Highlights of San Diego 2013 CCO Independent Conference Coverage of the 2013 ACR/ARHP Annual Meeting*

Highlights of San Diego 2013 CCO Independent Conference Coverage

of the 2013 ACR/ARHP Annual Meeting*

1FacultyVivian P. Bykerk, MD, FRCPCAssociate Professor of MedicineDivision of Rheumatology, Department of MedicineWeill Cornell Medical CollegeDirector, Inflammatory Arthritis Center of ExcellenceRheumatology AttendingDepartment of Rheumatology, Hospital for Special SurgeryNew York, New YorkCong-Qiu Chu, MD, PhDAssistant Professor of MedicineDirector, OHSU Early Arthritis ClinicArthritis and Rheumatic DiseasesOregon Health & Science UniversityPortland, Oregon2DisclosuresVivian P. Bykerk, MD, FRCPC, has disclosed that she has received consulting fees from Amgen, Antares, Astellas, Bristol-Myers Squibb, Crescendo, Genentech, Pfizer, Roche, and UCB; has received funds for research support from Boehringer Ingelheim; and that her spouse has ownership interest in Novartis.Cong-Qiu Chu, MD, PhD, has disclosed that he has received consulting fees from GlaxoSmithKline. 3Therapeutics4Bioavailability of Subcutaneous MTX Dosed by Autoinjector vs Oral MTX in RA PatientsRandomized, multicenter, 12-wk, open-label, 3-way crossover phase II studyPK analysis to determine relative bioavailability of methotrexate (MTX) administered subcutaneously (SC) by an investigational autoinjector (MTXAI) vs oral MTX54 pts screened; 50 randomized to different treatment sequenceEach pt received 1 dose of MTX via each route (SC abdomen, SC thigh, oral), separated by 1 wkMTX dosing (10 mg, 15 mg, 20 mg, or 25 mg/wk) determined by each pts current dose, disease statusPredose and postdose blood samplingSchiff M, et al. ACR 2013. Abstract 796.MTX, methotrexate; PK, pharmacokinetic; RA, rheumatoid arthritis; SC, subcutaneous.5Linear, Dose-Proportionate Increase in MTX Bioavailability With AutoinjectorMean MTX area under the curve consistently higher with subcutaneous (SC) MTX autoinjector (MTXAI) vs oral MTX at all dosesBioavailability of orally administered MTX plateaued at 15 mgMTX absorption with SC MTXAI increased in linear, dose-proportional mannerMTXAI generally safe and well toleratedSchiff M, et al. ACR 2013. Abstract 796.SC MTX autoinjector (n = 96, thigh + abdomen)Oral MTX (n = 47)MTX Dose (mg/wk)Mean AUC0-24 (ngh/mL) 30002500200015001000500010152025AUC, area under the curve; MTX, methotrexate; MTXAI, methotrexate autoinjector; SC, subcutaneous; SE, standard error.Other Outcomes With Subcutaneous MTX vs Oral MTXStudy examining erythrocyte methotrexate polyglutamates (MTXPG) for therapeutic drug monitoring[1]At the same dose, switching from oral MTX to subcutaneous MTX produced higher levels of erythrocyte MTXPGProspective study in juvenile idiopathic arthritis[2]Higher concentrations of erythrocyte MTXPGs associated with lower than baseline JADAS-27 joint counts at Mo 3 and Yr 11. Kaplan R, et al. ACR 2013. Abstract 797. 2. Bulatovic Calasan M, et al. ACR 2013. Abstract 792.JADAS-27, Juvenile Arthritis Disease Activity Score 27 joint count; MTX, methotrexate; MTXAI, methotrexate autoinjector; MTXPG, methotrexate polyglutamates; PK, pharmacokinetic.7PALACE 2: Apremilast 20 mg vs 30 mg vs Placebo in Psoriatic Arthritis at Wk 52Randomized, controlled, phase III trialPrimary endpoint: ACR20 at Wk 16Apremilast 30 mg BID(n = 162)Placebo(n = 159)

