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The aim of the work was to evaluate the frequency and nature of renal lesion in patients with cryoglobulinemic vasculitis. According to clinical, laboratory and sonographic data renal damage is observed in 2/3 of the number of patients that is associated with the presence of the pathology of myocardium, joints, lungs and peripheral nervous system, with the severity of integrated extrarenal signs of the disease, and kidney failure is diagnosed in every second observation, nephrotic syndrome — in every sixth one. Morphological lesion of glomeruli, tubules and stroma of the kidneys resembles primary mesangioproliferative or mesangiocapillary glomerulonephritis with severe tubulointerstitial component. Renal function and the rate of progression of nephropathy influence the levels of high molecular weight proteins in the urine (fibronectin, b2-microglobulin) and nitrogen products (uric acid, nitrites), as well as physical and chemical surface features of urine.

Aim. To study a possible association between cryoglobulinemia and cardiovascular and peripheral vascular disease in patients with symptomatic cryoglobulinemic vasculitis and rheumatoid arthritis patients with elevated cryoglobulins. Methods. Analysis of the coexistent cardiovascular system diseases prevalence, heart and carotid arteries echocardiography data of 32 patients with cryoglobulinemic vasculitis, and 129 patients with rheumatoid arthritis depending on the fact of high cryoglobulins titers in the blood plasma compared to 32 healthy volunteers in the control group was conducted. Cryoglobulins isolation from the blood was performed using the A.E. Kalovidoris method in N.A. Konstantinova modification. Results. In patients with cryoglobulinemic vasculitis and rheumatoid arthritis with asymptomatic cryoglobulinemia a high frequency of hypertension prevalence (46.8 and 34.4%, respectively), ischemic heart disease (15.6 and 7.9%), congestive heart failure (9.4 and 10.5%), chronic venous insufficiency (53.1 and 23.7%) and postthrombophlebetic syndrome (28.1 and 18.4%) was observed. When analyzing ultrasound data in patients with cryoglobulinemic vasculitis and rheumatoid arthritis it has been found that the cryoglobulinemia is accompanied by left ventricular myocardial geometry violation (in 81.3 and 65.7% respectively versus 12.5% of patients in the control group), myocardial diastolic dysfunction (71 9 and 65.7% versus 15.6%), an increase in the proportion of patients with the «intima-media» complex thickening (78.1 and 36.8% versus 31.2%) and atherosclerotic plaques (34.4 and 13, 2% versus 6.2%) in the carotid arteries. Conclusion. Cryoglobulinemia can be considered as adjuvant risk factor for cardiovascular disease in patients with rheumatism.

Purpose of review The present review discusses the evidence supporting the use of B-cell-targeted therapy in the treatment of various forms of systemic vasculitis with a focus on the use of rituximab (RTX), in the antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitides (AAV). Recent findings Long-term follow-up of the two studies establishing the efficacy of a RTX-based induction regimen for severe AAV have demonstrated noninferiority of a single course of RTX compared with conventional therapy for remission maintenance. In addition, these observations highlight an association between relapse and B-cell reconstitution in patients treated with RTX. The maintenance of remission using rituximab in systemic ANCA-associated vasculitis trial compared a regimen of RTX infusions every 6 months to azathioprine for remission maintenance and concluded that serial RTX lead to higher rates of sustained remission.RTX is also an established therapy for cryoglobulinemic vasculitis associated with hepatitis C viral (HCV) infection. Recently published data support the long-term efficacy and safety of RTX for cryoglobulinemic vasculitis. Summary B-cell depletion with RTX is an established therapy for both remission induction and maintenance in severe AAV and in HCV-related cryoglobulinemic vasculitis. There are limited data to support use of B-cell-targeted therapy in refractory cases of other forms of systemic vasculitis such as eosinophilic granulomatosis with polyangiitis and Takayasu's arteritis.

A 68-year-old man was admitted because of weakness of the left leg, dysesthesiae of the extremities and bilateral lower extremity purpura. A neurological examination showed mononeuritis multiplex with laboratory evidence of hypocomplementemia, cryoglobulinemia and leukocytoclastic vasculitis in the biopsy of a skin specimen. The patient also exhibited bilateral submandibular gland swelling, elevated serum IgG4 levels and infiltration of a large number of IgG4-positive plasma cells in the submandibular glands. These findings were consistent with both cryoglobulinemic vasculitis and IgG4-related disease. The administration of oral prednisolone (1 mg/kg/day) resolved the neurological manifestations and the swelling of the submandibular glands and cryoglobulinemia.

Background Cryoglobulinemia is an immune-complex-mediated small vessel vasculitis that classically involves the skin, kidneys and peripheral nerves. Antiphospholipid syndrome (APS) is an autoimmune hypercoagulable disorder which causes blood vessel thrombosis. It can present as a multi-organ microthrombotic disorder which is called catastrophic APS. Objective In this case series we aim to describe the diagnostic and management challenges that arise when these two severe disorders simultaneously present in the same patient. Methods We describe four patients who were admitted to our hospital due to multi-organ life threatening damage mediated by cryoglobulinemic vasculitis with concurrent APS. Results Clinical manifestations included leg ulcers, livedo reticularis, renal failure, and peripheral neuropathy. Suggested etiologies for the combined syndromes were hepatitis C, systemic lupus erythematosus and myeloproliferative disease rectal maltoma. All of our patients were treated with anticoagulation, high-dose corticosteroids, rituximab, intravenous gammaglobulins and plasma exchange. Conclusion The rare association of severe or catastrophic APS with cryoglobulinemia in patients should be considered by physicians who treat patients with multi-organ ischemia or necrosis.

