A defect in cortisol production in rheumatoid arthritis: why are we still looking?

D. S. Jessop and M. S. Harbuz

Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (LINE), University of Bristol, Bristol, UK.

Correspondence to: D. S. Jessop, Henry Wellcome Laboratories for Integrative Neuroscience and Endocrinology (LINE), University of Bristol, Dorothy Hodgkin Building, Whitson Street, Bristol BS1 3NY, UK. E-mail: David.Jessop{at}bris.ac.uk

The question of whether patients with rheumatoid arthritis (RA) might have a defective hypothalamo–pituitary–adrenal (HPA) axis was first raised when RA patients who were treated with glucocorticoids in the 1950s showed dramatic improvement in their symptoms. It was initially hypothesized that this was due to an impaired ability of RA patients to synthesize sufficient amounts of endogenous glucocorticoids, but intensive investigations over the next few decades failed to reveal any significant defects in HPA axis activity in RA patients. In our review of the literature [1] we found no compelling evidence for significant differences in either basal or stress-stimulated HPA axis activity in RA compared with normal healthy individuals. However, we did highlight an inherent defect, which resided in the inability of RA patients to mount an appropriately enhanced glucocorticoid response to increased secretion of proinflammatory cytokines such as interleukin (IL)-1, IL-6 and tumour necrosis factor (TNF)-{alpha}. ‘In other words’, we concluded, ‘the HPA axis response in RA is defective precisely because it is normal’.

Since then, studies by ourselves and others have suggested that this statement may be an oversimplification and that subtle differences in HPA axis activity may exist in subpopulations of RA patients. The purpose of this review is to evaluate progress in assessing the integrity of the HPA axis in RA since this area was previously reviewed [1–3], to determine whether generating information about HPA axis dysfunction in RA is clinically useful, and to discuss whether this area of research remains a fruitful line of enquiry.

Persuasive evidence for a major dysfunction in basal circadian HPA axis activity in RA patients remains elusive. In a study of 10 postmenopausal females, plasma adrenocorticotrophic hormone (ACTH) and cortisol were slightly decreased around midnight but were not different from those in healthy controls at other circadian time points [4]. In 17 RA patients of mixed sex with recent disease onset, morning ACTH and cortisol concentrations were similar to those of controls, although the correlation between these hormones was weaker in RA [5]. In contrast, Straub et al. observed significantly higher morning serum cortisol in untreated patients with early RA (34 subjects, largely females) compared with healthy subjects, but no difference in ACTH [6]. However, the ratios of ACTH and cortisol in RA patients in relation to the markedly elevated levels of proinflammatory cytokines IL-6 and TNF-{alpha} were significantly low compared with healthy controls. Furthermore, the number of swollen joints correlated inversely with the ratio of serum cortisol to IL-6. This suggests that measuring alterations in a single hormonal parameter may be less revealing of the underlying processes of inflammation in RA than measuring a change in the overall milieu of pro- and anti-inflammatory modulators. The low ratios of serum cortisol to IL-6 and TNF-{alpha} in RA cannot be explained by an increased metabolic clearance rate of cortisol [7, 8]. Curiously, in more recent studies by the same group, basal serum cortisol concentrations in RA patients with mild to moderate disease activity were slightly lower [9] and ACTH concentrations were significantly lower [7] compared with healthy controls. Serum cortisol and 24-h urinary cortisol were similar in the two groups [7]. These variations reported in the literature, which may be due to differences in disease duration and/or activity, age and sex of the patient, medication, or sampling time, emphasize the difficulty in pinpointing any specific and reproducible defect in HPA axis activity in RA. In a separate study, diurnal salivary cortisol was elevated in RA patients with recent onset compared with healthy controls, and this effect was positively correlated with disease activity but not with sex or age [10]. However, in these patients the awakening salivary cortisol rise, disruption in which has been associated with implications for health [11], was normal. Overall output of cortisol measured in salivary samples over the period from 08.00 to 22.00 h was higher in RA patients compared with controls, particularly in the morning, but the circadian pattern of cortisol secretion was similar in the two groups [12]. Elevated cortisol in these patients was not related to subjectively perceived levels of stress.

