Interleukin-6 and IgA-rheumatoid factor are crucial for baseline erosiveness, and anti-citrullinated peptide antibodies for radiographic progression in early rheumatoid arthritis treated according to a treat-to-target strategy.

OBJECTIVES: To define baseline clinical and immunological characteristics [anti-citrullinated peptide antibodies (ACPAs), immunoglobulin M (IgM)- and IgA-rheumatoid factor (RF), and interleukin-6 (IL-6) levels] involved in determining baseline erosiveness, outcome, and radiographic progression among seropositive and seronegative early rheumatoid arthritis (ERA) patients. METHOD: The 408 ERA patients enrolled in the study were monitored every 3 months according to the treat-to-target strategy. At baseline and after 12 months, hand and foot radiographs were evaluated using the Sharp/van der Heijde erosion score. RESULTS: At diagnosis, seronegative patients were older and had higher Disease Activity Scores (DASs) than seropositive patients. A higher risk of erosiveness at baseline was conferred by IgA-RF positivity and IL-6 plasma levels ≥7.6 pg/mL, particularly when simultaneously present. In multivariate analysis, disease duration and IL-6 plasma levels ≥7.6 pg/mL arose as independent variables associated with presence of erosions at onset. Radiographic progression at 1 year follow-up, which occurred in 11.1% of ERA patients, was predicted by ACPA positivity, together with higher age at diagnosis. Despite similar percentages of good European League Against Rheumatism response, DAS and Boolean remission being observed over time among seropositive and seronegative patients and between erosive and non-erosive subjects, ERA patients who were erosive at onset, IgA-RF seropositive, and simultaneously having high baseline IL-6 plasma levels (≥7.6 pg/mL) were treated to a greater extent with tumour necrosis factor blockers after 12 months. CONCLUSION: IgA-RF positivity and IL-6 plasma levels are crucial for baseline erosiveness, while ACPA positivity represents the strongest risk factor for developing radiographic progression in ERA.

Driving chronicity in rheumatoid arthritis: perpetuating role of myeloid cells.

Acute inflammation is a complex and tightly regulated homeostatic process that includes leucocyte migration from the vasculature into tissues to eliminate the pathogen/injury, followed by a pro-resolving response promoting tissue repair. However, if inflammation is uncontrolled as in chronic diseases such as rheumatoid arthritis (RA), it leads to tissue damage and disability. Synovial tissue inflammation in RA patients is maintained by sustained activation of multiple inflammatory positive-feedback regulatory pathways in a variety of cells, including myeloid cells. In this review, we will highlight recent evidence uncovering biological mechanisms contributing to the aberrant activation of myeloid cells that contributes to perpetuation of inflammation in RA, and discuss emerging data on anti-inflammatory mediators contributing to sustained remission that may inform a novel category of therapeutic targets.

Real-world experience of tocilizumab in rheumatoid arthritis: sub-analysis of data from the Italian biologics' register GISEA.

To assess the long-term effectiveness and safety of tocilizumab, abatacept, and tumor necrosis factor-α inhibitors (TNFi), in the Italian real-world setting of rheumatoid arthritis (RA). The records of adult RA patients from the Italian biologics' registry Gruppo Italiano Studio Early Arthritis (GISEA) were analyzed. Demographic and clinical data were obtained at entry. The disease remission rate (28-joint disease activity score calculated using the erythrocyte sedimentation rate [DAS28-ESR] ≤ 2.6) and frequency of adverse events (AEs) were evaluated at 2 years. From 1999 to 2014, 7539 patients were treated with biologics (61.3% in first- and 22.6% in second-line), 68% of cases received TNFi, 9.1% tocilizumab, and 8.6% abatacept. Treatment groups showed a similar DAS28 at entry. As first-line, tocilizumab induced a significantly higher remission rate than abatacept or TNFi at 6 (51 vs 23.3 and 26.2%, respectively; p < 0.0001) and 24 months (52.3 vs 33.3 and 34.4%, respectively; p < 0.01). A similar pattern was observed in later lines. The most common AEs reported were infections, reactions to biologics (more frequent among TNFi-treated patients), increased transaminase (more frequent among TCZ-treated patients), and cardiovascular events. In clinical practice, TCZ induced a rapid and long-lasting remission and in a higher percentage of patients compared to abatacept and TNFi, with a good safety profile.

B cell activating factor (BAFF) and BAFF receptors: fakes and facts.

