Mixed Cryoglobulinemia Vasculitis Research Articles

A comparative study of different antiviral treatment protocols in HCV related cryoglobulinemic vasculitis

The treatment of HCV and its sequelae are used to be predominantly based on Interferon (IFN). However, this was associated with significant adverse events as a result of its immunostimulant capabilities. Since their introduction, the directly acting antiviral drugs (DAAs), have become the standard of care to treat of HCV and its complications including mixed cryoglobulinemic vasculitis (MCV). In spite of achieving sustained viral response (SVR), there appeared many reports describing unwelcome complications such as hepatocellular and hematological malignancies as well as relapses. Prolonged inflammation induced by a multitude of factors, can lead to DNA damage and affects BAFF and APRIL, which serve as markers of B-cell proliferation. We compared, head-to-head, three antiviral protocols for HCV–MCV treatment As regards the treatment response and relapse, levels of BAFF and APRIL among pegylated interferon α-based and free regimens (Sofosbuvir + Ribavirin; SOF–RIBA, Sofosbuvir + Daclatasvir; SOF–DACLA). Regarding clinical response HCV–MCV and SVR; no significant differences could be identified among the 3 different treatment protocols, and this was also independent form using IFN. We found no significant differences between IFN-based and free regimens DNA damage, markers of DNA repair, or levels of BAFF and APRIL. However, individualized drug-to-drug comparisons showed many differences. Those who were treated with IFN-based protocol showed decreased levels of DNA damage, while the other two IFN-free groups showed increased DNA damage, being the worst in SOF–DACLA group. There were increased levels of BAFF through follow-up periods in the 3 protocols being the best in SOF–DACLA group (decreased at 24 weeks). In SOF–RIBA, CGs relapsed significantly during the follow-up period. None of our patients who were treated with IFN-based protocol had significant clinico-laboratory relapse. Those who received IFN-free DAAs showed a statistically significant relapse of constitutional manifestations. Our findings suggest that IFN-based protocols are effective in treating HCV–MCV similar to IFN-free protocols. They showed lower levels of DNA damage and repair. We believe that our findings may offer an explanation for the process of lymphoproliferation, occurrence of malignancies, and relapses by shedding light on such possible mechanisms.

Essential Mixed Cryoglobulinemic Vasculitis: Sole Onset with Acute Respiratory Distress Syndrome.

Essential Mixed Cryoglobulinemic Vasculitis: Sole Onset with Acute Respiratory Distress Syndrome.

Nonviral cryoglobulinemic vasculitis: an updated review for clinical practice

The clinical spectrum of cryoglobulinemic-associated diseases is broad and heterogeneous, with manifestations ranging from mild symptoms (e.g., isolated palpable purpura) to organ- and life-threatening involvement (e.g., membranoproliferative glomerulonephritis). Cryoglobulins are classified into three types. Type I cryoglobulinemia consists of one monoclonal immunoglobulin (Ig) and is practically always associated with B-cell lymphoproliferative disorders. In contrast, type II/III (mixed) cryoglobulinemia is composed of mono- or polyclonal IgM with rheumatoid factor activity bound to polyclonal IgG. Since the introduction of more efficient therapies for chronic hepatitis C virus (HCV), other diseases such as systemic autoimmune disorders and lymphoproliferative neoplasms have been established as the main causes of mixed cryoglobulinemic vasculitis. The pathogenesis of cryoglobulinemic vasculitis is a complex multifactorial process that involves B-cell aberrant lymphoproliferation and autoantibody production. Therefore, treatment of these patients may involve not only measures aimed to mitigate the severity of clinical manifestation but also those that address the associated underlying disease responsible for Ig production. The treatment of patients with type I cryoglobulinemia is primarily focused on controlling B lymphocyte clones responsible for cryoglobulin production, mostly with chemotherapy drugs. Treatment of mixed cryoglobulinemia syndrome is based on rituximab plus glucocorticoids, which induces remission in the vast majority of cases. In the rare patients that do not respond to rituximab administration, potential rescue approaches include alkylating agents, biologic therapies, conventional immunosuppression, and plasma exchange, although with partial efficacy. This narrative review explores the etiology, pathophysiology, clinical manifestations, treatment, and prognosis of nonviral cryoglobulinemic disease. A special focus is placed on the treatment of type I cryoglobulinemia and rituximab-resistant non-HCV cryoglobulinemic vasculitis.

