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Biomedical subjects

Maurizio Cutolo

Publications and source records attributed to Maurizio Cutolo.

At least 37 records · Page 2Linked to original sources
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↗
PubMed2005

Nocturnal hormones and clinical rhythms in rheumatoid arthritis.

It is well known that some clinical signs and symptoms of rheumatoid arthritis (RA) vary within a day and between days; the morning stiffness that is observed in patients who have RA has become one of the diagnostic criteria of the disease. The circadian changes in the metabolism or nocturnal secretion of endogenous corticosteroids is certainly responsible, in part, for the time-dependent changes that are observed in the inflammatory response and related clinical symptoms. More recently, melatonin (mLT), another circadian nocturnal hormone that is the secretory product of the pineal gland, has been implicated in time-dependent inflammatory reactions, with effects that are opposite of those of corticosteroids. Therefore, altered functioning of the hypothalamic-pituitary-adrenocortical axis (reduced corticosteroid production) and of the pineal gland (increased mLT production) found in RA patients seem to be important factors in the perpetuation and 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 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 mLT concentrations as well as some epidemiological features that are observed in northern European patients with RA versus southern European patients.

Arthritis, Rheumatoid↗
PubMed2005

Sex hormone concentrations in patients with rheumatoid arthritis are not normalized during 12 weeks of anti-tumor necrosis factor therapy.

OBJECTIVE: Androgens such as dehydroepiandrosterone sulfate (DHEAS) and testosterone are markedly lower in postmenopausal women with rheumatoid arthritis (RA) than in controls. In contrast, compared to controls, serum levels of estrogens are normal or elevated in women with RA. Since tumor necrosis factor (TNF) alters production of these hormones, we investigated changes of these hormones during anti-TNF antibody (anti-TNF) therapy with adalimumab in longstanding RA. METHODS: In this longitudinal anti-TNF therapy study in 13 patients with long-standing RA without prior prednisolone (7 infusions of anti-TNF: Week 0, 2, 4, 6, 8, 10, and 12), we measured serum concentrations of interleukin 6 (IL-6), androstenedione, DHEA, DHEAS, free testosterone, estrone, and 17ss-estradiol. Levels of these hormones in patients were compared to serum levels of 31 age and sex matched healthy controls. RESULTS: Upon treatment with anti-TNF, there was an impressive decrease of clinical markers of inflammation, erythrocyte sedimentation rate, and serum levels of IL-6. Serum levels of DHEAS and free testosterone were markedly lower at baseline in patients compared to controls, but this did not change during anti-TNF therapy. Serum levels of DHEA and 17ss-estradiol were significantly elevated in patients compared to controls, but similarly, anti-TNF therapy did not change initially increased levels. Molar ratios of hormones, which reflect hormone shifts via converting enzymes, showed typical alterations at baseline, but did not change markedly during anti-TNF therapy. CONCLUSION: Longterm therapy with anti-TNF did not change altered serum levels of typical sex hormones in patients with RA, although baseline values were largely different. In patients with RA, this indicates that alterations of sex hormones and altered activity of respective converting enzymes are imprinted for a long-lasting period over at least 12 weeks.

Adalimumab↗
PubMed2004

Pregnancy, cytokines, and disease activity in systemic lupus erythematosus.

OBJECTIVE: To evaluate levels of selected cytokines and soluble receptors involved in the humoral immune response during pregnancy in systemic lupus erythematosus (SLE) patients. METHODS: Seventeen consecutive SLE patients and 8 matched healthy controls were prospectively studied during pregnancy. Sera were obtained within the last 3 months prior to pregnancy; at 9, 17, and 29 weeks of pregnancy; and at 1 month after delivery. Serum levels of interleukin-10 (IL-10), interleukin-6 (IL-6), and soluble tumor necrosis factor receptors p55 (sTNFR I) and p75 (sTNFR II) were evaluated. SLE activity was measured by the European Consensus Lupus Activity Measurement score modified for pregnancy. RESULTS: IL-10 serum levels were found to be higher (P <0.0001) in patients than in controls before conception, and still higher (P <0.0001) in SLE patients during gestation, without intertrimester changes. In SLE patients, IL-6 serum levels did not increase in the third trimester of pregnancy, as was observed in controls (P=0.011). No significant differences between SLE patients and controls were found in either sTNFR I or II levels or profiles before and during pregnancy. IL-10 and sTNFR I levels were significantly higher during pregnancy and postpartum in SLE patients with active disease (P=0.03 and P=0.01, respectively). CONCLUSION: The levels of some cytokines involved in the humoral immune response seem to be modified in the peripheral circulation of pregnant SLE patients. The most relevant modifications are the lower than expected increase of IL-6 in the third trimester of gestation and persistently high levels of IL-10 during pregnancy.

