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Biomedical subjects

G Ferraccioli

Publications and source records attributed to G Ferraccioli.

At least 19 recordsLinked to original sources
PubMed2000

Gastric mucosa as an additional extrahepatic localization of hepatitis C virus: viral detection in gastric low-grade lymphoma associated with autoimmune disease and in chronic gastritis.

The hepatitis C virus (HCV) has been linked to B-cell lymphoproliferation and autoimmunity, and has been localized in several tissues. The clinical observation of an HCV-infected patient with Sjögren's syndrome (SS) and Helicobacter pylori (HP) positive gastric low-grade B-cell non-Hodgkin's lymphoma (NHL), which did not regress after HP eradication, led us to investigate the possible localization of HVC in the gastric microenvironment. HCV genome and antigens were searched in gastric biopsy specimens from the previously mentioned case, as well as from 9 additional HCV-infected patients (8 with chronic gastritis and 1 with gastric low-grade B-cell NHL). HCV-specific polymerase chain reaction (PCR) and immunohistochemistry procedures were used. The gastric B-cell NHL from the patient with SS was characterized by molecular analyses of B-cell clonality. HCV RNA was detected in both the gastric low-grade B-cell NHL and in 3 out of 6 gastric samples from the remaining cases. HCV antigens were detected in the residual glandular cells within the gastric B-cell NHL lesions, in glandular cells from 2 of the 3 additional gastric lesions that were HCV positive by PCR, and in 1 additional chronic gastritis sample in which HCV-RNA studies could not be performed. By molecular analyses, of immunoglobulin genes, the B-cell NHL from the patient with SS was confirmed to be a primary gastric lymphoma, subjected to ongoing antigenic stimulation and showing a significant similarity with rheumatoid factor (RF) and anti-HCV- antibody sequences. Our results show that HCV can localize in the gastric mucosa.

Aged↗
PubMed1999

T cell receptor repertoire in B cell lymphoproliferative lesions in primary Sjögren's syndrome.

OBJECTIVE: Studies have analyzed T cell receptor (TCR)-Vbeta in benign, minor salivary or lacrimal gland, or kidney lesions in Sjögren's syndrome (SS). We investigated SS related lymphoproliferative lesions. METHODS: By "family" reverse transcriptase polymerase chain reaction, we studied the expression of 20 different TCR-Vbeta families in parotid lymphoproliferative lesions and peripheral blood lymphocytes (PBL) from 7 patients with primary SS, in PBL from 6 primary SS patients with no associated lymphoproliferative disorder, and in activated PBL from 2 healthy controls. T cell clonal expansion was investigated in 10 Vbeta families (i.e., the most expanded ones and those previously implicated in SS pathogenesis) by single strand conformation polymorphism (SSCP) analysis. Frozen sections from parotid gland specimens were tested by immunohistochemistry for the expansion of selected Vbeta families. Viral infection within the parotid lesions and serum autoantibody response were also studied. RESULTS: An unrestricted Vbeta pattern was observed. The most widely expressed Vbeta family in parotid lesions was Vbeta2, and Vbeta immunohistochemistry results were concordant with Vbeta mRNA findings. A similar pattern was observed in PBL, although the Vbeta2 family was expressed at lower levels. The parotid/PBL ratio was occasionally > 1.8-2.0 (indicative of local Vbeta overexpression) in different Vbeta families. T cell expansion proved to be largely polyclonal by SSCP analysis, and scattered T cell clonotypes were detected within different Vbeta families, with a different pattern from patient to patient. CONCLUSION: Our observations in SS related lymphoproliferative lesions largely reflect previous evidence in fully benign lesions. The pathogenetic events involved in autoimmune benign lesions in SS may then persist and play a role in SS related lymphoproliferative disorders. The link between the observed TCR-Vbeta repertoire and specific local triggering (auto)antigens remains to be elucidated.

Adult↗
PubMed1998

Circulating levels of interleukin 10 and other cytokines in rheumatoid arthritis treated with cyclosporin A or combination therapy.

