Sindrome HCV dieci anni dopo:
     Nuovi algoritmi terapeutici
    nella crioglobulinemia mista
                   Dario R...
MIXED CRYOGLOBULINEMIA             7.8
WEGENER’S GRANULOMATOSIS           2.2
GIANT CELL ARTERITIS               1.6
POLYA...
PATHOGENESIS of TISSUE INJURY in MIXED CRYOGLOBULINEMIA




ROCCATELLO D, EXPERT. REV. CLIN. IMMUNOL. 2008   ALPERS CE, CU...
Kidney survival in patients with cryoglobulinemic nephritis
                                            female            ...
Sustained virological response in chronic Hepatitis C and MC:
cumulative data from Mazzaro (2005), Rossi (2003) and Kayali...
Drug           Pros                                                   Cons
Steroids       - Inhibition of the inflammatory...
Fornasieri e Roccatello
                Manuale di terapia delle glomerulonefriti




 Peg IFN a 2a (40 kD) 180 ug week
  ...
Drug           Pros                                                       Cons
Steroids       - Inhibition of the inflamma...
Anti TNF therapy and C virus hepatitis




    Parke, Arhtr & Rheum 2004
Treatment with Abatacept of a relapsing case of MC
                                               C4 mg/dl
               ...
Roccatello, NDT, 2004




                        Rituximab is expected
                  #     to improve the subclinical...
Roccatello, Expert Reviews in Clinical Immunology, 2008
Rituximab in patients with HCV-related cryoglobulimia
                                        HCV-
  Study       Year     ...
ANTI-
     ANTI-CD20 MONOCLONAL ANTIBODY THERAPY FOR TYPE II MC SYNDROME:
                                                ...
CMID’s open study

    22 pts, mean age years 61.7 (range 36-78 years), with HCV infection in 21
      cases, genotype 2a/...
Clinical profiles of 22 patients with severe crioglobulinemia
                                                            ...
Laboratory profiles of 12 patients with crioglobulinemic nephritis
               undergoing the 4 plus 2 infusion protoco...
59 yr-old man with hemophilia with NS and severe renal failure due to MC
       yr-


                                    ...
“4 plus 2” Rituximab protocol: effects of therapy
Symptom changes in 13 patients with polyneuropathy


       Previous treatments:
       CS (11), PE (3), CYC or MMF(4), IF...
Cryoglobulinemic polyneuropathy in 13 pts:
                                                   pts:
                 EMG ch...
Dario Roccatello
                                   Research Center of Immunopathology
                                   ...
Roccatello Dario Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità Com
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Roccatello Dario Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità Com

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Roccatello Dario Torino 13° Convegno Patologia Immune E Malattie Orfane 21 23 Gennaio 2010 [Modalità Com