Analysis of B cell activating factor (BAFF) receptors before and after B cell depletion therapy (BCDT) might offer a clue to the understanding of whether some B cell subsets may represent useful biomarkers of biological and clinical responses. Among the BAFF receptors in a cohort of rheumatoid arthritis (RA) patients, the AA have shown, by fluorescence activated cell sorter (FACS) analysis of median fluorescence intensity (MFI), that transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI) and B cell maturation antigen (BCMA) do not change, whereas the most important, BAFF receptor 3 (BR3), appears to be decreased before as well as after BCDT in all B cell subsets but not in plasmablasts, the most important subset, depleted by BCDT.

Evidence-based algorithm for diagnosis and assessment in psoriatic arthritis: results by Italian DElphi in psoriatic Arthritis (IDEA).

Psoriatic arthritis (PsA) is a chronic inflammatory disease involving skin, peripheral joints, entheses, and axial skeleton. The disease is frequently associated with extrarticular manifestations (EAMs) and comorbidities. In order to create a protocol for PsA diagnosis and global assessment of patients with an algorithm based on anamnestic, clinical, laboratory and imaging procedures, we established a DElphi study on a national scale, named Italian DElphi in psoriatic Arthritis (IDEA). After a literature search, a Delphi poll, involving 52 rheumatologists, was performed. On the basis of the literature search, 202 potential items were identified. The steering committee planned at least two Delphi rounds. In the first Delphi round, the experts judged each of the 202 items using a score ranging from 1 to 9 based on its increasing clinical relevance. The questions posed to experts were How relevant is this procedure/observation/sign/symptom for assessment of a psoriatic arthritis patient? Proposals of additional items, not included in the questionnaire, were also encouraged. The results of the poll were discussed by the Steering Committee, which evaluated the necessity for removing selected procedures or adding additional ones, according to criteria of clinical appropriateness and sustainability. A total of 43 recommended diagnosis and assessment procedures, recognized as items, were derived by combination of the Delphi survey and two National Expert Meetings, and grouped in different areas. Favourable opinion was reached in 100% of cases for several aspects covering the following areas: medical (familial and personal) history, physical evaluation, imaging tool, second level laboratory tests, disease activity measurement and extrarticular manifestations. After performing PsA diagnosis, identification of specific disease activity scores and clinimetric approaches were suggested for assessing the different clinical subsets. Further, results showed the need for investigation on the presence of several EAMs and risk factors. In the context of any area, a rank was assigned for each item by Expert Committee members, in order to create the logical sequence of the algorithm. The final list of recommended diagnosis and assessment procedures, by the Delphi survey and the two National Expert Meetings, was also reported as an algorithm. This study shows results obtained by the combination of a DElphi survey of a group of Italian rheumatologists and two National Expert Meetings, created with the aim of establishing a clinical procedure and algorithm for the diagnosis and the assessment of PsA patients. In order to find accurate and practical diagnostic and assessment items in clinical practice, we have focused our attention on evaluating the different PsA domains. Hence, we conceived the IDEA algorithm in order to address PsA diagnosis and assessment in the context of daily clinical practice. The IDEA algorithm might eventually lead to a multidimensional approach and could represent a useful and practical tool for addressing diagnosis and for assessing the disease appropriately. However, the elaborated algorithm needs to be further investigated in daily practice, for evidencing and proving its eventual efficacy in detecting and staging PsA and its heterogeneous spectrum appropriately.

The role of high-mobility group box protein 1 in collagen antibody-induced arthritis is dependent on vascular endothelial growth factor.

High-mobility group box 1 (HMGB1) has been implicated in angiogenesis and rheumatoid arthritis (RA). The aim of this study was to define more clearly the role of HMGB1 in the synovial angiogenesis and pathogenesis of an immune model of arthritis. BALB/c mice were injected with monoclonal anti-collagen antibody cocktail followed by lipopolysaccharide to induce arthritis. HMGB1 and vascular endothelial growth factor (VEGF) were over-expressed in the areas of the synovium where more inflammation and neoangiogenesis were present. The selective blockade of HMGB1 or VEGF resulted alternatively in a lower severity of arthritis evaluated by the arthritis index. Furthermore, exogenous HMGB1 administration caused a worsening of arthritis, associated with VEGF up-regulation and increased synovial angiogenesis. The selective inhibition of VEGF also resulted in no induction of arthritis in mice receiving exogenous HMGB1. Cytokine enzyme-linked immunosorbent assay (ELISA) analyses performed on peripheral blood and synovial fluid demonstrated a significant reduction of interleukin (IL)-1ß, IL-6 and tumour necrosis factor (TNF)-α in mice where HMGB1 and VEGF pathways were blocked. Interestingly, the selective blockade of HMGB1 and VEGF resulted in an increase of the peripheral IL-17A concentration. The development of arthritis mediated by HMGB1 and the synovial angiogenesis can be blocked by inhibiting the VEGF activity. The proinflammatory and proangiogenic cytokine IL-17A was increased when HMGB1 is inhibited, but the synovial angiogenesis was nevertheless reduced in this model of arthritis. Taken together, these findings shed new light on the role of this nuclear protein in the pathogenesis of arthritis in an RA-like model.