Mixed cryoglobulinaemia vasculitis secondary to marginal zone lymphoma in a patient with end-stage renal failure on haemodialysis

Cryoglobulinaemia vasculitis can present with a variety of symptoms and there is limited data on the incidence and presentation of cryoglobulinaemia vasculitis in haemodialysis patients. We report a case of a 63-year-old male who had a series of presentations with rash, visual changes, abdominal pain, weight loss, fevers and digital ischaemia. This is on a background of a congenital single kidney with end-stage renal failure secondary to diabetes and hypertension, receiving haemodialysis for nearly 5 years. He initially experienced a leukocytoclastic vasculitis rash confirmed on skin biopsy, followed by multiple hospital presentations for undifferentiated abdominal pain and fever of unknown source. Jejunal biopsy revealed intestinal vasculitis. His peripheral blood flow cytometry and bone marrow biopsy were consistent with marginal zone lymphoma (indolent subtype, IgM kappa clone). Further testing revealed a type II cryoglobulinaemia consisting of an IgM kappa monoclonal band with polyclonal IgG (cryocrit 5%). A diagnosis of cryoglobulinaemia vasculitis was established and he was treated with pulsed methylprednisolone and rituximab therapy. However, after receiving three doses of rituximab the patient developed a presumed vasculitis-associated pulmonary haemorrhage for which he received treatment with five sessions of plasma exchange. His symptoms resolved and cryocrit reduced to < 1% after his final dose of rituximab. The clinical features of cryoglobulinaemia may be difficult to detect in chronic haemodialysis patients and vigilance is required.

Cryoglobulinemia and Neuromyelitis optica: a case of progressive weakness and neurocognitive decline (P10-5.026)

<h3>Objective:</h3> Describe a case of a woman with mixed cryoglobulinemia who presented with progressive weakness and biopsy proven systemic vasculitis in the setting of Hepatitis C virus (HCV) negative serology. <h3>Background:</h3> The disease expression of mixed cryoglobulinemia vasculitis caused by HCV infection triggers the downstream B-cell arm of autoimmunity. <h3>Design/Methods:</h3> A 61 year old woman with a history of HCV infection, mixed cryoglobulinemia, mononeuritis multiplex secondary to nervous system vasculitis affecting peripheral nerves and hypertension presented with weakness that progressed to quadriparesis and neurocognitive decline over a period of eight months. <h3>Results:</h3> MRI examination of the brain showed bilateral ventral pontine lesions extending into the middle cerebellar peduncles, ventrolateral midbrain and cerebral peduncles as well as bilateral cortical frontal lobe lesions. Also present were intrinsic mixed intensity DWI/ADC lesions of undetermined etiology and extensive subcortical and periventricular white matter hyperintensities. CT angiography of her head and neck showed large vessel intracranial vasculopathy involving the bilateral MCA branches. Conventional angiogram, however, did not show any evidence of angiographic vasculitis. MRI spectroscopy was non-diagnostic. MRI of the neuroaxis showed a small focus of linear non-enhancing hyperintense lesion at the level of C3. EMG demonstrated severe generalized sensory-motor polyneuropathy with severe axonal loss. EEG showed mild to moderate diffuse slowing. CSF evaluation was negative, HCV viral load was undetectable, connective tissue markers (Anti-dsDNA, Anti-SCL70, Anti-CENTR, Anti-RNP, Anti-Smith, Anti-SSA/SSB, ANCA) were negative and the remaining serology was significant for elevated ESR, CRP, low C4 complements, positive anti-AQP4 antibodies titers (1:2560) and positive myelin basic protein. Brain biopsy showed perivascular lymphocytic inflammation, confirming vasculitis. Our patient completed courses of high dose steroids, IVIG and Rituximab with mild improvement in motor strength. <h3>Conclusions:</h3> Although an atypical feature of NMO, cryoglobulinemia with production of anti-AQP4 antibodies may, in part, contribute to development of a demyelinating process. <b>Disclosure:</b> Dr. Esechie has nothing to disclose. Dr. Harazeen has nothing to disclose. Dr. Rivera Vega has nothing to disclose. Dr. Thottempudi has nothing to disclose. Dr. Chhabra has stock in Pfizer. Dr. Chhabra has stock in Biogen. Dr. Chhabra has stock in Johnson and Johnson. Dr. Chhabra has stock in Medtronic. Dr. Shaltoni has nothing to disclose. Muhammad Zeeshan Memon, MD has nothing to disclose. Dr. Patel has nothing to disclose. Dr. Wu has nothing to disclose.

