In polymyalgia rheumatica serum prolactin is positively correlated with ...

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Mann–Whitney test (SPSSuPC for Windows 97, V10.0.0,. SPSS Inc., Chicago, IL, USA) ..... Richards SM, Garman RD, Keyes L, Kavanagh B,. McPherson JM.
Rheumatology 2002;41:423–429

In polymyalgia rheumatica serum prolactin is positively correlated with the number of typical symptoms but not with typical inflammatory markers R. H. Straub, J. Georgi1, K. Helmke2, P. Vaith3 and B. Lang4 Department of Internal Medicine, University Medical Centre Regensburg, D-93042 Regensburg, 1Ostseeklinik, D-24349 Damp, 2Hospital Mu¨nchenBogenhausen, D-81925 Mu¨nchen, 3Department of Internal Medicine, University Medical Centre Freiburg, D-79106 Freiburg and 4Centre for Rheumatic Diseases, D-76530 Baden-Baden, Germany Abstract Objectives. Hyperprolactinaemia has been associated with the active phase of human systemic lupus erythematosus and rheumatoid arthritis. In the present study, we investigated the role of prolactin (PRL) in relation to the number of typical symptoms and serum markers of systemic inflammation in patients with polymyalgia rheumatica (PMR). Methods. One hundred and two PMR patients presented with typical symptoms such as adynamia, bilateral muscular pain in shoulders, upper arms or neck, bilateral muscular pain in the pelvic girdle, headache, morning stiffness, arthralgia, symptoms of depression, fever, initial weight loss (>4 kgumonth), and transient visual symptoms. If one of the mentioned symptoms was present, the corresponding item was scored with one point (maximum unweighted item points = 10). PRL, interleukin-2 (IL-2), IL-6, IL-1 receptor antagonist (IL-1ra), tumour necrosis factor (TNF), soluble IL-2 receptor (sIL-2R), and soluble vascular cell adhesion molecule (sVCAM) were measured by enzyme-linked immunosorbent assay in patients and 31 age-matched healthy controls. Results. Fifteen PMR patients with elevated PRL had a higher number of symptoms as compared with patients with normal levels (P = 0.003). PRL was correlated with the number of symptoms (all PMR patients: rrank =+ 0.380, P < 0.001) and duration of morning stiffness (all PMR patients: rrank =+ 0.335, P = 0.002) irrespective of prior corticosteroid treatment. However, PRL did not correlate with markers of systemic inflammation such as erythrocyte sedimentation rate, C-reactive protein, serum IL-1ra, IL-2, sIL-2R, IL-6, TNF, and sVCAM. Conclusion. The number of symptoms in PMR patients was positively correlated with PRL, but PRL was not correlated with serum markers of inflammation. This indicates that PRL is not a pro-inflammatory stimulus in patients with PMR. The inter-relationship between PRL and symptoms or duration of morning stiffness may be more a sign of central nervous system involvement, as it can be observed in people with depressed mood or under psychological stress. KEY WORDS: Polymyalgia rheumatica, Prolactin, Cytokines, Inflammation, Depression.

Polymyalgia rheumatica (PMR) is a chronic inflammatory disease of unknown aetiology in elderly people. In PMR or giant cell arteritis (GCA), regional tissue inflammation is associated with the stimulation of immune competent cells w1x, which produce large amounts of soluble paracrine mediators such as interleukin-1 (IL-1) receptor antagonist (IL-1ra) w2x, soluble

IL-2 receptor (sIL-2R) w3x, IL-6 w4, 5x, and soluble vascular cell adhesion molecule (sVCAM) w6x. With respect to serum levels of these cytokines, IL-1ra w2x, sIL-2R w3x, and IL-6 w5x have been found to be markers of active inflammatory PMR. In the pathogenesis of GCA, distinct subsets of immune competent cells actively produce pro-inflammatory cytokines at local tissue sites (IL-1b, IL-2, interferon-c) w7, 8x, and express adhesion molecules w9x, HLA-DR, and IL-2R w7x. On the other hand, the anti-inflammatory cytokine IL-10 seems to have a favourable role in PMR w10x. Apart from these local pathogenic immune mechanisms,

Submitted 22 June 2001; revised version accepted 19 October 2001. Correspondence to: R. H. Straub.

