Rheumatoid Arthritis: De Vita S

De Vita S, Quartuccio L. · Rheumatology Clinic, DPMSC, University of Udine, 33100 Udine, Italy. · Autoimmun Rev. · Pubmed #16920570 No free full text.

Abstract: Based on new biologic and clinical insights, the number of drugs blocking different biologic targets in rheumatoid arthritis (RA) [e.g., tumor necrosis factor alpha (TNFalpha), CTLA4, interleukin (IL)-1, IL-6, IL-15, IL-18, B lymphocyte stimulator (BLyS), CD20] has increased considerably over the last decade. Rituximab, a chimeric monoclonal antibody that was developed for the treatment of B-cell lymphomas, has been used in different autoimmune diseases where B-cells are thought to play a pivotal role. However, blinded randomised controlled trials have been completed only for RA so far, indicating the clear efficacy of B-cell blockade in RA and highlighting the pathogenetic B-cell in rheumatoid synovitis. The use of rituximab in RA is herein updated, from early preliminary studies to more recent presentations in International Conferences. Key clinical and biologic issues are discussed, i.e., efficacy and safety of rituximab, role of concomitant therapies, use in the long term and retreatment strategies, differences with anti-TNFalpha therapy. The possible indications in RA are finally discussed, also on the ground of personal experience with rituximab in RA and other rheumatic diseases associated with B-cell lymphoproliferation. Further clinical research should go hand in hand with laboratory research, and tissue studies are now needed.

Ramos-Casals M, De Vita S, Tzioufas AG. · Department of Autoimmune Diseases, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), School of Medicine, University of Barcelona, Barcelona, Spain. · Autoimmun Rev. · Pubmed #15652773 No free full text.

Abstract: An increased prevalence of hematologic malignancies is often described in patients with Sjögren's syndrome (SS). Viruses have been proposed as possible etiologic or triggering agents of systemic autoimmune diseases (SADs), with hepatitis C virus (HCV) being one of the viruses most frequently associated with autoimmune features and with systemic autoimmune diseases such as mixed cryoglobulinemia or SS. Moreover, the association between HCV infection and hematologic malignancies, mainly non-Hodgkin's lymphoma (NHL), is supported by several studies. For these reasons, the recognized association of specific systemic autoimmune diseases (mainly SS and mixed cryoglobulinemia) with HCV infection, added to the possible evolution of any one of these entities into a B-cell NHL, suggests the possibility of a close relationship among SS, HCV and B-cell lymphoproliferative disorders, especially in patients with type II mixed cryoglobulinemia.

De Vita S, De Marchi G, Sacco S, Gremese E, Fabris M, Ferraccioli G. · Division of Rheumatology, DPMSC, University of Udine, Italy. · Blood Cells Mol Dis. · Pubmed #11778660 No free full text.

Abstract: A classification of nonmalignant lymphoproliferation in Sjögren's syndrome is presented, based on the results of international meetings regarding Sjögren's syndrome-associated lymphomagenesis and on our results of a clinico-pathologic and molecular study and long-term follow-up in well-characterized patients. Sjögren's syndrome pathobiology has similarities to hepatitis C virus-related B-cell lymphoproliferation. Antigen stimulation with the preferential expansion of rheumatoid factor-positive clones and specific immunoglobulin gene expression and recombination represent key biologic events in lymphoproliferation. This classification is based on the coupling of molecular and histological studies and may result in more selective treatment approaches.

Di Poi E, Perin A, Morassi MP, Del Frate M, Ferraccioli GF, De Vita S. · Division of Rheumatology, DPMSC,School of Medicine, University of Udine, Udine, Italy. · Clin Exp Rheumatol. · Pubmed #17417995 No free full text.