Although treatment with immune checkpoint inhibitors (ICIs) is associated with better survival in many cancer settings, these therapeutics can induce immune-related adverse events (IrAEs).1 ,2 REISAMICi is a French, prospective, multicentre, academic registry sponsored by the Gustave Roussy Institute cancer centre. The objective is to better detect, document and manage IrAEs. Connective tissue diseases (CTD) have not previously been reported in patients treated with anti-PD1/PDL-1 agents. The REISAMIC registry was screened for reports of CTD. Of the 447 patients supervised in the REISAMIC registry, three have developed CTD: two cases of Sjogren's syndrome and one case of cryoglobulinemic vasculitis as a complication of suspected Sjogren's syndrome (table 1). A case of ANA+ myositis registered in REISAMIC by another investigating centre …

Background:Patients with primary Sjogren’s syndrome (pSS) are at high risk of lymphoma. Signs of lymphomas in ACA+pSS were not widely reported, the descriptions were single [1, 2]. According to pSS treatment recommendations [3, 4, 5, 6], glandular forms require only symptomatic treatment, in the absence of systemic manifestations systemic therapy is not required.Objectives:to evaluate the incidence of lymphomas in ACA+pSS; to compare clinical and laboratory manifestations in 2 groups of ACA+pSS: with and without lymphomas.Methods:we examined 119 ACA+pSS patients. We evaluated both glandular and systemic manifestations. We diagnosed lymphomas based on study of biopsy specimens of affected organs.Results:MALT-lymphomas diagnosed in 19 (16%) ACA+pSS patients. Persistent enlargement of parotid salivary glands, decreased C4-complement, decreased CD19+cells in peripheral blood, cryoglobulinemic vasculitis, lymphoid infiltration of minor salivary glands (MSG) more than 200 cells in focus, severe xerostomia and xerophthalmia more often detected in patients with ACA+pSS+lymphomas. RF and antiRo were found in only 25% of patients with lymphomas and its frequency did not differ between groups. Only 20% of patients with lymphoma had monoclonal immunoglobulins secretion and its frequency also did not differ between groups. Anemia, leukopenia, thrombocytopenia, increased ESR, hypergammaglobulinemia, increased levels of immunoglobulins were found in the study groups with the same frequency. There were no differences in the frequency of detection of recurrent parotitis, lymphadenopathy, Raynaud phenomenon, arthritis/arthralgia, pleuritis/pericarditis, neuropathy, nephritis, hypergammaglobulinemic purpura.Conclusion:in the present study in patients with lymphomas, the course of pSS was characterized by minimal systemic manifestations and low immunological activity, but severe glandular manifestations with the development of late stage damages of salivary and lacrimal glands, severe lymphoid infiltration of MSG, which led to the frequent occurrence of MALT-lymphomas. Thus, in patients with pSS, regardless of the type of detected antibodies (antiRo/La, ACA, RF or others), regardless of the presence or absence of systemic manifestations, damage of salivary and lacrimal gland progresses, which in some cases leads to the development of lymphomas, therefore, therapy that can prevent this complication should be initiated immediately after diagnosis of pSS is confirmed. The signs of lymphoproliferation detected in the present study should be evaluated in all ACA+pSS patients for early diagnosis of lymphoma.References:[1]Baldini C, Mosca M, Della Rossa A, Pepe P, Notarstefano C, Ferro F, Luciano N, Talarico R, Tani C, Tavoni AG, Bombardieri S. Overlap of ACA-positive systemic sclerosis and Sjögren’s syndrome: a distinct clinical entity with mild organ involvement but at high risk of lymphoma[2]Dhiraj Gulati & Irving Kushner & Elizabeth File & Marina Magrey. Primary Sjogren’s syndrome with anticentromere antibodies—a clinically distinct subset. ClinRheumatol (2010) 29:789–791 DOI 10.1007/s10067-009-1359-9.[3]F. Vivino et al. Sjogren’s syndrome: An update on disease pathogenesis, clinical manifestations and treatment. Clinical Immunology 203 (2019) 81–121.https://doi.org/10.1016/j.clim.2019.04.009[4]Xavier Mariette et al. Primary Sjögren’s Syndrome. N Engl J Med 2018; 378:931-9. DOI: 10.1056/NEJMcp1702514[5]Xiaoyun Chen et al. Advances in the diagnosis and treatment of Sjogren’s syndrome. Clinical Rheumatology (2018) 37:1743–1749.https://doi.org/10.1007/s10067-018-4153-8[6]Ana-Luisa Stefanski et al. The Diagnosis and Treatment of Sjögren’s Syndrome. Deutsches Ärzteblatt International | Dtsch Arztebl Int 2017; 114: 354–61Disclosure of Interests:None declared

Background:B cells have important functions in the pathogenesis of systemic autoimmune rheumatic diseases (SARDs).Objectives:The purpose of the research was to study the therapeutic option of Rituximab (RTM), a chimeric anti-CD20 antibody, in SARDs such as ANCA-associated systemic vasculitis (AAV), cryoglobulinemic vasculitis (СV), systemic lupus erythematosus (SLE), systemic sclerosis (SS), primary Sjögren syndrome (pSS) and IgG4-related disease (IgG4-RD).Methods:We present data on efficacy and safety of RTM in 515 patients (pts) with SARDs. 103 pts had AAV (58- granulomatosis with polyangiitis, GPA; 35- microscopic polyangiitis, MPA and 10- eosinophilic granulomatosis with polyangiitis, EGPA), 21 pts had CV, 167- SLE, 90- SS, 100- pSS, 34- IgG4-RD. Characteristics of pts and results of RTM treatment are present in Table. Mean follow-up duration after initiation of RTM was 25- 58 months.Results:The average cumulative RTM dose in all groups exceeded 2.4 g, 71% of pts received repeated RTM courses (0.5-1.0 g) every 4 – 12 months. Complete (good) clinical response was achieved in 70-93% pts, except for the SLE (49%- complete response, 32- incomplete and 19%- no response). Usage of repeated RTM courses increased the clinical efficacy and reduced the risk of recurrence. Despite the fact that the study population included a high percentage of pts with severe or refractory SARDs, total mortality rate was about 6% during the follow-up period, highest in CV and AAV (14-11%). In AAV and SLE infections constitute a significant proportion of serious adverse reactions (10-11%). Late-onset neutropenia was only in pts with AAV (12%) and SLE (3%).Conclusion:Treatment with RTM was highly effective in SARDs. In certain SARDs RTM safety profile of should be considered during treatment planning. Further studies of the targeted anti-B-cell therapy, including RTM efficacy and safety in SARDs, clarification of the indications and optimal RTM regimens are needed.Table.ParametersАAVCVSLESSpSSIgG4-RDGPA, MPAEGPAN pts9310211679010034Age, years41(16-67)50(24-71)53,6 + 2941(18-52)47(17-71)42 + 12,247,4 + 15,9Percentage of females56%90%52%92%75%97%60%Duration of disease, months*14(1-288)11(1-180)72(3-96)18(2-47)70(7-264)90(36-168)24(6-60)Cumulative RTM dose, g*3 (0,5-8)3 (1,5-5,5)4,7 + 3,82,4 (1,8±0,8)2,9(0,5-6)5,5 + 1,54 + 1,5Follow-up duration after the first RTM course, month*37(1–96)36(14-94)52(6-108)38(12-67)27(12-42)58(24-96)25(3-60)Clinical response, %Complete (good)93%90%71%49%70%92,5%77%Incomplete response6%10%29%32%24%6,5%23%No response1%0%-19%6%1%-Relapse8%30%--nd--Glucocorticoids dose, mg/day*:Before RTMAfter RTM30(5–60)5(0-10)20(7,5-50)7,5(5-10)4,4(0-24)1,5(0-4)28(15-40)7,5(5-15)12(0-25)9(0-15)7,5(0-40)1,2510(2,5-40)0,5Immunosuppressants% pts before RTM72%90%38%65%43%44%40%% pts after RTM43%70%5%46%50%8%10%Infusion-related reactions,9%20%24%4%2%10%3%including severe-10%-0,6%1%1%-Pts with serious adverse reactions,26%40%5%14%2%5%3%including: infections,11%10%-10%2%5%3%neutropenia10%20%-3%---Deceased pts during the follow-up11%-14%5%6%2%-*Data are provided in the following format: median & min-max range in the bracketsDisclosure of Interests:None declared

