PATHOGENESIS of TISSUE INJURY in MIXED CRYOGLOBULINEMIA ROCCATELLO - - PowerPoint PPT Presentation

PATHOGENESIS of TISSUE INJURY in MIXED CRYOGLOBULINEMIA

ROCCATELLO D, EXPERT. REV. CLIN. IMMUNOL. 2008

Chimeric Mo Ab that binds to the B-cell surface Ag CD20, expressed at a pre-B stage and lost during the terminal differentiation into plasma cells

Rituximab

Roccatello, NDT, 2004

Rituximab in patients with HCV Rituximab in patients with HCV-

• related cryoglobulimia

related cryoglobulimia

Study Year Patients (# of nephritis) Rtx dose Other treatment Side effects HCV viral load Relapse (#) Sansonno 2003 20 (1) 375 mg/m2 weekly x 4 weeks S (low doses) Septic fever (1) Responder = nonrespond er 4 / 16 (> 7 months) Zaja 2003 15 (2) 375 mg/m2 weekly x 4 weeks S (< 0.5 mg/kg/day) Retinal thrombosis (1) 2 / 8 1 / 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 weeks S (one case) Transient neutropenia (1) NR 3 (>5, > 7 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 weeks S, IF, CYC, PE 2 / 5 = 3 / 5 NR Terrier 2009 12 (4) 375 mg/m2 weekly

• r 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

• r 1000 mg twice

Combined PEG-IFN and Ribavirin Serum sickness hematologic toxicity flare of psoriasis hepatocarcinoma poor compliance decreased 3/20(23±12 months) ROCCATELLO D, EXPERT. REV. CLIN. IMMUNOL. 2008 (modified)

criocrito

1 2 3 6 9 1 2 1 8 2 4 3 6 4 8 6 2 4 6

* * * * * *

Months %

IgG

1 2 3 6 9 1 2 1 8 2 4 3 6 4 8 6 5 10 15 20

Months

RF

1 2 3 6 9 12 18 24 36 48 60 1000 2000 3000 4000 5000 6000

** * ** ** * ** * * *

months

HCV RNA Immunoglobulin G Rheumatoid factor

Clinical profiles of 27 patients with severe crioglobulinemia undergoing the 4 plus 2 infusion protocol of anti-CD20 MoAb Cryocrit

• 4 plus 2

Rituximab protocol: effects of therapy

Symptom changes in 13 patients with polyneuropathy Symptom changes in 13 patients with polyneuropathy

5 10 15 pre 11 4 1 12 post 6 2 1 2 paresthesia burning foot RLS weakness

• 45%
• 83%
• 66%

Previous treatments: CS (11), PE (3), CYC or MMF(4), IFN (4) Cavallo and Roccatello J Neurol, 2009

Cryoglobulinemic polyneuropathy in 13 pts: Cryoglobulinemic polyneuropathy in 13 pts:

EMG changes after anti EMG changes after anti-

• CD 20 MoAb

CD 20 MoAb

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

0,5 1 1,5 2 2,5 3 3,5 4 4,5 5 pre post mV

1.50±1.32 1.08±0.95

p<0.04

* PEG-IFN alfa 2a (180 ug/ weekly) or alfa 2b (1.5 ug/kg weekly) Ribavirine 1000 mg or 1200 mg/day, according to body weight (

• r

75 kg)

*

Roccatello, Expert Reviews in Clinical Immunology, 2008

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 necrotizing

vasculitis

• 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 of

vascular manifestations

• 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 proliferation

and proliferative arteriopathy in animal model

• GI adverse events (liver toxicity)

Anti-TNF

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

• ↑ B cell number and activity in

peripheral blood

• Autoantibodies (ANA, anti nDNA)

Anti-CD20

Inhibition of B cells Effective targeting of autoreactive clones

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

CTLA4-Ig (Abatacept)

It induces anergy of activated T cells Preservation of immune responsiveness towards previously vaccinated antigens (such as tetanus and

• Limited experiences in MC

TARGETS OF RITUXIMAB

LOONEY RJ, ARTHRITIS & RHEUMATISM 2008; 58: 5-14

RAMOS-CASALS M, LUPUS. 2009 AUG;18(9):767-76.