Adult↗
PubMed2004

Synovial fluid estrogens in rheumatoid arthritis.

Experimental and clinical evidence suggest that immune reactivity is modulated by gender. Immune reactivity is greater in females than in males and lymphocytes and monocytes from female subjects shows higher antigen presenting activity and mitogenic responses. Steroid hormones can be converted along defined pathways to downstream hormones in the periphery. The conversion of dehydroepiandrosterone (DHEA) in target macrophages leads to an increase of downstream effector hormones (including estrogens), which may be an important factor for local immunomodulation at least in RA synovitis. The presence in the RA synovial fluids (SF) of an altered sex hormone balance resulting in lower immunosuppressive androgens and higher immunoenhancing estrogens, might determine a favorable condition for the development of the immuno-mediated RA synovitis and synovial hyperplasia. The increased estrogen concentration observed in RA SF of both sexes are characterized by the hydroxylated forms, in particular 16alpha-hydroxyestrone, that is a mitogenic and proliferative endogenous hormone. In contrast to 16alpha-hydroxylated estrogens, the 2-hydroxylated forms inhibit growth promoting effects of E2 and were found low in RA SF. Therefore, dose-related conversion to pro- or anti-inflammatory downstream metabolites of estrogens might support the dual role of estrogens (pro or anti-inflammatory) for example during estrogen replacement therapy, depending on local concentration (i.e. SF in RA) of 16alpha-hydroxyestrone or 2-hydroxyestrogens.

Arthritis, Rheumatoid↗
PubMed2003

Increased estrogen formation and estrogen to androgen ratio in the synovial fluid of patients with rheumatoid arthritis.

OBJECTIVE: It has been proposed that physiologic levels of estrogens stimulate immune responses whereas androgens suppress inflammatory reactions. Thus, prevalence of synovial androgens relative to estrogens would be favorable in rheumatoid arthritis (RA). We investigated synovial fluid (SF) concentrations of several estrogens and androgens and conversion products of the sex steroid precursor dehydroepiandrosterone (DHEA) in supernatants of mixed synoviocytes. METHODS: SF steroid concentrations were measured by high performance liquid chromotography and mass spectrometry in 12 patients with RA and 8 subjects with traumatic knee injury (noninflammatory controls). Conversion of DHEA to downstream hormones was measured by thin-layer chromatography and phosphorimaging detection in 3 patients with RA and 3 patients with osteoarthritis (OA). RESULTS: Overall, SF concentration of free estrogens tended to be higher in RA patients versus controls (p < 0.06). Molar ratio of free SF estrogens/free SF androgens was elevated in RA compared to controls (1.17 +/- 0.32 vs 0.29 +/- 0.08, without unit; p = 0.017). The free SF concentration of the precursor androstenedione was significantly higher in RA patients than in controls (104.6 +/- 32.6 vs 30.4 +/- 0.4 ng/ml; p = 0.011), and SF estrone the aromatase conversion product of androstenedione was also elevated in RA compared to controls (13.6 +/- 2.6 vs 6.6 +/- 0.8 ng/ml; p = 0.035). The biologically active estrogen derivatives, 16a-hydroxyestrone and 4-hydroxyestradiol, were both higher in RA compared to controls (p = 0.085 and p = 0.044, respectively). In mixed RA synoviocytes, DHEA conversion yielded high local levels of 17beta-estradiol (708 pmol/l = 0.193 ng/ml) compared to testosterone (88 pmol/l = 0.026 ng/ml). CONCLUSION: SF levels of estrogens relative to androgens are significantly elevated, while those of androgens are markedly reduced, in patients with RA compared to controls. This imbalance is most probably due to increased aromatase activity. Thus, an available steroid precursor, such as DHEA, may be rapidly converted to proinflammatory estrogens in the synovial tissue, which may in turn stimulate the inflammatory process in patients with RA.

