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Vasculitis is an uncommon but treatable and thus important cause of neuropathy. Vasculitic neuropathy can occur as an isolated entity (nonsystemic vasculitic neuropathy) but more frequently evolves in the setting of a systemic vasculitis. Polyarteritis nodosa, anti-neutrophil antibody-associated vasculitides (especially microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis), rheumatoid vasculitis, and cryoglobulinemic vasculitis are the systemic disorders most commonly associated with neuropathy. Both systemic vasculitic and nonsystemic vasculitic neuropathy usually present with a subacutely progressive, asymmetric/multifocal, painful, distal-predominant, axonal, sensory-motor phenotype. Available evidence suggests that nonsystemic and most systemic vasculitic neuropathies are mediated primarily by T-cell mechanisms, but immune complexes probably contribute. Evaluation of patients with suspected vasculitic neuropathy usually includes EMG, laboratory studies, and nerve/muscle biopsy. In patients lacking definite vasculitis in nerve biopsy, clinically probable vasculitic neuropathy can be diagnosed by recourse to supportive clinicopathologic findings. Vasculitic neuropathies occurring in the ANCA-associated vasculitides are treated in accordance with the underlying systemic vasculitis. About 50% of neuropathy-predominant primary systemic vasculitides are not controlled by initial corticosteroid monotherapy. IVIg or rituximab can induce remission in refractory or relapsing patients. Long-term outcome is reasonably good.

Background The mixed cryoglobulinemia (MC) syndrome is a systemic inflammatory syndrome that causes small-to-medium vessel vasculitis due to cryoglobulin-containing immune complexes most commonly caused by chronic hepatitis C virus (HCV), and rarely by chronic hepatitis B virus (HBV). Its clinical presentation is significantly varied, with manifestations ranging from purpura, arthralgia, and myalgia to more severe neurologic and renal involvement. Pulmonary involvement as organizing pneumonia, alveolar hemorrhage, and pulmonary vasculitis have been reported, but appear to be quite rare. Case presentation We report an uncommon case of a patient who presented with primary pulmonary syndrome without renal involvement in the setting of MC, due to untreated chronic hepatitis B infection. Early diagnosis and consequent institution of glucocorticoids, B-cell-depleting monoclonal antibody and antiviral therapy led to a favorable outcome and prevented any fatal sequelae. Conclusion Pulmonary compromise in MC syndrome is very uncommon and carries a high rate of mortality. Therefore, in patients with HBV presenting with hemoptysis, physicians must carry a high clinical suspicion for alveolar hemorrhage secondary to cryoglobulinemic vasculitis.

The case of chronic hepatitis C 1b genotype with grade 3 fibrosis according to Metavir, complicated by the development of mixed type III cryoglobulinemia, cryoglobulinemic vasculitis with damage to the skin vessels of the skin (hemorrhagic vasculitis), and the liver (alternatively proliferative vasculitis) is demonstrated. The introduction of daclatasvir + asunaprevir was virologically unsuccessful: mutations D168E and L31V were detected against the background of a virological breakthrough. A repeated course of antiviral therapy with the combination of Grazoprevir + Elbasvir in combination with sofosbuvir led to a stable virologic response, partial immunological and clinical remission.

The term cryoglobulinemia (CG) is used when detecting serum immunoglobulins that reversibly precipitate and form a gel at a temperature below 37 °C and dissolve when the temperature rises above 37 °C. Type I CG consists of only one isotype or a subclass of monoclonal immunoglobulins, while types II and III are classified as mixed CG (MCG) that is primarily characterized by the presence of immunoglobulins G and M. Types II and II-III MCG can result in cryoglobulinemic vasculitis (CGV) more frequently, whereas type III can lead to this condition less frequently. The presence of type I cryoglobulins is always associated with B-cell lymphoproliferative diseases. On the contrary, type II or type III MCG is more commonly associated with systemic autoimmune diseases and chronic infections. Thus, hepatitis C virus infection contributes to the development of MCG in 80–90% of cases. CGV is considered a rare disease worldwide (

Autoimmune systemic diseases (ASD) may show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed to evaluate the seroconversion after the vaccination cycle and at 6-12-month follow-up, as well the safety and efficacy of vaccines in preventing COVID-19. The study included 478 unselected ASD patients (mean age 59 ± 15 years), namely 101 rheumatoid arthritis (RA), 38 systemic lupus erythematosus (SLE), 265 systemic sclerosis (SSc), 61 cryoglobulinemic vasculitis (CV), and a miscellanea of 13 systemic vasculitis. The control group included 502 individuals from the general population (mean age 59 ± 14SD years). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was evaluated by measuring serum IgG-neutralizing antibody (NAb) (SARS-CoV-2 IgG II Quant antibody test kit; Abbott Laboratories, Chicago, IL) on samples obtained within 3 weeks after vaccination cycle. The short-term results of our prospective study revealed significantly lower NAb levels in ASD series compared to controls [286 (53–1203) vs 825 (451–1542) BAU/mL, p < 0.0001], as well as between single ASD subgroups and controls. More interestingly, higher percentage of non-responders to vaccine was recorded in ASD patients compared to controls [13.2% (63/478), vs 2.8% (14/502); p < 0.0001]. Increased prevalence of non-response to vaccine was also observed in different ASD subgroups, in patients with ASD-related interstitial lung disease (p = 0.009), and in those treated with glucocorticoids (p = 0.002), mycophenolate-mofetil (p < 0.0001), or rituximab (p < 0.0001). Comparable percentages of vaccine-related adverse effects were recorded among responder and non-responder ASD patients. Patients with weak/absent seroconversion, believed to be immune to SARS-CoV-2 infection, are at high risk to develop COVID-19. Early determination of serum NAb after vaccination cycle may allow to identify three main groups of ASD patients: responders, subjects with suboptimal response, non-responders. Patients with suboptimal response should be prioritized for a booster-dose of vaccine, while a different type of vaccine could be administered to non-responder individuals.

