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Type II cryoglobulinemia is a rare disorder characterized by abnormal immunoglobulins (Igs) precipitating in the blood at low temperatures and redissolving upon warming. Sjogren's disease (SjD) is an autoimmune disorder involving secretory gland malfunction that leads to persistent dryness of the mouth and eyes. Here, we report the case of a 61-year-old woman with a 7-year history of SjD who was diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). However, her complicated clinical features could not be sufficiently explained by this disease alone. Immunofixation electrophoresis revealed monoclonal IgM-κ and polyclonal IgG-κ. The presence of precipitated cryoglobulin and elevated rheumatoid factor levels confirmed a diagnosis of type II cryoglobulinemia for this patient. To the best of our knowledge, this case represents the first report of a patient with CLL/SLL, SjD, and type II cryoglobulinemia, which increased our understanding of immune system-related disorders. Because certain similar mechanisms are involved in the pathogenesis of these three diseases, a combination treatment of rituximab, ibrutinib, and dexamethasone resulted in a favorable prognosis for this patient., Competing Interests: Declaration of conflicting interestThe authors declare that there is no conflict of interest.

Mixed cryoglobulinemia vasculitis (MCV) is caused in ~90% of cases by chronic hepatitis C virus (HCV pos MCV) and more rarely by hepatitis B virus (HBV) infection, or apparently noninfectious. HCV pos MCV develops in only ~5% of patients with chronic hepatitis C (CHC), but risk factors other than female gender have not been identified so far. We conducted a retrospective case control study investigating whether past active HBV infection, defined by hepatitis B surface antigen (HBsAg) seroclearance and anti-core antibody (HBcAb) positivity, could be a risk factor for developing HCV pos MCV. The prevalence of HBsAg seroclearance was 48% within 123 HCV pos MCV patients and 29% within 257 CHC patients (p=0.0003). Multiple logistic regression including as variables gender, birth year, age at HBV testing, cirrhosis, and hepatocellular carcinoma, confirmed an association of HBsAg seroclearance with HCV pos MCV [adjusted odds ratio (OR) 2.82, 95% confidence interval (95% CI) 1.73-4.59, p<0.0001]. Stratification by gender, however, showed that HBsAg seroclearance was associated with HCV pos MCV in male [OR 4.63, 95% CI 2.27-9.48, p<0.0001] and not in female patients [OR 1.85, 95% 95% CI 0.94-3.66, p=0.076]. HBsAg seroclearance, and more likely occult HBV infection, is an independent risk factor for HCV pos MCV in male CHC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Morrone, Fiorilli, Cinti, Roberto, Ferri, Visentini, Pulsoni, Spinelli, De Santis, Antonelli, Basili, Tosti, Conti and Casato.)

Purpose: Cryoglobulinemia is a pathological condition characterized by the presence of cryoglobulins in the blood, with cryoglobulinemic glomerulonephritis being the most frequent form of renal involvement. Fanconi syndrome presents as a generalized dysfunction of the proximal tubule, characterized by the presence of polyuria, phosphaturia, glycosuria, proteinuria, proximal renal tubular acidosis, and osteomalacia. We aimed to present five cases co-occurring with Fanconi syndrome and cryoglobulinemia., Methods: We retrospectively summarized the cases of five patients with Fanconi syndrome and cryoglobulinemia at Peking Union Medical College Hospital from January 2012 to June 2022. The clinical features, diagnosis, treatment, and prognosis were systematically analyzed., Results: All five patients exhibited typical features of Fanconi syndrome, and cryoglobulinemia was concurrently detected in all cases. These patients also exhibit positive anti-nuclear antibody spectrum and hyperglobulinemia, and IgM constitutes the predominant monoclonal component in cryoglobulins. In addition to supplemental treatment, timely immunosuppressive therapy may potentially benefit the long-term renal prognosis of patients with this condition., Conclusion: Our findings highlight the rare co-occurrence of Fanconi syndrome and cryoglobulinemia in clinical practice. Despite the lack of causal evidence, the coexistence of Fanconi syndrome and tubulointerstitial injury is also noteworthy in patients with cryoglobulinemia, underscoring the importance of thorough evaluation and tailored management in patients presenting with overlapping renal manifestations. Key Points • Patients with mixed cryoglobulinemia can clinically present with tubulointerstitial injury, specifically manifesting as Fanconi syndrome. • In addition to typical symptoms of Fanconi syndrome, these patients also exhibit positive anti-nuclear antibody spectrum and hyperglobulinemia, while IgM constitutes the monoclonal component in cryoglobulins. • Timely immunosuppressive therapy may improve long-term renal prognosis in these patients., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

Background and Aims: Direct-acting antivirals (DAAs) usually lead to improvement/remission of cryoglobulinemic vasculitis (CV), although symptoms may persist/recur after a sustained virological response (SVR). We evaluated hematological and genetic markers in patients with HCV-SVR vasculitis with and without persisting/recurring symptoms to early predict the CV outcome., Approach and Results: Ninety-eight patients with HCV-CV were prospectively enrolled after a DAA-induced SVR: Group A: 52 with complete clinical response; Group B: 46 with symptom maintenance/recurrence. Monoclonal B-cell lymphocytosis, t(14;18) translocation, and abnormal free light chains κ/λ ratios were detected by flow cytometry or nested-PCR or nephelometry in 4% Group A versus 17% Group B (P = 0.04) patients, 17% Group A versus 40% Group B patients (P = 0.02), and 17% Group A versus 47% Group B (P = 0.003) patients, respectively. At least 1 out of 3 clonality markers was altered/positive in 29% of Group A versus 70% of Group B patients (P < 0.0001). When available, pretherapy samples were also tested for t(14;18) translocation (detected in 12/37 [32%] Group A and 21/38 [55%] Group B) and κ/λ ratios (abnormal in 5/35 [14%] Group A and 20/38 [53%] Group B) (P = 0.0006), whereas at least one clonality marker was detected/altered in 16/37 (43%) Group A and 30/38 (79%) Group B (P = 0.002). CV-associated single-nucleotide polymorphisms were tested by real-time PCR. Among them, notch4 rs2071286 T minor allele and TT genotype showed a higher frequency in Group B versus Group A (46% vs. 29%, P = 0.01, and 17% vs. 2%, P = 0.006, respectively)., Conclusions: Hematological or genetic analyses could be used to foresee the CV clinical response after DAA therapy and could be valuable to assess a rational flowchart to manage CV during follow-up., (© 2021 The Authors. Hepatology published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background: Some HCV patients present low/non-detected C2 hemolytic activity (C2h) without apparent consumption of other Complement components (selective low/non-detected C2h)., Aim: Characterization of the immunologic/clinical basis of this phenomenon., Methods: C2h, HCV-viral load, cryoglobulinemia and Complement components were determined in 726 HCV patients, with sequential C2h determination in 189 patients., Results: C2h was non-detected in 15.9%, low in 16.9% and normal in 67.2% subjects and showed temporal oscillation in 30.7% of patients. Samples with selective non-detected C2h presented lower C3/C4 than those with normal C2h, but still within the normal C3/C4 range. Selective non-detected C2h was associated with higher aspartate aminotransferase (AST) (p<0.001), alanine transferase (ALT) (p = 0.03) and APRI (Aspartate aminotransferase-to-Platelet Ratio Index) (p<0.001), lower serum albumin (p = 0.01) and platelet count (p = 0.012), more individuals at pre-treatment stage, with detectable HCV-RNA p<0.001), cryoglobulinemia (p<0.001) and with HCV genotype 3 (p = 0.003). Elevated ALT, HCV genotype 3, active disease and viral load were independent predictors of low/non-detected C2h. In vitro exposure of normal serum to exogenous HCV cryoglobulins caused dose-dependent decrease in C2h., Conclusions: Selective C2h decrease is a sensitive marker of Complement activation in HCV patients and is associated with cryoglobulinemia, active disease, elevated ALT, higher viral load, and HCV genotype 3., Competing Interests: Conflict of interest None declared., (Copyright © 2021 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