Yr 5Pts with active psoriatic arthritis ( 3 swollen, 3 tender joints; duration 6 mos) despite previous DMARD and/or biologic therapy* (N = 484)Cutolo M, et al. ACR/ARHP 2013. Abstract 815. Wk 16Wk 52Apremilast 20 mg BID(n = 163)Wk 24Apremilast 30 mg BIDApremilast 20 mg BID*Concurrent use of methotrexate, leflunomide, sulfasalazine permitted (stable doses).Placebo pts with < 20% decrease in swollen/tender joints from BL to Wk 16 rerandomized to apremilast 20 or 30 mg BID. All other placebo pts rerandomized to apremilast 20 or 30 mg BID at Wk 24. ACR20, American College of Rheumatology 20% improvement criteria; BL, baseline; BID, twice daily; DMARD, disease-modifying anti-rheumatic drug.8PALACE 2: Response Rates With Apremilast Through Wk 52ACR20 response rates at Wk 16 were higher with apremilast 20 mg (38%; P = .0002) or apremilast 30 mg (34%; P = .0024) vs placebo (20%) (per protocol)Endpoints in patients completing 52 wks:Endpoints at Wk 52*Apremilast 20 mgApremilast 30 mgACR20, %52.952.6PASI-50, %49.2 58.9 PASI-75, %27.139.3Mean change in HAQ-DI-0.192-0.330Mean change in SF36 Physical Functioning domain score4.054.97*Pts who received apremilast from baseline; observed data.Pts with baseline BSA 3%.

Cutolo M, et al. ACR/ARHP 2013. Abstract 815. ACR20, American College of Rheumatology 20% improvement criteria; BSA, body surface area; HAQ-DI, health assessment questionnaire-disability index; PASI, Psoriasis Activity and Severity Index; PASI-50, 50% reduction in PASI score; PASI-75, 75% reduction in PASI score.

9PALACE 2: Apremilast Safety OutcomesDiarrhea (5.0%/11.0%/14.8%) and nausea (1.9%/9.2%/16.0%) most frequently reported AEs through Wk 24 in pts receiving placebo, apremilast 20 mg, and apremilast 30 mg, respectivelyMost cases reported during first 2 wks of therapy, generally resolved in 4 wks even with continued therapySevere cases: 3 with apremilast 30 mg through Wk 24; 1 with apremilast 30 mg and 1 with apremilast 20 mg Wk 24-52Discontinuation rate in combined apremilast arms: < 2% over 52 wksEstimated-Adjusted Incidence Rate (/100 Pt-Yrs)*Placebo-Controlled Period (Wks 0-24)Apremilast Exposure Period (Wks 0-52)Placebo(n = 159)Apremilast 20 mg BID(n = 163)Apremilast 30 mg BID(n = 162)Apremilast 20 mg BID(n = 234)Apremilast 30 mg BID(n = 234) 1 AE182.1278.5251.4186.8191.3 1 SAE5.58.96.06.37.1D/C for AE5.47.317.86.711.0Cutolo M, et al. ACR/ARHP 2013. Abstract 815. *100 x number of pts reporting event divided by pt-yrs up to first event start date.AE, adverse event; BID, twice daily; EAIR, estimated-adjusted incidence rate; SAE, serious adverse event.10PALACE 1, 2, 3: Apremilast 20 mg vs 30 mg vs Placebo in Psoriatic ArthritisPooled analysis of 3 randomized, controlled phase III trials to assess efficacy for enthesitis and dactylitis and safetyApremilast 30 mg BID(n = 497)Yr 5Pts with active psoriatic arthritis despite previous DMARD and/or biologic therapy* (N = 1493)Gladman DD, et al. ACR/ARHP 2013. Abstract 816. 2. Mease PJ, et al. ACR/ARHP 2013. Abstract 310 Wk 16Wk 52Apremilast 20 mg BID(n = 500)Wk 24*Concurrent use of methotrexate, leflunomide, sulfasalazine permitted (stable doses).Placebo pts with < 20% decrease in swollen/tender joints from BL to Wk 16 re-randomized to apremilast 20 or 30 mg BID. All other placebo pts rerandomized to apremilast 20 or 30 mg BID at Wk 24.Placebo(n = 496)

