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1 RHEUMATOID ARTHRITIS: A FOCUS ON REDUCTION OF DISEASE PROGRESSION AND DISABILITY Geoffrey C. Wall, PharmD, FCCP, BCPS, CGP Professor of Clinical Sciences Drake University College of Pharmacy Internal Medicine Clinical Pharmacist Iowa Methodist Medical Center Des Moines, Iowa Pharmacy Accreditation Pharmacy Times Continuing Education is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This activity is approved for 1.0 contact hours (0.10 CEU) under the ACPE universal activity number L01-P. The activity is available for CE credit through May 3, Faculty Disclosure Geoffrey C. Wall, PharmD, FCCP, BCPS, CGP has the following relevant financial relationships with commercial interest to disclose: Speaker s Bureau: The Medicines Company, Boehringer Ingelheim and Janssen

2 This activity is sponsored by Pharmacy Times Continuing Education and supported by educational grants from Genentech and Bristol-Myers Squibb. Learning Objectives Differentiate between currently available pharmacologic options in treating rheumatoid arthritis (RA), as well as the differences for those that are in development Examine biomarkers that are predictive of disease progression Explore patient management processes to improve adherence Provide strategies for patient counseling on pharmacologic RA therapies Rheumatoid Arthritis (RA): The Scope of the Problem The prevalence of RA in most Caucasian populations approaches 1% among adults 18 and over, and increases with age, approaching 2% and 5% in men and women, respectively, by age million US adults with RA The annual incidence for all adults has been estimated at 67 per 100,000 Helmick CG. Arthritis Rheum. 2008;58(1):15-25

3 Symptoms of RA Description Morning stiffness Arthritis of 3 or more joints Arthritis of hand joints Symmetric arthritis Rheumatoid nodules Serum rheumatoid factor Radiographic changes Other Symptoms Fatigue Anemia Eye/Mouth Dryness Lung problems Accessed December 23, 2015.; Image printed with permission from hritis+joints&it=xg&req=4&npos=21. Accessed December 23, NonBiologic Era MTX SSZ HCQ CQ Gold Cyc-A AZA PNC Spectrum of RA Treatment Biologic drug clinical trials Leflunomide (1998) Etanercept(1998) Infliximab Anakinra Adalimumab Biologic Era Abatacept Rituximab Golimumab Certolizumab Tocilizumab Tofacitinib Year of FDA Approval 12 Adapted from Accessed February 22, Targets of Therapy in RA CD28 Signal BLocker Reprinted from Lancet, 370(9602), Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis, , Copyright (2007), with permission from Elsevier

4 Targets of Therapy in RA Il-1 Blockers IL-6 Blockers Anti TNF- Drugs CD20 (B-Cell Blockade Reprinted from Lancet, 370(9602), Smolen JS, Aletaha D, Koeller M, Weisman MH, Emery P. New therapies for treatment of rheumatoid arthritis, , Copyright (2007), with permission from Elsevier A New Therapeutic Objective: TREAT TO TARGET Sustained Remission Prevention / reversal of disability Prevention/ arrest of joint damage Remission Prevention of systemic comorbidities: CV diseases, osteoporosis Smolen JS, et al. Ann Rheum Dis. 2016;75(1):3-15. Why Treat to Target? More aggressive therapy has been shown to preserve joint function and quality of life (QoL) It also lessens disability More than simply targeting symptomatic relief The biologic revolution allows for treatment targeting to remission However: Must take into account toxicities, patient preference, costs Long-term large RCTs need to directly examine a strict TTT approach on outcomes Still both ACR and EULAR have adopted Solomon DH, et al. Arthritis Rheumatol. 2014; 66(4):

5 Definitions in the 2015 Guidelines Early RA RA with duration of disease/symptoms of <6 months RA Remission Tender joint count, swollen joint count, C- reactive protein level (mg/dl), and patient global assessment of <1 each (several validated systems such as the DAS exist to assess this) Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68(1):1-25 Disease Activity Score (DAS) Disease Activity Score (DAS) (range 0 9.4) Calculation involving counts of swollen joints, tender joints, Erythrocyte Sedimentation Rate (ESR), and patient s global assessment of their health Remission: <2.6 Low activity: 2.6 to <3.2 Moderate activity: 3.2 to 5.1 High activity: >5.1 Franson J, et al. Arthritis Rheum 2003;49 Suppl:S ACR Guideline on RA Early RA Low disease Activity DMARD (MTX preferred) Moderate-to-High MAY try DMARD or Combination DMARDS Biologics with or without MTX If failure of a TNFi, switch to a non-tnf drug OR add MTX Continue to try new biologics as needed to target Tofactinib +/- MTX if multiple failures Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68(1):1-25