Background and Aims: Mixed cryoglobulinemia is the most common HCV extrahepatic manifestation. We aimed to prospectively evaluate the cryoglobulinemic vasculitis (CV) clinical profile after a sustained virologic response (SVR) over a medium-term to long-term period. Approach and Results: Direct-acting antiviral–treated cryoglobulinemic patients, consecutively enrolled in the multicentric Italian Platform for the Study of Viral Hepatitis Therapy cohort, were prospectively evaluated. Cumulative incidence Kaplan-Meier curves were reported for response, clinical deterioration, relapse and relapse-free survival rates. Cox regression analysis evaluated factors associated with different outcomes. A clinical response was reported in at least one follow-up point for 373 of 423 (88%) patients with CV who achieved SVR. Clinical response increased over time with a 76% improvement rate at month 12 after the end of treatment. A full complete response (FCR) was reached by 164 (38.8%) patients in at least one follow-up point. CV clinical response fluctuated, with some deterioration of the initial response in 49.6% of patients (median time of deterioration, 19months). In patients who achieved FCR and had an available follow-up (137 patients) a relapse was observed in 13% and it was transient in 66.7% of patients. The rate of patients without any deterioration was 58% and 41% at 12 and 24months, respectively. After achieving SVR, a clinical nonresponse was associated with older age and renal involvement; a clinical deterioration/relapse was associated with high pretreatment rheumatoid factor values, and FCR was inversely associated with age, neuropathy, and high cryocrit levels. Conclusion: In patients with CV, HCV eradication may not correspond to a persistent clinical improvement, and clinical response may fluctuate. This implies an attentive approach to post-SVR evaluation through prognostic factors and tailored treatment.

Autoimmune systemic diseases (ASD) show impaired immunogenicity to COVID-19 vaccines. Our prospective observational multicenter study aimed at evaluating the seroconversion elicited by COVID-19 vaccine over the entire vaccination cycle including the booster dose. Among 478 unselected ASD patients originally evaluated at the end of the first vaccination cycle (time 1), 344 individuals were re-evaluated after a 6-month period (time 2), and 244 after the booster vaccine dose (time 3). The immunogenicity of mRNA COVID-19 vaccines (BNT162b2 and mRNA-1273) was assessed by measuring serum IgG-neutralizing antibody (NAb) on samples obtained at the three time points in both patients and 502 age-matched controls. In the 244 ASD group that received booster vaccine and monitored over the entire follow-up, the mean serum NAb levels (time 1, 2, and 3: 696.8±52.68, 370.8±41.92, and 1527±74.16SD BAU/mL, respectively; p&nbsp

Rituximab represents a milestone in the treatment of mixed cryoglobulinemic vasculitis. Despite usually well-tolerated, rituximab may induce different types of adverse drug reactions, including exacerbation of vasculitis. Rituximab biosimilar have been recently approved in Europe in the treatment of rheumatoid arthritis, but no data are available about effectiveness and safety of rituximab biosimilar in the treatment of mixed cryoglobulinemic vasculitis. We describe a severe skin vasculitis reactivation in a patient affected by rheumatoid arthritis and mixed cryoglobulinemic vasculitis treated with rituximab biosimilar. After 7 days from the first infusion, a severe purpuric rash at lower limbs appeared, that resolved in about 2 weeks with high dose-corticosteroid. Rituximab-induced vasculitis has also been described since 2001, but its pathophysiology is still controversial due to the anecdotical descriptions in literature and the variability of the time between the rituximab infusion and the onset of skin lesions. Up to date, this is the first report describing a vasculitic flare in a patient affected by mixed cryoglobulinemic vasculitis treated with rituximab biosimilar.

INTRODUCTION Mixed cryoglobulinemia (MC) is a B-cell lymphoproliferative disorder largely attributable to Hepatitis C virus (HCV) infection. MC clinical manifestations are determined by systemic vasculitis of low/medium sized vessels (mixed cryoglobulinemia syndrome or cryoglobulinemic vasculitis [CV]) caused by the deposition of cryoglobulins in blood vessels. EVIDENCE ACQUISITION A systematic review was performed via the Medline and Scopus databases to evaluate studies concerning CV treatment with new direct antiviral agents (DAAs) and their effect on the syndrome. EVIDENCE SYNTHESIS The introduction of interferon-free protocols has led to more evident positive effects than those observed in the treatment of hepatitis C. In fact, IFN-free, DAA-based therapy minimized side effects permitting the treatment of previously contraindicated patients and led to a particularly high SVR rate and to a clinical/immunological response in the majority of patients, even if at different levels in different patients, from restitutio ad integrum to partial response. In view of the clearly positive evolution in CV management, the persistence of CV manifestations, in partial or non-responders continues to pose problems in the clinical approach to patients who represent a new condition that is still not completely known. CONCLUSIONS Results of DAA-based therapy strongly confirm the use of anti-HCV therapy as the first-line therapeutic option in CV patients. However, growing evidence of a possible persistence or late relapse of CV suggests the need for longer/more accurate post-DAA follow-ups as well as biomarkers that are capable of predicting the risk of clinical relapse/persistence to allow for the design of rational post-HCV eradication clinical flow-charts.

