Practical RA Treatment: James R. O Dell, M.D. University of Nebraska Medical Center May 24, 2014

Transcription

1 Practical RA Treatment: 2014 James R. O Dell, M.D. University of Nebraska Medical Center May 24, 2014

2 Disclosures James R. O Dell PI of Multinational RA trial supported by VA and NIH (NIAMS) that receives placebo from Amgen Editor of Kelley s Textbook of Rheumatology Editor of several sections of UpToDate Advisory Boards for Lilly and Abbvie

3 Learning Objectives Participants will understand changes in therapy over the last 2 decades Understand the options for initial therapy Understand treatment options in patients with active disease despite methotrexate Understand options available after failing a TNF inhibitor

4 Since the biologicals. Changes the last 2 Decades More generalized and effective use of MTX Earlier Diagnosis Criteria and CCP Importance of Early DMARD treatment Treat to Target Universal use of Combinations of DMARDs < 5% used in 1994 Biologicals Effectiveness, Raised Expectations, Direct to Consumer Advertising

5 When a patient with arthritis comes in my front door I try to go out the back door. Sir William Osler

6 A Randomized Controlled Trial of Tight Control of Rheumatoid Arthritis (TICORA) 110 patients randomized, active RA, < 5 years duration, 18 mo Two groups: Usual therapy vs Intensive therapy Intensive Therapy: Goal of DAS < 2.4 Sulfasalazine + MTX & HCQ Dose Escalation Other DMARD MTX + CSA Oral Prednisolone * Intra-articular steroid injections used but biologicals were not. Grigor, Porter,Stirling,Capell Lancet 2004;364:263-9

7 What should the target be? Remission? Low disease activity? Significant Clinical improvement? No clear answer and is different for different clinical situations Should depend on risk/benefit including costs, etc.

8 RA Initial Therapy: Ms Jones 35 y/o lady with a 3 month history of symmetrical polyarthritis of PIPs, MCPs, 2 hours of AM stiffness ESR = 65 RF = 280 IU, CCP = ++ and MTPs.

9 Disease Modifying Anti- Rheumatic Drugs (DMARDs) Drugs that have the ability to slow or halt progression of RA; including radiographic progression Conventional Methotrexate Hydroxychloroquine Sulfasalazine Leflunomide Gold Azathioprine Minocycline Cyclosporine Prednisone Tofacitinib Biologicals Etanercept (Enbrel) Infliximab (Remicade) Anakinra (Kineret) Adalimumab (Humira) Abatacept (Orencia) Rituximab (Rituxan) Certolizumab (Cimzia) Golimumab (Simponi) Tocilizumab (Actemra)

10 So which drug or drugs for Ms Jones?

11 Questions for Initial Therapy Methotrexate or Combinations? If Combinations which one?

12 Tear Study Schema At Week 24, subjects in Arms 3 & 4 with DAS 3.2 will be stepped-up to additional active medications Toxicity Monitoring Every 6 Weeks; X-Ray at Screening, Weeks 48 and 102 DAS at Screening, Weeks 6, 12, 24, 30, 36, 48, 60, 72, 84, 96, 102 MTX 20mg/day; ETN 50mg/wk; SSZ 1000 mg BID; HCQ 200mg BID (or matching placebo) 12

13 Inclusion Criteria RA (ACR criteria) Disease duration < 3 years Active disease: 4 swollen, tender by 28 jt count RF + or CCP + or erosions = Poor Prognosis RA Limited Prior DMARD exposure Stable NSAIDs Oral prednisone allowed ( 10mg/day) No serious co-morbid conditions No significant renal, liver or hematologic lab abnormalities No active infections 13

14 Participant Demographics* Mean SD Range Disease Duration (months) mhaq HAQ Pain Age BMI DAS Painful Joints Swollen Joints * No difference by treatment groups 14

15 Observed DAS Week IE IT 5 SE ST DAS Week 0 (755) Week 12 (661) Step-up to Multiple DMARD at Week 24 if DAS Primary Analysis: Weeks 48 to 102 Week 24 (646) Week 36 (601) Week 48 (582) Comparison p-value Groups (IE, IT, SE, ST) 0.55 Time (I = S) 0.37 Trt (ETN > TT) wks 102 weeks Week 60 (522) Week 72 (518) Week 84 (508) Week 96 (485) Week 102 (476) 15

