Rheumatoid Arthritis: When to Start and when to Stop anti-tnf Therapy [ Cuando iniciar o detener la tx anti-tnf?] Asociacion Costatarricense Medicina Interna August 7, 2015 Arthur Weinstein, MD, FACP, FRCP, MACR Professor of Medicine, Georgetown University Rheumatology, MedStar Washington Hospital Center
Progression of RA 2
Rheumatoid Arthritis (RA): The Window of Treatment Opportunity RA Sx Onset 4 Months 2 Years Bony Erosions 70%-80% 10-20 Years Long-term Disability 80% Adapted from: Bykerk VP, Keystone EC. J Musculoskelet Med. 2004;21:133-146. 3
Rate of Development of New Damage of Joints Mean number of joints 3.0 2.5 2.0 1.5 1.0 Newly eroded Newly narrowed 0.5 1 2 3 4 5 6 Follow-up in years ulsmans r thritis Rheum. 2000.
Radiographic Score (Disease Progression) Window of Opportunity in RA: Disease Modifying anti-rheumatic Drugs (DMARDs) 70 DMARDs are associated with a decrease in radiographic progression 60 50 40 30 20 10 0 NO DMARD DMARD 0 1 2 3 4 5 Years of Disease P<0.05 at 2 years Lard LR, et al. Am J Med. 2001;111:446-451; Weisman M. Ann Rheum Dis. 2002;61:287-289. 5
Median Sharp Score Delayed treatment (median treatment lag time, 123 days; n = 109) Early treatment (median treatment lag time, 15 days; n = 97) 14 12 10 8 6 DMARD Treatment: The Earlier the Better DMARDs = chloroquine or salazopyrine 4 2 0 0 6 12 18 24 Time (months) * *p < 0.05 vs delayed-treatment group. Lard LR et al. Am J Med. 2001;111:446-451
Central Role of TNF in RA TNF osteoclasts synoviocytes chondrocytes bone resorption joint inflammation cartilage degradation bone erosion pain/joint inflammation joint space narrowing
TNF Antagonists 5 currently approved agents (USA): etanercept, adalimumab, infliximab, certolizumab pegol, golimumab Subcutaneous (etanercept, adalimumab, certolizumab pegol, golimumab) and intravenous administration (infliximab) Administration in combination with MTX is superior to monotherapy* Time to onset: rapid (weeks) Adverse events infection - bacterial, TB, fungal, H. Zoster malignancy - not higher rates than the background of lymphoma and solid tumors in RA population multiple sclerosis/demyelination, lupus-like syndrome, worsening CHF,?Hep B reactivation syndrome (esp infliximab) Monitoring TB screening including PPD prior to therapy, Hep B screenig Periodic CBC, LFTs Infection O'Dell JR. N Engl J Med. 2004;350:2591-2602. Klareskog L, et al Lancet. 2004;363:675-681*; Breedveld F, et al. Arthritis Rheum. 2006;54:26-37*. 8
ACR20 Response Infliximab / Methotrexate Combination (ATTRACT) Patients (%) 80 60 40 p < 0.05 vs recommended dose 50* 50* 52* 58* 42 48 59 59 Methotrexate + placebo Methotrexate + infliximab 3 mg/kg q 8 wk Methotrexate + infliximab 3 mg/kg q 4 wk Methotrexate + infliximab 10 mg/kg q 8 wk Methotrexate + infliximab 10 mg/kg q 4 wk 41 40 48 42 20 20 17 16 0 *p < 0.001 vs control p < 0.05 vs control 30 Weeks 54 Weeks 102 Weeks Maini. Lancet. 1999. Lipsky. Arthritis Rheum. 1999. Lipsky. Arthritis Rheum. 2000.
ATTRACT STUDY GROUP PERCENTAGE OF PATIENTS THAT REACHED ACR 50 35% 30% 25% 20% 15% 10% 5% 0% * * * 30 weeks * P<0.001 * Placebo 3mg/4W 3mg/8W 10mg/4W 10mg/8W
ATTRACT Trial Mean Change in Total Modified Sharp Score at Week 102 12 12.6 Mean change from BL 10 8 6 4 2 1.0* 1.0* 1.1* *p < 0.001 vs placebo + MTX 0 Placebo 3 mg/kg q 8 wk 3 mg/kg q 4 wk 10 mg/kg q 8 wk - 0.4* 10 mg/kg q 4 wk Lipsky. Arthritis Rheum. 2000.
