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  • Hepatitis C Induced Mixed Cryoglobulinemia7/28/09

  • Hepatitis C VirusHepatitis C virus (HCV) chronically infects over 170 million people worldwideLeading indication for liver transplantation in the United States and EuropeHCV is a positive-strand RNA virus with a 9.6-kb genome that replicates predominantly in the liverHCV frequently causes extrahepatic manifestations, the most common and severe of which is mixed cryoglobulinemia (MC)

  • Mixed CryoglobulinemiaCryoglobulins are immunoglobulin complex that precipitate in the cold and dissolve on rewarmingRheumatoid Factor: Ig capable of binding to IgG (IgM kappa in HCV MC)Type II or mixed cryoglobulinemia: Cryoglobulin that contains both a polyclonal IgG and a monoclonal IgM rheumatoid factor directed against the IgG.Since the identification of HCV in 1989, it has been recognized as the cause of >90% of MC

  • Mixed CryoglobulinemiaSystemic vasculitis affecting small- and medium-sized arteries and veins.Characterized by the deposition of immune complexes containing rheumatoid factor (RF), IgG, HCV RNA, and complement on endothelial surfacesIn HCV MC blood tests show elevated serum RF, positive cryoglobulins and low complement (particularly C4)

  • Testing for CryoglobulinsSerum preparation must be performed at 37degrees C to prevent premature immune complex precipitationSerum is stored at 4 degrees C for 7 days, inspected daily for a precipitate, and spun in a for calculation of cryocritA cryocrit >2% is positive (Cryocrit is % of cryoglobulin in serum)The cryocrit is then typed using immunofixation

    SPEP (2 upper lanes) shows both a dense band and a smear pattern in the gamma region (left side of the lanes), indicating a cryoglobulin composed of mixed monoclonal and polyclonal gamma globulin protein components.The IFE demonstrates the specific composition to be monoclonal IgM- (corresponding bands in IgM heavy chain and light chain lanes) and polyclonal IgG (corresponding smear in IgG heavy chain and light chain lanes).

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  • MC Clinical ManifestationsInitially described in 1966 as a clinical triad of palpable purpura, arthralgia, and weakness accompanied by organ involvement (e.g., nephropathy and neuropathy) and elevated serum RFNow known that this triad is rare, as many MC patients are asymptomaticPrimarily affects the small- and medium sized vessels of the skin, kidneys, and peripheral nerves

  • Skin InvolvementPalpable purpura, primarily of the lower legs, occurs in more than 90% of patients with symptomatic HCV MCFrequently intermittentOften initial manifestation of HCV MCPurpuric lesions may occasionally progress to chronic ulcers and frank gangrene

  • Kidney InvolvementUsually presents as a type I MPGNPresent in approximately 20 percent of patients at the time of diagnosis and eventually occurs in 35 to 60% of patients with HCV MCNew onset HTN can be seen in 80% of casesMay include hematuria, nephritic to nephrotic range proteinuria, and variable progression to chronic renal insufficiencyGlomerular disease may manifest acutely as oliguric acute renal failure in 5% of cases

  • Type 1 MPGNEndocapillary mesangial-cell proliferationGlomerular infiltration by activated macrophagesGlomerular basement membrane shows double contours Subendothelial deposits of IgM, IgG, and complement components are observed by immunofluorescence and electron microscopyVasculitis of small renal arteries is present in 30% of casesEosinophilic PAS-positive intraluminal deposits

  • Epidemiology of HCV MCEstimates of MC prevalence in HCV infection vary widely, ranging from 10 to 70%MC is associated with increased duration of HCV infection; usually patients with MC have had HCV infection twice as long as those without MCMC may be an independent risk factor for the development of cirrhosis?All HCV genotypes have been found in HCV MC, and there is no clear association with a particular genotypeMixed cryoglobulinemia is more prevalent in Southern Europe than in Northern Europe and North America (unclear if this is due to unidentified genetic factors)

  • HCV Related Lymphoproliferation

    Giordona. JAMA 2007. 297 2010-2017

    (Giordona. JAMA 2007) Large retrospective trial has confirmed that HCV is associated with: NHL, Waldenstrom macroglobulinemia, and MGUS*

  • HCV Related LymphoproliferationLikely that HCV MC represents an antigen-driven, relatively benign clonal B cell lymphoproliferationWith continued antigenic stimulation, HCV MC occasionally progresses toward overt NHLTypically, the NHL that arises in HCV MC patients is low-grade and is characterized by clonal RF B cellsConsistent with the hypothesis that continued antigenic presence is required for ongoing clonal B cell proliferation, eradication of HCV can lead to disappearance of the associated low-grade NHL

