Sindrome HCV dieci anni dopo:Nuovi algoritmi terapeutici Nuovi algoritmi terapeutici

nella crioglobulinemia mista

Dario Roccatello

Centro di Ricerche di Immunopatologia (CMID),Dipartimento di Malattie Rare, Immunologiche, Emato logiche,

Immunoematologiche,ASL 2 Torino Nord e Università di Torino

Coordinamento Interregionale delle Malattie Rare del Piemonte e della Valle d’Aosta

MIXED CRYOGLOBULINEMIA MIXED CRYOGLOBULINEMIA 7.87.8

WEGENER’S GRANULOMATOSISWEGENER’S GRANULOMATOSIS 2.22.2

GIANT CELL ARTERITIS GIANT CELL ARTERITIS 1.61.6

POLYARTERITIS NODOSAPOLYARTERITIS NODOSA 1.51.5

BEHÇET’S DISEASEBEHÇET’S DISEASE 1.31.3

MICROSCOPIC POLYANGIITISMICROSCOPIC POLYANGIITIS 1.31.3

KAWASAKI DISEASE KAWASAKI DISEASE 0.70.7

TROMBOTIC MICROANGIOPATHYTROMBOTIC MICROANGIOPATHY 0.70.7

CHURGCHURG--STRAUSS VASCULITISSTRAUSS VASCULITIS 0.40.4

TAKAYASU’S ARTERITIS TAKAYASU’S ARTERITIS 0.30.3

SISTEMIC VASCULITIS IN PIEDMONTSISTEMIC VASCULITIS IN PIEDMONT: : #/100000#/100000

5-10%

Prevalenza anti - HCV

>10%

1-5%< 1% Sconosciuta

RapportoRapporto OMS 2000OMS 2000

PATHOGENESIS of TISSUE INJURY in MIXED CRYOGLOBULIN EMIA

ROCCATELLO D, EXPERT. REV. CLIN. IMMUNOL. 20 08 ALPERS CE, CURR OP NEPHR HYPERT 2008

KidneyKidney survivalsurvival in in patientspatients withwith cryoglobulinemiccryoglobulinemic nephritisnephritis

GIIPR’ study AJKD, 2007

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

su

rviv

al p

rob

ab

ility

female male

Tarantino, KI,1995 GIIPR, AJKD, 2007

0 50 100 150 200 250months

SustainedSustained virologicalvirological responseresponse in in chronicchronic HepatitisHepatitis C and MC: C and MC: cumulative data cumulative data fromfrom MazzaroMazzaro (2005), Rossi (2003) and (2005), Rossi (2003) and KayaliKayali (2006)(2006)

Romero-Gòmez et al, Rev Esp de Enfermedades Digestiva, 2008

Drug Pros Cons

Steroids - Inhibition of the inflammatory cascade throughNFkB- Effects on mineral metab and endocrine system

- Direct or indirect ↑↑↑↑ of HCV replication in vivo and in vitro

Leflunomide -Inhibition of T lymphocyte clonal expansion- Anti-inflammatory properties- Inhibition of selected tyrosine kinases- L-analogue FK778 vasculoprotective in exp models

- Leflunomide induced necrotizingvasculitis- Liver toxicity

Cyclos A - Inhibition of IL-2 and proinflammatory cytokines- Inhibition of HCV replication in vitro and in vivo

- Vasospastic effect on macro and microcirculation-↑↑↑↑ Blood viscosity- ↑↑↑↑ PLT aggregattion ���� worseningof vascular manifestations-Nephrotoxicity , hypertension , -Nephrotoxicity , hypertension , neurotoxicity

Mycophenolate mofetil /Azathioprine

-Inhibition of T and B lymp clonal expansion-Ribavirin-like action in vitro-Prevention of arterial smooth muscle cellproliferation and proliferative arteriopathy in animal model

-GI adverse events (liver toxicity)

Anti-TNF Inhibition of TNF-αAnti-inflammatory activityTNF-α implicated in refractoriness to IFN

-↑ B cell number and activity in peripheral blood- Autoantibodies (ANA, anti nDNA)

Anti-CD20 Inhibition of B cellsEffective targeting of autoreactive clones

-↑ HCV RNA (?)- progression of HCV infection (??)

