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International audience; Hepatitis C virus (HCV) has been shown to induce many B-cell lymphoproliferative disorders. B lymphocytes are specialized in producing immunoglobulins, and within chronic HCV infection they can cause a range that goes from polyclonal hypergammaglobulinemia without clinical repercussions, passing by mixed cryoglobulinemic vasculitis and eventually reaching B-cell non-Hodgkin lymphoma. This spectrum is supported by substantial epidemiological, pathophysiological and therapeutic data. Many, although not all, pathogenic pathways leading from one extreme to another have been decrypted. Chronic viral antigen stimulation of B lymphocytes has a central role until the last steps towards overt malignancy. This has direct implications in treatment strategies, which always include the use of direct-acting antiviral agents sometimes associated with immunosuppressants. The role of direct-acting antiviral agents has been well established in patients with cryoglobulinemia vasculitis. Its positive impact on B cell non-Hodgkin lymphoma needs to be confirmed in larger studies with longer follow-up.

The objectives of this article are to present a case of type II cryoglobulinemic vasculitis, explain why mucosa-associated lymphoid tissue (MALT) lymphoma is an unusual cause of type II cryoglobulins and to discuss the aetiology, epidemiology, pathophysiology and treatment of cryoglobulinemic vasculitis. A 67-year-old woman presented with 4 months of weight loss, intermittent epistaxis and a purpuric skin rash. Prior to presentation, she was found to have an elevated rheumatoid factor. Further investigation revealed an acute kidney injury and elevated type II cryoglobulins suspicious for cryoglobulinemic vasculitis, which was confirmed by kidney biopsy. Additional workup for the weight loss included biopsy of newly found splenomegaly. Pathology revealed MALT lymphoma, a rare cause of type II cryoglobulinemic vasculitis. Successful medical therapy required treating the underlying malignancy with rituximab and high-dose steroids. After initial resolution of symptoms with this regimen, the patient’s vasculitis worsened, which was thought to be secondary to undertreatment of the lymphoma. Bendamustine was added to further treat the lymphoma, after which the patient recovered and was able to discharge without recurrence of symptoms at 6 months.

Background Patients with cryoglobulinemic vasculitis (CV) can develop disease flare after rituximab administration. The objective of our study was to describe the prevalence, clinical characteristics, predisposing factors, and outcomes of patients with rituximab-associated flare of CV. Methods We conducted a retrospective study in a tertiary referral center until March 25, 2020. Results Among 64 patients with CV who received rituximab therapy in our center, 14 (22%) developed disease flare. Median age was 67.5 years. Seven patients (50%) had type II CV and the other half had either type I (n = 6) or type III (n = 1). Twelve patients (86%) had an underlying B-cell lymphoproliferative disorder as the cause of their CV. CV flare occurred after a median time of 5.5 days (range: 2–8 days). The organ systems most involved were the skin (n = 10), kidneys (n = 5), and peripheral nerves (n = 3). Five patients (36%) developed acute kidney injury (AKI), 3 of whom presented with nephritic syndrome secondary to biopsy-proven membranoproliferative glomerulonephritis. Treatment was directed against the underlying disease in addition to supportive care. Patients who developed flare were more likely to have B-cell lymphoproliferative disorder as the underlying etiology of their CV (P = 0.03). Eight patients (57%) died after a median time of 27 months. Conclusions Rituximab-associated flare can occur in all types of CV, tends to arise approximately 2 days and less than 1 week after rituximab administration, and is more likely to happen in patients with an underlying B-cell lymphoproliferative disorder. It does not indicate treatment failure, and rituximab should not be abandoned altogether. AKI is a common manifestation, and mortality rate at 2 years is high., Graphical abstract