6 Does Early Combination Therapy Make a Difference? FUNCTION study MTX naïve patients with poor prognosis (High DAS, + biomarkers, etc) randomized to MTX, Tocilizumab (TCZ) alone or in combination 1 endpoint of remission at 52 weeks more common in combination group and TCZ group. Patient who switched to a TCZ in an OL phase had more evidence of early joint damage Combination therapy had higher incidence of LFT abnormalities Burmester GR, et al. Ann Rheum Dis 2015;0:1 11. doi: /annrheumdis Accessed March 28, Drugs Listed in 2015 ACR Guidelines Drug Class Drug Name Trade Name Salicylates Aspirin Bayer Aspirin Nonsteroidal Anti-inflammatory Ibuprofen Advil, Motrin Drugs (NSAIDs) Celecoxib Celebrex Glucocorticoids Prednisone Deltasone Disease-modifying Antirheumatic Hydroxychloroquine Plaquenil drugs (DMARD) Leflunomide Arava Methotrexate Trexall Sulfasalazine Azulfidine, Sulfazine Oral Synthetic Small Molecule Tofacitinib Xeljanz Tumor Necrosis Factor Inhibitors Adalimumab Humira (TNFi) Certolizumab pegol Cimzia Etanercept Enbrel Golimumab Simponi Infliximab Remicade Non-TNF Biologic Abatacept Orencia Rituximab Rituxan Tocilizumab Actemra Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68(1):1-25. Comparisons of Biologics in RA Intervention Comparator Symptoms or Disease Activity* (N Studies; N Patients) Function (N Studies; N Patients) Quality of Life (N Studies; N Patients) Etanercept Infliximab Faster response with etanercept, 2 of 3 studies reported but NSD in the longer term NSD (6; 5883) SOE = Low (3; 2239) Insufficient Insufficient Etanercept Adalimumab ACR70 at 6 months showed NSD (1; 2326) SOE = Low NSD (1; 707) SOE = Low NSD (1; 707) SOE = Low Adalimumab Infliximab Symptom response (ACR20 at 6 months) and DAS at 1 year greater with adalimumab (2; 3033) SOE = Low Greater improvement at 12 months with adalimumab but not greater than the MCID (1; 707) SOE = Low SF-36 physical component at 12 months favors adalimumab (1; 707) SOE = Insufficient Abatacept Infliximab Greater decrease in DAS and greater remission rate, both at 1 year, with abatacept. (3; 3464) SOE = Low NSD at 1 year (1; 431) SOE = Low SF-36 physical component at 1 year favors abatacept but not greater than the MCID (1; 431) SOE = Low *Radiographic progression not reported. Accessed December 13, 2015.

7 Tofacitinib First JAK inhibitor to be approved for RA JAKs are critical to immune cell activation Orally administered Inhibits JAKs 1,2,3 Approved in patients with RA who have failed other therapies With or without MTX Boxed warnings for infection and malignancy Recent network meta-analysis to assess efficacy Lee YH, et al. Rheumatol Int. 2015;35(12): ; Xeljanz [product information]. New York, NY: Pfizer; Other Therapies IL-17 Antagonist IL-17 is critical in pathogenesis of psoriasis May also decrease inflammatory markers in joints Currently secukinumab, ixekizumab, brodalumab in Phase II/III studies Data to date has been somewhat conflicting on efficacy GM-CSF receptor antagonists Augments proliferation, differentiation, and maturation of WBCs Increases pro-inflammatory cytokine production Mavrilimumab undergoing Phase II/III studies Siebert S, et al. Pharmacol Rev. 2015;67(2): Practical Issues with Biologics in RA Biomarkers and initiation of biologic therapy Can they be stopped if patient is in remission for a long period? Safety issues Infections TB, Histoplasmosis, others as well as common bacterial infections Malignancy Vaccinations

