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Maurizio Cutolo

Publications and source records attributed to Maurizio Cutolo.

At least 19 recordsLinked to original sources
PubMed2006

Etanercept maintains the clinical benefit achieved by infliximab in patients with rheumatoid arthritis who discontinued infliximab because of side effects.

OBJECTIVE: To evaluate the efficacy of switching to etanercept treatment in patients with rheumatoid arthritis who already responded to infliximab, but presented side effects. METHODS: Charts of 553 patients with rheumatoid arthritis were retrospectively reviewed to select patients who responded to the treatment with infliximab and switched to etanercept because of occurrence of adverse effects. Clinical data were gathered during 24 weeks of etanercept treatment and for the same period of infliximab treatment before infliximab was stopped. Disease Activity Score computed on 44 joints (DAS-44), erythrocyte sedimentation rate (ESR) 1st hour, Visual Analogue Scale (VAS) of pain, Health Assessment Questionnaire (HAQ), and C reactive protein (CRP) were assessed every 8 weeks. RESULTS: 37 patients were analysed. Adverse events to infliximab were mostly infusion reactions. No statistically significant difference between infliximab, before withdrawal, and etanercept, after 24 weeks, was detected in terms of DAS-44 (2.7 and 1.9, respectively), HAQ (0.75 and 0.75, respectively), ESR (21 and 14, respectively) and CRP (0.5 and 0.3, respectively). VAS pain decreased significantly after switching to etanercept treatment (40 and 24, respectively; p<0.05). CONCLUSIONS: Our study shows that etanercept maintains the clinical benefit achieved by infliximab, and suggests that a second tumour necrosis factor (TNF) alpha inhibitor can be the favourable treatment for rheumatoid arthritis when the first TNFalpha blocker has been withdrawn because of adverse events.

Adult↗
PubMed2006

Th2 immune deviation induced by pregnancy: the two faces of autoimmune rheumatic diseases.

One of the most important immunological modifications during pregnancy is the Th1/Th2 shift, due to the progressive increase of progesterone and estrogens during pregnancy, which reach their peak-level in the third trimester of gestation. At high levels, estrogens seem mainly to suppress Th1 cytokines and stimulate Th2-mediated immunological responses as well as antibody production. For this reason Th1-mediated diseases, like rheumatoid arthritis (RA), tend to improve and Th2-mediated disease, like systemic lupus erythematosus (SLE), tend to worsen during pregnancy. SLE is the autoimmune rheumatic disease in which pregnancy most frequently occurs because it predominantly affects young females in their childbearing age. Other autoimmune rheumatic diseases, including RA, are less frequently observed during pregnancy due to their low female-to-male ratio and peak onset after the age of 40. This review is focused on the disease course, gestational outcome and management of patients with SLE and RA during pregnancy.

Adrenal Cortex Hormones↗
PubMed2006

Effects of testosterone, 17beta-estradiol, and downstream estrogens on cytokine secretion from human leukocytes in the presence and absence of cortisol.

