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Interactive Hot Topics Series Implementing Treat to Target: A Case Study in RA MP-RA-0267 The Treat-to-Target Paradigm Main target Adapt therapy according to disease activity* (consider comorbidities and other patient factors) Active RA Adapt therapy if state is lost* (consider comorbidities and other patient factors) Sustained remission Remission Use a composite measure of disease activity every 1 ‒ 3 months Assess disease activity about every 3 ‒ 6 months Low disease activity Alternative target Adapt therapy according to disease activity* (consider comorbidities and other patient factors) Adapt therapy if state is lost* (consider comorbidities and other patient factors) RA, rheumatoid arthritis Reproduced from Smolen JS, et al. Ann Rheum Dis. 2016;75:3-15. © 2016, with permission from BMJ Publishing Group. Sustained low disease activity *Shared decision with patient 2 Key Principles in Treating to Target 1. The primary target for treatment of RA should be a state of clinical remission 2. Clinical remission is defined as the absence of signs and symptoms of significant inflammatory disease activity 3. While remission should be a clear target, based on available evidence, low disease activity (LDA) may be an acceptable alternative therapeutic goal, particularly in established, long-standing disease 4. Until the desired treatment target is reached, drug therapy should be adjusted at least every 3 to 6 months 5. Measures of disease activity must be obtained and documented regularly, as frequently as monthly for patients with high/moderate disease activity, or less frequently (such as every 3 to 6 months) for patients in sustained low disease activity or remission 6. The use of validated composite measures of disease activity, which include joint assessments, is needed in routine clinical practice to guide treatment decisions 7. Structural changes and functional impairment should be considered when making clinical decisions, in addition to assessing composite measures of disease activity 8. The desired treatment target should be maintained throughout the remaining course of the disease 9. The choice of the (composite) measure of disease activity and the level of the target value may be influenced by considerations of comorbidities, patient factors, and drug-related risks 10. The patient has to be appropriately informed about the treatment target and the strategy planned to reach this target under the supervision of the rheumatologist Treat to Target. 2015. Available at: http://www.t2t-ra.com/recommendations/target-to-treat-statements 3 Treating to Target in Practice: Case Study* Bob is a 45-year-old carpenter He presents with a 5-month history of joint pain in his hands, feet and knees and he also has morning stiffness with a duration of 3-4 hours * Hypothetical case; not based on actual patient 4 Case Study: Assessment of Disease Activity Physical examination: − 15 tender joints − 13 swollen joints − PtGA: 7.5/10 − EGA: 7.1/10 Imaging: − No erosions or joint space narrowing Laboratory values: − ESR: 36 mm − CRP: 4.2 mg/dL − RF: negative − Anti-CCP: 24 U Anti-CCP, anti-cyclic citrullinated protein antibody; CRP, C-reactive protein; EGA, Evaluator’s Global Assessment; ESR, erythrocyte sedimentation rate; PtGA, Patient’s Global Assessment; RF, rheumatoid factor 5 Case Study Question: What Composite Measure Would Be Suitable for Assessment of Disease Severity in This Patient? DAS-28? SDAI? CDAI? RAPID3? HAQ? Other? The CDAI for this patient = 42.6 (high disease activity)1,2 CDAI, Clinical Disease Activity Index; DAS-28, Disease Activity Scorse-28 joint; HAQ, Health Assessment Questionnaire; RAPID3, Routine Assessment of Patient Index Data 3); SDAI, Simplified Disease Activity Index 1. 2. Aletaha D, Smolen J Clin Exp Rheumatol. 2005;23(5 Suppl 39):S100-108. Amercian College of Rheumatology. 2015. Available at: http://www.rheumatology.org/Portals/0/Files/CDAI%20Form.pdf 6 Case Study: Initiation of Treatment The treatment goal for this patient is disease remission as reflected by an CDAI score ≤2.8 Treatment for Bob is initiated with: − 15 mg/week oral MTX − 1 mg/day folic acid (except on the day of MTX administration) − 10 mg/day prednisone with a plan to taper and discontinue by 3 months Bob will be re-evaluated in 6 weeks MTX, methotrexate; CDAI, Clinical Disease Activity Index 7 ACR Guidelines Support MTX As Initial Treatment for Early RA * † # Consider adding low-dose glucocorticoids (≤10 mg/day of prednisone or equivalent) in patients with moderate or high RA disease activity when starting disease-modifying antirheumatic drugs (DMARDs) and in patients with DMARD failure or biologic failure Also consider using short-term glucocorticoids (defined as <3 months treatment) for RA disease flares. Glucocorticoids should be used at the lowest possible dose and for the shortest possible duration to provide the best benefit-risk ratio for the patient Treatment target should ideally be low disease activity or remission Singh JA, et al. Arthritis Care Res. 2016;68:1-25. © 2015, American College of Rheumatology. 