Background: Hepatitis C virus infection is an important cause of many rheumatic diseases, especially cryoglobulinemic vasculitis, fibromyalgia, arthralgia and Sicca Syndrome. Direct acting antivirals are found to be highly effective for the treatment of chronic Hepatitis C virus infection. Objective: The aim of this study was to evaluate the clinical and serological course of extrahepatic rheumatic manifestations in chronic hepatitis C Egyptian patients after treatment with new direct-acting antivirals. Patients and Methods: This study was carried out on 60 Egyptian patients with chronic hepatitis C with one or more of the HCV- related rheumatic manifestations treated with sofosbuvir (400 mg daily) plus daclatasvir (60 mg daily) as a direct-acting antivirals for 3 months. All patients were subjected to clinical and serological course of extrahepatic rheumatic manifestations evaluation. Results: show that among the 60 patients, 21 patients (35.0%) met the criteria of mixed cryoglobulinemia syndrome (MC), 19 patients (31.7%) were complaining of arthralgia, 17 patients (28.3%) were complaining of fibromyalgia and 3 patients (5.0%) were complaining of Purpura without other criteria of mixed cryoglobulinemia syndrome. Complete clinical response was achieved in a significant number of patients with mixed cryoglobulinemia syndrome (MCS), the results also show significant clinical improvement in patients with fibromyalgia, arthralgia and purpura. Significant reduction but not complete normalization in auto-antibodies at short term follow-up was observed. Conclusion: It could be concluded that sustained virologic response correlates with clinical and immunological improvement in most patients with extrahepatic rheumatic manifestations among the studied group of chronic hepatitis C Egyptian populations.

Leukocytoclastic vasculitis (LCV) is a histopathologic description of a common form of small vessel vasculitis (SVV), that can be found in various types of vasculitis affecting the skin and internal organs. The leading clinical presentation of LCV is palpable purpura and the diagnosis relies on histopathological examination, in which the inflammatory infiltrate is composed of neutrophils with fibrinoid necrosis and disintegration of nuclei into fragments (“leukocytoclasia”). Several medications can cause LCV, as well as infections, or malignancy. Among systemic diseases, the most frequently associated with LCV are ANCA-associated vasculitides, connective tissue diseases, cryoglobulinemic vasculitis, IgA vasculitis (formerly known as Henoch–Schonlein purpura) and hypocomplementemic urticarial vasculitis (HUV). When LCV is suspected, an extensive workout is usually necessary to determine whether the process is skin-limited, or expression of a systemic vasculitis or disease. A comprehensive history and detailed physical examination must be performed; platelet count, renal function and urinalysis, serological tests for hepatitis B and C viruses, autoantibodies (anti-nuclear antibodies and anti-neutrophil cytoplasmic antibodies), complement fractions and IgA staining in biopsy specimens are part of the usual workout of LCV. The treatment is mainly focused on symptom management, based on rest (avoiding standing or walking), low dose corticosteroids, colchicine or different unproven therapies, if skin-limited. When a medication is the cause, the prognosis is favorable and the discontinuation of the culprit drug is usually resolutive. Conversely, when a systemic vasculitis is the cause of LCV, higher doses of corticosteroids or immunosuppressive agents are required, according to the severity of organ involvement and the underlying associated disease.

Human hepatitis viruses (HHVs) include hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis delta virus, and hepatitis E virus and can cause liver inflammation in their common human host. Usually, HHV is rapidly cleared by the immune system, following acute HHV invasion. The morbidities associated with hepatitis A virus and hepatitis E virus infection occur shortly after their intrusion, in the acute stage. Nevertheless, the viral infectious process can persist for a long period of time, especially in HBV and HCV infection, leading to chronic hepatitis and further progressing to hepatic cirrhosis and liver cancer. HHV infection brings about complications in other organs, and both acute and chronic hepatitis have been associated with clinical presentations outside the liver. Vascular involvement with cutaneous and systemic vasculitis is a well-known extrahepatic presentation; moreover, there is growing evidence for a possible causal relationship between viral pathogens and vasculitis. Except for hepatitis delta virus, other HHVs have participated in the etiopathogenesis of cutaneous and systemic vasculitis via different mechanisms, including direct viral invasion of vascular endothelial cells, immune complex-mediated vessel wall damage, and autoimmune responses with stimulation of autoreactive B-cells and impaired regulatory T-cells. Cryoglobulinemic vasculitis and polyarteritis nodosa are recognized for their association with chronic HHV infection. Although therapeutic guidelines for HHV-associated vasculitis have not yet been established, antiviral therapy should be initiated in HBV and HCV-related systemic vasculitis in addition to the use of corticosteroids. Plasma exchange and/or combined cyclophosphamide and corticosteroid therapy can be considered in patients with severe life-threatening vasculitis manifestations.