The aim of this study is to explore the role of labial minor salivary gland (LMSG) focus score (FS) in stratifying Sjögren's Syndrome (SS) patients, lymphoma development prediction and to facilitate early lymphoma diagnosis. Ιn an integrated cohort of 1997 patients, 618 patients with FS ≥ 1 and at least one-year elapsing time interval from SS diagnosis to lymphoma diagnosis or last follow up were identified. Clinical, laboratory and serological features were recorded. A data driven logistic regression model was applied to identify independent lymphoma associated risk factors. Furthermore, a FS threshold maximizing the difference of time interval from SS until lymphoma diagnosis between high and low FS lymphoma subgroups was investigated, to develop a follow up strategy for early lymphoma diagnosis. Of the 618 patients, 560 were non-lymphoma SS patients while the other 58 had SS and lymphoma. FS, cryoglobulinemia and salivary gland enlargement (SGE) were proven to be independent lymphoma associated risk factors. Lymphoma patients with FS ≥ 4 had a statistically significant shorter time interval from SS to lymphoma diagnosis, compared to those with FS < 4 (4 vs 9 years, respectively, p = 0,008). SS patients with FS ≥ 4 had more frequently B cell originated manifestations and lymphoma, while in patients with FS < 4, autoimmune thyroiditis was more prevalent. In the latter group SGE was the only lymphoma independent risk factor. A second LMSG biopsy is patients with a FS ≥ 4, 4 years after SS diagnosis and in those with FS < 4 and a history of SGE, at 9-years, may contribute to an early lymphoma diagnosis. Based on our results we conclude that LMSG FS, evaluated at the time of SS diagnosis, is an independent lymphoma associated risk factor and may serve as a predictive biomarker for the early diagnosis of SS-associated lymphomas., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Hepatitis C virus (HCV) represents the major risk factor for mixed cryoglobulinemia (MC), a small-vessel vasculitis that may evolve into an overt B-cell non-Hodgkin's lymphoma. Here, we aimed to identify a biomarker signature for the early diagnosis of minimal residual disease (MRD). We assessed free light chains (FLCs), IgM k,and IgM λ heavy/light chain (HLC) pairs, and vascular endothelial growth factor (VEGF) in sera from 34 patients with MC vasculitis (32 HCV- and 2 HBV-related), treated with low-dose rituximab (RTX). FLCs and IgM HLCs were measured by turbidimetric assay; VEGF by an enzyme-linked immunosorbent assay. After RTX, the positive (complete + partial) clinical and laboratory responses were of 85.29% and 50%, respectively; in contrast, the mean levels of FLCs, IgM HLCs, and VEGF were substantially unaffected in most patients and still above the normal range. In those achieving a reduction of FLCs and IgM k and λ chains values within the range of normality, we found that post-treatment free λ chains and IgM k values correlated with clinical and laboratory response. Our results suggest that high levels of FLCs, IgM HLCs, and VEGF could represent the signature of "dormant" B cell clones' activity that could be very useful to identify MRD indicative of possible relapse or worsening outcome., (© 2020 International Union of Biochemistry and Molecular Biology, Inc.)

Cryoglobulins consist of serum immunoglobulins that precipitate below 37°C and resolubilize upon warming. The clinical triad of cryoglobulinemia usually includes purpura, weakness, and arthralgia. Cryoglobulinemic syndrome, clinically defined as a systemic vasculitis, is associated with chronic infection with hepatitis C virus (HCV) and autoimmune disorders and can evolve into B-cell malignancies. While the current literature about HCV-associated cryoglobulinemia is not very limited, little is known about the immunologic and serologic profiles of affected patients. Therefore, comprehension of the pathogenetic mechanisms underlying cryoprecipitation could be very helpful. Due to the persistence of viral antigenic stimulation, biomarkers to use after the worsening progression of HCV infection to lymphoproliferative and/or autoimmune diseases are widely needed. Laboratory methods used to detect and characterize low concentrations of cryoprecipitates and immunotyping patterns could improve patient management. The most critical factor affecting cryoglobulin testing is that the pre-analytical phase is not fully completed at 37°C., Competing Interests: Competing interests The authors have no conflicts of interest to disclose., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The hepatitis C virus-positive (HCV+) mixed cryoglobulinaemia (MC) is associated with haematological alterations such as monoclonal B-cell lymphocytosis or non-Hodgkin lymphomas (NHLs). Antiviral therapy for MC, based on interferon and ribavirin, has been shown to be able to eliminate the viral replication as well as the B-cell monoclonal alterations. Many studies have reported the efficacy of direct-acting antivirals (DAAs) in the treatment of HCV+ MC. However, some authors noticed the persistence of haematological diseases despite HCV eradication. To verify the effects of DAAs on B-cell proliferation, we evaluated 67 patients with HCV+ MC. Six patients had an overt NHL and 30% had monoclonal B-lymphocytosis. In 20% of the patients, the mutation L265P of the myeloid differentiation factor 88 (MYD88) gene was detected in peripheral blood. All patients had negative HCV viraemia at week 12; one had a breakthrough, while two cases relapsed. A complete clinical response of vasculitis was seen in 60% of the patients. Among the six patients with NHL, one showed a complete response, whereas in the others there were no changes in the number and size of the nodes. Among the patients carrying a clonal population in peripheral blood, only 22% became negative. These data indicate that DAAs are not able to eliminate the clonal alterations induced by HCV in a large proportion of cases., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

Background: Many cutaneous manifestations have been described in possible association with the COVID-19 pandemic, including acral lesions resembling chilblains. The underlying pathomechanisms of COVID-19 chilblains are not fully understood. The aim of this study was to describe the clinical, pathological, and laboratory findings of a series of patients who developed chilblains during the COVID-19 outbreak and to investigate the possible factors that could be involved in the pathogenesis of these lesions., Methods: We conducted a prospective cohort study that included 54 patients who presented with chilblains during the highest peak in the incidence of COVID-19 in Cantabria (northern Spain). Skin biopsies were performed on 10 of these patients who presented with recent lesions. Laboratory investigations, including immunological analysis, serological studies, and the assessment of cryoproteins, were also performed., Results: Most patients presented erythematous plaques located on the toes and/or purpuric macules located on the feet. Histopathological findings were compatible with those of idiopathic chilblains. Immunohistochemical evaluation showed C3d and C4d deposits in the vessel walls in seven cases. The autoimmunity panel was negative in most of our series. Cryoprotein testing showed positive cryofibrinogen in two-thirds (66.7%) of the patients assessed. On follow-up, most patients presented almost complete resolution, although six patients required prednisone and antiaggregant drug treatment., Conclusions: This study shows, for the first time to our knowledge, a high prevalence of cryofibrinogenemia in patients with chilblains during the COVID-19 pandemic. Cryofibrinogenemia could be implicated in the pathogenesis of chilblains related to COVID-19., (© 2020 the International Society of Dermatology.)