Introduction Neurologic and neuropsychiatric manifestations sometimes provide the first evidence of an unknown HCV infection. These conditions develop with a variable ranging of morbidity, including: "brain fog," fatigue, subtle cognitive and attention impairment, but also with more severe complications or acute presentation, like encephalomyelitis, encephalopathy, stroke and peripheral nerves involvement. Evidence acquisition We performed a systematic literature search on PubMed, Cochrane Library and Web of Science databases for articles only in English language, that assessed the relationship between "DAA treatment and neurologic disorders" and after the attainment of SVR in full reports of cases that received the DAA schedule from January 2015 to December 2019. The following terms were used: "chronic Hepatitis C," "HCV," "DAA," "direct-acting antiviral," "SVR," "sustained virologic response," peripheral neuropathy" and "neurologic diseases or disorders." Evidence synthesis HCV infection does not only involve the liver, causing cirrhosis and hepatocellular carcinoma (HCC), but also induces extrahepatic manifestations (EHM), mainly due to a complex immune disease, that damage small and medium vessels, called "mixed cryoglobulinemic vasculitis" (MCV). This kind of mechanism generates most of the HCV-induced neurological damages. Since 2015, the availability of direct-acting antiviral (DAA) oral molecules interfering with HCV replication has completely revolutionized therapeutic options and the target population, which now includes patients aged 12 to 80 years and with advanced liver disease. Relevant was the highlighted DAA effectiveness by achievement of a sustained virologic response (SVR) in about 95% of cases, showing a great tolerability. Conclusions This favorable effect has arisen in a wide category of patients infected by HCV, including subjects with cirrhosis and complications and/or with EHM, who showed a significant improvement of their symptoms and the disease regression. In this concise review, we examine the clinical outcomes after the introduction of the DAA for the treatment of chronic hepatitis C (CHC), focusing on the neurologic disorders and concluding that there is a strong amelioration of neurologic conditions in several cases, particularly, after attaining the viral eradication with a favorable course in most treated cases.

Objectives Coxiella and Bartonella spp. display particular tropism for endothelial or endocardial tissues and an abnormal host response to infections with induced autoimmunity. We aimed, through a case series combined with a comprehensive literature review, to outline characteristics of Coxiella and Bartonella infections presenting as systemic vasculitis. Methods We retrospectively included cases of definite Coxiella and Bartonella infections presenting with vasculitis features and performed a comprehensive literature review. Results Six cases of Bartonella infections were added to 18 cases from literature review. Causative pathogens were mainly B. henselae. Bartonella infection mimicked ANCA-associated vasculitis in 83% with PR3-ANCA and presented as cryoglobulinaemic vasculitis in 8%. GN was present in 92%, and 88% had endocarditis. Complement fractions were low in 82% and rheumatoid factor positive in 85%. Kidney biopsies showed cell proliferation, mostly crescentic, with pauci-immune GN in 29%. Outcome was favourable, with the use of antibiotics alone in one-third. Five cases of Coxiella infections were added to 16 from literature review. Sixteen had small-vessel vasculitides, mainly cryoglobulinaemia vasculitis in 75%. One patient had polyarteritis nodosa-like vasculitis and four large-vessel vasculitis. Outcome was good except for one death. A highly sensitive next generation sequencing analysis on three Coxiella- and two Bartonella-related vasculitides biopsies did not find any bacterial DNA. Conclusion Coxiella and Bartonella are both able to induce vasculitis but display distinct vasculitis features. Bartonella mimics PR3-ANCA-associated vasculitis in the setting of endocarditis, whereas Coxiella may induce vasculitis involving all vessel sizes.