Terrier B , Arthritis Rheum. 2010

Patients and protocol Patients and protocol

6 women, 2 male (27 6 women, 2 male (27-

• 55 year

55 year-

• old), 6 W, 2 B,
• ld), 6 W, 2 B,

with involvement of kidney (5 cases) with involvement of kidney (5 cases) severe polyarthralgia with arthritis (8) severe polyarthralgia with arthritis (8) skin lesions (6) skin lesions (6) polysierositis (3) polysierositis (3) neurologic involvement (polyneuropathy 4, CNS 2) neurologic involvement (polyneuropathy 4, CNS 2) lymphoadenopathy (4) lymphoadenopathy (4) APS (2) APS (2)

Rituximab 375 mg/mq days # 2, 8, 15, 22 Rituximab 375 mg/mq days # 2, 8, 15, 22 + 2 more doses at 1 and 2 months + 2 more doses at 1 and 2 months Cyclophosphamide 750 mg iv days # 4 e 17 Cyclophosphamide 750 mg iv days # 4 e 17 Methylprednisolone 15 mg/kg iv days # 1, 4, 8 Methylprednisolone 15 mg/kg iv days # 1, 4, 8 Prednisone 50 mg /day for 2 weeks (tapered untill 5 mg /da Prednisone 50 mg /day for 2 weeks (tapered untill 5 mg /day in two months) y in two months)

B cell depletion B cell depletion baseline 18.9% (5.6 baseline 18.9% (5.6-

• 25)

25) 3 mths 0% 3 mths 0% 6 mths 0% 6 mths 0% 12 mths 0% 12 mths 0% 18 moths 14.2% (4.6 18 moths 14.2% (4.6-

• 22)

22)

Intolerance and/or resistance to current treatment: 6 cases; Intolerance and/or resistance to current treatment: 6 cases;

• front

front-

• line

line

• therapy: 2 cases

therapy: 2 cases

Proteinuria

3 6 12 1000 2000 3000 4000 5000 6000 7000

***

*** ***

months mg/24h

0 months 12

***p<0.01

Pt/Gender (age) ethinicty SLE duration before RTX (years) Responce duration (months) at the last follow-up visit Manifestations Prevoius immunosuppressive therapy

1/F (47) B* 10 15 A,S, APS, CNS, K (LN IV) S, HCQ 2/F (27) W 10 59 A, S, F, PN, L S, HCQ, Cs 3/M (41) W 18 25 A, SNC, S, H, K (LN IV) S, HCQ, Cyp, Cs, AZA, MMF, Ig e.v, Talido 4/M (35) W 12 12 A, H, K (LN V) S, Cyp, Cs, MMF, AZA 5/F (33) B 0 (1st cycle) 3,5 (2nd cycle) 41 (1st cycle) 7 (2nd cycle) A, H, S, Se, APS S, HCQ, MMF 6/F (46) W 12 54 A, S, L, N. K (LN III) S, HCQ, Cs 7/F (36) W* 3 (1st cycle) 3 (2nd cycle 36 (1st cycle) 13(2nd cycle) A, S, Se, L, K (LN V) S 8/F (55) W 12 48 A, Se, L HCQ, S, MTX, AZA

Baseline characteristics of the 8 patients treated with RTX and clinical response duration

Pt, patient; F, female; M, male; B, black; W, white. SLE, systemic lupus erythematosus; RTX, Rituximab. A, arthritis; S, skin involvement; APS, antiphospholipd syndrome; CNS, involvement of central nervous system; K, kidney involvement; PN, peripherical neurologic manifestations; L, lymphoadenopathy; H, haematologic manifestations; Se, serositis. S, steroids; HCQ, hydroxicloroquine; Cs, cyclosporin A; Cyp, cyclophosphamide; AZA azathioprine; MMF, mycophenolate mofetil; * 1° line treatment

3 BOLI di STEROIDI 2° BOLO di RTX 1° BOLO di RTX 3° BOLO di RTX 4° BOLO di RTX 2° BOLO di CF 1° BOLO di CF

Trials: Anti-Interleukin 6 (TOCILIZUMAB) [CNTo 136, Johnson & Johnson] CTLA-Ig (ABATACEPT) [The Efficacy and Safety of Abatacept in Patients with Non Life Threatening Manifestations