Adjuvants, Immunologic↗
PubMed2002

[Rheumatoid arthritis - pathogenetic role of neuroendocrine axes and the peripheral nervous system].

BACKGROUND: Local innate and adaptive immune processes are of importance during the acute phase of rheumatoid arthritis (RA). In the advanced inflammatory phase alterations of systemic anti-inflammatory feedback mechanisms might be important features which may support chronic inflammation. ALTERATIONS: Similarly, like in other chronic inflammatory diseases, inadequately low cortisol and androgen serum levels can be detected in RA patients. In addition, there is a marked reduction of anti-inflammatory sympathetic nerve fibers in the inflamed joints paralleled by an enhanced number of pro-inflammatory sensory nerve fibers. Thus, an uncoupling of synergistically acting endocrine and neuronal, anti-inflammatory mechanisms (cortisol, dehydroepiandrosterone, androgens, sympathetic neurotransmitters) and a preponderance of pro-inflammatory mechanisms (estrogens, sensory neurotransmitters) may lead to chronic inflammatory disease. CONCLUSION: From this pathogenetic point of view new therapeutic strategies could be developed for the treatment of patients with RA.

Androgens↗
PubMed2002

Steroid hormones and disease activity during pregnancy in systemic lupus erythematosus.

OBJECTIVES: To analyze the variation of steroid hormone levels during pregnancy in patients with systemic lupus erythematosus (SLE). Moreover, to investigate whether, during gestation, there is any relationship between steroid concentration and SLE activity. METHODS: Seventeen consecutive pregnant SLE patients and 8 matched healthy pregnant controls were studied prospectively. Disease activity was evaluated by European Consensus Lupus Activity Measure (ECLAM) score modified for pregnancy. The following hormones were evaluated: testosterone, 17beta-estradiol (estradiol), cortisol, dehydroepiandrosterone sulfate (DHEAS), and progesterone. RESULTS: Disease activity score significantly varied during pregnancy and postpartum (P< 0.05), being decreased in the third trimester and increased in the second trimester and postpartum. Serum levels of all steroids varied significantly during pregnancy and the postpartum period both in patients and in healthy subjects. In SLE patients, estradiol, progesterone, and DHEAS concentrations were found to be significantly reduced compared with controls. Serum level profiles of estradiol and progesterone were different from those observed in controls. No differences in the steroid levels were observed between patients taking prednisone 5 mg/day, apart from cortisol, which was, as expected, lower in the latter group. CONCLUSIONS: The major hormonal alteration observed during pregnancy in SLE patients was an unexpected lack of estrogen serum level increase, and, to a lesser extent, progesterone serum level increase, during the second and-even more-the third trimester of gestation. This lack of increase probably was due to placental compromise. Therefore, these steroid hormone variations may result in a lower humoral immune response activation, probably related to a change in the estrogen/androgen balance, that in turn could account for the decrease in disease activity observed during the third trimester in pregnant SLE patients.

Adult↗
PubMed2002

Sex hormones and rheumatoid arthritis.

Sex hormones are implicated in the immune response, with estrogens as enhancers at least of the humoral immunity and androgens and progesterone as natural immune-suppressors. In male rheumatoid arthritis (RA) patients, androgen replacement seems to ameliorate the disease and supports their involvement in the pathophysiology of the disease. The combination of androgens with cyclosporin A or methotrexate has been found to potentiate the apoptosis of monocytic inflammatory cells as well as to reduce the cell growth at least in vitro. Considerable interest has been devoted in the last years as to whether the use of oral contraceptive pills (OCs) may have a protective effect on the risk of RA. The results of many controlled studies have been found contradictory. At the present time, no consensus has been achieved regarding OCs administration and its relationship to the prevention or development of RA. In addition, an association of estrogen receptor gene polymorphism with age at onset of RA has been observed and might further explain inter-individual clinical and therapeutical-response variations. Local increased estrogen concentrations and decreased androgen levels have been observed in RA synovial fluids and seem to play a more important role in the immune/inflammatory local response.

