Various factors such as immunogenetic determinants, sex, age and stress play an important role in the pathogenesis of rheumatoid arthritis (RA). The relationship between stress and RA is still unclear and undefined; however, various lines of research are developing in order to evaluate environmental, psychologic, and biologic stressors as predisposing factors. The aim of our study was to evaluate whether stress-related psychologic factors and personality disorders might be involved in the development of RA, by using a psychometric investigation-methodology in a series of patients. Twenty-three patients underwent a clinical interview and other specific psychometric tests. Macro and microstressful life-events preceded RA in 83% of the cases. Sixty percent of the patients showed a correlation between flare-ups of the disease and appearance of microevents. An obsessive-compulsive personality was found in 26% of the patients. Anxia was detected in 40% of the patients. Among the group of patients with borderline disorder's was also detected alexithymia. The high prevalence of major life-events preceding the onset of RA and the presence of personality disorders support the role of the altered stress response system as an important pathogenetic factor in the disease.

A 78-year-old man with a prior ischemic stroke was diagnosed with incidental pituitary macroadenoma on CT, which was performed for the recent onset of psychomotor impairment. Along with interior global hypopituitarism there was a severe hypotonic hyponatremia. Glucocorticoid replacement therapy (combined with L-thyroxine for secondary hypothyroidism) improved clinical condition and normalized sodium levels. The assessment of pituitary function, and particularly of serum cortisol levels, is advised in elderly patients with otherwise unexplained hyponatremia.

This paper aims to evaluate adrenal gland hormone levels in patients with polymyalgia rheumatica (PMR) during glucocorticoid (GC) therapy. A lower than expected basal production of cortisol was found in active and glucocorticoid-untreated PMR patients, particularly females. The abrupt onset of PMR with clinical features similar to those of the steroid-withdrawal syndrome or adrenal insufficiency, as well as the clinical response to GC therapy in elderly people already age-disposed to an inadequate adrenal and anti-inflammatory response, might represent the most significant pathophysiological basis of the disease.

OBJECTIVE:To evaluate hypothalamic-pituitary-adrenal (HPA) axis function in patients with recent onset polymyalgia rheumatica (PMR) not previously treated with glucocorticoids; and to detect possible correlations between adrenal hormone levels, interleukin 6 (IL-6), and other acute phase reactants at baseline and during 12 months of glucocorticoid treatment.METHODS:Forty-one PMR patients of both sexes with recent onset disease and healthy sex and age matched controls were enrolled into a longitudinal study. Patients were monitored for serum cortisol, dehydroepiandrosterone sulfate (DHEAS), androstenedione (ASD), and clinical and laboratory measures of disease activity such as C-reactive protein and IL-6 concentrations at baseline and after 1, 3, 6, 9 and 12 months of glucocorticoid treatment. To assess dynamic HPA axis function, serum cortisol and plasma adrenocorticotropic hormone (ACTH) levels were evaluated in another 8 patients with recent onset PMR not treated with glucocorticoid in comparison to controls after challenge with ovine corticotropin releasing hormone (oCRH) test. In addition, serum cortisol and 17-hydroxyprogesterone (17-OHP) levels were evaluated after stimulation with low dose (1 microg) intravenous ACTH.RESULTS:Serum cortisol and ASD levels of all PMR patients at baseline did not differ from controls. During followup, cortisol levels dipped at one and 3 months. Serum DHEAS levels in all patients were significantly lower than in controls at baseline. In female PMR patients a significant correlation was found at baseline between cortisol levels and duration of disease. Serum concentrations of IL-6 at baseline were significantly higher in PMR patients than in controls. During 12 months of glucocorticoid treatment IL-6 levels dropped significantly at one month; thereafter they remained stable and did not increase again despite tapering of the glucocorticoid dose. After oCRH stimulation, a similar cortisol response was found in patients and controls. After ACTH administration, a significant cortisol peak was detected in patients and controls, whereas no significant difference in cortisol area-under-the-curve (AUC) was found between the groups. In contrast, ACTH induced a significantly higher (p < 0.05) peak of 17-OHP and AUC in PMR patients than in controls.CONCLUSION:This study found reduced production of adrenal hormones (cortisol, DHEAS) at baseline in patients with active and untreated PMR. The defect seems mainly related to altered adrenal responsiveness to the ACTH stimulation (i.e., increased 17-OHP), at least in untreated patients. The 12 month glucocorticoid treatment of patients reduced the production of inflammatory mediators (i.e., IL-6) in a stable manner that persisted after glucocorticoids were tapered.

