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Safety Profile of Biologic Agents in Rheumatoid Arthritis: A Systematic Review Ten Topics in Rheumatology Manila, Philippines Karina D. Torralba, MD Los.

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Presentation on theme: "Safety Profile of Biologic Agents in Rheumatoid Arthritis: A Systematic Review Ten Topics in Rheumatology Manila, Philippines Karina D. Torralba, MD Los."— Presentation transcript:

1 Safety Profile of Biologic Agents in Rheumatoid Arthritis: A Systematic Review Ten Topics in Rheumatology Manila, Philippines Karina D. Torralba, MD Los Angeles County Medical Center University of Southern California

2 Disclosures Wyeth, Medical Education Grant Roche, Medical Education Grant American College of Rheumatology Research and Education Foundation Clinician-Scholar Educator Award

3 Objectives, Clarification of Focus To review updated safety issues with regard to the use of biologic therapy –Rheumatoid arthritis populations –Sources of data: Registry studies Metanalysis Major Randomized controlled trials for more recently approved drugs Case reports, case series for unique situations

4 19902000‘05 MTX SSZ HCQ CQ Gold Cyc-A AZA PNC Biologic drug clinical trials Biologic EraNonBiologic Era Etanercept(1998) Adalimumab Abatacept Rituximab Anakinra Leflunomide (1998) Spectrum of RA Treatment Golimumab Certolizumab (Tocilizumab*) ‘06‘03 Year of FDA Approval ‘01‘09 Infliximab

5 Taken from Fig 4 – Tracey D, et al. Tumor necrosis factor antagonists mechanisms of action: A comprehensive review. Pharmacology & Therapeutics 117 (2008) 244–279. Anti-TNFα Biologics for RA

6 Biologic Therapy: Major Safety Issues Infections Infusion/injection-site reactions Autoimmune diseases Malignancy Immunogenicity, blocking antibodies Use in pregnancy Use in patients with congestive heart failure Use in patients with cardiovascular diseases

7 Predictive Factors of Serious Infections in RA Serious Infections (Definition) Life-threatening, fatal, requiring hospitalization, intravenous antibiotics, or resulting in persistent of significant disability ↑Age +RF Nodules ↑ESR ↓WBC Extraarticular Features Corticosteroid use Diabetes mellitus Alcoholism Chronic Lung Disease Organic Brain Disease Doran MF, et al. Predictors of infection n rheumatoid arthritis. Arthritis Rheum 2002;46:2294-300.

8 Serious Infections & anti-TNF use (BSRBR) Overall risk anti-TNF vs DMARD*: IRR 1.03, CI 0.68-1.57 Pneumonia, skin/soft tissue, bone/joint, UTI 4x ↑skin & soft tissue infection (IRR 4.28, CI 1.06-17.17) DMARD n=1354 ETA n=3596 INF n=2878 ADA n=1190 P Yrs1352407546181175 # infections5620925561 Rate/1000 pyrs (95%CI) 41.4 (31.4-53.5) 51.3 (44.7-58.5) 55.2 (48.8-62.2) 51.9 (39.9-66.2) Adj IRRReferent0.97 (0.63-1.5) 1.04 (0.68-1.61) 1.07 (0.67-1.72) Dixon WG, et al. Rates of serious infection, including site-specific and bacterial intracellular infection, in Rheumatoid Arthritis Patients Receiving Anti-Tumor Necrosis Factor Therapy. Arthritis Rheum 2006;54(8):2368-76.

9 Serious Infections with Rituximab, Abatacept, Anakinra Metanalysis : 495 →12 RCTs (3 RIT, 5 ABA, 4 ANA) 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 500mg)1.68 (0.64-4.35)0.24 (0.01-4.33)7.20 (0.43-120.66) ABA (<2 vs 10mg/kg) DMARD users excluded 1.35 (0.78-2.33) 1.24 (0.70-2.29) 0.84 (0.13-5.3)2.16 (0.52-8.98) 2.0 (0.48-8.33) ANA (<100 vs ≥100mg) Comorbidity factors excluded 3.40 (1.11-10.46) 1.67 (0.51-5.41) 0.51 (0.03-8.27)9.63 (1.31-70.91) 6.41 (0.81-50.30) Salliot C, et al. Risk of serious infections during rituximab, abatacept and anakinra treatments for rheumatoid arthritis: meta-analyses of randomised p lacebo-controlled trials. ARD 2009;68:25-32.