8 Biomarkers and RA Non-specific markers of inflammation Erythrocyte Sedimentation Rate (ESR) C-Reactive Protein (CRP) NOT sensitive nor specific for RA, but can be used indirectly to monitor therapy Specific Biomarkers for RA Rheumatoid Factor (RF) Anti-cyclic citrullinated peptide (anti-ccp) Autoantibodies present in RA BOTH much more specific for RA, though less sensitive May be used in diagnosis and response to treatment McArdle A, et al. Arthritis Res Ther. 2015;17:141 Use of RF and Anti-CCP Anti-CCP -/RF - Anti-CCP +/RF - Low probability of RA If RA+, mild disease may dictate conservative treatment Anti-CCP-/RF + Intermediate probability If RF +, moderate disease likely Up to 40% of RF- RA patients have If RA+, moderate disease likely Anti-CCP +/RF+ High probability of RA Development of Erosive RA likely Aggressive treatment should be strongly considered Systematic Review of biomarkers in RA and their use in diagnosis and treatment Complete literature review found 85 studies Intermediate probability patients may consider early biologic treatment Taylor P, et al. Autoimmune Dis. 2011;2011: Do Rheumatologists use Biomarkers for Treatment Decisions? Small study that used a validated algorithm combined with several biomarker levels to determine high-risk patients with RA 101 patients in 7 US areas recruited All had RA by ICD-9 coding All over age 18 Had RA a mean of 6 years Results of biomarker scoring given to providers Only 21 patients had their treatment regimens changed based on results This despite a positive correlation between biomarker score and disease activity in this cohort (r = 0.35, P<.001) Li W, et al. Curr Medl Res Opin. 2013; 29(1):

9 Tapering Therapy in Remission NEJM 2014 Patients with RA in remission (DAS < 2.6) on etanercept + MTX Etanercept tapered, then MTX in patients maintaining remission At 65 weeks, 44% of patients who had received combination therapy, 29% who had received MTX alone, and 15 (23%) who had received placebo were in remission (P=.10 for combination therapy vs MTX alone; P=.02 for combination therapy vs placebo; P=.55 for methotrexate alone vs placebo) Conclusion: Reduced or tapered therapy is feasible in a subset of patients with RA Several abstracts presented at ACR support this hypothesis and suggest that +Anti-CCP may be associated with less successful tapering Emery P, et al. N Engl J Med. 2014; 371(19): ; Dean K. Accessed December 27, Serious Infections & anti-tnf use DMARD n=1354 ETA n=3596 INF n=2878 ADA n=1190 P Yrs # infections Rate/1000 pyrs (95%CI) 41.4 ( ) 51.3 ( ) 55.2 ( ) 51.9 ( ) Adj IRR Referent 0.97 ( ) 1.04 ( ) 1.07 ( ) Overall risk anti-tnf vs DMARD: IRR 1.03, CI Pneumonia, skin/soft tissue, bone/joint, UTI 4x skin & soft tissue infection (IRR 4.28, CI ) Dixon WG, et al. Arthritis Rheum. 2006;54(8): Serious Infections with Rituximab, Abatacept, Anakinra Risk of serious infections, according to dose, OR (95% CI) High dose vs placebo Low dose vs placebo High dose vs low dose RIT (1000 vs 500 mg) 1.68 ( ) 0.24 ( ) 7.20 ( ) ABA (<2 vs 10 mg/kg) DMARD users excluded ANA (<100 vs 100 mg) Comorbidity factors excluded 1.35 ( ) 1.24 ( ) 3.40 ( ) 1.67 ( ) 0.84 ( ) 2.16 ( ) 2.0 ( ) 0.51 ( ) 9.63 ( ) 6.41 ( ) Metanalysis: RCTs (3 RIT, 5 ABA, 4 ANA) Printed with permission from Salliot C, et al. Ann Rheum Dis. 2009; 68(1):

10 Malignancy risk with Biologics subjects, p yrs ( ) US NDB data compared with US NCI SEER No increased risk for lymphoma, lung, breast, and colon cancer Increased risk for Skin cancer Melanoma OR 2.3 (95% CI ) Nonmelanotic skin cancer OR1.5 (95%CI ) 623 incident cases Wolfe F, et al. Arthritis Rheum. 2007; 56(9): Malignancy and Anti-TNFα Therapy Swedish Cohort, multi-source ( ) 240 cancers/6366 patients (25,693 pyrs) RR 1.00 (95% CI ), c/w TNF-naïve RR 0.99 (95% CI ), c/w MTX starters Organ-specific risk Agent-specific cancer risk Not Increased Risk with follow-up (6 years) Askling J, et al. Arthritis Rheum. 2009;60(11); Rituximab: Safety Issues Acute infusion reactions: 23% 1 st dose vs 18% PBO 8% 2 nd dose vs 11% PBO b Infection: 40-41% (38% in PBO) Serious infections: 5.2/100 p yrs (vs 3.7 PBO) 4.74/100 p yrs (2x1g) vs 0 (2x500mg) vs 3.19 (PBO) Progressive multifocal leukoencephalopathy Premedication - glucocorticoids PBO 2x500 mg 2x1000 mg With 17% 23% 32% Without 14% 32% 37% Emery P, et al. Arthritis Rheum. 2006;54(5): ; Cohen SB, et al. Arthritis Rheum. 2006;54(9):2793:806.