  1. 1. Sindrome HCV dieci anni dopo: Nuovi algoritmi terapeutici nella crioglobulinemia mista Dario Roccatello Centro di Ricerche di Immunopatologia (CMID), Dipartimento di Malattie Rare, Immunologiche, Ematologiche, Immunoematologiche, ASL 2 Torino Nord e Università di Torino Coordinamento Interregionale delle Malattie Rare del Piemonte e della Valle d’Aosta
  2. 2. MIXED CRYOGLOBULINEMIA 7.8 WEGENER’S GRANULOMATOSIS 2.2 GIANT CELL ARTERITIS 1.6 POLYARTERITIS NODOSA 1.5 BEHÇET’S DISEASE 1.3 MICROSCOPIC POLYANGIITIS 1.3 KAWASAKI DISEASE 0.7 TROMBOTIC MICROANGIOPATHY 0.7 CHURG- CHURG-STRAUSS VASCULITIS 0.4 TAKAYASU’S ARTERITIS 0.3 SISTEMIC VASCULITIS IN PIEDMONT: #/100000 Prevalenza anti - HCV >10% 5-10% 1-5% < 1% Sconosciuta Rapporto OMS 2000
  3. 3. PATHOGENESIS of TISSUE INJURY in MIXED CRYOGLOBULINEMIA ROCCATELLO D, EXPERT. REV. CLIN. IMMUNOL. 2008 ALPERS CE, CURR OP NEPHR HYPERT 2008
  4. 4. Kidney survival in patients with cryoglobulinemic nephritis female male 1,0 survival probability 0,9 GIIPR’ study 0,8 AJKD, 2007 0,7 0,6 0,5 0,4 0,3 0,2 0,1 0,0 0 50 100 150 200 250 months Tarantino, KI,1995 , AJKD, 2007 GIIPR
  5. 5. Sustained virological response in chronic Hepatitis C and MC: cumulative data from Mazzaro (2005), Rossi (2003) and Kayali (2006) Romero-Gòmez et al, Rev Esp de Enfermedades Digestiva, 2008
  6. 6. Drug Pros Cons Steroids - Inhibition of the inflammatory cascade through - Direct or indirect ↑ of HCV NFkB replication in vivo and in vitro - Effects on mineral metab and endocrine system Leflunomide -Inhibition of T lymphocyte clonal expansion - Leflunomide induced necrotizing - Anti-inflammatory properties vasculitis - Inhibition of selected tyrosine kinases - Liver toxicity - L-analogue FK778 vasculoprotective in exp models Cyclos A - Inhibition of IL-2 and proinflammatory cytokines - Vasospastic effect on macro and - Inhibition of HCV replication in vitro and in vivo microcirculation ↑ -↑ Blood viscosity - ↑ PLT aggregattion worsening of vascular manifestations -Nephrotoxicity, hypertension, neurotoxicity Mycophenola -Inhibition of T and B lymp clonal expansion -GI adverse events (liver toxicity) te mofetil / -Ribavirin-like action in vitro Azathioprine -Prevention of arterial smooth muscle cell proliferation and proliferative arteriopathy in animal model Anti-TNF Inhibition of TNF-α -↑ B cell number and activity in Anti-inflammatory activity peripheral blood TNF-α implicated in refractoriness to IFN - Autoantibodies (ANA, anti nDNA) Anti-CD20 Inhibition of B cells -↑ HCV RNA (?) Effective targeting of autoreactive clones - progression of HCV infection (??)
  7. 7. Fornasieri e Roccatello Manuale di terapia delle glomerulonefriti Peg IFN a 2a (40 kD) 180 ug week kD) Mycophenolate mofetil 2g/day 2g/day Peg IFN a 2b (12 kD)1.5 ug /kg week kD)1.5 plus Ribavirin 800-1200 mg/die 800- mg/die
  8. 8. Drug Pros Cons Steroids - Inhibition of the inflammatory cascade through NFkB - Direct or indirect ↑ of HCV - Effects on mineral metab and endocrine system replication in vivo and in vitro Leflunomide -Inhibition of T lymphocyte clonal expansion - Leflunomide induced necrotizing - Anti-inflammatory properties vasculitis - Inhibition of selected tyrosine kinases - Liver toxicity - L-analogue FK778 vasculoprotective in exp models Cyclos A - Inhibition of IL-2 and proinflammatory cytokines - Vasospastic effect on macro and - Inhibition of HCV replication in vitro and in vivo microcirculation -↑ Blood viscosity - ↑ PLT aggregattion worsening of vascular manifestations -Nephrotoxicity, hypertension, neurotoxicity Mycophenolat -Inhibition of T and B lymp clonal expansion -GI adverse events (liver toxicity) e mofetil / -Ribavirin-like action in vitro Azathioprine -Prevention of arterial smooth muscle cell proliferation and proliferative arteriopathy in animal model Anti-TNF α Inhibition of TNF-α ↑ -↑ B cell number and activity in Anti-inflammatory activity peripheral blood α TNF-α implicated in refractoriness to IFN - Autoantibodies (ANA, anti nDNA) Anti-CD20 Inhibition of B cells -↑ HCV RNA (?) Effective targeting of autoreactive clones - progression of HCV infection (??)