Detection of bone erosions in early rheumatoid arthritis: 3D ultrasonography versus computed tomography.

Three-dimensional (3D) volumetric ultrasonography (US) is an interesting tool that could improve the traditional approach to musculoskeletal US in rheumatology, due to its virtual operator independence and reduced examination time. The aim of this study was to investigate the performance of 3DUS in the detection of bone erosions in hand and wrist joints of early rheumatoid arthritis (ERA) patients, with computed tomography (CT) as the reference method. Twenty ERA patients without erosions on standard radiography of hands and wrists underwent 3DUS and CT evaluation of eleven joints: radiocarpal, intercarpal, ulnocarpal, second to fifth metacarpo-phalangeal (MCP), and second to fifth proximal interphalangeal (PIP) joints of dominant hand. Eleven (55.0%) patients were erosive with CT and ten of them were erosive also at 3DUS evaluation. In five patients, 3DUS identified cortical breaks that were not erosions at CT evaluation. Considering CT as the gold standard to identify erosive patients, the 3DUS sensitivity, specificity, PPV, and NPV were 0.9, 0.55, 0.71, and 0.83, respectively. A total of 32 erosions were detected with CT, 15 of them were also observed at the same sites with 3DUS, whereas 17 were not seen on 3DUS evaluation. The majority of these 3DUS false-negative erosions were in the wrist joints. Furthermore, 18 erosions recorded by 3DUS were false positive. The majority of these 3DUS false-positive erosions were located at PIP joints. This study underlines the limits of 3DUS in detecting individual bone erosion, mostly at the wrist, despite the good sensitivity in identifying erosive patients.

Systematic review of the literature and a case report informing biopsy-proven giant cell arteritis (GCA) with normal C-reactive protein.

Giant cell arteritis (GCA) is a vasculitis of large- vessels. A markedly elevated erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels are characteristics of GCA, although temporal artery biopsy remains the gold standard for the diagnosis. We describe a case of biopsy-proven GCA showing a heavy infiltration of CD68 macrophages and CD3 T cells and with normal ESR and CRP levels at diagnosis. Key points (1) GCA may occur with normal ESR in a percentage of about 4 to 15 % (although the American College of Rheumatology classification criteria for giant cell arteritis include an ESR of 50 mm/h or more), while it can occur with normal ESR and normal CRP in a percentage of about 0.8 %. So, the clinical suspicion must be confirmed with a positive biopsy. (2) GCA patients with ESR >40 mm/h are characterized by higher incidence of headache and jaw claudication compared to patients with normal ESR. In our case, it occurred with normal ESR. (3) Color duplex ultrasonography is a noninvasive, easy, and inexpensive method for supporting a diagnosis of TA, with a high sensitivity and specificity. It can predict which patient will need TAB.

Endothelial progenitors in pulmonary hypertension: new pathophysiology and therapeutic implications.

Pulmonary hypertension is a progressive and disabling disease with as yet unclear pathogenesis, limited treatment options and poor prognosis. This is why the discovery of new pathogenic mechanisms and therapeutic strategies are needed. Endothelial progenitor cells (EPCs) are bone marrow-derived cells involved in endothelial homeostasis, as well as physiological and pathological angiogenesis. Experimental and clinical studies have been conducted to understand the possible contribution of EPCs to the pathogenesis of pulmonary hypertension. Conflicting results have been obtained regarding the protective versus harmful effects of EPCs on the pulmonary vasculature. However, preliminary clinical trials using EPC-based therapies in patients with pulmonary hypertension show benefit of this approach, thus revealing EPCs as potential therapeutic targets. This review critically summarises the complex and conflicting data on EPCs and pulmonary hypertension, in both humans and animals, putting them into the context of lung (patho)physiology. The resulting scenario identifies EPCs as a novel and fascinating tool to study pathophysiology and therapy in the setting of pulmonary hypertension.

