Transcript Safety Profile of Biologic Agents in Rheumatoid Arthritis

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
Disclosures
• Wyeth, Medical Education Grant
• Roche, Medical Education Grant
• American College of Rheumatology Research
and Education Foundation Clinician-Scholar
Educator Award
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
Spectrum of RA Treatment
NonBiologic Era
Biologic Era
Leflunomide (1998)
MTX
SSZ
HCQ
CQ
Gold
Cyc-A
AZA
PNC
Etanercept(1998)
Infliximab
Biologic
drug
clinical
trials
1990
Rituximab
Golimumab
Certolizumab
(Tocilizumab*)
Abatacept
Adalimumab
Anakinra
2000 ‘01
‘03
Year of FDA Approval
‘05
‘06
‘09
Anti-TNFα 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) 244–279.
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
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 2002;46:2294-300.
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 Yrs
1352
4075
4618
1175
# infections
56
209
255
61
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 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 2006;54(8):2368-76.
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)
1.35 (0.78-2.33)
0.84 (0.13-5.3)
2.16 (0.52-8.98)
DMARD users excluded
1.24 (0.70-2.29)
ANA (<100 vs ≥100mg)
3.40 (1.11-10.46)
2.0 (0.48-8.33)
0.51 (0.03-8.27)
9.63 (1.31-70.91)
Comorbidity factors excluded
1.67 (0.51-5.41)
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.
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.
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 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)
Referent
3.1
(1.0, 9.5)
4.2
(1.4, 12.4)
IRR* (95% CI), age, gender-adjusted
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)
Referent
2.2
(0.9, 5.8)
4.2
(1.8, 9.9)
IRR* (95% CI), age& gender-adjusted
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
Pulmonary
N=15 (38%)
ETA
n=8 (5)
INF
n=12 (11)
ADA
n=20 (11)
All a-TNF
n=40 (27)
Lower Respiratory
4 (2)
2(2)
6(3)
12(7)
Pleural
-
2(2)
1(1)
3(3)
Total
4(2)
4(4)
7(4)
15(10)
1 (1)
-
-
1(1)
-
3(3)
-
3(3)
2(2)
2(2)
2(2)
6(6)
CNS
-
1(1)
2 (1)
3 (2)
Pharyngeal wall
-
-
1 (1)
1(1)
Disseminated
1(0)
2 (1)
8 (3)
11 (4)
TOTAL
4(3)
8 (7)
13 (7)
25(17)
ExtraBone/Joint
pulmonary
GI
(+ disseminated)
Lymph node
N=25 (62%)
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.
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.
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
TB Infections among US-Based
Immigrant RA Population
DV Cooray, GA Karpouzas, Harbor-UCLA, Los Angeles, CA
ACR 2009 Plenary Session, Abstract 1153
TB Infections among US-Based
Immigrant RA Population
DV Cooray, GA Karpouzas. Harbor-UCLA, Los Angeles, CA
ACR 2009 Plenary Session, Abstract 1153
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
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
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
118
Data extracted from tables - Ramos-Casals M, et al. Autoimmune
diseases induced by biological agents, Autoimmun Rev 2009.
SLE-Like Disease due to Biologics
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%
Ramos-Casals M, et al. Autoimmune diseases induced by biological agents, Autoimmun Rev 2009.
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.
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.
Immunogenicity: Antidrug antibodies
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) 244–279.
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..
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
Not Increased
• 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.
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.
GOLIMUMAB : Reported Adverse Events in Phase 3 24-week Trials
GO-FORWARD
PBO+MTX (n=134)
GOL100mg+PBO
(n=133)
GOL50mg+MTX
(n=212)
GOL100mg+MTX
(n=105)
S. Infections
1 (0.7%)
0.02 (<0.01-0.10)
4 (3%)
0.05 (0.02-0.11)
2 (0.9%)
0.02 (<0.01-0.06)
0
5 (4.8%)
0.08 (0. 03-0.17)
Malignancies
Active TB
Death
1 (0.7%);
0.02 (<0.01-0.10)
0
0
2 (1.5%);
0.02 (<0.01-0.06)
0
1 – ileus, aspn PNA
0
0
GO-AFTER
PBO (n=155)
GOL100mg (n=152)
GOL50mg (n=152)
S. Infections
Malignancies
5 (3%
1(1%)
5 (3%)
1 (1%)
1 (1%)
1 (1%)
Early RA trial
PBO+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
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
1 (1.0%);
0.01 (<0.01-0.06)
0
0
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.
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
0
0
8 (3.2%)
1 (0.4)
1 (0.4)
6 (2.4)
1 (0.4)
1 (0.4)
FAST4WARD -24 w
n (%); per 100 pyrs
PBO
(n=109)
CZP400mg
(n=111)
S. Infections
0
2 (1.8%);
4/100 pyrs
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
Testicular CA
colon CA
No deaths
No cancers
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..
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 2007;25 (5Suppl46):S46-56. bSimon TA et al. Malignancies In RA
Abatacept clinical development program. ARD 2008.
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 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.
Rituximab: Safety Issues
• Acute infusion reactionsa:
Premedication glucocorticoids
PBO
2x500mg
2x1000mg
With
18%
23%
32%
Without
14%
32%
37%
– 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
aEmery
P, et al. DANCER. Arthritis Rheum 2006;54:1390-1400. bCohen SB, et al. REFLEX. Arthritis Rheum 2006;54:2793:806.
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.
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 2009;5:382-90. UptoDate 2009
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