Cold urticaria (ColdU) is a common form of chronic inducible urticaria characterised by the development of wheals, angioedema or both in response to cold exposure. Recent research and guideline updates have advanced our understanding and management of ColdU. Today, its pathophysiology is thought to involve the cold-induced formation of autoallergens and IgE to these autoallergens, which provoke a release of proinflammatory mediators from skin mast cells. The classification of ColdU includes typical and atypical subtypes. We know that cold-induced wheals usually develop on rewarming and resolve within an hour and that anaphylaxis can occur. The diagnosis relies on the patient's history and cold stimulation testing. Additional diagnostic work-up, including a search for underlying infections, should only be done if indicated by the patient's history. The management of ColdU includes cold avoidance, the regular use of nonsedating antihistamines, and the off-label use of omalizumab. However, many questions regarding ColdU remain unanswered. Here, we review what is known about ColdU, and we present important unanswered questions on the epidemiology, underlying pathomechanisms, clinical heterogeneity and treatment outcomes. Our aim is to guide future efforts that will close these knowledge gaps and advance the management of ColdU.

Rheumatic diseases relate to the group of the immunoinflammatory diseases (IID), in pathogenesis of which have a value both autoimmune and autoinflammatory processes. Aim.To present the heterogeneous pathogenesis of inflammation in IID. Materials and methods.It is inspected 260 patients (pts) with IID: 242 pts with systemic autoimmune diseases (SAD): 65 systemic lupus erythematosis, 50 systemic sclerosis, 127 systemic vasculitides (SV) and 18 patients with autoinflammatory diseases (AID): 8 Behcets disease, 2 periodic disease, 5 familial cold fever, 2 idiopathic lobular panniculitis and 1 relapsing polychondritis. Is carried out a study of complement, antigen of von Willebrand factor (FW:AG), antinuclear antibodies, antibodies to DNA, anti-endothelial antibodies, antibodies to topoizomeraze I (anti-Scl-70), antineutrophilic cytoplasmic antibodies (ANCA), anticardiolipin antibodies (aCL IgG and aCL IgM), cryoglobulins, VS, CRP. Results.SAD were characterized by the synthesis of wide antibodies spectrum. As the basic serological marker at the screening it follows to consider antinuclear antibodies (75%). Practically in all groups it took place hypcomlemetemia with reduction of C3 and C4 complement. With systemic lupus erythematosis are revealed antibodies to DNA (71%), with ANCA-associated SV-ANCA (94%), aKL (14%); with SSD aScl-70 (17%). At Wegener granulomatosis ANCA are determined in 94% patients in the active stage. It is noted correlation ANCA with the index of the clinical activity of vasculitis. In the remaining SV groups ANCA were separated in the single cases. Cryoglobulins are noted in all patients with cryoglobulinemic vasculitis. aCL IgG and aCL IgM were the markers of antiphospholipid syndrome. Аnti-endothelial antibodies had significant oscillation spectrum. High indices FW:AG are noted with all above nosologic forms indicated, especially with Wegener granulomatosis and vasculitis hemorrhagic. Among the laboratory tests of inflammatory activity should be considered the determination of VS, CRP and FV:AG, which is also considered the marker of vascular wall defeat. Is given clinical characteristic and changes in the laboratory indices at AID: Conclusion.Isolation from the group IID of patients with AID serves as indication for a genetic study of this contingent with the approval of use for their treatment of biological therapy. Isolation from the group SAD patients with AID serves as indication for a genetic study of this contingent with the approval of use for their treatment of biological therapy.