[Copernican revolution in the therapy of rheumatoid arthritis: the contribution of anti-TNFalpha drugs]. / La rivoluzione copernicana nella terapia dell'artrite reumatoide: il contributo degli anti-TNFalpha.

TNFalpha has a key role in cell recruitment, proliferation and death, expression of adhesion molecules and immune responses. In RA, TNFalpha is involved in matrix degradation and osteoclastogenesis. TNFalpha inhibitors are either soluble receptors (etanercept) or monoclonal antibodies (infliximab and adalimumab; golimumab and certolizumab are in development). TNFalpha antagonists, alone or in combination with methotrexate, reduce bone erosions and thinning of cartilage, but they differ as regards ligand binding, pharmacokinetics, pharmacodynamics, and clinical indications. Etanercept is the only TNFalpha antagonist that also neutralises LFT-alpha. Infliximab and adalimumab are more immunogenic. Cytotoxicity and cellular lysis are also higher with infliximab and adalimumab. Etanercept slows progression of joint damage in recently diagnosed RA when given alone, but much more when given with methotrexate; anti-TNF monoclonal antibodies also were shown to slow progression alone and in combination with methotrexate. Patients with early and long-standing RA treated with etanercept have now shown improvement in ACR scores, inflammation and disability for up to 9 years. Outcomes with infliximab and adalimumab are similar to those with etanercept, but only in combination with methotrexate. As a result of neutralizing antibodies, increasing doses of anti-TNFalpha antibodies may be required to maintain clinical response. As regards side effects, opportunistic infections seem more frequent with monoclonal antibodies. TNFalpha antagonists produce more QALYs than traditional DMARDs, counteracting higher costs. The efficacy, safety, and quality of life benefits of TNFalpha antagonists suggest using them possibly earlier than today, even in clinically moderate RA. Thanks to its overall profile, etanercept might be considered as one of the first-choices in TNFalpha antagonism in RA management.

The -670G>A polymorphism in the FAS gene promoter region influences the susceptibility to systemic sclerosis.

OBJECTIVE: To evaluate the role of the single-nucleotide polymorphism (SNP) at position -670 in the FAS gene promoter (FAS-670G>A) in influencing the susceptibility, clinical features and severity of systemic sclerosis (SSc). METHODS: 350 white Italian SSc patients (259 with limited cutaneous SSc (lcSSc) and 91 with diffuse cutaneous SSc (dcSSc)) and 232 healthy individuals were studied. Patients were assessed for the presence of autoantibodies (anticentromere, anti-topoisomerase I (anti-Scl-70) antibodies), interstitial lung disease (ILD), pulmonary arterial hypertension and scleroderma renal crisis. FAS-670G>A SNP was genotyped by PCR restriction fragment length polymorphism assay. Serum levels of soluble FAS (sFAS) were analysed by ELISA. RESULTS: A significant difference in FAS-670 genotype distribution was observed between SSc patients and healthy individuals (p = 0.001). The frequency of the FAS-670A allele was significantly greater in SSc than in controls (p = 0.001). No significant difference in genotype distribution and allele frequencies was observed between lcSSc and dcSSc, although a greater frequency of the FAS-670A allele was found in dcSSc. The FAS-670AA genotype significantly influenced the predisposition to SSc (OR 1.97, 95% CI 1.35 to 2.88, p = 0.001) and to both lcSSc (OR 1.84, 95% CI 1.23 to 2.75, p = 0.003) and dcSSc (OR 2.37, 95% CI 1.41 to 3.99, p = 0.001). FAS-670A allele frequency was greater, although not significantly, in anti-Scl-70 antibody-positive dcSSc and ILD dcSSc. sFAS was significantly higher in patients and controls carrying the FAS-670AA genotype compared with those carrying the FAS-670GG genotype (p = 0.003 in SSc, p = 0.004 in controls). CONCLUSION: The FAS-670A allele is significantly associated with susceptibility to SSc, suggesting a role for a genetic control of apoptosis in the pathogenesis of the disease.

A paraneoplastic retroperitoneal fibrosis resistant to corticosteroids treated with tamoxifen.