Apremilast 30 mg BIDApremilast 20 mg BIDBID, twice daily; BL, baseline; DMARD, disease-modifying antirheumatic drug.11PALACE 1, 2, 3: Summary of Apremilast Efficacy in Patients With Psoriatic ArthritisIn all 3 PALACE trials, the ACR20 response rate at Wk 16 was higher with apremilast vs placebo (per protocol)Apremilast 20 mg: P < .05, PALACE 1 & 3; P < .005, PALACE 2Apremilast 30 mg: P .0001, PALACE 1 & 3; P < .005, PALACE 2Mean changes in MASES (P = .0159) and dactylitis counts (P = .0121) at Wk 24 significantly greater with apremilast 30 mg BID vs placebo1. Gladman DD, et al. ACR/ARHP 2013. Abstract 816. ACR20, American College of Rheumatology 20% improvement criteria; BID, twice daily; MASES, Maastricht Ankylosing Spondylitis Enthesitis Score.

12PALACE 1, 2, 3: Summary of Apremilast Safety in Patients With Psoriatic ArthritisLonger exposure to apremilast generally well tolerated[1] Most frequent adverse events in all 3 trials[2]:Diarrhea (14.3%)Nausea (12.6%)Headache (10.1%)Upper respiratory tract infection (10.3%)Nasopharyngitis (7.4%)Concerning laboratory abnormalities uncommon, transient[1,2]Study investigators concluded that laboratory monitoring not needed during apremilast treatment1. Gladman DD, et al. ACR/ARHP 2013. Abstract 816. 2. Mease PJ, et al. ACR/ARHP 2013. Abstract 310. 13Intra-articular Sustained Release Triamcinolone (TCA) vs Standard TCA in Osteoarthritis Patients 12-wk multicenter, randomized, double-blind, parallel group, dose-ranging trial in patients with knee osteoarthritis10 mg, 40 mg or 60 mg single IA injection of FX006 (sustained release TCA) vs IR TCA Both 10 mg and 40 mg doses of FX006 resulted in improvement in pain relief, functional and responder status vs TCA IRSafety profile of FX006 comparable to TCA IR; all doses well tolerated Bodick N, et al. ACR 2013. Abstract 2668.Wks Posttreatment123456789101112TCA IR 40 mgFX006 10 mgFX006 40 mgLS Mean Change From Baseline, 0-10 Scale-2.2-2.7-3.2-3.7-4.2-4.7Weekly Mean of Average Daily Pain Intensity****P < .1P < .05P < .01**IA, intra-articular; OA, osteoarthritis; TCA, triamcinolone acetonide, IR, immediate release