• f Systemic Lupus

Erythematosus." J. T. Merrill,. Arthritis & Rheumatism 2010]

Recommended therapy of AAV according to EULAR

Disease stage Recommendend treatment Generalized (induction) Cyc oral or i.V. + GCs Cyc oral: 2 mg/kg body weight/day; i.v.: 15 mg/kg (level 1°/1B, grade A) duration: 3-6 months or 6-9 pulses according to CYCLOPS protocol GCs: prednisolone 1 mg/kg/day for 1 month, taper to < 15 mg/day within 3 months Rituximab? Alentuzumab? Severe (sCr > 500 umol/l) (induction) Standard therapy for generalized disease + plasma separation Rituximab? Alemtuzumab? Early systemic (induction) Mtx 15 mg/week s.c. or oral initially, increase to 20-25 mg/week + GC (level 1B grade B), Folic acid substitution Rituximab? Anti-TNF? Maintenance of remission Aza 2 mg/kg/day (level 1B grade A) Lef 20 mg/day (level 1B grade B) Mtx 20-25 mg/week (level 2B grade B)* duration at least 18 months Anti-TNF? Refractory, relapsing, persistent (induction) IVIG 2 g/kg for 5 days Rituximab 375 mg/m2 weekly for 4 weeks Infliximab 3-5 mg/kg i.v. one to two monthly MMF 2 g/day 15-deoxyspergualin 0.5 mg/kg/day until nadir then stop until leukocyte recovery (six cycles) ATG 2.5 mg /kg/day for 10 days (adjusted to lymphocyte count)

Modified from Holle et al, J Autoimm., 2009

Infliximab Infliximab and and adalimumab adalimumab bind bind to to all all forms forms of

• f TNF

TNF-

• α

α

Transmembrane-bound TNFa Soluble TNFa Receptor-bound TNFa

Safety and efficacy of TNF Safety and efficacy of TNFα α blockade in blockade in relapsing vasculitis relapsing vasculitis

Booth, Ann Rheum Dis 2002

Prospective Study of TNF Blockade (Infliximab) in Systemic Vascu Prospective Study of TNF Blockade (Infliximab) in Systemic Vasculitis litis

Booth, JASN 15: 717, 2004 32 pts, WG or mPA, acute

• r grumbling

88% response in 6 wks Difficult to interpret acute case group Steroid-sparing effects in the 2nd group Relapses 18% Infections 21%

Infliximab use in Wegener granulomatosis Infliximab use in Wegener granulomatosis

Study tyoe Author # of pts and diseases Infliximab regimen Other immunosuppression Pts outcome Case series Booth et al 3 WG, 3 MPA 200mg every month x 3 months CS, others not reported 5 in remission, and 1 relapsed (unclear if patient had WG or MPA) Bartolucci et al 7 WG (as well as 2 RAAV, 1 MC) 5 mg/kg on days 1,14, 42, and then every 8 weeks CS maintained

• r

reduced,

• ther

immunosuppressants reintroduced on day 42 4 in CR and 3 in PR at 6 months. 2 flared while still receiving infliximab Lamprecht et al 6 WG 3 mg/kg (2 patients) or 5 mg/kg (4 patients) on day 1, 14, 42, and every 4 weeks until remission CTX and CS Remission induced for at least 6 months in 5, infliximab stopped in 1 due to suspicion of serious infection Josselin et al 10 WG (as well as 1 MPA, 3 RAAV, 1 MC; 9 were previously described ; all with refractory disease 5 mg/kg on day 0, 15, 45, and then every 46 weeks depending

• n clinical response

CS and others, including MTX, AZA, and CTX depending on the patient 11 entered remission and 4 with responses by day 45, but 10 subsequently relapsed (median 13 months) 7 after stopping infliximab, 3 while receiving infliximab Prospective

• pen label

trials Booth et al 32 WG (subgroup I: 16 with either first presentation or relapse; subgroup II: 16 with persistent disease) 5 mg/kg at 0, 2, 6, and 10 weeks CTX and CS 14 in each subgroup (88%) achieved remission by 14 weeks. 2 deaths (pulmonary vasculitis, bronchopneumonia), 6 additional infections. Relapse occurred in 5 of the 28 initial responders (18%) at a mean of 27 weeks

