TREG EULAR Conference Analysis Rome, Italy June 16-19, 21
Rheumatoid Arthritis: Management and Current Therapies Arthur Kavanaugh, MD Martin Bergman, MD John J Cush, MD Orrin Troum, MD Alvin Wells MD, PhD
EULAR treatment algorithm for RA No contraindication to MTX Clinical diagnosis of RA Contraindication to MTX Start MTX Combine with short-term high or low dose prednisone ± ± Start LEF, SSZ, Gold FAILURE go to Phase 2 NO Achieve target by 3-6 months YES Continue Adapted from Smolen JS, et al. Ann Rheum Dis. 21;69:964-75; EULAR 21, Rome, Plenary session
EULAR treatment algorithm for RA: Phase 2 Poor prognostic markers: ACPA+, RF+, Erosions, High Disease activity Failure to achieve goal (lack of efficacy or side effect) Lack of poor prognostic markers Add biologic (consider TNF-i) NO Achieve target by 3-6 months Start 2nd DMARD (LEF, SSZ, MTX) as monotherapy or combo ± steroids FAILURE go to Phase 3 NO Achieve target by 3-6 months YES Continue Adapted from Smolen JS, et al. Ann Rheum Dis. 21;69:964-75; EULAR 21, Rome, Plenary session
EULAR treatment algorithm for RA: Phase 3 Failure to achieve goal (lack of efficacy or side effect) Achieve target by 3-6 months YES Change biologic agent: 2ndTNFi + DMARD Abatacept + DMARD Rituximab + DMARD Tocilizumab ± DMARD NO Continue Adapted from Smolen JS, et al. Ann Rheum Dis. 21;69:964-75; EULAR 21, Rome, Plenary session
New ACR/EULAR RA criteria JOINT DISTRIBUTION 1 Large Joint 2-1 Large Joints 1 1-3 Small Joints (large jts excluded) 2 4-1 Small Joints (large jts excluded) 3 >1 Joints (at least 1 small joint) 5 SEROLOGY Negative RF and Negative ACPA Low Positive RF or ACPA ( 3x ULN) 2 High Positive RF or ACPA (>3x ULN) 3 SYMPTOM DURATION <6 weeks 6 weeks 1 ACUTE PHASE REACTANTS Normal CRP and ESR Abnormal CRP or ESR 1 RA can be classifiable or diagnosed with a score 6 Aletaha D, et al. EULAR 21, Rome, Plenary session
Validity of the revised ACR/EULAR classification criteria for RA How well do they predict persistent arthritis and joint erosions after 2 years, in a cohort of 566 pts with early undifferentiated inflammatory arthritis? Pts with risk score 6 at baseline had.74 probability of persistent arthritis;.68 probability to develop erosions Proposed cut-points: definite RA : held at 6 probable RA : 3 1 Also validated in REACH early inflammatory arthritis cohort: AUC.82 high specificity 2 ACR/EULAR criteria for RA are valid predicting persistent arthritis & erosions in early undifferentiated arthritis 1. Fransen J, et al. EULAR 21, Rome, OP277; 2. Alves CJ, et al. EULAR 21, Rome, OP39
Will ultrasound (US) alter the treatment of rheumatoid arthritis? US evaluation of 7 joints may be adequate to diagnose and monitor RA patients 1 Gray scale and power Doppler US are better tools at detecting patients in remission 2 US eval of 48 RA pts detected joint pathology which responds to antirheumatic drugs more accurately than joint examination 3 Various aspects of US may make it a useful tool to monitor disease activity and response to therapy, including progression of erosions 1. Ohrndorf S, et al. EULAR 21, Rome, FRI441; 2. Kitchen, et al. EULAR 21, Rome, OP143; 3. Ikeda I, et al. EULAR 21, Rome, FRI126
SWEFOT: Triple DMARD vs MTX / TNFi Early RA; Sx <1 yr No other DMARD DAS28 >3.2 n=487 Pt disposition MTX monotherapy (up to 2 mg/wk) 3 4 m Screening MTX responders followed over 2 years: clinical + X-ray 1% 8% Disease activity (using DAS28) at times shown MTX responders MTX intolerance Other disease Other Arm A Arm B 128 (26.3%) 145 (29.8%) 145 (29.8%) 13 (26.7%) 27 (5.5%) 9 (1.8%) 48 (9.9%) 6% 4% 2% % 3 m 6 m 12 m 18 m 24 m High Med Low Remission van Vollenhoven R, et al. Lancet. 29;374:459 66; van Vollenhoven RF, et al. ACR 29, Philadelphia, #11; Wallin H, et al. EULAR 21, Rome, THU198