Dual stimulation by autoantigen and CpG fosters the proliferation of exhausted rheumatoid factor-specific CD21low B cells in hepatitis C virus-cured mixed cryoglobulinemia.

Hepatitis C virus (HCV) causes mixed cryoglobulinemia (MC) by driving clonal expansion of B cells expressing B cell receptors (BCRs), often encoded by the VH1-69 variable gene, endowed with both rheumatoid factor (RF) and anti-HCV specificity. These cells display an atypical CD21low phenotype and functional exhaustion evidenced by unresponsiveness to BCR and Toll-like receptor 9 (TLR9) stimuli. Although antiviral therapy is effective on MC vasculitis, pathogenic B cell clones persist long thereafter and can cause virus-independent disease relapses. Clonal B cells from patients with HCV-associated type 2 MC or healthy donors were stimulated with CpG or heath-aggregated IgG (as surrogate immune complexes) alone or in combination; proliferation and differentiation were then evaluated by flow cytometry. Phosphorylation of AKT and of the p65 NF-kB subunit were measured by flow cytometry. TLR9 was quantified by qPCR and by intracellular flow cytometry, and MyD88 isoforms were analyzed using RT-PCR. We found that dual triggering with autoantigen and CpG restored the capacity of exhausted VH1-69pos B cells to proliferate. The signaling mechanism for this BCR/TLR9 crosstalk remains elusive, since TLR9 mRNA and protein as well as MyD88 mRNA were normally expressed and CpG-induced phosphorylation of p65 NF-kB was intact in MC clonal B cells, whereas BCR-induced p65 NF-kB phosphorylation was impaired and PI3K/Akt signaling was intact. Our findings indicate that autoantigen and CpG of microbial or cellular origin may unite to foster persistence of pathogenic RF B cells in HCV-cured MC patients. BCR/TLR9 crosstalk might represent a more general mechanism enhancing systemic autoimmunity by the rescue of exhausted autoreactive CD21low B cells.

Mixed Cryoglobulinaemia Vasculitis Treated with Obinutuzumab in a Patient Allergic to Rituximab.

Cryoglobulinaemia is defined as the presence of cryoglobulins in the serum, which are immunoglobulins that reversibly precipitate and form a gel when the temperature is <37ºC. Autoimmune diseases such as Sjogren’s syndrome, systemic lupus erythematosus and rheumatoid arthritis could be associated with mixed cryoglobulinaemia vasculitis (MCV). The treatment of MCV generally consists of glucocorticoids, cytotoxic agents such as cyclophosphamide, plasmapheresis or anti-CD20 monoclonal antibodies including rituximab. Here, we present a case of a 60-year-old woman who developed type II MCV in the context of overlap autoimmune disease and who has been treated with a new anti-CD20 agent, obinutuzumab.LEARNING POINTSMixed cryoglobulinaemia can occur in the context of autoimmune diseases such as Sjogren’s syndrome, systemic lupus erythematosus and rheumatoid arthritis.The treatment generally consists of glucocorticoids, cytotoxic agents such as cyclophosphamide, plasmapheresis or anti-CD20 monoclonal antibodies including rituximab.New generations of humanized anti-CD20 monoclonal antibodies such as obinutuzumab have been developed to increase complement-dependent cytotoxicity and/or antibody-dependent cellular cytotoxicity, while limiting immunogenicity. These new optimized B-cell depletion strategies could be very interesting and useful in autoimmune disease treatment.

Impact of direct acting antivirals (DAA) on neurologic disorders in chronic hepatitis C.

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. 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." 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. 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.

Mixed Cryoglobulinaemia Vasculitis after Persistent Hepatitis C Virus Eradication.

Mixed cryoglobulinaemia can occur after persistent hepatitis C virus eradication.Most cases described in the literature presented mixed cryoglobulinaemia vasculitis (MCV) after 1 year of HCV eradication compared with after 3 years of persistent eradication in our case.The exact mechanism linking HCV and B-cells is not fully understood, but the main factor seems to be the sustained HCV antigenic stimulation of the B-cell compartment.

Impact of direct acting antivirals on hepatitis C virus-related cryoglobulinemic syndrome.

