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Objective To conduct a long-term, prospective, randomized controlled trial evaluating rituximab (RTX) therapy for severe mixed cryoglobulinemia or cryoglobulinemic vasculitis (CV). Methods Fifty-nine patients with CV and related skin ulcers, active glomerulonephritis, or refractory peripheral neuropathy were enrolled. In CV patients who also had hepatitis C virus (HCV) infection, treatment of the HCV infection with antiviral agents had previously failed or was not indicated. Patients were randomized to the non-RTX group (to receive conventional treatment, consisting of 1 of the following 3: glucocorticoids; azathioprine or cyclophosphamide; or plasmapheresis) or the RTX group (to receive 2 infusions of 1 gm each, with a lowering of the glucocorticoid dosage when possible, and with a second course of RTX at relapse). Patients in the non-RTX group who did not respond to treatment could be switched to the RTX group. Study duration was 24 months. Results Survival of treatment at 12 months (i.e., the proportion of patients who continued taking their initial therapy), the primary end point, was statistically higher in the RTX group (64.3% versus 3.5% [P < 0.0001]), as well as at 3 months (92.9% versus 13.8% [P < 0.0001]), 6 months (71.4% versus 3.5% [P < 0.0001]), and 24 months (60.7% versus 3.5% [P < 0.0001]). The Birmingham Vasculitis Activity Score decreased only after treatment with RTX (from a mean ± SD of 11.9 ± 5.4 at baseline to 7.1 ± 5.7 at month 2; P < 0.001) up to month 24 (4.4 ± 4.6; P < 0.0001). RTX appeared to be superior therapy for all 3 target organ manifestations, and it was as effective as conventional therapy. The median duration of response to RTX was 18 months. Overall, RTX treatment was well tolerated. Conclusion RTX monotherapy represents a very good option for severe CV and can be maintained over the long term in most patients.

s / Digestive and Liver Disease 48S (2016) e1–e17 e5 eGFR was ≥60mL/min/1.73m2 in 92 patients (93.8%) and between45and59mL/min/1.73m2 in6patients (6.1%).Glomerular involvement was found in 19 patients (19.4%), tubular involvement in 31 (31.6%) and they co-occurred in 10 patients (p=0.034). Subjects with glomerular or tubular involvement, or both, showed significantly lower eGFRvalues (p=0.005). AROC curvewasdrafted and a cut point of 90ml/min predicted renal involvement (RI) (sensitivity 63%, specificity 75%), although it was unable to distinguish tubular vs glomerular involvement (p=0.914). Patients with RI were older, had higher ACR and 1MCR levels and exhibited a more severe KDIGO stage. No association was found between RI and: HCV-RNA levels, liver stiffness and liver function tests. L-FABP andKIM-1 levelswere significantlyhigher inpatientswithRI. Tubular involvement was significantly associated with increased levels of L-FABPandKIM-1,while glomerular involvementwas associated only with high L-FABP level. Conclusion: Tubular and/or glomerular involvement are quite frequent in HCV cirrhotic patients. The occurrence of eGFR

Mixed cryoglobulinaemia (MC) is a systemic vasculitis, secondary to the deposition in small and medium-sized blood vessels of circulating immune complexes, mainly the cryoglobulins, and complement. MC is characterised by a typical clinical triad (purpura, weakness, arthralgias) and by one or more organ involvement: chronic hepatitis, glomerulonephritis, peripheral neuropathy, skin ulcers and diffuse vasculitis. In a limited number of MC patients, a malignancy, that is B-cell non-Hodgkin's lymphoma or hepatocellular carcinoma, may also develop. Hepatitis C virus (HCV) infection has been found in the majority of patients with MC; the frequency of HCV markers (91%) was significantly higher than other rheumatic diseases (6.4%), namely systemic lupus, Sjùgren's syndrome, rheumatoid arthritis and systemic sclerosis, or healthy controls (1.2%). The HCV infection of lymphoid tissues may represent the remote event leading to B-lymphocyte proliferation responsible for autoantibodies and immune-complex production. In a similar way, HCV infection may also be involved in the pathogenesis of other autoimmune (glomerulonephritis, thyroiditis, lung fibrosis, autoimmune hepatitis, porphyria cutanea tarda) and lymphoproliferative disorders (monoclonal gammopathies, B-cell lymphomas). MC shares numerous clinico-serological and pathological features with the above disorders. HCV seems to be their common etiological agent; however, a variable combination of unknown co-factors (infectious, genetic, environmental) should be determinant for the appearance of different clinical patterns.

