Disclosure Statement Is Methotrexate A Disease Modifying Agent In Psoriatic Arthritis? Gabrielle H Kingsley Consultant and Reader in Rheumatology King s College London Lewisham Healthcare NHS Trust Dr Kingsley has received no funding from Pharmaceutical companies in the last 5 years The MIPA trial was funded by Arthritis Research UK (Leading UK Arthritis Charity) The methotrexate and matched placebos used in the MIPA trial were supplied by Wyeth without charge Key Publications 1. NOR-DMARD Registry Lie E, van der Heijde D, Uhlig T, Heiberg MS, Koldingsnes W, Rødevand E, Kaufmann C, Mikkelsen K, Kvien TK. Effectiveness and retention rates of methotrexate in psoriatic arthritis in comparison with methotrexate-treated patients with rheumatoid arthritis. Ann Rheum Dis 10; 69: 671-6. 2. MIPA Trial Kingsley GH, Kowalczyk A, Taylor H, Ibrahim F, Packham JC, McHugh NJ, Mulherin DM, Kitas GD, Chakravarty K, Tom BD, O Keeffe AG, Maddison PJ, Scott DL. A randomised placebo-controlled trial of methotrexate in psoriatic arthritis. Rheumatology, Submitted. 3. RESPOND Trial Baranauskaite A, Raffayová H, Kungurov N, Kubanova A, Venalis A, Helmle L, Srinivasan S, Nasonov E, Vastesaeger N; RESPOND investigators. Infliximab plus methotrexate is superior to methotrexate alone in the treatment of psoriatic arthritis in methotrexatenaive patients: the RESPOND study. Ann Rheum Dis, epub (doi:10.1136/ard.11.152223 ) Summary Existing Guidance Historic Data New Data NOR-DMARD registry MIPA Trial RESPOND Trial GRAPPA Treatment Guidelines For PsA Group for Research and Assessment of Psoriasis and Psoriatic Arthritis Psoriasis/Psoriatic Arthritis Guideline SIGN: Scottish Intercollegiate Guidelines Network 10 Peripheral arthritis AIDs IA steroids DMARDs (MTX,CsA, SSZ, LEF) Skin & nail disease Topicals PUVA/UVB Systemics (MTX, CsA etc) Axial disease AIDs Physio Dactylitis AIDs Injection Reassess response to therapy and toxicity Enthesitis AIDs Physio Dermatology/rheumatology teams Should work closely together Use methotrexate to treat psoriatic arthritis Especially when severe cutaneous psoriasis For peripheral psoriatic arthritis Use leflunomide or sulfasalazine as alternatives Treat with biologics Active psoriatic arthritis Failed to respond/intolerant/contra-indications to 2 DMARDs Ritchlin et al, Ann Rheum Dis 09;68:1397-94 1
EULAR Recommendations For Management of PsA EULAR Recommendations For Management of PsA Gossec et al, Ann Rheum Dis, 11 Gossec et al, Ann Rheum Dis, 11 Exploring the Evidence for DMARDs in Psoriatic Arthritis Guidelines all recommend methotrexate which implies strong evidence base But reality is different which is shown in rest of talk Aim of DMARD therapy is to improve outcome not just symptoms Improvement in disease outcome best predicted by disease activity scores (particularly swollen joint and acute phase response elements) function (HAQ) imaging? Definitive demonstration of DMARD activity is hard to confirm outside placebo-controlled RCTs Summary Existing Guidance Historic Data New Data NOR-DMARD registry MIPA Trial RESPOND Trial Sulfasalazine For Psoriatic Arthritis 221 patients, 2gm Sulfasalazine, 36 weeks treatment Sulphasalazine 7 P=0.05 6 5 4 3 2 1 PsARC Responder Results are on borderline for statistical significance Re-analysed using Odds Ratio Accounts for small numbers 1.7 0.5 0 5.0 Clegg et al, Arthritis Rheum, 1996 2
Leflunomide For Psoriatic Arthritis 190 patients, mg Leflunomide, 24 weeks treatment Methotrexate For PsA Historic -Controlled RCTs 7 6 5 4 Leflunomide P<0.0001 Results are of strong statistical and clinical significance IV Methotrexate (Black et al, 1964) 3 IV Pulses of MTX/placebo in 21 patients with PsA MTX improved joint counts and But one death (marrow aplasia) and many side effects Too toxic for routine use 3 2 1 PsARC Responder 3.4 0 Oral Methotrexate (Willkens et al, 1984) 3 months RCT of oral MTX (7.5-15mg weekly)/placebo in active PsA MTX improved physicians global assessment effect on joint counts/ Kaltwasser et al, Arthritis Rheum, 04 Other RCTs Of Methotrexate For PsA Immediate vs Delayed MTX (Scarpa et