MycophenolateMycophenolate mofetilmofetil 2g/2g/daydayPegPeg IFN a 2a IFN a 2a (40 (40 kDkD)) 180 180 ugug weekweek

PegPeg IFN a 2b IFN a 2b (12 (12 kDkD)1.5 )1.5 ugug /kg week/kg week

plusplus

Fornasieri e RoccatelloManuale di terapia delle glomerulonefriti

RibavirinRibavirin 800800--1200 mg/1200 mg/diedie

Drug Pros Cons

Steroids - Inhibition of the inflammatory cascade through NFkB- Effects on mineral metab and endocrine system

- Direct or indirect ↑ of HCV replication in vivo and in vitro

Leflunomide -Inhibition of T lymphocyte clonal expansion- Anti-inflammatory properties- Inhibition of selected tyrosine kinases- L-analogue FK778 vasculoprotective in exp models

- Leflunomide induced necrotizingvasculitis- Liver toxicity

Cyclos A - Inhibition of IL-2 and proinflammatory cytokines- Inhibition of HCV replication in vitro and in vivo

- Vasospastic effect on macro and microcirculation-↑ Blood viscosity- ↑ PLT aggregattion � worsening ofvascular manifestations-Nephrotoxicity, hypertension, -Nephrotoxicity, hypertension, neurotoxicity

Mycophenolate mofetil /Azathioprine

-Inhibition of T and B lymp clonal expansion-Ribavirin-like action in vitro-Prevention of arterial smooth muscle cell proliferationand proliferative arteriopathy in animal model

-GI adverse events (liver toxicity)

Anti-TNF Inhibition of TNF- ααααAnti-inflammatory activityTNF-αααα implicated in refractoriness to IFN

-↑↑↑↑ B cell number and activity in peripheral blood- Autoantibodies (ANA, anti nDNA)

Anti-CD20 Inhibition of B cellsEffective targeting of autoreactive clones

-↑ HCV RNA (?)- progression of HCV infection (??)

Anti TNF therapy and C virus hepatitis

Parke, Arhtr & Rheum 2004

0

2

4

6

8

10

12

14

C4 mg/dl

Treatment with Abatacept of a relapsing case of MC

0

200

400

600

800

1000

1200

Proteinuria mg/24h

0

0,5

1

1,5

2

2,5

3

Serum creatinine mg/dl

Roccatello, NDT, 2004

#Rituximab is expectedto improve the subclinical lymphoproliferation and interfere with IgM monoclonal productionand cryoglobulin synthesis

Roccatello, Expert Reviews in Clinical Immunology, 2008

Rituximab in patients with HCVRituximab in patients with HCV--related cryoglobuli miarelated cryoglobulimiaStudy Year Patients

(# of nephritis)Rtx dose Other

treatmentSide effects HCV viral

loadRelapse

(#)

Sansonno 2003 20 (1) 375 mg/m2

weekly x 4 weeksS (low doses)

Septic fever (1) Responder = nonresponder

4 / 16 (> 7 months)

Zaja 2003 15 (2) 375 mg/m2

weekly x 4 weeksS (< 0.5 mg/kg/day)

Retinal thrombosis (1)

2 / 81 / 8 = 5 / 8

6 (3-6 months)

Roccatello 2004 6 (5) 375 mg/m2

weekly x 4 weeks+ 375 mg/m2

monthly x 2 months

Transient bradycardia (2)

14 unchanged

2 (> 12 months)

Quartuccio 2008 5 (5) 375 mg/m2

weekly x 4 weeksS (one case)

Transient neutropenia (1)

NR 3 (>5, > 7 and > 12 weekly x 4 weeks case) neutropenia (1) and > 12 months)

Basse 2006 7 (7) (post kidney transplant)

375 mg/m2

weekly x 2-4 weeks

CNI, MM Lethal infection (2, fungal and HSV)