To explore the clinical characteristics and outcomes in Chinese patients with type I cryoglobulinemia (CG), we retrospectively analyzed the clinical data, management, and outcomes of 45 patients diagnosed with type I CG in our hospital from January 2015 to March 2019. In our study, all type I CGs were secondary to hematologic diseases, and monoclonal gammopathy of unknown significance was the most common primary disease, accounting for 48.9% (n = 22). Additionally, B cell non-Hodgkin lymphoma, Waldenström's macroglobulinemia, and multiple myeloma accounted for 24.4% (n = 11), 20.0% (n = 9), and 6.7% (n = 3), respectively. In patients with type I CG, skin damage was the most common symptom, presenting in 57.8% of the patients, followed by peripheral neuropathy (22.2%) and renal involvement (15.6%). Treatment was initiated in 29 patients (64.4%), and the most common choice was a rituximab-based regimen in 13 patients (44.8%), followed by bortezomib-based regimen in 11 patients (37.9%). Clinical symptoms were significantly improved after treatment, and the clinical remission rate was 86.2%, including 34.5% of complete clinical remission, while the laboratory response rate was 88.9%, including 33.3% of complete response and 55.6% of partial response. The expected 1-year overall survival was 97.8%. In conclusion, for patients with multisystemic involvement, such as skin damage, kidney damage, or peripheral neuropathy, the diagnosis of type I CG should be considered, and the underlying disease needs to be explored. Symptoms and primary diseases should be taken into consideration before choosing initial management.

Objective: Chronic Hepatitis C virus (HCV) infection can cause severe extrahepatic manifestations, such as mixed cryoglobulins (MC), up to the development of B cell nonHodgkin's lymphoma (B-NHL). Mechanisms transforming of HCV infection into lymphoproliferative and/or autoimmune disorders are still poorly understood. In course of HCV infection, the sustained virus-driven antigenic stimulation may probably induce a B-cell clonal expansion. Measurements of serum free light chains (FLCs) levels, considered as a direct marker of B cell activity, are analyzed with increasing interest in clinical practice, for diagnosis, monitoring and follow-up of plasma cell dyscrasia. Syndecan-1 (CD138) is a transmembrane heparan sulfate proteoglycan expressed and actively shed by most myeloma cells. Membrane CD138 represents the major receptor protein for HCV attachment to the hepatocyte surface and high levels of circulating sCD138 levels are detected in patients at early stage of B-cell chronic lymphocytic leukemia. This study is aimed to evaluate sCD138 and FLC levels as diagnostic biomarkers of HCV-related MC with B-NHL., Patients and Methods: We enrolled 35 HCV-MC-NHL patients, characterized for the specific type of cryoglobulins, and 25 healthy blood donors (HBD) as negative control. Serum sCD138 levels were determined using ELISA kits specific for human sCD138. Serum FLCs were assessed by means of the turbidimetric assay., Results: We found that serum levels of sCD138, as well as FLCs, were significantly higher in patients than in HBD (p<0.001)., Conclusions: In agreement with the definition of HCV-driven lymphoproliferative disorders as the consequence of a multifactorial and multistep pathogenetic process, we suggest that sCD138 and FLCs could be considered putative independent markers of worsening progression of the disease.

Background: Cryoglobulins are cold-precipitable immunoglobulins that may cause systemic vasculitis including cryoglobulinaemic glomerulonephritis (CGN). Type 1 cryoglobulins consist of isolated monoclonal immunoglobulin (mIg), whereas mixed cryoglobulins are typically immune complexes comprising either monoclonal (type 2) or polyclonal (type 3) Ig with rheumatoid activity against polyclonal IgG. Only CGN related to type 1 cryoglobulins has been clearly associated with monoclonal gammopathy of undetermined significance (MGUS) using the conventional serum-, urine- or tissue-based methods of paraprotein detection., Case Presentation: We present four patients with noninfectious mixed (type 2 or 3) CGN and MGUS. Two patients had type 2 cryoglobulinaemia, one had type 3 cryoglobulinaemia, and one lacked definitive typing of the serum cryoprecipitate. The serum monoclonal band was IgM-κ in all four cases. Treatments included corticosteroids, cyclophosphamide, plasma exchange, and rituximab. At median 3.5 years' follow-up, no patient had developed a haematological malignancy or advanced chronic kidney disease. Other potential causes of mixed cryoglobulinaemia were also present in our cohort, notably primary Sjögren's syndrome in three cases., Conclusion: Our study raises questions regarding the current designation of type 2 CGN as a monoclonal gammopathy of renal significance, and the role of clonally directed therapies for noninfectious mixed CGN outside the setting of haematological malignancy.

The study of the incidence of cryoglobulinemia is relevant in patients with an intestinal anastomotic leak. This study aims to determine a laboratory marker of the risk of small intestine anastomotic leak. The study was based on 96 patients who were subjected to resections of segments of the small intestine with the formation of intestinal anastomoses at the State Institution "Zaytsev V.T. Institute of General and Urgent Surgery of National Academy of Medical Sciences of Ukraine". Of all the operated patients, there were 55.2% women and 44.8% men. Of the 96 patients examined, cryoglobulinemia was detected in the majority - 62.5% of patients, of which 4 were later proved to have inactive hepatitis C; the remaining 38.5% had no cryoglobulinemia. According to the existing theory of the autoimmune mechanism of postoperative surgical complications formation, the revealed decrease in the level of cryoglobulins on the second day could be related to their fixation in the microcirculatory bed and the development of immunocomplex inflammation. While the increase in the content of cryoglobulins in serum on the third day can be caused by their entry into the circulatory bed from deposition or fixation sites and the development of a secondary immune response. In patients with intestinal anastomosis failure after resection of intestinal segments, cryoglobulinemia rates increased more than 80 mg/l; this indicator could be used as a marker of postoperative complications., (©Carol Davila University Press.)

