Canadian Society of Internal Medicine Annual Meeting 2016 Montreal, QC Update on the Treatment of Rheumatoid Arthritis Sabrina Fallavollita MDCM McGill University
Canadian Society of Internal Medicine Annual Meeting 2016 The following presentation represents the views of the speaker at the time of the presentation. This information is meant for educational purposes, and should not replace other sources of information or your medical judgment. peaker: Title - date
Canadian Society of Internal Medicine Annual Meeting 2016 Conflict Disclosures Definition: A Conflict of Interest may occur in situations where the personal and professional interests of individuals may have actual, potential or apparent influence over their judgment and actions. I have received fees/honoraria from the following sources: Roche, Amgen, Pfizer, Abbvie, Novartis, BMS, Sanofi, Jansen, UCB, Sobi,
Objectives Identify recent evidence for the treatment of rheumatoid arthritis Recommend evidence-informed treatments for rheumatoid arthritis as integrated into recent (2015)guidelines Discuss areas of uncertainty and future research
RA joint deformities: various stages Early RA Intermediate RA Severe RA Courtesy of J. Cush, 2002. Actual patient. May not be representative of all patients.
RA Disease Progression Early RA Intermediate Late Inflammation Severity (arbitrary units) Disability Radiographs 0 5 10 15 20 25 30 Duration of disease (years) Kirwan JR J Rheumatol 1999; 26:720-5. Kirwan JR J Rheumatol 2001; 28:881-6.
Non-biologic DMARDs 10-16 PRODUCT Methotrexate (p.o.) Hydroxychloroquine Sulfasalazine Leflunomide Cyclosporine Azathioprine Gold salts (auranofin).5 to 25 mg/week Dose 200 to 600 mg/day to a maximum of 6.5 mg/kg ideal (lean) body weight (400mg) 500 to 3000 mg BID (1g BID) 10 to 20 mg/day 2 to max 5 mg/kg/day 1 to max 2.5 mg/kg/day 6 to 9 mg/day Adapted from respective Product Monographs 10-16 Comparative clinical significance has not been established.
Methotrexate Designer compound first used for treatment of RA and Psoriasis in 1950 s Emerged at same time as steroids but received little attention until 1980 s Studies showed response was sustained Toxicity Manageable Clear superiority to placebo
Mechanism of Action Structural analogue of folic acid Competitively inhibits the binding of dihydrofolic acid (FH2) to the enzyme dihydrofolate reductase (DHFR) Methotrexate affects the metabolic pathways within the cell that are folate dependant Purine and pyrimidine metabolism Amino acid and polyamine synthesis Mechanism in RA is not certain
Effectiveness in RA Improves all clinical variables SJC, TJC, Global assessment, ESR, CRP significantly Long term benefit in all above parameters Significant reduction in prednisone dose Significant reduction in radiographic progression (50%)?survival benefit
Optimizing Methotrexate Dosing To optimize MTX dose: Increase dose to 20-25 mg/wk Ensure folic acid or folinic acid use is appropriate if toxicity is the limiting factor Switch to parenteral route if patient on oral therapy Pharmacokinetics of MTX: Absorption of MTX after oral administration varies from 20% to 95% (mean 80%) SC absorption similar to IM Mean MTX dose 19 mg/wk Genovese MC, et al. Arthritis Rheum 2002; 46(6):1443-50.
Duration of Therapy Continue it indefinitely in responders Stopping it completely may lead to flare in 3-6 weeks If patients achieve remission can try to titrate the dose down
MTX Suboptimal Responders: Step-Up Combination Therapies MTX + leflunomide Kremer JM, et al: Ann Intern Med 2002. MTX + cyclosporine Tugwell P, et al: N Engl J Med 1995. MTX + SSZ + HCQ O Dell JR, et al: Arthritis Rheum 2002. Mottonen T, et al: Lancet 1999. Grigor C, et al: Lancet 2004
COBRA Trial: Combination Therapy is More Effective in Early RA 1.6 Pooled index score 1.2 0.8 0.4 0 Combined tx Sulfasalazine 60 mg / d 7.5 mg / d 7.5 mg / d 2000 mg / d Combined treatment protocol Prednisolone Methotrexate Sulfasalazine 0 16 28 40 56 Time (weeks) Boers M, et al. Lancet 1997; 350(9074):309-18.