OBJECTIVE: To assess longitudinally over a 12 month period circulating serum levels of interleukin 10 (IL-10) and cytokines IL-3, IL-4, IL-6, and IL-12 in a cohort of patients with early onset rheumatoid arthritis (RA) treated with either cyclosporin A (CyA) or with combination therapy of CyA plus hydroxychloroquine as disease modifying antirheumatic drugs. METHODS: We studied 8 patients receiving CyA and 12 patients receiving CyA plus hydroxychloroquine. IL-3, IL-4, IL-6, IL-10, and IL-12 were determined by ELISA at entry, after 2 weeks, after one month, after 6 months, and after 12 months. Rheumatoid factor levels and the possible appearance of monoclonal gammopathies over time were studied by immunofixation and immunoblotting techniques. RESULTS: The pooled data show that at entry only the median baseline levels of IL-10 (3.9 vs 1.6 pg/ml; p < 0.01) and IL-6 (16.9 vs 1.4 pg/ml, p < 0.001) were higher in patients than in controls. IL-4 was not detectable. Some patients at entry (those with the longest disease duration) had detectable levels of IL-3. Only levels of IL-10 decreased significantly between entry and final values, in monotherapy and combination therapy as well. A single transient monoclonal band was observed after 6 months of treatment, which disappeared afterwards. No difference was seen in any of the cytokines between the CyA and the CyA plus hydroxychloroquine treated patients. CONCLUSION: During treatment with either CyA or CyA plus hydroxychloroquine, IL-10 levels decreased significantly. No additive effect of the 2 drugs was detected.

Adolescent↗
PubMed1997

Characterization of prelymphomatous stages of B cell lymphoproliferation in Sjögren's syndrome.

OBJECTIVE: To determine whether the prelymphomatous stages of B cell lymphoproliferation in Sjögren's syndrome (SS) may be better characterized by the integration of clinical, pathologic, and molecular data, the latter focusing on the expansion, persistence, and dissemination of clonal B cells in the course of the disease. METHODS: Multiple tissue lesions (synchronous from different tissues and metachronous from the same tissue) were evaluated in biopsy specimens obtained from 6 consecutive patients with SS who had an associated lymphoproliferative disorder. Fully benign gastric lesions were evaluated in tissue from an additional 11 patients with SS who had no associated lymphoproliferative disorder. Multiple and complementary molecular analyses of B cell clonality were used: Southern blot, polymerase chain reaction, single-strand conformation polymorphism, DNA sequencing, and hybridization with clonospecific oligoprobes. All the patients were then strictly followed up for the appearance of lymphoma. RESULTS: Different scenarios of SS-associated B cell lymphoproliferation were identified: 1) the ongoing expansion of the same dominant clone, localized or disseminated, in tissue from 2 patients, 1 of whom later developed an overt B cell lymphoma; 2) different dominant clones in different synchronous or metachronous tissues from the remaining 4 patients with an associated lymphoproliferative disorder; and 3) small oligoclonal expansions in 7 of the 11 benign gastric lymphoid infiltrates. CONCLUSION: Prelymphomatous B cell lymphoproliferation in SS was better characterized following integration of the findings. The different types of B cell clonal expansion (oligoclonal or monoclonal, smaller or larger in size, fluctuating or established, localized or disseminated) may imply a different risk of lymphoma progression. An accurate clinical, histopathologic, and molecular characterization may therefore be crucial in future studies aimed at clarifying the pathobiology of SS-associated lymphoproliferation.

Adult↗
PubMed1997

B-cell lymphomagenesis and human autoimmune models.

The concept that B-cell lymphomagenesis represents a multistep process is widely accepted. Pathogenetic events should be better defined both in early and late stages of lymphoproliferation. In the past few years, novel study approaches have been focused on understanding the mechanisms of lymphomagenesis. In particular, immune stimulation by infectious agents or autoantigens, T-cell help, altered immunocompetence, and local cytokine networks seem to be crucial in favouring B-cell expansions. In turn, actively proliferating B cells are at higher risk of undergoing genetic alterations that make the clone capable of fully autonomous growth, i.e., fully neoplastic. Peculiar human autoimmune diseases predisposing to B-cell lymphoma represent relevant models to characterize and dissect the temporal sequence of the different lyphomagenetic events. The present review, particularly, focuses on Sjoegren's syndrome, and on recent findings regarding the putative role of hepatitis C virus in B-cell lymphoproliferation. The biologic and clinical implications may be of major relevance for other B-cell disorders characterized by higher prevalence and morbidity.

