Objective Hepatitis B virus (HBV) infection causes chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Furthermore, about 20% of the patients develop extrahepatic manifestations such as cryoglobulinemic vasculitis (CV), polyarteritis nodosa, non-rheumatoid arthritis, glomerulonephritis and non-Hodgkin lymphoma. This review analyzed literature data on clinical manifestations of HBV-related CV and the impact of antiviral therapy with analoques nucleotide. Methods A PubMed search was performed to select eligible studies in the literature, up to July 2022. Results Some studies have analyzed clinical manifestations in HBV-related CV and have investigated the role of antiviral therapy with nucleotides analogues (NAs). Clinical manifestations of CV vary from mild to moderate (purpura, asthenia and arthralgias) to severe (leg ulcers, peripheral neuropathy, glomerulonephritis, and non-Hodking lymphoma). NAs therapy leads to suppression of HBV-DNA; therefore, it is capable of producing clinical response in the majority of patients with mild to moderate symptoms. Conclusion Antiviral therapy with NAs is the first choice for HBV suppression and control of mild to moderate disease. In severe vasculitis (glomerulonephritis, progressive peripheral neuropathy and leg ulcers), rituximab alone or with plasma-exchange is always indicated in combination with antiviral therapy.

Cryoglobulinemic vasculitis (CV) or mixed cryoglobulinemic syndrome (MCS) is a systemic small-vessel vasculitis characterized by the proliferation of B-cell clones producing pathogenic immune complexes, called cryoglobulins. It is often secondary to hepatitis C virus (HCV), autoimmune diseases, and hematological malignancies. CV usually has a mild benign clinical course, but severe organ damage and life-threatening manifestations can occur. Recently, evidence in favor of rituximab (RTX), an anti-CD 20 monoclonal antibody, is emerging in CV: nevertheless, questions upon the safety of this therapeutic approach, especially in HCV patients, are still being issued and universally accepted recommendations that can help physicians in MCS treatment are lacking. A Consensus Committee provided a prioritized list of research questions to perform a systematic literature review (SLR). A search was made in Medline, Embase, and Cochrane library, updated to August 2021. Of 1227 article abstracts evaluated, 27 studies were included in the SLR, of which one SLR, 4 RCTs, and 22 observational studies. Seventeen recommendations for the management of mixed cryoglobulinemia with rituximab from the Italian Study Group of Cryoglobulinemia (GISC) were developed to give a valuable tool to the physician approaching RTX treatment in CV.

People with cryoglobulinaemic vasculitis (CV) have an increased risk of infections, attributed to different causes: impairment of the immune system due to the disease itself, comorbidities, and immunosuppressive therapy. Therefore, these patients may be at high risk for a more severe course of COVID-19, including hospitalisation and death. Concerns about efficacy, immunogenicity and safety of vaccines, as well as doubts, not yet fully clarified in patients with systemic autoimmune diseases, represent other important factors for a low vaccination rate in people with (CV). Indeed, providing an expert position on the issues related to SARS-CoV-2 vaccination in patients suffering from CV is of critical relevance in order to help both patients and clinicians who are treating them in making the best choice in each case. A multidisciplinary task force of the Italian Group for the Study of Cryoglobulinaemia (GISC) was convened, and through a Delphi technique produced provisional recommendations regarding SARS-CoV-2 vaccination in cryoglobulinaemic patients.

Hepatitis B virus (HBV) chronic infection causes progressive liver damage, although about 20% of patients develop extrahepatic manifestations such as cryoglobulinemic vasculitis (CV). Clinical manifestations range from mild to moderate (purpura, asthenia, arthralgia) to severe (leg ulcers, peripheral neuropathy, glomerulonephritis, non-Hodgkin lymphoma). A comprehensive review of therapeutic options for HBV-related CV is lacking. Nucleos(t)ide analogues (NA) suppress HBV replication in 90–100% of cases and induce clinical response in most patients with mild-to-moderate CV. Plasma exchange can be performed in patients with severe CV and should be considered in severe or life-threatening cases combined with high doses of corticosteroids and antiviral treatment. A cautious use of rituximab can be considered only in association with NA treatment in refractory cases. A review of the literature and an analysis of data collected by six centers of the Italian Group for the Study of Cryoglobulinemia on 18 HBV-CV nucleotide/nucleoside analogues (NAs)-treated patients were carried out.