Estrogens at physiological concentrations are thought to play an immune-stimulating role, whereas androgens have an anti-inflammatory impact. However, their role on cytokine secretion in the presence or absence of cortisol has not been investigated. Furthermore, the role of hydroxylated estrogens downstream of 17beta-estradiol (E2) on secretion of tumor necrosis factor (TNF) is not known. In this study on peripheral blood leukocytes of healthy male subjects, we scrutinized the influence of prior sex hormones (for 24 h) with and without later addition of cortisol (for another 24 h) on stimulated secretion of TNF, IL-2, IL-4, IL-6, IL-10, and interferon-gamma (IFN-gamma). E2 stabilized or increased immune stimuli-induced secretion of TNF, IL-2, IL-4, IL-6, IL-10, and IFNgamma in relation to testosterone. Testosterone, in contrast, inhibited (IL-2, IL-4, IL-10) or tended to inhibit stimulated secretion of these cytokines (TNF, IFNgamma). This effect of E2 was pronounced at a concentration of 10(-10) M (testosterone: 10(-7) M) in the presence of cortisol. E2 (10(-8) M, 10(-10) M) and testosterone (10(-7) M) did not change glucocorticoid receptor expression. The downstream estrogens 2OH-estradiol(one), 4OH-estradiol(one), and 16OH-estradiol(one) did not stimulate TNF secretion at 10(-10) M, but even inhibited its secretion at 10(-11) M. However, the combination of 16OH-estradiol(one) on one side and 2OH-estradiol(one) or 4OH-estradiol(one) on the other side markedly stimulated TNF secretion that was only observable in the presence of cortisol. In conclusion, at physiological concentrations, E2 and a combination of downstream estrogens stabilized or increased immune stimuli-induced TNF secretion. These effects are dependent on the presence of physiological concentrations of cortisol. This study underlines the proinflammatory role of E2, which is probably dependent on conversion to a proinflammatory cocktail of downstream estrogens and the presence of cortisol.

Adult↗
PubMed2006

Estrogens in pregnancy and systemic lupus erythematosus.

Successful pregnancy depends on an adaptation of the maternal immune system that becomes tolerant to fetal antigens of paternal origin. The altered immune regulation induced by pregnancy occurs predominantly at the maternal-fetal interface, but it has also been observed in the maternal circulation. Th1/Th2 shift is one of the most important immunologic changes during gestation. It is due to the progressive increase of estrogens, which reach peak level in the third trimester of pregnancy. At these high levels, estrogens suppress the Th1-mediated responses and stimulate Th2-mediated immunologic responses. For this reason Th1-mediated diseases, such as rheumatoid arthritis, tend to improve, while Th2-mediated diseases, such as systemic lupus erythematosus (SLE) tend to worsen during pregnancy. However, in some recent studies SLE flare-ups were less frequently observed in the third trimester of gestation in comparison to the second trimester and postpartum period. These data are apparently in contrast to the Th2 immune-response polarization expected during pregnancy due to the progressive increase of estrogens. Some further data suggest that in SLE patients estradiol serum levels are surprisingly lower than expected during the third trimester of pregnancy, probably due to a placental compromise. This occurrence could lead to a lower-than-expected increase of IL-6, accounting for the low humoral immune response and the low disease activity observed in the third trimester of pregnancy in such patients.

Animals↗
PubMed2006

Role of estrogens in inflammatory response: expression of estrogen receptors in peritoneal fluid macrophages from endometriosis.

Estrogens are involved in the immune response, and macrophages express estrogen receptors (ER). Moreover, macrophages are the predominant cell type in the peritoneal fluid from endometriosis patients. On this basis, the aim of our study was to evaluate the expression of ER on peritoneal macrophages from endometriosis patients and to compare these results with what is already known about ER and macrophages in RA. After macrophage extraction from peritoneal fluids we performed the immunohistochemical localization of ERalpha and ERbeta and then the image analysis. We found that both ERs were significantly overexpressed in macrophages of women with endometriosis compared with controls. These results suggest that estrogens, through their functional receptors, might modulate the immune response at least on macrophages. Therefore, estrogens seem to play an important role in the immune response, independently from the pathology.

Endometriosis↗
PubMed2006

Circadian rhythms: glucocorticoids and arthritis.