Abstract: TNF-alpha is thought to play a pivotal role in the initiation and perpetuation of the chronic inflammatory process in rheumatoid arthritis. TNF-alpha blockers such as infliximab and etanercept are currently used in the treatment of active rheumatoid arthritis (RA) when traditional DMARDs have failed and are effective in a significant proportion of patients. However, about one third are non-responders to anti-TNF-alpha.The aim of this study was to verify whether rheumatoid patients, after failing infliximab, can benefit from etanercept.We analysed 18 patients with active RA with no response to at least 3 DMARDs and where infliximab therapy had failed. The patients had received infliximab associated with methotrexate: eleven of them did not show any significant response, while seven patients, after a good response, relapsed. Etanercept was then started. EULAR criteria of response were used with calculation of activity index DAS28 at baseline, after 2 weeks, 3 months and every third month until last follow-up. A moderate or good response was achieved with etanercept in 13 out of 18 patients. From our experience, etanercept can be considered as a good alternative choice when infliximab has failed.

De Vita S, Zaja F, Sacco S, De Candia A, Fanin R, Ferraccioli G. · University of Udine, Udine, Italy. · Arthritis Rheum. · Pubmed #12209504 links to  free full text

Abstract: OBJECTIVE: The pathogenetic role of B cells in rheumatoid arthritis (RA) is under debate, but it is currently believed to be marginal. The availability of selective anti-B cell treatment provides a unique opportunity to clarify this issue. This study was undertaken to investigate the effects of B cell blockade in the treatment of refractory RA, and to evaluate the implications with regard to the role of B cells in the disease. METHODS: Five female patients with active, evolving erosive RA were treated with rituximab, an anti-CD20 chimeric monoclonal antibody. All 5 patients had been nonresponders to combination therapy with methotrexate plus cyclosporin A. Two of the 5 had also failed to respond to anti-tumor necrosis factor alpha therapy. All of these treatments were discontinued 1 month before institution of anti-CD20 therapy. RESULTS: Marked clinical improvement was observed in 2 patients (American College of Rheumatology 70% response [ACR70] and ACR50, respectively), starting at the end of the second month after institution of anti-CD20 therapy (month 2) and lasting until month 10 in 1 patient (articular relapse) and month 12 in the other (last followup). ACR20 response was observed in 2 additional patients, lasting until month 5 and month 7, respectively (articular relapse in both). Decrease or normalization of serum C-reactive protein and rheumatoid factor levels were observed in these patients. In contrast, patient 3 had no response to the treatment. RA synovitis and evolving erosive damage were decreased in patients exhibiting a major response, as demonstrated by imaging studies. CONCLUSION: Our finding of the clinical efficacy of selective B cell blockade indicates that B cells play a critical role in rheumatoid synovitis, at least in a subset of patients. Qualitative or quantitative differences in B cell commitment in RA pathobiology might have a function in the different responses observed.

Ferraccioli GF, De Vita S. · No affiliation provided · Lancet. · Pubmed #10359440 No free full text.

This publication has no abstract.

Barone F, Bombardieri M, Rosado MM, Morgan PR, Challacombe SJ, De Vita S, Carsetti R, Spencer J, Valesini G, Pitzalis C. · Divisione di Reumatologia Dipartimento di Clinica e Terapia Applicata, Università La Sapienza Roma, Rome, Italy. · J Immunol. · Pubmed #18354239 links to  free full text

Abstract: The chemokines (CKs) CXCL13, CCL21, and CXCL12 are known to play differential roles in the organization of the lymphoid tissues and the development of lymphoid malignancies. We investigated the expression of these CKs and their receptors in the salivary glands of Sjogren's syndrome patients with lymphoepithelial lesions (lymphoepithelial sialadenitis or LESA) and in MALT lymphoma to understand their involvement in salivary gland lymphomagenesis. We demonstrate that within salivary glands with LESA and MALT lymphoma the lymphoid CKs CXCL13 and CCL21 are selectively associated with areas of reactive lymphoid proliferation, whereas no significant expression of these molecules was detected in the malignant lymphoid aggregate. Conversely, CXCL12 was observed predominantly in infiltrated ducts and malignant B cells. Accordingly, CXCL13 and CCL21 transcript levels were significantly increased in LESA samples while CXCL12 levels were increased in MALT lymphoma and isolated tumor cells. Low levels of CK receptors were detected on lymphoma-extracted lymphocytes, suggesting down-regulation in the abundance of ligands. Our findings suggest that in salivary gland MALT lymphoma the lymphoid CKs CXCL13 and CCL21 are directly implicated in the organization of ectopic reactive lymphoid tissue, whereas CXCL12 is associated with the infiltrated epithelium and malignant B cell component and is possibly involved in the regulation of malignant B cell survival.