Rituximab (RTX) represents a milestone in the treatment of mixed cryoglobulinemic vasculitis (MCV). Despite usually well-tolerated, RTX may induce different types of adverse drug reactions, including exacerbation of vasculitis. Recently, RTX biosimilar CT-P10 has been approved in Europe for the treatment of rheumatoid arthritis, but no data are available about effectiveness and safety of CT-P10 in the treatment of MCV. In this multicenter open-label study, we analyzed the safety of CT-P10 in patients with MCV treated in first-line or after a shift by RTX originator. Fifty-one consecutive MCV patients (females/males 35/16, median age 68 years, median disease duration 42 months, 51% HCV positive) were included in the study between July and December 2018 and were treated with CT-P10 (group 1). Safety and effectiveness of CT-P10 were compared with a retrospective group (group 2) including 75 consecutive patients treated with RTX originator between July 2017 and July 2018. Thirty-six patients were treated with CT-P10 for the first time, while the other 15 switched from RTX originator. RTX was administrated with high or dosage schemes (375 mg/m2 four times a week apart/1000 mg twice one week apart or 250 mg/m2 twice one week apart). During a month period after the last infusion, 13/51 adverse events (AE) were observed in group 1 and 17/75 in group 2 (p not significant). Among them, 7/13 and 6/17 (in group 1 and 2, respectively) could be considered immune-mediated AE (p not significant). At univariate analysis patients with IM-AE were more frequently males (p = 0.04) and with a lower disease duration (p = 0.03), but both the parameters were not significant at logistic regression. About clinical response after 6 months by the end of the treatment, no differences were observed between patients treated with originator and CT-P10 regarding the response to the therapy. No differences were observed in safety and effectiveness between patients naïve at RTX or switching from originator. Despite the higher prevalence of immune-mediated AE among patients treated with CT-P10 than originator, we have observed no significant differences between the 2 groups. The use of a low-dosage regimen is more common in group 1 than in group 2, representing a possible bias of the study, possibly influencing the appearance of AE. Considering the cost/efficacy ratio of biosimilars, their use could be helpful to treat a large number of MCV patients with an effectiveness and safety comparable to originator. Multicenter studies including a large number of patients and the new RTX biosimilars could be useful to fully elucidate the possible risk of immune-mediated adverse events with biosimilar drugs. Considering the cost/efficacy ratio of CT-P10, its use could help to treat a large number of MCV patients with an effectiveness and safety comparable to originator.

OBJECTIVE:Some of the manifestations of mixed cryoglobulinemia syndrome (MCS) can be severe or life-threatening, and should be rapidly contained but, as the therapeutic approaches to such conditions are largely based on anecdotal data, a consensus conference was organised by the Italian Group for the Study of Cryoglobulinemia (GISC) with the aim of providing a set of recommendations based on an in-depth survey of the available data and expert opinion.METHODS:The consensus panel, which included specialists working in different medical fields involved in the management of MCS patients, was first asked to divide the manifestations of MCS into severe or life-threatening conditions on the basis of their own experience, after which a complete literature review was carried out in accordance with the Cochrane guidelines for systematic reviews.RESULTS:Therapeutic plasma exchange (TPE) was considered the elective first-line treatment in the case of life-threatening manifestations of MCS (LT-MCS) and patients with severe clinical symptoms (S-MCS) who fail to respond to (or who are ineligible for) other treatments. The data supporting the combined use of cyclophosphamide and TPE were considered limited and inconclusive. High-dose pulsed glucocorticoid (GCS) therapy can be considered the first-line treatment of severe MCS, generally in association with TPE. Rituximab (RTX)-based treatments should be considered in patients with skin ulcers, peripheral neuropathy or glomerulonephritis, and in patients with persistent LT-MCS after TPE. In patients with hepatitis C virus-related MCS with S-MCS, viral eradication should be attempted as soon as a patient's condition allows the use of direct-acting antivirals.