Modified from Chung et al, Curr Op Rheum, 2009

Prospective study of TNF Prospective study of TNF

• blockade with Adalimumab in ANCA

blockade with Adalimumab in ANCA associated systemic vasculitis with renal involvement associated systemic vasculitis with renal involvement

Clinical trials of B-cell depletion with Rituximab in ANCA-associated vasculitis

Study # Pts (# nephr.s) Dose of RTX Concomitant therapies Remission B-cell depletion ANCA serology Relapse (months) Aries et al. 8 (2) 375 mg/m2/week × 4 CYC, MMF, MTX, GC 2/8 CR 1/8 PR 8/8 0/8 became negative NR Eriksson 9 (7) 500 mg/week × 4 MMF, AZA, CYC, GC 8/9 CR 1/9 PR 9/9 0/7 became negative 2 (12, 13) Keogh et al. 11 (4) 375 mg/m2/week × 4 PLEX, GC 10/11 CR 1/11 PR 11/11 8/11 became negative 2 (7, 12) Keogh et al. 10 (7) 375 mg/m2/week × 4 GC 10/10 CR 10/10 6/10 became negative 1 (9) Omdal et al. 3 (3) 375 mg/m2/week × 4 NR 3/3 CR 3/3 0/3 became negative 3/3 (8, 13, 15) Smith et al. 11 (6) 375 mg/m2/week × 4 MMF, GC 9/11 CR 1/11 PR 11/11 6/10 became negative 6/10 (median 16.5) Stasi et al. 10 (6) 375 mg/m2/week × 4 GC 9/10 CR 1/10 PR 10/10 8/10 became negative 3/10 (12, 16, 24) Henes et al. 6 375 mg/m2/week × 4 Leflunomide, GC 5/6 CR 1/6 PR 6/6 4/4 became negative 3/6 (3, 3, 18) Brihaye et al. 8 375 mg/m2/week × 4 MTX/AZA, GC 3/8 CR 3/8 PR 2/8 NR 8/8 4/6 became negative 1/8 (12) Roccatello et al. 7 375 mg/m2/week × 4, Various 5/7 CR 2/7 PR 7/7 5/6 became negative 2/7 (17, 30) Seo et al. 8 (0) 375 mg/m2/week × 4 8/8 CR 5/8 Lovric et al. 15 (5) 375 mg/m2/week × 4 AZA, MMF, CYC, ciclosporin, GC 6/15 CR 8/15 PR 1/15 NR 15/15 11/13 became negative 3/14 (7, 11, 14) Jones 2009 63 Various Various 75% CR 33% PR 2% NR 100% Significant falls Av.ge time to relapse 12 m.ths

Modified from Jayne , APMIS, 2009

Fervenza FC. Nephron Clin Pract. 2011

Roccatello et al, submitted, 2011

11patients

• 4 affected by idiopathic systemic

microscopic polyangiitis,

• 5 by Wegener's granulomatosis,
• 2 by Churg Strauss syndrome)

Intolerant or refractory to conventional therapies including cyclophosphamide were enrolled. All patients received Rituximab (4+2) as a rescue therapy and were followed for 30 54 months

Erkan D, Nat Clin Pract Rheumatol. 2009;5(3:160-70)

PROPOSED MECHANISM OF APL-MEDIATED THROMBOSIS

Sciascia et al, Lupus 2011, in press

Main clinical and laboratory variables at baseline (week 0), at the end

• f the treatment period (week 4), and every 4 weeks up to study end

Remuzzi G, Lancet 2002

Proteinuria reduction after Rituximab Therapy in two Cohorts of idiopatic membranous nephropathy patients with a baseline tubulo-interstitial score<1.7 or > 1.7 Ruggenenti P, Expert Opin Pharmacother. 2007

Ruggenenti P, Clin J Am Soc Nephrol 2008 Representative transmission electron micrographs of the capillary wall in a patient before (A, B) and after rituximab therapy (C, D)

Fervenza FC, Kidney Int. 2008 Time course of urinary protein excretion (g per 24 h) in individual patients with IMN from entry into the study (baseline) to end of study (month 12)