Measurement of salivary cortisol as the endpoint of HPA axis activity is a very useful non-invasive technique to determine unbound bioactive cortisol, but although salivary and serum cortisol concentrations correlate very well in normal subjects, it is at present uncertain whether this correlation is true for RA patients. In one study of 12 female RA patients, elimination profiles of serum and salivary cortisol following dexamethasone and hydrocortisone infusion were similar, although significant anomalies were observed in two patients [8]. Correlation of serum and salivary cortisol in RA patients, under basal conditions or pharmacological challenge, awaits rigorous examination.

Since we last reviewed the literature, there have been a number of reports on pharmacodynamic stimulation of the HPA axis in RA patients, with little evidence for a defective response. In one study, premenopausal patients mounted normal cortisol responses to boluses of synthetic ACTH or corticotrophin-releasing factor (CRF) [13]. In this study there was no difference in basal morning cortisol between RA patients and controls prior to the ACTH or CRF tests. Following insulin-induced hypoglycaemia, which tests the HPA axis at all levels, there were no differences in serum cortisol responses between patients with active RA and patients in remission [14]. This study did not include non-RA subjects as controls, and there was no ACTH response to hypoglycaemia in either test group, suggesting a possible methodological problem. Ten female patients with active RA and 10 control subjects mounted similar quantitative serum cortisol responses to hypoglycaemia, although a subtle difference in the kinetics of cortisol secretion was noted [15]. The two groups had similar baseline cortisol concentrations prior to injection of insulin. In male RA patients following insulin-induced hypoglycaemia, no differences in cortisol responses were observed compared with controls, and basal pre-insulin serum cortisol concentrations were slightly but not significantly higher in RA patients [16]. No significant differences in insulin-stimulated ACTH and cortisol were detected in premenopausal patients with low to moderate disease activity, although responses appeared slightly higher in the RA group compared with controls [17]. Baseline ACTH and cortisol concentrations in the RA group were normal. One small early study on four patients also showed a normal cortisol response to insulin-induced hypoglycaemia [18]. Given that this most potent test of HPA axis activity has so far been apparently unable to reveal a convincing and reproducible defect in RA patients, it is arguable that its further use cannot be justified on scientific or ethical grounds. However, all these pharmacodynamic tests were performed in the morning, and since there is evidence for windows of sensitivity in circadian HPA axis activity, a well-designed factorial study of ACTH and cortisol responses to insulin-induced hypoglycaemia (or another stressor of overall HPA axis activity, such as the CO2 test) in the morning and evening in RA patients compared with healthy controls might be instructive.

Following the dexamethasone suppression test combined with CRF stimulation (DEX/CRF test), we observed that post-dexamethasone/pre-CRF ACTH and cortisol concentrations were significantly higher in seven RA patients compared with six controls. Three RA patients exhibited an early escape of cortisol from DEX suppression, whereas four showed normal cortisol suppression [19]. This suggests that glucocorticoid feedback is impaired in a subgroup of RA patients, a phenomenon that may be associated with dysfunctional glucocorticoid receptor (GR) expression. Down-regulation of GR in peripheral blood mononuclear cells (PBMCs) has been noted in early diagnosed female, but not male, RA patients, a phenomenon that was not related to disease severity at the time of blood sampling [20]. In this latter study, serum cortisol levels were lower in female RA patients compared with healthy controls, but there was no difference between the two male groups. Initial down-regulation of GR was observed in both male and female RA patients, which tended towards normalization over a 2-yr period of treatment with steroids or placebo [21], a process that may reflect a pathophysiological response to the course of inflammation. It is important to emphasize that these GR measurements were all performed in PBMCs and therefore may not reflect changes in GR in cells targeted by cortisol at sites of inflammation. Altered GR expression in inflamed synovial tissues, as reported for sex steroid receptors [22], and putative increased activity of the isozyme 11ß-HSD-2 with the potential to convert cortisol into cortisone may confer resistance to glucocorticoids in RA irrespective of circulating concentrations of cortisol. A preliminary report suggests that the capacity for conversion of cortisone to cortisol is impaired in RA compared with OA [23]. These phenomena at sites of inflammation warrant further investigation, particularly in the light of the recent observations that genes for a subfamily of cytochrome P450, which regulates the rate of glucocorticoid synthesis, and 11ß-HSD-2, which regulates biological activity, are up-regulated in PBMCs of postmenopausal RA patients with recent onset of disease compared with patients with long-established disease [24].

