Hepatitis C Related Cryo Associated MPGN. Trina Banerjee

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1 Hepatitis C Related Cryo Associated MPGN Trina Banerjee

2 Outline Cryoglobulinemia Definition Prevalence Classification Cryo Associated MPGN Pathophysiology Presentation (Clinical/Lab/Histologic) Treatment

3 Part I: CRYOGLOBULINEMIA

4 Definition Cryoglobulin: Precipitation of blood proteins at 4*C, which reverses when the blood is brought back up to 37* C Consists of immunoglobulion and complement Cryoglobulinemia: Small and medium vessel vasculitis due to cryoglobulin deposition in these vessels

5 Prevalence 1:100,000 clinically significant 15-25% of patients with CTD and 40-50% of patients with hepatitis C are cryo positive, but it is not clinically significant

6 Brouet Classification Type I: 10-15% 15% of cases of cryo Monoclonal antibody, usually IgG or IgM, sometimes IgA Most commonly found in Waldenstrom s or multiple myeloma

7 Brouet Classification Type II: 50-60% of cases of cryo Monoclonal (usually IgM, sometimes IgA) and a polyclonal antibody usually IgG Monoclonal antibody binds IgG and is therefore RF positive 95% of cases are due to Hepatitis C. Other causes may be HIV, Hepatitis B, SLE, Sjogren s, and Systemic Sclerosis

8 Brouet Classification Type III: Combination polyclonal antibody Usually polyclonal M and polyclonal G Polyclonal M is bound to the polyclonal G, so this is also RF positive Usually present in connective tissue disorders

9 Part II: CRYO ASSOCIATED MPGN

10 Pathophysiology: Step 1 Alter B Cells B-cells are altered by 1 of 3 things: Malignancy, Infection (ie. Hepatitis C), or Autoimmunity (ie. SLE or RA)

11 Pathophysiology: Step II Form Cryo If Hepatitis C is attached to IgG: RF expressing B cells bind to IgG-antigen complexes. Complexes stimulate both B cells antigen receptors and Toll like receptors, which causes the B cell to turn into a RF producing plasma cell Hepatitis C is known to activate TLR 2 (which activates macrophages), 7, and 8. If hepatitis C is the antigen it is more likely to produce RF plasma cells

12 Pathophysiology: Step II Form Cryo If Hepatitis C is not attached to IgG: The envelope protein E2 on the Hepatitis C can attach to the CD-81 on B- B lymphocytes This leads to lymphoproliferation. One of the lymphocytes clones may react with IgG, causing RF production

13 Pathophysiology: Step III Deposit in the Kidney Monoclonal IgM has affinity for mesangium, allowing cryo to deposit in the glomeruli where cytokines cause endothelial cell damage and leukocyte diapedesis HCV associated cryoglobulinemia GN formation related to deposition of HCV antigen, anti-hcv IgG, and IgM Leads to MPGN

14 Clinical Presentation Proteinuria and hematuria, with or without an elevated Cr 20% of patients develop the nephotic syndrome 30% of patients develop the nephritic syndrome 80% of patients have HTN

15 Laboratory Presentation CH50 and c4 and c1q levels will be low in Type 2 and 3 Cryo c3 may be moderately lower RF (IgM kappa and IgG) will often be high

16 Histologic Abnormalities Infiltration of the glomerulus by macrophages GBM w/ double contours from interposition of monocytes between basement membrane and the endothelium Subendothelial depositis of IgM, IgG, and complement Large subendothelial deposits on EM Vasculitis of small renal arteries in 30% of cases

17 Part III: TREATMENT

18

19 Antiviral Therapy

20 Interferon Alpha and Ribavirin Dose: Int. alpha: 3 million units 3 times a week. Pegylated intereferon once a week. Ribavirin is 10-15mg/kg 15mg/kg per day Duration: Genotype 1, 4, and 5: 48 weeks Genotype 2 and 3: 24 weeks Sustained clinical and virologic responses in 60% of cases

21 Interferon Alpha with and without ribavirin: Sabry et al Prospective uncontrolled study 17 MPGN, 2 membranous, 1 with mesangioproliferative GN treated with alpha interferon, with or without ribavirin Started interferon alpha tiw. If persistent HCV RNA at 3 months, ribavirin was added

22 Interferon Alpha with and without ribavirin: Sabry et al Treatment duration was 12 months HCV RNA and proteinuria declined significantly, albumin, c3 and c4 increased significantly

23 Antiviral vs. Nonantiviral treatment: Alric et. al 25 patients with HCV related cryo associated MPGN 18 patients got anti HCV therapy, 7 did not have anti-hcv therapy Duration of treatment months. Range of follow-up months After Anti-HCV therapy proteinuria and cryo decreased, Albumin higher, Cr stable

24 Treatment with Nephrotic Syndrome

25 Options with Bad Disease Steroids Cytoxan: Suppresses B cell and cryo production Plasma exchange: Removes circulating immune complexes, therefore stop deposition in the kidney 3L per day tiw for weeks Rituximab

26 Rituximab: Chimeric mouse anti-human CD20 Ab Dose is 375mg/m2 once a week for four weeks Parameters to watch for are normalizing of the C4 and the RF Adverse Effects: Serum sickness 60-70% complete clinical response (9) 40% experience relapse

27 Combination Therapy

28 Ritux + antiviral vs. Antiviral: Saadoun et. al Prospective cohort 93 patients with cryo in France, not all renal 38 ritux/intereferon/ribavirin vs. 55 patients alpha intereferon/ribavirin Ritux/interferon/ribavirin: shorter time to clinical remission (5.4 +/- 4 vs 8.4 +/- 4.7 months, P=.004), better renal response (80.9% vs 40% for complete remission of MPGN)

29 Ritux in Cryo/MPGN: D. Roccatello et al 6 patients who had failed conventional therapy for cryo Treated with 375mg/m2 rituximab once a week for 4 weeks, plus 2 more doses 1 and 2 months later

30 Ritux in Cryo/MPGN: D. Roccatello et al Significant decrease in esr, poteinuria, and cryocrit at 2, 6, and 12 months after the first administration of ritux. Significant decrease in RF and IgM at 6 months. C4 increased at 2 and 6 months

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34 Ritux + antiviral vs. Ritux: Terrier et. al 32 patients with HCV associated vasculitis 20 ritux/interferon alpha/ribavirin, 12 ritux ritux :67% clinical response (complete response in 58%), 82% immunologic response (complete response in 46%), no virologic response

35 Ritux + antiviral vs. Ritux: Terrier et. al Ritux/antiviral therapy:95% clinical response (80% showed a complete response), 100% immunologic response (complete response in 67%),55% sustained virologic response.

36 Ritux + antiviral vs. Ritux: Terrier et. al Relapses assoc. with lack of virologic control Relapses retreated with ritux: 100% had a complete clinical response, 50% complete immunologic response, 50% had a partial immunologic response

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