Ksymena Le&sacute;niak, Aleksandra Rymarz, Arkadiusz Lubas, Stanis&lstrok;aw Niemczyk Department of Internal Medicine, Nephrology and Dialysis, Military Institute of Medicine, Warsaw, PolandCorrespondence: Ksymena Le&sacute;niakDepartment of Internal Medicine, Nephrology and Dialysis, Military Institute of Medicine, Warsaw, PolandEmail klesniak@wim.mil.plBackground: The management of nonviral cryoglobulinemic vasculitis (CV) has not been established yet. Randomized control trials are challenging to perform because of the rarity of the disease. The most promising biological therapy is rituximab (RTX), an anti-CD 20 monoclonal antibody. The aim of the study was to assess rituximab treatment’s safety and effectiveness in patients with severe noninfectious cryoglobulinemic vasculitis.Materials and Methods: We retrospectively reviewed 8 courses of RTX treatment in three patients with severe noninfectious CV. In 2 patients, the indication for the start of RTX therapy was the relapse of the disease despite the maintenance treatment, for the third patient, it was the first-line therapy.Results: Clinical, renal, and immunologic efficacy was observed in all evaluable RTX courses. We found a significant decrease of cryoglobulins in the 3-rd month from RTX treatment. However, 5 clinical relapses occurred and two patients experienced severe adverse events (SAEs) after RTX therapy. Patients with SAEs were relatively older and had a longer duration of disease. Lower levels of hemoglobin, C3 component of complement and eGFR as well as higher rheumatoid factor (RF) concentration were observed before RTX treatments complicated with SAEs.Conclusion: Data from our observation show the efficacy of rituximab in the refractory, nonviral cryoglobulinemic vasculitis with a severe course of the disease. However, the therapy is associated with the risk of SAEs, especially in elderly patients with kidney failure and significant immunologic alterations.Keywords: cryoglobulinemia, rituximab, systemic vasculitis

Up to 3% of people in the world are infected with HCV, and 75-80% of them have chronic currency of infection. In the clinical picture of HCV infection, a significant place is given to extrahepatic manifestations - more than half of patients suffer from lesions of the skin, kidneys, heart, blood vessels, autoimmune and lymphoproliferative syndromes associated with HCV. Usually, mortality from chronic hepatitis C is associated with liver cirrhosis and hepatocellular carcinoma, but in fact, more patients die from complications associated with the development of cryoglobulinemic vasculitis - chronic renal failure and cardiovascular catastrophes. 40-60% of patients with chronic HCV infection suffer from cryoglobulinemic vasculitis in a wide range of clinical manifestations: from minimal to life-threatening. The pathogenesis of mixed cryoglobulinemia syndrome is based on polyclonal activation of lymphocytes. The systemic nature of the lesion, which is observed in HCV infection, reflects its generalized nature with the involvement of many organs and tissues in the pathological process, which complicates timely diagnosis and treatment. A variety of systemic extrahepatic pathology, which often outstrips the clinical picture of hepatitis itself, masquerading as another disease means that a specialist of any profile can meet with chronic HCV infection and its consequences

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare, but severe systemic vasculitis that can affect skin and other organ systems. Diagnostic criteria have evolved, and many attempts have been made to classify the vasculitides based on clinical and/or histopathologic features, with an aim to develop standardized criteria. According to the EGPA Consensus Task Force recommendations, EGPA is a syndrome of asthma, eosinophilia, pulmonary infiltrates, and extrapulmonary vasculitis (such as cutaneous involvement with purpura). Histopathologic evidence of vasculitis in EGPA may be associated with eosinophilic infiltration and/or perivascular granulomatous inflammation. We review clinicopathologic criteria of this enigmatic vasculopathy.

Background and Aims Cryoglobulinaemic vasculitis (CV) leading to clinically apparent skin lesions, and in some cases also to internal organ involvement such as renal involvement. The SARS Cov2 infection in this field is very serious and in the case of our patient the outcome was fatal. The aim of this work is to highlight the particularities of CV in this case Case presentation We report a case of a 62-year-old woman followed since 2014 for CV type 1 IgG Lambda revealed by vascular purpura and nasal septal perforation. the etiological assessment was negative. Hepatitis C virus serology was negative. A corticosteroid therapy at a dose of 1 mg/kg/day was started with partial improvement. Then the cyclophosphamide at a dose of 150 mg/d was added with a fairly good clinical result but stopped for hemorrhagic cystitis. Chlorominophene was started at a dose of 6 mg/d and then reduced to 4 mg/d for leuconeutropenia but the peripheral arterial manifestations (acrocyanosis of the limbs and ears) were not treated. The evolution was marked by the appearance of renal failure (creatinine 482.33 umol/l) associated with proteinuria at 1.32 g/24h. An outbreak of cryoglobulinemia was suspected. Plasma exchange was discussed as a therapeutic alternative and the patient was scheduled for a renal biopsy. However, the patient became febrile with the appearance of a dry cough and the presence of a biological inflammatory syndrome (CRP at 72). A SARS-CoV-2 PCR was completed which was positive. Therefore, she was put on antibiotic therapy (Azythromycin and Cefotaxime) associated with vitamin therapy and anticoagulant treatment. The patient was stable in terms of respiration and hemodynema, but her renal function worsened and progressed well under hydration. In addition, she presented with a slippage syndrome and she was died Conclusion The natural history of CV is not predictable and strongly depends on concomitant diseases and complications and response to treatment. The SARS Cov2 infection can complicate its evolution. There is no association has been described between them to our knowledge

We report the case of a 47-year-old man with a 9-year history of psoriatic arthritis (PsA) in whom we detected renal involvement, hypocomplementemia, peripheral neuropathy, acral necrotic lesions and positive cryoglobulins. The results of the diagnosis led us to conclude that the clinical picture corresponded to cryoglobulinemic vasculitis concomitant with PsA. In addition, we present a review of the literature on the presence of these two diseases in a single patient.

