Methotrexate Is Not Disease Modifying In Psoriatic Arthritis

Transcription

1 Methotrexate Is Not Disease Modifying In Psoriatic Arthritis A New Treatment Paradigm Is Required Gabrielle H Kingsley*, Jonathan Packham, Neil McHugh, Diarmuid Mulherin George Kitas, Kuntal Chakravarty, Fowzia Ibrahim, Brian DM Tom, Helen Taylor, Anna Kowalczyk, Peter Maddison David L Scott Arthritis Research UK MIPA TRIAL Group, King s College London *The speaker and co-authors have no conflicts of interest

2 Psoriatic Arthritis Clinical Features Arthritis usually associated with psoriasis Enthesitis, dactylitis, nail changes and spondylitis Severity often under-recognised so under-treated Traditional Drug Treatment Paradigm Symptom relievers NSAIDs and analgesics DMARDs Drugs: sulfasalazine, methotrexate, leflunomide Biologics: etanercept, adalimumab Evidence base for DMARD treatment Systematic reviews emphasise limited evidence Sulfasalazine - mainly symptom reliever in large well-conducted RCTs Methotrexate: no DMARD effect in 2 small RCTs RCTs of Leflunomide and TNF inhibitors

3 Hypothesis And Design 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 ESR & CRP Composite Measures (ACR20)

4 Randomised, Completed and Withdrawn Consort Flow Chart Randomised 221 patients Methotrexate 109 patients Completed: 71 (65%) Withdrew: 38 (35%) Adverse event: 11 (11%) Worse disease: 8 (7%) Withdrew consent: 2 (2%) Did not attend: 9 (8%) Other: 8 (7%) Placebo 112 patients Completed: 77 (69%) Withdrew: 35 (31%) Adverse event: 8 (7%) Worse disease: 14 (13%) Withdrew consent: 2 (2%) Did not attend: 6 (5%) Other: 5 (4%)

5 Changes in Composite Measures Over 6 Months Completer Analysis With All Observed Data Most likely to show benefit as poor responders withdraw therefore over-estimating effect

6 Composite Measures Completer Analysis with Observed Data Psoriatic Arthritis Response Criteria 70% 6 Months Significant NS PsARC Components Tender joint count Swollen joint count Patient global assessment Physicians global assessment Responder Two measures improve including one joint count No measure worsens 60% 50% 40% 30% 20% 10% 0% PsARC ACR20

7 Composite Measures Completer Analysis with Observed Data 3 Months 6 Months 70% 60% Methotrexate Placebo 70% 60% Significant NS 50% NS NS 50% 40% 40% 30% 30% 20% 20% 10% 10% 0% 0% PsARC ACR20 PsARC ACR20

8 Composite Measures Over 6 Months Formal Statistical Analysis Intention to Treat Analysis with Imputed Data (Multiple Imputation Method) Analysis most likely to show true value

9 Composite Measures Formal Statistical Analysis Using Logistic Regression Multiple Imputation and Adjustment For Age and Gender 2.4 PsARC ACR

10 Composite Measures Comparisons With Other Treatments In PsA and RA 2.7 PsARC ACR

11 Individual Measures Over 6 Months Intention to Treat Analysis With All Observed Data Over-estimates benefit but allows exploration of data

12 Global Assessments And Pain 50 Physician Global 60 Patient Global Initial 3 months 6 months 20 Initial 3 months 6 months 60 Pain Initial 3 months 6 months

13 Joint Counts, ESR and HAQ Swollen Joint Count Initial 3 months 6 months Tender Joint Count Initial 3 months 6 months ESR Initial 3 months 6 months HAQ Initial 3 months 6 months

14 Individual Outcomes in MIPA Trial Outcome Tender joint count Swollen joint count ESR C-reactive Protein HAQ Pain Patient global Physician s global Effect No No No No No No Yes Yes Disease Modifying Symptom Modifying

15 Key Findings In MIPA Methotrexate In Psoriatic Arthritis Improves symptoms Has no effect on joint counts or acute phase response It is a symptom modifying agent and not a DMARD Replicates previous small trial Similar effect to sulfasalazine MIPA Data Reliable Substantial data: equal largest placebo-controlled PsA trial Replicates findings in routine practice

16 Other Studies of MTX in PsA Black, O Brien, van Scott et al JAMA 1964;189: patients 3 IV pulses (1-3mg/kg) in 2 mths Effects Improved in joint counts and ESR One death from marrow aplasia Multiple side effects Conclusion Too toxic for routine use Willkens, Williams, Ward et al Arthritis Rheum 1984; 27: patients Half had oral MTX (7.5-15mg/wk) Effects Reduced physicians global but not joint counts or ESR Conclusion Study underpowered Identical results to MIPA

17 Are MIPA Results Exceptional? Comparison to Routine Practice Findings in 430 Norwegian Patients Percent Improvement 60% 50% 40% 30% 20% 10% 0% MIPA Methotrexate Patients Norwegian PsA Cohort SJC TJC ESR Physician's global Patient's global 430 Norwegian Psoriatic Arthritis Patients in Observational Study Of Methotrexate Lie et al, Ann Rheum Dis, 2010

18 Lessons for Clinical Practice Drugs in Psoriatic Arthritis Value to Patients With Active Disease Symptomatic Effects Methotrexate Sulfasalazine NSAIDs Uncertain Effects Ciclosporin Hydroxychloroquine Gold Disease Modifying Leflunomide Etanercept Adalimumab Lessons For Practice Methotrexate is not the drug of choice for active Psoriatic Arthritis UK Guidelines/NICE guidance need redrafting Patients need effective treatment

19 Acknowledgements And Comment Centres Basildon Queen s Romford King s College Lewisham Queen Elizabeth Queen Mother/Kent & Canterbury Medway Northwick Park Orpington Queen Mary Whipps Cross Bath Cannock Dudley Derby Haywood Cardiff Freeman Glasgow Lancaster Trafford Withybush Plymouth St Helier Placebo Controlled Trials Using placebos in trials risks under-treatment of patients in one trial Not using placebos risks under-treatment of all patients in routine care