Recommendations for RA management: what has changed?

Transcription

1 The 2016 Update of the EULAR Recommendations for RA management: what has changed? Baltics Rheumatology Conference Vilnius, September Prof. Diego Kyburz University Hospital of Basel Switzerland

2 Multiple options: what is the right choice? 2

3 EULAR recommendations for the management of RA First publication 2010 Updates 2013 and 2016

4 EULAR recommendations: Methodology EULAR standardized operating procedures for the development of recommendations

5 EULAR recommendations: Methodology Convenor and Methodologist invite Steering committee 7 rheumatologists, 3 fellows, 1 patient representative Developed the research questions for the systematic literature reviews (SLR) Task force 50 individuals: rheumatologists, 3 patients, 2 health professionals, 2 delegates of EMEUNET Task force decided on recommendations in a consensus process

6 Research questions efficacy of synthetic (s)dmards (mono- or combination therapy, including csdmards and ts DMARDs) and glucocorticoids (GC) efficacy of bdmards (mono- or combined with csdmards) safety aspects of sdmards and biological (b)dmards.

7 Systematic literature review Update of the literature published

8 EULAR recommendations: structure Overarching principles General priniciples not based on specific literature search Specific recommendations

9 Overarching principles A: unchanged B: new, derived from recommendation 14 in the 2013 update C: unchanged (previously B) D: unchanged (previously C) Smolen et al, Ann Rheum Dis 2017;76,

10 Recommendations Unchanged to 2013 Level of Evidence 1a Level of agreement 9.9 (highest of all recommendations)

11 Recommendations «sustained» was introduced, otherwise unchanged Level of evidence 1a Level of agreement 9.6

12 Remission Which definition of remission? DAS28 < 2.6 not considered not sufficiently stringent Preferentially ACR-EULAR remission or index-based SDAI 3.3 CDAI 2.8 Felson et al, Ann Rheum Dis 2011;70,

13 Simplified disease activity index (SDAI) clinical disease activity index (CDAI) Aletaha and Smolen, Clin Exp Rheumatol 2005;23,S

14 Recommendations Unchanged Level of evidence 2b Level of agreement 9.5

15 Recommendations Previously: in patients with active RA. Level of evidence 1a Level of agreement 9.8

16 Methotrexate dosing Rapid escalation to 25(-30)mg/wk Orally or parenteral fast escalation with 5 mg/month to mg/week were associated with higher clinical effect sizes and more (gastrointestinal) adverse events in comparison with doses of 5 15 mg/week or slow escalation. Starting with 15 mg/week subcutaneous versus oral methotrexate was associated with higher clinical efficacy but more withdrawal due to toxicity in early RA.

17 Recommendations Wording slightly different («In cases of MTX contraindications») Dosing: Leflunomide 20mg/d without loading. SSZ escalated to 3g/d Hydroxychloroquine not recommended as monotherapy because of less potent suppression of joint damage 1 Level of evidence: 1a Level of agreement: Van der Heijde et al, Lancet 1990;335:539

18 Recommendations Previously recommendation 7 Level of evidence 1a Level of agreement 8.7 Low dose? 7.5mg/d

19 Prednisone as initial therapy Early RA, DMARD and GC naive: MTX + GC vs csdmard combination + GC

20 CareRA High risk patients randomized to - Cobra classic MTX 15mg/wk, SSZ 2g/d, GC 60mg step down - Cobra slim MTX 15mg/wk, GC 30mg step down - Cobra avant-garde MTX 15mg/wk, Leflunomide 10mg/d, GC 30mg s.d. Verschueren et al, Ann Rheum Dis 2015;74:27-34

21 CareRA Verschueren et al, Ann Rheum Dis 2015;74:27-34

22 CareRA DAS28 CRP remission rates Verschueren et al, Ann Rheum Dis 2015;74:27-34

23 CareRA Remission induction in >70% of early RA patients with MTX + GC 30mg initially csdmard combination and high dose GC not superior Verschueren et al, Ann Rheum Dis 2015;74:27-34

24 Recommendations: Glucocorticoids The EULAR task force recommends GC in combination with csdmards as bridging therapy With biologic DMARDs or tsdmards GC not needed because of rapid onset of action. Consider higher infection risk with bdmard/tsdmard GC should be gradually reduced and stopped, usually within 3 months, exceptionally 6 months Long-term GC therapy >5mg/d should be avoided 1,2 1 Ramiro et al, Ann Rheum Dis 2017;76: Del Rincon et al, Arthritis Rheumatol 2014;66;

25 Recommendations Essentially same as first part of previous recommendation 8 Level of evidence 5 Level of agreement 8.5

26 Poor prognostic factors Smolen et al, Ann Rheum Dis 2017;76,

27 Recommendations New: tsdmards included, preference for bdmard because of lack of long-term registry data for tsdmards all bdmards can be used, no hierarchical positioning Level of evidence 1b Level of agreement 9.0

28 Recommendations New: as monotherapy IL-6 inhibitors (tocilizumab) and tsdmards are preferred Level of evidence: 1a (bdmard), 1b (tsdmard) Level of agreement: 9.2

29 Tocilizumab as monotherapy SURPRISE trial RA pts MTX IR: Randomized to 2 groups: TCZ added (add on), TCZ monotherapy (switch) Kaneko et al, Ann Rheum Dis 2016;75:

30 SURPRISE study Primary endpoint: DAS28 remission at wk 24 Kaneko et al, Ann Rheum Dis 2016;75:

31 SURPRISE study Less Rx progression in the group with combi TCZ+MTX Kaneko et al, Ann Rheum Dis 2016;75:

32 Recommendations Similar to tsdmard added No data for bdmard after tsdmard failure, tsdmard after tsdmard failure etc Level of evidence 1a (bdmard), 5 (tsdmard) Level of agreement 9.5

33 Preference of bdmard after TNF failure? Pragmatic randomized trial in RA having failed anti-tnf Manders et al, Arthritis Res Ther 2015;17:134

34 Preference of bdmard after TNF failure? Manders et al, Arthritis Res Ther 2015;17:134

35 Preference of bdmard after TNF failure? No significant differences between ABA, RTX, anti-tnf Manders et al, Arthritis Res Ther 2015;17:134

36 Recommendations Unchanged to 2013 Level of evidence 2b Level of agreement 9.0

37 Withdrawal of biologics: PRIZE study PRIZE study: randomized controlled trial Patients with early RA (<1yr), no prior MTX or biologics DAS28 > 3.2 Open label phase: Etanercept 50mg/wk s.c. + MTX Prednison <10mg allowed Emery et al, New Engl J Med 2014;371:

38 PRIZE study study overview Pat. with DAS28 remission after phase 1 -> phase 2 Emery et al, New Engl J Med 2014;371:

39 PRIZE study disease activity Emery et al, New Engl J Med 2014;371:

40 Withdrawal of biologics: HONOR study Patients with established RA (mean disease duration 7.5yr) Patients for 6 months in remission with adalimumab + MTX, no steroids, stable MTX dose: open label continuation or withdrawal of ADA Tanaka et al, Ann Rheum Dis 2015;74:389-95

41 HONOR: results Remission/LDAS at 1 year ADA discontinuation: flare in 40% of patients When ADA was restarted: 100% achieved LDAS within 9mts Tanaka et al, Ann Rheum Dis 2015;74:389-95

42 HONOR: results: predictors DAS28 at baseline predicts maintenance of LDAS/Remission at 1 yr Tanaka et al, Ann Rheum Dis 2015;74:389-95

43 Predictors for relapse In which patients can bdmards be tapered successfully? Schett et al, Ann Rheum Dis 2016;75:

44 Recommendations Essentially unchanged Controversies in the expert panel stopping csdmard possible only in exceptional cases Many think that csdmard should never be stopped Level of evidence 4 Level of agreement 8.5

45 Recommendations: Overview Smolen et al, Ann Rheum Dis 2017;76,

46 Recommendations: Overview Smolen et al, Ann Rheum Dis 2017;76,

47 Recommendations: Overview Smolen et al, Ann Rheum Dis 2017;76,

48 EULAR recommendations for RA treatment Many open questions remain Smolen et al, Ann Rheum Dis 2017;76,

49 EULAR recommendations Helpful guidance to optimize treatment in RA patients But still far away from true personalized medicine

50 Thank you for your attention Diego Kyburz 09/

51 Level 1a 1b Therapy / Prevention, Aetiology / Harm SR (with homogeneity*) of RCTs Individual RCT (with narrow Confidence Interval ) Prognosis Diagnosis Differential diagnosis / symptom prevalence study SR (with homogeneity*) of inception cohort studies; CDR validated in different populations Individual inception cohort study with > 80% follow-up; CDR validated in a single population SR (with homogeneity*) of Level 1 diagnostic studies; CDR with 1b studies from different clinical centres Validating** cohort study with good reference standards; or CDR tested within one clinical centre 1c All or none All or none case-series Absolute SpPins and SnNouts 2a 2b 2c 3a 3b SR (with homogeneity*) of cohort studies Individual cohort study (including low quality RCT; e.g., <80% followup) Outcomes Research; Ecological studies SR (with homogeneity*) of case-control studies Individual Case-Control Study SR (with homogeneity*) SR (with homogeneity*) of either retrospective of Level >2 diagnostic cohort studies or studies untreated control groups in RCTs Retrospective cohort study or follow-up of untreated control patients in an RCT; Derivation of CDR or validated on splitsample only Exploratory** cohort study with good reference standards; CDR after derivation, or validated only on split-sample or databases SR (with homogeneity*) of prospective cohort studies Prospective cohort study with good follow-up**** All or none case-series SR (with homogeneity*) of 2b and better studies Retrospective cohort study, or poor follow-up Economic and decision analyses SR (with homogeneity*) of Level 1 economic studies Analysis based on clinically sensible costs or alternatives; systematic review(s) of the evidence; and including multi-way sensitivity analyses Absolute better-value or worse-value analyses SR (with homogeneity*) of Level >2 economic studies Analysis based on clinically sensible costs or alternatives; limited review(s) of the evidence, or single studies; and including multi-way sensitivity analyses Outcomes Research Ecological studies Audit or outcomes research SR (with homogeneity*) of 3b and better studies Non-consecutive study; or without consistently applied reference standards SR (with homogeneity*) of 3b and better studies Non-consecutive cohort study, or very limited population SR (with homogeneity*) of 3b and better studies Analysis based on limited alternatives or costs, poor quality estimates of data, but including sensitivity analyses incorporating clinically sensible