16 TEAR Cumulative Probability Initial Etanercept Initial Triple Step-up Etanercept Step-up Triple No difference among 4 groups

17 TEAR Trial DAS28 Over time 28% of MTX Group Had DAS28 < 3.2 Methotrexate Only Group MTX doses escalation: 10mg to 15 at 6 weeks; 15mg to 20mg at 24 weeks Escalation occurred if any tender or swollen joints

18

19 What is the right dose of MTX? How should you give it? How long should you wait for it to work? What is the chance the a poor prognosis RA patient will be controlled of MTX alone?

20 MTX Bioavailability Schiff et al. Eular 2013 THU0249

21 PREMIER Study ACR 20/50/70 at 1 and 2 Years ACR20 ACR50 ACR70 % of Patients * * Ada + MTX Ada Alone MTX Alone Non-responder imputation. *p<0.001 for adalimumab + MTX vs. adalimumab alone and MTX alone. p<0.05 for MTX alone vs. adalimumab alone, others not significant * * AdA + MTX Ada Alone MTX Alone * * Ada + MTX Ada Alone Week 52 Week 104 MTX Alone Breedveld et al Arthritis Rheum :26-37

22 PREMIER Study Change in TSS over 2 Years Adalimumab + MTX Adalimumab Alone MTX Alone *p<0.001 for adalimumab + MTX vs. adalimumab alone and MTX alone. **p<0.001 for adalimumab alone vs. MTX alone ** * * 10.4 Who cares? Certainly not you as a clinician. You would have switched therapy on patients who have less than optimal responses 3 ** long before 2 years. 1.9 ** Breedveld et al Arthritis Rheum :26-37 *

23 Prednisone and RA Early RA (< 1 year) 236 patients MTX vs MTX+ 10mg Prednisone 2 yr trial; Primary outcome x-rays at 2 yrs Total SHS and erosion score median 0 in both but less (P=0.022) in Prednisone 78% and 67% had no progression at 2 yrs ACR20/50/70; 70/66; 56/42; and 27/26 at 1 year (P=0.37 for ACR50) SE similar but Prednisone group gained 1.6Kg more Bakker et al Ann Intern Med 2012;156:329

24 COBRA: ESR RESPONSE 80 COBRA Improvement (%) SSA Weeks Boers; Personal communication 2002.

25 AUC of Improvement in CRP: The ERA Trial Mean % Improvement p < Etanercept 25 mg Methotrexate Months Bathon et al. NEJM 2000;343:1586

26 RA Active Despite MTX: HX: Ms Jones a 36 y/o lady returns for follow-up of her sero-positive, erosive RA of 1 year duration. Meds: MTX 25 mg/wk SC Sulindac 200mg BID; Exam: 5 swollen & 4 tender joints

27 80 MTX Failures: ACR Placebo Responders (%) Etanercept Infliximab Anakinra Adalimumab Weinblatt 24 Weeks 20 Lipsky 30 Weeks Cohen 24 Weeks 15 Weinblatt 24 Weeks 16 CSA Tugwell 24 Weeks SSZ HCQ SSZ & HCQ O'Dell 96 Weeks 20 Leflunomide Kremer 24 Weeks Gold Lehman 48 Weeks Abatacept Kremer 24 Weeks Rituximab Emery 24 Weeks Golimumab Kay 16 Weeks Tocilizumab Genevese 24 Weeks 14 Certizumab Keystone 24 Weeks Infliximab Abatacept Schiff 26 Weeks

28

29 RACAT: Study Design Randomization DAS28 Improved 1.2? Primary Outcome: ** DAS28 *SSZ + HCQ Yes No SSZ + HCQ *Etanercept Etanercept Yes Start 24 Weeks 48 Weeks *All patients continue to receive methotrexate Mean dose 19.6 mg/week

30 1 Patient Flow Chart Completed per protocol from each strategy 88% of Triple and 89% of Etanercept