Background: The powerful drugs with direct antiviral action (DAA) against hepatitis C virus (HCV) has made it possible to eliminate the trigger factor of Mixed Cryoglobulin Syndrome (MCS) and to extend the treatment to patients who could not tolerate IFN-based antiviral regimens. However, the persistence of cryoglobulin production and MCS-related symptoms despite SVR achievement is frequently reported. Objectives: The aim of this study was to assess the persistency rate of MCS-related clinical and laboratory indexes after successful treatment with DAA. Methods: CRESO (CRyoglobulinaemia Eradication Study Observational) is a multicentre observational study promoted by the Italian Society of Infectious and Tropical Diseases (SIMIT) and the Italian Group for the Study of Cryoglobulinaemias (GISC), aimed to assess the impact of DAA therapy on MCS symptoms and cryoglobulin production. Patients could be enrolled if they presented, during the 12 months before the enrolment, a cryocrit ≥0.5% and, at least, one episode of palpable purpura or, alternatively, arthralgia and fatigue with at least one symptom among peripheral neuropathy, Raynaud’s phenomenon, lower limb ulcers or nephropathy, and a C4 level ≤8 mg/dL. Results: The present analysis was based on clinical and laboratory data of 94 patients (75.5% female with a median age of 67.5 years) that have been followed up for a median time of 24 weeks (IQR 12-24) after SVR12 achievement. At baseline the cryocrit was frankly positive in 85 (90.43%), detectable (>0.5%) in 4 and negative in 4 cases; patients with type II cryoglobulins and C4levels ≤8 mg/dL were prevalent, respectively with 81.5% and 75.9%. Low eGFR values (≤45 mL/min/1.73m2) were present in 12 cases (12.8%), 10 patients (10.6%) had a history of B-cell non-Hodgkin’s lymphoma (NHL), and 1 of hepatocellular carcinoma, while liver cirrhosis was diagnosed in 22 cases (23.4%) and glomerulonephritis in 17 cases (18.1%). Patients were treated for 12 (72 cases) or 24 (21 cases) weeks with a total of ten different IFN-free DAA regimens. SVR12 was achieved in all 94 cases. Both prevalence and median cryocrit values decreased significantly after DAA treatment (p<0.0001), however, at the time of the last observation 56.4% of patients were still positive for MCs. The prevalence of purpura and fatigue significantly decreased (p<0.0001) as well sicca syndrome prevalence (p<0.015), while arthralgia and lower limb ulcers decrease did not reach statistical significance. In multivariate analysis, eGFR≤45 mL/min/1.73m2 was an independent predictor of persistence of cryoglobulin production (AOR 7.7, CI 95% 1.6-37.2; p<0.011). Conclusion: CRESO study data confirm the persistence of cryoglobulin production and MCS symptoms in some patients, despite the eradication of HCV. This finding rises questions about the possible further evolution of the disease over time regardless the persistence of its original trigger. Disclosure of Interests: None declared