  9. 9. Anti TNF therapy and C virus hepatitis Parke, Arhtr & Rheum 2004
  10. 10. Treatment with Abatacept of a relapsing case of MC C4 mg/dl 14 12 10 8 6 4 2 0 Proteinuria mg/24h 1200 Serum creatinine mg/dl 3 1000 2,5 800 2 600 1,5 400 1 200 0,5 0 0
  11. 11. Roccatello, NDT, 2004 Rituximab is expected # to improve the subclinical lymphoproliferation and interfere with IgM monoclonal production and cryoglobulin synthesis
  12. 12. Roccatello, Expert Reviews in Clinical Immunology, 2008
  13. 13. Rituximab in patients with HCV-related cryoglobulimia HCV- Study Year Patients Rtx dose Other Side effects HCV viral Relapse (# of nephritis) treatment load (#) Sansonno 2003 20 (1) 375 mg/m2 S (low Septic fever (1) Responder 4 / 16 weekly x 4 weeks doses) = (> 7 nonrespon months) der Zaja 2003 15 (2) 375 mg/m2 S (< 0.5 Retinal 2/8 6 (3-6 weekly x 4 weeks mg/kg/day) thrombosis (1) 1/8 months) =5/8 Roccatello 2004 6 (5) 375 mg/m2 Transient 14 2 weekly x 4 weeks bradycardia (2) unchanged (> 12 + 375 mg/m2 months) monthly x 2 months Quartuccio 2008 5 (5) 375 mg/m2 S (one Transient NR 3 (>5, > 7 weekly x 4 weeks case) neutropenia (1) and > 12 months) Basse 2006 7 (7) (post 375 mg/m2 CNI, MM Lethal infection NR NR kidney weekly x 2-4 (2, fungal and transplant) weeks HSV) Visentini 2007 5 (1) (available 250 mg/m2 S, IF, CYC, 2 /5 NR for analysis) weekly x 2 weeks PE =3/5 Terrier 2009 12 (4) 375 mg/m2 S, PE in Serum sickness Unchanged 4/12 (18±7 weekly or 1000 nephritic pts neutropenia months) mg twice Ibidem 2009 20 (10) 375 mg/m2 Combined Serum sickness decreased 3/20(23±12 weekly or 1000 PEG-IFN hematologic months) mg twice and toxicity Ribavirin flare of psoriasis hepatocarcinoma poor compliance
  14. 14. ANTI- ANTI-CD20 MONOCLONAL ANTIBODY THERAPY FOR TYPE II MC SYNDROME: SYNDROME: A CONTROLLED STUDY vs. BEST AVAILABLE TREATMENT vs. • Randomized, controlled multicentre study 1.Udine – S. De Vita (Co-Ordinating Centre) • Study phase III 2. Pordenone – C. Mazzaro • No sponsor – no profit study 3. Brescia – P. Scaini 4. Salerno – S. Scarpato • Duration 24 months (end of recruitment 31/12/2006) 5. Bologna – M. Lenzi 6. Novara – M. Campanini 7. Bergamo – M. Pietrogrande • Target population: population: 8. Pisa – A. Tavoni, S. Bombardieri 9. Modena – M.T. Mascia, C. Ferri patients with HCV-related or –unrelated mixed cryoglobulinemia HCV- 10. Torino – D. Roccatello with skin ulcers, active glomerulonephritis or peripheral neuropathy 11. Saronno – G. Monti, Saccardo 12. Napoli – S. Migliaresi 13. Napoli Cotugno – C. De Pascale Primary end point 14. Milano Niguarda – B. Canesi, Filippini To evaluate the efficacy of rituximab in comparison with the conventional, best currently 15. Ancona – A. Gabrielli available therapeutical approaches (as chosen by expert clinicians) 16. Firenze – A.L. Zignego, M. Matucci 17. Monza – P. Pioltelli Additional end points • To determine the steroid-sparing effects of rituximab, if any • To determine the duration of clinical and biologic efficacy of rituximab treatment in type II MC, to better plan retreatment and/or maintenance regimens in future studies • To determine the effects on the quality of life and disease • To determine whether rituximab may be useful to rescue patients where best available treatment has failed • Pharmacoeconomic assessments of rituximab therapy vs. best available treatment GROUP A: Best conventional treatment GROUP B: Rituximab (rescue from group A allowed) 1) corticosteroids (maximal initial doses 1 mg/kg/day of Rituximab 1000 mg IV on day +1 and +15 prednisone/eqivalents) with or without preceding 6- with or without concomitant corticosteroids. methylprednisolone pulses (500 to 1000 mg/day for 3 consecutive days Only corticosteroids are allowed as concomitant treatment 2) azathioprine or cyclophosphamide 1- 2 mg/kg/day, with or - if already administered without corticosteroids - if introduced concomitantly with rituximab treatment, only 3) Plasmapheresis with or without corticosteroids low doses (≤ 0.1 mg/kg/day) allowed. Randomization: GROUP A: 30, GROUP B: 29 Rescue therapy” to rituximab: 22/30 (73.3%)