al, 08) 6 month RCT of 35 patients with early PsA All clinical variables improved Swollen joint counts improved more rapidly with early MTX Methotrexate with ciclosporin (Spadaro et al, 1995) 12 month RCT of 35 patients with active PsA Similar improvements with both Adding Ciclosporin/ to MTX (Fraser et al, 05) 12 month RCT 72 patients with active PsA Both groups improved over time Only significant treatment effect was on PASI scores Summary Existing Guidance Historic Data New Data NOR-DMARD registry MIPA Trial RESPOND Trial NOR-DMARD: Routine Practice Registry Observational Comparison of PsA with RA NOR-DMARD Register MTX Has Apparently Similar Effect in PsA and RA Longitudinal observational multicentre study Based in rway MTX naive patients 430 with PsA 1218 with RA 6 month clinical and laboratory outcomes PsA 1197 regimens 887 patients MTX Mono 593 Regimens MTX Naive 430 Regimens NOR-DMARD 7045 regimens 4792 patients RA 4390 regimens 2787 patients MTX Mono 1615 Regimens MTX Naive 1281 Regimens Baseline Values RA PsA Patient Global Physician global CRP Tender Joints Swollen Joints 0 40 60 Changes At 6 Months RA PsA Patient Global Physician global CRP Tender Joints Swollen Joints 0 10 30 Lie et al, Ann Rheum Dis, 10 Lie et al, Ann Rheum Dis, 10 3
Synopsis of NOR-DMARD Findings Effectiveness and retention rates of MTX in PsA compared to RA After 6 months MTX PsA and RA patients show improvements in most disease activity measures and patient reported outcomes In adjusted analysis less improvement with PsA, but changes in same range as RA EULAR good/moderate responses were achieved by 24%/57% PsA and 33%/7 RA At 2 years Retention rates on methotrexate were 65% PsA and 66% RA Only minor differences in reasons for discontinuation MTX in Psoriatic Arthritis (MIPA) Trial Hypothesis: Methotrexate improves disease activity and function in psoriatic arthritis Design:6-month RCT comparing methotrexate with placebo Inclusion Synovitis in 1 joint Psoriasis skin/nails Exclusion Other arthropathies Recent steroids/dmards Contra-indications to MTX Intervention Methotrexate (target 15mg/wk) Matching placebo Primary outcome Psoriatic Arthritis Response Criteria Secondary outcomes Patient Global Assessments Assessor Global Assessments HAQ & Pain Tender & Swollen Joint Counts & CRP (ACR) Allocated To Active 109 Follow Up Lost to followed up (21) Adverse Events: 5 Worse disease: 3 Patient choice: 13 Discontinued Intervention (14) Adverse Events: 4 Worse disease: 7 Patient choice: 3 Analysed Intention to Treat: 109 (10) Valid Compliant Completer 67 (61%) Excluded from analysis (7) MIPA Consort Flowchart Screened 462 Randomised 221 Allocated To 112 Follow Up Lost to followed up (23) Adverse Events: 4 Worse disease: 7 Patient choice: 12 Discontinued Intervention (12) Adverse Events: 3 Worse disease: 7 Patient choice: 2 Analysed Intention to Treat: 112 (10) Valid Compliant Completer 61 (54%) Excluded from analysis (16) t Entered 241 Ineligible: 148 Previous methotrexate: 69 Inactive arthritis: 47 Concomitant disease: 21 Diagnostic uncertainty: 11 n-consent: 93 Over 6 Months Main Statistical Analysis Intention to Treat Analysis with Imputed Data (Multiple Imputation Method) Analysis most likely to show true value Formal Statistical Analysis Using Logistic Regression Multiple Imputation, Adjusted For Age, Gender and Disease Duration 1.70 Changes in Composite Measures Over 6 Months 2.00 1.77 Completer Analysis With All Observed Data Poor responders withdraw and effect may be over-estimated 4
Percent Improvement 11/7/11 Completer Analysis with Observed Data 7 6 5 4 3 2 1 3 Months 6 Months 7 Significant 6 5 4 3 2 1 PsARC ACR- PsARC ACR- Individual Measures Over 6 Months Intention to Treat Analysis With All Observed Data May over-estimate benefits but allows exploration of individual outcomes Global Assessments And Pain Joint Counts, and HAQ 50 40 30 Physician Global P=0.001 60 50 40 30 60 50 40 30 Patient Global P=0.03 Pain 12 10 8 6 4 2 25 15 10 Swollen Joint Count 17 15 13 11 9 7 5 1.5 1.3 1.1 0.9 0.7 0.5 Tender Joint Count HAQ Effect of Methotrexate on Individual Outcomes in the MIPA Trial Outcome Measure Tender joint count Swollen joint count C-reactive Protein HAQ Pain Patient global Physician s global Disease Modifying Effect in MIPA Yes Yes Symptom Modifying Impact Of Pattern Of PsA Arthritis Oligoarthritis, Polyarthritis & RA Like Show Statistically Significant MTX Effects 8 6 4 2-2 -4 Tender Joint Count Swollen Joint Count Oligo MTX Oligo Poly MTX Poly RA Like RA Like MTX 5
