DAS28 criteria for initiation of biologics in early RA: a clinician s view. Dr Patrick Kiely St George s Healthcare NHS Trust, London

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1 DAS28 criteria for initiation of biologics in early RA: a clinician s view Dr Patrick Kiely St George s Healthcare NHS Trust, London

2 History: NICE (E&W) guidelines for starting anti-tnf agents April 2001 > BSR issued guidelines - no cost effectiveness modelling 1 March 2002 > NICE issued TA36 2. Both concurred: DAS28 >5.1 on 2 occasions a month apart Failed at least 2 previous DMARDs, including methotrexate Satisfactory response defined by a drop in DAS28 >1.2 January 2005 > BSR updated guidelines no new evidence, no change 3 October 2007 > NICE review of TA36 updated TA130 4 No change in eligibility to start criteria 6 monthly assessments demonstrating maintained response 1. British Society for Rheumatology. Guidelines for prescribing TNF-α blockers in adults with rheumatoid arthritis, NICE TA 36. Guidance on the use of etanercept and infliximab for the treatment of rheumatoid arthritis, March Update on the British Society for Rheumatology guidelines for prescribing TNF blockers in adults with rheumatoid arthritis, April NICE TA 130. Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis, October 2007

3 Netherlands 1 Other anti-tnf guidelines Failure of one DMARD (usually MTX) and DAS28 >3.2 Norway/Denmark 1 France 2 Ireland 3 Failure of one DMARD (usually MTX) a. DAS28: >5.1 on 2 occasions a month apart, b. or DAS28: with >3 synovitic joints, ESR >28, c. or CRP>15 despite 0.1mg/kg/day prednisolone, d. or evidence of radiological progression despite DMARDs persistent active RA DAS28: >5.1 or lower & progressive erosive change or acute phase elevation or poor physician global suggest: on 2 occasions a month apart (not mandatory) failed at least one DMARD, usually MTX (target 25mg) 1. Deighton CM et al. Rheumatology 2006;45: Fautrel B. Rheumatology 2008;47: Irish Society for Rheumatology. Guidelines for Prescribing TNFalpha Blockers in Adults with Rheumatoid Arthritis (

4 Other anti-tnf guidelines EULAR recommendations Target driven therapy emphasised Remission (DAS<2.6) is the therapeutic primary aim, especially in early RA Low disease activity (DAS<3.2) may be an appropriate alternative, especially in patients with longstanding RA Poor prognosis defined: RF+, CCP+ (especially high level), high composite disease activity scores, early occurrence of erosions Recommended Initial DMARD IR (i.e. not at target) and poor prognostic markers NOT recommended Initial single DMARD IR (i.e. not at target) but no poor prognostic markers Switch these to another DMARD for 3-6 months then anti-tnf Also recommended in DMARD Naïve (with MTX) High activity, poor prognosis, early structural damage 1. Smolen et al Ann Rheum Dis 2010; 69: EULAR recommendations for the management of RA with synthetic and biologic DMARDs, June 2010

5 Problem for NICE-land: DAS28: moderate activity E&W not eligible for anti-tnf therapies Any other country or rheumatology society that has issued a guideline has recommended the use of biologics in patients with a persistent DAS >3.2 NL, NO, DK eligible F, IRL eligible as long as other active features EULAR eligible USA eligible if > 6 months disease and - MTX mono IR with poor prognosis - seq mono / combo MTX-DMARDs IR and any prognosis

6 Problem: Eligibility to start restricted to those with DAS28 > 5.1 TA247 also allows Tocilizumab in DMARD IR patients, same eligibility criteria, wth or without MTX NICE RA commissioning algorithm. 7/RA3.1WithGolimumab.pdf

7 What happens if stuck in DAS range and DMARDs continue? ERAN data: year 1 year 2 or 3 DAS28 at end of Yr 1 N of cohort with Yr 2 data Yr 2. DAS28 <3.2 Yr 2 DAS Odds Ratio of Yr. 2 DAS28 <3.2 (95% CI) N of cohort with Yr 3 data Yr 3. DAS28 <3.2 Yr 3. DAS Odds Ratio of Yr. 3 DAS28 <3.2 (95% CI) (42%) 242 (58%) (46%) 148 (54%) < (74%) 42 (26%) 7.64 ( ) vs yr 1 DAS (71%) 32 (29%) 4.49 ( ) vs yr 1 DAS (27%) 124 (73%) 2.56 ( ) vs yr 1 DAS > (35%) 71 (65%) 3.09 ( ) vs yr 1 DAS >5.1 > (13%) 76 (87%) 53 8 (15%) 45 (85%) (37%) 59 (63%) 3.12 ( ) vs yr 1 DAS (48%) 32 (52%) 4.06 ( ) vs yr 1 DAS (16%) 65 (84%) 48 9 (19%) 39 (81%) Kiely PDW et al. Rheumatology 2011; 50:

8 DAS28: moderate activity ERAS data: year 5 HAQ and erosion data: ongoing DMARD therapy DAS28 n HAQ <0.25 HAQ HAQ HAQ > % 14% 37% 37% > % 12% 30% 53% Larsen <2 Score > % 18% 26% 46% > % 11% 37% 41% Adapted Dixey J et al. Rheumatology 2009; 48 (Suppl 1): i136.