At present, healthcare systems all over the world are coping with the new coronavirus infection [1]. In particular, tremendous efforts are are being made in order to support governments in the policy of infection spread containment and early detection, and researchers are working on causal treatment and the treatment of the severe and critical manifestations downstream from the viral infection [2]. As largely known, coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with droplets and contact as the main way of transmission. Since the first case reported in Wuhan, China, in December 2019, the outbreak has gradually spread nationwide and then abroad, rapidly becoming a pandemic infection. Now, coronaviruses (CoVs) have come back into the limelight after the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003 and Middle East Respiratory Syndrome (MERS-CoV) outbreak in Saudi Arabia and South Korea. The Rheumatology scientific community has been involved in the management of this pandemic infection, since some treatments, usually employed in patients with inflammatory rheumatic diseases, might be useful to directly counteract the virus, as suggested for antimalarials [3], and more recently for baricitinib, or be effective in downregulating the dangerous inflammatory pathways triggered by the virus itself [4]. A first and crucial issue to address is whether and when it is important to target the viral infection or the downstream inflammatory events as a priority for clinical purposes. Our past experience in hepatitis C virus infection (HCV) and cryoglobulinemic vasculitis (i.e., an autoimmune and lymphoproliferative disease driven by a treatable infection) may be of value to this end, as it shows that, for life-threatening and severe disease manifestations, the immediate targeting of the events downstream of infection is mandatory [5]. Currently, the humanized monoclonal antibody anti-interleukin-6 receptor (anti-IL-6R), namely tocilizumab, appears as a promising tool to turn off the cytokine storm, which dramatically complicates the course of the infection in some patients, causing a rapidly fatal acute respiratory distress syndrome. The rationale for the use of anti-cytokine drugs is to play for time, by decreasing the dangerous inflammatory peak, while the immune system is building the adaptive response to the virus. As we write this paper, several protocols using anti-IL6R treatments are starting to recruit COVID-19 patients in different countries to build an evidence-based support for this treatment. Tocilizumab is an effective and safe treatment for rheumatoid arthritis, for systemic and polyarticular juvenile chronic arthritis and for the most frequent systemic vasculitis in adults, i.e., giant-cell arteritis. Moreover, it has been recently licensed for the treatment of cytokine storm syndrome in CAR-T protocols [6]. Interleukin-1 (IL-1) is another proinflammatory cytokine involved in the early phases of cytokine release syndrome and clinical protocols involving IL-1 blockade are being adopted in several countries. A second important open and urgent question is, however, at which stage of the infection this treatment approach has to be best applied. To answer this question, it is important to carefully consider what we already know about coronaviruses from the lessons of previous epidemic infections, and to compare with COVID-19 outbreak.

La vasculitis crioglobulinémica es una vasculitis de vasospequeños que se da en presencia de crioglobulinas séricas.Las crioglobulinemias mixtas son las más frecuentes y se asocian a infecciones crónicas, típicamente,al virus de la hepatitis C, así como a enfermedades linfoproliferativas y autoinmunes, más a menudo,al síndrome de Sjögren. Las manifestaciones clínicasincluyen púrpurade los miembros inferiores, neuropatía periférica, artralgias y glomerulonefritis. La presencia de vasculitis crioglobulinémica en el contexto de un síndrome de Sjögren es marcadora de peor pronóstico. Presentamos el caso de una paciente con vasculitis crioglobulinémica con compromiso cutáneo y renal, que condujo al diagnóstico de un síndrome de Sjögren primario.

Cryoglobulinemia is a condition in which circulating cryoprecipitate immune complexes are detected in serum. The cryoglobulin concentration above 50 mg/l is considered diagnostically significant for the statement of cryoglobulinemia. The production of cryoglobulins, as a rule, is a consequence of the underlying disease, which requires etiological evaluation. The diagnosis of cryoglobulinemic vasculitis (CV) is based on laboratory detection of serum cryoglobulinemia in combination with characteristic clinical signs and symptoms. The main clinical manifestations include common symptoms (severe fatigue, unexplained fever with or without weight loss), skin lesions (orthostatic palpable purpura, necrotic ulcers), joints (arthritis, arthralgia), peripheral nervous system (mononeuritis, polyneuritis) and kidney (membranoproliferative glomerulonephritis). Given the many signs and symptoms, a patient with CV rarely turns primarily to a rheumatologist. First contact doctors are often family doctors or dermatologists, along with the fact that the awareness of doctors of other specialties about this pathology is insufficient. The article presents modern data on the etiological factors, CV types and variants of the clinical course and treatment. CV classification criteria are highly informative and available to practitioners. Treatment of CV remains a challenge due to serious specific target organ damage and sometimes life-threatening manifestations. In secondary cryoglobulinemia, treatment of the underlying disease is crucial. In case of CV on the background of mixed cryoglobulinemia, the treatment strategy is based on antiviral, anti-inflammatory and immunosuppressive therapy. The therapy goals for CV include reducing the immunoglobulin level and removing the antigen. The first goal can be achieved with immunosuppressants, while the second goal depends on whether the antigen is known or not. With CV associated with HCV, antiviral therapy reduces the number of antigens. However, in autoimmune diseases, the potential antigen is usually not recognized, and only non-specific immunosuppressants are used.