Percent With Minimal Disease Activity Percent Improvement 11/7/11 Comparisons With Other Treatments In PsA and RA MIPA Results With Methotrexate Replicate Routine Practice in 430 Patients PsARC 2.7 3.0 1.7 1.8 6 5 4 3 MIPA rwegian PsA Cohort 3.1 2 2.4 1 ACR 2.3 2.1 SJC TJC Physican's global Patient's global 430 rwegian PsA Patients in NOR-DMARD Observational Study Of Methotrexate Lie et al, Ann Rheum Dis, 10 Key Findings In MIPA RESPOND Trial MTX In PsA Improves symptoms Has no effect on joint counts or acute phase response It is a symptom modifying agent and not a DMARD MIPA Data Reliable Substantial data Equal largest placebocontrolled PsA trial Replicates findings in routine practice MIPA Trial Limitations Trial Design Issues t long/large enough Patient Subtype t powered to study specific PsA subtypes Dose -25mg may be needed Combination Treatment TICOPA trial (currently recruiting in UK) RESPOND trial Open-label study Patients with active PsA MTX naive/no DMARDs Randomly assigned Infliximab (5 mg/kg) plus MTX (15 mg/week) MTX (15 mg/week) alone ACR Response Rates 2, 6, 12 and 14 weeks Baranauskaite et al, Ann Rheum Dis, 11 Randomised patients 115 MTX/Infliximab 57 patients Discontinued 10 patients Adverse events: 7 n-compliance: 2 Lost to follow up: 2 Completed 16 weeks 47 patients MTX Alone 58 patients Did t Start 4 patients Discontinued 7 patients Adverse events: 2 n-compliance: 2 Ineligible: 2 Completed 16 weeks 47 patients ACR Responses In RESPOND All patients taking methotrexate Minimal Disease Activity In RESPOND ACR Responders Infliximab ACR 50 Responders Infliximab 7 6 5 4 3 2 p<0.05 p<0.05 p<0.05 Infliximab/MTX MTX Alone 1 2 6 14 16 Weeks of Treatment 6
Synopsis Of RESPOND Trial Significant limitations Small sample size (243 planned, 115 recruited, 94 completed) Open label design without placebo group Shows infliximab is effective in PsA Larger changes than in IMPACT trials (previous infliximab RCTs) perhaps because patients had early disease Suggests patients may improve with MTX alone High ACR responses in MTX-alone group support recommendations to use MTX in active psoriatic arthritis Definitive conclusions cannot be drawn about MTX alone or in combination because of study design More adverse effects with combination therapy Etanercept For Psoriatic Arthritis 60 patients, 25mg Etanercept twice weekly, 12 weeks treatment 10 75% 5 25% Etanercept PsARC Responder Mease et al, Lancet, 00 ACR Responder Results are of very strong statistical and clinical significance 17.9 21.4 Treating Active Psoriatic Arthritis Value to Patients With Active Disease Symptomatic Effects Methotrexate Sulfasalazine AIDs Uncertain Effects Ciclosporin Hydroxychloroquine n-tnf biologics Disease Modifying Leflunomide TNF inhibitors Implications for Clinical Practice MTX (15mg weekly) not optimal for active PsA joints as not DMARD Appropriate if mild joint disease and severe cutaneous disease?effective at higher doses or in combination regimes but RCTs needed Guidelines for the treatment of psoriatic arthritis need reconsidering What should be recommended as a first choice DMARD? Should biologics be used as initial or early treatment in active PsA? Individualised regimes, recognising all aspects of PsA, may be needed Acknowledgements for MIPA We would like to acknowledge the help of the Kings Clinical Trials Unit, the support of our funders and the contribution of patients and staff at all the MIPA trial centres Trial Centres King s College Lewisham Basildon Bath Cardiff Cannock Dudley Derby East Kent Freeman Glasgow Haywood Lancaster Medway rthwick Park Orpington Plymouth QM, Sidcup Queen s Romford St Helier Trafford Whipps Cross Withybush 7