The possibility of hepatitis B virus (HBV) infection in HBsAg-negative patients has been shown. However, an "inapparent" coinfection by HBV in hepatitis C virus (HCV)-positive patients generally is not taken into account in clinical practice. Mechanisms responsible for resistance to interferon (IFN) have not been completely clarified. The aim of this study was to investigate whether an "inapparent" coinfection by HBV in anti-HCV-positive chronic liver disease patients may influence IFN response. Fourteen anti-HCV positive, HBsAg-negative but serum HBV DNA-positive patients by PCR and 111 anti-HCV-positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis were treated with 3 MU of recombinant alpha-2a IFN 3 times weekly for 12 months. Serum HBV DNA and HCV RNA were determined before treatment, after 6-12 months and in coincidence with ALT flare-up by PCR. HBV PCR was performed using primers specific for the S region of the HBV genome and HCV PCR with primers localised in the 5'NC region of HCV genome. IgM anti-HBc was tested using IMx Core-M Abbott assay. By the end of treatment, ALT values had become normal in 4/14 HBV DNA-positive patients (28%), but all "responders" (4/4) relapsed between 2 and 5 months after therapy. All but one patient were HCV RNA-positive before treatment, 6 were also both HBV DNA and HCV RNA-positive during ALT flare-ups. In 5 patients, only HBV DNA and in 3 patients, only HCV RNA was detected when transaminase values increased. All patients remained HBsAg-negative and anti-HCV-positive. IgM anti-HBc was detected both before treatment and during ALT elevation in 3 patients and only during ALT relapse in 3 others. Of the 111 anti-HCV positive, HBsAg-negative and HBV DNA (PCR)-negative patients with chronic hepatitis, a biochemical response to IFN treatment was observed in 54% of the cases. Relapse of ALT values was observed in 47% of the cases during a follow-up of 1 year after treatment. "Inapparent" HBV/HCV coinfection may be implicated in cases of resistance to IFN treatment. In addition, HBV replication may persist in patients in whom HCV replication was inhibited by IFN treatment. The pathogenic role of HBV in liver disease was confirmed by detection of IgM anti-HBc in some cases; the appearance of these antibodies only after IFN treatment suggests that IFN may exert a selective role in favour of HBV. Further studies will show the effect of different treatment schedules. HBV DNA and/or IgM anti-HBc detection with very sensitive methods may be important both as a prognostic factor and as a tool for better understanding interviral relationships and mechanisms involved in multiple hepatitis virus infections.

(C-X-C motif) ligand 9 and (C-X-C motif) ligand 11 (CXCL9 and CXCL11), are potent chemoattractants for activated T cells, and play an important role in T helper 1 (Th)1 cell recruitment in chronic hepatitis C. No study has evaluated CXCL9, together with CXCL11, circulating levels in patients with mixed cryoglobulinemia and hepatitis C (MC+HCV-p). The aim of the present study therefore was to measure serum CXCL9, and CXCL11 levels, in MC+HCV-p, and to relate the findings to the clinical phenotype. Serum CXCL9 and CXCL11 were measured in 71 MC+HCV-p and in matched controls. MC+HCV-p showed significantly higher mean CXCL9 and CXCL11 levels than controls (P less than 0.001, for both), in particular, in 32 patients with active vasculitis (P less than 0.001). By defining high CXCL9 or CXCL11 level as a value of at least 2 SD above the mean value of the control group ( greater than 100 pg/mL): 89 percent MC+HCV-p and 5 percent controls had high CXCL9 (P less than 0.0001, chi-square); 90 percent MC+HCV-p and 6 percent controls had high CXCL11 (P less than 0.0001, chi-square). In a multiple linear regression model of CXCL9 vs age, ALT, CXCL11, only CXCL11 was significantly (r = 0.452, P less than 0.0001) and independently related to CXCL9. Our study demonstrates in MC+HCV-p vs controls: (i) high serum CXCL9, and CXCL11, significantly associated with the presence of active vasculitis; (ii) a strong relationship between circulating CXCL9 and CXCL11. Future studies on a larger cohort of patients are needed to evaluate the relevance of serum CXCL9 and CXCL11 determination as clinico-prognostic marker of MC+HCV.