Introduction and Objectives Cryoglobulinemia is one of the most frequent extrahepatic manifestations of chronic hepatitis C virus (HCV) infection and it may evolve to cryoglobulinemic vasculitis (CryoVas) which is a systemic vasculitis that affects small-sized vessels. The objective of this study was to evaluate the prevalence of cryoglobulinemia and CryoVas in HCV patients in Sao Paulo, Brazil. Materials and methods A cross-sectional study was conducted and included sixty-eight viremic HCV patients, without HIV or hepatitis B coinfection. A thorough clinical and laboratory evaluation was performed including the detection of serum cryoglobulins and measurement of serum complement components. The classification criteria for CryoVas were applied. Results The study population comprised mainly women (61.8%) with long term HCV infection (median 11.0 years). Advanced hepatic fibrosis was detected in 20.6% (14/68) of cases. Cryoglobulins were detected in 48.5% (33/68) of HCV-patients with type III cryoglobulinemia being the most frequent. CryoVas was present in 10.3% (7/68) and the main manifestations were peripheral neuropathy (85.7%), palpable purpura (42.8%), arthralgias (42.8%) and renal involvement (42.8%). Life-threatening manifestations were rare. Low hemolytic C2, C4 and total hemolytic complement (CH100) levels were common findings in the cryoglobulinemia group. Low C4 levels were independently associated with the development of CryoVas. Conclusion A high prevalence of cryoglobulinemia and CryoVas was found in Brazilian HCV-patients. CryoVas patients mostly presented non-life-threatening manifestations, especially peripheral neuropathy. Complement abnormalities were common in patients with cryoglobulinemia and low serum C4 levels were associated with CryoVas.

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.

Newer treatment protocols involving direct-acting antiviral agents (DAAs) have been associated with high rates of sustained virologic response (SVR) and clinical remission in patients with hepatitis C virus (HCV) associated cryoglobulinemic vasculitis (HCV-CV), but clinical response in those with renal involvement is less clear. Our goal was to evaluate the clinical course following DAA therapy in one of the largest cohorts of patients with HCV-associated cryoglobulinemic glomerulonephritis (HCV-GN) reported to date. This is an observational study of patients with chronic HCV infection and circulating cryoglobulins (CC) treated with DAAs in our department from January 2015 to January 2019. We identified a total of 67 patients with HCV and CC out of which nine patients fulfilled the criteria of HCV-GN and had adequate clinical follow-up time. We describe a cohort of nine patients with a mean age of 57 years and known duration of HCV infection ranging 3-20 years (four with evidence of compensated cirrhosis). All patients received the ritonavir-boosted paritaprevir/ombitasvir/dasabuvir regimen for 12 weeks and achieved SVR without subsequent viral relapse. Following DAAs completion, one patient developed "new-onset" cryoglobulinemic glomerulonephritis, six showed either persistent or worsening glomerulonephritis, and only two patients had a complete clinical response (CCR). Of the six patients with either persistent or worsening CV, 67% received additional immunosuppressive (IS) therapy for uncontrolled CV. Of the two patients that had a CCR, one patient received prior IS therapy while the other one improved without any additional intervention. Newer HCV treatment protocols involving DAAs are highly successful in eradication of HCV infection; however, in our experience, DAA treatment alone is insufficient in improving the renal outcomes of patients with HCV-GN and additional IS therapies should be considered.

espanolObjetivo Revisar la eficacia y seguridad del rituximab en neuropatia vasculitica (NV). Metodos Se realizo una busqueda en la literatura de Medline y Embase hasta 2017. Los terminos incluidos guardaron relacion con «vasculitis», «neuropatia vasculitica» y «rituximab». Dicha busqueda fue realizada por 2 revisores. El resultado principal fue la eficacia del rituximab. Resultados Tras seleccionar inicialmente 702 articulos, 5 de ellos permanecieron con un nivel de evidencia de entre 1+ y 3, y un grado de recomendacion variable. En el unico ensayo clinico incluido, el rituximab fue superior a la terapia convencional para vasculitis crioglobulinemica, mostrando NV un incremento en la tasa de retencion farmacologica (64,3 vs. 3,5%; p Conclusiones Rituximab parece ser un tratamiento eficaz y seguro para NV, en el contexto de vasculitis crioglobulinemica. Se carece de evidencia sobre la eficacia especifica de NV en el contexto de otras vasculitis. EnglishObjective To review the efficacy and safety of rituximab in vasculitic neuropathy (VN). Methods A literature search was performed on Medline and Embase up until 2017. It included terms related to “vasculitis”,“vasculitic neuropathy” and “Rituximab”. Research was carried out by two reviewers. The main outcome was rituximab efficacy. Results Of an initial selection of 702 articles, 5 remained with a level of evidence between 1+ and 3 and variable recommendation degree. In the only clinical trial included, rituximab was superior to conventional therapy for cryoglobulinemic vasculitis with VN showing an increase in drug retention rate (64.3% vs. 3.5%; P Conclusions Rituximab seems an effective and safe treatment for VN in the context of cryoglobulinemic vasculitis. Evidence for specific efficacy in VN in the context of other types of vasculitis is lacking.