Tomietto P, Annese V, D'agostini S, Venturini P, La Torre G, De Vita S, Ferraccioli GF. · University of Udine, Udine, Italy. · Arthritis Rheum. · Pubmed #18050188 links to  free full text

Abstract: OBJECTIVE: To determine factors affecting the severity of cognitive impairment in systemic lupus erythematosus (SLE) and to analyze its anatomic location. METHODS: Fifteen cognitive functions grouped into 8 domains were evaluated in 52 patients with SLE and 20 with rheumatoid arthritis. Patients were classified according to severity of impairment as normal, mild, or moderate/severe. Multivariate analysis was performed to identify the main factors affecting severity of cognitive deficits. The most likely anatomic site of damage according to neuropsychological performance was compared with the lesion's location on magnetic resonance imaging (MRI). RESULTS: In SLE patients, a stepwise regression analysis showed that the number of impaired functions (dependent variable) was associated with antiphospholipid antibody positivity (aPL+; P = 0.04), the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI; P = 0.001), hypertension (P = 0.032), and was inversely related to educational level (P = 0.021). Including MRI, the number of impaired functions was associated with severity of MRI (P < 0.001), the SDI (P = 0.013), and the presence of Raynaud's phenomenon (P = 0.04). The contemporary presence of aPL+ and Raynaud's phenomenon resulted in a higher probability to develop moderate/severe cognitive deficits (P = 0.015). Two logistic multiple regression analyses identified hypertension (P < 0.05), the SDI (P < 0.01), and moderate/severe MRI findings as main predictors of moderate/severe impairment (dependent variable). The damage site hypothesized through neuropsychological testing corresponded with MRI findings in 71.7% of SLE patients K = 0.42, P = 0.005). CONCLUSION: Hypertension, aPL+, accumulated damage, and MRI lesions are the main factors affecting severity of cognitive impairment in SLE. The hypothesized sites of central nervous system involvement according to neuropsychological testing correlated with MRI findings in most patients.

De Vita S, Quartuccio L, Fabris M. · Rheumatology Clinic, DPMSC, University of Udine, Udine, Italy. · Dig Liver Dis. · Pubmed #17936213 No free full text.

Abstract: Type II mixed cryoglobulinemia syndrome (MCsn) is a systemic vasculitis mainly linked to immune complex deposition in several organs and to hepatitis C virus (HCV) infection. Therapeutic strategies can target either the viral trigger HCV if present, or pathogenic events downstream the triggering infection, e.g, the proliferating B-cells directly. Antiviral therapy should be considered as first-line treatment in many HCV-positive patients. However, it may prove ineffective, contraindicated, or poorly tolerated. On the other hand, the other available treatments (such as cytotoxic agents, plasma exchange and steroids) may lead to life-threatening complications and may be difficult to manage in the long term. Given the good safety profile in lymphomas, rituximab (RTX) has been used off-label for numerous patients suffering from a variety of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis/ polymyositis, and anti-neutrophil cytoplasmic antibody (ANCA)-positive vasculitis. Efficacy and safety of RTX in MCsn and in particular in MCsn-related glomerulonephritis was recently described. Based on these results, a multicentre, controlled, randomised, clinical trial is now ongoing to compare RTX versus the best available treatments in some severe MCsn manifestations (i.e. skin ulcers, sensory and/or motor neuropathy and active glomerulonephritis).

Bombardieri M, Barone F, Humby F, Kelly S, McGurk M, Morgan P, Challacombe S, De Vita S, Valesini G, Spencer J, Pitzalis C. · Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, St. Bartholomew's and Royal London School of Medicine, London, United Kingdom. · J Immunol. · Pubmed #17878393 links to  free full text

