EULAR/EFORT recommendations for management of patients older than 50†years with a fragility fracture and prevention of subsequent fractures.

The European League Against Rheumatism (EULAR) and the European Federation of National Associations of Orthopaedics and Traumatology (EFORT) have recognised the importance of optimal acute care for the patients aged 50 years and over with a recent fragility fracture and the prevention of subsequent fractures in high-risk patients, which can be facilitated by close collaboration between orthopaedic surgeons and rheumatologists or other metabolic bone experts. Therefore, the aim was to establish for the first time collaborative recommendations for these patients. According to the EULAR standard operating procedures for the elaboration and implementation of evidence-based recommendations, 7 rheumatologists, a geriatrician and 10 orthopaedic surgeons met twice under the leadership of 2 convenors, a senior advisor, a clinical epidemiologist and 3 research fellows. After defining the content and procedures of the task force, 10 research questions were formulated, a comprehensive and systematic literature search was performed and the results were presented to the entire committee. 10 recommendations were formulated based on evidence from the literature and after discussion and consensus building in the group. The recommendations included appropriate medical and surgical perioperative care, which requires, especially in the elderly, a multidisciplinary approach including orthogeriatric care. A coordinator should setup a process for the systematic investigations for future fracture risk in all elderly patients with a recent fracture. High-risk patients should have appropriate non-pharmacological and pharmacological treatment to decrease the risk of subsequent fracture.

Arthritis and osteoporosis: pathogenetic correlations in function of arthroplasty.

Osteoarthritis is being increasingly characterised as an inflammatory incoming and recurrent disease, with the specific symptoms of inflammation at every stage of the disease. With regard to the pathogenesis over time, the degenerative and inflammatory components are combined and lead to osteocartilaginous degeneration. Such deterioration involves other joint tissues as well as the subchondral bone tissue, the suffering of which is the key event of the beginning and progression of OA; its involvement concerns the same pathogenetic mechanisms and the same chemical mediators of the chondropathy. The increase in joint inflammatory events leads to suspect the onset or the worsening of the osteometabolic disorder, which is documented by the MR as “bone edema” or as algodystrophic syndrome. The pain appears both while moving and resting and with signs of inflammation. The treatment of OA requires drugs, such as paracetamol, selective and nonselective NSAIDs and opiates, for pain control. Treatment should ensure the pharmacological control of the pain related to the osteometabolic juxta-articular alteration, through bisphosphonates, favouring those which can control bone loss, inflammation and pain.

Osteoporosis in the elderly.

Osteoporosis is predominantly a condition of the elderly with a consequent increase in bone fragility and susceptibility to fracture. A number of clinical as well as biological studies have been pivotal in providing us with an understanding of the pathophysiology of this condition. This article discusses the current concepts of age-related osteoporosis.

Endothelin receptor antagonists: effects on extracellular matrix synthesis in primary cultures of skin fibroblasts from systemic sclerosis patients.

Endothelin-1 (ET-1) seems to enhance the pro-fibrotic protein synthesis by skin fibroblasts and its effects are mediated by endothelin-A and B (ETA and ETB) receptors. This study aimed to investigate the effects of ETA and ETB receptor antagonists (ETARA-sitaxsentan and ETA/BRA-bosentan) on type I collagen (COL-1), fibronectin (FN) and fibrillin-1 (FBL-1) synthesis in primary cultures of skin fibroblasts from systemic sclerosis patients. Primary cultures of fibroblasts were obtained from skin biopsies of 6 female systemic sclerosis patients and were treated with ET-1 (100 nM) for 24 and 48 hrs with or without pre-treatment (1 hr) with ETARA (2 µM) or ETA/BRA (10 µM). Primary culture of human scleroderma skin fibroblasts not treated with ET-1 or ET receptor antagonists (ETARA and ETA/BRA) were used as controls. COL-1, FN and FBL-1 synthesis was evaluated by immunocytochemistry and Western blot analysis. Immunocytochemistry and Western blot analysis showed that ET-1 significantly increased COL-1 and FN synthesis at 24 and 48 hrs and FBL-1 synthesis at 48 hrs vs untreated cells. ETARA significantly contrasted the ET-1-mediated increase in COL-1 and FN at 24 hrs as well as COL-1 and FBL-1 at 48 hrs, but not FN synthesis vs ET-1-treated fibroblasts. Conversely, ETA/BRA significantly antagonized the ET-1-mediated overproduction of COL-1 and FN both at 24 and 48 hrs and the FBL-1 synthesis at 48 hrs vs ET-1-treated cells. The single ETARA treatment seems to contrast significantly the increase in COL-1 synthesis, whereas the dual ETA/BRA treatment seems active in significantly antagonizing both COL-1 and FN overproduction induced by ET-1. In conclusion, ET-1 antagonism might have positive effects in contrasting the profibrotic activity of systemic sclerosis skin fibroblasts.