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.

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.

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.

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.

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.

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 (

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.

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.

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

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.

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

Extrahepatic manifestations are a feature of chronic hepatitis C virus (HCV) infection. In the course of chronic HCV infection, about 70% of patients have one or more extrahepatic manifestations. The latter are often the first and only clinical sign of infection. Experimental and clinical data support a causal association for many extrahepatic manifestations and HCV infection, which include mixed cryoglobulinemia, non-Hodgkin lymphomas (NHL), cardiovascular disease, insulin resistance, type 2 diabetes, neurological and psychiatric disease and other rheumatic diseases. All these extrahepatic conditions influence the morbidity, quality of life and mortality of HCV-infected patients. Currently, interferon-free therapeutic regimens with direct-acting antiviral agents (DAA) offer the possibility of treatment to almost the entire infected population, irrespective of stage of cirrhosis and associated serious comorbidities, always maintaining a high efficacy and tolerability. Several studies have shown a close association between HCV clearance by DAAs and an improvement or reduction in the risk of extrahepatic manifestations. Patients with HCV after a sustained virologic response (SVR) by DAA treatment have a lower risk than non-responders of developing cryoglobulinemic vasculitis and B-cell non-Hodgkin’s lymphomas. Furthermore, the SVR by DAA also reduces the risk of acute coronary syndrome, cardiovascular disease, insulin resistance and type 2 diabetes, and it improves atherosclerosis. HCV clearance by DAA also improves the quality of life and survival of patients with chronic HCV infection with associated extrahepatic diseases. Thus, DAAs should be initiated as early as possible in HCV patients with extrahepatic manifestations.

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

Objective Hepatitis C virus (HCV) causes neuropsychiatric disorders and quality of life impairment, especially in patients with cryoglobulinemic vasculitis (CV). Direct acting antivirals (DAAs) are effective in most extrahepatic HCV diseases, but limited information exists regarding the outcome of psychiatric disorders in patients with and without CV, after therapy. We aimed to evaluate psychiatric outcomes, in HCV-patients with and without CV, before and after successful DAA therapy. Methods We prospectively studied DAA-treated HCV-patients, stratified into presence (CV) or absence of CV (NON-CV). Four psychometric scales were administered to assess depression (HAM-D and MADRS), anxiety (HAM-A), and mania (MRS). Short-Form-36 questionnaires evaluated quality of life. Results Seventy-six patients were recruited, and 47 CV and 29 NON-CV were treated with antivirals. At baseline, depression and anxiety, from mild to severe, were frequently shown, with the most advanced cases in thee CV group; no patients achieved the scores for mania. A significant improvement emerged for all the psychometric scales in the entire population and in the subgroups, after viral eradication even in the short-term outcome. The Short-Form-36 summary components showed benefits. Conclusions After HCV eradication, the depression and anxiety scores significantly improved and severity grade generally lowered. DAA-positive effects on mental disorders should be considered part of the therapy outcome, being beneficial especially in CV patients who usually have worse baseline mental scores. Key Points• HCV frequently causes psychiatric disorders and an often-invalidating autoimmune/lymphoproliferative disease called cryoglobulinemic vasculitis.• The new direct acting antivirals (DAAs) are very effective and well tolerated by HCV-patients.• This study shows DAA-induced benefits on depression and anxiety in HCV-patients that are especially evident in CV patients who usually have worse baseline mental scores.• DAA-induced benefits are observed in the short-term post-therapy follow-up, in contrast with data previously obtained in HCV patients treated with IFN-based anti-HCV therapy.