9 DAS28: moderate activity NICE-land patients : how do we get them to target DAS28 <3.2?? Escalation from sequential DMARD mono-therapy to DMARD aggressive model e.g. combination DMARD +/- steroid (i.a., i.m.), parenteral MTX e.g. TIGHT control strategy, target to DAS<3.2? proportion would achieve DAS<3.2 No specific trial Theme that if delay step up, outcome not so good e.g. BeST arms 1 vs. 2 (3 monthly assessments, 6 months until add on) Tight control very effective in early RA: TICORA (19 mths), CAMERA (<1yr) Tight control in established disease?

10 Incorporating DAS into routine care 24 out patient centers in NL RA patients, mean dis. dur. ~ 6 years (3-14) All patients assessed at weeks 0, 4, 12, 24 (not monthly) Baseline DAS : ~60% DAS group : n=205 (12 centers) DAS28 measured on all visits Education - message aim to achieve target <3.2 no DMARD escalation algorithm, treatment choices independent Usual care group: n=179 (12 centers) no systematic monitoring of activity no treatment guidelines Fransen. Ann Rheum Dis 2005; 64:

11 Incorporating DAS into routine care DMARD changes occurred in 20% vs. 9% OP visits Sub group analysis of outcome Routine care n=81 DAS care n=61 Week 0 DAS28 <3.2 Week 24 DAS28 <3.2 Mean change DAS28 Week 0 DAS Week 24 DAS % 16% % 62% 13% 31% % 38% Fransen. Ann Rheum Dis 2005; 64:

12 Percentage of patients Incorporating DAS into routine care In the disease activity score (DAS) group, more patients reached low disease activity (DAS28 <3.2) than in the usual care (UC) group (p = 0.028). 100% 90% 80% 70% 60% 50% HIGH MODERATE LOW 40% 30% 20% 10% 0% DAS UC DAS UC Week 0 Week 24 Adapted from Fransen. Ann Rheum Dis 2005; 64:

13 Incorporating DAS into routine care Adherence to DAS28 assessments? DAS28 calculated on 99% visits 93% DMARD changes occurred when DAS28 >3.2 DMARD changed on only 20% occasions that DAS28 >3.2 - reasons : Awaiting effect of current medication 84% RA activity judged sufficiently low by Dr 54% Dose already maximal / adverse effects 42% Patient choice / patient satisfied 31% DAS28 high for non-ra reasons 9% Partial TIGHT control in established disease enforcing DAS measurement, stated target Some impact on DAS category: 58% 38% No trial in established disease has applied all 4 principles: target objective measure frequent assessments protocol dictated treatment changes Fransen. Ann Rheum Dis 2005; 64:

14 Response to anti-tnf agents HAQ as outcome drives cost effectiveness models Baseline DAS28 Treatment > 5.1 > 5.1 DMARD N=300 Anti-TNF N=224 DMARD N=344 Anti-TNF N=4687 HAQ baseline HAQ 12 months Mean change HAQ Adjusted mean Change HAQ Adjusted mean Change HAQ ref ref ref BSRBR: Hyrich KL et al. Rheumatology 2009; 48: 1323.

15 Arguments to drop DAS28 anti-tnf eligibility criteria Eminence In line with the opinions of other Nations & Rheum societies Evidence If current DAS : Outcome if continue DMARDs? Traditional model poor (HAQ, erosions, employment) TIGHT model: good in early disease? impact in established disease What happens if these patients DO GET anti-tnf Outcome is as good as those treated with DAS28 >5.1

16 New BSR guidelines (Rheumatology 2010; 49: ) Recommend anti-tnf therapies : Active RA : measured as DAS28 >3.2 no need for 2 assessments...and at least 3 swollen and tender joints i.e. must have synovitis (excludes fibromyalgia) could specify US/MRI confirmed synovial disease too soon...and have undergone trials of at least 2 DMARDs including MTX, usually given concurrently over a 6 month period Embracing NICE RA guidelines Embracing TIGHT control principles in early disease BUT... NICE TRUMPS BSR! Deighton et al Rheumatol. 2010; 49: 1197

17 Can we afford to treat all those with a persistent DAS>3.2? Decreasing DAS28 threshold to start anti-tnf means more treated Predicted to increase the use in RA patients from 6% 8% 12% (if match prescribing behaviour of EU neighbours with similar criteria) Adopting NICE RA guidelines may decrease No. eligible for anti-tnf It all comes down to Incremental Cost Effectiveness Ratio (ICER) Cost effectiveness models beyond most clinicians expertise Varying results according to assumptions and data used For me, akin to a conclave!

