Hepatitis B virus-infection related cryoglobulinemic vasculitis. Clinical manifestations and the effect of antiviral therapy: A review of the literature.

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.

COVID-19 vaccination rate and safety profile in a multicentre Italian population affected by mixed cryoglobulinaemic vasculitis.

OBJECTIVES: Mixed cryoglobulinaemic vasculitis (MCV) is an immune-complex-mediated systemic vasculitis characterised by heterogeneous clinical manifestations mainly involving lymphatic system, skin, kidney and peripheral nervous system. Although MCV patients have been included in priority programs for vaccination against SARS-CoV-2 in Italy, limited information is available for these patients. The aims of this multicentre Italian study were to investigate SARS-CoV-2 vaccination rate in MCV patients and its safety profile. METHODS: All MCV patients referring to participating centres were assessed with an interview-based survey about vaccination, reasons for not getting vaccinated, adverse events (AE), and disease flares within a month after vaccination. RESULTS: A total of 416 patients were included in the study. Among participants, 7.7% did not get vaccinated, mainly for fear related to vaccine side-effects (50%) or medical decision (18.8%). They were more frequently treated with chronic glucocorticoids or rituximab (p=0.049 and p=0.043, respectively). Mild and self-limiting AE were recorded in 31.7% of cases, while post-vaccination vasculitis flares were observed in 5.3% of subjects. Disease relapses were mainly observed in patients with peripheral neuropathy or skin vasculitis (40% and 25%, respectively). CONCLUSIONS: Vaccination against SARS-CoV-2 has been performed in a high percentage of MCV patients with encouraging safety profile. Vasculitis flares rate was in line with that observed for other autoimmune diseases, despite patients with purpura or peripheral neuropathy seem to be at risk for symptoms' exacerbation. Patients' hesitancy, rituximab and glucocorticoids treatment were the main reasons for delaying vaccination.

Management of mixed cryoglobulinemia with rituximab: evidence and consensus-based recommendations from the Italian Study Group of Cryoglobulinemia (GISC).

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.

Hepatitis B Virus-Related Cryoglobulinemic Vasculitis: Review of the Literature and Long-Term Follow-Up Analysis of 18 Patients Treated with Nucleos(t)ide Analogues from the Italian Study Group of Cryoglobulinemia (GISC).

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.

Provisional recommendations for SARS-CoV-2 vaccination in patients with cryoglobulinaemic vasculitis.

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.

Safety and effectiveness of biosimilar of Rituximab CT-P10 in the treatment of cryoglobulinemic vasculitis: the MARBLe study (Mixed cryoglobulinemiA Rituximab BiosimiLar).

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.

Peripheral neuropathy in mixed cryoglobulinaemia: clinical assessment and therapeutic approach.

Peripheral neuropathy (PN) has been detected in up to 69% of patients with mixed cryoglobulinaemic syndrome (MCS). PN should be considered in any patient with sensory and/or motor signs and symptoms in the limbs. Electrodiagnostic tests are mandatory for the diagnosis of PN. Several different sets of diagnostic criteria have been created to assess it. All patients suspected of having neuropathy should undergo a nerve conduction study. A complete neurological evaluation at baseline and periodically should be done possibly by the same neurologists. The authors recommend rigorous scientific evidences that may help to obtain superior tools for accurate diagnosis and management of these conditions. Clinicians, armed with experience and recommendations, can find in this review data-driven guidelines to apply treatments of MCS and closely related disorders.

Recommendations for managing the manifestations of severe and life-threatening mixed cryoglobulinemia syndrome.

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.

HCV-unrelated cryoglobulinaemic vasculitis: the results of a prospective observational study by the Italian Group for the Study of Cryoglobulinaemias (GISC).

OBJECTIVES: To investigate the clinical and laboratory patterns of HCV-unrelated cryoglobulinaemic vasculitis (CV), and the factors influencing its outcome. METHODS: Prospective 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). RESULTS: 175 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. CONCLUSIONS: HCV-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.

A First-Trimester Biomarker Panel for Predicting the Development of Gestational Diabetes.

OBJECTIVE: Serum markers measured early in pregnancy have been associated with the later diagnosis of gestational diabetes mellitus (GDM). This study aims to explore the performance of a panel of first-trimester biochemical markers for the prediction of GDM. METHODS: A case-control study was performed that included 12 women who developed GDM and 60 controls matched for maternal and gestational age at blood collection. Levels of pregnancy-associated plasma protein A (PAPP-A), soluble endoglin, pregnancy protein 13, and adiponectin (Adipo) were measured on residual sera used in first-trimester screening for Down syndrome. Data were analyzed by nonparametric methods. A receiver operating characteristic curve was used to calculate the detection rate (DR) obtained with a panel of significant predictors for GDM. RESULTS: Multiples of the median values for Adipo and PAPP-A were significantly reduced in GDM cases versus matched controls. Combination of Adipo and PAPP-A yielded a DR of 63.6% at a false-positive rate of 10%. Addition of body mass index (BMI) to this panel increased DR to 72.7%. CONCLUSION: This study suggests that first-trimester screening with Adipo, PAPP-A, and BMI may effectively identify women at high risk for the development of GDM.