Circadian rhythms are driven by biological clocks and are endogenous in origin. Therefore, circadian changes in the metabolism or secretion of endogenous glucocorticoids are certainly responsible in part for the time-dependent changes observed in the inflammatory response and arthritis. More recently, melatonin (MLT), another circadian hormone that is the secretory product of the pineal gland, has been found implicated in the time-dependent inflammatory reaction with effects opposite those of cortisol. Interestingly, cortisol and MLT show an opposite response to the light. The light conditions in the early morning have a strong impact on the morning cortisol peak, whereas MLT is synthesized in a strictly nocturnal pattern. Recently, a diurnal rhythmicity in healthy humans between cellular (Th1 type) or humoral (Th2 type) immune responses has been found and related to immunomodulatory actions of cortisol and MLT. The interferon (IFN)-gamma/interleukin (IL)-10 ratio peaked during the early morning and correlated negatively with plasma cortisol and positively with plasma MLT. Accordingly, the intensity of the arthritic pain varies consistently as a function of the hour of the day: pain is greater after waking up in the morning than in the afternoon or evening. The reduced cortisol and adrenal androgen secretion, observed during testing in rheumatoid arthritis (RA) patients not treated with glucocoticoids, should be clearly considered as a "relative adrenal insufficiency" in the presence of a sustained inflammatory process, and allows Th1 type cytokines to be produced in higher amounts during the late night. In conclusion, the right timing (early morning) for the glucocorticoid therapy in arthritis is fundamental and well justified by the circadian rhythms of the inflammatory mechanisms.

Animals↗
PubMed2006

Glucocorticoid effects on adrenal steroids and cytokine responsiveness in polymyalgia rheumatica and elderly onset rheumatoid arthritis.

Polymyalgia rheumatica (PMR) usually exhibits a good clinical response to glucocorticoid (GC) treatment, but early clinical symptoms may create some difficulties in the differential diagnosis with elderly onset rheumatoid arthritis (EORA), particularly in patients complaining of shoulder and pelvic girdle involvement at onset (PMR-like clinical onset) (EORA/PMR). Since neuroendocrine mechanisms seem to play a pathogenetic role in these clinical conditions, the aim of this study was to evaluate hormone and cytokine responsiveness to GC treatment in these patients. Cortisol (CO), dehydroepiandrosterone sulphate (DHEAS), 17-OH-progesterone (PRG), interleukin-1 receptor antagonist (IL-1Ra), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were evaluated at base line, and 1 month after GC treatment (prednisone 10 mg/day), in 14 PMR, 11 EORA/PMR, and 13 EORA patients (mean age 73 +/- 5 years, +/- SD, mean disease duration 3 +/- 2 months, +/- SD). No patient was taking GCs or immunosuppressive agents at base line. Following GC treatment, CO, DHEAS, and PRG decreased significantly in both PMR and EORA/PMR patients (P < 0.05), but not in EORA patients. On the contrary, IL-1Ra was significantly increased in both PMR and EORA/PMR patients (P < 0.05). IL-6 and TNF-alpha serum levels were significantly decreased in all groups of patients (P < 0.05). In conclusion, PMR and EORA/PMR seem to exhibit similar hormonal variations after GC administration, when compared to EORA patients. These differences suggest a deficient function of the hypothalamic-pituitary-adrenal (HPA) axis in PMR and EORA/PMR patients, with a related higher responsiveness to GC treatment. Interestingly, in PMR and EORA/PMR patients, GC treatment was found to downregulate PRG serum levels.

Adrenal Glands↗
PubMed2006

Anti-TNF and sex hormones.

Whenever serum estrogen concentrations are normal in rheumatoid arthritis (RA) patients, lower androgen concentrations (i.e., testosterone, androstenedione, and dehydroepiandrosterone sulfate [DHEAS]) are detected in the serum as well as in the synovial fluid of male and female RA patients. The presence in the RA synovial fluid of a significant altered sex hormone balance resulting in lower immunosuppressive androgens and higher immuno-enhancing estrogens, might determine a favorable condition for the development of the immunomediated RA synovitis. The inflammatory cytokines (i.e., TNF-alpha), particularly increased in RA synovitis, are able to markedly stimulate the aromatase activity in peripheral tissues and, therefore, induce the peripheral metabolism from androgens to estrogens. The effects of TNF blockers (and generally of anticytokine agents) on peripheral sex hormone levels seem exerted in a faster way at the level of the RA synovial tissue (before any influence on serum levels) where they seem to block the conversion from androgens (anti-inflammatory) to estrogens (proinflammatory) induced by aromatase. Therefore, the beneficial effects of restoring synovial androgens might be clinically more evident in male RA patients (as recently observed in ANTARES study) since they suffer more for the lack of androgens (anti-inflammatory) on account of the action of TNF-alpha on peripheral hormonal conversion. However, therapy (3 months) with anti-TNF did not change serum levels of typical sex hormones in patients with RA, although baseline values were largely different from controls. In patients with at least long-standing RA, this indicates that alterations of serum sex hormones and altered activity of respective converting enzymes are imprinted for a long-lasting period over at least 12 weeks.