[CTLA4-Ig interferes and downregulates the proinflammatory activities of rheumatoid synovial macrophages in monoculture]. / CTLA4-Ig influenza e inibisce le attività proinfiammatorie di macrofagi sinoviali reumatoidi in monocoltura.

OBJECTIVE: CTLA4-Ig, a biologic agent employed in rheumatoid arthritis (RA) treatment, downregulates the immune response and exerts anti-inflammatory effects acting on different cells including dendritic/T cells interaction and directly on osteoclasts. We investigated the anti-inflammatory effects of CTLA4-Ig in primary monocultures of RA synovial macrophages (SM). METHODS: SM were obtained, from 8 RA patients (7 F, 1 M; DAS28>5.2) who underwent therapeutic arthroscopic synoviectomy and were cultured in the absence and in the presence of CTLA4-Ig at the concentration of [500 microg/ml], the most reliable dose related to the previous pharmacological clinical and experimental experiences. Inflammatory cytokine (IL-6, TNFalpha, IL-1beta) expression was evaluated by immunocytochemistry (ICC with relative image analysis), western blot (WB), and quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: ICC analysis revealed that CTLA4-Ig treatment significantly downregulated cytokine expression (p<0.001 for IL-6, TNFalpha and IL-1beta) when compared to untreated RA SM. WB and qRT-PCR confirmed partially the data. CONCLUSIONS: CTLA4-Ig was found to exert a direct and significant anti-inflammatory effect on primary monocultures of RA SM, suggesting a therapeutic power in different phases of the disease activity.

Endothelin and sex hormones modulate the fibronectin synthesis by cultured human skin scleroderma fibroblasts.

OBJECTIVE: To evaluate the influence of endothelin-1 (ET-1) and sex hormones on cell proliferation and extracellular matrix (ECM) synthesis (ie, fibronectin, laminin) by cultured normal and scleroderma (SSc) human skin fibroblasts (FBs). METHODS: Primary cultures of FBs were treated with ET-1 and sex hormones (17beta-oestradiol or testosterone) for 24 h. Cell growth was analysed by methiltetrazolium salt test, ECM synthesis was evaluated by immunocytochemistry and western blot, both at 24 h. RESULTS: In normal FBs, ET-1 and 17beta-oestradiol, as well as their combination, increased cell growth (p<0.001, p<0.001, p<0.01 vs untreated cells (control), respectively) and fibronectin synthesis (p<0.05, p<0.05, p<0.01 vs control, respectively). By contrast, testosterone either alone or in combination with ET-1 did not influence cell proliferation, but decreased fibronectin synthesis (p<0.05, testosterone vs control). In SSc FBs, ET-1 and 17beta-oestradiol alone or their combination induced an increased fibronectin synthesis (p<0.05, p<0.05, p<0.01 vs control, respectively). Unexpectedly, testosterone induced an increase of fibronectin synthesis (p<0.05 vs control). CONCLUSIONS: ET-1 and 17beta-oestradiol seem to exert a profibrotic effect in normal and SSc culture FBs and might suggest their synergistic effect in the pathogenesis of the fibrotic process in SSc.

[Role of videocapillaroscopy in early detection of transition from primary to secondary Raynaud's phenomenon in systemic sclerosis]. / Ruolo della videocapillaroscopia periungueale nella identificazione precoce della progressione del fenomeno di Raynaud da primario a secondario nella sclerosi sistemica.