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. 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. 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. 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.

Clinico-immunological outcomes of HCV-cured cryoglobulinemia: Lower relapse rate with interferon-based than interferon-free therapy.

Sustained virological response (SVR) obtained with interferon (IFN) or with direct-acting antivirals (DAAs) is commonly followed by response of hepatitis C virus (HCV)-associated mixed cryoglobulinemia vasculitis (MCV), but relapse of MCV despite SVR has been reported in several patients after DAAs and rarely after IFN. Since relapses could have been overlooked in studies with IFN, we retrospectively compared the outcomes of MCV in SVR patients treated with DAAs (n=70) or IFN (n=39) followed-up, respectively, for 30.5 (range 11-51) or 48months. Groups were comparable for demographics and clinics and response rates of MCV were similar (92% and 86%); however, DAA-treated patients less efficiently reduced cryoglobulins (P=.006) and circulating B-cell clones (P=.004), and had more frequently relapses of MCV (18% vs 3%, P=.028) and need for rituximab therapy (P=.01). Although largely inferior on an intention-to-treat basis, IFN may be superior to DAAs on clinico-immunological outcomes possibly owing to its antiproliferative activity.

S2512 A Devastating Case of Hepatitis C-Induced Mixed Cryoglobulinemia

INTRODUCTION: Hepatitis C induced Mixed Cryoglobulinemia leading to rapidly progressive gangrene of all four extremities, necessitating amputations, is a rare presentation of cryoglobulinemia. It is postulated that precipitation of cold sensitive globulins in the presence of decreased vascular reserve are responsible for the occurrence of gangrene in cryoglobulinemia. CASE DESCRIPTION/METHODS: A 55-year-old male with treatment naive Hepatitis C (genotype 1a) presented to the emergency room with bilateral hand pain and diffuse purpuric rash. Physical examination showed palpable purpura and extensive gangrene affecting bilateral upper and lower extremities. Laboratory investigation revealed positive rheumatoid factor (>1,200 IU/mL), hypocomplementemia (C4 < 8.0 mg/dL), HCV RNA 2,390,000 IU/mL, and positive cryoglobulins. Cutaneous biopsy showed infiltrate with scattered small to mid-sized vessels with features of fibrin thrombi and associated vasculitis. He was diagnosed with mixed cryoglobulinemia complicated by severe cutaneous vasculitis with ischemic limbs. Plasmapheresis was initiated, however, gangrene continued to progressively worsen. He was transitioned to immunosuppressive therapy with high-dose pulse steroids followed by prednisone 60 mg daily for four weeks in combination with Rituximab. Sofosbuvir/velpatasvir was started for treatment of chronic Hepatitis C. HCV viral load was undetectable (<15 IU/mL) after one week and there was no further spread of gangrene. However, the necrotic limbs were unsalvageable, requiring serial limb amputations. DISCUSSION: There is a wide spectrum of manifestations associated with cryoglobulinemia with severe and life-threatening presentations being relatively rare (< 15% of cases). This case exemplifies a rare and devastating presentation of Hepatitis C induced mixed cryoglobulinemia. Upon literature review, this is one of the most aggressive cases of mixed cryoglobulinemia vasculitis reported thus far. There have been no other cases reported that have resulted in multiple limb amputations secondary to this extent of cryoglobulinemia. As such, this case serves to increase clinician awareness of the severe gangrene that may rapidly develop in mixed cryoglobulinemia. These cases require early recognition and aggressive treatment to prevent progression to the extent of limb amputation and even death. This highlights the necessity of universal screening for Hepatitis C and portrays the devastating effects that delayed screening and therefore delayed treatment may have.Figure 1.: Patient's left hand on initial presentation.Figure 2.: Patient's left hand weeks later, demonstrating progression of gangrene.Figure 3.: Bilateral gangrenous lower extremities.

