Taming the wolf: Treating to target, treating to remission new strategies for SLE

Transcription

1 Taming the wolf: Treating to target, treating to remission new strategies for SLE Ronald van Vollenhoven Seattle, April 28, 2017

2

3 Disclosures Research support, consultancy: Abbott (AbbVie), Biotest, BMS, Crescendo, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB Pharma, Vertex Member of steering or advisory committee for or investigator in clinical trials of atacicept, belimumab, epratuzumab, ocrelizumab, tabalumab, and other novel therapeutics The Treat-to-target-in-SLE initiative was supported by unrestricted grants from GSK and UCB Pharma

4

5 Criteria ACR or SLICC? No set of criteria can replace the clinical judgement by an experienced clinician!

6 Proliferative lupus nephritis: glomerulonephritis WHO class III, IV MMF 1-1,5 gram x2 Ginzler et al Euro-lupus: Cyclophosphamide (CyX) 500 mg every 2 weeks x6, followed by AZA Houssiau et al Repeat biopsy to assess Gunnarsson 2004

7 Proliferative lupus nephritis: glomerulonephritis WHO class III, IV The former gold standard: NIH protocol CyX 0,5-0,75 gm / m2 monthly x 6 Followed by CyX every 3rd month or AZA Steinberg et al, Boumpas et al Is now rarely used as firstline therapy May be considered in refractory patients

8 Patients, % BLISS-52 and BLISS-76 pooled data Response to belimumab 60 Placebo + routine therapy Belimumab 10 mg/kg + routine therapy * * * 0 Low C3/4 + Anti-dsDNA Low C3/4 + Corticosteroid Use General Pooled % of trial population 52% 56% 100% Difference in SRI 19.8% 21.1% 11.8% Van Vollenhoven et al, ARD2012

9 How are we doing today?

10 Euro-Lupus vs. NIH-CyX NIH-like regime Euro-Lupus regime All HD LD Houssiau FA et al. Ann Rheum Dis 2010; 69: 61 7% 9% 5%

11 SLE patient survey, Sweden, 2011 Patient characteristics (n = 339) Age, mean ± SD, years 55 ± 14.5 Sex (female), % 94 Years since diagnosis, mean ± SD, years 16 ± 10.8 EQ-5D Mean 5-item, mean ± SD, years 0.64 ± 0.25 VAS, mean ± SD, years 0.64 ± 0.20 Fatigue scale, mean ± SD, years 6.1 ± 2.3 Total mean annual costs, ± mean indirect annual costs ± mean direct annual costs 7818 ± Bexelius et al. Lupus Jul;22(8): doi: / Epub 2013 Jun 11

12 How are we doing in treating SLE? Mortality is down and renal survival are good Some patients are doing very well For many others, living with lupus means: Persistent disease activity Always risk of flare Always needs medications Progression of damage Lowered quality of life

13 How can we do better? 1. Better medications 2. Better use of existing therapies

14 Glucocorticoid-sparing effects of belimumab data from the BLISS trials. Van Vollenhoven et al., A&R, 2016.

15 CRR: up/c ratio (measured in a 24-h collection) < 0.5 (mg/mg) AND egfr >60ml/min, or, if <60ml/min at screening, not fallen by >20% compared to screening AND no need to increase GC (except per protocol) or introduce another IS The RING trial in lupus nephritis RING RItuximab for lupus Nephritis with remission as a Goal ELCY (3M) + AZA/MMF (3M) NIH CY (6M) + AZA/MMF (3M) AZA > 6M MMF > 6M ISN/RPS III/IV/V S R Proteinuria 1g/d confirmed Proteinuria 1g/d On max 10 mg/d prednisolone On ACEI/ARB at screening CRR RTX or placebo AZA or MMF Pred 10mg/d

16 We need you... Provided you have access to RTX

17 How can we do better? 1. Better medications 2. Better use of existing therapies 3. Better treatment strategies Does the treatment strategy really matter?