11 Tocilizumab: Safety Issues Infections Nasopharyngitis No TB occurences Laboratory Abnormalities 57% (4 mg), 76% (8 mg) Liver enzyme elevations CHARISMA: mild, transient TOC+MTX (11%) vs TOC alone (6%) Cholesterol elevation 44% Shetty A, et al. Drug Des Devel Ther. 2014;8: ; Maini RN, et al. Arthritis Rheum. 2006;54(9): Cost-related Adherence Prevalence of cost-related non adherence on RA drugs Prevalence of spending less on basic needs between based on morbidity burden Printed with permission from Harrold LR, et al. J Rheumatol. 2013;40(2): Cost Impact of Adherence $5,000 $4,500 $4,000 $3,500 $3,000 $2,500 $2,000 $1,500 $1,000 $500 $0 $1,894 $2,597 $3,141 Biologic Costs $2,236 $2,929 $3,598 RA-related Health Care Costs $3,042 $3,735 $4,500 All-cause Health Care Costs One analysis suggested tocilizumab (TCZ) had the lowest real-world health care costs compared to abatacept (ABA) and infliximab (INF) (Multivariate adjusted per patient per month health care costs) TCZ ARA INF Johnson SS, et al. Drugs-Real World Outcomes 2015;2:

12 How Can Pharmacists Rapidly Assess Adherence? Simplified version of the Compliance Questionnaire for Rheumatology (CQR), which, at 19 items, is too lengthy for common use Exploratory factor analysis (EFA) done to see if an 5-item selfreported version would be accurate Found that this simplified version had a high level of fit and accuracy compared to the full version (99%, P<.05) FREE excel calculator found at Download additional item 2 from end of article Hughes LD, et al. BMC Musculoskelet Disord. 2013;14:286 Key Safety/Monitoring Messages Non-Biologic DMARDS Methotrexate Hydroxychloroquine Leflunomide Sulfasalazine Counselling Points Take WEEKLY, folic acid 1 mg/daily mandatory, regular lab monitoring: Electrolytes, LFTS, CBC Rare but serious ocular toxicity associated with high doses; yearly eye exam is recommended, lab monitoring as above Similar toxicities and monitoring to MTX, folic acid not indicated Nausea a common ADR that should abate over time, lab monitoring as above Shea B, et al. J Rheumatol. 2014;41(6): ; Ruderman E. Rheumatology. 2012;51 Suppl 6:vi37-43.; Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68(1):1-25. Key Safety/Monitoring Messages Biologic DMARDS TNF-Inhibitors Anakinra Tocilizumab Counselling Points SQ Injection reactions are usually mild and can be avoided by rotating injection sites. Monitoring similar to DMARDs rare infections can occur, call MD with any fever Monitoring similar to DMARDs, rare infections can occur, call MD with any fever Monitoring similar to DMARDs, rare infections can occur, call MD with any fever or pain. May increase cholesterol levels Ruderman E. Rheumatology. 2012;51 Suppl 6:vi37-43.; Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68(1):1-25.

13 Key Safety/Monitoring Messages Biologic DMARD Abatacept Rituximab Tofacitinib Counselling Points Respiratory infections may increase with this medication, similar monitoring to DMARDS Report any post-infusion reactions (itching, swelling, SOB) to physician Newer oral agent to be used if other agents have failed. Similar monitoring to DMARDs, may increase risk of rare infections. Diarrhea and pedal edema common ADRs. Long-term safety still unknown Xeljanz (Tofacitinib) [Product information]. New York, NY: Pfizer Labs; 2015.; Ruderman E. Rheumatology. 2012;51 Suppl 6:vi37-43.; Singh JA, et al. Arthritis Care Res (Hoboken). 2016;68(1):1-25. Conclusion It s a good time to be a rheumatologist. Numerous new therapy available for RA, and many more on the way The dictum Treat to Target means more patients on biologics than ever before Pharmacists can play a role in adherence, patient counseling, and monitoring for ADRs As biosimilars come to market (the first slated for 2016), pharmacists also need to educate physicians on the similarities and differences of these agents compared to the innovator agent Additional Resources American College of Rheumatology European League Against Rheumatism UK National Rheumatoid Arthritis Society