STUDY N HISTOLOGY AGE AT RTX START (YRS) IMMUNOSUPP RESSION RTX DOSE RESP FOW-UP

(MONTHS)

RELAPSE Benz et al. 2004 1 FSGS 15 Pred, CyA, Tac, CP 375 mg/m² weekly 4× CRa 12 No Gilbert et al. 2006 1 MCNS 15 Pred, Tac, CyA, levamisol, CP 375 mg/m² weekly 4× CRa 16 After 9 months responding to RTX Hofstra et al. 2007 1 MCNS 13 Pred, CyA, MMF, CP 1 g every

• ther week

2× CRa 4 No Smith et al. 2007 1 MCNS 13 Pred, Tac, MMF 375 mg/m² 1× CRa 6 No Peters et al. 2008 1 MCNS 20 Pred, MMF, Tac 1 g 2× PRb 16 After 13 months resistant to RTX Guignois et

• al. 2008

22 MCNS 16, FSGS 3 14.3 (range: 6.322.1) Pred, CyA, Tac, MMF, CP 375 mg/m² weekly 2 4×; additional courses if CD19<1% CR 15/15a CR 3/7b 9.5 (range: 639) In 3/15 after 713 months responding to RTX RITUXIMAB IN CHILDREN WITH STEROID- OR CYCLOSPORINE-DEPENDENT NEPHROTIC SYNDROME

HAFFNER D, PED NEPHROL 2009; 24(8): 1433-1438

PRECAUTIONS FOR THE USE OF RITUXIMAB IN AUTOIMMUNE DISEASES

• 1. Patients informed about the potential effects of rituximab on immunocompetency

Decreased response to immunization Possible increased rate of infection Possible neutropenia and hypogammaglobulinemia Possible reactivation of infections, including HBV and JC virus

• 2. Screening prior to use of rituximab

History of severe, unusual, or frequent infections History of high risk for HIV or TB Routine laboratory tests: complete blood cell count with differential, metabolic survey, and urinalysis Serology for hepatitis B (HBsAg, anti-HBs, anti-HBc) Serology for VZV for patients who have not had chickenpox or been immunized should be consided

• 3. Immunization

Avoid live virus vaccines If possible, complete immunizations 1 month prior to starting rituximab Administer recommended vaccines, including yearly influenza, but as late as possible after the last dose

LOONEY RJ, ARTHRITIS & RHEUMATISM 2008; 58: 5-14

• 4. At the time of any serious or unusual infection, evaluate neutrophil count and IgG level

For IgG levels below normal, check IgG antibody titers (antitetanus, antipneumococcal polysaccharide); if IgG antibodies are low, response to immunization should be evaluated When to start IVIG and/or prophylactic antibiotics will depend on severity of hypogammaglobulinemia, IgG antibody titers, frequency and type of infections, comorbid conditions, concomitant medications, and patient age Neutropenia secondary to rituximab responds well to administration of G-CSF

• 5. Prophylaxis

Influenza: for patients who are unlikely to respond to immunization, consider antiviral chemotherapy during outbreak HBV: although the risk of reactivation after treatment with rituximab alone is not well established, risk is clearly dependent on the status of the infection before treatment, comorbidities, concomitant medications, and the primary diagnosis; for patients at high risk for reactivation, prophylaxis with lamovudine should be considered VZV: post-exposure prophylaxis should be considered in seronegative patients who have additional factors putting them at high risk

• 6. Early recognition of infections and treatment

Patients and caregivers need to be educated about the importance of early recognition of infections, and systems need to be in place to ensure rapid response by health professionals In addition to a general admonition to call their health care provider if they have questions or if they are ill, patients should be specifically instructed to call if they have shaking chills, fever >101°F, respiratory illness other than a mild cold, symptoms of a urinary infection, or if they think they may be developing the flu.

LOONEY RJ, ARTHRITIS & RHEUMATISM 2008; 58: 5-14

Medical Doctors Daniela Rossi Mirella Alpa Simone Baldovino Carla Naretto Savino Sciascia Alessandra Russo Rita La Grotta Biologists Elisa Menegatti Daniela Berardi Margherita Messina Debora Di Simone Laura Solfietti Consultants Vittorio Modena (Rheumatology) Roberto Cavallo (Neurology) Valerio Veglio (Infectious Diseases)