NR NR

Visentini 2007 5 (1) (available for analysis)

250 mg/m2

weekly x 2 weeksS, IF, CYC, PE

2 / 5 = 3 / 5

NR

Terrier 2009 12 (4) 375 mg/m2

weekly or 1000 mg twice

S, PE in nephritic pts

Serum sickness neutropenia

Unchanged 4/12 (18±7 months)

Ibidem 2009 20 (10) 375 mg/m2

weekly or 1000 mg twice

CombinedPEG-IFN and Ribavirin

Serum sicknesshematologictoxicityflare of psoriasishepatocarcinomapoor compliance

decreased 3/20(23±12 months)

ANTIANTI--CD20 MONOCLONAL ANTIBODY THERAPY FOR TYPE II CD20 MONOCLONAL ANTIBODY THERAPY FOR TYPE II MC MC SYNDROMESYNDROME::A CONTROLLED STUDY A CONTROLLED STUDY vsvs. BEST AVAILABLE TREATMENT. BEST AVAILABLE TREATMENT

• Randomized, controlled multicentre Randomized, controlled multicentre Randomized, controlled multicentre Randomized, controlled multicentre studystudystudystudy• Study phase Study phase Study phase Study phase IIIIIIIIIIII• No sponsor No sponsor No sponsor No sponsor –––– no profit no profit no profit no profit studystudystudystudy• Duration 24 Duration 24 Duration 24 Duration 24 months (end of recruitment 31/12/2006)months (end of recruitment 31/12/2006)months (end of recruitment 31/12/2006)months (end of recruitment 31/12/2006)

• Target populationTarget populationTarget populationTarget population: : : : patients with patients with patients with patients with HCVHCVHCVHCV----related or related or related or related or ––––unrelated mixed unrelated mixed unrelated mixed unrelated mixed cryoglobulinemiacryoglobulinemiacryoglobulinemiacryoglobulinemiawith with with with skin ulcers, active skin ulcers, active skin ulcers, active skin ulcers, active glomerulonephritisglomerulonephritisglomerulonephritisglomerulonephritis or peripheral neuropathyor peripheral neuropathyor peripheral neuropathyor peripheral neuropathy

Primary end pointTo evaluate the efficacy of rituximab in comparison with the conventional, b est currently available therapeutical approaches (as chosen by exp ert clinicians)

1.Udine – S. De Vita (Co-Ordinating Centre) 2. Pordenone – C. Mazzaro3. Brescia – P. Scaini4. Salerno – S. Scarpato5. Bologna – M. Lenzi6. Novara – M. Campanini 7. Bergamo – M. Pietrogrande8. Pisa – A. Tavoni, S. Bombardieri9. Modena – M.T. Mascia, C. Ferri10. Torino – D. Roccatello11. Saronno – G. Monti, Saccardo12. Napoli – S. Migliaresi13. Napoli Cotugno – C. De Pascale14. Milano Niguarda – B. Canesi, Filippini15. Ancona – A. Gabrielli16. Firenze – A.L. Zignego, M. Matucci17. 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 r egimens in future studies

• To determine the effects on the quality of life and disease

• To determine whether rituximab may be useful to resc ue patients where best available treatment has failed

• Pharmacoeconomic assessments of rituximab therapy vs. best available treatment

GROUP A: Best conventional treatment

1) corticosteroids (maximal initial doses 1 mg/kg/day of prednisone/eqivalents) with or without preceding 6-methylprednisolone pulses (500 to 1000 mg/day for 3 consecutive days

2) azathioprine or cyclophosphamide 1- 2 mg/kg/day, with or without corticosteroids

3) Plasmapheresis with or without corticosteroids

17. Monza – P. Pioltelli

GROUP B: Rituximab (rescue from group A allowed)

Rituximab 1000 mg IV on day +1 and +15 with or without concomitant corticosteroids.Only corticosteroids are allowed as concomitant tre atment

- if already administered- if introduced concomitantly with rituximab treatment, only

low doses (≤ 0.1 mg/kg/day) allowed.