Objectives: The prevalence and factors of hepatitis C virus (HCV) -associated mixed cryoglobulinaemia in Asia remain elusive, and we aimed to investigate these topics., Methods: An 8-year prospective cohort study was conducted in 678 consecutive Taiwanese individuals with chronic HCV infection (438 completed an anti-HCV therapy course)., Results: Of 678 individuals, 437 (64.5%) had mixed cryoglobulinaemia and 20 (2.9%) had mixed cryoglobulinaemic syndrome. At baseline, IgM (cut-off >122 mg/dL), triglycerides and IgG levels, and HCV genotype 3 were independently associated with mixed cryoglobulinaemia. Rheumatoid factor (RF) levels were associated with mixed cryoglobulinaemic syndrome (cut-off >12.2 IU/mL). At 24 weeks post-therapy, the 362 individuals with a sustained virological response (SVR) had higher cured (106/362 (29.3%) versus 10/76 (13.2%), p = 0.003) and lower persistent (100/362 (27.6%) versus 33/76 (43.4%), p = 0.003) mixed cryoglobulinaemia rates than non-SVR patients. Among SVR patients, compared with baseline levels, RF, IgG and IgM levels decreased, except in individuals with new mixed cryoglobulinaemia. Pre-therapy IgM levels were associated with 24-week post-therapy new (95% CI of OR 1.002-1.023) and persistent (95% CI of OR 1.004-1.015) mixed cryoglobulinaemia in SVR patients. After up to 8 years, 24-week post-therapy IgM levels were associated with mixed cryoglobulinaemia in SVR patients (9/51; 17.64%; 95% CI of HR 1.004-1.011). Among 17 SVR patients with pre-therapy mixed cryoglobulinaemic syndrome, 5 (29.4%) had long-term mixed cryoglobulinaemia and 4 (23.5%) had mixed cryoglobulinaemic syndrome., Conclusions: Over 60% of chronic HCV-infected individuals had mixed cryoglobulinaemia, and 17.64% of SVR patients had mixed cryoglobulinaemia 8 years post-therapy. Pre-therapy RF and IgM levels marked HCV-associated mixed cryoglobulinaemic syndrome and mixed cryoglobulinaemia, respectively., (Copyright © 2019 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Several reports have highlighted the abnormal increments of serum immunoglobulin free light chains (FLCs) in the course of systemic autoimmune rheumatic diseases (SARD), but a comparative analysis among different conditions is still lacking. A strong association between elevated FLC and hepatitis C virus (HCV)-related mixed cryoglobulinaemia (HCVMC) has been well established. Here, we aimed to analyse serum FLC levels in patients with four different SARD in comparison with HCVMC. Using a turbidimetric assay, free κ and λ chains were quantified in sera from 198 SARD patients (37 rheumatoid arthritis, RA; 47 systemic lupus erythematosus, SLE; 52 anti-phospholipid syndrome, APS; 62 primary Sjogren's syndrome, pSS), 62 HCVMC and 50 healthy blood donors (HD). All patient groups showed increased κ levels when compared to HD: 33·5 ± 2·6 mg/l in HCVMC, 26·7 ± 2·3 mg/l in RA, 29·7 ± 1·9 mg/l in SLE, 23·8 ± 1·1 mg/l in APS, 24·2 ± 1·1 mg/l in pSS; 10·1 ± 0·6 mg/l in HD. Free λ levels displayed a significant increase only for HCVMC (20·4 ± 1·4 mg/l) and SLE (18·4 ± 1·0 mg/l) compared to HD (13·6 ± 0·9 mg/l). The increase of κ compared to λ takes into account a κ /λ ratio of 1·6 for all groups. Our results substantially analyse and strengthen the association between FLC and SARD focusing the questions regarding their role in the pathogenesis and diagnosis of human diseases. Unfortunately, the biochemical differences distinguishing normal from pathological FLC have not been identified. Production of different isotypes is probably connected to still-unknown pathways., (© 2019 British Society for Immunology.)

Background: Infections, autoimmunity and cancer play a role as determinants of etiology in Hepatitis C virus (HCV) related mixed cryoglobulinemia (MC). Several factors of risk have been suggested as markers of pathogenesis and progression of HCV-related MC into B cell Non-Hodgkin's Lymphoma (B-NHL). Here, we evaluated IgG subclass distribution, free light chains (FLCs) and vascular endothelial growth factor (VEGF) as a new combination of biomarkers., Methods: We measured IgG1-4 subclasses, FLCs and VEGF levels in sera 53 from HCV-related MC, in comparison with 40 sera from HCV negative patients with rheumatoid arthritis (RA) and 30 from healthy blood donors (HBD)., Results: IgG3 levels were significantly higher in HCV-MC patients with a decrement of IgG2 and IgG4; FLC levels significantly increased in both MC and RA patients' groups; serological VEGF was higher in HCV-MC patients than in HBD in correlation with k and λ levels., Conclusion: Our results suggest that a specific IgG subclasses pattern together with raised levels of FLCs and VEGF could represent the biomarker "signature" of an inflammation multistage of acquired immune system., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Cryoglobulins are abnormal serum immunoglobulins that tend to precipitate in intravascular compartments at temperatures lower than 37°C causing blood flow restriction to vital organs. They are divided into type I, II and III based on the immunoglobulin subtypes of the cryoprecipitates. Type II cryoglobulinemia is most commonly associated with viral infections, autoimmune diseases and lymphoproliferative disorders. Here, we reported an 80-year-old man who presented with fatigue, acute kidney injury, palpable purpura, anaemia and altered mental status. He was diagnosed with type II cryoglobulinemia with concomitant positive autoimmune markers, varicella IgM antibody and IgM hepatitis B core antibody. The patient responded well to intravenous and oral steroid treatment., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction : The issue of predicting lymphoma in primary Sjögren's syndrome (pSS) starts from its clinical and biologic essence, i.e., an autoimmune exocrinopathy with sicca syndrome, inflammation and lymphoproliferation of MALT (mucosa-associated lymphoid tissue) in exocrine glands. Areas covered : The two major predictors to be firstly focused are persistent salivary gland (SG) swelling and cryoglobulinemic vasculitis with related features as purpura and low C4, or the sole serum cryoglobulinemia repeatedly detected. They are pathogenetically linked and reflect a heavier MALT involvement by histopathology, with the expansion of peculiar rheumatoid factor (RF)-positive clones/idiotypes. Other predictors include lymphadenopathy, splenomegaly, neutropenia, lymphopenia, serum beta2-microglobulin, monoclonal immunoglobulins, light chains, and RF. Composite indexes/scores may also predict lymphoma. Expert opinion : Prediction at baseline needs amelioration, and must be repeated in the follow-up. Careful clinical characterization, with harmonization and stratification of large cohorts, is a relevant preliminary step. Validated and new biomarkers are needed in biologic fluids and tissues. SG echography with automatic scoring could represent a future imaging biomarker, still lacking. Scoring MALT involvement in pSS, as an additional tool to evaluate disease activity and possibly to predict lymphoma, is welcomed. All these efforts are now ongoing within the HarmonicSS project and in other research initiatives in pSS.