INTRODUCTION Hepatitis C Virus (HCV) is a well-known worldwide infection, responsible for hepatic and extrahepatic complications. Among extrahepatic manifestation, the rheumatologic are the most common ones. With the arrival of Direct Antiviral Agents (DAA), the treatment and the clinical perspective have rapidly changed, permitting to achieve a sustained virological response (SVR) and preventing complications of chronic infection. EVIDENCE ACQUISITION We performed on PubMed a literature search for the articles published by using the search terms "HCV infection," "HCV syndrome," "HCV-related rheumatologic disorders," "cryoglobulinemia," "cryoglobulinemic vasculitis" and "mixed cryoglobulinemia." EVIDENCE SYNTHESIS Mixed cryoglobulinemia (MC) is the prototype of HCV-associated rheumatologic disorder. HCV-related MC is typically considered by physicians as a human model disease to linking infection with autoimmune diseases. Chronic HCV infection can lead to a multistep process from a simple serological alteration (presence of circulating serum cryoglobulins) to frank systemic vasculitis (cryoglobulinemic vasculitis [CV]) and ultimately to overt malignant B lymphoproliferation (such as non-Hodgkin lymphoma [NHL]). Antiviral therapy is indicated to eradicate the HCV infection and to prevent the complications of chronic infection. Immunosuppressive therapy is reserved in case of organ threatening manifestations of CV. In this review, we discuss the main clinical presentation, diagnostic approach and treatment of rheumatologic manifestations of HCV infection. CONCLUSIONS Chronic HCV infection is responsible for complex clinical condition, ranging from hepatic to extra-hepatic disorders. Cryoglobulins are the result of this prolonged immune system stimulation, caused by tropism of HCV for B-lymphocyte.

Hepatitis C virus (HCV) is a major public health problem. HCV is a hepatotropic and lymphotropic virus that leads to hepatocellular carcinoma (HCC) and lymphoproliferative disorders such as cryoglobulinemic vasculitis (CV) and non-Hodgkin&rsquo, s lymphoma (NHL). The molecular mechanisms by which HCV induces these diseases are not fully understood. MicroRNAs (miRNAs) are small non-coding molecules that negatively regulate post-transcriptional gene expression by decreasing their target gene expression. We will attempt to summarize the current knowledge on the role of miRNAs in the HCV life cycle, HCV-related HCC, and lymphoproliferative disorders, focusing on both the functional effects of their deregulation as well as on their putative role as biomarkers, based on association analyses. We will also provide original new data regarding the miR 17-92 cluster in chronically infected HCV patients with and without lymphoproliferative disorders who underwent antiviral therapy. All of the cluster members were significantly upregulated in CV patients compared to patients without CV and significantly decreased in those who achieved vasculitis clinical remission after viral eradication. To conclude, miRNAs play an important role in HCV infection and related oncogenic processes, but their molecular pathways are not completely clear. In some cases, they may be potential therapeutic targets or non-invasive biomarkers of tumor progression.

We sought to investigate the infection profile and associated risk factors in a compiled cohort of patients with autoimmune disorders with severe renal involvement treated with aggressive immunosuppressive (IS) regimens.A total of 162 patients with aggressive glomerulonephritis [101 with lupus nephritis (LN), 24 with cryoglobulinemic vasculitis (CryoVasc), and 37 with ANCA-associated vasculitis (AAV)] were retrospectively reviewed for any infection occurrence. Infection incidence, type, site, and grade (1-5) were recorded. Multivariate Cox proportional hazard regression analysis was performed to identify independent risk factors for infections.A total of 179 infection episodes occurred during a follow-up of 468 patient-years. Eighty-two patients (50.6%) had at least one infection. The incidence rates of infections and severe infections were 38.2 and 14.3 events per 100 patient-years. Patients with AAV had more infections than those with CryoVasc and LN (100.6, 47.5, and 26.6 infections per 100-patient-years, respectively; p = 0.002). Most patients developed infections early during the initial induction therapy (62.1% in the first 6 months of follow-up). In multivariate Cox regression analysis, high-dose oral corticosteroids (≥ 0.5 mg/kg/day in the first month of induction therapy) was an independent predictor of any infection (HR 2.66; 95% CI, 1.5-4.73), severe infections (HR 2.45; 95% CI, 1.03-5.82), and pulmonary infections (HR 2.91; 95% CI, 1.05-8.01). Pulmonary involvement increased the risk for pulmonary infections (HR 3.67; 95% CI, 1.32-10.1) and severe infections (HR 2.45; 95% CI, 1.01-5.92).Infections occur frequently with current IS regimens in aggressive glomerulonephritis. Pulmonary involvement and high-dose corticosteroid regimen were the most significant risk factors for infections. Key Points • Infections occur frequently with current immunosuppressive regimens in autoimmune aggressive glomerulonephritis. • High-dose corticosteroids are the major contributors to the risk for serious infections.