10 TB risk and anti-TNFα therapy 10712 anti-TNF α vs 3232 DMARD cohort 34026 p-yrs vs 7345 p-yrs –28447 pyrs actively on anti-TNF α 40 episodes in 39 patients on anti-TNF α Median time to diagnosis (mos) 5.5 (INF), 11-13(ETN), 15-18.5 (ADA) ↑↑3-4 -fold among INF, ADA users vs ETA –62% extrapulmonary, 28% disseminated –10/39 deaths within 12 months of diagnosis Dixon WG, et al. Drug-Specific risk of Tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: Results from the BSRBR. ARD Oct 2009.

11 DMARD n=3232 All a-TNF n=10712 ETA n=5521 INF N=3718 ADA N=4857 Numbers, Rates of Incident TB – ON DRUG p yrs7345284471274480697634 TB cases027511 Rate/100K pyrs (95% CI), age- & gender- adjusted 095 (63,138)39 (13,92) 136 (68,244) 144 (72,258) IRR* (95% CI), age-, gender-adjusted Referent3.1 (1.0, 9.5) 4.2 (1.4, 12.4) Dixon WG, et al. Drug-Specific risk of Tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: Results from the BSRBR. ARD Oct 2009. Numbers, Rates of Incident TB – MOST RECENT DRUG p yrs7345284471507097309224 TB cases04081220 Rate/100K pyrs (95% CI), age- & gender- adjusted 0118 (84,160) 53 (23, 205) 123 (64, 215) 217 (132, 335) IRR* (95% CI), age- & gender-adjusted Referent2.2 (0.9, 5.8) 4.2 (1.8, 9.9)

12 Dixon WG, et al. Drug-Specific risk of Tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: Results from the BSRBR. ARD Oct 2009. Classification and Sites of TB Infection ETA n=8 (5) INF n=12 (11) ADA n=20 (11) All a-TNF n=40 (27) Pulmonary N=15 (38%) Lower Respiratory4 (2)2(2)6(3)12(7) Pleural-2(2)1(1)3(3) Total4(2)4(4)7(4)15(10) Extra- pulmonary (+ disseminated) N=25 (62%) Bone/Joint1 (1)-- GI-3(3)- Lymph node2(2) 6(6) CNS-1(1)2 (1)3 (2) Pharyngeal wall--1 (1) Disseminated1(0)2 (1)8 (3)11 (4) TOTAL4(3)8 (7)13 (7)25(17)

13 TB Incidence Rates & Comparative Risks Seong SS, et al. Incidence of tuberculosis in Korean patients with rheumatoid arthritis: effects of RA itself and of tumor necrosis factor blockers. J Rheumatol 2007;34:706-11.

14 PPD screening, TB risk in US Immigrant Population D Cooray, G Karpouzas, Harbor-UCLA Baseline and yearly TST ADA, ETA, IFX (INF) 27% (109/400) TST+ 30 conversions Cultures, PCR, CT Chest –5 NTM, 2 MTB DV Cooray, GA Karpouzas, Harbor-UCLA, Los Angeles, CA ACR 2009 Plenary Session, Abstract 1153

15 TB Infections among US-Based Immigrant RA Population DV Cooray, GA Karpouzas, Harbor-UCLA, Los Angeles, CA ACR 2009 Plenary Session, Abstract 1153

16 DV Cooray, GA Karpouzas. Harbor-UCLA, Los Angeles, CA ACR 2009 Plenary Session, Abstract 1153 TB Infections among US-Based Immigrant RA Population

17 Autoimmune diseases induced by biologics SLE or lupus-like syndromes Vasculitis Psoriasis Sardoidosis Demyelinating CNS Disease Demyelinating peripheral neuropathies Antiphospholipid syndrome or APS-like features Interstitial lung diseases Ocular Autoimmne Diseases Autoimmune Hepatitis Inflammatory myopathies Ramos-Casals M, et al. Best Prac Res Clin Rheumatol 2008 Torralba KD, Quismorio FP. Curr Op Rheumatol 2009