No data are present in the literature regarding chemokine (CXC motif) ligand (CXCL)9 and CXCL11 circulating levels in cryoglobulinemia associated with hepatitis C (MC+HCV), in presence/absence of autoimmune thyroiditis (AT). Serum CXCL9 and CXCL11 have been measured in 38 MC+HCV patients without AT (MCo), 38 MC+HCV patients with AT (MC+AT), and in matched controls without (control 1) or with thyroiditis (control 2). Serum CXCL9 and CXCL11 were significantly higher: in control 2 than control 1 ( p

Objective: To compare the clinico-serological features of arthritis from two HCV+ patient groups characterised by mixed cryoglobulinemia (MC) or chronic hepatitis (CH). Methods: We retrospectively studied 157 MC patients (119 females, mean age 64.8 yrs, range 36-88) and 155 CH patients (103 females, mean age 58.8 yrs, range 30-81). Patients with HBV and/or HIV co-infections and a follow-up shorter than 1 year were excluded. MC was classified according to standard criteria, while CH classification was based on Desmet’s criteria. Results: No differences in epidemiology were demonstrated between the two series of patients. Although significantly prevalent in MC patients, extra-hepatic manifestations including nephropathy, neuropathy, pneumopathy, mixed cryoglobulins, RF positivity and hypocomplementemia were detected in both patient groups. Arthritis was present in 23 CH (15%) and 12 MC (8%) patients. A symmetrical polyarthritis was observed in 87% of 23 CH patients, while cryoglobulinemic arthritis was invariably asymmetrical and pauciarticular. Unlike MC patients, who had a constantly nonerosive arthritis, in 7/23 CH patients arthritis was erosive. Steroids and/or hydroxycloroquine or D-penicillamine were safe and useful in controlling the arthritis over the short-medium time, although clinical response was more evident in MC patients. Instead, in 5/23 CH and 3/12 MC patients, interferon-alpha treatment was able to trigger or exacerbate the arthritis despite a good control of liver function. Conclusions: HCV infection seems to be, possibly in genetically predisposed patients, responsible for arthritis at times similar to rheumatoid arthritis. In these patients a careful assessment of the interferon-alpha treatment is mandatory owing to the potential ‘arthritogenic effect’ due to its immunoregulatory properties.

Background To develop preliminary classifi cation criteria for the cryoglobulinaemic syndrome or cryoglobulinaemic vasculitis (CV). Methods Study part I developed a questionnaire for CV to be included in the formal, second part (study part II). Positivity of serum cryoglobulins was defi ned by experts as an essential condition for CV classifi cation. In study part II, a core set of classifi cation items (questionnaire, clinical and laboratory items, as agreed) was tested in three groups of patients and controls—that is, group A (new patients with the CV), group B (controls with serum cryoglobulins but lacking CV) and group C (controls without serum cryoglobulins but with features which can be observed in CV). Results In study part I (188 cases, 284 controls), a positive response to at least two of three selected questions showed a sensitivity of 81.9% and a specifi city of 83.5% for CV. This questionnaire was employed and validated in study part II, which included 272 patients in group A and 228 controls in group B. The fi nal classifi cation criteria for CV, by pooling data from group A and group B, required the positivity of questionnaire plus clinical, questionnaire plus laboratory, or clinical plus laboratory items, or all the three, providing a sensitivity of 88.5% and a specifi city of 93.6% for CV. By comparing data in group A versus group C (425 controls), the same classifi cation criteria showed a sensitivity 88.5% and a specifi city 97.0% for CV. Conclusion Classifi cation criteria for CV were developed, and now need validation.

Hepatitis C virus (HCV) chronic infection may be associated with a great number of both hepatic and extrahepatic manifestations. HCV lymphotropism is responsible for poly-oligoclonal B-lymphocyte expansion, which is the common underlying alteration in a significant percentage of HCV-infected individuals. The consequent production of different autoantibodies and immune-complexes, including cryoglobulins, may lead to organ- and non-organ-specific immunological alterations. Mixed cryoglobulinemia, a small-vessel systemic vasculitis, is characterized by the coexistence of autoimmune and lymphoproliferative alterations; therefore, it represents the prototype of HCV-associated disorders. Moreover, HCV shows an oncogenic potential; several studies support its pathogenetic link with some malignancies, mainly hepatocellular carcinoma and B-cell lymphomas. On the whole, HCV-related disorders present a heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. While the majority of HCV-infected individuals is asymptomatic or may develop only liver manifestations, a significant percentage of them may develop a variable combination of autoimmune lymphoproliferative disorders. The resulting multiform clinico-pathological condition can be termed HCV syndrome. The natural history of HCV syndrome is the expression of multifactorial and multistep pathogenetic process, which usually proceeds from mild, often isolated manifestations to systemic immune-mediated disorders, and less frequently to overt malignancies.

