Nouveautés dans le traitement des microangiopathies thrombotiques: Place de l’eculizumab Chantal Loirat Service de Néphrologie Pédiatrique, Hôpital Robert Debré, Paris CREUF,Chartres, 2 Octobre 2014 The various forms of TMAs according to etiology / pathophysiology HELLP syndrome HUS with coexisting disease / condition • Bone marrow transplantation Solid organ transplantation Malignancy/ cancer chemotherapy Autoimmune disease (SLE, antiphospholipids syndrome, scleroderma, dermatomyositis) Drugs (calcineurin inhibitors, sirolimus and anti-VEGF agents) • Malignant hypertension HIV infection Cocaïne Thrombotic thrombocytopenic purpura ADAMTS13 < 10% Congenital ADAMTS13 deficiency Infection-induced HUS • S pneumoniae STEC Cbl-C deficiency-HUS TMA Alternative complement pathway dysregulation-HUS* Mutations in CFH, CFI, MCP, C3, CFB, THBD AntiADAMTS13 antibodies Unexplained HUS Anti-FH antibodies HUS with DGKE mutation * Including pregnancy- HUS Treatment of aHUS up to 2009 Pre-eculizumab era Plasma exchange (PE) or plasma infusion (PI) Poor prognosis in aHUS patients in the pre-eculizumab era • Mortality higher in children than in adults • High risk of rapid progression to end stage renal disease at all ages but higher in adults than in children Overall renal survival (%) 100 Pediatric onset, n=89 Adult onset, n=125 80 French cohort, 214 patients Mortality: 8% in children, 2% in adults 60 End stage renal failure or death 40 20 p<0.0001 0 0 5 10 Years 15 20 Number of aHUS patients at risk Paediatric onset 89 34 17 13 6 Adult onset 18 7 2 0 125 Children Adults First episode 16% 46% 1-year follow-up 29% 56% 5-year follow-up 36% 64% 39% of children and 80% of adults received PE/PI at first episode Fremeaux-Bacchi et al. Clin J Am Soc Nephrol 2013 Eculizumab blocks terminal complement Terminal Proximal Complement cascade2,3 C3 C3a C3b C5 C5a Eculizumab • Eculizumab binds with high affinity to C51,2 • Terminal complement – C5a and C5b-9 formation blocked1,2 • Proximal functions of complement remain intact1,2 – Weak anaphylatoxin2,4 C5b C5b-9 – Immune complex clearance2 – Microbial opsonisation2 Eculizumab Prescribing Information. Alexion Pharmaceuticvals, Inc.; 2013 1. Eculizumab Summary of Product Characteristics. Alexion Europe SAS, 2012; 2. Rother RP et al. Nat Biotechnol 2007;25:1256–64 3. Walport MJ. N Engl J Med 2001;344:1058–66; 4. Figueroa JE, Densen P. Clin Microbiol Rev 1991;4:359–95 Efficacy of eculizumab in aHUS 180 patients (124 adults, 56 children) 100 treated within protocols, 80 outside of protocols • aHUS in native kidneys, n=124 • Post-transplant recurrence, n=43 • Prophylaxis of post-transplant recurrence, n=13 Data from case reports Patients treated with eculizumab outside of protocols Eculizumab to treat aHUS in native kidneys in adult patients Historical controls treated by PE (between 2004 and 2008) had a poorer outcome compared to patients treated with eculizumab since 2009 French cohort Features at presentation Kidney disease outcome Eculizumab (n=18) p Female sex 28 (68) 13 (72) 0.8 Age, years 34 (1885) 27 (1953) 0.4 Complement gene mutations 28 (68) 13 (72) 0.2 Haemodialysis 29 (71) 12 (63) 0.8 Platelet count >150 109/L 6/36 (17) 4 (21) 0.6 Plasma exchange 24/38 (63) 15 (83) 0.1 80 Percentage of patients Controls (n=41) p=0.04 63% 60 p=0.02 46% 40 25% 20 0 Fakhouri F et al. Am J Kidney Dis 2014 PE Eculizumab 17% ESRD within 3 months of HUS ESRD at 1 year Eculizumab efficacy to rescue renal function: the earlier, the better ! Median duration from HUS onset and eculizumab initiation: 6 days (1–60) eGFR at last follow-up 9.5 months (4–22) >60 mL/min/1.73m2 <60 mL/min/1.73m2 Haemodialysis Eculizumab initiation Bars: PE treatment duration Patient Eculizumab ongoing at 3 m 2 3 10 12 1 15 11 18 19 9 4 7 14 8 5 16 13 17 6 + + + + + + + + + + + + + + + + 0 10 20 30 40 50 Time after aHUS onset (days) 60 Haemodialysis Median Screatinine (non-dialysed patients) µmol/L (range) At eculizumab initiation At last follow-up 47% 16% 251 (145–655) 89 (55–340) Patients who received eculizumab within 6 days of onset (n=10) tended to have lower Screatinine at last follow-up compared to those treated after 6 days of onset (n=9) (p=0.5) 90 Fakhouri et al. Am J Kidney Dis 2014 Eculizumab was successful to treat aHUS on native kidneys in 19 children, including 14 who failed to improve under PE/PI Median age: 1.5 years (11 days -11 y) (≤ 1 year in 9) Complement mutation identified 15/18 (83%) PE/PI resistant 12, dependent 2;1st line Eculizumab 5 Median duration from current HUS onset to eculizumab initiation (range) 19 days (<1- 225) Hematological remission under eculizumab 19 (100%) Dialysis required at baseline, n (%) Dialysis required at last follow-up, n (%) Median Screatinine, µmol/L (range) At baseline (6 non-dialysed patients) At last follow-up (18 non-dialysed patients) Screatinine <50 µmol/L at last follow-up, n (%) (18 non-dialysed patients) Median follow-up, months ( range) 13 (68) 1 (6) 99 (20-264) 43 (20-90) 13 (72) 13 (2.5-42) Zuber et al, Nat Rev Nephrol 2012 (pooled analysis of 7 cases reported in 2009-2012); Vilalta et al, Pediatr Nephrol 2012 ; Cayci et al, Pediatr Nephrol 2012 ; Giordano et al, Pediatrics 2012; Besbas et al, Pediatr Nephrol 2012; Gulleroglu et al, Pediatr Nephrol 2013; Malina et al, Pediatrics 2013; Gilbert et al, Pediatr Nephrol 2013; Vaisbich et al, J Bras Nefrol 2013; Hu et al, Pediatr Nephrol 2013; Christmann et al, Pediatrics 2014; Michaux et al, Pediatr Nephrol 2014 Eculizumab for extra-renal manifestations of thrombotic microangiopathy Eculizumab rescues distal ischaemic manifestations of aHUS Ariceta et al. AJKD 2012 28-day-old child, 3.6 kg • No mutation • Leg skin necrosis, intestinal perforation • Eculizumab remission within 3 days • Recovery of skin lesions and renal function • Follow-up 18 months, Screatinine 23 µmol/L, remission Malina et al. Pediatrics 2013 2-month-old child • ESRD, multiple relapses despite plasma infusions • C3 gain of function mutation • At 9 months, acute ischaemia of feet and hands, resistant to PE • Eculizumab immediate reversal of distal ischaemia • Follow-up 22 months, remission Right hand Left hand Day 5 Day 8 Day 11 Day 120 Eculizumab Day 21, then every 3 weeks Day 360 Ulcerative-necrotic skin lesions in aHUS Recovery under eculizumab Before eculizumab After eculizumab 19-year-old man (no mutation) • On dialysis • Skin lesions for 10 months + thrombocytopenia • Skin biopsy: TMA lesions • Recovery after one dose of eculizumab 19-year-old man (factor H mutation) • Functioning kidney graft under PE/PI • Skin lesions for several months • Switch from PE to eculizumab • Improvement of skin lesions after first dose with further complete reversal Ardissino G et al. Am J Kidney Dis 2013 Eculizumab appears efficient to rescue CNS involvement in aHUS 9 case reports (PE resistant :7; 1st line eculizumab:2) Author Age (years) Neurological manifestations MRI Time to eculizumab initiation (days) Outcome Pu 2013 85 Seizures, mental