Hepatitis B virus related cryoglobulinemic vasculitis: A multicentre open label study from the Gruppo Italiano di Studio delle Crioglobulinemie - GISC.

BACKGROUND: Cryoglobulinemic vasculitis (CV) related to Hepatitis-B Virus (HBV) is rare and its treatment is ill-defined. AIMS: To describe clinical and treatment characteristics of HBV-related CV patients. In addition, the efficacy of treatment with antiviral agent nucleotide (NUC), including Entecavir, Adefovir, and Lamivudine, was explored. METHODS: In four Italian centres, 17 HBV-positive CV patients (median age 56 years, range 45-70) were enrolled. RESULTS: The extrahepatic manifestations were: purpura (100%), arthralgias (71%), peripheral neuropathy (29%), chronic hepatitis (47%), liver cirrhosis (29%), and glomerulonephritis (18%). Mixed cryoglobulinemias were type II (88%) and type III (12%). The median cryocrit was 3% (range 1-14), rheumatoid factor was 200U/L (range 20-5850), C4 was 12mg/dl (range 2-31), ALT 71U/L (range 36-114). All patients were HBsAg-positive and 80% anti-HbeAg-positive. At enrollment, they were treated with steroids (eight), Entecavir (five), Alpha-IFN (two), Adefovir and Lamivudine (one each). After NUC treatment, no disease progression was observed and, in all patients, HBV-DNA became undetectable. Moreover, a regression of purpura and a reduction of cryocrit were observed. Four patients died during therapy, two of kidney failure and two of liver cirrhosis. CONCLUSION: NUC therapy appeared to be safe and effective in CV-related HBV.

Pain management in cryoglobulinaemic syndrome.

Cryoglobulinaemic syndrome (CS) includes clinical signs and symptoms that range from the classic triad of Meltzer and Franklin (purpura, weakness and arthralgias) to multiple organ involvement, and it may be characterised by nociceptive or neuropathic pain. Both types of pain use the same pathways and neurotransmitters, but nociceptive pain has an adaptive system and biological function whereas neuropathic pain does not. Managing CS means dealing with often very different clinical patterns, activity and severity with the aim of preventing irreversible organ damage, reducing pain, improving the patients' quality of life and reducing social costs. However, treatment is still largely empirical, and it is often delayed. The Italian Group for the Study of Cryoglobulinaemia (GISC) strongly recommended a low-antigen-content diet and colchicine for all symptomatic CS patients. Patients with mild-moderate symptoms (such as purpura, weakness, arthralgia and initial neuropathy) have been treated with low or medium doses of steroids, and, in the presence of chronic hepatitis C virus (HCV)-related hepatitis, an attempt has been made to eradicate HCV with pegylated interferon plus ribavirin. In the case of severe or rapidly progressive disease (glomerulonephritis, neuropathy, leg ulcers, widespread vasculitis or hyperviscosity syndrome), more aggressive treatment should be used (e.g., high doses of corticosteroids, plasma exchange plus cyclophosphamide or rituximab). Pain management in CS therefore depends on the type of pain (nociceptive, neuropathic or mixed), the characteristics of the patients and their co-morbidities. Drug therapy should be carefully monitored in order to obtain prompt and beneficial results.

Retreatment regimen of rituximab monotherapy given at the relapse of severe HCV-related cryoglobulinemic vasculitis: Long-term follow up data of a randomized controlled multicentre study.

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.

A New APEH Cluster with Antioxidant Functions in the Antarctic Hemoglobinless Icefish Chionodraco hamatus.

Acylpeptide hydrolase (APEH) is a ubiquitous cytosolic protease that plays an important role in the detoxification of oxidised proteins. In this work, to further explore the physiological role of this enzyme, two apeh cDNAs were isolated from the Chionodraco hamatus icefish, which lives in the highly oxygenated Antarctic marine environment. The encoded proteins (APEH-1(Ch) and APEH-2(Ch)) were characterised in comparison with the uniquely expressed isoform from the temperate fish Dicentrarchus labrax (APEH-1Dl) and the two APEHs from the red-blooded Antarctic fish Trematomus bernacchii (APEH-1(Tb) and APEH-2(Tb)). Homology modelling and kinetic characterisation of the APEH isoforms provided new insights into their structure/function properties. APEH-2 isoforms were the only ones capable of hydrolysing oxidised proteins, with APEH-2(Ch) being more efficient than APEH-2(Tb) at this specific function. Therefore, this ability of APEH-2 isoforms is the result of an evolutionary adaptation due to the pressure of a richly oxygenated environment. The lack of expression of APEH-2 in the tissues of the temperate fish used as the controls further supported this hypothesis. In addition, analysis of gene expression showed a significant discrepancy between the levels of transcripts and those of proteins, especially for apeh-2 genes, which suggests the presence of post-transcriptional regulation mechanisms, triggered by cold-induced oxidative stress, that produce high basal levels of APEH-2 mRNA as a reserve that is ready to use in case of the accumulation of oxidised proteins.