18 What can we do to implement the BSR guidelines? Attempts to breakaway from NICE guidelines Certolizumab pegol Moderate Accessibility Scheme DAS28 > months free to all starters, including those with DAS28 >5.1 Stop after 3 months if DAS28 not <1.2 baseline Requires PCT to agree

19 Living with the Guidelines Getting it right from the start Disease modifying and biological drugs In newly diagnosed offer a combination of DMARDs (including MTX and at least one other DMARD, plus short term steroids) as 1 st line treatment asap, ideally within 3 months of onset of persistent symptoms If combination DMARD therapy is not appropriate, start DMARD monotherapy placing greater emphasis on fast escalation to a clinically effective dose rather than on the choice of DMARD Once sustained & satisfactory levels of disease control are achieved then cautiously try to reduce drug doses to levels that still maintain disease control NICE (RA) clinical guideline No. 79 Key priorities for implementation

20 ideally within 3 months of onset of persistent symptoms How are we doing? UK practice? Early Rheumatoid Arthritis Network (ERAN) 638 newly diagnosed patients Mean time from symptom onset to start of therapy 8 months Waterford

21 months ERAN cohort , n= Onset 1 st DMARD: Onset of first symptoms to first DMARD median 8 months (IQR 4-13) Onset - GP: Onset of first symptoms to GP referral median 4 months (IQR 2-9) Birmingham cohort: Onset symptoms to 1 st secondary care assessment median 23 weeks (IQR 12 54) -3 N = 655 Onset->GP Onset->OPD Onset->1st DMARD 578 Canadian cohort: 8.4 months GP->OPD Onset->Steroids OPD->1st DMARD QUEST RA: 4 15 months (15 countries)

22 ... offer a combination of DMARDs Early Rheumatoid Arthritis Network (ERAN) 735 newly diagnosed patients Current UK practice? Treating with one drug initially is the norm 1st DMARD treatment was monotherapy in 93% 2 nd DMARD was in combination in 70% Waterford Kiely PDW. Rheumatology 2009; 48: 57-60

23 Starting treatment not so early mono or combination therapy? FinRA Co study (Mottonen, Arthritis Rheum 2002; 46: 894) Early Rheumatoid arthritis patients (< 2 years) DMARD sequential monotherapy versus Combination MTX/SSZ/HCQ therapy, including prednisolone Delay in institution of DMARD Monotherapy: median 7 months symptoms < 4 months in 23/86, 27% Combination: median 6 months symptoms < 4 months in 26/79, 33%

24 FinRA Co: early versus delayed therapy in early RA: 2 year remission rates

25 CRP (mg/l) Fundamental concept Minimizing cumulative inflammation (inflammationtime AUC) improves all outcomes Placebo + MTX Infliximab + MTX Weeks This means Detect & refer early Treat early, with a fast acting agent to suppress inflammation quickly

26 % change Median DAS28 % change Time to achieve remission fast escalation effect on function and Quality of Life Quinn, Arthritis Rheum 2005; 52: 27 DAS28 HAQ Placebo+MTX Infliximab+MTX Placebo+MTX Infliximab+MTX Severe Weeks RAQoL Infliximab Rx Weeks Remission RAQoL Placebo RAQoL Infliximab Benefit of an initial fast acting component -100 Weeks

27 Difference between NICE and EULAR guidelines BOTH recommend STEROIDS 1 st line NICE emphasis on combination DMARDs 1 st line monthly monitoring to a level previously agreed with the person with RA mindful that require failure of 2 DMARDs prior to commencing anti-tnf EULAR allows DMARD monotherapy 1 st line Explicit treat to target remission; 1-3 month monitoring Allows anti-tnf if 1 st DMARD strategy fails after 3-6 months

28 NICE guideline New cost effectiveness analysis : Clear benefits of a combination strategy versus monotherapy. Step down combinations most cost-effective, even cost saving. Other combination strategies also cost-effective. NAO 2009 similar findings All combination regimens have used steroids in one form or another, therefore recommended in an initiation protocol

29 Tight control/treat-2-target Aim to suppress inflammation to a low level / remission use a valid objective measure of current RA activity decide on a target outcome A protocol dictates whether to increase or decrease treatment; not doctor-patient conspiracy Assess frequently (monthly 6 weekly) Use adequate treatment fast acting induction regime Steroids currently available (evidence for anti-tnf agents) more than one drug at a time