disturbances ND 18 Improvement over 2 weeks Full recovery Salem 2012 66 Seizures, mental disturbances, coma Focal lesions 3 Awoke and verbal after 8 weeks Nearly complete recovery Beye 2013 64 Status epilepticus, focal defects, nystagmus, confusion Normal CTS 9 Improvement within 24 hours Full recovery Ohanian 2011 50 Seizures, unresponsiveness Right parietal infarction 3 Improvement after 1 week Full recovery Chaudhary 2014 20 Seizures, lethargy ND 42 Slow initial improvement (subtherapeutic doses) Full recovery after dose increase Gulleroglu 2013 11 Seizures, visual loss, confusion Bilateral occipital and posterior parietal hyperdensities/oedema 2 Improvement after 4 days Full recovery after 1 month Gulleroglu 2013 6 Seizures, visual loss Bilateral occipital and posterior parietal hyperdensities <1 Normal vision within 24 hours Full recovery after 5 weeks Diamante Chiodini 2014 8 Confusion, delirium Persistant psychocognitive impairment under PE/PI Multifocal hypersignals 20 Full recovery within 2 weeks 1.7 Seizures, hemiparesis, lethargy, unresponsiveness Subtle bilateral anomalies <1 Improvement over 3 weeks Full recovery with residual weakness of right thumb/index Hu 2013 Eculizumab appears efficient to rescue ischemic cardiomyopathy in aHUS Author Age (yrs) Cardiac manifestations Response to PE Time to eculizumab initiation (days) 80 Vilalta 2012 1.5 Day 60 under PE: Dilated cardiomyopathy Cardiorespiratory arrest Resistance to PE Hu 2013 1.6 Day 0: Dilated cardiomyopathy EF 30% Cardiovascular instability, hypotension First line eculizumab Day 20 under PE: Dilated cardiomyopathy EF 37% Repolarization anomalies High troponine level Resistance to daily PE + plasma intolerance Diamante Chiodini 2014 8 < 12 hours 37 Outcome Improvement of cardiac function over 6 days. Subsequent full recovery. Recovery over 9 days Normalization of LV volume and function over 2 weeks Eculizumab in aHUS Prospective trials in adult / adolescent patients under prior plasmatherapy Results at 26 and 64 weeks Legendre CM et al. N Engl J Med 2013 Results at 2 years Greenbaum L et al. ASH; Atlanta, USA; 8–11 Dec 2012. Abstract and Poster 2084 Legendre CM et al. WCN; Hong Kong; 31 May–4 Jun 2013. Abstract and Poster MO065 Prospective trials of eculizumab C08-002: 17 patients with progressing TMA (≥4 PE/PI in the week prior to screening) C08-003: 20 patients with a long duration of aHUS and chronic kidney disease under long-term PE/PI 1200 mg every 2 weeks through 26 weeks C08-002: no OP 900 mg/week C08-003: 8-week OP Wk 1 Plasma exchange/ infusion removed OP, observation period Wk 5 All patients offered to continue into long-term extension study: 86% (32/37) continued eculizumab treatment, median duration 100 weeks (002) and 114 weeks (003) Prospective trials Patients’ baseline characteristics C08-002 Progressing TMA (N=17) C08-003 Long disease duration (N=20) 28 (17–68) 28 (13–63) Identified complement mutations or anti-CFH Ab, % 76 70 Prior kidney transplant, % 41 40 Median time from onset of current aHUS manifestation to screening, months (range) 0.8 (0.2-3.7) 8.6 (1.2-45.0) Median platelet count, x109/L (range) 118 (62-161) 218 (105-421) 22.9 (14.5) 30.8 (19.0) 35 10 6 (0-7)* 1.5 (1-3) Median age, years (range) Mean baseline eGFR, mL/min/1.73 m2 (SD) Dialysis at baseline, % Median number of PE/PI 7 days prior to first eculizumab dose (range) * One patient had no PE/PI 7 days prior to eculizumab due to severe allergic reaction after 2 sessions Patients with