Journal Article↗
PubMed1996

Slow progression of joint damage in early rheumatoid arthritis treated with cyclosporin A.

OBJECTIVE: To evaluate the ability of low-dose cyclosporin A (CsA) to control radiologic disease progression, and to assess the clinical efficacy and tolerability of CsA, compared with conventional disease-modifying antirheumatic drugs (DMARDs), in patients with early active rheumatoid arthritis (RA). METHODS: In this long-term, multicenter, prospective, open, blinded end point, randomized trial, 361 consenting patients with early (<4 years since diagnosis) active RA were enrolled. Of the eligible patients, 167 were treated with CsA at 3 mg/kg/day, and 173 with DMARDs. The decision to use conventional antirheumatic drugs as controls was based on the fact that joint erosion could be expected to occur after 1 year regardless of the type of DMARD being used. The possibility of switching therapies in both groups was intended to keep the largest possible number of patients in the study. RESULTS: Blinded evaluation of hand and foot radiographs after 12 months of treatment showed that CsA led to a significant (P < 0.001) delay in the mean +/- SD progression in the eroded joint count (1.3 +/- 3.1 versus 2.4 +/- 3.0 for the control group) and in the joint damage score (3.6 +/- 8.9 versus 6.9 +/- 9.1 for the control group), both measured by the Larsen-Dale method. When only the patients without erosion at baseline were considered (37 in the CsA-treated group and 54 in the control group), erosion appeared in only 10.8% of the CsA-treated patients, but in 51.8% of the controls (P = 0.00005). Low-dose CsA was as effective as traditional DMARDs in controlling clinical symptoms. Maintenance on the initially prescribed treatment regimen ("survival on treatment") was also better at 12 months with CsA than with DMARDs (89.2% versus 77.5%; P = 0.002). The tolerability of CsA was acceptable. CONCLUSION: These 12-month results suggest that low-dose CsA decreases the rate of further joint damage in previously involved joints as well as the rate of new joint involvement in previously uninvolved joints, in patients with early RA.

Adult↗
PubMed1996

Widespread clonal B-cell disorder in Sjögren's syndrome predisposing to Helicobacter pylori-related gastric lymphoma.

Helicobacter pylori has been identified as a critical antigenic stimulus to the development of gastric lymphoma, but additional factors should be required for such evolution. This topic is now of major importance to clarify the pathobiology of gastric lymphomagenesis. Peculiar autoimmune diseases, such as Sjögren's syndrome, are well known to predispose to B-cell lymphomas. We report on a patient with Sjögren's syndrome and a widespread B-cell lymphoproliferative disorder. A pathological picture of low-grade lymphoma was observed in the stomach, concomitantly with H. pylori infection. However, the B-cell disorder was definitely nonmalignant in the other tissues involved, i.e., the parotid gland and lymph nodes, which are the characteristic targets of Sjögren's syndrome-associated lymphoproliferation. After H. pylori eradication, a dramatic regression of gastric lymphoma into chronic gastritis was observed, but no amelioration occurred in the parotid and nodal involvement. Multiple molecular analyses showed the expansion of the same B-cell clone in synchronous and metachronous lymph node, parotid, and gastric lesions before and after H. pylori eradication. Thus, H. pylori played a crucial role in the local boosting of B-cell lymphoproliferation, but the underlying B-cell disorder was that associated with the autoimmune disease and was nonmalignant. The comprehensive clinical, pathological, and molecular approach allowed us to then distinguish the role of peculiar individual predisposing factors and of local infection in the pathobiology of mucosa-associated lymphoid tissue-associated lymphoproliferation.

Aged↗
PubMed1996

Methotrexate in polymyalgia rheumatica: preliminary results of an open, randomized study.