The role of CD5 + B cells in patients with HCV infection and HCV-related disorders, including mixed cryoglobulinemia (MC), has been addressed in previous reports with conflicting results. We established a correlation between CD5/CD20 expression on circulating B lymphocytes, characterizing monoclonal B cell lymphocytosis (MBL), and clinical features in a cohort of 45 patients with chronic HCV hepatitis [without MC: 23 patients (MC- group); with MC: 22 patients (MC+ group)], and 45 HCV-negative healthy subjects as controls. By flow cytometry analysis, three B cells phenotypes were singled out: 1) CD5 + CD20 dim (CLL-like phenotype); 2) CD5 + CD20 bright (atypical phenotype); and 3) CD5 - CD20 + phenotype. CD5 + CD20 bright cells were reduced in MC- patients (p=0.049). CD5 + CD20 dim B cells were significantly higher in group B than in the control group (p=0.003). ROC curve analysis in MC+ patients showed the highest positive likelihood ratio at ≥7.35% (p=0.008) for CLL-like phenotype and at ≤63.6% (p=0.03) for the CD5 - CD20 + B cell phenotype. HCV infection was associated with a higher frequency of CLL-like (odds ratio=16, p=0.002) and a lower frequency of atypical (odds ratio: 3.1, p=0.02) and CD5 - CD20 + (odds ratio: 11, p=0.01) phenotypes. The association with higher levels of CLL-like phenotype progressively increased from group of MC- patients (odds ratio: 9.3, p=0.04) to the group of MC+ patients (odds ratio: 25.1, p=0.0003). CONCLUSIONS: The occurrence of a CLL-like pattern may allow to identify HCV-infected patients at risk of developing MC and eventually non-Hodgkin lymphoma, who should require a closer surveillance and a longer follow-up., (Copyright © 2019. Published by Elsevier B.V.)

Objective: Cryoglobulinemia often causes systemic vasculitis, thereby damaging to skin and internal organs including kidneys, even life-threatening. This review aimed to introduce the advances in understanding, detection, and treatment of this disease in recent years, with a particular concern to clinical practice., Data Sources: All the data in this review were from the English or Chinese literature in the PubMed and China National Knowledge Infrastructure databases as of March 2019., Study Selection: This review selected important original articles, meaningful reviews, and some reports on cryoglobulinemia published in recent years and in history, as well as the guidelines for treatment of underlying diseases which lead to cryoglobulinemia., Results: Diagnosis of cryoglobulinemia relies on serum cryoglobulin test, in which to ensure that the blood sample temperature is not less than 37°C in the entire pre-analysis phase is the key to avoid false negative results. Cryoglobulinemic vasculitis (Cryo Vas), including cryoglobulinemic glomerulonephritis (Cryo GN), usually occurs in types II and III mixed cryoglobulinemia, and can also be seen in type I cryoglobulinemia caused by monoclonal IgG3 or IgG1. Skin purpura, positive serum rheumatoid factor, and decreased serum levels of C4 and C3 are important clues for prompting types II and III Cryo Vas. Renal biopsy is an important means for diagnosis of Cryo GN, while membranous proliferative GN is the most common pathological type of Cryo GN. In recent years, great advances have been made in the treatment of Cryo Vas and its underlying diseases, and this review has briefly introduced these advances., Conclusions: Laboratory examinations of serum cryoglobulins urgently need standardization. The recent advances in the diagnosis and treatment of Cryo Vas and GN need to be popularized among the clinicians in related disciplines.

Clinical spectrum of hepatitis C virus (HCV)-related cryoglobulinemia varies from an asymptomatic presentation to severe vasculitis and lymphoma. A recent study in HCV-negative patients suggests that low cryoglobulins (CGs) levels are responsible for severe renal and neurological complications. The aim of this study was to identify a panel of serological biomarkers associated with low levels of CGs in HCV-positive patients. We studied a population of 79 untreated patients with chronic HCV infection: 13 naïve patients without CGs; 28 patients with asymptomatic mixed cryoglobulinemia (MC) and low levels of CGs (16/28 with polyclonal type III and 12/28 with microheterogeneous type III CGs); 38 patients with symptomatic MC and high levels of type II CGs. Serum samples were collected and examined for rheumatoid factor (RF) IgG and IgM, free light chains (FLCs) and C3 and C4 complement components. We found that RF-IgG and IgM, free k chains and k+λ were increased while C4 component was reduced, both in symptomatic and asymptomatic patients. Our results suggest that, even in absence of MC symptoms, the low levels of CGs may represent a trigger of activation for immune system in course of HCV infection. The identification of a correlated biomarkers panel could improve the clinical management of these patients and pave the way for target treatment strategies. © 2018 BioFactors, 45(3):318-325, 2019., (© 2018 International Union of Biochemistry and Molecular Biology.)