Purpose of review Cryoglobulins (CG) are immunoglobulins that precipitate in the cold, and dissolve at 37°C. In vivo, in cold exposed tissues and organs, they can induce vasculitis and occlusive vasculopathy after deposition on vascular endothelium under low temperature and high concentration conditions. Clinical manifestations are cutaneous (purpura, ulcers, vasomotor symptoms, and livedo reticularis), rheumatological (arthralgia and arthritis), and peripheral neuropathy (paresthesia and pain in the lower limbs). In profound organs such as the kidneys, CG deposition is less temperature-dependent, favored by local protein and anion concentrations, and can lead to glomerulonephritis. This review will focus on cryoglobulinemic vasculitis and vascular lesion, and their diagnosis. Recent findings The mechanisms of vascular lesions of pathogenic CG in function of CG type and their characteristics are better defined. Optimal conditions for CG detection are critical. The importance of looking for underlying diseases, especially hepatitis C virus status in mixed CG, is reminded. Summary A decision diagram for CG vasculitis diagnosis based on clinical and biological parameters is proposed.

Case report - Introduction Primary Sjögren’s patients are a higher risk of developing non-Hodgkin lymphoma (NHL) compared with patients with other autoimmune disorders and to the general population. Parotid and submandibular salivary glands are the most frequent localization of MALT lymphomas in pSS. Here we report a case of marginal zone lymphoma of the breast in a patient with long-standing primary Sjögren’s, and we will discuss the clinical and serological predictors for the development of lymphoma. Case report - Case description A 79-year-old female with a 19-year history of primary Sjögren’s syndrome (anti-Ro, anti-La positive) was reviewed in the rheumatology clinic for progressive worsening of sicca symptoms. Her past medical history included recurrent pulmonary emboli, osteoporosis of the spine, asthma, microscopic colitis, Ischemic heart disease and hypothyroidism. She was a non – smoker and consumed minimal alcohol. Her past surgical history included excision of her left salivary gland, 10 years ago. She was undergoing investigation for a new left breast mass for which a biopsy revealed possible involvement by marginal zone lymphoma. A PCR was performed which was equivocal. Subsequently, she developed a right breast lump and an ultrasound scan showed a well-defined 23 x 10 mm oval hyperechoic lesion in the right upper quadrant and a 29 x 9 mm right axillary lymph node. A staging CT chest abdomen and pelvis and bone marrow sample revealed localized disease. Biopsy of breast lump was performed with PCR analysis. This revealed morphological and immunophenotypical appearances most consistent with a low-grade B –Cell lymphoma and favour a marginal zone lymphoma. The patient was reviewed by an oncologist and was treated with 24 Gy radiotherapy in 12 daily fractions and followed up by the advanced practitioner. Case report - Discussion Primary Sjögren’s Syndrome is an autoimmune disease characterised by lymphocytic infiltration of exocrine glands which can manifest in specific organs or as a systemic illness. Patients are at elevated risk of developing lymphoproliferative diseases including non-Hodgkin's lymphoma with a reported prevalence of 5%. On histological analysis, most patients demonstrate low-grade marginal zone B cell lymphoma with approximately 85% occurring in extranodal locations including the parotid and submandibular glands. Some patients may go on to develop high-grade lymphoma. Concerning overall disease activity, it has been recently demonstrated that a stable moderate/high disease activity, calculated either with the EULAR Sjögren’s syndrome disease activity index (ESSDAI) or with the ClinESSDAI, an ESSDAI variant excluding the biological domain, was independently associated with subsequent lymphoma occurrence. Symptomatic cryoglobulinaemic vasculitis (CV) is observed in about 3–4% of pSS patients and has been linked to the development of lymphoma. Other clinical markers of lymphoma such as palpable purpura, low levels of C4, lymphocytopenia, low levels of IgM, elevated levels of β2-microglobulin Malignant proliferation has been reported in the literature and, to the best of our knowledge, only two case reports of a marginal zone lymphoma of the breast complicating primary Sjögren’s syndrome exist. Case report - Key learning points 1/ This case emphasises the need for careful clinical examination in this exceedingly rare entity. 2/ Although parotid and submandibular gland are commonest extranodal site for NHL, other organs such as thyroid, ovaries and breast might be rarely be affected. 3/ Clinicians should be alert if there are some clinical and serological features such as cryoglobulin and persistently low complement which usually predicts the development of lymphoma.

