Silvano Accardo

Bio: Silvano Accardo is an academic researcher from University of Genoa. The author has contributed to research in topics: Rheumatoid arthritis & Arthritis. The author has an hindex of 22, co-authored 61 publications receiving 2559 citations. Previous affiliations of Silvano Accardo include University of Turin.

Nailfold videocapillaroscopy assessment of microvascular damage in systemic sclerosis.

Abstract: Objective. To correlate microvascular abnormalities, evaluated by nailfold videocapillaroscopy (NVC), with the duration of both Raynaud's phenomenon (RP) and systemic sclerosis (SSc) from the date of diagnosis, in a large number of patients with SSc. Methods. Ninety-seven consecutive patients were recruited and distributed into 3 groups on the basis of the morphological NVC patterns observed: early (E), active (A), and late (L). In each group the age of patients, age at onset, and the duration of RP as well as of overt SSc were investigated and correlated with the different NVC pattern variables. Results. The early appearance of giant capillaries and hemorrhages (E pattern) is of great relevance for the early diagnosis of SSc. Therefore, these alterations are more evident in the active phase of the disease (A pattern). Conversely, the NVC observation of loss of capillaries and vascular architectural disorganization and the presence of ramified/bushy capillaries (L pattern) represents the clearest aspect of advanced SSc microvascular damage. These morphological alterations were found to correlate significantly with the duration of both RP and SSc, as well as with age of patients (p = 0.0001). No significant differences were observed when the variables were analyzed in the patients classified as having limited cutaneous SSc or diffuse cutaneous SSc. Conclusion. Classification of defined major nailfold patterns may be useful in assessing the appearance and progression of sclerodermic microangiopathy. As well, nailfold changes might represent a morphological reproduction of the evolution of SSc.

Estrogens, the immune response and autoimmunity

Abstract: 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 (ie 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

Androgen replacement therapy in male patients with rheumatoid arthritis.

Abstract: A hypogonadic condition characterized by low serum testosterone levels has been identified in male patients with rheumatoid arthritis (RA). Seven men with active RA were treated daily for 6 months with oral testosterone undecanoate plus a nonsteroidal antiinflammatory drug in an attempt to evaluate the immunologic response, the overall clinical response, and the sex hormone response to such replacement therapy. At the end of the 6 months, there was a significant increase in serum testosterone levels (P less than 0.05), an increase in the number of CD8+ T cells, and a decrease in the CD4+:CD8+ T cell ratio. The IgM rheumatoid factor concentration decreased significantly (P less than 0.05). There was a concurrent significant reduction in the number of affected joints (P less than 0.05) and in the daily intake of nonsteroidal antiinflammatory drugs (P less than 0.01). The well-known immunosuppressive action of androgens probably contributed to our findings in these RA patients.

Hypothalamic-pituitary-adrenocortical axis function in premenopausal women with rheumatoid arthritis not treated with glucocorticoids.

Abstract: Objective. To assess hypothalamic-pituitary-adrenocortical axis function in patients with rheumatoid arthritis (RA) not previously treated with glucocorticoids in relation to their inflammatory condition and in comparison to healthy controls. Methods. We evaluated, in 10 premenopausal patients with RA and 7 age matched controls, plasma dehydroepiandrosterone (DHEA), its sulfate (DHEAS), and cortisol concentrations, together with inflammatory cytokine levels [interleukin 6 (IL-6) and IL-12], both in basal conditions and after stimulation with ovine corticotropin releasing hormone (oCRH) and with low dose intravenous (5 μg) adrenocorticotropic hormone (ACTH). Results. DHEA and DHEAS basal concentrations were found to be significantly lower (p < 0.05) in premenopausal patients with RA than in controls. As expected, significantly higher basal levels of IL-6 and IL-12 (p < 0.05) were found in patients with RA. After the low dose ACTH testing, the DHEA area under the curve value was found to be significantly lower (p < 0.01) in patients than controls. Similar results, but without statistical significance, were observed after oCRH stimulation. DHEA levels at basal time showed a significant negative correlation with the erythrocyte sedimentation rate and platelet count, as well as with the Steinbrocker class of the disease (p < 0.05). Normal plasma cortisol levels during oCRH and ACTH testing were found in patients with RA in spite of their inflammatory condition. After ACTH testing. IL-6 levels decreased significantly (p < 0.05), whereas IL-12 levels were unchanged. No significant changes in IL-6 and IL-12 levels were found after oCRH testing. Conclusion. The abnormal androgen concentrations observed during testing in patients with RA might support the implication of adrenal androgens in the immune/inflammatory cytokine mediated mechanisms involved in the pathophysiology and clinical aspects of RA.