Autoimmunity Autoantibodies are proteins produced by the immune system that attack a person's own tissues and organs, leading to autoimmune disease. Autoantibodies can be present in the serum years before the clinical onset of autoimmunity, but it is not understood how they cause disease. Singh et al. used multi-omics single-cell technology to trace the evolution of “rogue” cell clones responsible for producing pathogenic autoantibodies in the blood of patients with the autoimmune disease cryoglobulinemic vasculitis. The researchers found that a benign antibody can transform into one that causes inflammation of blood vessels in the skin, kidney, nerves, and joints. The gene mutations that accumulate in the rogue cells during the early stages of autoimmune disease have also been identified in cancer cells from patients with lymphoma. Cell 180 , 878 (2020).

Pathogenic autoantibodies arise in many autoimmune diseases, but it is not understood how the cells making them evade immune checkpoints. Here, single-cell multi-omics analysis demonstrates a shared mechanism with lymphoid malignancy in the formation of public rheumatoid factor autoantibodies responsible for mixed cryoglobulinemic vasculitis. By combining single-cell DNA and RNA sequencing with serum antibody peptide sequencing and antibody synthesis, rare circulating B lymphocytes making pathogenic autoantibodies were found to comprise clonal trees accumulating mutations. Lymphoma driver mutations in genes regulating B cell proliferation and V(D)J mutation (CARD11, TNFAIP3, CCND3, ID3, BTG2, and KLHL6) were present in rogue B cells producing the pathogenic autoantibody. Antibody V(D)J mutations conferred pathogenicity by causing the antigen-bound autoantibodies to undergo phase transition to insoluble aggregates at lower temperatures. These results reveal a pre-neoplastic stage in human lymphomagenesis and a cascade of somatic mutations leading to an iconic pathogenic autoantibody.

Mantle cell lymphoma (MCL) is an uncommon subtype of B-cell lymphoproliferative neoplasm which often presents as lymphadenopathy or organomegaly. Herein, we present the case of a 69-year-old male who developed the rapid onset of cyanotic digits and nose. Cryoglobulin was detected, and a skin biopsy showed occlusive vasculopathy, which suggested cryoglobulinemic vasculitis. A bone marrow biopsy confirmed the diagnosis of cyclin D1-negative, SOX11-positive MCL. He received systemic immunochemotherapy including bortezomib and rituximab, and his cryoglobulinemia completely resolved. In addition, his lymphoma remains in complete remission 2 years after the diagnosis.

Mixed cryoglobulinemia (MC) and cryoglobulinemic vasculitis (CV) are the most common extrahepatic manifestations of chronic hepatitis C virus (HCV) infection. With novel interferon-free regimens ba...

OBJECTIVE 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

Staphylococcus-associated glomerulonephritis (SAGN) is a rare immune complex-mediated glomerulonephritis associated with activeWe report the case of a 64-year-old man with alcohol-associated cirrhosis, type 2 diabetes mellitus, and hypertension who presented to hospital with lower back and abdominal pain, rectal bleeding, a purpuric lower extremity rash, and oliguric acute kidney injury with microscopic hematuria and nephrotic-range proteinuria.Skin biopsy revealed IgA leukocytoclastic vasculitis. Serum cryoglobulins were positive and there was hypocomplementemia with a low C3 level. Magnetic resonance imaging of the lumbar spine revealed septic discitis and epidural abscesses caused by a recentUrgent hemodialysis was initiated along with a prolonged course of intravenous cefazolin.Remarkably, the patient demonstrated a complete recovery of renal function after 2 months of dialysis dependence and successful treatment of the epidural abscesses.This case shows that SAGN can closely mimic the clinical, laboratory, and histological presentation of Henoch-Schönlein Purpura or cryoglobulinemic vasculitis. Clinical history and kidney biopsy, particularly electron microscopic analysis, are essential to establishing the correct diagnosis to avoid the unnecessary and potentially harmful administration of immunosuppression. Despite the typically poor prognosis of SAGN, this case report illustrates that full renal recovery remains possible with supportive care and eradication of the underlying infection.La glomérulonéphrite aigüe post-infection à Staphylococcus (GNAS) est une glomérulonéphrite rare, médiée par un complexe immunitaire et associée à une infection active àNous rapportons le cas d’un homme de 64 ans atteint d’une cirrhose alcoolique, de diabète de type 2 et d’hypertension qui s’est présenté à l’hôpital avec des douleurs lombaires et abdominales, un saignement rectal, une éruption purpurique des extrémités inférieures et une insuffisance rénale aigüe oligurique avec hématurie microscopique et protéinurie néphrotique.La biopsie cutanée a révélé une vascularite leucocytoclastique à IgA. Les cryoglobulines sériques étaient positives et une hypocomplémentémie avec un faible taux de C3 a été constatée. L’imagerie par résonnance magnétique du rachis lombal a permis de détecter une discite septique et des abcès périduraux causés par une récente bactériémie àOn a amorcé une hémodialyse d’urgence et un traitement prolongé à la céfazoline par voie intraveineuse.Fait remarquable, après le traitement des abcès périduraux et deux mois de dépendance à l’hémodialyse, la fonction rénale du patient a été complètement rétablie.Ce cas démontre que la GNAS peut simuler la présentation clinique, biologique et histologique du purpura d’Henoch-Schönlein ou celle de la vascularite cryoglobulinémique. La revue des antécédents médicaux et l’analyse d’une biopsie rénale (particulièrement par microscopie électronique) sont essentielles pour établir un diagnostic juste et pour éviter l’administration superflue, voire néfaste, d’immunosuppresseurs. Malgré le pronostic sombre normalement associé à la GNAS, ce cas démontre que le rétablissement complet de la fonction rénale demeure possible, pour autant que l’on procède à un traitement symptomatique et que l’on éradique l’infection sous-jacente.