Another possible explanation for impaired glucocorticoid feedback in RA may involve GR polymorphisms [25, 26]. GR polymorphisms are common in the normal human population and two have recently been linked to altered HPA axis responses to psychosocial stress [27]. Although there is as yet no firm evidence for a functional correlation between GR polymorphisms and susceptibility to arthritis, these mutations may blunt the effectiveness of glucocorticoid feedback in RA patients. Correlation of severity of disease with cortisol escape from dexamethasone suppression in RA patients, combined with analysis of GR polymorphisms, may cast valuable light on any such associations. There is also potential to identify RA patients who have defective glucocorticoid feedback through GR polymorphisms and abnormal responses to the CRF/DEX test as likely to be less responsive to steroid treatment, although decreased GR numbers in RA are not a predictor of clinical efficacy of steroid treatment [21]. GR polymorphisms in RA may also be linked with the wide variability noted between patients in inflammatory flare responses to stress.

One critical question is whether the inability of RA patients to mount a robust glucocorticoid response to increased inflammatory cytokines is a pre-existing defect that predisposes to onset of the disease, or whether it is a defective HPA axis after onset which exacerbates the severity of the disease. In one study a negative correlation between plasma concentrations of cortisol and DHEAS was observed in healthy women who later developed RA before the age of 50, whereas cortisol and DHEAS were positively correlated in healthy women who did not develop RA until after the age of 50 [28]. Serum DHEAS concentrations were normal in healthy males who went on to develop RA [29], whereas DHEAS was decreased in males following onset of the disease [30]. These types of prospective study, unfortunately rare, may be invaluable in identifying subjects at risk of developing RA on the basis of serum cortisol and sex steroid ratios to aid early intervention in treatment, a strategy now recognized as being of crucial importance in disease control [31]. Larger prospective studies of this nature are required to establish any causal relationships between imbalance in glucocorticoid and sex steroid secretion and disease onset.

There have been comparatively few studies in which the effects of stress on HPA axis activity in RA patients have been assessed. Patients with recently diagnosed RA who were subjected to a complex series of physical and psychological stressors mounted an attenuated ACTH response, and no cortisol response, compared with healthy controls [32]. However, the majority of the controls also failed to mount a cortisol response, which calls into question the effectiveness of this stress paradigm on HPA axis activity. A steeper decline in cortisol was observed in RA patients compared with the control group during the experimental period, but it is difficult to determine whether this was due to the stress or to an alteration in circadian rhythm, since no unstressed control group was included. In another study, RA patients with established disease who were solely on non-steroidal medication for at least 2 yr demonstrated a significant reduction in their cortisol responses to physical exercise compared with healthy controls [33]. Pre-exercise baseline cortisol was not different between the groups. This was a small study (seven patients and 10 controls) and the effects of physical or psychological stress on HPA axis activity in larger groups of RA patients under experimental conditions have yet to be fully investigated.

The separate but related issue of the effects of environmental and adverse life event stress on inflammation and disease processes in RA has been reviewed recently [34]. This is a very important area since there have been many reports that stress can exacerbate, or even trigger, chronic inflammatory diseases. It is important to emphasize that each stressor has its own specific neurochemical and endocrine profile [35], and different types of stress may affect disease processes in selective ways, depending on their influence on T-helper cell differentiation and consequent cytokine release [36]. This is also true for responses of the autonomic nervous system to stressors. Therefore, we may yet learn much from studying HPA axis activity in relation to disease activity in RA patients in response to a range of physical or psychological stressors. In the light of the reported defective relationship between the HPA axis and the sympathetic nervous system in RA [37], closer attention could be paid to the profiles of catecholamines and glucocorticoids following stressors.