14Disease Assessment15Determining Minimally Important Difference in Clinical Disease Activity Index (CDAI) in Early RAObservational cohort of patients with ERA used to determine MID for CDAI improvementAbsolute change > 5 units was best cutpoint to define MID (AUROC: 0.87) Different MID cutpoints based on starting disease activity: Low disease: MID > 2Moderate Disease: MID > 6High Disease: MID > 11Cutpoints useful for evaluating improvement; increases usefulness of real-world CDAI measurements Probability Density Function of CDAI Change With DAS28-ESR Improvement StratificationCurtis J, et al. ACR 2013. Abstract 2866.-80 -60 -40 -20 0 20 40CDAI Improvement Normal CurvesPercentRed bars indicate DAS28ESR improvement (> 1.2 units) in responders; green bars indicate no DAS28ESR improvement/ worsening (< 0.6 units); brown bars indicate areas of overlapDAS ESR IMPROVE > 1.2 curveDAS ESR IMPROVE > 1.2DAS ESR IMPROVE 1.2 curveDAS ESR IMPROVE 1.22520151050AUROC, area under receiver operating characteristic; CDAI, Clinical Disease Activity Index; DAS, disease activity score; ERA, early rheumatoid arthritis; ESR, erythrocyte sedimentation rate; MID, minimally important difference; RA, rheumatoid arthritis .16Biomarkers for the Diagnosis of RASerum 14-3-3 protein and autoantibodies are highly specific and discriminated early RA from controls[1]In combination with RF and ACPA, 14-3-3 biomarkers Identified large proportion of early RA pts[1]Established RA pts who are serum 14-3-3 protein negative and 14-3-3 autoantibody positive are more likely to achieve DAS remission and good EULAR response with anti-TNF therapy[2]1. Maksymowych W, et al. ACR 2013. Abstract 1786. 2. Maksymowych W, et al. ACR 2013. Abstract 1315. ACPA, anticitrullinated protein antibodies; DAS, disease activity scale; EULAR, European League Against Rheumatism; RA, rheumatoid arthritis; RF, rheumatoid factor; TNF, tumor necrosis factor.17Biomarkers for RA ProgressionThe multibiomarker disease activity (MBDA) blood test assessed radiographic progression in DMARD-treated pts with established RA[1]Radiographic progression increased nonlinearly with increasing MBDALow MBDA score associated with infrequent radiographic progressionHigh MBDA score associated with increased progression even when DAS28-CRP or CRP were lowIn early RA pts, high MBDA scorealong with elevated inflammatory biomarkers (CRP, SSA, and IL-6), MMP-1, MMP-3 and TNF-R1, and VEGFwas associated with radiographic progression at 1 yr[2]Early RA pts not responding (DAS28 > 3.2) to MTX after 3 mos had significantly higher BL CRP (P = .048) and IL-6 (P = .051) values and lower TNF-R1 (P = .002) and VCAM-1 (P < .001) values vs responders[2]1. Li W, et al. ACR 2013. Abstract 1788. 2. Hambardzumyan K, et al. ACR 2013. Abstract 1789.BL, baseline; CRP, c-reactive protein; DAS28, 28-joint count disease activity score; DMARD, disease modifying antirheumatic drugs; IL-6, interleukin-6; MBDA, multibiomarker disease activity; MMP, metalomatrix proteinase; MTX, methotrexate; RA, rheumatoid arthritis; SSA, serum amyloid A; TNF-R1, tumor necrosis factor receptor-1; VEGF, vascular endothelial growth factor; VCAM, vascular cell adhesion protein.18Angiogenic Factor Dysregulation Predicts Poor Pregnancy Outcome Risk in SLEAlterations in balance of angiogenic factors early in pregnancy predict poor pregnancy outcomes in SLE and/or aPL ptsDysregulation of placentally derived angiogenic factors (sFlt1, PlGF, and VEGF) disrupts vascular homeostasis and placental developmentContributes to placental insufficiency and preeclampsiaElevated sFlt1 levels early in pregnancy are strongly associated with subsequent PE and other poor pregnancy outcomesRatio of sFLt1/PlGF may be used as early as 16-19 wks gestation to identify pts at risk of poor pregnancy outcomes

Salmon J et al. ACR 2013. Abstract 765.aPL, anti-phospholipid antibody syndrome; PE, pre-eclampsia; PIGF, placental growth factor; sFlt-1, soluble fms-like tyrosine kinase-1; SLE, systemic lupus erythematosus; VEGF, vascular endothelial growth factor.19Treatment Approaches20OPERA: Methotrexate vs Methotrexate + Adalimumab in Early Rheumatoid ArthritisRandomized, double-blind, placebo-controlled phase III 2-yr trial[1,2]Endpoints: 1 DAS28CRP < 3.2; 2 remission and improved function ratesHigher remission rates and improved physical function in adalimumab arm at Yr 1[1]; current analysis reports Yr 2 data[2]Methotrexate 20 mg/wk + Adalimumab 40 mg Q2W* (n = 89)Methotrexate 20 mg/wkMethotrexate 20 mg/wkMethotrexate 20 mg/wk + Placebo*(n = 91)