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

Infections with DNA viruses are found in patients with autoimmune rheumatic diseases, but whether or not there is a causal link between the infectious agent and the rheumatic disease is not clear. For a few rheumatic diseases, such as polyarteritis nodosa and cryoglobulinemic vasculitis, the causal link between the disease and the virus, in these cases hepatitis B virus and hepatitis C virus, respectively, is obvious. In other diseases, there is more speculation rather than solid evidence that the diseases are indeed induced by a DNA virus. We must acknowledge, however, the tremendous work which is done in this field at the experimental level, either through research on experimental models of rheumatic diseases or through translational research performed in biological material obtained from patients. A significant pitfall for translational research is the inability to perform proper assessment in patients at the very early stages of the disease or even long before the disease appears as this would assist efforts to delineate the hierarchy of events leading to the induction of the disease as a consequence of viral infection. Irrespective of the pathogenic mechanisms at play between the virus and the host, an important issue is that of reactivation of the viral infection in immunosuppressed patients, especially those under biologic treatment.

The term “vasculitis” stands for a spectrum of diseases characterized by an inflammatory injury of the vascular wall which may affect arteries and veins; it may lead to necrosis or to granulomatous inflammation of the vascular wall, occlusion of the vascular lumen, and ischemic injury of the affected tissues. Depending on the size of vessels affected, vasculitides are categorized into large-vessel vasculitis – affecting the aorta and its direct branches – such as giant cell arteritis (GCA) and Takayasu arteritis (TA); medium-vessel vasculitis, such as polyarteritis nodosa (PAN) and Kawasaki disease (KD); as well as small-vessel vasculitis. The small-vessel vasculitides comprise the ANCA-associated vasculitides (AAV), which are associated with the presence of circulating antineutrophil cytoplasmic antibodies (ANCA), and the ones without autoantibodies. The AAV are granulomatosis with polyangiitis (GPA, formerly known as Wegener’s granulomatosis), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA, formerly known as Churg-Strauss syndrome). Other non-ANCA-associated small-vessel vasculitides are typically characterized by either the presence of immune complex deposition (cryoglobulinemic and IgA vasculitis/Henoch-Schonlein purpura) or are the result of a neoplasia (paraneoplastic phenomenon).

Cryoglobulinemic vasculitis is a rare and frequently fatal type of myocarditis. Cardiac manifestations in type 1 cryoglobulinemic vasculitis have never been reported to our knowledge. We report a rare case of type 1 cryoglobulinemic vasculitis with cardiac involvement in a patient who experienced progressive heart failure during the diagnosis. The diagnosis was made by the presence of cryoglobulins and endomyocardial biopsy results. After bortezomib-containing treatments, plasma cryoglobulin levels returned to normal, and the patient's clinical condition gradually improved.

Hepatitis C Virus (HCV)-related Mixed Cryoglobulinemia (MC) is a unique condition with complex pathogenesis that involves HCV antigen-driven B-lymphocyte clonal proliferation and mutagenesis. Clinical spectrum of MC ranges from asymptomatic state to clinically-apparent vasculitis involving multiple organs. In the era of Direct-Acting Antiviral (DAA) therapy, patients with HCV-related MC achieve high rates of viral clearance that is commonly accompanied by an improvement in clinical symptoms as well as immunological profiles. Rituximab, either alone or in combination with DAA, has also been shown to be effective. Nevertheless, there have been limited and somewhat conflicting data, particularly over the long-term, regarding the rate and degree of clinical response of MC following DAA therapy. It appears that we have come quite a long way in the last decade with this condition. As with non-MC related HCV, undoubtedly long term outcome data will be forthcoming over the next few years. As we move forward successful therapy of HCV is not likely to be a challenge in contrast to access to therapy.

The paper gives an update on the pathogenesis, clinical presentation, and pathomorphology of cognitive impairments (CIs) in different autoimmune, endocrine, and infectious diseases, such as systemic lupus erythematosus, Sjogren's syndrome, BehНet's disease, primary angiitis of the central nervous system, polyarteritis nodosa, cryoglobulinemic vasculitis, hypothyroidism, herpetic lesion, and neurosyphilis. These patients are observed to have ischemic-hypoxic brain damage, the causes of which are free radical-induced cell injury, oxidative stress, excitation toxicity, cell necrosis and/or apoptosis, inflammation and immune disease, molecular sequestration, and cell death. There is enhanced imbalance in the pro-oxidant and antioxidant systems as cerebrovascular insufficiency progresses; as this takes place, the nerve cells are most susceptible to the induction of free radical reactions. In these cases, antioxidants that block the effects of free radicals and may potentially improve brain perfusion, by assisting the coupling of neurons and vessels, are first-choice drugs. To improve the cognitive status and to prevent the progression of CIs, it is important to build a cognitive reserve in a patient; this is largely favored by the preservation of a proactive approach to life and social bonds, as well as intellectual work.