Although the HPA axis in RA is defective because its activity is not increased in response to inflammatory cytokines, as might be predicted from observations of increased corticosterone in rodent models of inflammation [38], we conclude from the literature that the HPA axis is not materially different in RA compared with normal healthy subjects under most experimental conditions. In that sense it can be said to equate to normal. Most groups report normal HPA axis activity in RA, and while there is some evidence suggesting subtle variations in cortisol secretion in RA, there is little consistency between these reports of abnormal activity. Whether the discrepancies between these studies can be explained by differences in experimental protocols or other factors is not the relevant issue. The key question that must drive all future research in this area is: how will knowledge of a defect in HPA axis activity in RA assist in treatment? There is little point in continuing to test the HPA axis in RA patients in an attempt to identify a major, or even a subtle dysfunction, unless the aim of the study is to identify a defect in cortisol secretion in a subset of patients or in an individual patient, which may suggest the utility of a modified or novel treatment regimen. For example, would the DEX/CRF test permit identification of a subset of RA patients likely to develop steroid resistance? This principle may also be applied to test the hypothesis that inadequate cortisol secretion during the night might in some patients be correlated with inflammatory symptoms, such as morning joint stiffness [39–41]. One very interesting study showed that administration of small physiological doses of prednisolone at 02.00 h, but not at 07.30 h, significantly attenuated morning stiffness and joint pain [42]. Symptom variability in response to prednisolone at 02.00 h was quite marked and one might hypothesize that the optimal responders were those patients with abnormally low early morning cortisol. It is conceivable that steroid therapy could be optimized to the needs of individual patients on the basis of information about their night-time cortisol profiles.

In conclusion, we suggest that two areas of research be pursued. First, it is important to determine whether a defect in HPA axis activity pre-exists in subjects who develop RA, i.e. whether HPA axis dysfunction is a component of the aetiology of RA. If such a defect were to be identified, it is possible that, in association with information about genetic risk, it might be possible to target subjects predisposed to the disease for early intervention. This may be pertinent where stressful life events that challenge the HPA axis may trigger mechanisms underlying onset of inflammation. Secondly, if a defect in HPA axis activity is subsequent to the development of inflammation, can this information lead to improved pharmacogenetics in terms of optimizing individual patient responses to steroids in the most efficacious doses, or suggest the benefit of non-steroidal treatments? There is still some mileage in testing HPA axis activity in RA patients, but we should now move away from performing such tests per se and invoke the question of how we can relate any information gained from such a test to designing more efficacious treatments.


    Acknowledgments
 
The authors are grateful to The Wellcome Trust for continued funding for research into novel anti-inflammatory compounds.

The authors have declared no conflicts of interest.