Animals↗
PubMed2006

Effects of anti-TNF-alpha treatment on lipid profile in patients with active rheumatoid arthritis.

UNLABELLED: Cardiovascular morbidity and mortality appear to be increased in rheumatoid arthritis (RA), which might be due to increased prevalence of risk factors for cardiovascular disease, such as an accelerated progression of atherosclerosis. Patients with active RA frequently show an atherogenic lipid profile, which has been linked with the inflammatory reaction. Tumor necrosis factor-alpha (TNF-alpha), a pivotal proinflammatory cytokine implicated in the pathogenesis of atherosclerosis in RA, may be involved in the development of the altered lipid profile observed in active RA. Our aim was to investigate the effects of anti-TNF-alpha treatment in combination with methotrexate (MTX) and corticosteroid therapy on lipid profile in patients with active RA. In this prospective study 34 consecutive RA patients were included (all women, mean age 51.6 +/- 7.9 years, range 46-72 years) with active (defined as Disease Activity Index 28 joint score [DAS-28], of at least 3.2) and refractory RA, in stable treatment with MTX (7.5-10 mg/week) and prednisone (7.5-10 mg/day) for 3 months. All patients received TNF-alpha blockers (n = 16, etanercept 25 mg twice weekly; n = 14, infliximab 3 mg/kg on 0, 2, 6, and every 8 weeks thereafter; and finally, n = 4, adalimumab 40 mg every other week). Total cholesterol, high-density lipoprotein cholesterol (HDL cholesterol), triglycerides (TG) and lipoprotein (a) [Lp(a)] levels and the atherogenic index (ratio cholesterol/HDL cholesterol) were measured at base line, and at 16 and 24 weeks. Results were as follows: The DAS-28 was 6.9 +/- 2.1 at base line and decreased to 4.6 +/- 1.8 after 16 weeks, and further to 4.1 +/- 1.3 after 24 weeks (both, P < 0.01). Following anti-TNF-alpha treatment, the mean levels of total cholesterol were 168 +/- 24 mg/dL at base line and increased to 188 +/- 28 mg/dL at 16 weeks (P < 0.01), and 197 +/- 26 mg/dL at 24 weeks (P < 0.001). However, also the mean levels of HDL cholesterol were significantly higher than basal values after 16 and 24 weeks of treatment (34 +/- 12 mg/dL versus 36 +/- 18 mg/dL [P < 0.05] and 38 +/- 14 mg/dL [P < 0.01], respectively). TG and Lp(a) levels, as well as the atherogenic index were not significantly changed. Interestingly, variations in disease activity were significantly and inversely correlated with HDL cholesterol levels. IN CONCLUSION: Short anti-TNF-alpha treatment was associated with a significant increase of both total cholesterol and HDL cholesterol levels, and correlated with decreased disease activity. The atherogenic index showed no changes during the study. Therefore, anti-TNF-alpha treatment might affect lipid profile in RA patients.

Adrenal Cortex Hormones↗
PubMed2006

Bone metabolism changes during anti-TNF-alpha therapy in patients with active rheumatoid arthritis.