Introduction: Limited information is available describing the spectrum of neurological complications of cryoglobulinemia., Methods: Single center retrospective review of patients with neurologic symptoms and elevated serum cryoglobulins, with their potential association being classified as definite, possible, or unlikely using defined criteria., Results: Among 492 patients, 131 (87 classified as definite and 44 as possible) had neurologic symptoms associated with cryoglobulinemia. Common comorbidities included hepatitis C (N = 43), monoclonal gammopathy of undetermined significance (N = 20), Sjogren's syndrome (N = 17), membranoproliferative glomerulonephritis (N = 17), and systemic lupus erythematosus (N = 10). Features supporting an association between cryoglobulinemia and neurological symptoms were the presence of purpura (p < .001), positive rheumatoid factor (p = .001) and low C4 (p = .002). Common peripheral neurological diagnoses were symmetric polyneuropathy (N = 84), small fiber neuropathy (N = 25), and mononeuritis multiplex (N = 16). Central neurological manifestations were infrequent and included seizures (N = 3), posterior reversible encephalopathy syndrome (N = 2), intracerebral hemorrhage (N = 1), vasculitis (N = 1), rapidly progressive dementia (N = 1), lymphoma (N = 1), and myelitis/meningitis (N = 1). Treatments utilized included corticosteroids (N = 74), rituximab (N = 42), cyclophosphamide (N = 27), methotrexate, azathioprine, or mycophenolate mofetil (N = 28), anti-viral therapy (N = 20), plasmapheresis (N = 16), and intravenous immunoglobulin (N = 20). Neurologic symptoms associated with cryoglobulinemia remained stable or improved in 86% of patients., Conclusion: This study describes a wide spectrum of patients with neurologic symptoms attributed to cryoglobulinemia and provides a framework to approach this challenging diagnosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background and Aim: The prevalence of mixed cryoglobulinemia is 15-50% in chronic hepatitis C (CHC) patients, and these patients are in an increased risk of liver fibrosis and cirrhosis, but it is controversial. This study aimed to reveal the prevalence of mixed cryoglobulinemia in Asian population and to determine the relationship between presence of serum cryoglobulinemia and liver fibrosis in CHC patients with or without liver biopsy., Methods: In total, 2255 treatment-naïve patients retrospectively enrolled in our study. Serum cryoglobulinemia precipitation, liver biopsy, and four indexes of fibrosis (FIB4) were assessed to detect the associated factors., Results: Three hundred sixty-four (32%) out of 1135 liver biopsy patients and 341 (30.4%) out of 1120 non-biopsy patients were positive for serum cryoglobulinemia. Multivariate analysis revealed that male gender, hepatitis C virus RNA, platelet and advanced fibrosis (odds ratio [OR] 1.40, 95% confidence interval [CI] 1.05-1.87, P = 0.021) were significantly associated with the presence of cryoglobulinemia in the liver biopsy proven patients. The presence of serum cryoglobulinemia (OR 1.43, 95% CI 1.04-1.96, P = 0.026) was associated with advanced liver fibrosis (F3 and F4) by multivariate logistic regression analysis. In patients without liver biopsy, FIB4 (OR 1.72, 95% CI 1.30-2.27, P = 0.0001) was associated with the presence of serum cryoglobulinemia, and also cryoglobulinemia (OR 1.74, 95% CI 1.32-2.30, P = 0.0001) was associated with high FIB4 (≥ 3.25) patients., Conclusion: The prevalence of the presence of serum cryoglobulinemia is 30.4-32% in CHC patients and associated with advanced fibrosis in liver biopsy proven patients and high-FIB4 (≥ 3.25) patients without liver biopsy., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Objectives: Hepatitis C virus (HCV) is the major cause of cryoglobulinemia. Direct-acting antivirals (DAAs) have markedly changed the therapeutic outcomes in the treatment of patients with HCV. We evaluate the efficacy, safety, immunological, and clinical response of different DAA regimens in HCV-cryoglobulinemia., Patients and Methods: Ninety-three cryoglobulinemic patients, divided into symptomatic [symptomatic cryoglobulinemic patients (SCP; n=35)] and asymptomatic [nonsymptomatic cryoglobulinemic patients (NSCP; n=60)], underwent DAAs. Eighty-nine comparable noncryoglobulinemic patients were selected as a control group. We evaluated the sustained virological response (SVR), the adverse effects, and the immune and symptomatic response., Results: Percentages of patients who achieved SVR and experienced adverse effects were not statistically different between the three groups (100, 95, 93.3% and 57.1, 53.3, 48.3%). In 68.5% of SCP and in 76.7% of NSCP, cryoglobulins disappeared at SVR. No risk factor was associated with the persistence of cryoglobulins. An increase was observed both in C4 (P=0.002; P=0.018) and in C3 (P=0.0037; P=0.031) in SCP and NSCP. About 70% of symptomatic patients showed a complete or partial symptomatic remission: persistence of symptoms is correlated to the type of clinical picture., Conclusion: DAA regimens are safe and effective in patients with HCV-cryoglobulinemia. The achievement of SVR is necessary, but not sufficient, to achieve a complete immunological and clinical response.

Plasma hyperviscosity is a rare complication of both monoclonal and polyclonal disorders associated with elevation of immunoglobulins. Asymptomatic patients with an elevation in the serum viscosity do not require plasma exchange, and the majority will have other indications for therapeutic intervention. For patients with hemorrhagic or central nervous system manifestations, plasma exchange is the therapy of choice and is relatively safe. Viscosity measurements are not required to initiate therapy if the index of suspicion is high and the clinical presentation is typical. However, patients should have a sample sent for confirmation of the diagnosis. Whole-blood hyperviscosity is seen in patients with extreme elevation of the red cell and white cell count. Phlebotomy of patients with primary and secondary elevation of the red cell count is a well-established therapy., (© 2018 by The American Society of Hematology.)

Background: Reversible cryoprecipitability of proteins is observed as a concomitant feature of immune complex formation. Mixed cryoglobulinemia (MC) is systemic vasculitis, associated with mixed IgM and IgG cryoglobulins (CGs) showing rheumatoid factor (RF) activity. It is frequently associated with hepatitis C virus (HCV). This study investigates the presence of IgG RF and anti-nuclear antibodies (ANA) in cryoprecipitates of patients with type III and type II MC, to understand the biochemical patterns associated with different types of MC to a greater degree., Methods: Sera from 70 HCV untreated patients with type III or type II MC were tested by immunofixation for IgG3 and through ELISA for IgG RF. Cryoprecipitates were analysed for ANA by indirect immunofluorescence to identify specific patterns., Results: After stratification according to MC type, the ANA patterns between type II and type III MC were statistically different. IgG3 levels and IgG-RF positivity were significantly higher in type III cryoprecipitate. We observed a higher positivity of IgG3 and a significant difference between the liver fibrosis stage, ANA and IgG-RF in the cryoprecipitate., Conclusion: Results show a combination of biochemical markers and autoantibodies associated to mixed cryoglobulinemia; these findings could be further investigated in order to ascertain their usefulness in assessing the risk for the development of mixed cryoglobulinemia., (Copyright © 2018 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Patients with hepatitis C virus-associated cryoglobulinemic vasculitis (HCV-CV) have high rates of clinical remission after treatment with direct-acting antivirals (DAAs), but circulating cryoglobulins persist, and vascular disorders reappear in some patients shortly after DAA treatment ends. We performed a prospective study to assess the long-term clinical and immune system effects of HCV eradication with DAAs in 46 patients with HCV-CV and 42 asymptomatic patients with circulating cryoglobulins. A median of 24 months after DAA treatment (range, 17-41 months), 66% of patients with HCV-CV and 70% of asymptomatic patients with circulating cryoglobulins had an immunologic response, with comparable reductions in cryocrit from 2.6% to 0% (P < .05). However, 20% of patients still had positive test results for cryoglobulins after DAA therapy. Among patients with HCV-CV, 42 (91%) had a clinical response, in that their Birmingham Vasculitis Activity Score (version 3) decreased from 7 to 0 (P < .01). Nevertheless, within 2 years after a sustained viral response to DAA therapy, 5 patients with HCV-CV (11%, 4 with cirrhosis) had relapses of vasculitis that included severe organ damage and death., (Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.)

A 53-year-old man with active hepatitis C and cirrhosis presented with a vasculitic rash, myalgias, and fatigue, and was found to have an elevated cardiac troponin I up to 15.7 ng/mL with normal electrocardiogram, echocardiogram, and coronary angiogram prior to being discharged. Subsequently, during a similar presentation to another academically affiliated hospital, the patient had a normal cardiac troponin T (< 0.01 ng/mL). Upon his third presentation with significantly elevated troponin I to 15.98 ng/mL, the patient was found to have cryoglobulinemic vasculitis and elevated rheumatoid factor due to active hepatitis C, causing interference with the troponin I immunoassay. In conclusion, troponin I assays may have high false-positive values due to interference by rheumatoid factor and/or a polyclonal antibody found in cryoglobulinemia., Competing Interests: The authors declare no competing interests., (©2018 Odish et al. Published by IMR press. All rights reserved.)