18 BIOGEAS: Autoimmune Diseases nINFETAADA DIL140373325 Vasculitis13943427 APS/APS-like4245415 Sarcoidosis38266110 Optic neuritis12343497 ILD11843473 Ocular AutoID8718792 MS/MS-like55205127 Peripheral neuropathies 44741214 AIHepatitis197910 Data extracted from tables - Ramos-Casals M, et al. Autoimmune diseases induced by biological agents, Autoimmun Rev 2009.

19 SLE-Like Disease due to Biologics Ramos-Casals M, et al. Autoimmune diseases induced by biological agents, Autoimmun Rev 2009. Drug-Induced Lupus 140 cases Less renal & CNS Asthenia, malaise, fever, rashes, arthralgia, myalgia Incidence with anti-TNFα: –17 RCTs: 0.76% (14/1842) –Post-marketing data 0.19-0.22% INF 0.18% ETA, 0.19% ADA Autoantibodies ANA 25-80% Anti-dsDNA 5-15%

20 Systemic Autoimmune Diseases due to Biologics Vasculitis –88% cutaneous Sarcoidosis –74% pulmonary, 29% cutaneous APS –aPL (+) - 8/13 cases –Thromboses (30), thrombocytopenia (9), thrombophlebitis (4) Peripheral Neuropathy EMG (n=28, INF) ↑amplitude, median nerve; ↓velocity - tibial, sural ILD –66% on MTX ?Potentiate MTX lung toxicity Ramos-Casals M, et al. Autoimmune diseases induced by biological agents, Autoimmun Rev 2009. Torralba KD, Quismorio FP. Sarcoidosis and the Rheumatologist. Curr Op Rheumatol 2009.

21 Psoriasis & anti-TNF α therapy: The Paradox Cytokine alteration: IFN-α production by plasmacytoid dendritic cells 25/9826 anti-TNF α group –IR: 1.04 (95% CI 0.67-1.54)/1000 pyrs Majority – due to ADA 79% continue anti-TNFα therapy –25% resolution while on therapy May respond anti-psoriatics Resolves with drug discontinuation –4% with continued psoriasis Harrison MJ, et al. Rates of new-onset psoriasis in patients with rheumatoid arthritis receiving anti-tumour necrosis factor α therapy: BSRBR. ARD 1009;68:209-15. Collamer AN, et al. Psoriatic Skin Lesions Induced by Tumor Necrosis Factor Antagonist Therapy: A Literature Review and Potential Mechanisms of Action. Arthritis & Rheumatism 2008; 59:996-1001.

22 Immunogenicity: Antidrug antibodies Clinical Consequences Drug resistance –Increased clearance –Inactivation of product Drug Reactions –definite mechanism unclear Immunogenicity with anti-TNF agents INFETAADACZPGOL Monotherapy+++++ND With MTX++/- +ND Taken from Table 1, Fig 6 – Tracey D, et al. Tumor necrosis factor antagonists mechanisms of action: A comprehensive review. Pharmacology & Therapeutics 117 (2008) 244–279.

23 Malignancy risk with Biologics 13001 subjects, 49000 p yrs (1998-2005) US NDB data compared with US NCI SEER No increased risk for lymphoma, lung, breast, and colon cancer Increased risk for skin cancer Nonmelanotic skin cancer –OR1.5 (95%CI 1.2-1.8) 623 incident cases Melanoma - OR 2.3 (95% CI 0.9-5.4) Wolfe F, Michaud K. Biologic treatment of rheumatoid arthritis and the risk of malignancy: Analyses from a large US observational study. Arthritis Rheum 2007; 56(9):2886-95..