Abstract: Demonstration of ectopic germinal center-like structures (GC-LSs) in chronically inflamed tissues in patients with autoimmune disorders is a relatively common finding. However, to what extent ectopic lymphoid structures behave as true GC and are able to support class switch recombination (CSR) and somatic hypermutation (SHM) of the Ig genes is still debated. In addition, no information is available on whether CSR and SHM can take place in the absence of GCs at extrafollicular sites in an ectopic lymphoid tissue. In this study, we show that in salivary glands (SGs) of Sjögren's syndrome (SS) activation-induced cytidine deaminase (AID), the enzyme responsible for CSR and SHM is invariably expressed within follicular dendritic cell (FDC) networks but is not detectable in SGs in the absence of ectopic GC-LSs, suggesting that FDC networks play an essential role in sustaining the Ag-driven B cell proliferation within SS-SGs. We also show that the recently described population of interfollicular large B cells selectively expresses AID outside ectopic GC in the T cell-rich areas of periductal aggregates. Finally, we report that AID retains its exclusive association with numerous, residual GCs in parotid SS-MALT lymphomas, whereas neoplastic marginal zone-like B cells are consistently AID negative. These results strongly support the notion that ectopic lymphoid structures in SS-SGs express the molecular machinery to support local autoantibody production and B cell expansion and may play a crucial role toward lymphomagenesis.

Vitali C, Palombi G, Baldini C, Benucci M, Bombardieri S, Covelli M, Del Papa N, De Vita S, Epis O, Franceschini F, Gerli R, Govoni M, Bongi SM, Maglione W, Migliaresi S, Montecucco C, Orefice M, Priori R, Tavoni A, Valesini G. · Villamarina Hospital, Piombino, Italy. · Arthritis Rheum. · Pubmed #17599741 links to  free full text

Abstract: OBJECTIVE: To develop valid instruments for the assessment of disease-related damage and disease activity in Sjögren's syndrome (SS). METHODS: Data on 206 patients with primary SS were collected in 12 Italian centers. Each patient was scored by 1 investigator, on the basis of a global assessment of the degree of disease damage and disease activity. Patients judged to have active disease at the time of enrollment underwent a second evaluation after 3 months. Univariate and multivariate analyses were performed to select the clinical and serologic variables that were the best predictors of damage and of disease activity, and these variables were used to construct the Sjögren's Syndrome Disease Damage Index (SSDDI) and the Sjögren's Syndrome Disease Activity Index (SSDAI). The weight of each variable in the index was determined by the beta coefficients in multivariate regression models. Scores obtained using the SSDDI and the SSDAI were compared with scores initially given by the investigators. Finally, a receiver operating characteristic (ROC) curve was used to determine the cutoff value in the SSDAI with the highest level of accuracy in identifying patients with a significant level of disease activity. RESULTS: A multivariate model with 9 variables was the best predictor of investigator scores of damage. The scores obtained using the SSDDI were closely correlated with investigator ratings (R = 0.760, P < 0.0001). A model composed of 11 variables was the best predictor of investigator scores of disease activity. The scores obtained using the SSDAI were strongly correlated with the investigator ratings both at the time of enrollment and 3 months after enrollment (R = 0.872, P < 0.0001, and R = 0.817, P < 0.0001, respectively). The differences between scores given by investigators at study enrollment and after 3 months, a measure of variation of disease activity over time, were also closely correlated with the differences calculated using the SSDAI (R = 0.683, P < 0.0001). The ROC curve analysis showed that patients with the highest level of disease activity could be identified on the basis of an SSDAI score of >or=5. CONCLUSION: Our findings indicate that the SSDDI is an adequate instrument to objectively measure damage in patients with SS, and that the SSDAI is a valid tool to measure disease activity when used either as a single-state index or as a transition index.

Quartuccio L, Ferraccioli GF, De Vita S. · No affiliation provided · Scand J Rheumatol. · Pubmed #17062445 No free full text.

This publication has no abstract.

Quartuccio L, De Re V, Fabris M, Marzotto A, Franzolini N, Gasparotto D, Caggiari L, Ferraccioli G, Scott CA, De Vita S. · Rheumatology Clinic, DPMSC, University of Udine, Italy. · Haematologica. · Pubmed #16670074 links to  free full text

Abstract: A patient with rheumatoid arthritis (RA) developed an atypical lymphoproliferative disorder (LPD) after methotrexate and cyclosporine A, which regressed after suspension of both drugs. After subsequent treatment with rituximab, the LPD was still undetectable. Anti-tumor necrosis factor a therapy was used when the arthritis relapsed, but an aggressive B-cell non Hodgkin's lymphoma developed. Molecular analyses showed an oligoclonal B-cell expansion at the LPD step. A minor clone with significant sequence homology to B-cell lymphomas arising in Sjogren's syndrome and mixed cryoglobulinemia syndrome, given rise to the non-Hodgkin's lymphoma. Treatment of rheumatoid arthritis associated with lymphoproliferation represents a clinical challenge, and common pathogenetic pathways to lymphoma may occur in different autoimmune diseases.