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the anti-inflammatory feedback systems, such as the probably defective hypothalamic–pituitary–adrenal axis, may play an important role in this disease w11, 12x. From this systemic point of view, the pituitary hormone prolactin (PRL) may have a pro-inflammatory impact on the disease process in PMR. PRL modulates lymphocytes w13–17x. It has been demonstrated that PRL activates T-lymphocyte and B-lymphocyte proliferation w17–20x, stimulates immunoglobulin secretion w21, 22x, and increases cytokine secretion from various cells, such as IL-1b, IL-6, tumour necrosis factor (TNF), and interferon-c w23–25x. Due to these stimulatory effects on immune cells, a proinflammatory role of PRL was suspected in autoimmune diseases w26–30x. Elevated levels of PRL have been associated with a more severe form of progressive systemic sclerosis w31x, the active phase of human systemic lupus erythematosus, rheumatoid arthritis, human autoimmune thyroid disease, and adjuvant arthritis w26, 27, 29x. Hyperprolactinaemia was associated with the presence of autoantibodies in otherwise healthy women, which indicates the stimulating effect of this hormone on immunoglobulin secretion w32x. Furthermore, therapeutic PRL antagonism with bromocriptine was found to have some beneficial effects on autoimmune disease in humans and animals w33x, which does not seem to depend on direct immunomodulating effects of bromocriptine w34x. At this point, it has to be mentioned that the pro-inflammatory role of PRL has clearly been found in animal models of inflammatory diseases w35–38x. However, its proinflammatory role in human diseases is still open for discussion. On the other hand, pro-inflammatory stimuli such as administration of intravenous IL-1, IL-2, or IL-6 to human subjects can increase serum levels of PRL w39– 41x. Because PRL stimulates immune cells and products of immune cells can stimulate PRL secretion, a positive feedback loop may develop (Fig. 1). The question remains whether, or not, this positive loop leads to hyperprolactinaemia and an overall pro-inflammatory situation with continuous stimulation of a disease process. In PMR the role of PRL in relation to disease manifestations and serum concentration of immune mediators has never been investigated. Thus, it was the aim of this study to investigate the role of PRL in PMR with respect to clinical symptoms and laboratory markers of active inflammatory disease such as IL-1ra, IL-2, sIL-2R, IL-6, TNF, and sVCAM.

Subjects and methods One hundred and two patients with PMR with complete data sets and without clinical signs of GCA (artery tenderness, swollen scalp arteries, decreased artery pulses, fixed visual symptoms, jaw claudication, tongue claudication) were included. The same patients were involved in two recent studies which investigated different aspects of PMR w10, 11x. These patients were referred to the participating teaching hospitals which

FIG. 1. Possible pro-inflammatory role of PRL in chronic inflammatory diseases. PRL stimulates T and B lymphocytes which leads to a more pro-inflammatory situation with elevated serum levels of cytokines. These cytokines can stimulate hypothalamic–pituitary PRL secretion. Thus, a positive feedback loop may develop with a secondary increase in serum PRL levels. Changes of the set point of the regulatory circuit occur so that a higher inflammatory state may develop. A primary increase in PRL due to prolactinoma stimulates the immune system but does not provoke an inflammatory disease w32x.

specialized in rheumatology. All patients were clinically evaluated by a rheumatologist and PMR was diagnosed according to the criteria of Bird et al. w42x. Thirty-two patients had recent-onset active PMR wdisease duration (mean " S.E.M., median): 0.64 " 0.05 yr, 0.5 yrx and had never been treated with corticosteroids at the time blood was drawn (due to the late diagnosis) as compared with 70 patients with chronic disease with prior long-term corticosteroid therapy and less active disease wdisease duration (mean " S.E.M., median): 3.46 " 0.40 yr, 2.0 yr, P < 0.001 as compared with patients without prior corticosteroids; prednisolone was administered before breakfast; mean prednisolone dose 29.0 " 4.8 mguday). Because patients under prior long-standing corticosteroid treatment had either low (50% of all patients) or moderate disease activity (20% of all patients, including patients with unstable disease or relapses), the daily prednisolone dose was variable, according to clinical requirements. The two PMR patient groups did not differ in age or gender. Clinical and demographic data are shown in Table 1. For comparison, 31 healthy age-matched and body mass index-matched control subjects were recruited

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TABLE 1. Basic characteristics of the patients with PMR and the healthy subjects. Data are given as mean " S.E.M., percentages in parentheses, median in braced brackets and ranges in brackets