Hyperviscosity syndrome (HVS) develops most commonly in Waldenström's macroglobulinemia (WM) and multiple myeloma (MM). Plasmapheresis is the immediate therapy and very effective at relieving symptoms by removing paraprotein. The most commonly used replacement fluid is 4%-5% human albumin in physiologic saline. FFP may be used in patients with coagulation abnormalities. Plasmapheresis should be continued until acute symptoms abate. Hyperviscosity impairs the circulation in the retina and causes hemorrhages around the small retinal vessels. Early diagnosis and urgent plasmapheresis may reduce blindness caused by retinal hemorrhages and/or retinal detachment. In HCV related mixed cryoglobulinemias, plasmapheresis is indicated if rapidly evolving life-threatening disease with immunosuppressive agent exists. In non-infectious mixed cryoglobulinemia plasmapheresis is indicated when the disease manifestations are severe, as a second line option. In WM patients with hyperviscosity symptoms and IgM > 4 g/dL, preemptive plasmapheresis is recommended to prevent an IgM flare with rituximab. Certain IgG/A MGUS-associated neuropathy patients may benefit from plasmapheresis. For cast nephropathy (suspected or biopsy proven), plasmapheresis is recommended when the sFLC ≥ 500 mg/l and as early as possible (<1 month with kidney injury). Theoretically, extracorporeal removal alone, without efficient tumor killing, could not reduce sFLC due to high production by the tumor mass and rapid rebound between compartments., (Copyright © 2018. Published by Elsevier Ltd.)

Introduction: Maintenance of temperature during collection and transport of blood is an important pre-requisite for cryoglobulin assays. In this manuscript, we describe 'cryodevice', a low-cost device for transportation and/or incubation of vials of whole blood at 37°C. Such a device would reduce false negatives in cryoglobulin assays., Method: The 'cryodevice' takes the embodiment of a portable, light, insulated water bath, which can be used as an incubator in a plugged-in state, or as a transport container after it is set up and disconnected from the power supply. The design of the cryodevice is described here, with focus on its construction and electronic control circuit. Computer simulations and in vitro trials were performed to study the temperature drop in the blood samples placed in the device. Subsequently, the cryodevice was also used with actual patient blood samples., Results: Thermal simulations and in vitro testing of the cryodevice predicted that the design would meet the temperature maintenance goals. When the cryodevice was put in to use for screening 45 patient blood samples, it helped identify positive cryoglobulinemia in three of the samples., Conclusion: The description of the cryodevice envisions enabling the construction of a low-cost device in resource-limited healthcare settings in India created with locally available resources. On testing, the device was found to be satisfactory in performance and is expected to bring down incidences of false negatives in cryoglobulin tests., (© 2017 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

Hepatitis C virus (HCV) infection is associated with a morbidity and mortality due to liver complications. HCV infection is also frequently associated with rheumatic disorders, such as arthralgia, myalgia, cryoglobulinemia vasculitis, and sicca syndrome, as well as the production of autoantibodies. The treatment of HCV infection with interferon alpha (IFN) has been contraindicated for a long time in many rheumatologic autoimmune/inflammatory disorders. New oral IFN-free combinations offer an opportunity for HCV-infected patients with extrahepatic manifestations, including rheumatologic autoimmune/inflammatory disorders, to be cured with a short treatment duration and a low risk of side effects., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In this brief review, we have examined some clinical disorders which are associated to an altered hemorheological profile and at times accompanied by skin ulcers. This skin condition may be, in fact, observed in patients with primary plasma hyperviscosity such as multiple myeloma, Waldenstrom macroglobulinemia, cryoglobulinemia, cryofibrinogenemia, dysfibrinogenemia and connective tissue diseases. It must be underlined that the altered hemorheological pattern is not the only responsible for this skin complication but, as it worsens the microcirculatory flow, it contributes to determine the occurrence of the skin ulcers., (Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Circulating mixed cryoglobulins are detected in 40%-60% of patients with hepatitis C virus (HCV) infection, and overt cryoglobulinemia vasculitis (CryoVas) develops in approximately 15% of patients. Remission of vasculitis has been associated with viral clearance, but few studies have reported the effectiveness of direct-acting antiviral drugs in these patients. We performed an open-label, prospective, multicenter study of the effectiveness and tolerance of an all-oral, interferon- and ribavirin-free regimen of sofosbuvir plus daclatasvir in patients with HCV-associated CryoVas. Forty-one consecutive patients with active HCV-associated CryoVas (median age, 56 y; 53.6% women) were recruited from hospitals in Paris, France, from 2014 through 2016. They received sofosbuvir (400 mg/day) plus daclatasvir (60 mg/day) for 12 weeks (n = 32) or 24 weeks (n = 9), and were evaluated every 4 weeks until week 24 and at week 36. Blood samples were analyzed for complete blood count, serum chemistry profile, level of alanine aminotransferase, rheumatoid factor activity, C4 fraction of complement, and cryoglobulin; peripheral blood mononuclear cells were isolated for flow cytometry analysis. Thirty-seven patients (90.2%) had a complete clinical response (defined by improvement of all the affected organs involved at baseline and no clinical relapse) after a median time of 12 weeks of therapy; all had a sustained virologic response (no detectable serum HCV RNA 12 weeks after the end of antiviral therapy). Patients' mean cryoglobulin level decreased from 0.56 ± 0.18 at baseline to 0.21 ± 0.14 g/L at week 36, and no cryoglobulin was detected in 50% of patients at this time point. After antiviral therapy, patients had increased numbers of T-regulatory cells, IgM+CD21-/low-memory B cells, CD4+CXCR5+ interleukin 21+ cells, and T-helper 17 cells, compared with before therapy. After a median follow-up period of 26 months (interquartile range, 20-30 mo), no patients had a serious adverse event or relapse of vasculitis., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Mixed cryoglobulinemia is frequently secondary to hepatitis C virus infection. Diagnosis and therapeutic management are challenging, depending on the spectrum and severity of manifestations, as well as on the presence of comorbidities. We describe a case of a 79-year-old woman with a non-cirrhotic hepatitis C virus infection presenting with weakness, arthralgias, purpuric rash with left leg ulcerative lesions, bilateral peripheral sensorimotor polyneuropathy, renal impairment and cardiac failure. The investigation was compatible with a severe type II mixed cryoglobulinemia with multisystemic involvement, including a low-grade B cell lymphoma and concomitant intestinal tuberculosis. Initial management with immunosuppressive therapy with glucocorticoids to control symptoms and simultaneous tuberculosis treatment was required. Unavailability of adequate antiviral treatment led to the need to control the severity of systemic manifestations with rituximab, before the effective aetiological treatment with sofosbuvir and ledipasvir was possible, allowing the definitive resolution of the disease., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Systemic vasculitis is a group of heterogeneous, disabling disorders. Great interest has recently arisen in pathophysiology, clinical phenotypes and therapy of large- and small-vessel vasculitis. The general work hypothesis has been to promote research focused on disease-related pathogenetic pathways, with the ultimate goal of identifying novel diagnostic and prognostic biomarkers, thus leading towards more effective targeted treatments. Following the previous annual reviews of this series, we will hereby provide a critical digest of the recent literature on small- and large-vessel systemic vasculitis, with a specific focus on novel possible disease-related biomarkers and their impact on current and future therapies.

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.

