Deplezione B linfocitaria e sindrome di Sjögren primaria: esiste un ruolo per il rituximab? = B-cell depletion and primary Sjögren’s syndrome: is there a role for rituximab?

L\u2019idea che la deplezione dei B linfociti potesse essere utilizzata per il trattamento delle malattie reumatiche sistemiche deriva dall\u2019ipotesi che, eliminando le cellule alterate dal circolo, si possa curare la malattia. In realt\ue0, nelle malattie reumatiche sistemiche, contrariamente a quanto accade nei linfomi, la deplezione dei B linfociti persiste per alcuni mesi e successivamente si assiste alla riacutizzazione della malattia. Molteplici sono le ipotesi che possono spiegare tale evento: a) insufficiente deplezione dei cloni patogeni; b) persistenza di anticorpi patogeni; c) alterazione primaria o secondaria della tolleranza dei B linfociti; d) ricomparsa delle B cellule; e) reminiscenza della malattie da parte di cellule diverse dai B linfociti, probabilmente T linfociti (1, 2)..

Artrite reumatoide all’esordio = Early rheumatoid arthritis

Rheumatoid arthritis (RA) is a systemic disease characterized by chronic inflammation of the synovial joints damage and loss of the function. The ultimate goal in managing RA is to prevent joint damage and to maintain functional ability. Consequently, early diagnosis and treatment is important, but predictive markers for RA are still confined to autoantibodies and also magnetic resonance imaging (MRI) and sonography do not appear to sufficiently distinguish between early RA and non RA. Evidence shows that substantial and irreversible joint damage already occurs within the first 2 years after disease onset. This "window of opportunity" hypothesis for therapeutic intervention in RA is based on the existence of a time frame within which there is a potential for a greater response to therapy, resulting in sustained benefits or, perhaps most important, a chance of cure. There is increasing evidence for beneficial effects of early DMARDs (disease-modifying anti-rheumatic drugs) therapy over delayed treatment in patients who present with arthritis of recent onset. However, no universal consensus exists concerning the choice of initial drug or whether single drug or combination should be given as initial treatments. Most studies demonstrated superiority of aggressive over conventional approaches. Because the tumor necrosis factor (TNF)-alpha inhibitors have proved to stop joint damage progression in severe progressive RA, the achievement of these agents in early RA are currently of great interest

Vaccination with endosomal unknown epitopes produces therapeutic response in rheumatoid arthritis patients and modulates adjuvant arthritis of rats

BACKGROUND: Our previous results showed that intrasynovial Rifamycin SV caused the lysis of synoviocites and freed the autoantigens which in turn stimulated the immunoregulatory rather than autoreactive T cell response in rheumatoid patients. Here, we hypothesize that disruption in vitro of peripheral blood mononuclear cells, by freeze/thawing or by lytic action of Rifamycin SV, would induce the release of endosomal pathogenic autoantigens from APCs present in the circulation, which could then be isolated from degrading enzymes by ultrafiltration. METHODS: The preparation of the ultrafiltrates are based on the rupture of PBMCs (5 7 10(6) cells/mL) by the addition of Rifamycin SV in culture (250 \u3bcg/mL), which causes the lysis of 90 % of the cells in 3 h, or by three cycles of freeze/thawing of the PBMC, from -80 \ub0C to room temperature. The lysate and the fragmented cells were then centrifuged and ultrafiltered by passage through a filtration device with a cut-off of 10 kDa. Also the synovial fluid was subjected to ultrafiltration. RESULTS AND CONCLUSIONS: At clinical monitoring of the 30th day, 22/58 (38 %) patients subcutaneously treated with the autologous ultrafiltrate prepared by the freeze/thawing of PBMCs reached an ACR20. Comparable results were obtained with the other two ultrafiltrates. Cell cultures The addition of ultrafiltrates to rheumatoid PBMCs cultures led to the upregulation of a marker for T-regulatory cells, and downregulation of a cell proliferation marker; changes that together have the meaning of a global immunomodulatory response and that only a specific antigen (ultrafiltrate UF-f/t) might induce in the rheumatoid patient, probably by activating pre-existing protective network. Experimental arthritis All the ultrafiltrates except that prepared by Rifamycin SV were able to modulate the adjuvant arthritis in rats. In particular, longlasting synovial fluid induced a significant reduction of the severity of subsequent arthritis (p < 0.01) while SF from recent RA effusion (5-10 days after a previous complete extraction) and knee osteoarthrosis were ineffective. It is reasonable to assume there are at least two unknown endosomal immunoactive epitopes; one developing its immunotherapeutic property in RA, and the other, related to the molecule of HSP60, reduces the severity of oncoming arthritis. Both epitopes are present in humans, have a molecular weight of 6410 kDa and do not appear to be bystander antigens. Please see Additional file 1 for the abstract in Italian