Yr 2Yr 1*In both tx arms: pts with DAS28 3.2 and 1 swollen joint after 12 wks add sulfasalazine 2 g/day + hydroxychloroquine 200 mg/d after 3 mos; if DAS28 3.2 and 1 swollen joint after 3 mos triple therapy, biologic agent (not adalimumab) added through Wk 52, then switched to adalimumab 40 mg Q2W; intra-articular triamcinolone administered at clinic visits if any joint swollen.Pts with early (duration < 6 mos) rheumatoid arthritis (N = 180)1. Hrslev-Petersen K, et al. Ann Rheum Dis. 2013;[Epub ahead of print]. 2. Hrslev-Petersen K, et al. ACR/ARHP 2013. Abstract 2687. DAS28CRP, disease activity score 28 based on C-reactive protein; Q2W, every 2 weeks.21OPERA: No Significant Difference in Yr 2 Outcomes Between Treatment GroupsMethotrexate dose and use of intra-articular glucocorticoid, triple therapy, and biologics similar between treatment armsRates of DAS28CRP < 3.2 at Mos 12, 16, 20, and 24 similar between armsHrslev-Petersen K, et al. ACR/ARHP 2013. Abstract 2687. Outcome, %Yr 1Yr 2DMARDDMARD + AdalimumabP ValueDMARDDMARD + AdalimumabP ValueDAS28CRP < 2.64974.0016966.79CDAI 2.84161.015557.87SDAI < 3.33657.0075450.66ACR/EULAR Boolean (28)3048.01744451.00HAQ < 0.56375.096470.49ACR, American College of Rheumatology; CDAI, clinical disease activity index; DAS28CRP, disease activity score 28 based on C-reactive protein; DMARD, disease-modifying antirheumatic drug; EULAR, European League Against Rheumatism; HAQ, health assessment questionnaire; SDAI, simplified disease activity index.22TICOPA: Tight Control vs Standard Care in Early Psoriatic ArthritisRandomized, controlled, single-blind trialPrimary endpoint: ACR20 at Wk 48Minimal disease activity assessed every 4 wksIntensive Management to Achieve Minimal Disease Activity* (n = 101)Standard Care per Treating Physician(n = 105)

Yr 1*Minimal disease activity criteria: tender joint count 1; swollen joint count 1; PASI 1 or BSA 3; pt pain VAS 15; pt global activity VAS 20; HAQ 0.5; tender entheseal points 1.DMARD-naive pts with early (< 24 mos), active psoriatic arthritis (N = 206)Coates LC, et al. ACR/ARHP 2013. Abstract 814. ACR20, American College of Rheumatology 20% improvement criteria; BSA, body surface area; DMARD, disease-modifying anti-rheumatic drug; HAQ, health assessment questionnaire; PASI, Psoriasis Activity and Severity Index; VAS, visual analogue scale.23TICOPA: Treatment AlgorithmCoates LC, et al. ACR/ARHP 2013. Abstract 814. Intensive Management GroupMTXStart at 15 mg/wk escalating to 25 mg/wk at Wk 6MTX and SSZEscalating to 1g BID at Wks 4-8, then to 40 mg/kg/day maxMTX and CyAIncreasing by 1 mg/kg/day every 4 wksMTX and LEFInitially 10 mg/day increasing to 20 mg/day at Wk 4MTX and CyAIncreasing by 1 mg/kg/day every 4 wksMTX and LEFInitially 10 mg/day increasing to 20 mg/day at Wk 4Standard Therapy GroupStandard therapy as per treating physician1st-line anti-TNF therapy for 12 wks2nd-line anti-TNF therapy for 12 wksContinueContinueMDAMDAMDAMDAMDANot MDANot MDANot MDA ( 3T/S Jts)Not MDA ( 3T/S Jts)Not MDA (< 3T/S Jts)Not MDA (< 3T/S Jts)ORORBID, twice daily; CyA, cyclosporin A; Jts, joints; LEF, leflunomide; MDA, minimal disease activity; MTX, methotrexate; SSZ, sulfasalazine; TNF, Tumor necrosis factor.