Aim: Hepatitis C virus (HCV) is sialotropic. The pathogenesis of sicca manifestations in patients with chronic HCV infection is not fully understood. We aimed to detect changes in magnetic resonance sialography (MRS) of HCV patients with and without vasculitis., Method: We studied 32 HCV patients (19 female, mean age 48.8 ± 10.3 years) and 20 age- and gender-matched healthy controls. Half of the patients had vasculitis. Demographic, clinical and serological data were prospectively evaluated. In patients with vasculitis, the disease activity was assessed by the Birmingham Vasculitis Activity Score (BVAS). MRS was performed on all patients and controls., Results: Abnormal MRS was found in 25% of patients, (6/16 and 2/16 in patients with and without vasculitis, respectively). Among patients with vasculitis, those with abnormal MRS had longer disease duration, higher leukocytic and lymphocytic counts and more frequent cryoglobulinemia (P < 0.01, P < 0.001, P < 0.001 and P < 0.008, respectively), while BVAS scores were not significantly different., Conclusion: Among HCV patients with vasculitis, longer disease duration and cryoglobulinemia were associated with abnormal findings on MRS. To confirm our results, we propose larger-scale, multicentre studies with longer evaluation periods., (© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Background: Mixed cryoglobulinemia (MC) is a rare multisystem disease whose aetiopathogenesis is not completely understood. Hepatitis C virus (HCV) infection may have a causative role, and genetic and/or environmental factors may also contribute., Aims: To investigate the presence and possible role of environmental agents in MC., Methods: We recruited 30 HCV-infected MC patients with different clinical manifestations and a control group of 30 healthy, sex-/age-matched volunteers. We collected serum samples from each patient and incubated at 4°C for 7 days to obtain cryoprecipitate samples. We used environmental scanning electron microscopy (ESEM) and energy dispersive X-ray spectroscopy microanalysis to verify the presence of microparticles (MPs) and nanoparticles (NPs) in serum and cryoprecipitate samples. We evaluated environmental exposure using a medical and occupational history questionnaire for each subject., Results: MC patients had a significantly higher risk of occupational exposure (OR 5.6; 95% CI 1.84-17.50) than controls. ESEM evaluation revealed a significantly higher concentration, expressed as number of positive spots (NS), of serum inorganic particles in MC patients compared with controls (mean NS 18, SD = 16 versus NS 5.4, SD = 5.1; P < 0.05). Cryoprecipitate samples of MC patients showed high concentrations of inorganic particles (mean NS 49, SD = 19). We found a strong correlation between NS and cryocrit (i.e. percentage of cryoprecipitate/total serum after centrifugation at 4°C) levels (P < 0.001)., Conclusions: In addition to HCV infection, MPs and NPs might play an important role in the aetiopathogenesis of MC., (© The Author 2016. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Recently, high prevalence of cryofibrinogenaemia has been observed in plasma of untreated dermatitis herpetiformis (DH) patients, and the pathological IgA and TG3 deposits in the papillary dermis were found to co-localize with fibrin and fibrinogen., Objective: To study the fibrinolytic potential in plasma of untreated, dapsone and or/gluten-free diet treated DH patients as well as the in vitro effect of dapsone on the fibrinolytic profile., Method: Plasma samples of 23 DH patients, 19 healthy subjects and 5 pemphigus vulgaris patients were investigated by a turbidimetric-clot lysis assay. Out of them 5 DH plasma samples representing different fibrinolytic parameters, and 3 healthy controls were selected for parallel fibrin clot preparation. The clot fibrin structure was examined by scanning electron microscopy (SEM), and the diameters of 900 fibrin fibres were determined in each clot., Results: A significantly prolonged clot lysis time was detected in untreated DH patients. The turbidity values of DH plasma clots indicated an altered fibrin structure that was also confirmed by SEM: significantly thicker fibrin fibers were observed in untreated, TG3 antibody positive DH patients compared to healthy controls, whereas the fiber diameters of dapsone-treated patients were similar or thinner than the control values. In line with the structural changes of fibrin, the fibrinolytic profile of 5 DH patients under dapsone treatment approached the control values., Conclusion: This study revealed that the fibrinolytic potential was impaired in the plasma of untreated DH patients, whereas dapsone corrected the fibrinolytic defect. These data suggest a pathogenic role for plasma-derived factors in the development of skin symptoms and add a new aspect to the long-known beneficial, symptomatic effect of dapsone in active DH., (Copyright © 2016 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objectives: To evaluate the frequency, co-occurrence, and risk factors for hematological complications at the time of diagnosis of chronic hepatitis C (CHC)., Methods: This study included 1237 patients with CHC aged 18-88 years diagnosed in the years 1998-2010 in the Pomeranian region of Poland. Clinical data, cell blood count, liver biopsy, and biochemistry results were obtained retrospectively., Results: Hematological complications were found in 31% of patients. The most frequent complication was thrombocytopenia (23.8%). The multivariate analysis showed a 5.1-fold increased risk (P<0.05) of at least one additional hematological complication in patients with thrombocytopenia. The greatest increase in risk (7.3) was related to leukopenia and cryoglobulinemia (2.3). The risk of leukopenia was correlated with the severity of thrombocytopenia. The risk of leukopenia and thrombocytopenia increased significantly from, respectively, stages 3 and 2 of liver fibrosis compared with patients without fibrosis., Conclusion: In patients with CHC, decreases in cell blood count occur quite frequently. The most often is mild and solitary thrombocytopenia, but if severe, it may be accompanied by leukopenia, especially in women. The presence of thrombocytopenia and leukopenia in patients with CHC may indicate advanced liver fibrosis or its final stage: cirrhosis.

Background: HCV can lead to both chronic liver disease and B-cell lymphoproliferative disorders. A strong association exists between HCV and mixed cryoglobulinaemia (MC)., Methods: Anti-nuclear antibodies (ANA), rheumatoid factor Ig-G (RF-IgG), free light chain κ and λ (FLC-κ, FLC-λ) levels and κ/λ ratio were evaluated in 50/420 subjects unexpectedly resulted anti-HCV positive after routine screenings for non-hepathological procedures., Results: Three/fifty patients had HCV-RNA undetectable in the serum and were excluded from the analysis. Thirty-nine/fifty patients had laboratory evidence of circulating cryoglobulins without liver disease and MC-related symptoms. Among them, 17 resulted ANA-positive. The mean cryocrit was higher in ANA-positive patients, while no other demographic/clinical differences were observed between the groups. Significantly higher levels of RF-IgG were observed in ANA-positive vs ANA-negative patients. κ and λ FLC were higher in ANA-positive patients. A ROC analysis, based on ANA-positivity vs ANA-negativity, confirmed a high sensitivity and specificity of RF-IgG test., Conclusions: Published data concerning MC come mostly from symptomatic vasculitis. We analyzed HCV-patients without MC symptoms, founding cryoglobulins in the majority of them. The increased levels of FR-IgG and FLC in CGs-ANA-positive patients, suggest these test could be used to identify a state of silent autoimmune and/or lymphoproliferative condition before the transition to a frank disease in naïve HCV-patients without symptoms of extrahepatic manifestations., (Copyright © 2016 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)