  15. 15. CMID’s open study 22 pts, mean age years 61.7 (range 36-78 years), with HCV infection in 21 cases, genotype 2a/2c (7 cases), 3 (2 cases) , 1b (10 cases) – intolerance to standard therapy 6 – resistance to standard therapy 6 – severe BM lymphocyte infiltration 5 – front-line therapy 5 12 with severe renal involvement, 10 with MPGN, 1 with renal vasculitis 13 with multiple mononeuritis (extremely severe in 5) 9 large skin ulcers (necrotizing in 8) Rituximab was administered intravenously according to the 4 plus 2 protocol (Roccatello, NDT 2004): 375 mg/m2 on days 1, 8, 15 and 22 with two more doses administered 1 and 2 months later 13 pts were given further infusions: 8 received a re-induction (2 doses in 2 weeks plus 1 monthly infusion for 2 months) after 12-51 months 5 were allocated in a maintenance protocol (1 infusion at 3 months interval) 3 out of 18 pts developed low levels of anti-Rituximab abs (14-22 AU/ml, normal<12)
  16. 16. Clinical profiles of 22 patients with severe crioglobulinemia Arthralgia 15/15 improved VAS >50% undergoing the 4 plus 2 infusion protocol of anti-CD20 MoAb BM ab reversal or improvement : 5/5 re- examined pts re-
  17. 17. Laboratory profiles of 12 patients with crioglobulinemic nephritis undergoing the 4 plus 2 infusion protocol of anti-CD20 MoAb P<0.001 • Mean follow-up 55.4 months (range 8-87 months) • Re-inductions in 4 cases at 12,13,17 and 45 months, respectively • Two cases allocated in a maintenance protocol (1 infusion at 3 months interval for 1 year) • Dose prednisone at the last observation: 8 pts without maintenance treatment 2 pts with 2.5 mg/d 2 pts with 5 mg/d
  18. 18. 59 yr-old man with hemophilia with NS and severe renal failure due to MC yr- Pre 2 m 6 m 12 24 36 48 1997: nephrotic syndrome sCr 6.8 4.6 4.9 5.0 3.5 3.5 3.7 full clinical picture of MC HCV infection (genotype 1b) Pu g/d 3.5 0.9 0.6 0.6 0.4 0.3 0.8 Given CS, cyclo and PE TP 6.5 6.5 6.5 7.5 7.6 7.6 7.1 2003: scheduled for artero- artero- ESR 54 30 19 19 19 20 28 venous fistula to start dialysis RF 298 24 30 249 105 95 102 Consultation in our Unit (CMID) CMID) Severe renal insufficiency IgM 397 80 60 142 69 75 96 with nephrotic syndrome 4-drug resistant hypertension C3 65 80 78 79 78 82 81 4-limb sensitive motor C4 4 11 28 16 28 24 18 polyneuritis Arthralgia, Arthralgia, weakness Cryo 4% 2% 0.5 0 1 0.5 0.5 Iatrogenic diabetes, purpura VL 1.3 nd 1.0 0.7 0.3 0.4 0.4 ALT 26 27 16 44 43 36 38
  19. 19. “4 plus 2” Rituximab protocol: effects of therapy
  20. 20. Symptom changes in 13 patients with polyneuropathy Previous treatments: CS (11), PE (3), CYC or MMF(4), IFN (4) 15 - 45% - 66% - 83% 10 5 0 paresthesia burning foot RLS weakness pre 11 4 1 12 post 6 2 1 2 Cavallo and Roccatello J Neurol, 2009
  21. 21. Cryoglobulinemic polyneuropathy in 13 pts: pts: EMG changes after anti-CD 20 MoAb anti- PRE POST p SPE ampl mV 1.08±0.95 1.50±1.32 0.04 SPE MCV m/s 41.29±8.0 41.77±7.35 n.s. SPE Lat ms 4.16±1.05 4.38±1.32 n.s. Sural ampl µV 0.39 7.13 0.085 Sural SCV m/s 33.85±0.77 47.48±5.72 0.018 Cavallo and Roccatello J Neurol, 2009 CMAP changes 5 4,5 4 3,5 3 mV 2,5 2 1,5 1 0,5 0 1.08±0.95 pre pos t 1.50±1.32 p<0.04
  22. 22. Dario Roccatello Research Center of Immunopathology University of Turin, Italy Inter-regional Coordinating Center for Rare Diseases of Piedmont and Aosta Valley NorthTurin Emergency Hospital San Giovanni Bosco,Turin, Italy effective therapeutic option severe worsening of renal function, mononeuritis multiplex, extensive skin ulcers, and distal necrosis persistence of effects is often finite, but long lasting response (48 mths) is observed in about a half of the patients Roccatello, Expert Reviews in Clinical Immunology, 2008

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