Androgens↗
PubMed2002

Assessment of safety and the immune response to the CD4 "internal antigen" mouse anti-idiotypic Mab 16D7 in four patients with SLE.

We have analyzed the immune response elicited with the human CD4 internal antigen anti-idiotypic monoclonal antibody 16D7 in four patients with active systemic lupus erythematosus and assessed the safety of the treatment. Patients I and 2 received three 2-mg 16D7 subcutaneous (SC) injections at 3-week intervals and mainly developed IgGI, whereas IgG1, IgG3, and IgG4 were detected in the sera of the other two patients (3 and 4) who received the same amount of 16D7 on days 0, 28, and 70. 16D7-F(ab')2 isotypic determinant-specific antibodies levels, evaluated by sera reactivity with the 16D7-isotype matched anti-idiotypic monoclonal antibody 14D6-F(ab')2, were low or undetectable in patient 1 and became detectable following the first and second boosters in patient 3 and patients 2 and 4, respectively. The highest level was seen in patients 3 and 4. The focusing pattern (spectrotype) of 16D7 idiotypic-specific antibodies suggested that multiple V genes are involved or many somatic mutations occur. Once established, each patient's spectrotype remained stable. Although spectrotype were individually distinct, all four patients produced CD4-specific antibodies, indicating that this response crosses the genetic barrier. Disease relapsed after 11 (patient 2), 40 (patients 3 and 4), and 125 (patient 1) weeks. The lack of side effects and the prolonged periods of disease control (33 and 103 weeks after the last booster) warrants an extension of this study.

Animals↗
PubMed2002

Acral localized acquired cutis laxa associated with rheumatoid arthritis.

We report the first case of the acral localization of the acquired form of cutis laxa associated with severe rheumatoid arthritis. The skin laxity was preceded by episodes of itching and swelling of the hands and feet. Histopathology showed that the elastic fibers were lost in the areas of cutis laxa and decreased in adjacent skin. The pathogenetic relationship with rheumatoid arthritis or the intake of related drugs is discussed.

Arthritis, Rheumatoid↗
PubMed2002

Anti-inflammatory cooperativity of corticosteroids and norepinephrine in rheumatoid arthritis synovial tissue in vivo and in vitro.

Corticosteroids (CS) and norepinephrine (NE) support each other's biological effects. Thus, deficiency of cortisol and reduced synovial sympathetic innervation (SSI) may be proinflammatory in rheumatoid arthritis (RA). This study tested the anti-inflammatory cooperativity of CS and NE in human RA synovial tissue. In an in vivo study, 32 patients with RA (with prior CS therapy/without SSI: n=7; without prior CS therapy/with SSI: 6; with prior CS therapy/with SSI: 19) were investigated for synovial inflammation. In an in vitro study with synoviocytes from RA and OA patients, the separate and combined effects of cortisol and NE were studied. In the in vivo study, patients with prior CS therapy/with SSI showed lower secretion of synovial IL-8 than the other groups, lower synovial density of T cells and macrophages, and lower overall inflammation. In the in vitro study, a cooperative suppressive effect of NE (10(-6) M to 10(-8) M) and cortisol (10(-6) M and 10(-7) M) on secretion of IL-8 and TNF from primary early culture mixed RA synoviocytes was observed. This cooperative effect was not observed in OA synoviocytes. In the same RA and OA patients, the cooperative effect was lost in 3rd passage synovial fibroblasts. This study demonstrates the cooperativity of cortisol and NE for inhibition of proinflammatory mediators produced in the synovial tissue of RA patients. These results underscore that coupling of an efficient secretion of systemic cortisol together with local production of NE is important in order to lower synovial inflammation.

Aged↗