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

Rituximab 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

Roccatello, NDT, 2004

Rituximab in patients with HCV- -related cryoglobulimia related cryoglobulimia Rituximab in patients with HCV Study Year Patients Rtx dose Other Side effects HCV viral Relapse (#) (# of nephritis) treatment load 375 mg/m 2 weekly Sansonno 2003 20 (1) S (low doses) Septic fever (1) Responder 4 / 16 x 4 weeks = (> 7 months) nonrespond er 375 mg/m 2 weekly Zaja 2003 15 (2) S (< 0.5 Retinal thrombosis 2 / 8 6 (3-6 x 4 weeks mg/kg/day) (1) 1 / 8 months) = 5 / 8 375 mg/m 2 weekly Roccatello 2004 6 (5) Transient 14 2 x 4 weeks bradycardia (2) unchanged (> 12 + 375 mg/m 2 months) monthly x 2 months 375 mg/m 2 weekly Quartuccio 2008 5 (5) S (one case) Transient NR 3 ( >5, > 7 and x 4 weeks neutropenia (1) > 12 months) 375 mg/m 2 weekly Basse 2006 7 (7) (post kidney CNI, MM Lethal infection (2, NR NR transplant) x 2-4 weeks fungal and HSV) 250 mg/m 2 weekly Visentini 2007 5 (1) (available S, IF, CYC, PE 2 / 5 NR for analysis) x 2 weeks = 3 / 5 375 mg/m 2 weekly Terrier 2009 12 (4) S, PE in Serum sickness Unchanged 4/12 (18 ± 7 or 1000 mg twice nephritic pts neutropenia months) 375 mg/m 2 weekly Ibidem 2009 20 (10) Combined Serum sickness decreased 3/20(23 ± 12 or 1000 mg twice PEG-IFN and hematologic months) Ribavirin toxicity flare of psoriasis hepatocarcinoma poor compliance ROCCATELLO D, EXPERT. REV. CLIN. IMMUNOL. 2008 (modified)

Clinical profiles of 27 patients with severe crioglobulinemia undergoing the 4 plus 2 infusion protocol of anti-CD20 MoAb HCV RNA Immunoglobulin G IgG 20 15 10 5 0 0 1 2 3 6 9 2 8 4 6 8 0 1 1 2 3 4 6 Months criocrito 6 Cryocrit Rheumatoid factor RF 6000 * 4 5000 % 4000 * * * * 3000 2 * * ** ** * * ** 2000 ** * * 1000 0 0 0 1 2 3 6 9 2 8 4 6 8 0 1 1 2 3 4 6 0 1 2 3 6 9 12 18 24 36 48 60 Months months

� 4 plus 2 � Rituximab protocol: effects of therapy

Symptom changes in 13 patients with polyneuropathy 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 11 4 1 12 pre 6 2 1 2 post Cavallo and Roccatello J Neurol, 2009

Cryoglobulinemic polyneuropathy in 13 pts: Cryoglobulinemic polyneuropathy in 13 pts: EMG changes after anti- -CD 20 MoAb CD 20 MoAb EMG changes after anti PRE POST p 1.08 ± 0.95 1.50 ± 1.32 SPE ampl mV 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 µ V 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 2,5 mV 2 1,5 1 0,5 0 pre post 1.08±0.95 1.50±1.32 p<0.04

Roccatello, Expert Reviews in Clinical Immunology, 2008 * * 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 ( � or � 75 kg)

Drug Pros Cons - Direct or indirect ↑ of HCV replication Steroids - Inhibition of the inflammatory cascade through NFkB - Effects on mineral metab and endocrine system in vivo and in vitro - Inhibition of T lymphocyte clonal expansion - Leflunomide induced necrotizing Leflunomide - 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 Mycophenolate - Inhibition of T and B lymp clonal expansion - GI adverse events (liver toxicity) - Ribavirin-like action in vitro mofetil / -Prevention of arterial smooth muscle cell proliferation Azathioprine and proliferative arteriopathy in animal model Inhibition of TNF- α - ↑ B cell number and activity in Anti-TNF Anti-inflammatory activity peripheral blood TNF- α implicated in refractoriness to IFN - Autoantibodies (ANA, anti nDNA) - ↑ HCV RNA (?) Anti-CD20 Inhibition of B cells Effective targeting of autoreactive clones - progression of HCV infection (??) CTLA4-Ig It induces anergy of activated T cells - Limited experiences in MC Preservation of immune responsiveness towards (Abatacept) previously vaccinated antigens (such as tetanus and

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- -55 year 55 year- -old), 6 W, 2 B, old), 6 W, 2 B, 6 women, 2 male (27 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 /day in two months) y in two months) Prednisone 50 mg /day for 2 weeks (tapered untill 5 mg /da Intolerance and/or resistance to current treatment: 6 cases; Intolerance and/or resistance to current treatment: 6 cases; � � � line � front- -line therapy: 2 cases front therapy: 2 cases B cell depletion B cell depletion baseline 18.9% (5.6- -25) 25) baseline 18.9% (5.6 3 mths 0% 3 mths 0% 6 mths 0% 6 mths 0% 12 mths 0% 12 mths 0% 18 moths 14.2% (4.6- -22) 22) 18 moths 14.2% (4.6

Proteinuria 7000 6000 ***p<0.01 5000 4000 mg/24h 3000 *** 2000 *** 1000 *** 0 0 3 6 12 months 0 months 12

Baseline characteristics of the 8 patients treated with RTX and clinical response duration Pt/Gender (age) SLE duration Responce duration Manifestations Prevoius ethinicty before RTX (years) (months) at the last immunosuppressive follow-up visit therapy 1/F (47) B* 10 15 A,S, APS, CNS, K (LN S, HCQ IV) 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 S, HCQ, Cyp, Cs, AZA, MMF, IV) 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) 41 (1st cycle) A, H, S, Se, APS S, HCQ, MMF 3,5 (2nd cycle) 7 (2nd cycle) 6/F (46) W 12 54 A, S, L, N. K (LN III) S, HCQ, Cs 7/F (36) W* 3 (1st cycle) 36 (1st cycle) A, S, Se, L, K (LN V) S 3 (2nd cycle 13(2nd cycle) 8/F (55) W 12 48 A, Se, L HCQ, S, MTX, AZA 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

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

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