Patients initially diagnosed as having primary Raynaud's phenomenon (PRP) may shift to secondary (SRP) during the follow-up. Nailfold videocapillaroscopy (NVC) is a tool that allows to distinguish between PRP and SRP through the identification of the "early" scleroderma-pattern of microangiopathy. The aim of this study was to evaluate the transition from PRP to SRP in an Italian cohort of patients during their follow-up. 129 patients with PRP were identified and followed-up for 2721 months. The diagnosis of PRP was achieved as suggested by LeRoy. The NVC diagnosis of scleroderma-pattern was based on the presence of specific "early" capillary abnormalities (i.e. giant capillaries, microhaemorrhages, and/or slight reduction of capillary density). Based on the identification of the "early" scleroderma-pattern by NVC, 14% of patients changed from PRP to SRP during the follow-up. Interestingly, 4.6% of these patients showed at baseline a fully normal NVC pattern (transition from normal to scleroderma NVC pattern in 3427 months), and 10% showed slight and not-specific nailfold capillary abnormalities (i.e. dystrophic capillaries and/or enlarged capillaries) at baseline (transition to scleroderma NVC pattern in 2515 months). Following a careful NVC analysis, we showed the progression from PRP to SRP in 14% of the analyzed patients. We suggest the capillaroscopic analysis twice a year in presence of PRP, in order to early detect the transition to SRP in patients showing at the beginning a normal pattern or not-specific nailfold capillary abnormalities, as assessed by NVC.

Circannual vitamin d serum levels and disease activity in rheumatoid arthritis: Northern versus Southern Europe.

BACKGROUND: Greater intake of vitamin D has been associated with a lower risk of rheumatoid arthritis (RA) and low serum vitamin D together with higher prevalence of RA seem common among North European people when compared to Southern Europe. OBJECTIVES: To evaluate serum 25-hydroxyvitamin D [25(OH)D] levels in female RA patients from North (Estonia) and South (Italy) Europe and to correlate them with the disease activity score (DAS28) during winter and summer. METHODS: Fifty-four RA Italian patients (IP) and 64 RA Estonian patients (EP) were evaluated for serum 25(OH)D levels in winter and summer time, as well as for DAS28 score. Normal female controls (C) were 35 (IC) and 30 (EC) age-matched subjects, respectively. 25(OH)D concentrations were measured by a competitive radioimmunoassay. Statistical analysis was performed by "r" Pearson correlation, "t" Student with Bonferroni correction and by repeated ANOVA measures (summer and winter) with two factors (country and clinical status). RESULTS: 25(OH)D levels were found significantly higher in IP versus EP (p = 0.0116) both in winter and in summer time. Differences were observed also in controls. The variations (increase) of 25(OH)D levels between winter and summer were found significant (p = 0.0005) in both IP and EP. Differences were observed also in controls. No significant differences were found concerning 25(OH)D levels between RA patients and their controls in either country. Interestingly, a significant negative correlation between 25(OH)D and DAS28, was found in summer only in IP (r =-0.57, p < 0.0001) and in winter in EP (r =-0.40, p < 0.05). CONCLUSION: Significantly lower 25(OH)D serum levels were observed in RA patients from North versus South Europe with a circannual rhythm in winter and summer time. In addition, 25(OH)D values showed a significant correlation (negative) with RA clinical status (DAS28) in both North and South European RA patients, suggesting possible effects of vitamin D among other factors on disease activity.

[Are there any positive effects of TNF-alpha blockers on bone metabolism?]. / La terapia con anti TNF-alfa ha effetti positivi sul metabolismo osseo?

UNLABELLED: Secondary osteoporosis (OP) is a well-recognized complication of rheumatoid arthritis (RA). Treatment with TNF-alpha blockers, might influence bone metabolism and prevent structural bone damage in RA, in particular at the periarticular regions. OBJECTIVE: To assess the influence of anti-TNF-alpha therapy, on bone metabolism in RA patients. 36 RA patients were treated with stable therapy of prednisone (7.5 mg/day) and methotrexate (MTX=10 mg/week). Nine of these RA patients further received etanercept (25 mg, twice/weekly) and eleven infliximab (3mg/kg on 0, 2, 6, and every 8 weeks thereafter). A control group included 16 RA patients only with stable therapy (some dosage of prednisone and MTX). Quantitative Ultrasound (QUS) bone densitometry was obtained at the metaphyses of the proximal phalanges of both hands with a DBM Sonic 1200 QUS device (IGEA, Carpi, Italy). Bone mineral density (BMD) of the hip and lumbar spine were performed with a densitometer ( Lunar Prodigy, GE, USA) at baseline and after 12 months. Soluble bone turnover markers [osteocalcin (OC), bone alkaline phospatase (ALP) deoxypyridinoline/creatinine ratio (Dpd/Cr) and cross-linked N-telopeptide of type I collagen / creatinine ratio (NTx/Cr)] were measured using ELISA tests. RESULTS: AD-SoS values were found increased by +4.55% after 12 months of treatment in the RA patients treated with anti-TNF-alpha therapy. On the contrary, the Ad-SoS levels decreased by -4.48% during the same period in the control RA group. BMD increased by +3.64% at lumbar spine and +2.90% at the hip (both p<0.001) in TNF-alpha blockers-treated patients and decreased by -2.89% and -3.10% (both p<0.001, respectively at lumbar spine and at the hip) in RA patients without anti-TNF-alpha therapy. In RA patients treated with TNF-alpha blockers, OC and bone ALP levels were found significantly increased (p<0.01) and Dpd/Cr or NTx/Cr levels were found significantly decreased (p<0.01) at 12 months when compared to baseline values. CONCLUSION: During 12 months of treatment of RA patients with TNF-alpha blockers, bone formation seems increased while bone resorption seems decreased. The reduced rate of OP seems supported by the same mechanisms involved in the decreased bone joint resorption during anti-TNF-alpha therapy (i.e. increase of osteoblastic activity and decrease osteoclastic activity).