31 Primary Outcome: DAS 28 at 48 wks DAS Triple Strategy Etanercept Strategy Non- Inferior P< In both Directions Week

32 DAS28 By Strategy - By Switch DAS Triple-Triple Triple-Etanercept Etanercept-Triple Etanercept-Etanercept Switch rate = 27% for both P < For improvement After switch in both groups Week

33 Change from Baseline to 48 Weeks Triple Strategy Etanercept Strategy Change in Sharp Score Radiographic Progression: Triple 0.54 Etanercept 0.29 P = Cumulative Probability

34 DAS28 Response at 24 weeks and 48 weeks by treatment group DAS28 Response at 48 Weeks 45% Proportion with DAS28 Response (%) P=0.04 P=0.03 DAS % Proportion with DAS28 Response (%) 35% 30% 25% 20% 15% 10% 5% 0% P=0.38 DAS P=0.36 DAS Triple Entanercept

35 Toxicity Triple patients more likely to have GI complaints (30% vs 22%) Etanercept patients more likely to have infections (37% vs 25%) - and serious infections 12 vs 4

36 TNF Inhibitors Which One?: Differential Efficacy &/or Toxicity? All data from the FDA s Adverse Event Reporting System Granulomatous Infections Infliximab: 239 per 100,000 patients Etanercept: 74 per 100,000 patients M. tuberculosis Infliximab: 144 per 100,000 Etanercept: 35 per 100,000 Candidiasis, coccidioidomycosis, histoplasmosis, listeriosis, nocardiosis also increase with Infliximab compared to etanercept Varicella-Zoster - with all appears < with etancept Wallis et al. Clin Inf Dis 2004; 38:1261 Kim, Solomon Nature Reviews 2010;6:165

37 RA Established Disease Therapy: HX: Ms Jones returns for follow-up of seropositive, erosive RA of 4 yrs duration. Exam: 5 swollen and 5 tender joints (an ACR 40% response) Meds: MTX 20 mg/wk SQ; Adalimumab 40 mg SQ q o wk Prednisone 5 mg/day

38 Are Anti-Drug Antibodies Present or Important?

39 Ann Rheum Dis 2013;72: studies reviewed 17 included Adalimumub and Infliximab, Anti-Etanercept not detected. Combined RA, Psoriatic and Inflammatory Bowel

40 Garces et al. Ann Rheum Dis 2013;72:

41 Summary/Significance: Anti-Drug Antibodies (ADA) to Infliximab and Adalimumab markedly decrease efficacy 68% Mtx protects against development of ADA 77% Immunosuppression with azathioprine (in IBD) appears to protect as well 50% Anti-Etanercept antibodies were not clinically significant Garces et al. Ann Rheum Dis 2013;72:

42 Inadequate Response Despite TNF Inhibition (ACR 20) Active Placebo Rituximab Cohen et al A&R 2006 Abatacept Genovese et al NEJM 2005 Tocilizumab Emery et al Ann Rheum 2008 Golimumab Smolen et al Lancet 2009 Tofacitinib Burmester et al Lancet 2013

43 Combinations of Biologicals? Etanercept and Anakinra (1) Combination not better Significant increase in infections Etanercept and Abatacept (2) Efficacy: Combination ACR 20 48% vs 31% (p=.07) Toxicity: Significant in Combination: SAE 16.5% vs 2.8% TNF (etanercept or adalimumab) and Rituximab (3) Small efficacy benefit (ACR 20 30% vs 17%) Significant increase in infections 1. Genovese et al Arthritis Rheum 2004;50: Weinblatt et al Ann Rheum Dis 2007;66: Greenwald et al. Arthritis Rheum 63:622-32, 2011

44 JAKs Inbititors have come to the RA Market* Tofacitinib (XELJANZ) Approved dose is 5 mg BID Trials most effective dose is 10 BID Data: Early, MTX IR, TNF Failure Toxicity increases with increased dose Black box: Malignancies and Serious Infections Others Toxicities: Decrease Hgb and WBCs Caveat: Screen for Tb * Not approved in Europe