24TICOPA: Prescribed Treatment at Wk 48Coates LC, et al. ACR/ARHP 2013. Abstract 814. Patients (%)LeflunomideMethotrexateSulfasalazineIntensive ManagementStandard CareBiologicCombination DMARDNo treatment100908070605040302010037.022.829.36.57.612.055.414.1DMARD, disease-modifying antirheumatic drugs.25TICOPA: Higher Response Rates With Intensive Management vs Standard CareIntensive management to achieve minimal disease criteria associated with significantly higher ACR20, ACR50, and ACR70 rates at Wk 48 vs standard care in early psoriatic arthritis patients

Coates LC, et al. ACR/ARHP 2013. Abstract 814. Patients (%)Intensive managementStandard careACR20(n = 172)ACR50(n = 170)ACR70(n = 172)100806040200624551253817P = .02P = .0004P =.002ACR20, American College of Rheumatology 20% improvement criteria; ACR50, American College of Rheumatology 50% improvement criteria; ACR70, American College of Rheumatology 70% improvement criteria.

26TICOPA: More AEs With Intensive Management vs Standard CareNo deaths in either treatment armSafety OutcomeIntensive ManagementStandard CareAny AE, n 622249Drug-related AEs, n (%)423 (68.0)179 (71.8)Serious AEs, n (%)258Drug-related serious AEs, n82Common AEs, nNauseaAbnormal liver function testUpper respiratory tract infection (common cold)Gastrointestinal upsetFatigue5437

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14138Coates LC, et al. ACR/ARHP 2013. Abstract 814. AE, adverse event.27Rituximab Retreatment in Relapsing ANCA-Associated VasculitisRAVE: randomized, double-blind, noninferiority trial compared cyclophosphamide followed by azathioprine vs rituximab in ANCA-associated vasculitis[1] Primary endpoint: BVAS/WG = 0 and no prednisone at 6 mos51% of pts in RAVE trial had relapsing disease at baselineRituximab more effective than cyclophosphamide/azathioprine in this subgroup: 67% vs 42% met primary endpoint (P = .01)[1]Pts in RAVE with severe flare between 6-18 mos eligible for open-label rituximab 375 mg/m2 once/wk x 4 wksSevere flare defined as BVAS/WG > 3 or 1 major item* Current analysis evaluated outcomes for patients (N = 17) treated with open-label rituximab for severe flare[2]1. Stone JH, et al. N Engl J Med. 2010;363:221-232. 2. Miloslavsky E, et al. ACR/ARHP 2013. Abstract 2782. ANCA, antineutrophil cytoplasmic antibody; BVAS/WG, Birmingham Vasculitis Activity Score for Wegeners Granulomatosis.