No study evaluates serum levels of CXCL10 and CCL2 chemokines in patients with hepatitis C associated mixed cryoglobulinaemia.To measure circulating CXCL10 and CCL2 in cryoglobulinaemic patients.Serum CXCL10 and CCL2 were assayed in 70 consecutive cryoglobulinaemic patients, and in 2 control groups (1:1, gender- and age-matched) of healthy (controls), or of chronic hepatitis C subjects without cryoglobulinaemia.Cryoglobulinaemic patients showed higher CXCL10 serum levels than controls (p0.0001), or hepatitis C patients (p=0.001) (389 +/- 141, 91 +/- 51, 311 +/- 142 pg/ml, respectively). By defining a "high CXCL10" as a value at least 2 S.D. above the mean value of the control group (193 pg/ml), 79% of cryoglobulinaemic patients, 5% of the controls and 69% of hepatitis C patients had high CXCL10 (p0.0001). CXCL10 levels were (p0.01) increased in cryoglobulinaemic patients with active vasculitis, with respect to those without (445+/-108, 339 +/- 161 pg/ml, respectively). Cryoglobulinaemic patients showed significantly higher CCL2 serum level than controls (p0.01), but not than hepatitis C patients (541 +/- 493, 387 +/- 173 and 451 +/- 281 pg/ml, respectively).Our study first demonstrates high serum levels of CXCL10 and CCL2 chemokines in cryoglobulinaemic patients. Circulating CXCL10 is higher overall in cryoglobulinaemic patients with active vasculitis, suggesting a prevalence of the Th1 immune response in this phase.

Background Serum cryoglobulins (SC) may be found in many diseases (1), and the presence of serum cryoglobulins is a known risk factor for lymphoma evolution in some non malignant diseases. Objectives The aim of this study was to distiguish the role of cryoglobulinemic vasculitis (CV), classified according to the recent validated criteria (1,2), and primary Sjogren9s syndrome (pSS) as risk factors of lymphoma in patients positive serum cryoglobulins. Importantly, SC, CV and pSS may occur together. Methods 950 charts from consecutive patients with positive SC were evaluated. Patients carrying both pSS and HCV infection, as well as incomplete charts, were excluded. Results 657 patients with SC were selected, 374 with CV and 283 without CV, according to the published criteria (2,3). PSS, classified according to the American-European Group Criteria was present in 96 patients (44 with CV, 52 without). Lymphoma was reported in 61/657 (9.8%) patients with SC. Among them, CV was present in 44/61 (72,1%; 14 also with pSS), and pSS in 17/61 (27,9%; and 14/17 had CV). Patients with SC with CV showed an higher prevalence of lymphoma than patients with SC without CV (44/374, 11.5% vs.17/283, 6.3%; p=0.025, OR=1.93 [95%IC: 1.08-3.39]. Patients with pSS, SC and CV also showed a higher prevalence of lymphoma than patients with pSS, SC but without CV (14/44, 31.8% vs. 3/52, 7.4%; p=0.001, OR=7.62 [95%CI 2.02-28.74]. CV and pSS were confirmed as independent risk factor for lymphoma by multivariate analysis (OR 2,18 95%CI 1,18-3,83, p=0,012; OR 2,65 95%CI 1,04-6,76, p=0,042, respectively). Infection by the hepatitis C virus (HCV) was detected in 467/561 (83,2%) patients with SC without pSS, and did not statistically predispose to lymphoma when associated with CV in this subset (p=1,0). Conclusions Cryoglobulinemic vasculitis and pSS are independent risk factors for lymphoma in patients with evidence of SC. Patients with both the conditions (CV and pSS) have the highest risk. In the follow-up of SC positive patients, a very high attention should be deserved to pSS, in particular when CV is present. References De Vita S, et al. Ann Rheum Dis. 2011; 2) Quartuccio L, et al. Rheumatology (Oxford). 2014 Disclosure of Interest None declared

s / Digestive and Liver Disease 47S (2015) e1–e18 e13 escape the demonstration of arterial hypervascularity, CEUS must be performed immediately after conventional US to contrast the malignant fate of small lesions arising in cirrhotics. http://dx.doi.org/10.1016/j.dld.2015.01.030