Mixed cryoglobulinemic glomerulonephritis and vasculitis in primary Sjögren’s syndrome

Introduction: Cryoglobulinemia is a condition where complexes of one or more different classes of immunoglobulins precipitate at low temperatures and become soluble again at higher temperatures. Cryoglobulins are typically categorized as types I to III, based on their immunoglobulin composition. Mixed cryoglobulinemia (type II and III) is most often associated with constitutional symptoms, such as fatigue, myalgia, arthralgia, sensory or motor changes (peripheral neuropathy) and palpable purpura (cutaneous vasculitis). Twenty to thirty percent of the affected patients suffer from membranoproliferative glomerulonephritis. Case Presentaion: We discuss a case of a 45-year-old woman with a history of Sjogren’s syndrome and mixed cryoglobulinemia who presented with acute renal failure, nephritic syndrome, vasculitislike rash on the legs and non-healing skin ulcer. Further investigations confirmed type II mixed cryoglobulinemia associated with cutaneous leukocytoclastic vasculitis and membranoproliferative glomerulonephritis leading to end-stage renal disease (ESRD). Conclusion: Mixed cryoglobulinemia secondary to primary Sjogren’s syndrome (pSS) is rare and reported in 22.5% of cases of non-infectious cryoglobulinemic glomerulonephritis. Long-term renal prognosis is good with only 9% of these patients evolving to ESRD. Nevertheless, the long-term overall survival is poor with severe infections as the leading cause of death.

Biomarkers of minimal residual disease in rituximab-treated patients with mixed cryoglobulinemia.

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

Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody

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.

Genetic and B-cell clonality markers in HCV-related cryoglobulinemic vasculitis persisting after DAA therapy

INTRODUCTION: HCV-related mixed cryoglobulinemic vasculitis (CV) is a lymphoproliferative disorder that can evolve into lymphoma. DAA treatment usually improves CV, but symptoms can recur after a SVR due to genetic factors and B-cell clonal expansion persistence. METHODS: Patients: Group A: SVR-CV patients with clinical response; Group B: SVR-CV patients with symptom persistence/recurrence. A SNP genetic analysis of notch4 rs2071286, hla rs9461776, baff gene rs12428930, baff promoter rs9514828, and baff receptor rs61756766 was performed.

PALPABLE PURPURA, RENAL FAILURE, AND DIFFUSE ALVEOLAR HEMORRHAGE SECONDARY TO STREPTOCOCCAL MUTANS INFECTION: A CASE REPORT

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Cryoglobulins are defined as immunoglobulins that precipitate in the cold and dissolve upon rewarming. Mixed cryoglobulinemia is a condition characterized by the presence of cryoglobulins in the serum that have both IgG and IgM components. Although typically associated with hepatitis C, this disease can also be due to an infectious etiology. Cryoglobulins can occasionally deposit in small blood vessels throughout the body, leading to a mixed cryoglobulinemic vasculitis. CASE PRESENTATION: A 66-year-old male presented with an extensive purpuric lower extremity rash and shortness of breath. Lab work initially was remarkable for acute renal failure and a normocytic, normochromic anemia. The patient was found to be bacteremic with Streptococcus mutans and started on a four-week course of penicillin. Transesophageal echocardiogram showed aortic valve thickening without frank vegetations, leading to a diagnosis of presumed endocarditis. Five days into his hospital stay, the patient developed hemoptysis and acute hypoxic respiratory failure. He was subsequently intubated and transferred to intensive care. Bronchoscopy revealed diffuse alveolar hemorrhage (DAH). Rheumatologic work up was positive for C3 hypocomplementemia and cryoglobulinemia; however, the patient was negative for hepatitis C. Extensive autoimmune workup was unremarkable. Renal biopsy ultimately revealed focal necrotizing and crescentric glomerulonephritis (GN) with mesangial C3 staining, most consistent with endocarditis-associated GN. The patient had improvement in symptoms with antimicrobial therapy alone and demonstrated no benefit from corticosteroids or plasma exchange. He was ultimately extubated and discharged home. DISCUSSION: Mixed cryoglobulinemic vasculitis typically presents with palpable purpura and arthralgias. One atypical sequela is pulmonary capillaritis, leading to diffuse alveolar hemorrhage. While there is no clear association with endocarditis-associated GN and mixed cryoglobulinemia, they are both immune-mediated conditions that result in the deposition of immune complexes. The standard treatments of those diagnosed with mixed cryoglobulinemic vasculitis are immunosuppressive therapy and plasma exchange. However, initiating immunosuppressive therapy without antimicrobial therapy in patients with disease secondary to infection could lead to increased mortality and recurrence rates. CONCLUSIONS: This was a patient who not only presented with S. mutans bacteremia but also developed multiple potentially fatal sequelae that are not typically seen. He was fortunate to have recovered following antimicrobial therapy. Therefore, although mixed cryoglobulinemic vasculitis is typically secondary to hepatitis C infection, less common etiologies must remain on the differential in order to ensure prompt and appropriate treatment. Reference #1: Cryoglobulinemia. Background, Pathophysiology, Epidemiology. https://emedicine.medscape.com/article/329255-overview. Published February 3, 2019. Accessed March 14, 2019. Reference #2: Belizna CC, Hamidou MA, Levesque H, Guillevin L, Shoenfeld Y. Infection and vasculitis. Rheumatology (Oxford, England). https://www.ncbi.nlm.nih.gov/pubmed?term=19258377. Published May 2009. Accessed March 14, 2019. DISCLOSURES: No relevant relationships by Soorya Aggarwal, source=Web Response No relevant relationships by Nathan Brewster, source=Web Response No relevant relationships by Breanna Goldner, source=Web Response no disclosure on file for Jennifer Rovella