28Rituximab Retreatment for ANCA-Assocd Vasculitis Flare: Baseline CharacteristicsCharacteristicPts Treated With Open-Label Rituximab for Vasculitis Flare (N = 17)Originally assigned to rituximab in RAVE trial, n (%)16 (94)PR3-ANCA positive, n (%)14 (82)GPA, n (%)15 (88)Relapsing disease at RAVE trial entry, n (%)11 (65)Received cyclophosphamide before RAVE entry, n (%)9 (53)Mean time to open-label rituximab, days (range)367 (225-556)Mean prednisone dose at time of open-label rituximab treatment (n = 5), mg (range)8.5 (2.5-15.0)Renal flare, n (%)5 (29)Diffuse alveolar hemorrhage, n (%)1 (6)Detectable B cells at flare, n (%)15 (94)Rising ANCA at flare, n (%)14 (82)Miloslavsky E, et al. ACR/ARHP 2013. Abstract 2782. ANCA, antineutrophil cytoplasmic antibody; GPA, granulomatosis with polyangiitis; PR3, proteinase 3.29Rituximab Retreatment for ANCA-Assocd Vasculitis Flare: Efficacy OutcomesOutcomePts Treated With Open-Label Rituximab for Vasculitis Flare (N = 17)Remission,* n (%)15 (88)Time to remission, days (range)57 (27-181)Complete response,* n (%)12 (71)Time to complete response, days (range)142 (95-256)Complete remission,* n (%)8 (47)Time to complete remission, days (range)182 (121-256)Flares within 1 yr after open-label rituximab, n (%)4 (27)BVAS/WG at flare (range)2.5 (2-3)Time to flare from open-label rituximab, days (range)244 (78-428)*Remission: BVAS/WG = 0; complete response: BVAS/WG = 0 and prednisone 10 mg; complete remission: BVAS/WG = 0 and prednisone = 0.Miloslavsky E, et al. ACR/ARHP 2013. Abstract 2782. ANCA, antineutrophil cytoplasmic antibody; BVAS/WG, Birmingham Vasculitis Activity Score for Wegeners Granulomatosis.30Rituximab Retreatment for ANCA-Assocd Vasculitis Flare: AEsSafety OutcomePts Treated With Open-Label Rituximab for Vasculitis Flare(N = 17)AEGrade 1Grade 2Grade 365242AE rate in pts receiving open-label rituximab, per pt-yrGrade 1Grade 2Grade 34.51.70.1AE rate in all pts, per pt-yrGrade 1Grade 2Grade 39.42.10.5Miloslavsky E, et al. ACR/ARHP 2013. Abstract 2782. All AEs graded according to National Cancer Institutes Common Terminology Criteria; grade 1: mild AE; grade 2: moderate AE; grade 3: severe AEAE, adverse event; ANCA, antineutrophil cytoplasmic antibody.31Drug free(n = 46)Drug free(n = 32)Drug free(n = 53)Placebo injections +Placebo capsules(n = 65)Placebo injections + MTX(n = 65)ETN 25 mg QW + MTX(n = 63)PRIZE: Drug-Free Maintenance of Remission in Early RA Patients3-phase PRIZE study evaluated induction and maintenance of clinical remission in adults with early moderate to severe RA and evaluated impact of treatment reduction and withdrawal Emery P, et al. ACR 2013. Abstract 2689.Wk 52: Pts achieving DAS28 3.2 at Wk 39 and DAS28 < 2.6 at Wk 52 randomizedPts with early, moderate to severe RA treated with open-label ETN 50 mg QW + MTX 10-25 mg QWPatients who did not achieve LDA at Wks 13, 26, 56, and 64 were given corticosteroid boosts.

Over 2-4 wks. Wk 117Wk 91: Pts achieving DAS28 3.2 at Wk 91 assigned to dose-tapering then monitoring drug freeDAS28, 28-joint count disease activity score; ETN, etanercept; LDA, low disease activity; MTX, methotrexate; PBO, placebo; QW, once weekly; RA, rheumatoid arthritis.32PRIZE: Phase II and III Clinical OutcomesIn phase II (Wks 52-91), DAS28 remission and ACR/EULAR Boolean remission maintained in high % of pts receiving ETN25 + MTX vs MTX alone or placeboIn phase 3 (Wks 92-117) following withdrawal of randomized treatment, remission rates declined in all groups; significantly more pts in ETN25 + MTX group maintained remission vs placeboP < .05 for DAS28 remission (< 2.6) at Wk 117P < .001 for ACR/EULAR Boolean remission at Wk 117No unexpected safety findingsEmery P, et al. ACR 2013. Abstract 2689. ACR, American college of rheumatology; DAS28, 28-joint count disease activity score; ETN, etanercept; EULAR, European league against rheumatism; HAQ, HAQ-DI, health assessment questionnaire; LDA, low disease activity; MTX, methotrexate; PBO, placebo.33HOPEFUL 2: Biologic-Free Disease Control in Early RA Patients Observational study to assess effect of withdrawal of biologic therapy on disease activity and identify predictors of biologic-free disease control in pts with early RA*ADA 40 mg every other wk; MTX 6-8 mg every wk.Outcome assessments: DAS28-ESR, HAQ-DI, mTSS; DAS28-ESR, HAQ-DI.ADA-continued: MTX + ADA(n = 106)ADA-withdrawal: MTX alone(n = 114)HOPEFUL 1HOPEFUL 2ObservationalDouble blindOpen labelAdalimumab (ADA) + MTX*ADA + MTXMTXTanaka Y, et al. ACR 2013. Abstract 2769.Wk 0Wk 26Wk 52Wk 78Wk 104Pts with early RA ( 2 yrs) and high disease activity, naive for MTX or leflunomide or not treated with > 2 DMARDs(N = 334)Assigned at investigators discretionADA, adalimumab; DAS28-ESR, 28-joint count disease activity score-erythrocyte sedimentation rate; DMARD, disease-modifying antirheumatic drug; HAQ-DI, health assessment questionnaire-disability index; mTSS, modified total Sharp score; MTX, methotrexate; RA, rheumatoid arthritis.