OBJECTIVESTo investigate the clinical and laboratory patterns of HCV-unrelated cryoglobulinaemic vasculitis (CV), and the factors influencing its outcome.METHODSProspective study of all anti-HCV and HCV-RNA negative patients with CV who have been observed since January 2004 in 17 centres participating in the Italian Group for the Study of Cryoglobulinaemias (GISC).RESULTS175 enrolled were followed up for 677 person-years. The associated conditions were primary Sjögren's syndrome (21.1%), SLE (10.9%), other autoimmune disorders (10.9%), lymphoproliferative diseases (6.8%), solid tumours (2.3%) and HBsAg positivity (8.6%), whereas 69 patients (39.4%) had essential CV. There were significant differences in age (p<0.001), gender (p=0.002), the presence of purpura (p=0.005), arthralgia (p=0.009), liver abnormalities (p<0.001), sicca syndrome (p<0.001), lymphadenopathy (p=0.003), splenomegaly (p=0.002), and rheumatoid factor titres (p<0.001) among these groups. Type II mixed cryoglobulins were present in 96 cases (54.9%) and were independently associated with purpura and fatigue (odds ratio [OR]4.3; 95% confidence interval [CI] 1.8-10.2; p=0.001; and OR2.8; 95%CI 1.3-6.3; p=0.012). Thirty-one patients died during follow-up, a mortality rate of 46/1000 person-years. Older age (for each additional year, adjusted hazard ratio [aHR] 1.13; 95%CI 1.06-1.20; p<0.001), male gender (aHR 3.45; 95%CI 1.27-9.40; p=0.015), type II MCG (aHR 3.31; 95%CI 0.09-1.38; p=0.047) and HBsAg positivity (aHR 7.84; 95%CI 1.20-36.04; p=0.008) were independently associated with greater mortality.CONCLUSIONSHCV-unrelated CV is a multifaceted and often disabling disorder. The associated conditions influence its clinical severity, giving rise to significantly different clinical and laboratory profiles and outcomes.

Globe artichoke (Cynara cardunculus L. subsp. scolymus) hybrids are not Mendelian F-1 with the consequent uniformity postulated by Mendel. This is due to the fact that hybrids are not originated from crosses between two pure lines; in fact, globe artichoke suffers strong inbreeding depression. Hence, the hybrid uniformity is one of the most important characteristics together with their improved characteristics for quality and morphological traits. To select hybrids lines, to be introduced for fresh consumption and industry processes, some uniform lines with promising characteristics have been selected in California in spring 2014 and evaluated in two contrasting environments such as the California desert of Brawley (33 degrees 02'48"N; 115 degrees 31'43"W) in spring 2014 and the Italian Mediterranean environmental conditions of Ladispoli (Rome) (41 degrees 57'29"N; 12 degrees 07' 10"E) in spring 2015. The same procedures have been also adopted in the following year. The characteristics distribution among the evaluated hybrids has been studied utilizing multivariate and regression analyses. Hybrids have been also characterized by molecular markers to assess their genetic distance and parents' effects. Hybrids, on the base of their morphological traits, could be divided into 3 or 4 clusters the most important traits to discriminate the hybrids in all the years are earliness, spiny, distance between main head and first shoot, head shape, receptacle shape, bracts density, bract shape, and bract color. Hereditability values, of some important traits such as: earliness, plant height, presence of spines, presence of mucron, colour, head shape, and head compactness, have been estimated in globe artichoke. The differences between maternal and paternal hereditability are also reported and discussed.

Artichoke [Cynara cardunculus var. scolymus (L.) Fiori], one of the most important Italian vegetables, presents the typical problems of a multi-year crop with lack of contemporary production, heterogeneity of the genetic material and often uncertain phytosanitary conditions. The almost exclusive cultivation of traditional local landraces along with the agamic propagation are obstacles to the development of the artichoke nursery and to the rational agronomic management of the crop. Seeded artichoke implies a substantial quality and quantity improvements since it (i) reduces the bedding costs due to the lower initial ones of the young plants, (ii) enhances the phytosanitary conditions of cultivation, reducing the uprising of diseases that usually cannot be seed transmitted, (iii) reduces the use of fertilizers and the need of watering, thanks to the development of a deep root system by the plant, (iv) shows a full productive capability from the first year. Within a close and long collaboration among Tuscia University, ENEA, and BHSC, research aimed at creating seed propagated materials that allows to develop artichoke hybrids lines capable of modernizing the artichoke crop. The seed propagated hybrids 'Romolo' and 'Istar', both without spines, were recently released. 'Romolo' is a hybrid of Romanesco type, medium late growing, high productive and uniform with green-violet and round-shaped heads characterized by tender heart and sweet taste. It is sown in late spring and is harvested at the end of winter/early spring of the following year. 'Istar', re-flowering hybrid selected from the 'Imperial Star' American cultivar, has a very early growth; if seeded in late spring, it starts its fructification in November continuing until the following spring. This is a high productive genotype with brilliant green heads that, if harvested during winter, shows a slightly violet shading off on the calyx. The hybrids, 'Romolo' and 'Istar', both suitable for fresh consumption, are already commercialized by Top Seed s.r.l. in Italy where, in the same time, the nursery technique of artichoke is developed, so far lacking in the country for producing healthy and low cost seedlings.