Altered circadian rhythms in rheumatoid arthritis patients play a role in the disease's symptoms.

The circadian changes in the metabolism or nocturnal secretion of endogenous corticosteroids (reduction) observed in rheumatoid arthritis (RA) patients are responsible, in part, for the time-dependent changes that are observed in the inflammatory response and related early morning clinical symptoms of the disease. Melatonin (MLT), another circadian nocturnal hormone that is the secretory product of the pineal gland, has been implicated in the time-dependent RA inflammatory reaction with effects that are opposite to those of corticosteroids. As a consequence, altered functioning of the HPA axis (early morning reduced corticosteroid production) and of the pineal gland (night increased MLT production) found in RA patients, seem to be important factors in the appearance and perpetuation of the clinical circadian symptoms of the disease. Consistently, human proinflammatory Th1-type cytokine production (related to MLT stimulation) exhibits a diurnal rhythmicity with peak levels during the night and early morning, at a time when plasma cortisol (inducing the Th2-type cytokine production) is lowest and MLT is highest. Reduced daily light exposure as observed in northern Europe (Estonia), at least during the winter, might explain the higher and more prolonged serum MLT concentrations that were observed in northern RA patients, as well as some epidemiological features versus southern Europe patients.

Eradication of Helicobacter pylori may reduce disease severity in rheumatoid arthritis.

BACKGROUND: A triggering infectious agent has long been postulated in rheumatoid arthritis. Data on the possible role of Helicobacter pylori infection are lacking. AIM: To assess the effect of H. pylori eradication in patients with rheumatoid arthritis. METHODS: Fifty-eight adult patients with established rheumatoid arthritis and dyspeptic symptoms were recruited - 28 were H. pylori-positive and 30 were H. pylori-negative on the basis of invasive tests. All infected patients were treated successfully. We evaluated the disease activity using clinical and laboratory parameters at baseline and every 4 months during 2 years, and compared the variations in the two subgroups. RESULTS: H. pylori-eradicated rheumatoid arthritis patients showed progressive improvement over time (P < 0.0001) of all clinical indices compared with baseline, whereas H. pylori-negative rheumatoid arthritis patients remained substantially unchanged. After 2 years, H. pylori-eradicated rheumatoid arthritis patients differed significantly (P < 0.04-0.0001) from patients without H. pylori infection in terms of improvement of all clinical parameters. At the same time point, several laboratory indices (erythrocyte sedimentation rate, fibrinogen, alpha2-globulins and antinuclear antibody) showed significantly lower values (P < 0.02-0.0003) in the H. pylori-eradicated subgroup compared to the H. pylori-negative subgroup. CONCLUSIONS: Our data suggest that H. pylori infection is implicated in the pathogenesis of rheumatoid arthritis, in that its eradication may induce a significant improvement of disease activity over 24 months. H. pylori eradication seems to be advantageous in infected rheumatoid arthritis patients, but controlled studies are needed.

Desmopressin and low-dose ACTH test in rheumatoid arthritis.