Hepatitis C virus (HCV) causes hepatitis, liver cirrhosis and hepatocellular carcinoma, and may also induce type II mixed cryoglobulinemia syndrome (MC), a disease characterized by clonal B-cell lymphoproliferations that can evolve into non-Hodgkin's lymphoma (NHL). Interleukin-1 (IL-1) is a cytokine that plays an important role in initiating the cascade of events of immunoinflammatory responses through costimulation of T lymphocytes, B-cell proliferation, induction of adhesion molecules and stimulation of the production of other inflammatory cytokines. The role of IL-1 in immunoinflammatory responses is highlighted by the presence of endogenous regulators (IL-1 receptor antagonist, soluble receptors type 1 and II, human IL-1 accessory protein) that, when secreted into the blood stream may serve as endogenous regulators of IL-1 action. The aim of this study was to evaluate whether abnormalities in the blood levels of IL-1beta IL-1 receptor antagonist, soluble IL-1 receptor type II and human IL-1 accessory protein in HCV+ patients are associated with development of MC and/or NHL. Relative to healthy controls, we observed: i) an increase in the circulating levels of IL-1beta in HCV+ patients simultaneously affected by NHL; ii) increased levels of IL-1 accessory protein in patients singly infected by HCV; iii) increase of IL-1 receptor antagonist in HCV+ patients and in those affected also by NHL with or without MC; iv) a homogeneous increase of sIL-1R type II in all the subgroup of patients. These data indicate that an attempt to increased circulating levels of IL-1 inhibitors occurs at different extent in the course of HCV infection as well as in its progression to NHL and/or MC.

Background Two independent controlled randomized trials demonstrated the efficacy and safety of rituximab (RTX) monotherapy in severe cryoglobulinemic vasculitis (CV) (1, 2), with one reporting a prolonged follow-up (1). Objectives To report the very long term efficacy and safety of RTX monotherapy in severe CV since a regimen of RTX monotherapy was maintained after the end of the abovementioned trial (1). Methods Long term follow up data of a trial of RTX in severe CV (1) were analysed. During this follow-up, only RTX monotherapy was used. Disease activity at the last follow-up visit, adverse events and survival were registered. Clinical response was evaluated at the last follow-up visit, and was scored as follows: i) complete remission (no activity), partial remission (response >50% of at least one manifestation among glomerulonephritis, severe neuropathy or skin ulcers) (1), and active disease. Results After the end of the 2-year controlled trial (1), follow-up data were available in 36 patients undergoing RTX, all HCV positive. The mean follow up after the beginning of RTX therapy (1) was 70.22±20.41 months, including 29 patients followed for more than 4 years (78.4±12.6 months) and 7 patients followed for 2.4-4 years (36.4±6 months). Of them, 3 patients were lost from follow-up shortly after the end of the trial, and 9 patients died. Of the remaining 24 patients, 14/24 (58.3%) showed complete clinical remission at the last follow-up, 6/24 (25%) a partial remission, while 4/24 (16.7%) had an active disease. A first repeated RTX course (1 g two weeks apart) was required in 50% of the patients (12/24), while 25% of the patients (6/24) needed more than one course, for a total of 19 retreatments. Patients were retreated for nephritis (7/19), neuropathy (6/19), skin ulcers (7/19) or diffuse purpura (6/19). Three patients underwent a maintenance RTX regimen, all with 1 g × 2 every 6 months, with a complete and partial remission at the last follow-up noticed in 2/3 and 1/3, respectively. Recurrent infections occurred only in three patients (8%; urinary and upper respiratory), and they were related to persistent hypogammaglobulinemia in 2/3. Death occurred in 9 patients, all showing persistent active disease. Conclusions A long-term RTX therapy lasting several years is effective and safe in about two thirds of the patients with severe CV. The advantage of retreatment at relapse regimen instead of a maintenance therapy, and whether this may occur in a further subset of patients, needs further investigation. References De Vita S, et al. Arthritis Rheumatol. 2012;64(3):843-53. Sneller MC, et al. Arthritis Rheumatol. 2012;64(3):835-42. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.3872