OBJECTIVE: Steroids are the only treatment of polymyalgia rheumatica (PMR). We report the effects of methotrexate (MTX) plus prednisone versus prednisone alone in PMR. METHODS: Twenty-four patients with recent onset PMR were studied in a randomized prospective study lasting one year. Patients were given MTX (MTX arm) 10 mg intramuscularly plus prednisone every week, or prednisone alone (Pred arm). After 6 months an attempt was made to stop prednisone, and to use the lowest possible dose over the next 6 months. RESULTS: At the 12th month, all patients were in clinical remission, acute phase reactants were in the normal range in both arms of the study, 6 patients were no longer taking steroids in the MTX arm versus 0/12 in the Pred arm, and the amount of prednisone in the 2 groups was statistically different (1.84 versus 3.2 g; p < 0.0001). In addition, bone mineral density was significantly decreased in the Pred arm, but not in the MTX arm. CONCLUSION: The MTX regimen allowed the use of much less prednisone over one year to obtain full control of PMR with no loss of efficacy. It also allowed sparing of bone in elderly patients at increased risk of osteoporotic fractures.

Aged↗
PubMed1996

Increase of bone mineral density and anabolic variables in patients with rheumatoid arthritis resistant to methotrexate after cyclosporin A therapy.

OBJECTIVE: To determine the bone mineral density (BMD) and anabolic variables in a cohort of patients with severe, early rheumatoid arthritis (RA) resistant to weekly doses of methotrexate (MTX), after addition of cyclosporin A (CyA) therapy. METHODS: We studied 10 rheumatoid factor positive patients of 58 with early erosive, aggressive RA with poor response to a 6 month course of MTX (< 20% improvement in the American College of Rheumatology core set of criteria). BMD was assessed at entry, after 6 months of MTX, and after a further 6 months of combination therapy of MTX plus CyA. Bone Gla protein (BGP) dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor-1 (IGF-1, somatomedin C) levels were determined along with clinical variables and acute phase reactants (C-reactive protein, erythrocyte sedimentation rate). RESULTS: An average BMD decline of 4.05 +/- 0.8% (mean, SD) occurred in the first 6 months of MTX treatment, along with a statistically significant decline of IGF-1 (-24.8%), DHEAS (-21.6%), and BGP (-19.7%) levels. After adding CyA 3 mg/kg daily for 6 months, BMD had increased by 3.9 +/- 0.97%, IGF-1 by 42.4%, DHEAS by 34.2%, BGP by +34.3%. These changes mirrored the clinical variables (Health Assessment Questionnaire, morning stiffness, joint count) and acute phase reactants, which improved in a statistically significant manner. CONCLUSION: Patients with active RA, even in the early phases, lose bone very rapidly. Effective control of systemic inflammation allowed a rapid rescue of BMD, at least in the short term. This happened with a simultaneous increase in some anabolic variables such as IGF-1, BGP, and DHEAS.

Acute-Phase Proteins↗
PubMed1995

Hepatitis C virus within a malignant lymphoma lesion in the course of type II mixed cryoglobulinemia.

Hepatitis C virus (HCV) has been implicated as the major etiologic factor sustaining B-cell clonal expansion in type II mixed cryoglobulinemia (MC). A putative pathogenetic role of HCV in the development of MC-associated B-cell malignancies has also been speculated. We report for the first time the localization of HCV within a parotid non-Hodgkin's lymphoma (NHL) lesion in the course of HCV-related type II essential MC, an important step to implicate any infectious agent in the lymphomagenesis. Plus and minus strand HCV RNA was first demonstrated by polymerase chain reaction on the whole RNA from the lesion. Further immunohistochemical studies localized HCV c22 proteins in the residual ductal or acinar parotid structures, which also abnormally expressed HLA-DR antigens. Weak c22 signals were inconstantly detected in cells strictly confined around the residual epithelium, while all the remaining infiltrating cells in the parotid lesion stained c-22-negative. Staining for c33 and c100 HCV antigens was negative. In situ hybridization (ISH) studies again identified the residual parotid epithelial cells as the site of HCV infection and replication in the NHL lesion. Sialotropic viruses previously involved in lymphoproliferation, ie, Epstein-Barr virus and human herpesvirus-6, were absent in the same tissue lesion. According to the current models of B-cell lymphomagenesis, a role of HCV as an exogenous antigenic stimulus should be considered for NHL development in the present case, whereas malignant B cells do not appear permissive of active HCV replication. Further efforts would be worthwhile to clarify a role of HCV infection in the development of some B-cell malignancies.