The skin is one of the organs most frequently involved in vasculitides. Cutaneous vasculitis may present (1) part of a systemic vasculitis (e.g., IgA vasculitis), (2) a skin-restricted or skin-dominant variant of the corresponding systemic vasculitis without clinically apparent visceral involvement (e.g., cutaneous IgA vasculitis), or (3) a vasculitis occurring exclusively in the skin (e.g., erythema elevatun diutinum). The clinical symptoms of vasculitides are markedly determined by the size of the predominantly affected blood vessels. Systemic polyarteritis nodosa is regarded as a medium vessel vasculitis and is associated with multiple skin symptoms: (1) vasculitis of digital arteries with ensuing digital infarction, (2) livedo racemosa and subcutaneous nodules, and (3) in some patients even purpura and hemorrhagic macules due to additional small vessel vasculitis. In contrast, in its skin-restricted entity (i.e., cutaneous polyarteritis nodosa), the predominant symptoms are subcutaneous nodules surrounded by livedo racemosa, often on the lower legs. Among small-vessel vasculitides palpable purpura with predilection for the legs is a nearly pathognomonic feature of immune complex vasculitis. Variations in clinical symptoms indicate additional pathophysiological mechanisms or different vascultides: (1) ANCA-associated vasculitides often also entail nodules or sometimes livedo, (2) cryoglobulinemic vasculitis additionally may present with necrosis at cold exposed areas and involvement of vessels of various size, (3) small vessel vasculitis associated with systemic lupus erythematosus or rheumatoid arthritis shows predilection for additional sites (e.g., nailfolds) and also involvement of vessels beyond postcapillary venules, (4) recurrent macular vasculitis in hypergammaglobulinemia also occurs on dependent parts, but shows numerous small hemorrhagic macules instead of palpable purpura, (5) erythema elevatum diutinum begins with brightly red to violaceous plaques at extensor sites, followed by fibrotic nodules. Consequently, cutaneous symptoms provide pivotal clues for further diagnosis and ensuing management of vasculitides.

Given the hypothesis of an initial exogenous agent attacking/infecting ocular and oral glands in Sjogren’s syndrome, we propose a primarily T cell-guided reaction with ensuing recruitment of B cells and finally resulting in auto-antibody production. From an immunological standpoint, the first clinical signs do represent established disease. Nevertheless, targeted therapy should start as early as possible, and they may target B as well as T cells. A primarily local therapy by CsA eye-drops is worthwhile applying in case of strictly ocular involvement only. Otherwise, a short cycle of leflunomide might prove efficient. If not, based on the most possibly underlying pathophysiology of T and B cell interaction and our own experience, a 6-month treatment with abatacept during the early phase of disease can reach the target cells and lead to clinical improvement. In the later stages, especially in case of cryoglobulinemic vasculitis or pulmonary involvement, a B cell depletional therapy may be highly effective. Based on the available data, it would be interesting to initiate a study targeting both cellular arms of the adaptive immune system, i.e., B cell depletion with, e.g., rituximab and T cell inhibition using abatacept. Trials with alefacept have shown T cell-targeted, positive effects on exocrine gland function in a primary SS (pSS)-associated non-obese diabetic (NOD) mouse model. Whether this molecular intervention is beneficial in human disease will have to be shown.

Rituximab (RTX), a B-lymphocytes depleting monoclonal antibody, deeply changed the therapeutic landscape of secondary glomerulonephritis in the past decade.RTX has proved to be as effective as cyclophosphamide in inducing remission in ANCA-associated vasculitis and better than azathioprine as maintenance therapy in three different RCT. Treatment's duration and modality, however, remain debated.RTX has been widely used in resistant or relapsing proliferative lupus nephritis (LN), with positive results reported by retrospective studies; however, when employed as an “add-on” induction therapy in a RCT, it did not show a definite additive effect to standard therapy with mycophenolate mofetil and steroid in moderate forms of LN. In prospect, it remains a promising tool both as second-line therapy for resistant forms and as a “steroid-sparing” agent to strengthen induction and to allow reduced or minimal maintenance therapy.RTX is effective in the treatment of HCV-related cryoglobulinemic vasculitis, including ...

The paper gives an update on the pathogenesis, clinical presentation, and pathomorphology of cognitive impairments (CIs) in different autoimmune, endocrine, and infectious diseases: systemic lupus erythematosus, Sjogren’s syndrome, Behchet’s disease, primary angiitis of the central nervous system, polyarteritis nodosa, cryoglobulinemic vasculitis, hypothyroidism, herpetic lesion, and neurosyphilis. It is noted that treatment for CIs should be individual in terms of virulence factors. In vascular CIs, therapy should be aimed primarily at modifying risk factors and eliminating or reducing chronic brain ischemia. The prevention of progressive CI encompasses antihypertensive and antithrombotic therapies and surgical correction of atherosclerotic great artery stenosis. Control of hyperlipidemia, hyperglycemia and treatment of other somatic diseases are also of great importance. Such patients are usually given cetylcholinesterase inhibitors, acetylcholine precursors, antiglutamatergic agents, and metabolic and vascular drugs. By taking into account brain ischemia/ hypoxia in the above diseases, it is shown to be advisable to use antioxidants, cerebral active agents in particular, which have a complex neurometabolic effect.

Cryoglobulinemia is a heterogeneous systemic autoimmune disease with a wide variety of causes, symptoms and outcomes, and different etiopathogenic pathways involved in the vasculitic organ damage. The discovery of the hepatitis C virus (HCV) in 1989 changed radically the focus of research of the so-called «essential» cryoglobulinemia. Cryoglobulins can be detected in 25-30% of patients with HCV, overwhelmingly representing mixed cryoglobulins. However, only 10-15% of patients present with cryoglobulinemic vasculitis, with a broad spectrum of symptoms including mild or life-threatening manifestations. Consequently, not all patients can be uniformly treated. The key therapeutic points in HCV+ patients with cryoglobulinemic vasculitis cover different aspects. The first is to treat the underlying cause of cryoglobulinemia whenever possible, hence the use of antiviral therapies must always be considered in these patients. An individualized diagnostic approach to assess the number of organs involved and the severity of organ involvement is also essential in the therapeutic planning. This complex clinical scenario leads to an equally complex therapeutic scenario. There are three main treatment strategies for HCV-associated cryoglobulinemic vasculitis: conventional immunosuppression, antiviral treatment and biological therapies. The most recent studies are suggesting a change from the classical therapeutic approach (monotherapeutic regimens) to combination/sequential regimens, including treatments targeting the virus and those directed against the induced autoimmune disease, with the aim of blocking the various etiopathogenic pathways involved.