progressing TMA under PE/PI C08-002 Hematologic normalization after the switch to eculizumab Mean increase 73x109/L p<0.001 Significant increase in platelet count as early as day 7 (p=0.027) 53% of patients with abnormal platelet count at baseline had normal platelet count at day 7 Median delay before 1st normal value Platelets (≥150X109/L): 7days (1-218) LDH: 14 days (0-56) C08-002 Patients with progressing TMA under PE/PI Eculizumab allowed rapid improvement in eGFR, that was sustained under ongoing treatment over 2 years p<0.001 Mean increase in eGFR from baseline, mL/min/1.73m2 (SD) • Week 26: 33.1 (33.3); p=0.001 • Week 100: 36.6 (29.8); p=0.006 p=NS p<0.001 p=0.03 1 2 3 eGFR mean change from baseline Slope Mean eGFR, mL/min/1.73 m2 (SD) •Baseline: 22.9 (14.5) •Week 26: 55.9 (40.2) •Week 100: 55.8 (30.0) 4/5 patients (80%) eliminated the need for dialysis and remained dialysis free through week 100 At median 100 weeks, only 2*/17 patients (12%) on dialysis *One patient started dialysis at week 64 (baseline eGFR 19 mL/min/1.73m2 ) Patients 5 5 6 17 1716151515151515151315 15 14 13 12 11 12 11 13 12 13 13 12 9 12 12 10 9 9 9 Shorter time from clinical manifestation predicted greater eGFR gain (p=0.009) C08-003 Patients with long duration of aHUS Eculizumab allowed rapid improvement in eGFR, that was sustained under ongoing treatment over 2 years p=0.007 p=NS p=0.001 p=NS Mean increase in eGFR from baseline, mL/min/1.73 m2 (95% CI) •Week 26: 6.1 (3.3–8.8); p=0.0001 •Week 104: 7.2 (0.76–13.6); p<0.05 Slope 1 2 3 Mean eGFR, mL/min/1.73 m2 (SD) • Baseline: 30.8 (18.9) • Week 104: 40.1 (17.5) 2 patients on dialysis at baseline remained on dialysis at week 104 (10%). No patient not on dialysis at baseline initiated dialysis Patients 20 20 20 20 20 19 17 18 17 18 18 13 17 17 15 Shorter time from clinical manifestation predicted greater eGFR gain (p<0.0001) 21 C08-002 and C08-003 Conclusions These data suggest early switch to eculizumab or eculizumab as first line therapy may be warranted to offer patients the best chance of full recovery of renal function The new prospective trials in pediatric and adult patients with aHUS, with or without prior plasmatherapy Presented at Am Soc Nephrol, Atlanta USA; 5–9 Nov 2013 Paediatric trial: Greenbaum L et al. Abstract 5579 and Poster SA-PO849 Adult trial: Fakhouri F et al. Abstract 5593 and Presentation FR-OR057 Early/first line eculizumab initiation as adopted by pediatricians may offer the best chance of full renal recovery C10-003, children, n=22 Median delay before eculizumab: 6 d (<1 d–4.3 m) 12/22 (55%) without prior PE Mean eGFR at baseline: 33±30 mL/min/1.73 m2 eGFR mean increase at week 27 64 mL/min/1.73m2 • 11/22 (50%) on dialysis at baseline • 9/11(82%) discontinued dialysis • 0/11 not on dialysis at baseline initiated dialysis • 2/22 (9%) on dialysis at 6 months C10-004, adults, n=41 Median delay before eculizumab: 15 d (<1 d–19.2 m) 6/41 (15%) without prior PE Mean eGFR at baseline: 17±12 mL/min/1.73m2 eGFR mean increase at week 26 29.3 mL/min/1.73m2 • 24/41 (58%) on dialysis at baseline • 20/24 (83%) discontinued dialysis • 4/17 (24%) not on dialysis at baseline initiated dialysis (2 short course) • 6/41 (15%) on dialysis at 6 months In practice Proposals from 1. The French Study Group for aHUS and C3G (Zuber et al, Nat Rev Nephrol 2012) Coordinated by V Fremeaux-Bacchi, F Fakhouri, J Zuber and C Loirat Working group: M Buchler, S Burtey, D Chauveau, Y Delmas, G Deschenes, A Garnier, A