Number Age (yr) Gendera (femaleumale) Disease duration (yr) Disease characteristics initially presented wn (%)x Bilateral muscular pain in shoulders anduor pelvic girdle Adynamia Headache Weight loss (>1 kguweek) Arthralgia Fever Symptoms of depression Morning stiffness (h) ESR (mm 1st h) CRP (mgul) Current medication wn (%)x Patients on prednisolone only Patients on prednisolone plus azathioprine Patients on prednisolone plus methotrexate

Patients

Normal subjects

102 68.4 " 0.7 $70.1% w51–79x 77u25 (75.5u24.5) 2.6 " 0.3 $2.0%

31 66.5 " 1.0 $66.0% w58–75x 20u11 (64.5u35.5) –

78 (76.5) 77 (75.5) 46 (45.1) 40 (39.2) 36 (35.3) 28 (27.5) 28 (27.5) 1.2 " 0.2 $1.0% w0–10x 34.4 " 2.7 $31% w18–120x 19.8 " 3.5 $8.0% w1–190x

– – – – – – – – – –

54 (52.9) 3 (2.9) 13 (12.7)

– – –

Gender in both groups was similar, P for the comparison >0.3.

a

and their state of health was validated by means of a 33-item questionnaire (Table 1) w43x. The questionnaire addressed known diseases in the past and at present, current symptoms of diseases, current medication, alcohol intake, smoking habits, family history, and surgical history. The patients and healthy controls were not on hormone replacement therapy or psychotropic medication. Blood was drawn by venipuncture between 9.00 and 12.00 a.m. and serum was immediately stored at –808C in adequate aliquots. The PMR patients presented with typical symptoms such as: (1) adynamia (sudden appearance of either pronounced change in daily routine behaviour, pronounced fatigue, loss of normal power, or loss of interest); (2) bilateral muscular pain in shoulders, upper arms or neck; (3) bilateral muscular pain in the pelvic girdle; (4) headache; (5) morning stiffness; (6) arthralgia; (7) symptoms of depressed mood (apparent sadness, inner tension, pessimistic thoughts, concentration difficulties, reduced sleep); (8) fever; (9) initial weight loss (>4 kgumonth); (10) very brief, transient visual symptoms (in the follow-up in the out-patient clinic: not fixed to discriminate from GCA). The symptoms were assessed by means of standard record forms from the medical histories (at the time point when serum was collected; retrospective study). If one of the mentioned 10 symptoms was present, the corresponding item was scored with one point (maximum sum of the unweighted item points =10). None of the patients had overt major depression (with suicidality or dependence on psychotropic medication). Serum PRL (DPC Biermann, Bad Nauheim, Germany; detection limit: 1.1 nguml), serum IL-1ra (Quantikine, R&D Systems, Minneapolis, MN, USA; detection limit: 25 pguml), IL-2 (Quantikine, R&D

Systems; detection limit: 7.0 pguml), sIL-2R (IL-2R a chain; DPC Biermann; detection limit: 16 Uuml), IL-6 (high sensitivity Quantikine, R&D Systems; detection limit: 0.2 pguml), TNF (high sensitivity Quantikine, R&D Systems; detection limit: 0.2 pguml), and sVCAM (R&D Systems; detection limit: 5 nguml) were measured by means of immunometric enzyme immunoassay. Intra-assay and interassay coefficients of variation were below 10% in each test. Erythrocyte sedimentation rate (ESR) and serum levels of C-reactive protein (CRP) were measured by standard methods. p All data are given as mean " S.E.M. (S.E.M. = S.D.u n) and the median is given in braced brackets when the data were not normally distributed. The non-parametric Mann–Whitney test (SPSSuPC for Windows 97, V10.0.0, SPSS Inc., Chicago, IL, USA) was used to compare the means of the different subgroups (healthy controls, patients with PMR without prior corticosteroids, patients with PMR with prior corticosteroids). Correlations were demonstrated by linear regression lines and significance was tested by Spearman rank correlation analysis (SPSSuPC for Windows 97, V10.0.0, SPSS Inc.). The significance level was set at P < 0.05.