Within the frame of REBIOCHEM project funded by the Italian Ministry of Education, University and Research within the cluster on Green Chemistry, the paper aims at (i) assessing the potential ability of different cardoon accessions in terms of biomass production, (ii) selecting the most interesting genotypes and stabilizing them for genetic performances, (iii) evaluating selected genotypes for salt tolerance. Six accessions were evaluated by previously established morphological descriptors along a 3-year experiment, while 29 new accessions were recently collected and are currently being analyzed; all germplasm is now grown in a regional farmland of central Italy. Levels of genetic diversity in relation to biomass production and relatedness among accessions have been assessed. Development of stable selected lines is in progress. Some cardoon genotypes have been selected for specifically targeted raw material utilization such as aboveground biomass for extraction of useful compounds. The versatility of the cardoon biomass suggests its use as feedstock for different purposes, also implying an added value to the crop within a biorefinery context.

Verticillium dahliae is recognized as one of the main fungal diseases limiting crop yields. Grafting could represent an important integrated strategy to manage this soilborne pathogen of artichoke, as commonly made in high value Solanaceae and Cucurbitaceae crops. In addition, grafting application allows to grow and valorize in a sustainable way traditional landraces of artichoke in soils where the fungus is present endemically. Out of 51 cultivated and wild cardoon accessions, screened for resistance to the fungus, nine of them have been selected as resistant rootstocks. In order to develop the best grafting technique, the tongue and the cleft ones have been compared, applying them onto wild and cultivated cardoon rootstocks; the artichoke F-1 hybrid 'Romolo' has been used as scion. In the cleft grafting, shoot re-growth from the rootstock was observed; this criticism, not evidenced in the tongue grafting, could be anyway overcome by cotyledon elimination. Anatomical and physiological study of grafting union formation, performed by Scanning Electron Microscopy (SEM), showed that the cleft procedure assures the best contact surface between bionts. The vessel distribution and their number can be related to the wounded surface cicatrisation. In relation to artichoke yield and quality, the grafted plants did not show any significant differences with respect to the ungrafted ones. Thereby, the high grafting cost could be overcome by cultivating, despite stress conditions, artichoke high quality genotypes.

In the last half century the world population has doubled to 7 billion, while the land under cultivation increased just by 12%, from 1.37 to 1.53 billion ha. In what manner, then, did agricultural production triple? By increasing productivity, with a combination of improved agronomical practices and improved crops. In this context the exploitation of plant heterosis has been an effective approach in crop enhancement, hybrid cultivars in major crops can show more than 20% yield advantage over the best conventional ones under the same cultivation conditions. In this attempt, trying to meet commercial and industrial needs, academy (University of Tuscia, Italy) and industry (BHS, USA) encountered over again aiming to produce artichoke commercial hybrid seed through the use of male sterility. The project started in 2007, with 3 male sterile clones and 5 stable open pollinated cultivars, since then, more than 200 male sterile clones and 20 open pollinated cultivars have been developed to produce more than 500 crosses; around 30 of them, with interesting agro-morphological traits and uniformity, have been tested in different countries of the new and old world. The selected hybrids are under evaluation to assess their reproducibility and possibility of success in the global seed market. The different market requests in term of artichoke typologies and quality characteristics, which vary between the fresh market (green, purple, spiny, ovate, round heads) and the processing industry market characterized for green ovate typologies; hence it is required to allow the production/ registration of a wide range of hybrids covering the different requests. Currently, one hybrid of Romanesco type, named 'Romolo' has been registered in Italy and is been sold successfully by La Semiorto Sementi srl. and its commercial firm Top Seed. The project results show how artichokes hybrids combine advantages that contribute to more vigorous plant growth, earliness, healthier plants which require lower input in pesticides and fungicides. In addition, plants from seeds are cheaper than plants derived by meristem practices. In other words, seed planting is a viable approach that makes globe artichoke friendlier both to the grower and to the environment.