Background Both testosterone (T) and methotrexate (MTX) seem to exert negative effects on cell growth that might partially explain some of their antiproliferative/antiinflammatory effects exerted in rheumatoid arthritis (RA).1,2 Objectives Therefore, we evaluated the T and MTX effects on cell apoptosis (apo) in cultured human myeloid monocytic cells (THP-1) differentiating into macrophages (M) and in cultured synovial M obtained from RA patients. Since extracellular adenosine increase seems implicated in the MTX action, we evaluated also the enzyme adenosine deaminase (ADA) levels. ADA is involved in adenosine metabolism. Methods Synovial RA M as well as the THP-1 cells induced to differentiate into M (IFN gamma 500U), were cultured in presence of T (10–8M) and 17-beta estradiol (E2,10–8M) alone. The cells were also treated with the MTX concentrations present in vivo during RA therapy (= 50 microg/ml) again alone, or in association with T plus MTX or E2 plus MTX. After 24 h early and late apo were evaluated by immunofluorescence (annexin V and propidium iodide assay, respectively). ADA was evaluated on supernatants by spectrophotometry. Results By considering the THP-1 cells, a significant induction of the late apo in T (17%) (p less 0.05), MTX (80%) alone, and T (72%), E2 (74%) plus MTX-treated cells was observed (all p < 0.001). No significant differences were observed during the early apo for all the treatments during the 24 hr. By evaluating the RA synovial M, a significant (p < 0.001) induction of the late apo (50%) was observed in the T plus MTX-treated M when compared with the alone MTX- or E2-treated M. The treatment of RA M with T alone was found to induce an evident cell apo (30%) (although non significant). ADA levels increased only in the supernatants from all the MTX-treated cells vs MTX-untreated controls, mainly in THP-1 cells. Conclusion The T and MTX-induced apoptotic effects were more evident in cultured THP-1 cells than in cultured RA M. Therefore, immature differentiating monocytes (i.e. infiltrating monocytes) seem more sensible to the pharmacologic effects of MTX than differentiated cells (i.e. resident M). The significant increase of ADA levels found only in MTX-treated cells, might support the already suggested implication of adenosine level increase as part of the pharmacologic effects exerted by MTX. References Cutolo M, Wilder R. Rheum Dis Clin North Am. 2000;26:825 Cutolo M, et al. J Rheumatol. 2000;27:2551

Background The pineal hormone melatonin (MLT) exerts a variety of effects on the immune system. MLT activates Th1 lymphocytes and monocytes; moreover MLT enhances the production of inflammatory cytokines, like IL-1, IL-6, IL-12 and TNFa, as well as nitric oxide production. Objectives Several symptoms of rheumatoid arthritis (RA), i.e. morning gelling, stiffness and swelling, are more evident in the early morning and might be related to the neuroimmunomodulatory effects exerted by MLT on synovitis. On the other hand, it is well known that MLT reaches its physiological serum peak level during the first hours of the morning. Methods Nocturnal MLT serum levels (8 pm, 12 pm, 2 am, 4 am, 6 am, 8 am o’clock) were evaluated in ten RA patients (pts) (mean age 57 ± 13 SD ys) and in six healthy controls (cnts) (mean age 50 ± 18 SD ys). RA pts were taking only nonsteroidal antiinflammatory drugs and the mean disease duration was 4 ± 2 SD ys. MLT assay was performed by RIA and statistical analysis was carry out by nonparametric tests. Results MLT serum levels at 8 pm and 8 am o’clock resulted higher in RA pts than in cnts (p < 0.05). The differences were more evident in the older RA pts (age > 60 ys) when compared to the younger ones (age < 60 ys). In both RA pts and cnts, MLT progressively increased from 8 o’clock pm to the first hours of the morning, reaching the peak level that gradually decreased (p < 0.02). However, MLT serum level reached the peak at least three hours before in RA pts than in cnts (p < 0.05); subsequently, in RA pts, MLT concentration showed a plateau lasting two-three hours. After 2 am o’clock MLT levels decreased similarly in both RA pts and cnts. MLT levels progressively decreased with ageing in all subjects; nevertheless, MLT serum levels resulted significantly lower only in RA pts at 4 am and 6 am o’clock (p < 0.05). Conclusion The results of this study confirm the existence of a nocturnal rhythm of MLT also in RA pts, with the peak level in the early morning. However, RA pts showed higher mean MLT serum levels, that reached earlier the peak of concentration, and maintained the high levels for longer time when compared to cnts. The imbalance between cortisol serum levels (notably lower in RA pts) and MLT serum levels (higher in RA pts) might explain several clinical aspects related to the neuroimmunomodulatory effects on RA synovitis, such as morning gelling, stiffness and swelling.