Results As compared with healthy subjects, IL-1ra, IL-2, sIL-2R, IL-6, and sVCAM were significantly increased in patients with PMR, irrespective of prior prednisolone treatment (Fig. 2A, B). For IL-6, sIL-2R, and sVCAM, the serum concentration tended to be lower in patients with prior prednisolone therapy as compared with patients without prednisolone (Fig. 2A, B). However, this was not statistically significant. With respect to

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FIG. 2. Comparison of soluble immune mediators in healthy subjects (open bars), PMR patients without prior prednisolone therapy (hatched bars) and PMR patients with prior prednisolone treatment (cross-hatched bars). (A) Serum IL-6 and IL-2 ( pguml). (B) Ratio of sIL-2R and IL-2 (Uumlupguml), serum concentration of IL-1ra, sIL-2R, and sVCAM ( pguml). *P < 0.001 for the comparison of healthy subjects vs PMR patients withoutuwith prior prednisolone therapy.

TNF, healthy subjects and patients demonstrated similar levels irrespective of prior prednisolone treatment in PMR (data not shown). This indicates that IL-1ra, IL-2, sIL-2R, IL-6, and sVCAM were good parameters to distinguish patients with an inflammatory state of PMR from healthy subjects, which is corroborated by increased ESR and elevated serum levels of CRP in our PMR patients (Table 1). Interestingly, the mean serum level of PRL was not significantly different in patients and healthy subjects irrespective of prior prednisolone therapy (healthy subjects: 10.6 " 1.1 nguml; PMR without prior prednisolone: 10.9 " 1.3 nguml, PMR with prior prednisolone: 14.4 " 1.5 nguml; n.s. for all comparisons). Fifteen patients with PMR had elevated PRL levels above 20 nguml (upper normal cut-off according to w44x). In these patients, ESR, serum CRP, and serum levels of IL-1ra, IL-2, sIL-2R, IL-6, and sVCAM were similar to patients with normal PRL serum levels (data not shown). In a rank correlation analysis, the number of typical PMR symptoms was positively correlated with serum levels of PRL in all patients with PMR (Fig. 3). This was also observed in the subgroups of PMR patients without prior prednisolone therapy (rrank = 0.455, P = 0.009) and with prior prednisolone therapy (rrank = 0.301, P = 0.011). Patients with elevated serum levels of PRL (>20 nguml; upper normal cut-off according to w44x) had significantly more symptoms as compared with patients with normal PRL serum concentrations (6.3 " 0.7 vs 4.1 " 0.3 symptoms; P = 0.003). Furthermore, the duration of morning stiffness in hours correlated positively with serum concentrations of PRL in all patients with PMR (rrank = 0.335, P = 0.002). This was also observed in the subgroups of PMR patients without prior prednisolone therapy (rrank = 0.669, P = 0.002) and with prior prednisolone therapy (rrank = 0.270, P = 0.034). However, under consideration of Bonferroni adjustment (significance level changed, due to the number of

FIG. 3. Inter-relationship of the number of disease manifestations and serum levels of PRL in all patients with PMR. The linear regression line is demonstrated, and the Spearman rank correlation coefficient and its P value are given. The variable on the x-axis is a non-continuous variable.

correlation analyses, from 0.05 to 0.05u8 = 0.0063), serum PRL did not correlate with any marker of inflammation, such as ESR (rrank =20.029, not corrected P = 0.8), serum CRP (rrank =20.119, P = 0.3), serum levels of IL-1ra (rrank = 0.054, P = 0.6), IL-2 (rrank =20.219, P = 0.027), sIL-2R (rrank = 0.243, P = 0.014), IL-6 (rrank = 0.101, P = 0.3), and sVCAM (rrank = 0.084, P = 0.4). These results were also obtained in the subgroups of PMR patients withoutu with prior prednisolone therapy (data not shown). Furthermore, serum levels of PRL did not correlate with the titre of antinuclear antibodies (rrank = 0.020, P = 0.8). Because it was demonstrated that patients with depression had elevated serum levels of PRL w45, 46x, we built two patient groups with and without symptoms of depression. Serum PRL was significantly higher in patients with symptoms of depression as compared with patients without symptoms of depression (16.9 " 1.2 vs 11.5 " 0.9 nguml, P = 0.028). This indicates that secondary to the disease, elderly patients may have symptoms of depression which are associated with elevated serum PRL.