S. Bruno1, S. Bollani1, A.L. Zignego2, V. Calvaruso3, C. Magni4, S. Landonio4, M. Rizzetto5, A. Ciancio5, A. Mangia6, V. Piazzolla6, M. Caremani7, S. Piovesan8, L. Cavalletto9, S. Babudieri9, A. Moretti 10, C. Colletta11, M. Massari12, S. Fangazio13, F. Mazzotta14, L. Muratori15, A.E. Colombo16, M. Zuin17, A. Traverso18, T. Santantonio19, F. Farina20, E. Marchionne21, G. Serviddio22, M. Russello23, A. Licata24, A. Craxi3, V. Di Marco3 1 Internal Medicine, AO Fatebenefratelli e Oftalmico, Milano, Italy 2 Internal Medicine, Universita di Firenze, Italy 3 Gastroenterology, Universita di Palermo, Italy 4 Infectiuos Diseases, Ospedale Sacco, Milano, Italy 5 Gastroenterology, Universita di Torino, Turin, Italy 6 Liver Unit, IRCCS Casa del Sollievo e della Sofferenza, San Giovanni Rotondo, Italy 7 Infectious Diseases, Azienda Ospedaliera, Arezzo, Italy 8 Internal Medicine, Universita di Padova, Italy 9 Infectious Disease, Universita di Sassari, Italy 10 Gastroenterology, San Filippo Neri, Roma, Italy 11 Internal Medicine, COQ Ospedale Madonna del Popolo, Omegna, Italy 12 Infectious Diseases, IRCCS – ASMN Reggio Emilia, Italy 13 Internal Medicine, Universita di Novara, Italy 14 Infectious Diseases, Azienda Ospedaliera, Siena, Italy 15 Internal Medicine, Universita di Bologna, Italy 16 Gastroenterology, Ospedale S. Anna, Como, Italy 17 Internal Medicine, Universita di Milano, Italy 18 Infectious Disease, AOU, Parini, Aosta, Italy 19 Infectious Diseases, Universita di Foggia, Italy 20 Infectious Diseases, Ospedale Ca Foncello, Treviso, Italy 21 Infectious Diseases, AOU Ospedali Riuniti, Ancona, Italy 22 Internal Medicine, Universita di Foggia, Italy 23 Liver Unit, ARNAS Garibaldi, Catania, Italy 24 Liver Unit, Universita di Palermo, Italy

Background Mixed cryoglobulinemia syndrome (MCS) is a HCV-related, invalidating lymphoproliferative disorder (LPD) whose manifestations are related to a systemic vasculitis. The pathogenesis of MCS is a multistep process involving a strong and sustained B-cell proliferation and genetic events on the basis of host predisposing factors [1]. Standard of care (SOC: PegIFN+RBV) anti-HCV therapy is now the first therapeutic option in HCV+ MCS, however, due to its side effects, the therapeutic decision is often difficult, especially in MCS patients with HCV-G1/4 [2]. Consequently, the possibility to better predict the therapy outcome would be precious. In hepatitis C, genetic variations in the IL28B gene, are strongly associated with the response to anti-HCV therapy [3]. Nowadays, IL28B polymorphisms in HCV-related MCS has been never investigated and it is not possible to exclude that the complex modifications of the immune system characterizing MCS could modify its predictive value. Objectives The aim of this study was to evaluate the role of IL28B genotype in influencing the response to IFN-based treatment and in predisposing to MCS. Methods The IL28B polymorphism was investigated by using allele-specific real-time PCR tecniques in 515 HCV-positive patients: 267 with MCS and 248 without MCS or any LPD (controls). Results A comparable distribution of the IL28B alleles (rs12979860/rs8099917) for HCV-positive patients with and without MCS was recorded, suggesting that this polymorphism do not play a major role in conditioning MCS evolution. Among the 267 HCV-MCS, 123 patients completed a SOC anti-HCV treatment and at least 24 weeks of follow-up. A significant correlation between IL28B major allele homozygosis and MCS response was observed (p=0.0021); the clinical response almost coincided with the virological one. The logistic regression analysis defined the IL28B genotype as a strong independent predictor of MCS response (p=0.0069, odds ratio 6.11; C.I. 1.58-21.22). According to HCV genotype, the predictive value was limited to the most frequent and difficult-to-treat HCV genotypes. Conclusions For the first time, we showed that in HCV-G1/4-MCS patients, IL28B genotype is an useful predictor of response to IFN-based therapy. This would greatly help in the management of this difficult category of HCV patients. This study also suggests that IL28B genotype do not influence the evolution of HCV infection to MCS References Zignego AL, Giannini C, Ferri C: Hepatitis C virus-related lymphoproliferative disorders: an overview. World J Gastroenterol 2007, 13:2467-2478. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2011, 55:245-264. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009; 461:399-401 Disclosure of Interest None Declared