24 Malignancy and anti-TNFα therapy Swedish Cohort, multi-source (1999-2006) 240 cancers/6366 patients (25,693 pyrs) –RR 1.00 (95% CI 0.87–1.17), c/w TNF-naïve –RR 0.99 (95% CI 0.79-1.24), c/w MTX starters Organ-specific risk Agent-specific cancer risk risk with follow-up (6 years) Askling J, et al. Cancer Risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor α therapies; Does the risk change with the time since start of treatment? Arthritis & Rheum 2009;60(11);3180-9. Not Increased

25 New Anti-TNFα agents: Safety Issues Certolizumab Pegol –Pegylated Fab fragment, human anti-TNF Ab –t1/2 14 days; q 2 week dosing –UTI, URTI (200mg); Hypertension (400mg); Headache Golimumab –Humanized anti-TNF monoclonal antibody –SQ injection once monthly –URTI/Nasopharyngitis, Diarrhea – most common AEs Smolen J, et al. GO-AFTER. Lancet 2009; 374: 210–21. Smolen J, et al. RAPID 2. Ann Rheum Dis. 2009 Jun;68(6):797-804. Fleischmann R, et al.FAST4WARD. Ann Rheum Dis. 2009 Jun;68(6):805-11.

26 GOLIMUMAB : Reported Adverse Events in Phase 3 24-week Trials GO-FORWARDPBO+MTX (n=134)GOL100mg+PBO (n=133) GOL50mg+MTX (n=212) GOL100mg+MTX (n=105) S. Infections Malignancies Active TB Death 1 (0.7%) 0.02 (<0.01-0.10) 1 (0.7%); 0.02 (<0.01-0.10) 0 4 (3%) 0.05 (0.02-0.11) 2 (1.5%); 0.02 (<0.01-0.06) 0 1 – ileus, aspn PNA 2 (0.9%) 0.02 (<0.01-0.06) 0 5 (4.8%) 0.08 (0. 03-0.17) 1 (1.0%); 0.01 (<0.01-0.06) 0 GO-AFTERPBO (n=155)GOL100mg (n=152)GOL50mg (n=152) S. Infections Malignancies 5 (3% 1(1%) 5 (3%) 1 (1%) Early RA trialPBO+MTX (n=160)GOL100+PBO (n=157) GOL50mg+MTX (n=158) GOL100mg+MTX (n=159) S. Infections Malignancies TB Death 3 (1.9%) 2 (1.3%) 0 2 (1.3%) 0 1 0 2 (1.3%) 1 (0.6%) 0 1 - suicide 7 (4.4%) 1 (0.6%) 0 1 – postop CRArrest Partial Data from tables: Keystone EC, et al GO-FORWARD. Ann Rheum Dis 2009;68:789–796.Smolen J, et al. GO-AFTER. Lancet 2009; 374: 210–21.Emery P, et al. Arthritis Rheum. 2009;60(8):2272-83.

27 CERTOLIZUMAB : Reported Adverse Events in 3 Phase 3 Trials RAPID 2 -24 w Results - n (%) PBO+MTX (n=125) CZP200mg+MTX (n=248) CZP400mg+MTX (n=246) S. Infections Death Cancer 0000 8 (3.2%) 1 (0.4) 6 (2.4) 1 (0.4) 5 TB cases Testicular CA colon CA FAST4WARD -24 w n (%); per 100 pyrs PBO (n=109) CZP400mg (n=111) S. Infections02 (1.8%); 4/100 pyrs No deaths No cancers RAPID 1 -52w n; per 100 pyrs PBO+MTX (n=199) CZP200mg+MTX (n=393) CZP400mg+MTX (n=390) S. Infections TB Death 2.2/100 pyrs 0 1; 1.1/100 pyrs 5.3/100 pyrs 0.7/100 pyrs 2; 0.7/100 pyrs 7.3/100 pyrs 1.0/100 pyrs 3; 1.3/100 pyrs *4 in text 5 TB Cases 12 Cancers – 11 CZP Partial Data from Tables: Smolen J, et al. RAPID 2. Ann Rheum Dis. 2009 Jun;68(6):797-804. Fleischmann R, et al.FAST4WARD. Ann Rheum Dis. 2009 Jun;68(6):805-11. Keystone E, et al., RAPID 1. Arthritis Rheum. 2008 Nov;58(11):3319-29..,.

