Safety Profile of Biologic Agents in Rheumatoid Arthritis: A Systematic Review Ten Topics in Rheumatology Manila, Philippines

1
Safety Profile of Biologic Agents in Rheumatoid
Arthritis A Systematic ReviewTen Topics in
RheumatologyManila, 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
Spectrum of RA Treatment
Biologic Era
NonBiologic Era
Leflunomide (1998)
MTX SSZ HCQ CQ Gold Cyc-A AZA PNC
Etanercept(1998)
Rituximab
Golimumab Certolizumab (Tocilizumab)
Infliximab
Abatacept
Adalimumab
Biologic drug clinical trials
Anakinra
1990
2000
05
06
03
01
09
Year of FDA Approval
5
Anti-TNFa Biologics for RA
Taken from Fig 4 Tracey D, et al. Tumor
necrosis factor antagonists mechanisms of action
A comprehensive review. Pharmacology
Therapeutics 117 (2008) 244279.
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

• ?Age
• RF
• Nodules
• ?ESR
• ?WBC

• Extraarticular Features
• Corticosteroid use
• Diabetes mellitus
• Alcoholism

• Chronic Lung Disease
• Organic Brain Disease

• Serious Infections (Definition)
• Life-threatening, fatal, requiring
  hospitalization, intravenous antibiotics, or
  resulting in persistent of significant disability

Doran MF, et al. Predictors of infection n
rheumatoid arthritis. Arthritis Rheum
2002462294-300.
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 n1354 ETA n3596 INF n2878 ADA n1190
P Yrs 1352 4075 4618 1175
infections 56 209 255 61
Rate/1000 pyrs (95CI) 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 IRR Referent 0.97 (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
200654(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) Risk of serious infections, according to dose, OR (95 CI) Risk of serious infections, according to dose, OR (95 CI) 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 (lt2 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 (lt100 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 20096825-32.
10
TB risk and anti-TNFa therapy

• 10712 anti-TNF a vs 3232 DMARD cohort
• 34026 p-yrs vs 7345 p-yrs
• 28447 pyrs actively on anti-TNF a
• 40 episodes in 39 patients on anti-TNF a
• 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 n3232 All a-TNF n10712 ETA n5521 INF N3718 ADA N4857
Numbers, Rates of Incident TB ON DRUG Numbers, Rates of Incident TB ON DRUG Numbers, Rates of Incident TB ON DRUG Numbers, Rates of Incident TB ON DRUG Numbers, Rates of Incident TB ON DRUG Numbers, Rates of Incident TB ON DRUG
p yrs 7345 28447 12744 8069 7634
TB cases 0 27 5 11 11
Rate/100K pyrs (95 CI), age- gender- adjusted 0 95 (63,138) 39 (13,92) 136 (68,244) 144 (72,258)
IRR (95 CI), age-, gender-adjusted Referent 3.1 (1.0, 9.5) 4.2 (1.4, 12.4)
Numbers, Rates of Incident TB MOST RECENT DRUG Numbers, Rates of Incident TB MOST RECENT DRUG Numbers, Rates of Incident TB MOST RECENT DRUG Numbers, Rates of Incident TB MOST RECENT DRUG Numbers, Rates of Incident TB MOST RECENT DRUG Numbers, Rates of Incident TB MOST RECENT DRUG
p yrs 7345 28447 15070 9730 9224
TB cases 0 40 8 12 20
Rate/100K pyrs (95 CI), age- gender- adjusted 0 118 (84,160) 53 (23, 205) 123 (64, 215) 217 (132, 335)
IRR (95 CI), age- gender-adjusted Referent 2.2 (0.9, 5.8) 4.2 (1.8, 9.9)
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.
12
Classification and Sites of TB Infection Classification and Sites of TB Infection Classification and Sites of TB Infection Classification and Sites of TB Infection Classification and Sites of TB Infection Classification and Sites of TB Infection
ETA n8 (5) INF n12 (11) ADA n20 (11) All a-TNF n40 (27)
Pulmonary N15 (38) Lower Respiratory 4 (2) 2(2) 6(3) 12(7)
Pulmonary N15 (38) Pleural - 2(2) 1(1) 3(3)
Pulmonary N15 (38) Total 4(2) 4(4) 7(4) 15(10)
Extra-pulmonary ( disseminated) N25 (62) Bone/Joint 1 (1) - - 1(1)
Extra-pulmonary ( disseminated) N25 (62) GI - 3(3) - 3(3)
Extra-pulmonary ( disseminated) N25 (62) Lymph node 2(2) 2(2) 2(2) 6(6)
Extra-pulmonary ( disseminated) N25 (62) CNS - 1(1) 2 (1) 3 (2)
Extra-pulmonary ( disseminated) N25 (62) Pharyngeal wall - - 1 (1) 1(1)
Extra-pulmonary ( disseminated) N25 (62) Disseminated 1(0) 2 (1) 8 (3) 11 (4)
TOTAL 4(3) 8 (7) 13 (7) 25(17)
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.
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 200734706-11.
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
TB Infections among US-Based Immigrant RA
Population
DV Cooray, GA Karpouzas. Harbor-UCLA, Los
Angeles, CA ACR 2009 Plenary Session, Abstract
1153
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
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BIOGEAS Autoimmune Diseases
n INF ETA ADA
DIL 140 37 33 25
Vasculitis 139 43 42 7
APS/APS-like 42 45 41 5
Sarcoidosis 38 26 61 10