Background the preliminary Classification Criteria for cryoglobulinemic vasculitis (CV) have been developed in 2011 by an European cooperative study (1). Objectives to validate these Classification Criteria for CV with the participation of non-European Countries. Methods 20 Centres from Europe, Egypt, and Japan partecipated. New consecutive, unselected patients with CV (Group A) and controls (subjects with cryoglobulins without a CV based on the golden standard clinical judgment; Group B) were studied. A sample size of 140 patients for each group was estimated to obtain a sensitivity (SE) and a specificity (SP) of at least 90±5%, according to the previous results (1). A dedicated chart was distributed to the Centres. The sensitivity and specificity of the 2011 Classification Criteria were calculated in the present validation series by comparing Group A versus Group B. Results 251 patients in Group A and 175 controls in Group B were recruited. The questionnaire (at least 2/3 positive answers) showed a SE of 89.2% (95% CI 85.4-93.1) and a SP of 93.7% (95% CI 90.1-97.3); the clinical item (at least 3/4 clinical items among constitutional, articular, vascular and neurologic involvement) showed a SE of 76.1% (95% CI 70.8-81.4) and a SP of 88.6% (95% CI 83.8-93.9), and the laboratory item (at least 2/3 tests, among positive rheumatoid factor, low C4, and the presence of serum monoclonal component) showed 75.1% (95% CI 69.5-80.7) of SE and 71.5% (95% CI 64.6-78.4) of SP. The final 2011 Classification Criteria (at least 2/3 positive items) showed a SE of 89.3% (95% CI 85.3-93.3) and a SP of 93.9 % (95% CI 90.3-97.6). Conclusions: Conclusion : The 2011 International Classification Criteria for the cryoglobulinemic vasculitis have been validated in a new cohort of real cases and controls. Patients where CV is suspected on clinical grounds, but where cryoglobulins are negative, cannot be classified, since positive serum cryoglobulinemia is a conditio sine qua non for classification (1). However, the performance of these criteria on this subset of patients is under evaluation. References De Vita S, et al. Ann Rheum Dis 2011;70:1183-90. Disclosure of Interest None Declared

Material and methods: 418 consecutive NUC-naive patients with chronic hepatitis B were recruited in 18 Liver Units in Italy and treated with ETV 0.5 mg for 30 months (2-38). Liver function tests and HBV DNA, assessed by a sensitive assays, were performed every 3 months. Virological breakthrough was defined as >1 log U increase of viremia, a “blip” was the reoccurrence of detectable viremia ( 9.0) and ALT were elevated in 85% of the patients. During ETV treatment, 90% of the patients achieved undetectable HBV DNA: virological response rates were 67%, 86%, 92%, 95% and 96% at month 6, 12, 18, 24, and 30. The corresponding features for ALT normalization were 69%, 81%, 85%, 87% and 93%. After achieving undetectable HBV DNA, few patients had blips of viremia which were not confirmed in the following visits in the vast majority of cases. Primary non response at week 12, partial virological response at week 48 and virological breakthroughs occurred in < 1%, 14% and < 1% of the patients. TDF was added to ETV in 17 patients with partial virological response. Of the 39 partial virologial responders at week 48 not rescued with TDF and followed for additional 6-9 months, only 20 (50%) cleared viremia spontaneously. No major safety issues were reported. Median serum creatinine remained unchanged during treatment: from 0.90 (0.50-9.0) at baseline to 0.90 (0.91 (0.50-8.0) mg/dl at the last visit. A greater than 0.3 or 0.5 mg/dl increase of serum creatinine in the last visit versus baseline occurred in 3% and 0.6% of the patients, respectively. Blood phosphorus levels dropped below 2.3 mg/dl in 1% of the patients. Conclusions: The vast majority of NUC-naive patients treated with ETV monotherapy in field practice achieved and maintained a virological response through 30 months.

s of the A.I.S.F. Annual Meeting 2010 /Digestive and Liver Disease 43S (2011), S65–S108 S71