Ramos-Casals M, Loustaud-Ratti V, De Vita S, Zeher M, Bosch JA, Toussirot E, Medina F, Rosas J, Anaya JM, Font J, Anonymous00012. · Department of Autoimmune Diseases, Hospital Clínic, Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), School of Medicine, University of Barcelona, Barcelona, Spain. · Medicine (Baltimore). · Pubmed #15758837 No free full text.

Abstract: To define the clinical and immunologic pattern of expression of Sjögren syndrome (SS) associated with chronic hepatitis C virus (HCV) infection, we conducted a multicenter study aiming to collect a large number of patients with SS and HCV infection. Inclusion criteria were the fulfillment of at least 4 of the classification criteria for SS proposed by the European Community Study Group and repeated positive HCV serology, confirmed by recombinant immunoblot assay and/or detection of serum HCV-RNA by polymerase chain reaction. One hundred thirty-seven patients were included (104 female and 33 male; mean age, 65 yr). Seventy-nine (58%) patients presented a systemic process with diverse extraglandular manifestations, with articular involvement (44%), vasculitis (20%), and neuropathy (16%) being the most frequent features observed. The main immunologic features were antinuclear antibodies (65%), hypocomplementemia (51%), and cryoglobulinemia (50%). Cryoglobulins were associated with a higher frequency of cutaneous vasculitis, rheumatoid factor, and hypocomplementemia. Thirty-two (23%) patients had positive anti-Ro/SS-A and/or anti-La/SS-B antibodies; these patients were predominantly women and had a higher prevalence of some extraglandular features and a lower frequency of liver involvement. Nineteen (14%) patients developed neoplasia, with hematologic neoplasia (8 cases) and hepatocellular carcinoma (6 cases) being the most frequent types. Eighty-five percent of SS-HCV patients also fulfilled the recently proposed 2002 classification criteria for SS.In conclusion, HCV-associated SS is indistinguishable in most cases from the primary form using the most recent set of classification criteria. Chronic HCV infection should be considered an exclusion criterion for the classification of primary SS, not because it mimics primary SS, but because the virus may be implicated in the development of SS in a specific subset of patients. We propose the term "SS secondary to HCV" when these patients fulfill the 2002 classification criteria for SS.

Gasparotto D, De Vita S, De Re V, Marzotto A, De Marchi G, Scott CA, Gloghini A, Ferraccioli G, Boiocchi M. · Centro di Riferimento Oncologico, Istituto di Ricovero e Cura a Carattere Scientifico, Aviano, Italy. · Arthritis Rheum. · Pubmed #14613281 links to  free full text

Abstract: OBJECTIVE: To characterize Sjögren's syndrome (SS)-related B cell lymphoproliferation at the premalignant stage and during the evolution to B cell lymphoma, and to better understand the pathobiologic mechanisms associated with clonal expansion and the possible influence of different microenvironments on neoplastic transformation. METHODS: We analyzed sequential parotid and lung biopsy specimens that were obtained from a single patient with SS at multiple time points over a 7-year period. Polymerase chain reaction DNA amplification, cloning, and sequencing of the immunoglobulin heavy chain variable region showed clonality, somatic mutations, intraclonal heterogeneity, and genealogic relationships of the B cell clones in the different biopsy specimens. RESULTS: The evolution of a nonmalignant B cell clone that was present in the parotid gland and evolved into a B cell lymphoma was documented. During such a process, one subclone was selected that accumulated somatic mutations in a pattern consistent with the preservation of antigen receptor functionality, possibly attributable to continued hypermutation and selection. Intraclonal diversity indicated the presence of local triggers in both the parotid and lung microenvironments. CONCLUSION: Molecular followup of B cell lymphoproliferation in SS, from nonmalignant stage to overt B cell lymphoma, indicated a role for B cell receptor engagement in clonal survival. The outgrowth of one subclone, with malignant transformation in the lung, a target organ different from the initial site of the lymphoproliferative process (the parotid gland), indicates that resident stimuli in different microenvironments may locally sustain ongoing lymphoproliferation and B cell transformation.