OBJECTIVE: To ascertain whether a different regulation and sensitivity of the hypothalamic-pituitary-adrenal axis exists and whether a type of cortisol resistance is present in rheumatoid arthritis (RA) patients, a chronic disease in whose pathogenesis modifications of the steroid milieu are involved. DESIGN: We studied the basal and dynamic response of ACTH and adrenal steroids to various stimuli acting on the hypophysis or directly on the adrenal gland. METHODS: We studied ten RA patients (39.8 +/- 7.4 (S.D.) years), defined according to the American Rheumatism Association, and seven healthy control patients (34.1 +/- 9.6 (S.D.) years). All subjects underwent testing, in random order, with placebo, desmopressin (DDAVP) (10 microg i.v.), ovine corticotropin-releasing hormone (oCRH) (1 microg/kg body weight) and low-dose ACTH (5 microg i.v.), during the follicular phase of two different menstrual cycles. Blood samples were collected at different times for ACTH and adrenal steroids assay. Baseline estradiol (E2), testosterone and IGF-I levels were also evaluated. All subjects collected urine specimens for 24 h urine free cortisol (UFC). RESULTS: No difference in E2, testosterone or UFC was found between RA patients and controls. IGF-I levels were significantly (P < 0.01) lower in RA patients (110.6 +/- 6.4 microg/l) than in controls (207.0 +/- 37.9 microg/l). Mean baseline dehydroepiandrosterone (DHEA) and delta4-androstenedione levels of the four tests were significantly (P < 0.05) lower in RA patients than in controls. In RA, a negative correlation was found between mean DHEA levels, class of disease (r = -0.67, P < 0.05) and erythrocyte sedimentation rate (r = -0.63, P < 0.05). After placebo no difference in ACTH and cortisol area under curves (AUCs) was found between RA patients and controls. After DDAVP no cortisol or ACTH response was found in RA patients, while a significant (P < 0.05) ACTH release was found in controls. Only in RA patients was DDAVP able to induce a significant (P < 0.01) DHEA increase. After oCRH a similar significant response in ACTH (P < 0.05), cortisol (P < 0.01), and DHEA (P < 0.01) was found in both groups. After low-dose ACTH, a similar significant (P < 0.01) cortisol response was found in both RA patients and controls; indeed in RA patients DHEA AUC (2196.0 +/- 321.8 nmol/l per 90 min) was significantly lower (P < 0.01) than DHEA AUC (4280.8 +/- 749.0 nmol/l per 90 min) in controls. A similar significant (P < 0.01), though not abnormal, 17-hydroxyprogesterone response to ACTH was found in both groups. CONCLUSIONS: Our study underlines reduced adrenal steroid and IGF-I levels, but not the previously described cortisol resistance in RA patients; it shows that baseline and dynamic cortisol levels are 'normal' but inadequate in the setting of a sustained inflammatory disease like RA. The reduced basal and low-dose ACTH-induced DHEA levels could reflect both a reduced sensitivity of the adrenal gland to exogenous corticotropin and a decreased steroid synthesis due to a partial adrenal enzymatic defect (P450 17,20 lyase).

Cortisol, dehydroepiandrosterone sulfate, and androstenedione levels in patients with polymyalgia rheumatica during twelve months of glucocorticoid therapy.

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.

Melatonin serum levels in rheumatoid arthritis.

The pineal hormone melatonin (MLT) exerts a variety of effects on the immune system. MLT activates immune cells and enhances inflammatory cytokine and nitric oxide production. Cytokines are strongly involved in the synovial immune and inflammatory response in rheumatoid arthritis (RA) and reach the peak of concentration in the early morning, when MLT serum level is higher. Nocturnal MLT serum levels were evaluated in 10 RA patients and in 6 healthy controls. Blood samples were obtained at 8 and 12 p.m., as well as at 2, 4, 6, and 8 a.m. MLT serum levels at 8 p.m. and 8 a.m. were found to be higher in RA patients than in controls (p < 0.05). In both RA patients and healthy subjects, MLT progressively increased from 8 p.m. to the first hours of the morning, when the peak level was reached (p < 0.02). However, MLT serum level reached the peak at least two hours before in RA patients than in controls (p < 0.05). Subsequently, in RA patients, MLT concentration showed a plateau level lasting two to three hours, an effect not observed in healthy controls. After 2 a.m., MLT levels decreased similarly in both RA patients and healthy subjects. Several clinical symptoms of RA, such as morning gelling, stiffness, and swelling, which are more evident in the early morning, might be related to the neuroimmunomodulatory effects exerted by MLT on synovitis and might be explained by the imbalance between cortisol serum levels (lower in RA patients) and MLT serum levels (higher in RA patients).

The hypothalamic-pituitary-adrenal and gonadal axes in rheumatoid arthritis.

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.

Homocysteine and antiphospholipid antibodies in rheumatoid arthritis patients: relationships with thrombotic events.