Sex hormone status of male patients with rheumatoid arthritis: evidence of low serum concentrations of testosterone at baseline and after human chorionic gonadotropin stimulation.

Abstract: Serum concentrations of luteinizing hormone, follicle-stimulating hormone, prolactin, 17 beta-estradiol, testosterone, androstenedione, dehydrotestosterone, dehydroepiandrosterone sulfate, and cortisol were examined in 14 men with rheumatoid arthritis (RA) and in age-matched osteoarthritis controls. Hypophyseal, adrenal, and testicular responses to stimulation with luteinizing hormone-releasing hormone, adrenocorticotropin, and human chorionic gonadotropin, respectively, were evaluated in 8 RA patients and in 8 age-matched healthy volunteers. Basal serum testosterone concentrations were significantly lower in male RA patients than in the osteoarthritis control subjects (P less than 0.01). After human chorionic gonadotropin stimulation, serum concentrations of testosterone were also lower in the RA patients than in normal healthy controls (P less than 0.05). These findings suggest that diminished testicular steroid biosynthesis might contribute to the serum testosterone deficiency observed in male RA patients.

Principal components analysis corrects for stratification in genome-wide association studies

Abstract: Population stratification—allele frequency differences between cases and controls due to systematic ancestry differences—can cause spurious associations in disease studies. We describe a method that enables explicit detection and correction of population stratification on a genome-wide scale. Our method uses principal components analysis to explicitly model ancestry differences between cases and controls. The resulting correction is specific to a candidate marker’s variation in frequency across ancestral populations, minimizing spurious associations while maximizing power to detect true associations. Our simple, efficient approach can easily be applied to disease studies with hundreds of thousands of markers. Population stratification—allele frequency differences between cases and controls due to systematic ancestry differences—can cause spurious associations in disease studies 1‐8 . Because the effects of stratification vary in proportion to the number of samples 9 , stratification will be an increasing problem in the large-scale association studies of the future, which will analyze thousands of samples in an effort to detect common genetic variants of weak effect. The two prevailing methods for dealing with stratification are genomic control and structured association 9‐14 . Although genomic control and structured association have proven useful in a variety of contexts, they have limitations. Genomic control corrects for stratification by adjusting association statistics at each marker by a uniform overall inflation factor. However, some markers differ in their allele frequencies across ancestral populations more than others. Thus, the uniform adjustment applied by genomic control may be insufficient at markers having unusually strong differentiation across ancestral populations and may be superfluous at markers devoid of such differentiation, leading to a loss in power. Structured association uses a program such as STRUCTURE 15 to assign the samples to discrete subpopulation clusters and then aggregates evidence of association within each cluster. If fractional membership in more than one cluster is allowed, the method cannot currently be applied to genome-wide association studies because of its intensive computational cost on large data sets. Furthermore, assignments of individuals to clusters are highly sensitive to the number of clusters, which is not well defined 14,16 .