    References
 Top
 References
 

  1. Harbuz MS, Jessop DS. Is there a defect in cortisol production in rheumatoid arthritis? Rheumatology 1999;38:298–302.[Free Full Text]
  2. Masi AT, Bijlsma JW, Chikanza IC, Pitzalis C, Cutolo M. Neuroendocrine, immunologic, and microvascular systems interactions in rheumatoid arthritis: physiopathogenetic and therapeutic perspectives. Semin Arthritis Rheum 1999;29:65–81.[CrossRef][ISI][Medline]
  3. Cutolo M, Giusti M, Foppiani L et al. The hypothalamic-pituitary-adrenocortical and gonadal axis function in rheumatoid arthritis. Z Rheumatol 2000;59(Suppl. 2):II/65–9.[CrossRef]
  4. Zoli A, Lizzio MM, Ferlisi EM et al. ACTH, cortisol and prolactin in active rheumatoid arthritis. Clin Rheumatol 2002;21:289–93.[CrossRef][ISI][Medline]
  5. 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]
  6. Straub RH, Paimela L, Peltomaa R, Scholmerich 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]
  7. Straub RH, Weidler C, Demmel B et al. Renal clearance and daily excretion of cortisol and adrenal androgens in patients with rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis 2004;63:961–8.[Abstract/Free Full Text]
  8. Rovensky J, Imrich R, Koska J et al. Cortisol elimination from plasma in premenopausal women with rheumatoid arthritis. Ann Rheum Dis 2003;62:674–6.[Abstract/Free Full Text]
  9. Vogl D, Falk W, Dorner M, Scholmerich J, Straub RH. Serum levels of pregnenolone and 17-hydroxypregnenolone in patients with rheumatoid arthritis and systemic lupus erythematosus: relation to other adrenal hormones. J Rheumatol 2003;30:269–75.[ISI][Medline]
  10. Dekkers JC, Geenen R, Godaert GL, van Doornen LJ, Bijlsma JW. Diurnal rhythm of salivary cortisol levels in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 2000;43:465–7.[CrossRef][ISI][Medline]
  11. Clow A, Thorn L, Evans P, Hucklebridge F. The awakening cortisol response: methodological issues and significance. Stress 2004;7:29–37.[ISI][Medline]
  12. Catley D, Kaell AT, Kirschbaum C, Stone AA. A naturalistic evaluation of cortisol secretion in persons with fibromyalgia and rheumatoid arthritis. Arthritis Care Res 2000;13:51–61.[CrossRef][ISI][Medline]
  13. 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 1999;26:282–8.[ISI][Medline]
  14. Demir H, Kelestimur F, Tunc M, Kirnap M, Ozugul Y. Hypothalamo-pituitary-adrenal axis and growth hormone axis in patients with rheumatoid arthritis. Scand J Rheumatol 1999;28:41–6.[CrossRef][ISI][Medline]
  15. 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]
  16. 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]
  17. Imrich R, Rovensky J, Malis F et al. Low levels of dehydroepiandrosterone sulphate in plasma, and reduced sympathoadrenal response to hypoglycaemia in premenopausal women with rheumatoid arthritis. Ann Rheum Dis 2005;64:202–6.[Abstract/Free Full Text]
  18. Streeten HP, Phillips PE. Measurement of the HPA response to hypoglycaemic stress in human rheumatoid arthritis. Arthritis Rheum 1991;34(Suppl.):S156.
  19. Harbuz MS, Korendowych E, Jessop DS, Crown AL, Lightman 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]
  20. van Everdingen AA, Huisman AM, Wenting MJ, van Reesema S, Jacobs JW, Bijlsma JW. Down regulation of glucocorticoid receptors in early-diagnosed rheumatoid arthritis. Clin Exp Rheumatol 2002;20:463–8.[ISI][Medline]
  21. Huisman AM, Siewertsz van Everdingen AA, Wenting MJ et al. Glucocorticoid receptor up-regulation in early rheumatoid arthritis treated with low dose prednisone or placebo. Clin Exp Rheumatol 2003;21:217–20.[ISI][Medline]
  22. Ishizuka M, Hatori M, Suzuki T et al. Sex steroid receptors in rheumatoid arthritis. Clin Sci (Lond) 2004;106:293–300.[Medline]