Optic neuritis 123 43 49 7
ILD 118 43 47 3
Ocular AutoID 87 18 79 2
MS/MS-like 55 20 51 27
Peripheral neuropathies 44 74 12 14
AIHepatitis 19 79 10 10
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
Drug-Induced Lupus

• 140 cases
• Less renal CNS
• Asthenia, malaise, fever, rashes, arthralgia,
  myalgia
• Incidence with anti-TNFa
• 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

Ramos-Casals M, et al. Autoimmune diseases
induced by biological agents, Autoimmun Rev 2009.
20
Systemic Autoimmune Diseasesdue to Biologics

• Vasculitis
• 88 cutaneous
• Sarcoidosis
• 74 pulmonary, 29 cutaneous
• APS
• aPL () - 8/13 cases
• Thromboses (30), thrombocytopenia (9),
  thrombophlebitis (4)

• Peripheral Neuropathy
• EMG (n28, 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 a therapy The Paradox

• Cytokine alteration IFN-a production by
  plasmacytoid dendritic cells
• 25/9826 anti-TNF a group
• IR 1.04 (95 CI 0.67-1.54)/1000 pyrs
• Majority due to ADA
• 79 continue anti-TNFa 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 a therapy BSRBR. ARD
100968209-15. 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 59996-1001.
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Immunogenicity Antidrug antibodies
Immunogenicity with anti-TNF agents Immunogenicity with anti-TNF agents Immunogenicity with anti-TNF agents Immunogenicity with anti-TNF agents Immunogenicity with anti-TNF agents Immunogenicity with anti-TNF agents
INF ETA ADA CZP GOL
Monotherapy ND ND
With MTX /- /- ND

• Clinical Consequences
• Drug resistance
• Increased clearance
• Inactivation of product
• Drug Reactions
• definite mechanism unclear

Taken from Table 1, Fig 6 Tracey D, et al.
Tumor necrosis factor antagonists mechanisms of
action A comprehensive review. Pharmacology
Therapeutics 117 (2008) 244279.
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 (95CI 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-TNFa therapy

• Swedish Cohort, multi-source (1999-2006)
• 240 cancers/6366 patients (25,693 pyrs)
• RR 1.00 (95 CI 0.871.17), 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)