Retroperitoneal fibrosis (RPF) is a rare disease characterized by an inflammatory proliferative fibrosing process occurring in the retroperitoneum, often causing urinary tract obstruction. Medical therapy is not well-defined, but glucocorticoids have been the mainstay of therapy. Recently, positive response to tamoxifen, an antiestrogen drug, has been reported among patients with RPF. We report the case of a 65-year-old male with a renal cell carcinoma in the upper pole of the right kidney showing acute renal failure due to a biopsy-confirmed RPF determining bilateral hydronephrosis. After polar resection of the right kidney, a high-dose oral steroid therapy did not modify the hydronephrosis. At 6 months, therapy with tamoxifen determined the retroperitoneal fibrotic mass regression and resolved the ureteral obstruction, that persists at the 13th month of follow-up. Tamoxifen can be considered as an effective alternative to corticosteroids and immunosuppressors in treating RPF.

Renal interstitial cells, proteinuria and progression of lupus nephritis: new frontiers for old factors.

Interstitial cells, inflammatory-immune cells, tubular cells and endothelial cells of the peritubular capillaries have arisen as possible major players of the nephron damage in lupus nephritis. Increased ICAM-1, Von Willebrand factor, soluble endothelial protein C receptors and decreased ADAMS-13 point to a diffuse vascular damage. Albuminuria elicits a rapid generation of hydrogen peroxide in proximal tubular cells along with nuclear factor-kB activation, endothelin-1 and transforming growth factor (TGF-beta1) upregulation. TGF-beta1 enhances epithelial-to-mesenchymal transdifferentiation. Albuminuria also enhances the expression of macrophage chemotactic protein-1 and macrophage inflammatory protein-1alpha, thus leading to increased interstitial inflammation. TGF-beta1 and thrombospondin-1, a putative activator of TGF-beta, induce apoptosis of peritubular capillaries, as well as of glomerular endothelial cells. All these events can be counteracted by hepatocyte growth factor (HGF), which is expressed by the epithelial tubular cells and stimulates the growth of epithelial cells (mitogen), enhances the motility of epithelial cells (motogen), induces renal epithelial tubule regeneration (morphogen) and enhances angiogenesis (angiogen). The balance between TGF-beta1 and HGF could be a key to define the prognostic value of kidney histopathology at baseline and during follow-up, in lupus nephritis. Therapeutic strategies aiming at altering the biological balance in the patients are at hand to test and prove the experimental evidences.

Proteomic study of salivary peptides and proteins in patients with Sjögren's syndrome before and after pilocarpine treatment.

OBJECTIVE: To investigate the effect of pilocarpine on the salivary peptide and protein profile in patients with primary Sjögren's syndrome (SS) and to study the differences between patients with primary SS, patients with SS associated with other rheumatic diseases, and healthy control subjects. METHODS: Saliva specimens were obtained from 9 primary SS patients, 9 secondary SS patients, and 10 healthy controls. Samples were analyzed for levels of 62 different salivary proteins using high-performance liquid chromatography coupled with mass spectrometry using a spectrometer equipped with an electrospray ionization source. In 6 of the primary SS patients, saliva was collected at 30 minutes, 60 minutes, and 24 hours after taking 5 mg of pilocarpine. RESULTS: Before pilocarpine, approximately 60% of salivary proteins in samples from primary SS patients were not identifiable or showed lower levels than those in healthy controls. After 30-60 minutes following pilocarpine treatment, approximately one-third of the less represented proteins was found in a similar percentage of primary SS patients and controls. Almost all of the proteins that were detectable at lower levels in primary SS patients compared with controls reached levels similar to those in controls at 30-60 minutes after pilocarpine. The parotid gland proteins had the best response to pilocarpine. Primary SS patients were characterized by higher alpha-defensin 1 levels and by the presence of beta-defensin 2. Secondary SS patients showed an intermediate protein profile between that of the primary SS patients and the controls. CONCLUSION: Pilocarpine partially restored the levels and numbers of identifiable proteins in saliva from patients with primary SS. Higher levels of alpha-defensin 1 and the presence of beta-defensin 2 in the saliva of patients with primary SS could be markers of oral inflammation in this patient group.

Treatment of inclusion body myositis with cyclosporin-A or tacrolimus: successful long-term management in patients with earlier active disease and concomitant autoimmune features.