Case report - Introduction We present the case of a 70-year-old female with a background of anti-Ro positive Sjögren’s syndrome with difficult sicca symptoms who presented with worsening Raynaud’s, bilateral lower limb petechiae/purpura, fatigue, and progressive peripheral neuropathy. Blood tests revealed positive cryoglobulins with hypocomplementemia, and nerve conduction studies objectively confirmed the peripheral neuropathy. The patient was diagnosed with cryoglobulinaemic vasculitis and treated with pulsed intravenous cyclophosphamide and oral prednisolone, which resolved her rash and halted the progression of her symptoms. Cryoglobulinaemic vasculitis is a rare complication of Sjögren’s syndrome occurring in only 3–4% of patients with the disease. Case report - Case description A 70-year-old female with known Sjögren’s syndrome presented with a two-month history of an intermittent red, pin-prick rash affecting her lower legs, worsening fatigue and Raynaud’s, and a progression of longstanding symptoms of pins and needles from her ankles up to her knees, shortly after an acute Epstein-Barr virus infection. Her Sjögren’s syndrome was diagnosed after she presented with difficult sicca symptoms, fatigue and Raynaud’s phenomenon, and strongly positive ANA and anti-Ro antibodies (>240 u/mL). Past medical history was notable for microscopic colitis. On examination, she had bilateral pitting oedema with a purpuric rash affecting both legs. She had reduced sensation to both knees, but with normal power and downgoing plantars. Her joints examined normally. There were no ischaemic changes in her peripheries. Blood tests showed a positive cryoglobulin consisting of a monoclonal IgM paraprotein with polyclonal lambda light chains. She had a normal kappa: lambda ratio and Bence-Jones proteins. Inflammatory markers were raised (CRP 34mg/L, ESR 93mm/hour), with hypocomplementemia (C4 0.05g/L, normal C3). Otherwise, her full blood count, electrolytes, renal and liver function tests, chest X-ray, urine dipstick, hepatitis serology, ANCA profile, B12, folate and ferritin were unremarkable. Nerve conduction studies showed a length-dependent, moderately severe sensory motor axonal peripheral neuropathy, which Neurology agreed was due to a vasculitic process. The patient was diagnosed with a cryoglobulinaemic vasculitis with peripheral nerve involvement secondary to her Sjögren’s syndrome. This was initially treated with prednisolone 40mg daily, intravenous pulsed cyclophosphamide, which resolved her rash and halted the progression of her peripheral neuropathy. Pregabalin was prescribed for pain relief. After completing six cycles of cyclophosphamide, the patient was commenced on azathioprine. This was then replaced with mycophenolate due to leukopenia. She was gradually weaned off steroids, and her vasculitis to date remains biochemically and clinically stable. Case report - Discussion The presence of the combination of a petechial/purpuric rash on her lower limbs, worsening fatigue and Raynaud’s, and symptoms consistent with a progressive peripheral neuropathy raised the suspicion of a vasculitic process in this patient, which warranted urgent investigation. She had a type II mixed cryoglobulinemia which is the most common type of cryoglobulinemia found in Sjögren’s syndrome, evidenced by the presence of a monoclonal IgM paraprotein with polyclonal lambda light chains. Cryoglobulinaemic vasculitis is a systemic vasculitis characterised by the deposition of immune complexes into