  23. Straub RH, Dhabhar FS, Bijlsma JW, Cutolo M. How psychological stress via hormones and nerve fibers may exacerbate rheumatoid arthritis. Arthritis Rheum 2005;52:16–26.[CrossRef][ISI][Medline]
  24. Olsen N, Sokka T, Seehorn CL et al. A gene expression signature for recent onset rheumatoid arthritis in peripheral blood mononuclear cells. Ann Rheum Dis 2004;63:1387–92.[Abstract/Free Full Text]
  25. DeRijk RH, Schaaf MJ, Turner G et al. A human glucocorticoid receptor gene variant that increases the stability of the glucocorticoid receptor beta-isoform mRNA is associated with rheumatoid arthritis. J Rheumatol 2001;28:2383–8.[ISI][Medline]
  26. DeRijk RH, Schaaf M, de Kloet ER. Glucocorticoid receptor variants: clinical implications. J Steroid Biochem Mol Biol 2002;81:103–22.[CrossRef][ISI][Medline]
  27. Wust S, Van Rossum EF, Federenko IS, Koper JW, Kumsta R, Hellhammer DH. Common polymorphisms in the glucocorticoid receptor gene are associated with adrenocortical responses to psychosocial stress. J Clin Endocrinol Metab 2004;89:565–73.[Abstract/Free Full Text]
  28. Masi AT, Aldag JC, Chatterton RT, Adams RF, Kitabchi AE. Adrenal androgen and glucocorticoid dissociation in premenopausal rheumatoid arthritis: a significant correlate or precursor to onset? Z Rheumatol 2000;59:54–61.[ISI]
  29. Masi AT. Hormonal and immunologic risk factors for the development of rheumatoid arthritis: an integrative physiopathogenetic perspective. Rheum Dis Clin North Am 2000;26:775–803.[ISI][Medline]
  30. Tengstrand B, Carlstrom K, Fellander-Tsai L, Hafstrom I. Abnormal levels of serum dehydroepiandrosterone, estrone, and estradiol in men with rheumatoid arthritis: high correlation between serum estradiol and current degree of inflammation. J Rheumatol 2003;30:2338–43.[ISI][Medline]
  31. Nell VP, Machold KP, Eberl G, Stamm TA, Uffmann M, Smolen JS. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology 2004;43:906–14.[Abstract/Free Full Text]
  32. Dekkers JC, Geenen R, Godaert GL et al. Experimentally challenged reactivity of the hypothalamic pituitary adrenal axis in patients with recently diagnosed rheumatoid arthritis. J Rheumatol 2001;28:1496–504.[ISI][Medline]
  33. Pool AJ, Whipp BJ, Skasick AJ, Alavi A, Bland JM, Axford JS. Serum cortisol reduction and abnormal prolactin and CD4+/CD8+ T-cell response as a result of controlled exercise in patients with rheumatoid arthritis and systemic lupus erythematosus despite unaltered muscle energetics. Rheumatology 2004;43:43–8.[Abstract/Free Full Text]
  34. Jessop DS, Richards LJ, Harbuz MS. Effects of stress on inflammatory autoimmune disease: destructive or protective? Stress 2005, in press.
  35. Jessop DS. Central non-glucocorticoid inhibitors of the hypothalamo-pituitary-adrenal axis. J Endocrinol 1999;160:169–80.[Free Full Text]
  36. Elenkov IJ. Systemic stress-induced Th2 shift and its clinical implications. Int Rev Neurobiol 2002;52:163–86.[ISI][Medline]
  37. Schmidt M, Weidler C, Naumann H, Grifka J, Scholmerich J, Straub RH. Arthritis Rheum 2004;50(Suppl.):S155.
  38. Harbuz M. Neuroendocrinology of autoimmunity. Int Rev Neurobiol 2002;52:133–61.[ISI][Medline]
  39. Harkness JA, Richter MB, Panayi GS et al. Circadian variation in disease activity in rheumatoid arthritis. Br Med J 1982;284:551–4.[ISI][Medline]
  40. Cutolo M, Seriolo B, Craviotto C, Pizzorni C, Sulli A. Circadian rhythms in RA. Ann Rheum Dis 2003;62:593–6.[Free Full Text]
  41. Cutolo M, Masi AT. Circadian rhythms and arthritis. Rheum Dis Clin North Am 2005;31:115–29.[CrossRef][ISI][Medline]
  42. Arvidson NG, Gudbjornsson B, Larsson A, Hallgren R. The timing of glucocorticoid administration in rheumatoid arthritis. Ann Rheum Dis 1997;56:27–31.[Abstract/Free Full Text]
Submitted 25 January 2005; revised version accepted 8 March 2005.



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