Background/objective The epidemiology of vasculitis is variable in different geographic areas, and this issue has not been approached in Brazil yet. The objective of this study was to assess the frequency of vasculitis in specialized centers in Brazil. Methods This cross-sectional study was performed in 9 vasculitis outpatient clinics from 6 different states mainly from the Southeast and the Northeast regions of Brazil between 2015 and 2017. Diagnosis and/or classification criteria for Behcet disease (BD), Takayasu arteritis (TA), giant cell arteritis (GCA), polyarteritis nodosa (PAN), granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis (EGPA), and cryoglobulinemic vasculitis (CryoVas) were used to include patients with at least 6 months of follow-up in this hospital-based survey. Results A total of 1233 patients with systemic vasculitis were included from the Southeast region. Behcet disease was the most frequent vasculitis (35.0%) followed by TA (26.4%), GPA (16.2%), PAN (5.8%), GCA (5.8%), EGPA (4.3%), MPA (3.4%), and CryoVas (3.0%). Up to 7.8% of vasculitis patients had a juvenile onset, and the frequency of vasculitides found in children and adolescents was as follows: TA (52.6%), BD (24.7%), GPA (12.4%), and PAN (10.3%). No cases of EGPA, MPA, and CryoVas were diagnosed before the age of 18 years. As a comparator, 103 vasculitis patients were included in the Northeast of Brazil where TA was found in 36.9% and BD in 31.1% of vasculitis cases. No GCA cases were found in the Northeast part of Brazil. Conclusions Similar to the epidemiology of vasculitis in Asia, BD and TA are the most frequent vasculitis in Southeastern Brazilian referral centers.

Chronic viral hepatitis can remain unrecognized but may nevertheless lead to liver cirrhosis and hepatocellular carcinoma. Thus, patients with elevated liver enzymes as well as risk groups need to be screened and treated for viral hepatitis. These groups include, in particular, migrants from countries with high HBV or HCV prevalence, persons with previous or current intravenous drug use, and homosexual men. For HBV- or HCV-associated diseases, such as panarteriitis nodosa, cryoglobulinemic vasculitis or B-cell lymphoma, antiviral therapy may lead to remission. Prior to high-dose immunosuppressive therapy, especially with regimes containing rituximab, chronic or resolved HBV infection must be ruled out or antiviral prophylaxis may be required to avoid a potentially fatal HBV reactivation.

Aim. To investigate risk factors of unfavorable prognosis in patients with chronic hepatitis C (CHC), including liver cirrhosis (LC), decompensated cirrhosis, hepatocellular carcinoma (HCC), cryoglobulinemic vasculitis (CryoVas) and B-cell non-Hodgkin’s lymphoma. Materials and methods. This was a retrospective study using data of 824 patients with CHC hospitalized between 2010 and 2016 in clinic named after E.M. Tareev. We used multivariate analysis including logistic regression to calculate odds ratios (ORs) for potential risk factors/predictors associated with unfavorable outcomes in patients with CHC. Results and discussion. The rate of LC, decompensated LC, HCC, serious CryoVas and B-cell lymphoma in patients with CHC was 39.1% (322/824), 14.0% (115/824), 2.8% (23/824), 5.2% (43/824) and 1.2% (10/824), respectively. After adjustment for sex and age the rate of LC, decompensated LC, HCC was 22.8, 8.0 and 1.5%, respectively. Annual rate of LC in patients with CHC was 1.5%; in cirrhotic patients annual rate of decompensated LC and HCC was 2.9 and 1%, respectively. Risk factors independently associated with development of LC were elevated body mass index (OR 1.43), immunosuppressive therapy (OR 1.67), diabetes type 2 (OR 2.03), absence of antiviral therapy (OR 2.15), alcohol abuse (OR 2.34), duration of infection ≥20 years (ОR 2.74) and an absence of sustained virological responce (SVR) (OR 2.98). Independent risk factors for decompensation in cirrhotic patients included diabetes type 2 (OR 1.47), alcohol abuse (OR 1.53), an absence of antiviral therapy (OR 2.36) and an absence of SVR (OR 1.94). An episode of decompensation was the independent predictor of HCC in cirrhotic patients (OR 3.99). Genotype 1b (OR 1.66) and an absence of antiviral therapy (OR 3.31) were independently associated with serious CryoVas. Two prognostic scales were offered for risk evaluation of LC and its complications. Conclusions. Multivariate analysis showed several factors independently associated with higher risk for LC, decompensation of LC, HCC, serious CryoVas in patients with CHC. The rate of unfavorable outcomes of CHC is found, including rare extrahepatic manifestations.

Cryoglobulins are circulating immunoglobulins that reversibly precipitate at temperatures below 37 °C. Type-II cryoglobulins consist of monoclonal IgM/polyclonal IgG immune complexes (ICs), whereas in type-III cryoglobulins both IgM and IgG are polyclonal. The clinical condition resulting from the presence of cryoglobulins in the blood is called mixed cryoglobulinemia (MC), which can be asymptomatic or manifest as cryoglobulinemic vasculitis (CV). Type-I cryoglobulins, consisting of a single monoclonal isotype, are detected in patients with lymphoproliferative disorders. It is now established that > 90% of MCs are associated with HCV infection. Clinically, the spectrum of symptoms may range in severity from occasional purpuric eruptions to life-threatening features. In addition to the development of liver cirrhosis and hepatocellular carcinoma, the possible progression of HCV-positive CV patients to B-cell non-Hodgkin lymphoma (B-NHL) has been reported. The pathogenetic role played by HCV infection in the onset of B-NHL is suggested by regression of the latter following the achievement of a sustained virologic response (SVR). For several years, interferon-α alone or combined with ribavirin has been the standard of care. However, the rates of clinical, biochemical, and virologic responses have been low, and the occurrence of relapse frequent. The addition of rituximab has resulted in a higher rate of responses. With the advent of direct-acting antiviral agents, SVR has been achieved in ~ 95% of CV patients. However, in a minority of patients, despite SVR, CV may persist or reappear over variable lengths of time from the completion of therapy. The eventual appearance of B-NHL is also possible.

