Hepatitis C Induced Mixed Cryoglobulinemia

7/28/09

Hepatitis C Virus

• Hepatitis C virus (HCV) chronically infects over 170 million people worldwide

• Leading indication for liver transplantation in the United States and Europe

• HCV is a positive-strand RNA virus with a 9.6-kb genome that replicates predominantly in the liver

• HCV frequently causes extrahepatic manifestations, the most common and severe of which is mixed cryoglobulinemia (MC)

Mixed Cryoglobulinemia

• Cryoglobulins are immunoglobulin complex that precipitate in the cold and dissolve on rewarming

• Rheumatoid 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 Cryoglobulinemia• Systemic 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 surfaces

• In HCV MC blood tests show elevated serum RF, positive cryoglobulins and low complement (particularly C4)

Testing for Cryoglobulins

• Serum preparation must be performed at 37degrees C to prevent premature immune complex precipitation

• Serum is stored at 4 degrees C for 7 days, inspected daily for a precipitate, and spun in a for calculation of cryocrit

• A cryocrit >2% is positive (Cryocrit is % of cryoglobulin in serum)• The cryocrit is then typed using immunofixation

MC Clinical Manifestations

• Initially 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 RF

• Now known that this triad is rare, as many MC patients are asymptomatic

• Primarily affects the small- and medium sized vessels of the skin, kidneys, and peripheral nerves

Skin Involvement

• Palpable purpura, primarily of the lower legs, occurs in more than 90% of patients with symptomatic HCV MC

• Frequently intermittent• Often initial manifestation of HCV MC• Purpuric lesions may occasionally progress to chronic ulcers and frank

gangrene

Kidney Involvement• Usually presents as a type I MPGN• Present in approximately 20 percent of patients

at the time of diagnosis and eventually occurs in 35 to 60% of patients with HCV MC

• New onset HTN can be seen in 80% of cases• May include hematuria, nephritic to nephrotic

range proteinuria, and variable progression to chronic renal insufficiency

• Glomerular disease may manifest acutely as oliguric acute renal failure in 5% of cases

Type 1 MPGN

• Endocapillary mesangial-cell proliferation• Glomerular infiltration by activated macrophages• Glomerular basement membrane shows double contours • Subendothelial deposits of IgM, IgG, and complement components are observed by

immunofluorescence and electron microscopy• Vasculitis of small renal arteries is present in 30% of cases• Eosinophilic PAS-positive intraluminal deposits

Epidemiology of HCV MC• Estimates 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 MC

• MC 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 genotype

• Mixed 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

HCV Related Lymphoproliferation• Likely that HCV MC represents an antigen-driven,

relatively benign clonal B cell lymphoproliferation• With continued antigenic stimulation, HCV MC

occasionally progresses toward overt NHL• Typically, the NHL that arises in HCV MC patients is

low-grade and is characterized by clonal RF B cells• Consistent 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 Lymphoproliferation

• The mechanisms by which HCV leads to the development of B-cell lymphoma remain unclear

• HCV MC is characterized by aberrant RF B-cell lymphoproliferation• Elevated 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 cells

• Been 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 oncogenesis

• HCV-associated bcl-2 (proto-oncogene) over-expression in the RF producing B cells has been convincingly demonstrated

• B 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

A.L. Zignego et al. / Autoimmunity Reviews 8 (2008) 107–111

Charles ED. KI June 2009

Treatment• The most effective treatment for HCV MC is eradication of the

underlying HCV infection• HCV RNA relapse is associated with recurrence of MC and clinical

symptoms• The 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 45–50% in genotypes 1 and 4, and 70–80% in genotypes 2 and 3 in HCV monoinfected patients

• RBV is contraindicated in individuals with creatinine clearance <50 ml/min and pIFN/RBV is poorly tolerated in ESRD

• For patients unable to tolerate antivirals, or for those with severe renal disease, or for those who have failed to reach sustained virological response after antiviral therapy, symptomatic treatment of vasculitis with plasmapheresis, rituximab, or prednisone should be considered

Antiviral Therapy – IFN alpha• Randomized 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 discontinued

• Interferon alfa therapy may induce and/or exacerbate glomerulonephritis in some patients with chronic hepatitis C virus infection

Antiviral Therapy – Pegylated IFN

• Studies have shown reduced clearance of pegylated interferon in patients on hemodialysis; however felt safe to use in eGFR > 15ml/min

• Side effects in dialysis patients include: anemia, flu-like syndrome, myalgias, and fatigue

Antiviral Therapy – Pegylated IFN + Ribavirin

• Ribavirin 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.

Rituximab• Chimeric monoclonal antibody that binds to the pan B cell marker,

CD20• CD20 antigen, is a transmembrane protein expressed on pre-B

lymphocytes and mature lymphocytes• Effects B cell destruction through complement-dependent and

antibody-mediated cellular cytotoxicity• Following a standard course of 375 mg/m2/week4 weeks, B cells are

typically undetectable in the periphery, and take 6–18 months to recover

• Several small studies have shown that 80–93% of patients with HCV MC vasculitis respond to rituximab, and the reduction of peripheral VH1-69 memory B cells persists 12 months after treatment

• Symptoms usually reappear with reconstitution of peripheral B cells• Its use has been associated with modestly elevated (up to two-fold)

levels of HCV viremia

Treatment

Saadoun. Rheumatology 2007;46:1234–1242

KDIGO Recommendations• For eGFR >50 mL/min/1.73 m2, pegylated

interferon and ribavirin• For eGFR 15 to <50 mL/min per 1.73 m2,

monotherapy with pegylated interferon • For eGFR <15 mL/min per 1.73 m2 (including

patients on hemodialysis); monotherapy with standard interferon that is dose adjusted for a glomerular filtration rate less than 15 mL/min per 1.73 m

• Antiviral treatment is recommended for at least 12 months

Additional KDIGO Recommendations• Among MPGN patients with nephrotic-range proteinuria and/or rapid loss of

kidney function and an acute flare of cryoglobulinemia, one of the following therapies should be considered:

Plasma exchange (3 liters of plasma thrice weekly for two to three weeks)

Rituximab (375 mg/m2 per week for four weeks); OR

Cyclophosphamide (2 mg/kg per day for two to four months)

Plus Methylprednisolone pulses (0.5 to 1 g/day for three days).

• Treated with ACEI or ARB to reduce proteinuria and achieve target blood pressure goals

• Relapses of systemic cryoglobulinemia and membranoproliferative glomerulonephropathy may be treated with additional doses of rituximab

Saadoun. Rheumatology 2007;46:1234–1242