  • Pathogenesis of HCV-induced B-cell LymphoproliferationThe mechanisms by which HCV leads to the development of B-cell lymphoma remain unclearHCV MC is characterized by aberrant RF B-cell lymphoproliferationElevated B cell-activating factor has been described in HCV MC; B cell-activating factor inhibits B-cell apoptosis, and high levels may allow the survival of autoreactive B cellsBeen proposed that HCV infects B cells, leading to direct malignant transformation via LDL receptors or CD81; however this is less likely as B cells do not support HCV replication, there is no DNA intermediate in HCV replication for insertional oncogenesisHCV-associated bcl-2 (proto-oncogene) over-expression in the RF producing B cells has been convincingly demonstratedB cell clones in HCV-associated MC and lymphomas often use the VH1-69 gene and VkA27 segment which is also used by anti-E2 antibodies elicited by HCV

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  • A.L. Zignego et al. / Autoimmunity Reviews 8 (2008) 107111

    1) Possible mechanisms involved in the pathogenesis of MC and/or otherHCV-related LPDs2) HCV chronic infection is responsible for sustained B-cell proliferation which could favor the occurrence of errors during V(D)J rearrangement processesnamely t(14;18) translocation3) Bcl-2 over-expression could lead to abnormally prolonged B-cell life.4) The inhibition of B-cell apoptosis may favor the lack of silencing RF B-cells as well as the acquisitionof additional genetic aberrations, which might ultimately lead to transformation to a frank malignancy.*

  • Charles ED. KI June 2009

    IgG-bound HCV specifically drives the clonal expansion of RF B cells

    2) During chronic HCV infection, immune-complexed HCV stimulates the expansion of VH1-69 B cells, which on continued antigenic exposure (usually over several years) become clonally predominant.3) These cells have expanded independently of T cell help in response to dual ligation of BCR and toll-like receptor 7 by IgG and HCV RNA, respectively.*

  • TreatmentThe most effective treatment for HCV MC is eradication of the underlying HCV infectionHCV RNA relapse is associated with recurrence of MC and clinical symptomsThe current standard of care for HCV infection is pegylated interferon-a-2a/2b (pIFN) in combination with ribavirin (RBV), which results in a sustained virological response rate of 4550% in genotypes 1 and 4, and 7080% in genotypes 2 and 3 in HCV monoinfected patientsRBV is contraindicated in individuals with creatinine clearance
  • Antiviral Therapy IFN alphaRandomized trial of 53 patients with HCV MC got either INF alpha or conventional treatment; about 60% of the IFN alpha responded with undetectable HCV VL; improvement of cutaneous lesions, serum Cre, cryoglobulin and RF titers (Misiani NEJM 1994)All patients that that responded had recurrence of viremia and cryoglobulinemia once interferon alfa-2a was discontinuedInterferon alfa therapy may induce and/or exacerbate glomerulonephritis in some patients with chronic hepatitis C virus infection

  • Antiviral Therapy Pegylated IFNStudies have shown reduced clearance of pegylated interferon in patients on hemodialysis; however felt safe to use in eGFR > 15ml/minSide effects in dialysis patients include: anemia, flu-like syndrome, myalgias, and fatigue

  • Antiviral Therapy Pegylated IFN + RibavirinRibavirin improves the rate of sustained virologic clearance when given in combination with standard or pegylated interferon alfa The use of ribavirin is limited by renal insufficiency.Among patients with renal insufficiency, the accumulation of ribavirin induces a severe hemolytic anemia and iron overload due to chronic hemolyisis which can lead to an acceleration in liver fibrosis progression.Ribavirin should be used with caution in patients with mild renal insufficiency. It is NOT recommended for patients with estimated glomerular filtration rate less than 50 mL/min per 1.73 m2.

  • RituximabChimeric monoclonal antibody that binds to the pan B cell marker, CD20CD20 antigen, is a transmembrane protein expressed on pre-B lymphocytes and mature lymphocytesEffects B cell destruction through complement-dependent and antibody-mediated cellular cytotoxicityFollowing a standard course of 375 mg/m2/week4 weeks, B cells are typically undetectable in the periphery, and take 618 months to recoverSeveral small studies have shown that 8093% of patients with HCV MC vasculitis respond to rituximab, and the reduction of peripheral VH1-69 memory B cells persists 12 months after treatmentSymptoms usually reappear with reconstitution of peripheral B cellsIts use has been associated with modestly elevated (up to two-fold) levels of HCV viremia

  • TreatmentSaadoun. Rheumatology 2007;46:12341242

    Antiviral therapy may clear the antigen (i.e. HCV) trigger of MC vasculitis.Anti-CD20 mAb target the B-cell, involve in the cryoglobulin formation and possibly in the antigen presentation to T lymphocytesImmunosu

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