Randomization : GROUP A: 30, GROUP B: 29 Rescue therapy ” to rituximab: 22/30 (73.3%)

CMID’s open studyCMID’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 vasculitis13 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/m 2 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 m onths) after 12-51 months 5 were allocated in a maintenance protocol (1 infus ion at 3 months interval)

3 out of 18 pts developed low levels of anti-Rituxi mab abs (14-22 AU/ml, normal<12)

ArthralgiaArthralgia 15/15 15/15 improvedimproved VAS >50% VAS >50%

BM BM abab reversal or improvement :reversal or improvement :

5/5 re5/5 re-- examined ptsexamined pts

Clinical profiles of 22 patients with severe criogl obulinemiaundergoing the 4 plus 2 infusion protocol of anti-C D20 MoAb

Laboratory profiles of 12 patients with crioglobuli nemic nephritisundergoing the 4 plus 2 infusion protocol of anti-C D20 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 in fusion at 3 months interval for 1 year)• Dose prednisone at the last observation:

8 pts without maintenance treatment2 pts with 2.5 mg/d2 pts with 5 mg/d

Pre 2 m 6 m 12 24 36 48

sCr 6.8 4.6 4.9 5.0 3.5 3.5 3.7Pu g/d 3.5 0.9 0.6 0.6 0.4 0.3 0.8

TP 6.5 6.5 6.5 7.5 7.6 7.6 7.1

ESR 54 30 19 19 19 20 28

1997: 1997: nephroticnephrotic syndromesyndromefull clinical picture of MC full clinical picture of MC HCV infection (genotype 1b)HCV infection (genotype 1b)

Given Given CS, CS, cyclocyclo and PEand PE

2003: scheduled for 2003: scheduled for arteroartero --

59 yr59 yr--old man withold man with hemophiliahemophilia with NS and severe renal failure due to MCwith NS and severe renal failure due to MC

ESR 54 30 19 19 19 20 28

RF 298 24 30 249 105 95 102

IgM 397 80 60 142 69 75 96

C3 65 80 78 79 78 82 81

C4 4 11 28 16 28 24 18Cryo 4% 2% 0.5 0 1 0.5 0.5

V L 1.3 nd 1.0 0.7 0.3 0.4 0.4

ALT 26 27 16 44 43 36 38

2003: scheduled for 2003: scheduled for arteroartero --venous fistula to start dialysisvenous fistula to start dialysisCConsultation in our Unit onsultation in our Unit ((CMIDCMID))

Severe renal insufficiency Severe renal insufficiency with with nephroticnephrotic syndromesyndrome

44--drug resistant hypertensiondrug resistant hypertension44--limb sensitive motor limb sensitive motor

polyneuritispolyneuritisArthralgiaArthralgia, weakness, weaknessIatrogenic diabetes, Iatrogenic diabetes, purpurapurpura

“4 plus 2” Rituximab protocol: effects of therapy

Symptom changes in 13 patients with Symptom changes in 13 patients with polyneuropathypolyneuropathy

15 - 45% - 83%- 66%

Previous treatments:CS (11), PE (3), CYC or MMF(4), IFN (4)

0

5

10

pre 11 4 1 12

post 6 2 1 2

paresthesia burning foot RLS weakness

Cavallo and Roccatello J Neurol, 2009

CryoglobulinemicCryoglobulinemic polyneuropathypolyneuropathy in 13 in 13 ptspts: : EMG EMG changeschanges afterafter antianti--CD 20 CD 20 MoAbMoAb

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

CMAP changes

00,5

11,5

22,5

33,5

44,5

5

pre post

mV

1.50±1.321.08±0.95p<0.04

Cavallo and Roccatello J Neurol, 2009

Dario Roccatello

Research Center of Immunopathology University of Turin, Italy

Inter-regional Coordinating Center for Rare Disease s of Piedmont and Aosta ValleyNorthTurin Emergency Hospital San Giovanni Bosco,Tu rin, 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, 20 08