Globe artichoke (Cynara cardunculus var. scolymus L. Fiori) is a traditional component of the Mediterranean diet, it is considered a rich source of phenolic compounds. Globe artichoke production is traditionally based on vegetatively propagated varietal types. As for pathologic and economic disadvantages of the former multiplication method, Italian artichoke breeding programs have produced some potential seed propagated hybrids. An experiment was conducted to assess the yield, mineral and polyphenolic profiles of two potential seed-propagated F-1 hybrid 'Istar' and 'Romolo'. The artichoke yield recorded on 'Romolo' was significantly higher by 33% in comparison to 'Istar'. The N and K concentrations were significantly lower by 25.5% and higher by 10.1%, respectively, in 'Romolo' in comparison to 'Istar'. Among the macronutrients studied, K was the mineral with the higher concentration, with a mean of 24.9 g kg(-1) dw. In addition, the Na concentration and Na/K ratio observed in both cultivars were low. Amongst the caffeoylquinic acids, 5-O-caffeoylquinic acid and 1,5-diO-caffeoylquinic acid were the main compounds. The remaining caffeoylquinic acids (i.e., 1- and 3-O-caffeoylquinic acids, 3,4-, 3,5- and 4,5-di-O-caffeoylquinic acids) were minor compounds in the analyzed samples. Regarding the cultivar effect, the 5-O-caffeoylquinic acid, apigenin 7-O-glucoronide, total caffeoylquinic acids, total apigenin derivatives, were significantly higher in 'Romolo' by 23.1, 180.0, 20.5, and 149.5%, respectively, in comparison to 'Istar', suggesting that specific cultivar should be selected to obtain the desired profile of bioactive compounds. Overall, the seed-propagated cultivars can represent a suitable alternative to the vegetative propagated ones, thus opening new perspectives for the artichoke production.

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 Sjögren's 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

Objective: To evaluate the efficacy and safety in the long term of a retreatment regimen with Rituximab (RTX) alone administered at clinical relapse in cryoglobulinemic vasculitis (CV).Methods: Thirty patients with severe HCV-related CV, previously enrolled in the multicentre Italian trial on RTX in the treatment of CV, were retrospectively evaluated after the end of the trial. All of them were managed with RTX alone at clinical relapse, if any. Disease activity at the last available follow up was defined as complete remission (absence of active disease), partial remission (response > 50% of at least one manifestation among glomerulonephritis, peripheral neuropathy or skin ulcers) or active disease.Results: The mean follow up after the first RTX cycle was 72.6 (20.4) months. After the end of the trial, 21/30 (70%) patients showed an active follow up [81.7 (10.9) months)], 3/30 (10%) lost follow up and 6/30 (20%) died. 12/21 (57.1%) patients were in complete disease remission, 5/21 (23.8%) showed a partial response and 4/21 (19%) had an active disease.17/30 (56.7%) patients needed retreatment for relapse with a mean time to retreatment of 22.3 (12.1) months. Treatment survival of this regimen was 7.6 (0.3) years. Recurrent non-severe infections occurred in 3/30, with chronic hypogammaglobulinemia in 2/3 patients.Conclusions: A long-term regimen of retreatment with RTX alone given at clinical relapse seems to be effective and safe in CV, with a low rate of infections and severe hypogammaglobulinemia. (C) 2015 Elsevier Ltd. All rights reserved.