Cryoglobulinemia is a heterogeneous systemic autoimmune disease with a wide variety of causes, symptoms and outcomes, and different etiopathogenic pathways involved in the vasculitic organ damage. The discovery of the hepatitis C virus (HCV) in 1989 changed radically the focus of research of the so-called “essential” cryoglobulinemia. Cryoglobulins can be detected in 25–30% of patients with HCV, overwhelmingly representing mixed cryoglobulins. However, only 10–15% of patients present with cryoglobulinemic vasculitis, with a broad spectrum of symptoms including mild or life-threatening manifestations. Consequently, not all patients can be uniformly treated. The key therapeutic points in HCV+ patients with cryoglobulinemic vasculitis cover different aspects. The first is to treat the underlying cause of cryoglobulinemia whenever possible, hence the use of antiviral therapies must always be considered in these patients. An individualised diagnostic approach to assess the number of organs involved and the severity of organ involvement is also essential in the therapeutic planning. This complex clinical scenario leads to an equally complex therapeutic scenario. There are three main treatment strategies for HCV-associated cryoglobulinemic vasculitis: conventional immunosuppression, antiviral treatment and biological therapies. The most recent studies are suggesting a change from the classical therapeutic approach (monotherapeutic regimens) to combination/sequential regimens, including treatments targeting the virus and those directed against the induced autoimmune disease, with the aim of blocking the various etiopathogenic pathways involved.

Cryoglobulinemic vasculitis (CV) involving small- and medium-sized vessels is very frequently associated with hepatitis C virus and may be responsible for multiple organ involvement and skin ulcers (SU). Skin ulcers are often non-healing cutaneous lesions, possibly complicated by local infection and gangrene; they may severely affect the patients׳ quality of life and the overall prognosis. Therefore, the treatment of cryoglobulinemic SU is particularly challenging in the clinical practice. The present work evaluated the prevalence and correlations of cryoglobulinemic SU with other clinico-epidemiological features of CV; moreover, our long-term experience with the management strategies of these cutaneous lesions was compared with the world literature on this topic.The study included 126 CV patients (24 male and 102 female, aged 69 ± 11.2 SD years, disease duration 7 ± 6.9 SD years), followed at our Rheumatology Unit during the past decade. All patients were carefully evaluated regarding the entire cryoglobulinemic syndrome with particular concern for clinical characteristics and treatment of SU.Among 126 CV patients, 36 individuals (29%) experienced at least one episode of SU, more commonly localized at the lower limbs. Patients with complicating SU showed significantly higher percentage of purpuric manifestations (p0.01) and liver (p0.001), peripheral nerve (p0.02), and/or thyroid involvement (p = 0.019). Therapeutic approach to SU included both systemic (immunosuppressors, corticosteroids, and/or plasma exchange) and local treatments. Local treatments consisted of sharp or surgical debridement as well as interactive dressing according to the condition of wound bed, perilesional skin, and the possible presence of infection, detected in 29 of 36 (81%) individuals in our Rheumatology unit. All patients underwent analgesic treatment for SU-related background pain as well as procedural pain, which was critical for an effective local SU management. The large majority of patients with SU healed at a variable time interval according to the severity of the single lesion; only five patients with very severe, non-healing SU needed amputation. The updated review of the literature revealed the presence of SU in around a quarter of CV patients. Among systemic treatments, the anti-CD20 monoclonal antibody rituximab represents one of the most effective and frequently employed therapies; however, the available data focusing on local therapeutic approach are generally limited to anecdotal observations.Overall, the treatment of cryoglobulinemic SU should be tailored to the single patient׳s conditions using combined systemic and local treatments; lesional sharp debridement and interactive dressing as well as procedural pain management were decisive, particularly for more severe, non-healing cutaneous lesions.

The aim and the objectives: to investigate the frequency and the character of renal lesion in systemic vasculitis, as well as aspects of the pathogenesis of nephropathy in this category of patients. Material and methods: investigate 525 patients, including 193 - with vasculitis Shenlayna-Henoch, 116- with microscopic polyangiitis, 93 - with cryoglobulinemic vasculitis, 39 - with polyarteritis nodosa, 29 - with aortoarteritis Takayasu, 28 - withWegener’s granulomatosis and 27 - with eosinophilic vasculitis Churg-Strauss. Results: the renal lesion is observed in 52-68% cases of vasculitis depends on the age and the sex of the patients, the duration of the disease, the degree of activity of the pathological process, alteration in the heart and lungs, integrated severity extrarenal signs of the disease, at that, the rate ofprogression of nephropathy associated with the character of the disorders of the immune system, the rheological properties of blood and endothelial vessels’function. Conclusions: kidney disease is one of the leading signs of systemic vasculitis and observed in most patients, it is determine the course of the disease.

Cryoglobulins are immunoglobulins that precipitate at temperatures less than 37°C. They occur secondary to infectious, autoimmune, and malignant processes. In the Brouet classification, type I cryoglobulinemia is caused by hyperviscosity, whereas type II and III manifestations are caused by vasculitis in target organs (primarily skin, peripheral nerves, and kidney). New classification criteria were recently proposed that may help with study and treatment of cryoglobulinemic vasculitis (CryoVas). Hepatitis C virus is the most common cause of CryoVas and treatment with antivirals can be curative in mild cases, whereas rituximab is highly effective in treating active vasculitis in more severe cases.

HCV chronic infection is characterized by possible development of both hepatic and extrahepatic manifestations. The infection by this both hepatotropic and lymphotropic virus is responsible for polyoligoclonal B-lymphocyte expansion, leading to several immune-mediated disorders. Mixed cryoglobulinemia syndrome that in some cases may evolve to frank B-cell non-Hodgkin's lymphoma is the prototype of HCV-driven autoimmune and lymphoproliferative disorders. The HCV oncogenic potential has been suggested by several clinicoepidemiological and laboratory studies; it includes hepatocellular carcinoma, B-cell non-Hodgkin's lymphoma and papillary thyroid cancer. The definition HCV syndrome refers to the complex of HCV-driven diseases; these latter are characterized by heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. The natural history of HCV syndrome is the result of a multifactorial and multistep pathogenetic process, which may evolve from mild manifestations to systemic autoimmune disorders, and less frequently to malignant neoplasias. The present updated review analyzes the clinical and pathogenetic aspects of the main HCV-associated diseases.