OBJECTIVE: To investigate the possible relationships between plasma homocysteine levels and thrombotic events in a select population of rheumatoid arthritis (RA) patients with or without antiphospholipid (aPL) antibody positivity. METHODS: 168 female RA patients attending the Extra-articular Involvement RA Clinic of University of Genova and 72 female subjects matched for age and vascular diseases as controls were included in the study. 30 of the RA patients showed aPL antibody positivity and 138 aPL antibody negativity on the basis of the concomitant presence or absence of high concentrations of anticardiolipin (aCL) antibodies or the presence of lupus anticoagulant (LA). All subjects were evaluated for plasma homocysteine concentrations and for the occurrence of thrombotic events. RESULTS: Twenty-five RA patients and 5 controls reported a history of thrombotic events. Eleven and 5 of RA patients were found to have been previously affected by venous or arterial thrombosis, respectively. Plasma levels of homocysteine in aPL antibody positive patients with thrombosis were found to be significantly higher than in aPL antibody positive RA patients without thrombosis (p < 0.001). When RA patients with thromboses were analyzed, a significant increase of plasma homocysteine levels was found in aPL antibody-positive RA patients versus aPL antibody-negative RA patients (p < 0.04) and versus related controls (p < 0.003). CONCLUSIONS: The association observed between aPL antibody positivity and high levels of plasma homocysteine in RA patients may represent a possible risk factor for thrombotic events. Therefore, it is suggested that hyperhomocysteinemia might be involved in the vascular-related mortality observed in RA patients with a history of thrombosis.

Macrophages, synovial tissue and rheumatoid arthritis.

Macrophage-like synoviocytes originate in the bone marrow, like other mononuclear phagocytes, and are constantly replaced via the circulation. In rheumatoid synovium sections, 80-100% of the synovial lining cells are macrophage-like cells functioning as antigen processing- and antigen-presenting cells to T lymphocytes. Monocyte and lymphocyte traffic into the rheumatoid arthritis (RA) synovium is mediated by adhesion molecules such as endothelial-leukocyte adhesion molecule-1 (ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecules-1 and -2 (ICAM-1 and ICAM-2), as well as monocyte chemotactic protein 1 (MCP-1) and beta 2 integrins (CD11 a,b,c/CD18). Macrophage-like cells in the RA synovium are highly activated based on their morphology, surface class II HLA antigen expression, and synthesis of cytokines such as interleukin-1 beta (IL-1 beta), tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), macrophage CSF, and transforming growth-factor beta (TGF-beta). Evidence for type 1 (higher affinity) and type 2 (lower affinity) androgen (ARs) and estrogen receptors (ERs) on macrophage-like synoviocytes in either male or female synovial samples from both RA patients and controls has been reported. In particular, ERs have also been found on CD8+CD29+ CD45R0+ T lymphocytes (memory), infiltrating rheumatoid synovial tissues. Sex hormones have been found to influence macrophage activity in experimental and clinical conditions such as RA. Generally estrogens have immunostimulatory effects, whereas androgens are immuno-suppressive.(ABSTRACT TRUNCATED AT 250 WORDS)

Estrogens, the immune response and autoimmunity.

Estrogens appear to play a central role in the immune response and immune-mediated diseases. Recent studies have shown the presence of estrogen receptors on the cells involved in the immune response, namely thymocytes, macrophages and endothelial cells. Particular attention has been focused on the dose-dependent influence of estrogen on the immune response, which appears to be related to the clinical symptoms of autoimmunity (i.e. the effects of pregnancy or oral contraceptive pills). The influence of estrogens on cytokine production by target cells, through interference with their transcriptional activity, has also been the focus of various studies. The effect of estrogens on the expression of the protooncogenes and oncosuppressor genes involved in programmed cell death (apoptosis) might also be relevant to human autoimmunity, in particular the uncontrolled synovial lining cell hyperplasia associated with rheumatoid arthritis and the prolonged T-cell survival in systemic lupus erythematosus. Estrogen-induced immunomodulation is a subject of growing interest and stimulating research.

Methotrexate in psoriatic arthritis.

Methotrexate (MTX) is a folic acid analogue with antiproliferative and antiinflammatory effects. In the past several years, MTX has become the most commonly used agent in patients with severe, destructive psoriatic arthritis (PsA), with positive clinical results. Liver changes and serum enzyme level increases do not seem to be a major problem in PSA patients treated with MTX. In addition, PSA patients treated with low-dose MTX were not associated with pulmonary fibrosis as evaluated by means of sensitive imaging techniques and pulmonary function tests. The concomitant use of folic acid reduces both the frequency of serum liver enzyme level increases but also the efficacy of MTX by competing with the folate receptors.