Aged↗
PubMed1995

Cyclosporin A increases somatomedin C insulin-like growth factor I levels in chronic rheumatic diseases.

OBJECTIVE: To determine whether anabolic hormones that affect the musculoskeletal system and active on the immune cells changed during cyclosporin A (CysA) therapy. METHODS: We carried out a randomized study of patients with rheumatic disease attending the outpatient clinic for rheumatic diseases. Twenty-four patients with chronic arthritis [20 with rheumatoid arthritis (RA) and 4 with psoriatic arthritis (PsA)] were divided into 2 groups (10 RA, 2 PsA) and randomly given CysA 5 mg/kg daily or hydroxychloroquine (OH-Chlor) 6 mg/kg daily in divided doses. RESULTS: A significant increase of insulin-like growth factor I (IGF-I) (somatomedin C) levels and of bone Gla protein was shown after 2 months in the CysA treated group, but not in the OH-Chlor group. A statistically significant correlation was observed between changes of IGF-I levels and of dehydroepiandrosterone sulphate (DHEAS). This finding was confirmed in a further series of 39 patients. No changes were seen in 25 OH-D, 1-25(OH)2-D3 or parathyroid hormone after CysA. CONCLUSION: The effects of CysA on IGF-I may explain some of the clinical, immunologic, and metabolic results during CysA treatment of rheumatic diseases.

Arthritis, Psoriatic↗
PubMed1995

Local cytokine expression in the progression toward B cell malignancy in Sjögren's syndrome.

OBJECTIVE: Sjögren's syndrome (SS) has been indicated as an ideal human model to investigate B cell lymphomagenesis. Our aim was to investigate similarities or differences in cytokine expression in both prelymphomatous and frank B cell lymphomatous SS lesions, as well as in SS related lesions versus SS unrelated malignant B cell non-Hodgkin's lymphomas. METHODS: The mRNA expression of interleukin (IL)-1 beta, IL-2, IL-3, IL-4, IL-6, IL-6R, IL-9, IL-10, IL-12, tumor necrosis factor alpha (TNF-alpha), interferon gamma (IFN-gamma), and transforming growth factor beta (TGF-beta) was analyzed by a sensitive reverse transcriptase polymerase chain reaction technique in 10 SS tissue samples from 10 consecutive patients [7 nonmalignant parotid myoepithelial sialadenitis (MESA) lesions with evidence of B cell clonal expansion, and 3 B cell non-Hodgkin's lymphomas] as well as a series of 11 SS unrelated B cell non-Hodgkin's lymphomas. RESULTS: IL-1, IL-2, IL-3, IL-6, IL-6R, IL-10, IL-12, IFN-gamma, TNF-alpha, and TGF-beta mRNA was expressed in all or in the vast majority of the samples analyzed. IL-4 mRNA was detected in 2/3 SS related and in 3/11 SS unrelated non-Hodgkin's lymphomas, while SS related MESA samples were characterized by an IL-4 negative pattern and lacked IL-3 or IFN-gamma expression in 3/7 cases and in 2/7 cases, respectively. CONCLUSION: Many cytokines may be involved in the evolution of prelymphomatous to definite B cell malignant lesions in SS, as well as in the development of SS unrelated B cell non-Hodgkin's lymphomas. A putative pathobiological role of the IL-12/IL-4 balance, in the presence of cytokines that may sustain B cell proliferation (i.e., IL-3, IL-6, IL-10), may represent a major point for future research. Finally, our data reinforce the view of SS as a human model of B cell lymphomagenesis.

Adult↗
PubMed1994

Mild sialoadenitis: a common finding in patients with hepatitis C virus infection.