Osteoporosis (OP) occurs more frequently in patients with rheumatoid arthritis (RA) than in healthy individuals. Specific treatments of RA may increase susceptibility to OP, but at the same time decrease inflammatory activity, which is associated with accelerated bone loss. Treatment with TNF-alpha blockers might influence bone metabolism and prevent structural bone damage in RA, in particular at the periarticular level. Our aim was to assess the influence of anti-TNF-alpha therapy on bone metabolism in RA patients. To that end we evaluated a group of 30 RA patients [mean age 50.6 +/- 6.8 years; median disease duration 82 +/- 38 months; median disease activity score (DAS-28) 5.8 +/- 1.2: 70% of whom were positive for the rheumatoid factor IgM (>40 IU/mL)]. Patients were treated with stable therapy of prednisone (7.5 mg/day) and methotrexate (MTX = 10 mg/week). Eleven of these RA patients further received etanercept (25 mg, twice/weekly) and 10 infliximab (3 mg/kg on 0, 2, 6, and every 8 weeks thereafter). A control group included 10 RA patients with stable therapy (prednisone and MTX) and without anti-TNF-alpha therapy. All the patients fulfilled the ACR criteria for the diagnosis of adult RA and were treated for 6 months. Quantitative ultrasound (QUS) bone densitometry was performed at the metaphyses of the proximal phalanges of both hands with a DBM Sonic 1200 QUS device (IGEA, Carpi, Italy). Amplitude-dependent speed of sound (AD-SoS) was evaluated at base line and at 3 and 6 months. Bone mineral density (BMD) of the hip and lumbar spine (L1-L4) was determined by a densitometer (GE Lunar Prodigy, USA) at base line at after 6 months. Soluble bone turnover markers [osteocalcin (BGP) and deoxypyridinoline/creatinine (Dpd/Cr) ratio] were measured in all patients at the same times, using enzyme-linked immunosorbent assay tests. All data were compared using Wilcoxon signed rank test. Results were as follows: AD-SoS values were found increased by 1.3% after 6 months of treatment in the RA patients treated with anti-TNF-alpha therapy. On the contrary, the Ad-SoS levels decreased by 4.6% during the same period in the untreated RA group. BMD increased by 0.2% at lumbar spine and 0.1% at the hip in TNF-alpha-blocker-treated patients and decreased by 0.8% and 0.6% (at lumbar spine and at the hip, respectively) in RA patients without anti-TNF-alpha therapy. However, BMD variations were not significant. In RA patients treated with TNF-alpha blockers, BGP levels were found significantly increased (14.8 +/- 3.8 mg/mL vs. 22.4 +/- 4.2 mg/mL; P < 0.01) and Dpd/Cr levels were found significantly decreased (8.2 +/- 2.1 nM vs. 4.6 +/- 1.8 nM; P < 0.01) at 6 months when compared to base line values. On the contrary, there were no significant differences in the untreated RA patients concerning these latter parameters (BGP = 12.2 +/- 3.1 mg/mL vs. 10.8 +/- 2.8 mg/mL and Dpd/Cr = 8.9 +/- 2.4 nM vs. 10.2 +/- 1.8 nM, respectively). In conclusion, during 6 months of treatment of RA patients with TNF blockers, bone formation seems increased while bone resorption seems decreased. The reduced rate of OP appears to be supported by the same mechanisms involved in the decreased bone joint resorption during anti-TNF-alpha therapy, that is, the marked decrease of the proinflammatory (i.e., TNF-alpha) cytokine effects on bone metabolism.

Aged↗
PubMed2005

Sex hormone modulation of cell growth and apoptosis of the human monocytic/macrophage cell line.