28 Abatacept: Safety Issues Acute infusion reactions a –9.8% vs 6.7% placebo, mild-moderate Malignancy outcomes – 4134 Abatacept-treated patients compared with 41,529 DMARD treated patients in 5 cohorts –No increased rates of malignancy, infection over 6 years b a Sibilia J, Westhovens R. Safety of T-cell costimulation modulation with abatacept in patients with rheumatoid arthritis. Clin Exp Rheumatol 2007;25 (5Suppl46):S46-56. b Simon TA et al. Malignancies In RA Abatacept clinical development program. ARD 2008.

29 Abatacept – 5 year Safety Data Part of Table 1. Safety Summary Double Blind Study Period ABA 10 and 2mg/kg groups, 1 year Cumulative Study Period ALL treatment groups combined, 5 years Death, n (%)1 (0.5)5 (1.7) SAE events/100 pt yrs20 (14.03, 27.74)18.9 (15.78, 22.37) Serious Infections/100 pt yrs 21. (0.57, 5.38)3.0 (1.97, 4.35) Malignancies/100 pt yrs2.1 (0.57, 5.38)1.5 (1.07, 2.93) Westhovens R, et al. Safety and Efficacy of the selective costimulation modulator abatacept in patients with rheumatoid arthritis receiving background methotrexate: A 5-year extended phase IIB study. J Rheumatol Feb 2009.

30 Rituximab: Safety Issues Acute infusion reactions a : –23% 1 st dose vs 18% PBO→→ 8% 2 nd dose vs 11% PBO b Infection: 40-41% (38% in PBO) b Serious infections: –5.2/100 p yrs (vs 3.7 PBO) b –4.74/100 p yrs (2x1g) vs 0 (2x500mg) vs 3.19 (PBO) a Progressive multifocal leukoencephalopathy a Emery P, et al. DANCER. Arthritis Rheum 2006;54:1390-1400. b Cohen SB, et al. REFLEX. Arthritis Rheum 2006;54:2793:806. Premedication - glucocorticoids PBO2x500mg2x1000mg With18%23%32% Without14%32%37%

31 Tocilizumab: Safety Issues Infections –Nasopharyngitis –No TB occurences Laboratory Abnormalities –57% (4mg), 76% (8mg) Liver enzyme elevations CHARISMA: mild, transient ↑↑TOC+MTX (11%) vs TOC alone (6%) Cholesterol elevation – 44% Maini R, et al. Arthritis Rheum 2003;48 Suppl:S652; Nishimoto N, et al. Arthritis Rheum 2004;50:1761-9; Emery P, et al. Arthritis Rheum 2008;58Suppl:S617.

32 BIOLOGICS AND PREGNANCY Drug# cases Developmental toxicity - animals Fetal problems – HumansDrug Discontinuation? ETA51-Preterm, VACTERLAt missed period, (+) pregnancy test INF81-TOF, intestinal malrotationAt missed period, (+) pregnancy test ADA13-Preterm, PDA, limb reduction, Tracheobronchomalacia At missed period, (+) pregnancy test RIT10B cell depletion (2 nd /3 rd tri) Lymphopenia (1 st tri)12 mos pre-pregnancy ABAT0+/None (?)unknown10 wks pre-pregnancy “Biologics in Pregnancy: an Update on Everything You are Too Afraid Your Patients Are Going to Ask” by Dr. C. Chambers (OTIS), ACR 2009; OTIS registry data; ; Ostensen M, Forger F. Management of RA medications in pregnant patients. Nat Rev Rheumatol 2009;5:382-90. UptoDate 2009 *1 case each - CZP, ANA, 0 - GOL and ABA; no animal and human/fetal toxicity reported; drug discontinuation recommended for GOL, CZP, ANA

33 Take Home Points Vigilant monitoring is needed for infections, malignancy, infusion/injection reactions, and other safety issues –Vaccination early into RA treatment should be considered –TB screening Risk:benefit should be considered on an individual basis Biologics are relatively safe, however long-term studies especially for recently approved drugs are needed Use of biologics in pregnancy/lactation – needs further study


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