45 Where does Tofacitinib fit? Major questions/concerns? 5 mg BID vs 10 mg BID Opportunistic infections European approval Cost

46 RA Initial Therapy: A 35 y/o lady with a 3 month history of symmetrical polyarthritis of PIPs, MCPs, wrists, and MTPs. 2 hrs of AM stiffness, ESR = 65, CCP Ab = ++ Hepatitis C Ab positive The DMARD of choice is: A. Methotrexate B. Sulfasalazine C. Etanercept D. Minocycline E. None are recommended in this situation

47 RA Treatment: The Hepatitis C Positive Patient 24 RA patients with Hepatitis C treated with Etanercept or infliximab no significant increase in liver enzymes or viraemia (1) Randomized trial (n=50) Hep C patients treated with interferon and ribavirin ± etanercept (2). Etanercept patients decreased side effects HCV RNA absent: Etanercept 12/19 vs. 8/25 (P=0.04) 1. Peterson J et al Ann Rheum Dis 2003;62: Zein et al J Hepatology 2005;42:315-22

48 Hepatitis C and RA MTX and Leflunomide relatively contraindicated Hydroxychloroquine Sulfasalazine Cyclosporine may be option Anti-TNF therapy not FDA approved Etanercept, adalimumab, infliximab?

49 Lancet 2013;381: RA patients intolerant or inappropriate for MTX. Double-blind, randomized to mono-therapy with Tocilizumab 8 mg/kg q 4 wks vs Adalimumab 40 mg q 2 wks. Primary End Point: DAS28 at 24 weeks: Toc = -3.3 vs Ada -1.8 (p < ) * Funded by Hoffman-La Roche

50 Gabay et al. Lancet 2013;381:

51 Primary End Point - DAS28 at 24 weeks Tocil -3.3 vs Ada -1.8 p< wks Gabay et al. Lancet 2013;381:

52 Summary/Conclusions: In patients who cannot take MTX (or I guess other DMARDs) Efficacy of high dose Tocilizumab is superior to Adalimumab at 24 weeks p < Elevated LDL and ALT and reduced platelets and neutrophils more common in Tocilizumab group. Two deaths both in Tocilizumab group cause unknown. *Patients with long-standing RA who recently stopped taking MTX Gabay et al. Lancet 2013;381:

53 What is the right dose of Etanercept?

54 Predicted and Actual Annual Change in Total Sharp Score Mean Change Etanercept 25 mg Etanercept 10 mg Methotrexate Predicted Actual Predicted Actual Predicted Actual Bathon et al. NEJM 2000;343:1586

55 Do you use Azathioprine in the treatment of RA?

56 The McCarty Combination: Azathioprine-Methotrexate- Hydroxychloroquine Open observational study of 169 patients Drugs added sequentially to control disease Combination well tolerated 41% of cohort required all 3 drugs Overall 43% Complete Remission Rate McCarty et al. J Rheumatol 1995;22:1636

57 Azathioprine and RA Very effective therapy Indications may include patients who don t tolerate or can t take MTX Works well in combination Decreases anti-drug antibodies

58 RA: DMARDs and Pregnancy Methotrexate and Leflunomide Strongly contraindicated!!!!! Azathioprine (Probably safe) Rudolph et al. Transplantation 1979;27:26 Sulfasalazine (Probably safe) Mogadam et al. Gastroenterol 1981;80:72 Hydroxychloroquine (Probably safe) Levy et al. Arthritis and Rheum 1998;41:S241? TNF Inhibitors (Jury out) Case reports without problems VACTERL (J Rheum 2009;36:635 and? miscarriages Arthritis Rheum 2008;58:S542? Increased safety margin for certolizumab?

59 Optimal Economic Management of RA Start with MTX monotherapy push to at least 25 mg/wk ; consider Sub Q (control 35-45% of patients) At 6 months add SSA and HCQ (20-30% of the rest) At 6 months switch to MTX + TNF Inhibitor (about 30 to 45% of patients will need biologicals). However, many of these will not reach targets and many others will need < full dose biological therapy. Remember in MTX TNF failure Triple therapy can be successful (RACAT trial data).

60