Triple Therapy is not inferior to Etanercept/Methotrexate combination therapy in patients with RA who have failed methotrexate 48 week randomized double blind placebo controlled trial N Engl J Med 2013;369:307-18. Crossover at 24 weeks for non responders No difference in DAS28 CRP in either group Trend towards radiographic progression in triple therapy group Not clinically significant Mean methotrexate dose was 22.5 mg/week Patients treated with TTT method
Failure of DMARD therapy Failure to achieve remission or low disease activity within 3-6 month of DMARD (MTX, Arava) in maximally tolerated doses Chronic glucocorticoid therapy in a dose of greater than about 5 to 7.5 mg/day of prednisone or equivalent
Biologic Agents: Overview Definition: Agents designed to target specific components of the immune system (e.g., cytokines) to reduce inflammation Agents available: Abatacept (Orencia ) Adalimumab (Humira ) Anakinra (Kineret ) Etanercept (Enbrel Tocilizumab (Actemra) Infliximab (Remicade ) Golimumab (Simponi) Belimumab (Benlysta) Rituximab (Rituxan ) More agents in pipeline: Oral Tyrosine Kinases Mechanisms of action: Blockade of the effects of key inflammatory cytokines (e.g., TNFα, L-1) Efficacy: shown in monotherapy and in combination with traditional DMARDs
Anti TNF agents: Pharmacologic characteristics Biologic Structure Half-life Labelled dose in RA Adalimumab (Humira) Cetrolizumab (Cimzia) Etanercept (Enbrel) Golimumab (Simponi) Infliximab (Remicade) Adapted from respective Product Monographs. Fully human monoclonal antibody Humanized antibody Fab fragment Human dimeric fusion protein Human monoclonal antibody Chimeric human-mouse monoclonal antibody Comparative clinical significance has not been established. 10-20 days 40 mg SC every other week 14 days 2 x 200 mg SC at weeks 0, 2 and 4, then 200 mg every other week 3-5.5 days 50 mg SC per week 11 days 50 mg SC once a month, on the same day each month 8-9.1 days 3 mg/kg at weeks 0, 2 and 6, then every 8 weeks thereafter When treated with HUMIRA as monotherapy, some RA patients who experience a decrease in their response to HUMIRA 40 mg every other eek, may benefit from an increase in dose intensity to 40 mg HUMIRA every week. For maintenance therapy, 400 mg every 4 weeks may be considered. For patients who have an incomplete response to Remicade, consideration may be given to adjusting the dose up to 10 mg/kg and/or treating as often as every 4 weeks. SC = subcutaneous
PREMIER Study: ACR 20/50/70 at Weeks 52 and 104 ACR20 ACR50 ACR70 % patients 80 70 60 50 40 30 20 10 0 * * 73 69 # 63 54 56 50 80 70 60 50 40 30 20 10 0 * * 62 59 46 42 43 37 ADA + MTX ADA MTX ADA + MTX ADA MTX ADA + MTX ADA MTX 80 70 60 50 40 30 20 10 0 * * 46 47 Week 52 Week 104 26 28 28 28 *p<0.001 for adalimumab + MTX vs MTX alone and adalimumab alone # p=0.043 for MTX vs adalimumab, others NS Non-responder imputation
Three-year ACR Data from TEMPO Methotrexate Etanercept Methotrexate + Etanercept 100 ACR 20 ACR 50 ACR 70 80 85 86 85 69 71* 67 * 60 40 * 43 49 49 20 0 52 100 164 52 100 164 52 100 164 *p 0.05, Etanercept versus Methotrexate Weeks p 0.05, combination versus Methotrexate p 0.05, combination versus Etanercept van der Heijde D, et al. Presented at EULAR 2006, Amsterdam. Abstract SAT0194.
Proportions of patients meeting efficacy endpoints in the subcutaneous (SC) abatacept or adalimumab treatment groups over 2 years. Michael Schiff et al. Ann Rheum Dis 2014;73:86-94 2014 by BMJ Publishing Group Ltd and European League Against Rheumatism
Rituximab for rheumatoid arthritis refractory to anti tumor necrosis factor therapy: Results of a multicenter, randomized, double blind, placebo controlled, phase III trial evaluating primary efficacy and safety at twenty four weeks Arthritis & Rheumatism Volume 54, Issue 9, pages 2793-2806, 31 AUG 2006 DOI: 10.1002/art.22025 http://onlinelibrary.wiley.com/doi/10.1002/art.22025/full#fig4
Tocilizumab Monotherapy vs Methotrexate Monotherapy G Jones et al. Ann Rheum Dis 2010;69:88-96 2010 by BMJ Publishing Group Ltd and European League Against Rheumatism
Safety
Incidence of Adverse Effects During Long-term, Low-dose Corticosteroid Use Steroid users Non-users Incidence of AE (%) 60 50 40 30 20 10 0 p < 0.02 52.3 p < 0.003 33.9 30.2 p < 0.04 p = ns p = ns 18.9 16.0 10.7 12.0 11.6 p = ns 8.9 7.1 5.0 1.7 Fractures Hypertension Diabetes Cataracts Infections Any AE Mazzantini M, et al: Presented at EULAR 2006, Amsterdam. Abstract FRI0087.
2015 ACR treatment of Rheumatoid Arthritis Guidelines
Treat to Target Ann Rhem Dis. 2010;69(4):631-637
The future
Questions?