30 MD in change of DAS-28 between usual care and tight control, according to a fixed-effects model Grigor et al. (3) Goekoop-Ruiterman et al. (29) Verstappen et al. (18) Protocolized tight control Van Hulst et al. (28) Fransen et al. (27) Fransen et al. (8) Non-protocolized tight control Monitoring with protocolized treatment adjustments Monitoring without protocolized treatment adjustments Data are presented as MD in change of DAS-28 between usual care and tight control Overall effect is presented as a WMD in change of DAS-28 between usual care and tight control Schipper LG et al. Rheumatol. 2010; 49:

31 DAS28 criteria for initiation of biologics in early RA: a clinician s view NICE-land is a challenging (frustrating) place to work Concern is for patients with persistent DAS Poor prognosis is HIGHLY LIKELY if Delay in onset of first DMARD Model of care is sequential monotherapy with infrequent visits or treatment changes To maximise the chance of getting everyone to target Adopt NICE RA management guidelines!! Start treatment early Use step down combination with steroid Adjust treatment frequently, aiming for DAS<3.2

32 DAS28 criteria for initiation of biologics in early RA: a clinician s view Thank-you

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34 Author/Acronym Active treatment Frequent assessments Objective disease activity measure Mandatory treatment change Target Fransen DMARDs steroid p.o. allowed NO 0, 4, 12, 24 weeks YES NO DAS28<3.2 Goekoop- Ruiterman ( BeSt arms 1 & 2 versus usual care) Sequential monotherapy or step up combination steroid only very late NO 3 monthly YES YES DAS44 <2.4 CAMERA Verstappen TICORA Grigor MTX monotherapy MTX +CyA no steroid p.o. or i.a. Step up combination therapy + steroid ia/im YES, monthly YES YES Composite response in SJC, TJC, ESR, VAS YES, monthly YES YES DAS44 <2.4

35 NICE RA commissioning algorithm. 7/RA3.1WithGolimumab.pdf

36 MTX tolerant MTX intolerant Scenario NICE approved Licensed options NICE approved Licensed options DMARD IR DMARD IR, anti-tnf CI Anti-TNF intolerant Adalimumab, Certolizumab pegol, Etanercept, Infliximab Alternative from: Adalimumab, Certolizumab pegol, Etanercept, Infliximab Adalimumab, Certolizumab pegol, Etanercept, Golimumab, Infliximab, Abatacept, Tocilizumab Abatacept, Tocilizumab Adalimumab, Certolizumab pegol, Etanercept, Golimumab, Infliximab, Abatacept, Rituximab, Tocilizumab Adalimumab, Certolizumab pegol, Etanercept Alternative from: Adalimumab, Certolizumab pegol, Etanercept Anti-TNF ineffective Rituximab As anti-tnf intolerant Alternative from: Adalimumab, Etanercept Anti-TNF ineffective, Rituximab CI Adalimumab, Etanercept, Infliximab, Abatacept, Tocilizumab As DMARD IR Alternative from: Adalimumab, Etanercept Adalimumab, Certolizumab pegol, Etanercept, Tocilizumab Tocilizumab As DMARD IR As DMARD IR As DMARD IR Rituximab intolerant As Anti-TNF ineffective, Rituximab CI As DMARD IR Not applicable Not applicable Rituximab ineffective Tocilizumab As DMARD IR Not applicable Not applicable

37 New BSR guidelines - notes Use of DAS28 should be retained until better alternatives can be validated ACR mentions: simplified DAS, Clinical DAI, RA DAI Why 3 swollen and tender joints? Consistent with NICE psoriatic treatment guidelines Consistent with eligibility criteria for RA trials e.g. FINRACO BSR & BHPR Rheumatoid Arthritis Biologics Guidelines (Draft Guidelines)

38 Switching between anti-tnf drugs Ireland > YES EULAR > YES ACR > not mentioned BSR 09 > in patients who lack or lose response to their first anti-tnf agent, a second anti-tnf agent should be made available NICE > updated TA130 September 2010; allowed if : 1 st anti-tnf agent intolerant anti-tnf IR and Rituximab CI anti-tnf IR and Rituximab intolerant (not if Rituximab IR) NICE TA 130. Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis,

39 NICE RA commissioning algorithm. Problem only switch if anti- TNF AE, and only within first 6 months. No switch if late AE? Problem no switch if anti- TNF IR and no CI to Rituximab Problem only switch if Rituximab AE, not if IR

40 EULAR guidelines Ann Rheum Dis 2010; 69: MTX should be part of the first treatment strategy in patients with active RA if contraindicated then Lef, SSZ, i.m. gold In DMARD naive patients, irrespective of the addition of GCs, synthetic DMARD monotherapy rather than combination therapy, may be applied GCs added at low to moderately high doses... provide benefit as initial short term treatment