Karras, B Knebelmann, Y Lebranchu, B Legallicier, C Legendre, M Lequintrec, B Moulin, P Niaudet, C Pouteil-Noble, F Provot, B Ranchin, E Rondeau 2. HUS International (Loirat et al, Pediatr Nephrol 2014, in press) Is it necessary to know whether the patient with a first episode of aHUS has a complement anomaly and which one it is before starting eculizumab? NO Eculizumab is efficacious and thus can be administered to patients with aHUS and Any type of complement mutation No mutation identified (However, uncertain efficacy in patients with DGKE mutation) However Obtain anti-factor H antibody results rapidly Genetic screening is recommended for further decisions First episode of aHUS Which first-line treatment? PE or eculizumab? In children Eculizumab first-line, within 24 hours, to avoid PE/central catheter In adults Diagnosis of aHUS needs confirmation Diagnosis of aHUS unequivocal (e.g. eliminate cancer, TTP…) (e.g. familial history, relapse of HUS, post-transplant recurrence) PE first Switch to eculizumab if • plasma resistance* • relapse at PE tapering or cessation Eculizumab first-line, within 24 hours * Definition of plasma resistance: no constant upward trend of platelet count ( particularly if still < 150x109/l) or no constant downward trend of LDH (particularly if still >ULN) or no significant decrease of Screatinine (at a minimum ≥25% decrease) after 5 daily PE Conclusion • Eculizumab offers aHUS patients the best chance of sustained remission and full rescue of renal function if started early • Prospective studies are now required to establish whether treatment withdrawal is safe, in whom and when. Prevention of meningococcal infections Risk of invasive meningococcal infection in PNH patients under eculizumab 0.5/year /100 patients One aHUS patient out of approximately 65 outside of protocoles* and 2 patients out of 100 within trials** had invasive meningococcal infection (favourable outcome). Anti-meningococcal vaccine mandatory Quadrivalent conjugate vaccines (anti-A, C, W, Y) (Menveo® (≥2y) or Nimenrix® (≥1y)) should be used Anti-B vaccine available in France since Dec 11, 2013 and recommended. However, further data on its clinical efficacy and duration of protection are still pending. The bactericidal activity of immune response after vaccination is uncertain in patients with complement deficiency and/or receiving eculizumab and/or immunosuppressive therapy. This justifies immediate antibioprophylaxis allowing prompt initiation of eculizumab. Repeated information to the patient, his family and family doctor Information card Continuous antibioprophylaxis obligatory in some countries (France, UK) Oral methyl penicillin (full dose, twice daily) To our opinion, should be recommended for children *Struijik et al, AJT 2013 ; ** Fakhouri et al, ASN, Nov 5-10 2013, FR-OR057, Atlanta Complications of plasma exchanges in children with aHUS 71 children from 11 European countries and North America with aHUS between 1 July 2009 to 31 Dec 2010 Audit of the 2009 Guidelines for initial therapy of aHUS (Ariceta et al, Pediatr Nephrol 2009) Central venous catheters n = 51 • 17 complications in 16 children (31%) • Infection n= 8, thrombosis n=3, limb ischemia n=1, haemorrhage n= 2, chylothorax n= 1. Plasma hypersensitivity n=8, leading to withdrawal of therapy in 1 Johnson S et al, for the European Paediatric Study Group for HUS, Pediatr Nephrol 2014 Eculizumab treatment Which duration? Outcome after eculizumab discontinuation in 20 patients Relapse