Free Radicals in the Physiological Control of Cell Function

Abstract: At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

The complex role of estrogens in inflammation

Abstract: There is still an unresolved paradox with respect to the immunomodulating role of estrogens. On one side, we recognize inhibition of bone resorption and suppression of inflammation in several animal models of chronic inflammatory diseases. On the other hand, we realize the immunosupportive role of estrogens in trauma/sepsis and the proinflammatory effects in some chronic autoimmune diseases in humans. This review examines possible causes for this paradox. This review delineates how the effects of estrogens are dependent on criteria such as: 1) the immune stimulus (foreign antigens or autoantigens) and subsequent antigen-specific immune responses (e.g., T cell inhibited by estrogens vs. activation of B cell); 2) the cell types involved during different phases of the disease; 3) the target organ with its specific microenvironment; 4) timing of 17beta-estradiol administration in relation to the disease course (and the reproductive status of a woman); 5) the concentration of estrogens; 6) the variability in expression of estrogen receptor alpha and beta depending on the microenvironment and the cell type; and 7) intracellular metabolism of estrogens leading to important biologically active metabolites with quite different anti- and proinflammatory function. Also mentioned are systemic supersystems such as the hypothalamic-pituitary-adrenal axis, the sensory nervous system, and the sympathetic nervous system and how they are influenced by estrogens. This review reinforces the concept that estrogens have antiinflammatory but also proinflammatory roles depending on above-mentioned criteria. It also explains that a uniform concept as to the action of estrogens cannot be found for all inflammatory diseases due to the enormous variable responses of immune and repair systems.

Epidemiology and genetics of rheumatoid arthritis.

Abstract: The prevalence of rheumatoid arthritis (RA) is relatively constant in many populations, at 0.5–1.0%. However, a high prevalence of RA has been reported in the Pima Indians (5.3%) and in the Chippewa Indians (6.8%). In contrast, low occurrences have been reported in populations from China and Japan. These data support a genetic role in disease risk. Studies have so far shown that the familial recurrence risk in RA is small compared with other autoimmune diseases. The main genetic risk factor of RA is the HLA DRB1 alleles, and this has consistently been shown in many populations throughout the world. The strongest susceptibility factor so far has been the HLA DRB1*0404 allele. Tumour necrosis factor alleles have also been linked with RA. However, it is estimated that these genes can explain only 50% of the genetic effect. A number of other non-MHC genes have thus been investigated and linked with RA (e.g. corticotrophin releasing hormone, oestrogen synthase, IFN-γ and other cytokines). Environmental factors have also been studied in relation to RA. Female sex hormones may play a protective role in RA; for example, the use of the oral contraceptive pill and pregnancy are both associated with a decreased risk. However, the postpartum period has been highlighted as a risk period for the development of RA. Furthermore, breastfeeding after a first pregnancy poses the greatest risk. Exposure to infection may act as a trigger for RA, and a number of agents have been implicated (e.g. Epstein–Barr virus, parvovirus and some bacteria such as Proteus and Mycoplasma). However, the epidemiological data so far are inconclusive. There has recently been renewed interest in the link between cigarette smoking and RA, and the data presented so far are consistent with and suggestive of an increased risk.

Neuroendocrine Regulation of Immunity

Abstract: A reciprocal regulation exists between the central nervous and immune systems through which the CNS signals the immune system via hormonal and neuronal pathways and the immune system signals the CNS through cytokines. The primary hormonal pathway by which the CNS regulates the immune system is the hypothalamic-pituitary-adrenal axis, through the hormones of the neuroendocrine stress response. The sympathetic nervous system regulates the function of the immune system primarily via adrenergic neurotransmitters released through neuronal routes. Neuroendocrine regulation of immune function is essential for survival during stress or infection and to modulate immune responses in inflammatory disease. Glucocorticoids are the main effector end point of this neuroendocrine system and, through the glucocorticoid receptor, have multiple effects on immune cells and molecules. This review focuses on the regulation of the immune response via the neuroendocrine system. Particular details are presented on the effects of interruptions of this regulatory loop at multiple levels in predisposition and expression of immune diseases and on mechanisms of glucocorticoid effects on immune cells and molecules.