Safety Profile of Biologic Agents in Rheumatoid Arthritis: A Systematic Review

Ten Topics in RheumatologyManila, Philippines

Karina D. Torralba, MDLos 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

1990 2000 ‘05

MTXSSZHCQCQGoldCyc-AAZAPNC

Biologic drugclinical trials

Biologic EraNonBiologic Era

Etanercept(1998)

Adalimumab

Abatacept

Rituximab

Anakinra

Leflunomide (1998)

Spectrum of RA Treatment

GolimumabCertolizumab(Tocilizumab*)

‘06‘03

Year of FDA Approval

‘01 ‘09

Infliximab

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

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

• 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.

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)

DMARDn=1354

ETAn=3596

INFn=2878

ADAn=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)

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.

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.

DMARDn=3232

All a-TNFn=10712

ETAn=5521

INFN=3718

ADAN=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)

IRR* (95% CI), age-, gender-adjusted

Referent 3.1 (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 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.

Classification and Sites of TB Infection

ETAn=8 (5)

INFn=12 (11)

ADAn=20 (11)

All a-TNF n=40 (27)

PulmonaryN=15 (38%)

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)

Extra-pulmonary (+ disseminated) N=25 (62%)

Bone/Joint 1 (1) - - 1(1)

GI - 3(3) - 3(3)

Lymph node 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)

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, CAACR 2009 Plenary Session, Abstract 1153

TB Infections among US-Based Immigrant RA Population

DV Cooray, GA Karpouzas, Harbor-UCLA, Los Angeles, CAACR 2009 Plenary Session, Abstract 1153

DV Cooray, GA Karpouzas. Harbor-UCLA, Los Angeles, CAACR 2009 Plenary Session, Abstract 1153

TB Infections among US-Based Immigrant RA Population

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 2008Torralba KD, Quismorio FP. Curr Op Rheumatol 2009

BIOGEAS: Autoimmune Diseasesn 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.

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%

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 (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

Clinical Consequences• Drug resistance

– Increased clearance– Inactivation of product

• Drug Reactions – definite mechanism unclear

Immunogenicity with anti-TNF agents

INF ETA ADA CZP GOL

Monotherapy +++ + + ND 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.

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• 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

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 TrialsGO-FORWARD PBO+MTX (n=134) GOL100mg+PBO

(n=133)GOL50mg+MTX (n=212)

GOL100mg+MTX (n=105)

S. Infections

Malignancies

Active TBDeath

1 (0.7%)0.02 (<0.01-0.10)

1 (0.7%); 0.02 (<0.01-0.10)00

4 (3%)0.05 (0.02-0.11)

2 (1.5%); 0.02 (<0.01-0.06)01 – ileus, aspn PNA

2 (0.9%) 0.02 (<0.01-0.06)0

00

5 (4.8%)0.08 (0. 03-0.17)

1 (1.0%); 0.01 (<0.01-0.06)00

GO-AFTER PBO (n=155) GOL100mg (n=152) GOL50mg (n=152)

S. InfectionsMalignancies

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. InfectionsMalignanciesTBDeath

3 (1.9%)2 (1.3%)00

2 (1.3%)010

2 (1.3%)1 (0.6%)01 - suicide

7 (4.4%)1 (0.6%)01 – 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.

CERTOLIZUMAB : Reported Adverse Events in 3 Phase 3 TrialsRAPID 2 -24 wResults - n (%)

PBO+MTX (n=125)

CZP200mg+MTX (n=248)

CZP400mg+MTX (n=246)

S. InfectionsDeathCancer

00

8 (3.2%)1 (0.4)1 (0.4)

6 (2.4)1 (0.4)1 (0.4)

5 TB casesTesticular CA colon CA

FAST4WARD -24 wn (%); per 100 pyrs

PBO (n=109)

CZP400mg (n=111)

S. Infections 0 2 (1.8%); 4/100 pyrs

No deathsNo cancers

RAPID 1 -52wn; per 100 pyrs

PBO+MTX(n=199)

CZP200mg+MTX (n=393)

CZP400mg+MTX (n=390)

S. InfectionsTBDeath

2.2/100 pyrs01; 1.1/100 pyrs

5.3/100 pyrs0.7/100 pyrs2; 0.7/100 pyrs

7.3/100 pyrs1.0/100 pyrs3; 1.3/100 pyrs *4 in text

5 TB Cases12 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 DataPart of Table 1. Safety Summary

Double Blind Study Period ABA 10 and 2mg/kg groups, 1 year

Cumulative Study PeriodALL 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:

– 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.

Premedication - glucocorticoids

PBO 2x500mg 2x1000mg

With 18% 23% 32%

Without 14% 32% 37%

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 PREGNANCYDrug #

casesDevelopmentaltoxicity - 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

“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

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