Most emergencies in dermatology comprise a variety of entities with a usually benign course. However, vasculopathies and vasculitis are not common, but they could represent respectively 1.9% and 4.4% of these entities according to some studies of Emergency Dermatology Department. They become an important disease which has to be identified early to establish appropriate management and treatment. Some of them are well known, such as the leukocitoclastic vasculitis, Schölein-Henoch, panarteritis nodosa, antineutrophil cytoplasmic antibody associated vasculitis, giant cell arteritis, cryoglobulinemic vasculitis and antiphospholipid syndrome. More frequent vasculopathies are livedoid vasculopathy, pigmented purpuric dermatosis and calciphylaxis. Less common ones are caused by interferon and cholesterol crystal embolization. Others are very infrequent as Degos disease and Sneddon Syndrome. Among the more recently described ones there are deficiency of adenosine deaminase type 2 and crystalglobulinemia. The other group is composed of vasculopathies associated to microorganism as infective endocarditis, septic vasculopathy, aspergillosis, fusariosis, strongiloidosis, ecthyma gangrenosum, lucio phenomenon of leprosy and necrotic arachnidism. Finally, among these entities we can also find diseases associated with proinflammatory stages as disseminated intravascular coagulation, myeloproliferative disorders, intravascular lymphoma, metastasis intravascular. When we face cutaneous lesions characterized by reticulated violaceous lesions, palpable purpura or cutaneous necrosis, a careful clinico-pathological correlation as well as some laboratory or radiological tests are mandatory to further delineate a diagnosis and a proper first line empirical treatment.

To summarize the experience of a multidisciplinary therapy hospital in treating patients with hepatitis C virus (HCV)-associated cryoglobulinemic vasculitis (CV).Seventy-two patients (mean age, 49.4±10.3 years) with HCV-associated CV were examined and followed up for an average period of 2.8±3.6 years. The efficiency of traditional (corticosteroids ± cyclophosphamide) and selective (rituximab) immunosuppressive therapy (IST) was estimated in 31 and 15 observations, respectively, and that of antiviral therapy (AVT) in 25. Vasculitis activity was assessed using the Birmingham vasculitis activity score (BVAS). The patients' survival was studied; multivariate logistic regression analysis was carried out.24 (33.4%) of the 72 patients had a stage of liver cirrhosis (LC). The pretreatment mean BVAS was 11.9±7.2 (range 2 to 36). Severe CV (BVAS ≥15) was present in 30.6% of the patients. AVT was accompanied by achievement of sustained virologic response in 48% of the patients, clinical remission in 68% and had an advantage over IST in relation to long-term treatment results. Rituximab was significantly more effective than traditional immunosuppressants (remission rates of 73 and 13%, respectively). Combined therapy (rituximab and AVT) was most effective in patients with severe forms of vasculitis. Sixteen patients died from complications of vasculitis (37.5%), infection (37.5%), and LC (25%). The factors adversely affecting prognosis were age55 years (odds ratio (OR), 4.49), the presence of LC (OR, 3.68), renal failure (OR, 4.66) and the use of glucocorticosteroids (OR, 3.91).HCV-associated CV can determine the prognosis of chronic HСV infection. AVT is the treatment of choice in all patients with HСV-associated CV. AVT must be combined with rituximab therapy in patients with severe forms of vasculitis.Цель исследования. Обобщить опыт многопрофильного терапевтического стационара в лечении больных криоглобулинемическим васкулитом (КВ), ассоциированным с вирусом гепатита С (HСV). Материалы и методы. Обследовали и наблюдали в среднем 2,8±3,6 года 72 больных хроническим гепатитом С (ХГС) с ассоциированным с HСV КВ (средний возраст 49,4±10,3 года). Эффективность традиционной (глюкокортикостероиды ± циклофосфамид) и селективной (ритуксимаб) иммуносупрессивной терапии (ИСТ) оценена в 31 и 15 наблюдениях соответственно, противовирусной терапии (ПВТ) - в 25. Активность васкулита оценивали с помощью BVAS (Birmingham vasculitis activity score). Изучали выживаемость больных, проводили многофакторный логистический регрессионный анализ. Результаты. У 24 (33,4%) из 72 больных имелась стадия цирроза печени (ЦП). Средняя оценка по BVAS до лечения составила 11,9±7,2 балла (от 2 до 36 баллов). Тяжелая форма КВ (BVAS ≥15 баллов) имелась у 30,6% больных. ПВТ сопровождалась достижением устойчивого вирусологического ответа у 48%, клинической ремиссии - у 68% больных и имела преимущество перед ИСТ в отношении отдаленных результатов лечения. Ритуксимаб оказался статистически значимо эффективнее традиционных иммуносупрессоров (ремиссия 73 и 13% соответственно). У больных с тяжелыми формами васкулита наиболее эффективна сочетанная терапия (ритуксимаб и ПВТ). Умерли 16 больных: от осложнений васкулита 37,5%, инфекции 37,5%, осложнений ЦП 25%. Факторами, негативно влияющими на прогноз, явились возраст55 лет (отношение шансов - ОШ 4,49), наличие ЦП (ОШ 3,68), почечной недостаточности (ОШ 4,66) и применение глюкокортикостероидов (ОШ 3,91). Заключение. КВ, ассоциированный с HСV, может определять прогноз хронической инфекции HСV. ПВТ является терапией выбора у всех больных HСV КВ. У больных с тяжелыми формами васкулита ПВТ должна сочетаться с терапией ритуксимабом.