Not Increased
Askling J, et al. Cancer Risk in patients with
rheumatoid arthritis treated with anti-tumor
necrosis factor a therapies Does the risk
change with the time since start of treatment?
Arthritis Rheum 200960(11)3180-9.
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New Anti-TNFa 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
21021. Smolen J, et al. RAPID 2. Ann Rheum Dis.
2009 Jun68(6)797-804. Fleischmann R, et
al.FAST4WARD. Ann Rheum Dis. 2009
Jun68(6)805-11.
26
GOLIMUMAB Reported Adverse Events in Phase 3 24-week Trials GOLIMUMAB Reported Adverse Events in Phase 3 24-week Trials GOLIMUMAB Reported Adverse Events in Phase 3 24-week Trials GOLIMUMAB Reported Adverse Events in Phase 3 24-week Trials GOLIMUMAB Reported Adverse Events in Phase 3 24-week Trials
GO-FORWARD PBOMTX (n134) GOL100mgPBO (n133) GOL50mgMTX (n212) GOL100mgMTX (n105)
S. Infections Malignancies Active TB Death 1 (0.7) 0.02 (lt0.01-0.10) 1 (0.7) 0.02 (lt0.01-0.10) 0 0 4 (3) 0.05 (0.02-0.11) 2 (1.5) 0.02 (lt0.01-0.06) 0 1 ileus, aspn PNA 2 (0.9) 0.02 (lt0.01-0.06) 0 0 0 5 (4.8) 0.08 (0. 03-0.17) 1 (1.0) 0.01 (lt0.01-0.06) 0 0
GO-AFTER PBO (n155) GOL100mg (n152) GOL50mg (n152)
S. Infections Malignancies 5 (3 1(1) 5 (3) 1 (1) 1 (1) 1 (1)
Early RA trial PBOMTX (n160) GOL100PBO (n157) GOL50mgMTX (n158) GOL100mgMTX (n159)
S. Infections Malignancies TB Death 3 (1.9) 2 (1.3) 0 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 200968789796.Smolen
J, et al. GO-AFTER. Lancet 2009 374
21021.Emery P, et al. Arthritis Rheum.
200960(8)2272-83.
27
CERTOLIZUMAB Reported Adverse Events in 3 Phase 3 Trials CERTOLIZUMAB Reported Adverse Events in 3 Phase 3 Trials CERTOLIZUMAB Reported Adverse Events in 3 Phase 3 Trials CERTOLIZUMAB Reported Adverse Events in 3 Phase 3 Trials CERTOLIZUMAB Reported Adverse Events in 3 Phase 3 Trials
RAPID 2 -24 w Results - n () PBOMTX (n125) CZP200mgMTX (n248) CZP400mgMTX (n246)
S. Infections Death Cancer 0 0 8 (3.2) 1 (0.4) 1 (0.4) 6 (2.4) 1 (0.4) 1 (0.4) 5 TB cases Testicular CA colon CA

FAST4WARD -24 w n () per 100 pyrs PBO (n109) CZP400mg (n111)
S. Infections 0 2 (1.8) 4/100 pyrs No deaths No cancers

RAPID 1 -52w n per 100 pyrs PBOMTX (n199) CZP200mgMTX (n393) CZP400mgMTX (n390)
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 Jun68(6)797-804.
Fleischmann R, et al.FAST4WARD. Ann Rheum Dis.
2009 Jun68(6)805-11. Keystone E, et al., RAPID
1. Arthritis Rheum. 2008 Nov58(11)3319-29..
28
Abatacept Safety Issues

• Acute infusion reactionsa
• 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 yearsb

aSibilia J, Westhovens R. Safety of T-cell
costimulation modulation with abatacept in
patients with rheumatoid arthritis. Clin Exp
Rheumatol 200725 (5Suppl46)S46-56. bSimon TA et
al. Malignancies In RA Abatacept clinical
development program. ARD 2008.
29
Abatacept 5 year Safety Data
Part of Table 1. Safety Summary Part of Table 1. Safety Summary 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 yrs 20 (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 yrs 2.1 (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 reactionsa
• 23 1st dose vs 18 PBO?? 8 2nd dose vs 11 PBOb
• 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

Premedication - glucocorticoids PBO 2x500mg 2x1000mg
With 18 23 32
Without 14 32 37
aEmery P, et al. DANCER. Arthritis Rheum
2006541390-1400. bCohen SB, et al. REFLEX.
Arthritis Rheum 2006542793806.
31
Tocilizumab Safety Issues

• Infections
• Nasopharyngitis
• No TB occurences
• Laboratory Abnormalities
• 57 (4mg), 76 (8mg)
• Liver enzyme elevations
• CHARISMA mild, transient
• ??TOCMTX (11) vs TOC alone (6)
• Cholesterol elevation 44

Maini R, et al. Arthritis Rheum 200348
SupplS652 Nishimoto N, et al. Arthritis Rheum
2004501761-9 Emery P, et al. Arthritis Rheum
200858SupplS617.
32
BIOLOGICS AND PREGNANCY BIOLOGICS AND PREGNANCY BIOLOGICS AND PREGNANCY BIOLOGICS AND PREGNANCY BIOLOGICS AND PREGNANCY
Drug cases Developmental toxicity - animals Fetal problems Humans Drug Discontinuation?
ETA 51 - Preterm, VACTERL At missed period, () pregnancy test
INF 81 - TOF, intestinal malrotation At missed period, () pregnancy test
ADA 13 - Preterm, PDA, limb reduction, Tracheobronchomalacia At missed period, () pregnancy test
RIT 10 B cell depletion (2nd/3rd tri) Lymphopenia (1st tri) 12 mos pre-pregnancy
ABAT 0 /None (?) unknown 10 wks pre-pregnancy
1 case each - CZP, ANA, 0 - GOL and ABA no
animal and human/fetal toxicity reported drug
discontinuation recommended for GOL, CZP, ANA
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 20095382-90. UptoDate 2009
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
• Riskbenefit 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