small vessels, commonly affecting the peripheral nerves, skin, and joints. Clinically, this can manifest with arthralgias/arthritis; constitutional symptoms, such as fatigue and fever; neurologically, with peripheral neuropathies, cranial nerve and central nervous system involvement; and with vascular symptoms, such as petechiae/purpura, skin ulcers, hyperviscosity syndrome, and Raynaud’s. Laboratory features consistent with a diagnosis of cryoglobulinaemic vasculitis aside from the sine qua non of positive cryoglobulins include hypocomplementemia (especially complement C4), positive rheumatoid factor, and a positive serum monoclonal component. We suspect that her cryoglobulinaemic vasculitis was most likely due to Sjögren’s syndrome, although it could have been triggered by the preceding Epstein-Barr virus infection, as this can be associated with cryoglobulinemia also. The decision to treat aggressively with pulsed intravenous cyclophosphamide and prednisolone was made given the severity of the patient’s symptoms, especially her progressive peripheral neuropathy. Given the paucity of data in the literature on the management of cryoglobulinaemic vasculitis secondary to rheumatological conditions, cyclophosphamide and prednisolone were chosen as these are proven in the other small vessel vasculitides, such as ANCA-associated vasculitis. This case is of interest as cryoglobulins are found in approximately 7–16% of patients with Sjögren’s syndrome, with cryoglobulinaemic vasculitis seen in only 3–4% of patients with the disease. Case report - Key learning points Cryoglobulins are uncommon in Sjögren’s syndrome, occurring in 7–16% of those with the disease. Symptomatic cryoglobulinaemic vasculitis among those with Sjögren’s syndrome is rare, seen in only 3–4% of cases. The presence of cryoglobulins in Sjögren’s syndrome is of clinical significance, as it is associated with higher global systemic disease activity and extra glandular involvement. Compared to non-cryoglobulinaemic patients with Sjögren’s syndrome, those with cryoglobulinemia are more likely to have lymphadenopathy, constitutional symptoms, peripheral nervous system and pulmonary involvement, and glandular, articular, and cutaneous features of the disease. The type of cryoglobulinemia found in Sjögren’s syndrome is the mixed type, which are either formed from a monoclonal immunoglobulin (usually IgM) and a polyclonal immunoglobulin (type II), or two polyclonal immunoglobulins (type III). Other conditions associated with mixed cryoglobulinemia include rheumatoid arthritis and systemic lupus erythematosus (SLE), although the most common cause of these is chronic hepatitis C (80–90% of cases). Other causes of mixed cryoglobulinemia include other viral infections, including Epstein-Barr virus and hepatitis B, and certain bacterial and parasitic infections. Most of the literature on the management of cryoglobulinaemic vasculitis is in the context of patients with this due to chronic hepatitis C and revolves around treating this with the appropriate antiviral therapy. Consequently, the current treatment options for moderate-to-severe cryoglobulinaemic vasculitis secondary to rheumatological conditions are the same as those for the other small vessel vasculitides, using a combination of cyclophosphamide and glucocorticoids to induce remission, and azathioprine as maintenance therapy. In severe cases, plasma exchange and rituximab can also be considered as agents to induce remission in cryoglobulinaemic vasculitis.