SWEFOT: X-ray progression despite good MTX response Despite favorable clinical outcome, radiographic progression occurs in patients on MTX Majority of patients have little to no progression 5 4 3 2 1 All Progress in vdh-s total score In remission at every timepoint (n=16) MTX monotherapy Increase in -24 mos in total SvDH score Increase in total vdh-s score Probability plot 4 3 2 1-1 -2 2 4 6 8 1 12 Number of patients Despite good clinical response on MTX monotherapy, radiographic progression may continue Wallin H, et al. EULAR 21, Rome, THU198
COMET: Very early MTX+TNFi increases remission rates in RA Post-hoc analysis of the COMET VERY early RA (<4 mos) (VERA, n = 113) Early (> 4 mos) (ERA, n=35) Baseline values equal; Less X-ray damage in VERA Earlier aggressive Rx remission Yet, HAQ unchanged by earlier Rx Remission rates differ in VERA and ERA groups suggesting a window of opportunity in early RA % subjects P=.35 69.8 Remission 47.8 MeanTSS Change in mean TSS score 5 VERA 4 ERA 3 2 1 P=.737 34.7 31.8 P=.7483.31 ETN+MTX P=.138.21 LDAS 79.4 61.8 P=.293 1.12 MTX VERA ERA P=.9692 46.9 46.6 ETN+MTX MTX ETN+ MTX MTX 3.32 Emery P, et al. EULAR 21, Rome, LB1
Maintaining remission is more important than attaining remission 8 year follow-up of BARFOT early RA patients; Three groups: 1. Sustained-all 4 visits DAS28<2.6; 2. Sporadic-at least 1 visit DAS28 2.6; 3. Never-no visit DAS28 2.6 3. SHS (total Sharp score) 1.2 HAQ Persistent disease Sporadic remission Sustained remission Error Bars: 95% CI 1. mean: 95% CI Mean 2. Mean.8.6 1..4.2 Baseline 1 year 2 years 5 years 8 years Time Only sustained remission was able to demonstrate superiority in terms of X-ray changes and the ability to stop DMARDs/ Prednisone Svensson B, et al. EULAR 21, Rome, SAT53. Baseline 6 months 1 year 2 years 5 years 8 years Time
JESMR: MTX + etanercept is superior to etanercept alone % patients 4 35 3 25 2 15 1 5 Remission rate on DAS28 P=.1 P=.38 RCT 151 pts x 52 wks P=.16 2 4 8 12 24 52 14 Treatment period (weeks) ACR-N at 14 weeks MTX-IR ETN vs ETN+MTX (MTX 6-8 mg/wk) ACR-N 1 8 6 4 2..1.2.3.4.5.6.7.8.9 1. Cumulative probability ETN + MTX ETN Even small doses of MTX significantly augment TNFi responses in RA Kameda H, et al. EULAR 21, Rome, THU175
Serious skin & soft tissue infections (SSI) in RA pts: Effect of TNFi therapy Risk of SSI from BSRBR 11,798 RA pts on TNFi vs 3598 on DMARD Rx Hazard ratio = 1.9 (1.2-2.8) No difference between agents Mean hospital stays equal Staph most common (65%) & equal in both groups More pseudomonas in TNFi treated pts (16% vs 6%) SSI Risk is increased w/ TNF inhibitors, esp. in 1 st 6 months Group (N) DMARD (3598) Anti-TNF (11,798) Exposure (ptyrs) Events 1,69 4 45,135 3 ADA 13,187 71 ETN 2,782 144 INF 12,511 85 Galloway, J et al. FRI17 EULAR 21 Rome, Italy 3 Galloway J, et al. EULAR 21, Rome, FRI17 IR/1 ptyrs (95% CI) 3.7 (2.7, 5.1) 6.5 (5.7, 7.2) 5.4 (4.2, 6.8) 6.9 (5.8, 8.2) 6.8 (5.4, 8.4)
Comparable risk of MI in RA and DM Population study All Danes age 1 on 1/1/97 RA = 1,3 DM (Type I & II) = 132,189 Overall MI risk RA: 1.75 (1.56-1.96) DM: 1.89 (1.8-1.96) MI risk in RA comparable to DM, esp young & women. RA patients have MIs 1 years earlier than normals Lindhardsen J, et al. EULAR 21, Rome, OP164 IRR Event rate (MI/1 patients-years) 8 7 6 5 4 3 2 1 16 14 12 1 8 6 4 2 <5 Risk of myocardial infarction Controls RA DM Women * 5-65 >65 Age *P<.5 * NS Men <5 5-65 >65 Rates of myocardial infarction 4-5 Controls NS NS 4-5 5-6 RA NS Age NS NS 6-7 7-8 >8
Different factors are important for RA pts & rheumatologists regarding DMARD escalation Five most important reasons to escalate DMARDS RA patients Current level of physical function Trust in rheumatologist # of painful joints Satisfaction w/ current DMARDS Overall general health Rheumatologists # of swollen joints DAS 28 Global assessment of RA disease activity Worsening of erosions RA disease activity now compared to 3 mos ago 5 top reasons between MDs & pts don t correspond. Improved communication between MDs and pts may increase appropriate treatment re: published guidelines Van Hulst L, et al. EULAR 21, Rome, OP272; Kievit W, et al. A&R/AC&R 21;62:842-7 17