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Discussion In autoimmune diseases, it is not clear whether PRL has a causal role or whether the elevation of PRL in some patients is a sort of stress response secondary to the disease. It has been demonstrated that pro-inflammatory stimulation of the central nervous system by circulating cytokines w39– 41, 47– 49x or depressed mood can increase serum PRL w45, 46x. The common denominator is increased hypothalamic serotonin secretion which stimulates pituitary PRL release w50–52x. The question remains whether hyperprolactinaemia per se can induce autoimmune disease. A study by Buskila et al. w32x has demonstrated that hyperprolactinaemic patients due to endocrine tumours had more autoantibodies but no patient had overt autoimmune disease. This indicates that PRL has immunostimulatory capacities but is unable to induce an autoimmune disease. Furthermore, some studies have shown that serum PRL is not elevated in autoimmune diseases w53–58x. In conclusion, this indicates that PRL is not a primary autoimmune disease-inducing hormone w59x. However, it has to be mentioned that the pro-inflammatory role of PRL has clearly been found in animal models of inflammatory diseases w35–38x. Due to its many immunostimulatory effects in vivo and in vitro w13–25x, this hormone could play a pro-inflammatory role in autoimmune diseases w26–30x. Some reported positive effects of a PRL antagonistic therapy with bromocriptine may indicate that PRL has a role for disease modulation w33, 60–63x. Thus, elevation of PRL due to increased circulating cytokines or the stressful disabling disease may result in a positive vicious cycle leading to ongoing immune system stimulation (Fig. 1). This may be a problem in autoantibody-mediated diseases such as systemic lupus erythematosus due to PRL-mediated B-lymphocyte stimulation w21, 22, 64, 65x. This problem would mainly be obvious in the third trimester of pregnancy or the post-partum period because PRL serum levels are 10 times higher as compared with the normal situation w44x. Physiologically, high PRL serum levels are important to activate the immune system during the post-partum period in the mother and the child, particularly with respect to immunoglobulin production in the mother. In this context, PRL may substantially contribute to the manifestation of flares in the post-partum period in mothers with autoimmune diseases. In this study we focused on patients with PMR, which may be an autoimmune-mediated disease in elderly people. We expected a positive correlation between typical inflammatory markers in this disease and PRL serum levels. However, no such correlation was found and serum PRL levels were normal in most of the patients (83.3%). This confirms studies in a variety of other rheumatic diseases where elevated PRL serum levels were not detected w53–58x. In the subgroup of our patients with increased serum PRL (>20 nguml), the number of PMR typical symptoms was significantly higher as compared with patients with normal PRL

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levels. This justified a rank correlation analysis for serum PRL and the number of symptoms, which demonstrated a significantly positive inter-relationship irrespective of prior prednisolone therapy. However, serum PRL did not correlate with laboratory markers of inflammation such as ESR, CRP, IL-1ra, IL-2, sIL2R, IL-6, and sVCAM. These parameters were significantly elevated in PMR patients as compared with age-matched healthy subjects, which demonstrates their inflammation-associated role in this disease. The absence of an inter-relationship between serum levels of inflammatory markers and PRL indicates that PRL does not markedly stimulate the inflammation process in this disease. This further indicates that subjectively experienced symptoms are not necessarily linked to objectively measured inflammatory markers. Because it was demonstrated that patients with depression have elevated serum levels of PRL w45, 46x, we investigated patients with symptoms of depression as compared with patients without symptoms of depression. Indeed, the group with symptoms of depression had higher serum levels of PRL as compared with the other group. This indicates that elevated PRL levels may be due to depressed mood, which further depends on the number of symptoms. It further indicates that depressed mood and subsequently elevated PRL levels per se may not lead to a positive vicious cycle of immune stimulation in PMR (Fig. 1). Psychological stress is a typical phenomenon of disabling rheumatic diseases and psychological stress itself can modulate the course of rheumatic diseases w66–68x. Thus, the increase in PRL might be a secondary phenomenon due to increased psychological stress. In conclusion, this study demonstrates that elevated serum levels of PRL were associated with a higher number of disease manifestations but not with increased serum levels of inflammatory markers or titre of antinuclear antibodies. It was demonstrated that patients with symptoms of depression or a higher number of disease manifestations had increased serum PRL as compared with patients without symptoms of depression and with a lower number of disease manifestations. In PMR patients, an increase in serum PRL in some patients is a secondary phenomenon which most probably does not influence the inflammatory process.

Acknowledgements We thank Angelika Gra¨ber for excellent technical assistance. The study was partly supported by the Deutsche Forschungsgemeinschaft (Str 511u5–1).

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