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Interactive Hot Topics Series Rethinking the Treatment Paradigm in RA: What Is the Best Way to Initiate MTX Treatment? MP-RA-0252 ACR Guidelines Support Methotrexate (MTX) As Initial DMARD for Established RA Low Disease Activity Without Poor Prognosis† DMARD Monotherapy Low Disease Activity With Poor Prognosis† or Moderate/High Disease Activity MTX Monotherapy or Combination DMARD Therapy (Including Double or Triple Therapy) ‡ † Features of poor prognosis include functional limitation, extra-articular disease, positive rheumatoid factor, anti-cyclic citrullinated peptide antibodies, and bony erosions by radiograph. ‡ Combination DMARD therapy with 2 DMARDs, which is most commonly MTX based. DMARD, disease-modifying antirheumatic drug; RA, rheumatoid arthritis. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Singh JA, et al. Arthritis Care Res, 2016;64:1-25. © 2015, American College of Rheumatology. 2 ACR Guidelines Support MTX As Initial Treatment for Early RA Low Without DMARD Monotherapy Disease Activity High With Without MTX Monotherapy or Combination DMARD Therapy (Including Double or Triple Therapy) ‡ DMARD Monotherapy or HCQ and MTX Features of Poor Prognosis† Features of Poor Prognosis† With Anti-TNF With or Without MTX or Combination DMARD Therapy (Including Double or Triple Therapy)‡ Monotherapy or HCQ and MTX † Features of poor prognosis include functional limitation, extra-articular disease, positive rheumatoid factor, anti-cyclic citrullinated peptide antibodies, and bony erosions by radiograph. ‡ Combination DMARD therapy with 2 DMARDs, which is most commonly MTX based. RA, rheumatoid arthritis; DMARD, disease-modifying antirheumatic drug; HCQ, hydroxychloroquine. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Singh JA, et al. Arthritis Care Res. 2016;68:1-25. © 2015, American College of Rheumatology. 3 Initial Treatment With MTX: Oral or Subcutaneous The vast majority of RA patients in the United States initiate treatment with oral drug Results for 39,440 RA patients starting MTX treatment in the United States: 9.6% SC MTX Oral MTX 90.4% MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous Medac, Pharma, Inc. Data on file. 2015. 4 Significantly Better Disease Control With SC vs Oral MTX ACR Responses† EULAR Remission† 40 *P<0.05 * 80 78 70 59 60 62 * 41 40 33 20 Percentage of Patients Percentage of Patients 100 0 34 30 24 20 10 0 ACR20 ACR50 ACR70 Week 24 Results1 Oral MTX 15 mg (n=187) † P<0.05 SC MTX 15 mg (n=188) Oral MTX 15 mg (n=187) SC MTX 15 mg (n=188) Week 24 Results2 Week 16 results were carried forward for patients who switched from oral to SC MTX or had their SC MTX doses increased from 15 to 20 mg/wk. SC, subcutaneous. 1. Braun J, et al. Arthritis Rheum. 2008;58:73-81. © 2008, American College of Rheumatology. 2. Adapted from Braun J. Clin Exp Rheumatol. 2010;28(suppl 61):S46-S51. 5 Prospective Comparison of SC and Oral MTX Prospective 6-month study to assess the efficacy, safety, and compliance of SC vs oral MTX in 92 patients with active RA according to ACR criteria SC MTX (n=46) Oral MTX (n=46) 45.54 ± 12.42 44.63 ± 13.99 Male (%) 5 (11) 12 (26) Disease duration months, mean 49.74 49.0 Age years, mean ± SD ACR, American College of Rheumatology; MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous; SD, standard deviation Adapted from Islam MS, et al. Mymensingh Med J. 2013;22:483-488. 6 Prospective Comparison of SC and Oral MTX: ACR Responses P=0.02 100% 93% 89% 90% 80% P=0.03 SC MTX (n=46) 80% Oral MTX (n=46) 72% Patients % 70% 60% 50% 40% 30% P=0.72 20% 11% 10% 9% 0% ACR20 ACR50 ACR, American College of Rheumatology; MTX, methotrexate; SC, subcutaneous; SD, standard deviation Adapted from Islam MS, et al. Mymensingh Med J. 2013;22:483-488. ACR70 7 Prospective Comparison of SC and Oral MTX: Adverse Events 90% 85% SC MTX (n=46) 80% Oral MTX (n=46) Patients % 70% 72% 63% 60% 52% 48% 50% 41% 40% 37% 30% 30% 29% 20% 11% 10% 0% Nausea Vomiting MTX, methotrexate; SC, subcutaneous; SD Adapted from Islam MS, et al. Mymensingh Med J. 2013;22:483-488. Dyspepsia Dizziness Alopecia 8 Parenteral MTX: Higher Achieved Dose and Lower Risk for Change in Therapy vs Oral MTX Hazard Ratio for Change in Treatment MTX Dosing 100% Oral (n=6741) 90% 70% 60% 1 Parenteral (n=276) 80% 0.8 Mean oral dose 16.6 mg/wk and mean parenteral dose 22.1 mg/wk (P<0.01) 0.64 0.6 40% 40% 31.70% 28.30% 18.50% 20% 10% P<0.01 76.10% 50% 30% * 1.00 0.4 0.2 5.40% 0 0% <15 mg 15 to <20 mg MTX, methotrexate Adapted from Ng B, Chu A. Clin Rheumatol. 