Methotrexate plus leflunomide in RA 395 RA pts seen between 1/ - 6/9 15 Rx w/ MTX + LEF 97% RF+; 67% erosive Mean DMARDs = 2 33% prior DMARD use Discontinuations = 23.8% (w/in a median of 14 mos) None for LFT elevation 5.7% for AE (rash, HA, N/V, Plts) LFT Elevations % pts Events/ 1PY AST or ALT 1.5-2x ULN 11.4 5.6 AST + ALT 1.5-2xULN 2.8 1.1 AST or ALT 2-3x ULN 2.8 1.85 AST + ALT 2-3x ULN 1.9.74 AST or ALT >3x ULN 1.9 1.48 2 AST +/or ALT 1.5-2x (consecutive) 2 AST +/or ALT>3x ULN (consecutive) 1.9.74 Significant LFT elevations were infrequent, transient, reverted to normal in <3 mos, and did not lead to discontinuations Hensley G, et al. EULAR 21, Rome, THU28
Decrease in sick leave in RA with TNFi therapy Proportion of pts w/ ongoing sick leave (SL) & disability pension (DP) in 3-day intervals from 36 days before until 36 days after TNFi Rx started Results: At Rx start: 38.6% of pts SL registered At 6 mo: 28.5%. It remained stable throughout the 1 st Rx yr Comparing RA pts vs controls, the RR of SL from 6.6 at start of TNFi Rx to 5.2 after 1 yr RR of DP unchanged 3.4 at Rx start & 3.2 after 1 yr Percentage of subjects on SL (95% CI) 5 4 3 2 1 p<.1 p=1. Treatment start p<.1 p=.91-36-3-24 -18-12 -6 6 12 18 24 3 36 Days before and after treatment start RA patients Reference group n=365 n=146 Marked decline in SL after TNFi Rx; sustained through 1 year Olofsson T, et al. EULAR 21, Rome, OP21 19
Sick leave/disability pension in RA before and after biologic use: ARTIS Biologic therapy effective but expensive; value depends on functional status/work ability ARTIS registry: 6,347 Swedish RA pts; matched to 5 controls. Annual sick days / disability pension Baseline: 42% RA pts vs 12% controls part/full time disability pension Until start of biologics, RA pts had markedly increasing disability: This stabilized after Rx began Mean Days of Sick Leave and Disability Pension/Year 25 2 15 1 5 1997 RA Patients (bio start 21) RA Patients (bio start 25) Population Controls (matching 21) Population Controls (matching 25) 1998 1999 2 21 22 23 24 25 26 27 Biologic therapy may prevent the progression of work disability in RA Neovius M, et al. EULAR 21, Rome, OP93
Risk of cancer in children receiving TNFi 29 FDA warns of risk of cancer & lymphoma w/ TNFi use in kids 1 Focus 4 EULAR abstracts examined risk of neoplasia in JIA and w/ TNFi Rx Risk of Cancer in JIA patients Risk of Cancer with TNFi Rx Simard, et al. 2 Harrison, et al. 3 Harrison, et al. 4 Horneff, et al. 5 Swedish JIA Cohort showed no increase in cancer rates; However, after 1987 higher rates for all cancers (RR=2.6) and lymphoproliferative cancers (HR=3.8) 365 biologic naïve JIA pts (US claims database) trended towards an cancer risk in JIA (HR=2.8 (.9-8.3); SIR=4) 1691 JIA patients followed in 3 ETN Cohorts; Only 2 cancers seen (SIR=3.7; CI.5-13.7) 12 JIA patients on TNFi compared w/ 1 nontnfi pts; No cancer increase on TNFi (.4%) vs off TNFi (.3%) Background cancer rates are increased in JIA. Few cases & wide confidence intervals preclude inference of cancer risk due to TNFi 1. ACR Drug safety quarterly Winter 21; 2. Simard, et al. EULAR 21, Rome, OP86; 3. Harrison M, et al. Ibid. SAT444; 4. Harrison M, et al. Ibid. OP274; 5. Horneff, et al. Ibid. SAT448
TENDER: TCZ in Systemic Onset JIA DB, RPCT: 12 wks; 112 pts with SoJIA with joint & systemic manifestations 1 o outcome: ACRJIA3; secondary absence of fever Patients: 9-1 yrs, Dz duration ~5 yrs, 17-21 active joints, fever 7% Response: 85.3% vs 24.3% (TCZ vs Placebo) Responders (%) 9 8 7 6 5 4 3 2 1 p<.1* 85 p=.8* 64 21 11 8 p<.1* 71 Fever-free Rash-free JIA ACR7 Placebo (n=37) TCZ (n=75) TCZ is highly effective in control of articular & systemic manifestations of SoJIA De Benedetti F, et al. EULAR 21, Rome, OP273