34HOPEFUL 2: Low Disease Activity (LDA) and Remission Following Biologic WithdrawalPts in biologic withdrawal group had significantly higher mean DAS28-ESR scores at Wk 104 vs biologic-continued group (3.2 vs 2.7; P = .006)Tanaka Y, et al. ACR 2013. Abstract 2769.DAS28-ESR < 3.2 LDAP = .750P = .093P = .021Patients (%) 0 52 78 10469.271.670.357.972.555.80 0 0 52 78 1040 0 DAS28-ESR < 2.6 RemissionADA continued (n = 91) ADA withdrawal (n = 95)P = .077P = .01737.450.551.633.753.836.8100806040200100806040200WkWkP = .026ESR, erythrocyte sedimentation rate; LDA, low disease activity; ADA, adalimumab; DAS, disease activity score.35HOPEFUL 2: Other OutcomesNo significant difference in HAQ-DI score and mTSS in biologic-continued and biologic-withdrawal groups at Wk 104 Achieving DAS28-ESR remission at Wk 52 was a key predictor of maintaining biologic-free disease controlTanaka Y, et al. ACR 2013. Abstract 2769.DAS28-ESR, 28-joint count disease activity score-erythrocyte sedimentation rate; HAQ-DI, health assessment questionnaire-disability index; mTSS, modified total Sharp score.36TREAT: Predictors of Clinically Inactive Disease in PJIA Treated With Aggressive, Early TherapySecondary analysis[1] of randomized, double-blind, placebo-controlled TREAT study[2] to assess:Time on therapy to first indication of clinically inactive disease (CID) Duration of CID Predictors/sustainability of CID1. Wallace CA, et al. ACR/ARHP 2013. Abstract 790. 2. Wallace CA, et al. Arthritis Rheum. 2012;64:2012-2021. Methotrexate + Etanercept + Prednisolone (tapered to 0 by 17 wks)(n = 42)Methotrexate(n = 43)

Yr 1Patients aged 2-16 yrs with active PJIA for < 12 mos(N = 85)Mo 4*Mo 6**Pts without ACR Pedi 70 by Mo 4 and pts without CID by Mo 6 switched to open-label methotrexate, etanercept, prednisolone. CID is defined[2] as: 1. No joints having active arthritis, 2. No rash, fever, splenomegaly, serositis, or generalized lymphadenopathy caused by JIA. 3. No active uveitis. 4. Normal range ESR in laboratory where tested. 5. Physicians global assessment of disease activity score = 0.

ACR Pedi 70, American College of Rheumatology pediatric 70 criteria for improvement; CID, clinically inactive disease; ESR, erythrocyte sedimentation rate; PJIA, polyarticular juvenile idiopathic arthritis.

37TREAT: Baseline Disease Duration and Month-4 Response Predict Clinically Inactive Disease68% of all pts in TREAT reached clinically inactive disease (CID) during studyHigher % of follow-up days with CID with methotrexate, etanercept, prednisone vs methotrexate alone42% vs 24% (P = .048)Higher % of visits with CID in pts with vs without ACR Pedi 70 at 4 mos (P < .00001)BL disease duration associated with proportion of visits with CIDP = .002Wallace CA, et al. ACR/ARHP 2013. Abstract 790. 0.50.40.30.20.1Predicted Probability (95% CI)100200300Duration of S&S at BL (Days)ACR Pedi 70, American College of Rheumatology pediatric 70 criteria for improvement; ANA, antinuclear antibody; BL, baseline; CID, clinically inactive disease; ESR, erythrocyte sedimentation rate; RF, rheumatoid factor; S & S, signs and symptoms.38