Hypothalamic-pituitary-adrenal axis function in patients with active rheumatoid arthritis: a controlled study using insulin hypoglycemia stress test and prolactin stimulation. J Rheumatol 1999;26:277–81.[ISI][Medline]
  59. Templ E, Koeller M, Riedl M, Wagner O, Graninger W, Luger A. Anterior pituitary function in patients with newly diagnosed rheumatoid arthritis. Br J Rheumatol 1996;35:350–6.[ISI][Medline]
  60. Crofford LJ, Kalogeras KT, Mastorakos G et al. Circadian relationships between interleukin (IL)-6 and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to cause sustained hypercortisolism in patients with early untreated rheumatoid arthritis. J Clin Endocrinol Metab 1997;82:1279–83.[Abstract/Free Full Text]
  61. Huisman AM, Van Everdingen AA, Wenting MJ et al. Glucocorticoid receptor downregulation in early diagnosed rheumatoid arthritis. Ann N Y Acad Sci 2002;966:64–7.[Abstract/Free Full Text]
  62. Straub RH, Kittner JM, Heijnen C, Schedlowski M, Schmidt RE, Jacobs R. Infusion of epinephrine decreases serum levels of cortisol and 17-hydroxyprogesterone in patients with rheumatoid arthritis. J Rheumatol 2002;29:1659–64.[ISI][Medline]
  63. Chikanza IC. Prolactin and neuroimmunomodulation: in vitro and in vivo observations. Ann N Y Acad Sci 1999;876:119–30.[Abstract/Free Full Text]
  64. Stenstrom CH, Alexanderson H, Lundberg I, Lundeberg T, Theodorsson E, Nisell R. Exercise and variations in neuropeptide concentrations in rheumatoid arthritis. Neuropeptides 1999;33:260–4.[CrossRef][ISI][Medline]
  65. Straub RH, Glück T, Zeuner M, Schölmerich J, Lang B. Association of pupillary parasympathetic hyperreflexia and systemic inflammation in patients with systemic lupus erythematosus. Br J Rheumatol 1998; 37:665–70.[CrossRef][ISI][Medline]
  66. Straub RH, Antoniou E, Zeuner M, Gross V, Schölmerich J, Andus T. Association of autonomic nervous hyperreflexia and systemic inflammation in patients with Crohn's disease and ulcerative colitis. J Neuroimmunol 1997;80:149–57.[CrossRef][ISI][Medline]
Submitted 31 March 2004; revised version accepted 19 November 2004.



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