Sex hormones seem to modulate the immune/inflammatory responses by different mechanisms in female and male rheumatoid arthritis patients. The effects of 17beta-oestradiol and of testosterone were tested on the cultured human monocytic/macrophage cell line (THP-1) activated with IFN-gamma in order to investigate their role in cell proliferation and apoptosis. Activated human THP-1 cells were cultured in the presence of 17beta-oestradiol and testosterone (final concentration, 10 nM). The evaluation of markers of cell proliferation included the NF-kappaB DNA-binding assay, the NF-kappaB inhibition complex, the proliferating cell nuclear antigen expression and the methyl-tetrazolium salt test. Apoptosis was detected by the annexin V-propidium assay and by the cleaved poly-ADP ribose polymerase expression. Specific methods included flow analysis cytometry scatter analysis, immunocytochemistry and western blot analysis. Cell growth inhibition and increased apoptosis were observed in testosterone-treated THP-1 cells. Increased poly-ADP ribose polymerase-cleaved expression and decreased proliferating cell nuclear antigen expression, as well as an increase of IkappaB-alpha and a decrease of the IkappaB-alpha phosphorylated form (ser 32), were found in testosterone-treated THP-1 cells. However, the NF-kappaB DNA binding was found increased in 17beta-oestradiol-treated THP-1 cells. The treatment with staurosporine (enhancer of apoptosis) induced decreased NF-kappaB DNA binding in all conditions, but particularly in testosterone-treated THP-1 cells. Treatment of THP-1 by sex hormones was found to influence cell proliferation and apoptosis. Androgens were found to increase the apoptosis, and oestrogens showed a protective trend on cell death--both acting as modulators of the NF-kappaB complex.

Apoptosis↗
PubMed2005

Capillaroscopy.

Raynaud's phenomenon (RP) is the most common and significant clinical condition with an indication for a microvascular analysis to be carried out as soon as possible. Microvascular involvement is a key feature of RP and several rheumatic diseases are characterised by the presence of RP. Nailfold capillary microscopy shows an impressive cost/effectiveness ratio: it is simple, non-invasive and inexpensive. Well recognised nailfold videocapillaroscopic patterns (NVC) have been described mainly in systemic sclerosis (SSc) patients with secondary RP. The peripheral microvascular damage in SSc is characterised by increasing structural alterations of the capillaries (giant capillaries and microhaemorrhagies) with a progressive decrease in their density. The detection of the scleroderma NVC pattern allows an early distinction between the primary RP (functional, not disease associated) and the secondary RP (disease associated). Other major NVC patterns have been described in the field of rheumatic diseases. Interestingly, correlations are evident between the NVC and the clinical symptoms, severity of the disease and the laboratory findings.

Clinical Trials as Topic↗
PubMed2005

Circadian rhythms and arthritis.

The clinical symptoms of rheumatoid arthritis (RA) show a circadian variation; joint stiffness and pain are more prominent in the early morning. An altered functioning of the hypothalamic-pituitary-adrenal axis (cortisol) and of the pineal gland (melatonin) seems to be important factors in the perpetuation and clinical circadian symptoms of RA. Consistently, human proinflammatory cytokine production exhibits a diurnal rhythmicity with peak levels during the night and early morning, at a time when plasma cortisol (anti-inflammatory) is lowest and melatonin (proinflammatory) is highest. Sex hormones also seem to be involved in circadian rhythms of RA symptoms. Increased pain intensity and sleep disturbances are observed during the luteal phase in patients who have RA, when estrogen (and progesterone) levels would be higher than in the follicular phase. The occurrence of circadian rhythms of the inflammatory reaction suggest important implications for scheduling activities of daily living, for measurements in clinical trials, and possibly for the time at which antirheumatic drugs--including corticosteroids and nonsteroidal anti-inflammatory drugs--are administered.

Arthritis, Rheumatoid↗
PubMed2005

Estrogens and arthritis.

Sex hormones seem to play an important role as modulators and perpetuators of rheumatic disorders with autoimmune involvement, such as rheumatoid arthritis or systemic lupus erythematosus. Estrogens are implicated in the immune response as enhancers of the humoral immunity. Sex hormones can exert local actions (paracrine) in the tissues in which they are formed; an accelerated peripheral metabolic conversion of upstream androgen precursors to estrogens has been well-assessed. Local effects of sex hormones in autoimmune rheumatic diseases seem to consist mainly of the modulation of cell proliferation and cytokine production. All of these data further suggest caution in exogenous estrogen administration in patients who have autoimmune diseases.

Arthritis, Rheumatoid↗