De Vita S, Damato R, De Marchi G, Sacco S, Ferraccioli G. · Department of Rheumatology, DPMSC, University of Udine, Udine, Italy. · Isr Med Assoc J. · Pubmed #12516900 links to  free full text

Abstract: BACKGROUND: Hepatis C virus infection is presently an exclusion criterion to classify Sjögren's syndrome; however, there are distinct clinicopathologic and biologic similarities between HCV-related and SS-related chronic inflammation of mucosa-associated lymphoid tissue and lymphoproliferation that suggest common pathogenetic pathways. OBJECTIVES: To determine whether a subset of patients with sicca syndrome and HCV infection may present a true primary SS rather than a distinct clinicobiologic entity. METHODS: We extensively characterized 20 consecutive patients with positive anti-HCV antibodies and heavy subjective dry eye and/or dry mouth symptoms, plus positive unstimulated sialometry and/or Shirmer's test. We then compared these features with those in HCV-negative primary SS controls (classified according to the latest American-European Consensus Group Classification Criteria for SS). RESULTS: Of the 20 HCV-positive patients with sicca manifestations, 12 (60%) had positive anti-SSA/SSB antibodies (3/12 by enzyme-linked immunosorbent assay and 6/12 by immunoblot) and/or positive salivary gland biopsy (at least 1 focus/4 mm2), which met the strict classification criteria for SS, as in the case of HCV-negative SS controls. Comparing the HCV-positive SS subset with HCV-negative SS controls showed similar female to male ratio (11/1 vs. 46/4), major salivary gland swelling (17% vs. 26%), positive antinuclear antibodies (75 vs. 94%) and positive rheumatoid factor (58 vs. 52%). Significant differences (P < 0.05) were seen in mean age (69 vs. 56 years), liver disease (50 vs. 2%), lung disease (25 vs. 0%), anti-SSA/SSB positivity (25 vs. 90%), and low C3 or C4 (83 vs. 36%). HCV-positive SS patients exhibited a trend for more frequent chronic gastritis (50 vs. 22%), fibromyalgia (33 vs. 14%), peripheral neuropathy (33 vs. 18%), purpura (33 vs. 19%) and cryoglobulinemia (33 vs. 6%). CONCLUSIONS: A major subset of HCV-positive patients with definite subjective sicca symptoms and positive objective tests may indeed present a true, though peculiar, subset of SS. There are strict similarities with key clinical, pathologic and immunologic findings of definite HCV-negative SS. Other features appear more characteristic of HCV infection. When also considering that HCV is sialotropic and may be treated, HCV-related chronic sialadenitis represents a unique opportunity to clarify key pathogenetic events occurring in the large majority of HCV-negative SS; and similarities to typical primary SS, rather than differences, should be taken into account.

De Re V, De Vita S, Gasparotto D, Marzotto A, Carbone A, Ferraccioli G, Boiocchi M. · Division of Experimental Oncology 1, Centro di Riferimento Oncologico, IRCS, Aviano, Italy. · Eur J Immunol. · Pubmed #11870635 No free full text.