of HUS after eculizumab withdrawal Delay between eculizumab withdrawal and relapse (m) Screatinine at relapse (µmol/l) Screatinine at last f-up (µmol/l) F-up after eculizumab withdrawal or re-initiation (m) Age (y) Complement anomaly Eculizumab treatment duration until withdrawal 20 (PP) CFH 9m Yes 6 Normal 451 (3 weeks dialysis ) ND (off dialysis) ND 26 (PP) CFH + CFI 18 m No NA NA 70 18 4.3 CFH 5.5 m Yes 1.5 71 248 71 25 37.7 CFH 14 m Yes 0.9 124203 115 10 11 CFI 2w No NA NA 48 11 52.7 CFI 1.5 m No NA NA 88.5 22 34.8 CFI 11.5 m No NA NA 221 10 2.6 CFI 5.5 m No NA NA 35 15.5 6 MCP 5w No NA NA Normal 9 22 MCP 8w No NA NA 84 11 5.4 MCP 0.5 m No NA NA 44 13.5 49 Anti-CFH 8w No NA NA 88.5 10 19.1 Anti-CFH 5.5 m No NA NA 106 14.5 13.3 Anti-CFH 2.5 m No NA NA 53 8.5 10.9 Anti-CFH (high titer) 0.4 m Yes 1 62 301 53 5 85 None 3m No NA NA Normal 12 64 ND 13 w No NA NA 60 6 32 (PP) None 6m No NA NA 88.5 12 20 None 9m No NA NA 70.8 ≈9 1.3 None 13.5 m No NA NA 26 6.5 Cayci 2012; Beye 2013; Canigral 2013; Carr 2013; Delmas 2013; Pu 2013; Fakhouri 2014; Ardissino 2014; Chaudhary 2014 The specific subgroup of anti- factor H antibodyassociated aHUS First described in 2005 : 3 cases in children1 Approximately 200 cases reported currently2-4, mainly in childhood Frequency 6-10% (up to 25%) of aHUS in European children, 50% in Indian children Ref 2 All patients (n = 45) mean : 9 years (8 months – 52 years) Children (n = 38) 9 years (8 months – 14 years) Adults (n=7) 41 years (28 - 52 years) 7 Number of cases 6 5 4 females males 3 2 1 1 Dragon-Durey 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 28 30 35 41 45 50 52 Age at onset (Years) et al, JASN 2005 Dragon-Durey et al JASN 2010 3 Hofer et al, CJASN 2013 4 Sinha et al, KI 2013 2 Anti-CFH antibody-associated HUS Benefit from early PE+ immunosuppression with subsequent maintenance immunosuppression guided by anti-CFH antibodies titer 92% 76% Combined PE+IS 71% 69% Maintenance IS 87% P= 0.010 P<0.0001 46% 41% No maintenance IS 33% No combined therapy Probability of renal survival with respect to induction combined therapy with plasma exchanges and immunosuppression Probability of relapse free survival with respect to maintenance immunosuppression Renal survival free of adverse outcome: alive with eGFR ≥ 30 ml/min/1.73m2 Sinha et al, KI 2013 New prospective trials in paediatric and adult patients: Haematologic normalisation in most patients 41 adults C10-004 95% 82% 98% 88% (95% CI 77–100) (95% CI 60–95) (95% CI 88–100) (95% CI 74–96) Haematologic normalisation Platelet count normalisation Haematologic normalisation 55 (1–153) 8 (0–84) 55 (2–146) 100 100 80 80 Percentage Percentage 22 children C10-003 60 40 60 40 20 20 0 0 Platelet count normalisation Median days to endpoint (range) 7 (1–80) Haematologic normalisation: platelet count ≥150 x 109/L and LDH ≤ULN for at least 2 consecutive measurements over ≥4 weeks Clinical characteristics at first episode according to age French cohort Children (n=89) Trigerring event Diarrhea Upper respiratory tract infection Pregnancy (post-partum ) 47% 39% 8% Adults (n=125) 33% 15% 1% 19% of women Complete triad Platelets > 150G/L Hb>10g/dl 74% 15% 6% 83% 16% 11% CNS involvement 16% 8% Dialysis required 59% 81% Fremeaux-Bacchi et al, CJASN 2013 The late 2000s: Recommended schedule for PE/PI for aHUS at presentation and during the first month • • PE with plasma for restitution (or PI if PE not possible) within 24 hours of onset Daily for at least 5 days and until