8 Case Study: 6-week Follow-up Physical examination: − 5 tender joints − 3 swollen joints − PtGA: 3.1/10 − EGA: 2.7/10 Imaging: − No erosions or joint space narrowing Laboratory values: − ESR: 22 mm − CRP: 2.6 mg/dL − RF: negative − Anti-CCP: 23 U The CDAI for this patient = 13.8 (moderate disease activity and a moderate response to treatment)1 Anti-CCP, anti-cyclic citrullinated protein antibody; CRP, C-reactive protein; EGA, Evaluator’s Global Assessment; ESR, erythrocyte sedimentation rate; PtGA, Patient’s Global Assessment; RF, rheumatoid factor 1. Smolen JS, Aletaha D. Clin Exp Rheumatol. 2014;32 (Suppl 85):S75-S79. 9 Case Study: Question What changes in treatment might be appropriate for Bob? − − − − Increase the oral MTX dose? Add a second synthetic DMARD? Switch to subcutaneously delivered MTX? Switch to a biologic agent? DMARD, disease-modifying antirheumatic drug; MTX, methotrexate 10 Case Study: Augmentation of Treatment Treatment for Bob is changed to: − 20 mg/week oral MTX − 1 mg/day folic acid (except on the day of MTX administration) − 5 mg/day prednisone with a plan to discontinue at the next visit Bob will be re-evaluated at 3 months after treatment initiation MTX, methotrexate 11 Higher MTX Doses Are Associated with Better Clinical Efficacy Systematic review of the literature on optimal dosage of MTX in patients with RA Starting doses of 25 mg/week or fast escalation with 5 mg/month to 25-30 mg/week were associated with higher clinical effect sizes in comparison with doses of 5-15 mg/week or slow escalation 2.5 12.5–20 mg/week 5–10 mg/week 2.0 Placebo Effect size 1.5 1.0 0.5 0 -0.5 -1.0 SJC TJC Pain Global RA, rheumatoid arthritis; SJC, swollen joint count; TJC, tender joint count Reproduced from Visser K, van der Heijde D. Ann Rheum Dis. 2009;68:1094-1099. © 2009 with permission from BMJ Publishing Group. 12 Case Study: 3-month Follow-up Physical examination: − 3 tender joints − 3 swollen joints − PtGA: 2.6/10 − EGA: 2.3/10 − Bob also complains of nausea and mild abdominal pain Imaging: − No evidence of structural lesions Laboratory values: − ESR: 20 mm/hr − CRP: 2.3 mg/dL − RF: negative The CDAI for this patient = 10.9 (moderate disease activity)1 − Anti-CCP: 24 U Anti-CCP, anti-cyclic citrullinated protein antibody; CRP, C-reactive protein; EGA, Evaluator’s Global Assessment; ESR, erythrocyte sedimentation rate; PtGA, Patient’s Global Assessment; RF, rheumatoid factor 1. Smolen JS, Aletaha D. Clin Exp Rheumatol. 2014;32 (Suppl 85):S75-S79. 13 Case Study: Question What changes in treatment might be appropriate for Bob? − − − − Increase the oral MTX dose? Add a second synthetic DMARD? Switch to subcutaneously delivered MTX? Switch to a biologic agent? DMARD, disease-modifying antirheumatic drug; MTX, methotrexate 14 Case Study: Augmentation of Treatment Treatment for Bob is changed to: − 25 mg/week MTX delivered by subcutaneous injection − 1 mg/day folic acid (except on the day of MTX administration) − Prednisone is discontinued Bob will be re-evaluated in 3 months MTX, methotrexate 15 SC Administration Improves MTX Bioavailability Single center, open label, randomized, 2-period, 2-sequence, single-dose crossover study in 4 dose groups (7.5 mg, 15 mg, 22.5 mg, and 30 mg) with 54 healthy adults MTX, methotrexate; SC, subcutaneous Pichlmeier U, Heuer KU. Clin Exp Rheumatol. 2014 ;32:563-571. 16 Improved GI Tolerability with SC vs Oral MTX VAS Score (0-100) P=0.015 MTX, methotrexate; SC, subcutaneous; VAS, visual analog scale Adapted from Kromann CB, et al. J Dermatolog Treat. 2014;17:1-3. P=0.047 P=0.002 N=37 P=0.053 17 Significant Improvement of Disease Control Following Switch From Oral to SC MTX Retrospective analysis of 103 RA patients switched from oral to SC MTX: P=0.006 − 40 switched due to inadequate efficacy of oral MTX − 63 patients switched due to GI side effects of oral MTX P=0.0001 MTX, methotrexate; SC, subcutaneous; DAS, disease activity score Hameed B, Jones H. Int J Rheum Dis. 2010;13:e83-e84. © 2010 Asia Pacific League of Associations for Rheumatology and Blackwell Publishing Asia Pty Ltd. 18 Case Study: 6-month Follow-up Physical examination: − 1 tender joints − 0 swollen joints − PtGA: 0.5/10 − EGA: 0.7/10 − Nausea and mild abdominal pain have resolved Imaging: − No erosions or joint space narrowing Laboratory values: − ESR: 20 mm/hr − CRP: 1.6 mg/dL − RF: negative − Anti-CCP: 24 U The CDAI for this patient = 2.2 (low disease activity approaching remission)1 Anti-CCP, anti-cyclic citrullinated protein antibody; CRP, C-reactive protein; EGA, Evaluator’s Global Assessment; ESR, erythrocyte sedimentation rate; PtGA, Patient’s Global Assessment; RF, rheumatoid factor 1. Smolen JS, Aletaha D. Clin Exp Rheumatol. 2014;32 (Suppl 85):S75-S79. 19 Case Study: Treatment Treatment for Bob: − 25 mg/week MTX delivered by subcutaneous injection will be continued − 1 mg/day folic acid (except on the day of MTX administration) Bob will be re-evaluated in 3 months: − If remission is sustained, current treatment will be continued. If not, a further augmentation of therapy will be considered MTX, methotrexate; SDAI, Simplified Disease Activity Index 20 Summary: Multiple Steps in Treatment May Be Needed to Achieve Goals Initiate Treatment with Oral MTX/Dose Titration Inadequate Response/ Intolerance Switch to SC MTX Clinical Remission or LDA/Limited Radiographic Progression One Approach to Treating to Target SC, subcutaneous; LDA, low disease activity Adapted from Yazici Y, Bata Y. Bulletin of the Hospital for Joint Diseases. 2013;71(Suppl 1):S46-48; Bykerk VP, et al. J Rheumatol. 2012;39:1559-1582; Alsaeedi S, Keystone EC. Nat Rev Rheumatol. Advance online publication 5 August 2014. 21