Abstract: Sjögren's syndrome (SS) represents a pathological model of the evolution from polyclonal B lymphocyte activation to oligoclonal/monoclonal B cell expansion, which may culminate in the development of a malignant lymphoproliferative disease. The different phases of this process are usually marked by the appearance of antigen-driven activated B cell clones, which are commonly IgM-positive and with rheumatoid factor (RF) activity. However, the agent(s) able to trigger B cell proliferation is still unknown. A similar pathogenetic mechanism exist in mixed cryoglobulinemia, another autoimmune disease that often evolves to non-Hodgkin's lymphoma (NHL) and in which hepatitis C virus (HCV) infection has been demonstrated to play an etiopathogenetic role. In the present study, we cloned and sequenced the antigen receptor (IgR) variable region genes of SS-associated monoclonal non-neoplastic lymphoproliferations and compared them with those of our previous reported HCV-associated NHL, to derive clues on the antigen(s) that sustains SS. The results obtained showed remarkable homologies between the antigen combinatory regions of the IgR expressed by both diseases. These homologies concern: a) the specific combinations of heavy and light variable region genes; b) the limited length of complementarity-determining regions (CDR3); c) the homology with antibodies with RF activity; d)the amino acid sequences of CDR3 in which common somatic mutations are present that possibly determine the antigen-binding specificity. In conclusion, although there are significant differences between SS and HCV-associated lymphoproliferative diseases, they share many molecular characteristics, which suggest an immunological cross-reactivity or molecular mimicry among the agents that underlie these disorders.

De Vita S, De Re V, Sansonno D, Sorrentino D, Corte RL, Pivetta B, Gasparotto D, Racanelli V, Marzotto A, Labombarda A, Gloghini A, Ferraccioli G, Monteverde A, Carbone A, Dammacco F, Boiocchi M. · Rheumatology Unit, Department of Internal Medicine, University of Udine, UD, Italy. · Hepatology. · Pubmed #10613744 No free full text.

Abstract: 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.

Bertolo F, De Vita S, Dolcetti R, Carbone A, Ferraccioli GF, Bartoli E, Boiocchi M. · Division of Experimental Oncology I, Centro di Riferimento Oncologico, Aviano, Italy. · Clin Exp Rheumatol. · Pubmed #10410268 No free full text.

Abstract: OBJECTIVE: Murine models (MRL/gld/gld mice) and recent evidence in humans suggest a possible role of Fas and Fas ligand (Fas-L) germline mutations in the pathogenesis of autoimmune-related lymphoproliferation, including adult cases. In this study, the presence of Fas and Fas-L germline mutations was investigated in a consecutive series of adult patients with lymphoproliferative disorders occurring in the context of Sjögren's syndrome (SS) and type II mixed cryoglobulinemia (MC). METHODS: 11 patients (8 primary SS and 3 type II MC; F/M: 10/1; mean age 64 yrs.) were investigated. All patients were suffering from atypical lymphoproliferative disorders or MALT lymphoproliferative lesions (mean duration 3.5 yrs.). Four patients later developed a malignant lymphoma. DNA from peripheral blood mononuclear cells from 11 patients and 10 controls was tested for germline mutations in the Fas gene (exons 4, 8 and 9) and Fas-L gene (exon 4) by the polymerase chain reaction-single strand conformation polymorphism (SSCP) method. RESULTS: All DNA samples from both patients and controls showed amplification of Fas and Fas-L specific fragments. Identical SSCP migration patterns were observed in all the cases, indicating the lack of mutations in the whole series. CONCLUSION: Although it cannot be excluded that Fas and Fas-L mutations might be present in exons different from those analyzed, our data do not support the hypothesis that germline mutations in these genes are responsible for a major subset of lymphoproliferative syndromes in adult patients with SS and type II MC. Additional studies would be worthwhile in SLE-related lymphoproliferation, which is, however, a subset of limited clinical relevance when considering all cases with autoimmune-related lymphoproliferation.

Pivetta B, De Vita S, Ferraccioli G, De Re V, Gloghini A, Marzotto A, Caruso G, Dolcetti R, Bartoli E, Carbone A, Boiocchi M. · Division of Experimental Oncology 1, Centro di Riferimento Oncologico, Aviano (PN), Italy. · J Rheumatol. · Pubmed #10332975 No free full text.

Abstract: 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.

Quartuccio L, De Vita S. · No affiliation provided · J Rheumatol. · Pubmed #17407250 links to  free full text

This publication has no abstract.

De Re V, De Vita S, Battistella V, Marzotto A, Libra M, Ferraccioli G, Boiocchi M. · No affiliation provided · Ann Rheum Dis. · Pubmed #12176821 links to  free full text

This publication has no abstract.

Ferraccioli G, Damato R, De Vita S, Fanin R, Damiani D, Baccarani M. · No affiliation provided · Ann Rheum Dis. · Pubmed #11203719 links to  free full text

This publication has no abstract.