normalisation of platelet count and LDH, and improvement of renal function – Then five sessions per week during 2 weeks followed by three sessions per week for 2 weeks – Followed by empirical treatment schedule (modality and interval) per patient Ariceta G et al. for the European Pediatric Study Group for HUS. Pediatr Nephrol 2009; Taylor CM et al. for the Renal Association, the British Committee for Standards in Hematology and the British Transplantation Society. Br J Hematol 2010 The risk of meningococcal infection in patients with terminal complement factors deficiency or blockade • Immunity against Neisseria meningitis is mainly mediated by the lytic terminal complement complex C5b-9 • Walport MJ, NEJM 2001: « The risk of meningococcal disease for a person with a complement deficiency …can be calculated to be 0.5 percent per year. This is a relative risk of 5000, as compared with … persons without a complement deficiency » . • Invasive meningococcal infection in PNH patients under eculizumab: 0.5 / year / 100 patients (Hillmen et al, 2013) • Invasive meningococcal infection in aHUS patients under eculizumab : -1 patient out of 80 treated outside of trials (Struijk 2013) and 2 patients out of 100 within trials (Fakhouri, ASN 2013) (favourable outcome). Prevention of meningococcal infections Obligatory anti-meningococcal vaccine + antibioprophylaxis for 2 weeks • Conjugate tetravalent vaccines protect against serogroups A, C, W135 and Y, not against serogroup B • Anti-B vaccine now available (since Dec 11, 2013 in France) must be associated • Education/information to the patient, his family and family doctor • Information card Continuous antibioprophylaxis obligatory in some countries (France, UK) • Oral methyl penicillin (full dose, twice daily) • To our opinion, should be recommended for children Early initiation of eculizumab as adopted in children seems to offer the best chance of renal function full recovery C10-003, Children, N=22 Median delay before eculizumab: 6d (<1d-4.3m) 12/22 (55%) without prior PE Mean eGFR at baseline : 33±30 ml/min/1.73 m2 C10-004, Adults, N=41 Median delay before eculizumab: 15d (<1d-19.2m) 6/41 (15%) without prior PE Mean eGFR at baseline : 17±12 ml/min/1.73m2 eGFR mean Increase at Week 27 64 ml/min/1.73m2 11/22 (50%) on dialysis at baseline 9/11(82%) discontinued dialysis 0 not on dialysis at baseline initiated dialysis 2/22 (9%) on dialysis at 6 months eGFR mean Increase at Week 26 29.3 ml/min/1.73m2 24/41 (58%) on dialysis at baseline 20/24 (83%) discontinued dialysis 4/17not dialysed at baseline initiated dialysis (short course in 2) 6/41 (15%) on dialysis at 6 months C10-003 The new prospective trials in pediatric and adult patients Hematologic normalization in most patients 22 Children C10-003 41 Adults C10-004 (95% CI: 77-100 ) 21/22 Median days to endpoint (range) 7 (1-80) 18/22 55 (1-153) 14/22 8 (0–84) 60.0 (7.0–153.0) 55 (2-146) Hematologic normalization: platelet count ≥150x109/l and LDH ≤ ULN for at least 2 consecutive measurements over ≥ 4 weeks 43 Conclusion • Eculizumab offers aHUS patients the chance of sustained remission and full rescue of renal function if started early • Let’s make the best use of this revolution through: – registries – treatment duration studies C10-003 C10-003 and C10-004 Conclusions The results of the two current studies support the recommendation of eculizumab as first line treatment in pediatric patients and also in adults once unequivocal diagnosis of aHUS is made. 45