The hypothalamic-pituitary-adrenal (HPA) and the hypothalamic-pituitary-gonadal (HPG) axes involvement or response to immune activation seems crucial for the control of excessive inflammatory and immune conditions such as autoimmune rheumatic diseases, including rheumatoid arthritis (RA). However, female patients seem to depend more on the HPA axis, whereas male patients seem to depend more on the HPG axis. In particular, hypoandrogenism may play a pathogenetic role in male RA patients because adrenal and gonadal androgens, both products of the HPA and HPG axes, are considered natural immunosuppressors. A significantly altered steroidogenesis of adrenal androgens (i.e., dehydroepiandrosterone sulfate, DHEAS and DHEA) in nonglucocorticoid-treated premenopausal RA patients has been described. The menopausal peak of RA suggests that estrogens and/or progesterone deficiency also play a role in the disease, and many data indicate that estrogens suppress cellular immunity, but stimulate humoral immunity (i.e., deficiency promotes cellular Th1-type immunity). A range of physical and psychosocial stressors are also implicated in the activation of the HPA axis and related HPG changes. Chronic and acute stressors appear to have different actions on immune mechanisms with experimental and human studies indicating that acute severe stressors may be even immunosuppressive, while chronic stress may enhance immune responses. The interactions between the immunological and neuroendocrine circuits is the subject of active and extensive ongoing research and might in the near future offer highly promising strategies for hormone-replacement therapies in RA.

The altered cortisol and adrenal androgen (i.e., dehydroepiandrosterone sulfate = DHEAS) secretion, observed during testing in rheumatoid arthritis (RA) patients not treated with corticosteroids, should be clearly regarded as a "relative adrenal insufficiency" in the setting of a sustained inflammatory process, as shown by high serum IL-6 levels. Androgens seem implicated in the pathophysiology of autoimmune disorders, including RA, as natural immunosuppressors. Low plasma and synovial fluid testosterone concentrations are observed in male RA patients; low plasma DHEAS levels are mainly observed in female RA patients. The menopausal peak of RA suggests that estrogens and/or progesterone deficiency also play a role in the disease, and many data indicate that estrogens suppress cellular immunity, but stimulate humoral immunity (i.e., deficiency promotes cellular Th1-type immunity). Gene polymorphisms for enzymes involved in the steroidogenesis seem to further complicate the role of sex hormones in the susceptibility to autoimmunity. Acquired changes of sex steroid metabolism seem to also play a role in the peripheral sex hormone levels. In conclusion, a complex interaction between the hypothalamus-pituitary-adrenocortical and gonadal axis functions is evident in RA.