Rituximab-associated Vasculitis Flare: Incidence, Predictors, and Outcome.

To report the incidence, predictors, and outcome of rituximab (RTX)-associated autoimmune disease flare. We conducted a retrospective study in a tertiary referral center from 2005 to 2015. Disease flare was defined as the onset of a new organ involvement or worsening of autoimmune disease within 4 weeks following RTX. Among the 185 patients, we identified 7 disease flares (3.4%). All were due to type II mixed cryoglobulinemia vasculitis. Vasculitis flare occurred after a median time of 8 days (range 2-16) following RTX infusion and included acute kidney insufficiency (n = 7), purpura with cutaneous (n = 7), gastrointestinal (GI) tract involvement (n = 4), and myocarditis (n = 1). Patients with RTX-associated cryoglobulinemia vasculitis flare had these conditions more frequently: renal involvement (p = 0.0008), B cell lymphoproliferation (p = 0.015), higher level of cryoglobulin (2.1 vs 0.4 g/l, p = 0.0004), and lower level of C4 (0.02 vs 0.05, p = 0.023) compared to patients without flare after RTX (n = 43). Four patients (57%) died after a median time of 3.3 months. The 1-year survival rate was poorer in patients with vasculitis flare after RTX compared to their negative counterpart [43% (95% CI 18-100) vs 97% (95% CI 92-100), p < 0.001]. Immunofluorescence analysis of kidney biopsy in patients with worsening RTX-associated vasculitis highlighted the presence of RTX-, IgM-, and IgG1-positive staining of endomembranous deposits and thrombi within kidney lesions. RTX-associated cryoglobulinemia vasculitis flare is associated with high mortality rate. We provided evidence that kidney lesions are due to immune complex deposition and to glomerular obstruction by cryoglobulinemia and RTX.

Absence of HCV RNA in serum and cryoprecipitate of patients with persisting mixed cryoglobulinaemia vasculitis after direct‐acting antiviral agents

Absence of HCV RNA in serum and cryoprecipitate of patients with persisting mixed cryoglobulinaemia vasculitis after direct‐acting antiviral agents

Long-lasting persistence of large B-cell clones in hepatitis C virus-cured patients with complete response of mixed cryoglobulinaemia vasculitis.

Hepatitis C virus (HCV)-related mixed cryoglobulinaemia vasculitis (MCV) is characterized by the expansion of rheumatoid factor-producing B-cell clones. The aim of this study was to assess whether B-cell clones may persist in these patients after the clearance of the virus with antiviral therapy, and whether their persistence influences clinical outcomes. Forty-five HCV-cured MCV patients were followed up for a median of 18.5 (range 9-38) months after the clearance of HCV. Circulating B-cell clones were detected using flow cytometry either by the skewing of kappa/lambda ratio or by the expression of a VH 1-69-encoded idiotype. The clinical response of vasculitis was 78% complete, 18% partial and 4% null. However, cryoglobulins remained detectable in 42% of patients for more than 12months. Circulating B-cell clones were detected in 18 of 45 patients, and in 17 of them persisted through the follow-up; nine of the latter patients cleared cryoglobulins and had complete response of vasculitis. Several months later, two of these patients had relapse of MCV. B-cell clones persist in MCV patients long after HCV infection has been cleared but halt the production of pathogenic antibody. These 'dormant' cells may be reactivated by events that perturb B-cell homeostasis and can give rise to the relapse of cryoglobulinaemic vasculitis.