OBJECTIVE: Sporadic inclusion body myositis (s-IBM) is a chronic, progressive, inflammatory myopathy of unknown aetiology, generally resistant to immunosuppressive therapy. Given that lymphocyte infiltrates in s-IBM muscle tissue are CD8+ T cells, targeting these cells may represent a valid approach. PATIENTS AND METHODS: Three patients with biopsy-proven s-IBM, high creatine kinase levels at diagnosis, two of whom with associated immune disorders, were treated with either cyclosporin-A (CyA) or tacrolimus, in combination with high doses of corticosteroids (CS), followed by rapid CS tapering. Clinical assessment and laboratory evaluation were performed every three months for the first year and then every six months for the second year. RESULTS: Based on muscle strength assessment and muscle enzyme serum levels, a major clinical response was observed at month +3 in two out of the three patients. A complete clinical response and major clinical response were obtained at month +6, in two and one patient, respectively. Normalization of serum muscle enzymes was observed in all. Steroids could be tapered to very low doses in all patients and were suspended early in one. Laboratory, but not clinical relapse occurred in one patient and was controlled by increasing the CyA dose. Treatment was well tolerated, with no serious adverse events occurring. All three patients are maintaining immunosuppressive therapy. CONCLUSION: Calcineurin inhibitors may represent a useful option for the long-term management of s-IBM, possibly in a subset characterized by a short duration with high disease activity or associated autoimmune manifestations.

Switching to etanercept in patients with rheumatoid arthritis with no response to infliximab.

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.

BAFF and rheumatic autoimmune disorders: implications for disease management and therapy.

Interest in B-cells has been revived due to the description of new functions. Supporting a role for B-cells in the genesis of autoimmune diseases is the fact that the B-cell activating factor of the TNF ligand family (BAFF) is essential in their physiology. However, in each disease, this is restricted to a subgroup of patients. Based on experiments in mice, and validated in humans, this new cytokine has been highlighted. Excessive production of BAFF alters immune tolerance by rescuing self-binding B-cells. Overexpression in mice leads to autoimmune manifestation, and BAFF levels are elevated in the serum of autoimmune patients. Similar abnormalities occur in chronic lymphocytic leukemia. Recent works suggest that antagonizing the protein (or competing for its receptors) is relevant to the treatment. Advances in our understanding of the BAFF system offers the opportunity to improve our therapeutic approach.

B-Lymphocyte stimulator (BLyS) up-regulation in mixed cryoglobulinaemia syndrome and hepatitis-C virus infection.

OBJECTIVES: To investigate the role of B-Lymphocyte stimulator (BLyS) in mixed cryoglobulinaemia syndrome (MCsn), a systemic vasculitis associated with a high risk to develop lymphoma, since BLyS up-regulation may favour both autoimmunity and lymphoproliferation. METHODS: BLyS serum levels were analysed by enzyme-linked immunosorbent assay (positive when >0.85 ng/ml) in 66 patients with MCsn, 54 (81.8%) of whom were positive for hepatitis-C virus (HCV) infection. Thirty-three HCV-positive patients without MCsn were also studied. Patients were compared with 48 healthy blood donors (HBDs). BLyS modifications after antiviral therapy were also studied. RESULTS: A significantly higher frequency of BLyS serum positivity was detected both in MCsn patients and in HCV-positive patients without MCsn (37.9 and 30.3%, respectively) when compared with HBDs (4.2%) (P < 0.0001 vs MCsn and P = 0.0026 vs HCV-positive patients without MCsn, respectively). BLyS appeared significantly higher in MCsn (3.70 +/- 2.97 ng/ml) than in HCV-positive patients without MCsn (1.56 +/- 0.63 ng/ml; P = 0.0044). BLyS expression did not correlate with rheumatoid factor levels, cryoglobulin levels or definite MCsn-related systemic features. High BLyS levels were significantly associated only with MCsn-related overt lymphoproliferative disorder. Finally, antiviral treatment significantly increased BLyS levels, independently from HCV-RNA negativization. However, BLyS normalization was noticed after both HCV-RNA negativization and suspension of antiviral therapy by preliminary data. CONCLUSIONS: BLyS is up-regulated and may play a pathogenetic role in a fraction of patients with MCsn, similarly to other autoimmune diseases. HCV infection likely represents the early event leading to BLyS up-regulation in this setting. BLyS is up-regulated during antiviral treatment. Overall, these data provide new insights for BLyS and virus-related autoimmunity, lymphoproliferation and possible treatment strategies.

Consensus statement on the use of rituximab in patients with rheumatoid arthritis.

A large number of experts experienced in the treatment of rheumatoid arthritis were involved in formulating a consensus statement on the use of B cell-targeted treatment with rituximab in patients with rheumatoid arthritis. The statement was supported by data from randomised controlled clinical trials and the substantial literature on oncology. The statement underwent three rounds of discussions until its ultimate formulation. It should guide clinicians in the use of this newly approved biological agent in treating patients with rheumatoid arthritis.