Background Renal involvement is common in patients with systemic autoimmune conditions, mainly systemic lupus erythematosus (SLE) and vasculitis, including cryoglobulinemia. Despite the advances in percutaneous kidney biopsy (PKB) techniques and overall improved safety of the procedure, clinically significant bleeding complications do occur. Objectives to investigate the safety of performing percutaneous native kidney biopsy (PKB) as an outpatient procedure (implying an observation period of 6 hrs) compared to the traditional inpatient policy in patients with systemic autoimmune conditions. Methods Group I, in whom PKB was performed in the outpatient department (2012–2016) and followed by 6 hours9 observation period and then by regular outpatient visits and group II, in whom PKB was performed and followed by at least 1-day hospital admission. Group II included retrospectively retrieved patients who underwent PKB in our Institution between January 2000 and November 2012 as in patient procedure. All biopsies were performed by a single nephrologist following a structured protocol. Results A total of 81 biopsies (group I and group II) were included in this study, 44 (54%) of patients were female and the mean age was 49.9±17.6 years. Twenty-six per cent of biopsies were performed for the diagnostic workup of nephrotic range proteinuria, 21% for rapidly progressive renal insufficiency, and the remaining 53% for non-nephrotic proteinuria and/or hematuria. No patient suffered for a major complication and only 3 (3.7%) patients (one with cryoglobulinemic vasculitis and 2 with ANCA associated vasculits) developed a minor complication, including gross hematuria in one case and sub-capsular perinephric hematoma on sonography not requiring intervention in 2 patients Conclusions The lack of major complications and the very limited rate of minor bleeding support that outpatient biopsy could be a valuable, safe, and perhaps cost-effective method of obtaining diagnostic renal tissue in the majority of patients with systemic autoimmune diseases. Disclosure of Interest None declared

Systemic vasculitis may present with life-threatening complications that need to be promptly recognized and appropriately managed to ensure patient survival and minimize irreversible organ damage. The most common life-threatening events differ between large and medium or small-vessel vasculitis. In large-vessel vasculitis, particularly giant-cell artertis (GCA), vascular remodelling in response to inflammation may lead to severe stenosis leading to ischemic stroke in 3–6% of patients and, rarely, myocardial infarction, mesenteric ischemia or critical extremity ischemia. For these complications, particularly when happening in treated patients, intensifying immunosuppressive therapy is not the best or only option and additional interventions may be required. Stroke occurs as a consequence of carotid or vertebral stenosis. Stenosis of the carotid siphon has been repeatedly reported. In necropsy studies, vasculitic involvement and thrombosis of proximal intracranial branches has been observed. Infarcts are usually multiple, usually happen shortly after the initiation of glucocorticoid therapy, convey a 30% mortality or lead to remarkable disability. If critical stenosis is suspected before irreversible infarction, percutaneous intraluminal angioplasty may be function and life saving. Acute aortic syndrome (aortic dissection or intramural haematoma) is an increasingly recognized hurdle in patients with GCA. It is usually a delayed complication occurring months and frequently years after diagnosis. Its frequency has not been delimitated but in a recent prospective follow-up study it was demonstrated to affect at least 2% of patients. Emergency open surgery repair, when feasible, is the best option for ascending aorta involvement (type A) and endovascular repair for involvement of the descending aorta (type B). In small-vessel vasculitis, life-threatening presentations include rapidly progressive glomerulonephritis leading to kidney failure, alveolar haemorrhage, alithiasic colecistitis with perforation and intestinal ischemia. Rapidly progressive glomerulonephritis and alveolar haemorrhage are more frequently seen in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and anti glomerular basement membrane disease. Alveolar haemorrhage can be occasionally seen in cryoglobulinemic or IgA vasculitis. In addition to supportive measures, these patients are usually treated with high-dose methyl-prednisolone, cyclophosphamide or rituximab and plasma exchange. Plasma exchange has been found superior to IV methyl prednisolone mega-doses in preserving or recovering renal function but this advantage do not seem to persist over long-term follow-up. This approach is usually applied also to alveolar haemorrhage although there is not strong evidence supporting it. Gastrointestinal complications, particularly intestinal ischemia and intestinal or gallbladder perforation are life-threatening complications which may require emergent surgery. These may be observed in polyarteritis nodosa, cryoglobulinemic vasculitis, eosinophilic granulomatosis with polyangiitis and other AAV. High-dose glucocorticoids and cyclophosphamide are usually applied.Children with IgA vasculitis may develop bowel intussusception Deep venous thrombosis and pulmonary embolisms are significantly more frequent in AAV and Behcet disease than in the general population, especially during active disease. Anti-coagulation may be needed in AAV, although this approach is controversial in Behcet9s disease. By contrast, aneurysm formation is typical in polyarteritis nodosa and Behcet9s disease and may be occasionally seen in AAV. Massive bleeding derived form aneurysm rupture usually requires arterial embolization. It is important to keep in mind that during the early course of diagnosed vasculitis, intense immunosuppressive therapy may favour life-threatening infections including opportunistic infections such as pneumocystis jiroveci pneumonia or disseminated CMV. In summary, systemic vasculitis may present with a variety of severe complications and other may develop during follow-up. These complications are heterogeneous, vary according to the size of vessels involved, and usually require specific procedures or treatments in addition to immunosuppressive therapy. Due to the life-threatening nature of these complications their immediate recognition and management are crucial to patient survival. Supported by SAF 577–8R and Maratό TV3 2014/201507 Disclosure of Interest None declared

We read with interest the paper “Effectiveness and cost of hepatitis C virus cryoglobulinemia vasculitis treatment: from interferon-based to direct acting antivirals era”(1), and we feel that the combination of effectiveness with a cost analysis is original and increases the awareness about patients with Mixed Cryoglobulinemia (MC). A dedicated approach, focusing on the diagnosis and on the impact of treatment of MC, have been included within the Italian Platform for the Study of Viral Hepatitis Therapies (PITER) (2). Of the 8005 HCV+ patients enrolled in PITER, only 1678 (21%) have been evaluated for the presence of MC, that was shown in 771 (46%) patients, 266 (35%) of whom were symptomatic (cryoglobulinemic vasculitis -CryoVas- or MC syndrome –MCS-). This article is protected by copyright. All rights reserved.

Relapse of hepatitis C virus (HCV) genotype 1 infection after combination therapy with sofosbuvir and ledipasvir is unusual. We report a treatment-naive, non-cirrhotic patient in whom the relapse of genotype 1b HCV infection was accompanied by de novo cryoglobulinemic vasculitis and glomerulonephritis, requiring hemodialysis for acute renal failure. Sequence analysis revealed several resistance-associated variants in the HCV NS5a gene but not in NS3/4A. The patient's vasculitis was successfully treated with immunosuppression and plasmapheresis, followed by retreatment of HCV with a combination of sofosbuvir, simeprevir, and ribavirin. The patient achieved sustained virological response, recovered his renal function, and remains in remission from cryoglobulinemia.