18 Radiological damage at 18 months Targeted versus routine care in RA: the TICORA study 10 p = "Routine" management "DAS" management *Grigor C et al. Lancet, 2004;364:263-9

19 What is treating-to-target 1. Identify a target for each patient 2. Intervene 3. Agree on when to re-assess 4. If target not met: modify the intervention

20 Treating to target: the example of hypertension Target a BP value Better long-term results

21 Treating-to-target in Cardiovascular disease

22 Recommendations T2T/SLE recommendations The treatment target of SLE should be remission of systemic symptoms and organ manifestations or, where remission cannot be reached, the lowest possible disease activity, measured by a validated lupus activity index and/or by organ- specific markers GoR (A C) C (SLE) / A (LN) SoR (0 10) 9,52 Prevention of flares (especially severe flares) is a realistic target in SLE and should be a therapeutic goal. B (SLE) / A (LN) 9,32 It is not recommended that the treatment in clinically asymptomatic patients be escalated based solely on stable B 9,03 or persistent serological activity. Since damage predicts subsequent damage and death, prevention of damage accrual should be a major therapeutic goal in SLE. A 9,71 Van Vollenhoven RF et al Ann Rheum Dis. 2014;73:958-67

23 Definitions of remission in SLE Author(s) Year Remission Definition Serologic Activity Permitted Duration of remission required Treatments Permitted Dubois Not specified Not specified No Not specified Dubois, 1964 Not specified Not specified No Not specified Tuffanelli 10 Gladman et al Asymptomatic patient Yes No None Tozman et al Absence of clinical manifestations of disease No No None Heller, Schur Asymptomatic without active organ involvement No No Antimalarials and low-dose glucocorticoids LeBlanc et al Clinical SLEDAI = O Yes >3 consecutive clinic visits Any Drenkard et al lack of disease activity permitting SLE Yes > 1 yr None treatment withdrawal Barr et al Clinical SLEDAI = 0 Yes > 1 yr Not specified or PGA <1.0 Formiga et al lack of disease activity permitted SLE treatment withdrawal Yes > 1 yr None Swaak et al Absence of disease-related signs with no need Not specified No None for treatment Urowitz et al Clinical SLEDAI = O Yes > 5 yrs None Nossent et al Physician assessed Not specified No Not specified Steiman et al Clinical SLEDAI-2K = O Yes > 2 yrs Antimalarials only Conti et al Clinical SLEDAI-2K = O Yes > 2 yrs Antimalarials only Adapted from Steiman et al, J Rheumatol 2014;41:1808

24 Definition of Remission in SLE: the DORIS project Large international task-force experts & patients multispecialty Formal process Goal: to provide a framework for defining remission in SLE

25 Remission in SLE A state that is highly favorable but not a cure and certainly much more than just symptom control Van Vollenhoven R, et al. Ann Rheum Dis. 2017;76:

26 DORIS: Definitions Framework Remission in SLE is a durable state characterized by absence of symptoms, signs, or abnormal labs

27 DORIS: Definitions Framework Remission in SLE is a durable state characterized by absence of symptoms, signs, or abnormal labs How do we define that?

28 DORIS: Definitions Framework The absence of clinical signs and symptoms must be defined using a validated index: clinical-sledai = 0 BILAG D/E only clinical ECLAM =0 supplemented with PhysGA < 0.5 (0-3) Routine labs included Serology will be investigated Duration will be investigated Van Vollenhoven R, et al. Ann Rheum Dis. 2017;76:

29 DORIS: Definitions Framework (2) We will distinguish Remission-off-therapy Remission-on-therapy Complete remission Partial remission Clinical remission Serological remission Quiescent lupus Lupus under control etc Van Vollenhoven R, et al. Ann Rheum Dis. 2017;76:

30 DORIS: Definitions Framework (2) Remission-off-therapy AML allowed Remission-on-therapy AML, low-dose steroids, immunosuppressives, and biologics allowed Van Vollenhoven R, et al. Ann Rheum Dis. 2017;76:

31 Conclusions The work of this international consensus panel has provided a framework for testing individual definitions of remission against longer-term outcomes*, providing a pathway for developing criteria for remission in SLE. *death, damage, flare, HR-QOL

32 Taming the wolf: Treating to target, treating to remission new strategies for SLE Ronald van Vollenhoven Seattle, April 28, 2017