Neurophysiological background for physical therapies in fibromyalgia

This paper describes the techniques for controlling pain by the physical means that are most widely used clinically, particularly in the case of fibromyalgia. They are grouped on the basis of the physical energy used: mechanical, thermal (including magnetic and electromagnetic), and light (LASER). The main underlying neu-rophysiological mechanisms are gate activation, the stimulation of descending systems of pain control, and the endogenous opiate system

Reumatismo : cambio della guardia

Cosa significa prendere nelle mani la direzione di una delle pi\uf9 antiche riviste di reumatologia al mondo? Un ritorno al passato ed un tuffo nel futuro: nel passato ritrovo il ricordo di uno specializzando in reumatologia alle prime armi coinvolto nella redazione di Reumatismo, diretta allora dal Prof. Vittorio Bianchi. Nel futuro alcune idee e progetti ambiziosi per rendere la nostra rivista sempre pi\uf9 incisiva nel mondo della reumatologia. Questi sono stati suggeriti e discussi con i due codirettori Roberto Caporali e Piercarlo Sarzi-Puttini: sapere che loro facevano parte del team ha reso di molto pi\uf9 facile la decisione di accettare questo incarico, del quale sono, ovviamente, onorato. Il momento \ue8 senza dubbio propizio ed entusiasmante: la reumatologia italiana sta confermando il suo ruolo in Europa (EULAR 2010 a Roma, primato nella partecipazione scientifica dei reumatologi italiani ai congressi europei, pubblicazioni internazionali, presidenze di commissioni, ecc.) e questo non potr\ue0 non avere ricadute anche su Reumatismo

Microbial Agents as Putative Inducers of B Cell Lymphoma in Sj&#246;gren&apos;s Syndrome through an Impaired Epigenetic Control : The State-of-The-Art

Introduction: Understanding the mechanisms underlying the pathogenesis of Sj\uf6gren's syndrome (SS) is crucially important in order to be able to discriminate the steps that lead to B cell transformation and promptly identify the patients at risk of lymphomagenesis. The aim of this narrative review is to describe the evidence concerning the role that infections or dysbiosis plays in the epigenetic control of gene expression in SS patients and their possible involvement in B cell lymphomagenesis. Materials and Methods: We searched the PubMed and Google Scholar databases and selected a total of 92 articles published during the last 25 years that describe experimental and clinical studies of the potential associations of microbiota and epigenetic aberrations with the risk of B cell lymphoma in SS patients. Results and Discussion: The genetic background of SS patients is characterized by the hyperexpression of genes that are mainly involved in regulating the innate and adaptive immune responses and oncogenesis. In addition, salivary gland epithelial cells and lymphocytes both have an altered epigenetic background that enhances the activation of proinflammatory and survival pathways. Dysbiosis or chronic latent infections may tune the immune response and modify the cell epigenetic machinery in such a way as to give B lymphocytes an activated or transformed phenotype. It is also worth noting that transposable integrated retroelements may participate in the pathogenesis of SS and B cell lymphomagenesis by inducing DNA breaks, modulating cell gene expression, or generating aberrant transcripts that chronically stimulate the immune system. Conclusions: Microorganisms may epigenetically modify target cells and induce their transcriptome to generate an activated or transformed phenotype. The occurrence of lymphoma in more than 15% of SS patients may be the end result of a combination of genetics, epigenetics, and dysbiosis or latent infections

Determinants of Risk Infection During Therapy with Anti TNF-Alpha Blocking Agents in Rheumatoid Arthritis