2014;33:21-30. ≥20 mg Oral MTX (n=6741) * Reference. Parenteral MTX (n=276) 9 Initiation of Treatment With SC or Oral MTX: Real-world Results From the Canadian Early Arthritis Cohort (CATCH) Multicenter prospective study of patients with early RA (symptoms ≤1 year) initiating MTX therapy Comparison of the effectiveness of starting with SC or oral MTX over the first year Longitudinal multivariable models, adjusted for potential baseline and time-varying confounders, were used to compare treatment changes due to inefficacy or toxicity and treatment efficacy MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous Hazlewood GS, et al. Ann Rheum Dis. 2016;75:1003-1008. 10 CATCH Cohort: Patient Characteristics Oral MTX (n=417) SC MTX (n=249) P-value 54 (14) 51 (15) 0.068 75.1 73.1 0.57 Number of comorbidities, mean (SD) 2.2 (1.8) 2.5 (1.9) 0.041 Symptom duration, mean months (SD) 5.2 (2.7) 5.2 (2.8) 0.61 Seropositive (RF or ACPA), % 78.8 82.0 0.35 Erosions present on hand or foot x-rays (%) 24.4 31.1 0.08 HAQ-Dl (0-3) 1.1 (0.69) 1.1 (0.69) 0.52 DAS28, mean (SD) 5.5 (1.4) 5.5 (1.4) 0.86 Starting dose of MTX, mean mg (SD) >20, % 15-20, % <15, % 17.2 (3.8) 5.0 56.8 38.1 22.3 (3.6) 45.2 27.8 27.0 <0.001 Concurrent use of systemic glucocorticoids, % Oral, % Intramuscular or intra-articular, % 48.0 24.2 27.8 51.8 13.7 41.4 0.34 0.001 <0.001 Concurrent use of other DMARDs, % 53.0 42.6 0.009 Concurrent use of biological therapy, % 2.2 0.4 0.071 Characteristic Age, mean years (SD) Female, % ACPA, anti-citrullinated protein antibodies; DAS, Disease Activity Score; DMARD, disease-modifying antirheumatic drug; HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate; RF, rheumatoid factor; SC, subcutaneous; SD, standard deviation Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75:1003-1008. © 2016 with permission from BMJ Publishing Group. 11 Better Persistence Is Achieved With SC vs Oral MTX: CATCH Cohort Proportion of Initial Treatment 1 SC MTX (n=249) Oral MTX (n=417) 0.8 Failed Initial Treatment 0.6 49% 0.4 Log-rank P<0.001 77% 0.2 0 417 249 233 184 130 136 104 117 66 88 0 3 6 9 12 PO SC Time (months) MTX, methotrexate; SC, subcutaneous; PO, oral Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75:1003-1008. © 2016 with permission from BMJ Publishing Group. 12 Reasons for Treatment Failure: SC vs Oral MTX SC MTX (n=249) % Oral MTX (n=417) % P-Value Total treatment failures 49% 77% <0.001 Inadequate efficacy only 28% 59% <0.001 Toxicity only 3% 2% 0.63 Both inadequate efficacy and toxicity 18% 16% 0.57 Reason for Treatment Failure SC, subcutaneous. Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75:1003-1008. © 2016 with permission from BMJ Publishing Group. 13 CATCH Cohort: Changes in Treatment SC MTX Oral MTX P-value Changed route of MTX 3 20 <0.001 Increased dose of MTX after 3 months 24 58 <0.001 Added/switched a non-biological DMARD 22 33 0.004 Added a biologic 10 12 0.41 Decreased dose of MTX after 3 months* 10 4 0.006 Stopped a non-biological DMARD* 7 7 1 Patients may have had more than one change. * Must have had another treatment change, side effect or increased DAS28 to be considered a treatment failure. DAS, Disease Activity Score; DMARD, disease-modifying antirheumatic drug; MTX, methotrexate; SC, subcutaneous Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75:1003-1008. © 2016 with permission from BMJ Publishing Group. 14 Mean DAS28 Score Lower DAS28 Scores Are Achieved With SC vs Oral MTX: CATCH Cohort P<0.05 for SC vs oral SC MTX at 3, 6, and 9 months Month MTX, methotrexate; SC, subcutaneous. Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75:1003-1008. © 2016 with permission from BMJ Publishing Group. 15 CATCH Cohort: DAS28 Outcomes Estimate for SC MTX (95% Cl) P-value -0.38 (-0.64 to -0.10) 0.04 DAS28 remission, OR 1.15 (1.05 to 1.25) 0.002 DAS28 sustained remission*, OR 1.02 (0.96 to 1.06) 0.43 -0.02 (-0.13 to 0.10) 0.75 Outcome DAS28, mean difference HAQ-DI, mean difference * Defined as DAS28 <2.6 on 2 consecutive visits CI, confidence interval; DAS, Disease Activity Score; HAQ-DI, Health Assessment Questionnaire-Disability Index; MTX, methotrexate; OR, odds ratio; SC, subcutaneous Reproduced from Hazlewood GS, et al. Ann Rheum Dis. 2016;75:1003-1008. © 2016 with permission from BMJ Publishing Group. 16 CATCH Cohort Sites: Relation Between SC MTX Use and Patient Outcomes Percentage of Patients Receiving SC MTX 0 10 20 30 40 50 60 70 Mean Change from Baseline in DAS28 (0-6 months) 0 -0.5 -1 -1.5 -2 -2.5 DAS, Disease Activity Score; MTX, methotrexate; SC, subcutaneous Adapted from Harris JA, et al. J Rheumatol. 2013;40;1823-1830. 17 Conclusions SC MTX is an attractive alternative to oral drug delivery for the treatment of RA Initial treatment with SC vs oral MTX has been associated with: − Greater efficacy − Better disease control − Lower rates of treatment changes − Decreased frequency of gastrointestinal adverse events MTX, methotrexate; RA, rheumatoid arthritis; SC, subcutaneous 18