Validation of the classification criteria for cryoglobulinaemic vasculitis.

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.

Prevalence of mixed cryoglobulinaemia syndrome and circulating cryoglobulins in a population-based survey: the Origgio study.

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 (54.3% women, 64.5% aged >49years) 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 >70years (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 <16mg/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% CI 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.

Performance of the preliminary classification criteria for cryoglobulinaemic vasculitis and clinical manifestations in hepatitis C virus-unrelated cryoglobulinaemic vasculitis.

BACKGROUND: Cryoglobulinaemic vasculitis (CV) is often related to hepatitis C virus (HCV) infection, but it can develop in other diseases (e.g. other infections, connective tissue diseases, malignancies) in the absence of HCV infection. A comparison of the performance of the recently published classification criteria for the CV was made between HCV-positive and HCV negative patients with serum cryoglobulins. METHODS: 500 patients with serum cryoglobulins were studied. Their mean age was 60.77±13.75 years, they were 356 females (71.2%) and 144 males (28.8%). CV was diagnosed in 272 patients (54.4%), while other diseases associated with serum cryoglobulins without CV (CwV) were diagnosed in 228 patients (45.6%). RESULTS: 117 HCV negative patients were collected (23.4%) and they were 42/272 (15.4%) among the CV group, while they were 75/228 (32.9%) among the CwV. In HCV negative patients the sensitivity and specificity of the classification criteria of CV were 89.5% CI 95% [79.5-99.5] and 90.3% CI 95% [82.8-97.8], respectively, while in HCV positive patients they were 88.3% CI 95% [83.6%-93.1%] and 96.1% CI 95% [91.8-100], respectively. The most frequent disease recognised among the HCV negative patients was Sjögren's syndrome (SS) (55/117, 47.0%), and the sensitivity and the specificity of the CV classification criteria were 88.9% CI 95% [76.5-100] and 91.3% CI 95% [79.2-100], respectively. CONCLUSIONS: The classification criteria for CV showed a good performance even in HCV-unrelated patients. A slightly lower specificity was observed for the classification of HCV-unrelated CV, since some clinical manifestations included in the clinical item for the classification criteria occurred more frequently in HCV-negative rather than HCV-positive controls with CWV.

Efficacy and safety of peginterferon alfa-2b plus ribavirin for HCV-positive mixed cryoglobulinemia: a multicentre open-label study.

OBJECTIVES: The aim of the present study is to provide information on clinical outcome of the patients affected by HCV-positive mixed cryoglobulinemia (MC) treated with PEG-IFN and Ribavirin for 6 or 12 months according to the HCV genotype. METHODS: Eighty-six patients (42 women and 44 men) were enrolled in 8 Italian centres. All the patients had MC in the active phase of the disease. The patients received Peginterferon alfa-2b 1.5 mcg/kg/once a week (QW) and daily oral Ribavirin (800/1,000/1,200) according to their body weight for 48 weeks for genotype 1 and 4 and for 24 weeks for genotypes 2 and 3. RESULTS: In the 44 patients who underwent 12 months of therapy, 17 cases (39%) could be considered as 'non-responders' and 11 relapsed, therefore only 16 patients (36%) obtained a sustained virological response. In the 42 patients who underwent six months of therapy only 7 cases (17%) could be considered as 'non-responders' and 8 relapsed, therefore 27 patients (64%) obtained a sustained virological response. Purpura score dropped in both group (p<5.79 x 10-17) and only 5 cases of the group A (11%) and 5 of the group B (12%) did not show any improvement. Arthralgias showed a similar behaviour. Many patients relapsed after the end of the treatment. CONCLUSIONS: This study documents a lower response rate than that observed in the clinical trials with HCV chronic hepatitis, but the presence of comorbidities and older age should be taken into consideration. Most patients (88.5%) showed a complete and persistent recovery from clinical symptoms.

[Neuroendocrine target therapies for prostate cancer]. / "Neuroendocrine target therapies" per il carcinoma prostatico.

It is important to determine whether an increase in Chromogranin A levels and neuroendocrine (NE) cell activation are associated with progression towards on hormone-independent prostate-cancer. We proposed a combination of estrogens and somatostatin analogues as therapy of NE activation in hormone-independent prostate cancer. The combined therapy with ethinyl estradiol and lanreotide offered objective and symptomatic responses in patients with limited treatment options and refractoriness to conventional hormonal therapy strategies; in particular, it offered a median overall survival that was superior to the 10-month median survival in patients with hormone refractory disease. This combined therapy also sustains the new concept in cancer treatment in which therapies may target not only cancer cells but also its microenvironment, which can yield protection against apoptosis.