The use of TNF-alpha antagonists (infliximab, etanercept, adalimumab) has changed the course of many rheumatic diseases including rheumatoid arthritis (RA). Since their approval, some questions regarding their safety including infections have been observed. The aim of the study was to evaluate the changes in cytokines levels and cells subsets in patients with RA during anti TNF blocking agents treatment and the possible effect on infections’ development. We evaluated in 89 RA patients [39 treated with etanercept (ETN), 29 with adalimumab (ADA) and 21 with infliximab (IFN)] at baseline and after 6 months the following parameters: procalcitonin, ESR, CRP, cytokines as TNF, IL-6, IL-10, IL-8 and the TNF/IL-10 ratio, and peripheral mononuclear cells as CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD3- /CD16+/56+, CD14+HLADR+, CD20+, CD19+/CD38+. Peripheral mononuclear cells were detected by flow cytometric system Cytomics FC500 and cytokines circulating levels by a quantitative sandwich enzyme immunoassay technique (Human IL-8 Instant ELISAe Bioscience, Human IL-6 Instant ELISA e Bioscience, Human IL-10 Instant ELISAe Bioscience and Human TNF-a Quantikine immunoassay RD system). A lower reduction of CD14+HLADR+ in ADA group 54.6±10.4% vs ETA 48.4±15.7% vs INF 40.7±16.5%, p<0.039 was found. No differences in all three groups on peripheral mononuclear cells CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD 20+, CD19+/CD38+, CD3-/CD16+/56+, and cytokine circulating levels were found. The number of infections at 6 months was: 10.3% in ADA group, 12.8% in ETN group and 19.04% in IFN group. A correlation was found between the reduction in CD14+HLADR+ cells and IFN treatment. Our data showed that the level of CD14+HLADR+ cells was reduced during therapy with IFN. ADA and ETN don’t reduce lymphocyte populations and their subsets such as CD14+HLADR+ cells that play an important role host defence

Psychiatric problems in fibromyalgia : clinical and neurobiological links between mood disorders and fibromyalgia

Objective. To review the literature addressing the relationship between mood disorders and fibromyalgia/chron-ic pain and our current understanding of overlapping pathophysiological processes and pain and depression circuitry. Methods. We selectively reviewed articles on the co-occurrence of mood disorders and fibromyalgia/chronic pain published between 1990 and July 2012 in PubMed. Bibliographies and cross references were considered and included when appropriate. Results. Forty-nine out of 138 publications were retained for review. The vast majority of the studies found an association between depression and fibromyalgia. There is evidence that depression is often accompanied by symptoms of opposite polarity characterised by heights of mood, thinking and behaviour that have a considerable impact on pharmacological treatment. Recent developments support the view that the high rates of fibromyalgia and mood disorder comorbidity is generated by largely overlapping pathophysiological processes in the brain, that provide a neurobiological basis for the bidirectional, mutually exacerbating and disabling relationship between pain and depression. Conclusions. The finding of comparable pathophysiological characteristics of pain and depression provides a framework for understanding the relationship between the two conditions and sheds some light on neurobio-logical and therapeutic aspects

Safety of rituximab in rheumatoid arthritis

La artrite reumatoide \ue8 una malattia cronica che predispone alla comparsa di complicanze rappresentate da malattie infettive, neoplasie e malattie cardiovascolari. Il rischio \ue8 aumentato dalla necessit\ue0 di assumere a lungo farmaci immunomodultori, quali ad esempio i farmaci biotecnologici. La sicurezza del rituximab \ue8 stata valutata in un periodo di tempo medio (non superiore ai 10 anni) e i dati disponibili sono rassicuranti. Nei trials clinici condotti sia in pazienti gi\ue0 trattati (con antagonisti del TNF e/o con methotrexate) sia in pazienti naive \ue8 emerso che il rituximab \ue8 tollerato anche dopo diversi cicli di terapia. La percentuale totale di eventi avversi \ue8 infatti rimasta stabile nei vari cicli. L\u2019evento avverso pi\uf9 frequente era rappresentato dalla comparsa di reazioni infusionali. La percentuale di infezioni serie non aumentava dopo diversi cicli. I dati ottenuti da esperienze condotte nella vita quotidiana confermano il buon profilo di tollerabilit\ue0.Rheumatoid arthritis (RA) is a chronic disease that requires long-term administration of immunomodulatory drugs with a greater risk of side effects like malignancies, serious infections and cardiovascular diseases. Furthermore, patients with RA are more prone than the general population to these manifestations. Safety of rituximab has been evaluated in the short-term (6 months) and in the medium-term (up to 10 years) in patients who had been previously treated with antagonists of tumor necrosis factor (a-TNF) and/or with methotrexate (MTX) and in patients who were not. Data obtained from clinical trials demonstrated that rituximab is well tolerated either after a single course or after multiple courses. The overall rate of adverse events (AEs) was stable after the first three courses. The most frequent adverse event was infusion-related reactions (IRR). Serious infections did not increase after multiple courses. Data from "real life" confirm that treatment with rituximab is well tolerated