Other biologics and small molecule for RA Abatacept (Orencia) recombinant CTLA4-Ig (co-stimulatory blockade) Rituximab (Rituxan) Bell-cell depletion (anti-cd20) Tocilizumab (Actemra) IL-6 receptor antagonist Anakinra (Kineret) recombinant IL-1 receptor Tofacitinib (XELJANZ, Jakvinus) oral JAK inhibitor (JAK 3, JAK 1) 12
Poor Prognostic Factors in RA Early age at onset Polyarticular disease (increasing number of joints) Systemic extra-articular disease (nodules, vasculitis, eye disease, interstitial lung disease) High-titer RF positive Anti-CCP antibody positive Persistent disease activity (high ESR, CRP, disease activity scores) HLA-DRB1 shared epitope positive (strongest known genetic risk factor for RA) Lindqvist E, et al. Ann Rheum Dis. 2005;64:196-201; Erhardt CC, et al. Ann Rheum Dis. 1989;48:7-13; Wolfe F, et al. Arthritis Rheum. 2003;48:1530-1542. 13
Standard Treatment in Early RA (< 6 months) Singh et al. Arthritis Rheum 2012 DISEASE ACTIVITY LOW MOD HIGH POOR PROGNOSIS DMARD MONOTHERAPY MTX LEF SSZ/HCQ COMBO DMARD (2/3) DMARD + ANTI-TNF
Inadequate response to MTX Smolen JS et al. Ann Rheum Dis 2013 sub-optimal MTX response (3 months) combination other biologics DMARDs DMARD? monotherapy combination therapy anti-tnf switching change biologic
Optimizing Treatment Response Target low disease activity/remission Weinblatt ME et al: Arthritis Rheum 2008; Dervieux T et al: Rheumatology 2010 O Dell JR et al: NEJM 2013; Scott et al : BMJ 2015 O Dell JR et al: Arthritis Rheum 2013; Villeneuve E, Haroui B: Int J Adv Rheumatol 2006 De Punder YMR et al: Rheumatology 2012 Saevarsdottir S et al. Arthritis Rheum 2011 Optimizing MTX response (monotherapy or combination therapy) Dose can increase to 20-25 mg/week Route SC, IM? Role of MTX polyglutamate levels (whole blood MTX levels) 30% achieve low disease activity/remission with MTX alone Use combination DMARDs or MTX plus anti-tnf early (step up) another 30-40% achieve low disease activity/remission Stop smoking Switch anti-tnfs or to other biologics as needed dose increase not effective with anti-tnfs Monitor disease activity clinical, ultrasound, biomarkers CRP, Vectra (MBDA score) - TREAT TO TARGET (LDA/REM) 16
What about corticosteroids? Wassenberg S et al: Arthritis Rheum 2005; Smolen JS et al. Ann Rheum Dis 2013 Low dose prednisone/prednisolone (<7.5mg/day) reduces inflammation and radiographic progression EULAR recommendation consider at start High doses should not be used IM methylprednisolone can be used for flares, bridge therapy Concern regarding long term side effects - glucose intolerance, osteoporosis, infections, H Zoster, CV risk 17
Stopping biologics (anti-tnfs) Why Stop? Remission is achievable (?20-30%) with DMARD + anti- TNF agents and low disease activity is attained in the majority but is it lasting off drug? Short and long term side effects of anti-tnf agents skin, infection, opportunistic infection, granulomatous inflammation Cost of anti-tnf agents Patient preference these are injectables, infusions
Stopping anti-tnfs Uncontrolled Studies Van den Broek et al. ARD 2011: BeSt study. Active early RA (< 2years) IFX + MTX. 104 pts DAS<2.4 (mean 1.3) for >6 mos IFX d/c. 50/104 (48%) flared in 3-6mos. Successfully reintroduced in 84% Tanaka et al. A&R 2012 (abstract): HONOR Study: 51 pts on ADA + MTX - DAS 28-ESR< 2.6 > 6 mos, ADA d/c followed for 12 mos. Mean disease dur n 7.1yrs - 27/42 (64%) flared. Deeper remission (DAS<1.9) and shorter disease duration correlated with remission maintenance
Stopping Anti-TNFs Recent Controlled Trials Smolen JS et al. Lancet 2013; Smolen JS et al. Lancet 2014; Emery P et al. NEJM 2014 PRESERVE Trial: Patients with active RA (mean disease duration app 7yrs) put on MTX + ETA (50mg/wk). Those with LDA for 3-9mos randomized (blinded) to: MTX + placebo (ETA stopped); MTX + ETA 25mg; MTX + ETA 50mg LDA maintained @ 36 wks? 43% vs 79% vs 83% OPTIMA TRIAL: Patients with active RA (< 1 yr) in RCT for ADA +MTX. Those achieving LDA randomized to ADA withdrawal or not. LDA maintained @ app 52 weeks? 54% vs 70% PRIZE TRIAL: ETA + MTX similar to PRESERVE but early RA (< 1 yr) to 3 gps: placebo (no MTX or ETA); MTX + placebo (no ETA); MTX + ETA 25mg LDA/REM maintained @ 39 wks? 23% vs 40% vs 63%
Stopping anti- TNFs Is it possible yes.flare Rate: 30-65% Predictors of sustained remission (clinical): deep remission (DAS28<1.9), low HAQ, prolonged duration of remission, short duration RA (early RA) Predictors of flare (imaging): MSKUS Power Doppler (PD) (Saleem et al. Ann Rheum Dis 2012, Foltz et al. A&R 2012) If PD present flare OR 4-6
Stopping Anti-TNF Agents in Rheumatoid Arthritis (STARA) Trial Double-blind Placebo-controlled (2:1 placebo:drug) Stopping trial 48 weeks (8 week run in, 52 week FU) Patients taking infliximab, adalimumab or etanercept Taking traditional DMARD NIAMS/Extramural site collaboration- academic and priivate practice sites Flare Rate and Predictors of Flare
STARA Trial 1. Baseline depth of remission (DAS 28, SDAI<3.3, ACR/EULAR) and other clinical data, smoking 2. Baseline imaging (ultrasound, MRI) 3. Baseline flow cytometry, genetics (shared epitope) and gene expression profiles, cytokine profiles CAN A CLINICAL/ IMAGING/LABORATORY PROFILE PREDICT WHICH PATIENTS WILL FLARE AND WHICH WILL NOT?
RA: It s Not Just the Joints!! CVD 10 Years Earlier Osteoporosis 2X Rate Malignancy Joint Destruction Disability Pain 6-9X Serious Infection Rate Pulmonary Disease GI Bleeding Deane K. J Musculoskel Med. 2006;23:S24-S31. 24
What has Modern RA Therapy Accomplished? A GREAT DEAL Chronic deforming/ destructive RA greatly reduced and delayed Quality of life greatly improved Secondary amyloidosis almost gone Rheumatoid vasculitis (high mortality) now very rare CV fatality rate has decreased RA with LDA Meek IL et al. BMC Musculoskeletal Disorders 2014 GRACIAS 25