Annals of the New York Academy of SciencesVolume 876, Issue 1 p. 83-87 Desmopressin, Ovine CRH, and Low-Dose ACTH Tests: Tools for the Study of the Hypothalamic-Pituitary-Adrenal Axis in Premenopausal Rheumatoid Arthritis Patients L. FOPPIANI, Corresponding Author L. FOPPIANI DiSEM, Cattedra di Endocrinologia e DiMI, Università di Genova, Genova, Italy Address correspondence to Luca Foppiani, M.D., DiSEM, Dipartimento di Scienze Endocrine e Metaboliche, Cattedra di Endocrinologia, Viale Benedetto XV, no. 6, I-16132, Genova, Italy. Tel: 0039-010-3537953; fax: 0039-010-3538977; e-mail: [email protected]Search for more papers by this authorA. SULLI, A. SULLI Cattedra di Reumatologia, Università di Genova, Genova, ItalySearch for more papers by this authorC. PRETE, C. PRETE Cattedra di Reumatologia, Università di Genova, Genova, ItalySearch for more papers by this authorP. SESSAREGO, P. SESSAREGO DiSEM, Cattedra di Endocrinologia e DiMI, Università di Genova, Genova, ItalySearch for more papers by this authorS. PIREDDA, S. PIREDDA DiSEM, Cattedra di Endocrinologia e DiMI, Università di Genova, Genova, ItalySearch for more papers by this authorB. SERIOLO, B. SERIOLO Cattedra di Reumatologia, Università di Genova, Genova, ItalySearch for more papers by this authorM. CUTOLO, M. CUTOLO Cattedra di Reumatologia, Università di Genova, Genova, ItalySearch for more papers by this authorM. GIUSTI, M. GIUSTI DiSEM, Cattedra di Endocrinologia e DiMI, Università di Genova, Genova, ItalySearch for more papers by this author L. FOPPIANI, Corresponding Author L. FOPPIANI DiSEM, Cattedra di Endocrinologia e DiMI, Università di Genova, Genova, Italy Address correspondence to Luca Foppiani, M.D., DiSEM, Dipartimento di Scienze Endocrine e Metaboliche, Cattedra di Endocrinologia, Viale Benedetto XV, no. 6, I-16132, Genova, Italy. Tel: 0039-010-3537953; fax: 0039-010-3538977; e-mail: [email protected]Search for more papers by this authorA. SULLI, A. SULLI Cattedra di Reumatologia, Università di Genova, Genova, ItalySearch for more papers by this authorC. PRETE, C. PRETE Cattedra di Reumatologia, Università di Genova, Genova, ItalySearch for more papers by this authorP. SESSAREGO, P. SESSAREGO DiSEM, Cattedra di Endocrinologia e DiMI, Università di Genova, Genova, ItalySearch for more papers by this authorS. PIREDDA, S. PIREDDA DiSEM, Cattedra di Endocrinologia e DiMI, Università di Genova, Genova, ItalySearch for more papers by this authorB. SERIOLO, B. SERIOLO Cattedra di Reumatologia, Università di Genova, Genova, ItalySearch for more papers by this authorM. CUTOLO, M. CUTOLO Cattedra di Reumatologia, Università di Genova, Genova, ItalySearch for more papers by this authorM. GIUSTI, M. GIUSTI DiSEM, Cattedra di Endocrinologia e DiMI, Università di Genova, Genova, ItalySearch for more papers by this author First published: 06 February 2006 https://doi.org/10.1111/j.1749-6632.1999.tb07625.xCitations: 5Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Citing Literature Volume876, Issue1NEUROENDOCRINE IMMUNE BASIS OF THE RHEUMATIC DISEASESJune 1999Pages 83-87 RelatedInformation

Rheumatoid arthritis (RA) is an inflammatory chronic disease with an autoimmune pathogenesis and a complex multifactorial etiology. Various factors such as immunogenetic determinants, sex, age, and stress play an important role. The relationship between stress and RA is still unclear and undefined; however, various lines of research are developing in order to evaluate environmental, psychologic, and biologic stressors as predisposing factors. The aim of our study was to evaluate whether stress-related psychologic factors and personality disorders might be involved in the development of RA, by using a psychometric investigation-methodology in a series of patients. Fifteen in- and outpatients underwent a clinical interview and other specific psychometric tests. Macro- and microstressful life-events preceded RA onset in 86% of the cases. Sixty percent of the patients showed a correlation between flare-ups of the disease and appearance of microevents. Forty percent of the patients showed an obsessive-compulsive personality disorder (OCPD), 40% showed a borderline personality disorder (BPD), 7% showed a schizoid and a dependent disorder. Only 13% of the patients showed no personality disorders. Among the BPD group we also detected alexithymia. Our results should be considered as preliminary; on the other hand, the high prevalence of major life-events preceding the onset of RA and the presence of personality disorders support the role of the altered stress response system as an important pathogenetic factor and will be a matter of further studies.