INTRODUCTION Hepatitis C virus (HCV) infection affects about 170 million people worldwide. HCV is responsible for both hepatitis and extra-hepatic manifestations. Chronic infection has been shown to develop in about 70% of cases, and it can progress to cirrhosis or hepatocellular carcinoma. Ten percent of HCV patients may develop extra-hepatic manifestations, including mixed cryoglobulinemia (MC) and non-Hodgkin lymphomas (NHL). Cryoglobulinemic vasculitis (CV) varies, ranging from mild-moderate clinical symptoms (purpura on the legs, asthenia and arthralgias) and chronic hepatitis to severe symptoms (ulcers on the legs, peripheral neuropathy, glomerulonephritis, low-grade NHL to life threatening complications (rapid progressive glomerulonephritis, gastrointestinal vasculitis, acute hyper-viscosity). EVIDENCE ACQUISITION CV is associated with significant morbidity and mortality. Some studies have shown kidney involvement, cirrhosis, central nervous system involvement, and heart involvement as unfavorable prognostic factors. Many studies have demonstrated that, after antiviral therapy, CV can disappear along with HCV. After the introduction of the new direct antiviral agents (DAAs), the combination of pegylated interferon and ribavirin has been abandoned. EVIDENCE SYNTHESIS Several studies on new DAAs have reported remarkable 90% to 100% HCV eradication rates, regardless of genotype. Treatment with DAAs has comparable efficacy on viral eradication in CV patients but definite clinical improvements of vasculitis can be observed only in half the patients. CONCLUSIONS In patients with mild to moderate CV disease, DAAs therapy should be used as first line approach. In patients with severe vasculitis, DAAs therapy and a second-line treatment with RTX with or without aphaeresis are a required.

Extrahepatic Manifestations of Chronic HCV Infection Hepatitis C virus infection is associated with nonhepatic diseases, including mixed cryoglobulinemic vasculitis, B-cell lymphoma, cardiovascular...

Type I cryoglobulins are monoclonal immunoglobulins produced due to underlying hematological malignancy. Cryoglobulins spontaneously precipitate from serum and plasma at low temperatures and become soluble again on rewarming to 37 °C. Processing of blood at temperature lower than 37 °C in the laboratory may cause precipitation of cryoglobulins resulting in interferences in the automated cell counter analysis. We report three patients with cryoglobulinemic vasculitis wherein each case had different morphology of cryoglobulin precipitates on peripheral blood film, like needle shaped bluish-gray crystals, amorphous weakly basophilic extracellular deposits extraneously indenting red blood cells and basophilic neutrophilic inclusions respectively. The effect of cryoglobulins on two technologically different automated cell counters based on principles of impedance, Volume-Conductivity-Scatter (VCS) and fluorescence flow cytometry was assessed. This case series provides interesting insight into the varying morphological features of cryoglobulins on May-Grunwald-Giemsa stained blood films and interference caused by cryoglobulins in different automated cell counter analysis resulting in pseudo-leucocytosis, pseudo-thrombocytosis, abnormal histograms and scatterplots. Identification of these hematologic abnormalities and artifacts induced by cryoglobulins is necessary since it may be the first clue leading to the timely diagnosis of cryoglobulinemia and hence the underlying hematological malignancy, as in our cases.

Infection with hepatotropic viruses is not limited to the liver and can lead to the development of various immunological disorders (the formation of cryoglobulins, rheumatoid factor, antinuclear antibodies, autoantibodies specific for autoimmune hepatitis and primary biliary cholangitis, and others), which can manifest as glomerulonephritis, arthritis, uveitis, vasculitis (cryoglobulinemic vasculitis, polyarteritis nodosa, Henoch-Schonlein purpura, isolated cutaneous necrotizing vasculitis), and other rheumatologic disorders, and be a trigger for the subsequent development of autoimmune hepatitis and primary biliary cholangitis. A further study of the association between autoimmune liver diseases and hepatotropic virus infection would be useful to assess the results of treatment of these associated diseases with antiviral drugs. The relationship of these immune disorders and their manifestations with hepatotropic viruses is best studied for chronic hepatitis B and C. Only isolated cases of these associations are described for hepatitis A. These links are least studied, and are often controversial for hepatitis E, possibly due to their relatively rare diagnoses. Patients with uveitis, glomerulonephritis, arthritis, vasculitis, autoimmune liver diseases should be tested for biomarkers of viral hepatitis, and if present, these patients should be treated with antiviral drugs.