Cryoglobulinaemic vasculitis (CV) is a systemic vasculitis affecting small and medium-sized vessels that is caused by immune complexes of cryoprecipitating immunoglobulins and is sustained by benign B-cell clonal proliferation. Palpable purpura is the clinical hallmark of the disease; other classic symptoms are asthenia and arthralgia. The clinical diagnosis of CV must be confirmed by the detection of cryoglobulins. The most frequent pathological trigger is hepatitis C virus (HCV) and it is likely that the prevalence of HCV infection in different geographical areas is decisive in determining the local CV incidence. Systemic autoimmune diseases are probably the second leading cause of CV. Other associated conditions include malignancies and chronic liver disorders. The biochemical mechanisms of cryoprecipitation are not fully understood and this may be different in monoclonal and mixed cryoglobulins. The therapeutic approach to CV should have three objectives: to remove the causes (HCV or other underlying diseases); to block the pathogenetic mechanisms (suppressing B-lymphocyte proliferation); and to reduce the symptoms, including pain.

OBJECTIVE:The aim of this study was to validate the classification criteria for cryoglobulinaemic vasculitis (CV).METHODS:Twenty-three centres were involved. New patients with CV (group A) and controls, i.e. subjects with serum cryoglobulins but lacking CV based on the gold standard of clinical judgment (group B) and subjects without cryoglobulins but with clinical features that can be observed in the course of CV (group C), were studied. Positivity of serum cryoglobulins was necessary for CV classification. Sensitivity and specificity of the criteria were calculated by comparing group A vs group B. The group A vs group C comparison was done to demonstrate the possible diagnostic utility of the criteria.RESULTS:The study included 268 patients in group A, 182 controls in group B and 193 controls in group C (small vessel vasculitis, 51.8%). The questionnaire (at least 2/3 positive answers) showed 89.0% sensitivity and 93.4% specificity; the clinical item (at least 3/4 clinical involvement) showed 75.7% sensitivity and 89.0% specificity and the laboratory item (at least 2/3 laboratory data) showed 80.2% sensitivity and 62.4% specificity. The sensitivity and specificity of the classification criteria (at least 2/3 positive items) were 89.9% and 93.5%, respectively. The comparison of group A with group C demonstrated the clinical utility of the criteria in differentiating CV from CV mimickers.CONCLUSION:Classification criteria for CV were validated in a second, large, international study confirming good sensitivity and specificity in a complex systemic disease.

Mixed cryoglobulinaemia syndrome (MCS) is associated with a number of infectious, autoimmune and lymphoproliferative disorders, particularly chronic hepatitis C infection. Although circulating mixed cryoglobulins (cMCGs) are a frequent finding in HCV-infected patients, only a minority of them develop a frank MCS. The only available data concerning the prevalence of MCS, which is generally considered a rare disease, come from hospital records. The aim of this investigation was to estimate the prevalence of cMCGs and MCS in a population-based study.All of the adult residents in Origgio, a town of about seven thousand inhabitants in northern Italy, were mailed a validated questionnaire, and a randomly selected sample of respondents was invited to undergo a clinical examination and laboratory tests including the determination of cMCGs. The 1594 respondents to the questionnaire (543% women, 64.5% aged > 49 years) accounted for 26.4% of the total adult population. Forty-nine (3.1%) positively responded to at least two questions, including a disproportionately high number of people aged > 70 years (p = 0.001). Of the 266 randomly selected subjects invited to undergo a clinical examination and laboratory tests, 147 accepted, 30 (20.4%) of whom had asymptomatic type III cMCGs and four MCS. The risk of cMCG positivity was independently associated with C4 levels of < 16 mg/dL (adjusted odds ratio [AOR] 4.40, 95% confidence interval [CI] 1.07-18.08; p = 0.040) and HCV positivity (AOR 6.87, 95% Cl 1.16-40.79; p = 0.034). No co-morbidities known to be related to cMCG production could be detected in more than 50% of the positive cases. After including the other positive respondents who agreed to undergo a clinical examination, the number of diagnosed MCS increased to seven: five HCV-related, one HBV-related, and one essential MCS.In conclusion, MCS seems to be more frequent than expected for a 'rare' disease, and the unexpectedly high prevalence of cMCGs raises questions about the frequency with which they are triggered, the spectrum of diseases involved in triggering them, and their real role as disease indicators. (C) 2014 Elsevier B.V. All rights reserved.