BACKGROUND: Sjögren's syndrome (SS) is an autoimmune disease of presumed viral origin; sialoadenitis has been reported to occur in hepatitis C virus (HCV) infection. METHODS: Lip biopsy specimens were graded in 32 consecutive patients with either HCV-related chronic liver disease or SS. RESULTS: Seventeen of 22 HCV-positive patients had sialoadenitis, although generally mild (15 of 17, grades I-II). Severe inflammation (grades III-IV) was observed in 8 of 10 patients with SS (chi-square = 12.6; P < 0.0005). Moreover, HCV-positive patients with sialoadenitis differed from patients with SS in female sex prevalence (6 of 17 versus 10 of 10; chi-square = 10.9; P = 0.0001) and presence of serum antinuclear autoantibodies (0 of 17 versus 9 of 10; chi-square = 23.0; P < 0.0001). Five of 13 HCV-positive patients and 7 of 8 patients with SS were HLA-DR3-positive (chi-square = 4.9; P < 0.05). CONCLUSIONS: Sialoadenitis of HCV-related liver disease is common but differs from SS with regard to predisposing genetic factors, expression of autoimmune markers, and histopathologic severity.

Adult↗
PubMed1994

Progression of erosion and joint space narrowing scores in rheumatoid arthritis assessed by nonlinear models.

OBJECTIVE: To determine whether the first order kinetics model or the function proportional to the square root of disease duration better represents the progression of radiographic damage according to the disease duration than a linear model in rheumatoid patients. METHODS: Two hundred twenty-eight patients assessed at a single time point were studied by using 2 nonlinear models of radiographic damage. In 44 patients a second radiographic analysis was taken within a 3-year period. RESULTS: In this data set, both models reveal the highest rate of progression in the first 3 years of the disease. The square root of the disease duration seems to better depict the whole disease course. CONCLUSION: Nonlinear models should be compulsory in the assessment of radiographic damage, especially when slow acting antirheumatic drug effects after 5 years of disease duration are studied.

Adolescent↗
PubMed1994

Somatomedin C (insulin-like growth factor 1) levels decrease during acute changes of stress related hormones. Relevance for fibromyalgia.

OBJECTIVE: To determine the effects of stress hormones on insulin-like growth factor 1 (IGF-1). METHODS: Insulin induced hypoglycemia (< 3 mmol/l) and clonidine induced depression of noradrenergic tone were used to assess the acute effects of cortisol, human growth hormone (hGH), and norepinephrine (NE). RESULTS: Despite the increase of hGH during hypoglycemia, a statistically significant decrease of IGF-1 was observed along with the expected rise of cortisol and NE. To eliminate the role played by NE, NE tone was depressed by administering clonidine. A statistically significant decrease of IGF-1 was also observed. CONCLUSION: Acute cortisol release or a NE decrease induce low IGF-1 levels.

Clonidine↗
PubMed1994

The polymerase chain reaction detects B cell clonalities in patients with Sjögren's syndrome and suspected malignant lymphoma.

OBJECTIVE: To investigate the usefulness of the polymerase chain reaction (PCR) to detect B cell clonal expansions in tissues where lymphoproliferative disease was suspected in the course of Sjögren's syndrome (SS). METHODS: Tissue samples from 7 patients with definite (5 cases) or probable (2 cases) SS were subjected to routine histopathologic studies, immunophenotyping, and genotypic analysis, including Southern blotting and PCR amplification of immunoglobulin heavy chain (IgH) variable-diversity-joining (VDJ) region gene rearrangements. RESULTS: Malignant lymphoma was detected in 3 cases, and myoepithelial sialadenitis in the remaining 4. B cell clonal expansion was detected in 7/7 cases by PCR, 5/7 by Southern blotting, and in no case of myoepithelial sialadenitis by kappa/lambda light chain immunophenotyping. CONCLUSION: PCR may represent a quick and powerful tool to detect B cell clonalities in SS. Such information may provide new insights into the pathogenesis of the disease and may improve the clinical approach to the patients.

Adult↗