Annual Rheumatology &

Therapeutics Review for

Organizations & Societies

Safety of Biologics

Biologics* in Rheumatoid Arthritis

* Tofacitinib & Apremilast are not biologics

Agent Biologic Target Construct

Infliximab TNF Chimeric MAb

Etanercept TNF IgG-p75 receptor

Adalimumab TNF Human MAb

Goliumumab TNF Human MAb

Certolizumab TNF Peg-Fab’

Abatacept T-cell costimulation IgG-CTLA4 fusion

Rituximab B-cells Chimeric MAb

Anakinra IL-1 IL-1 receptor antagonist

Tocilizumab IL-6 Anti-IL6 receptor MAb

Mouse

Human

Chimeric

monoclonal

antibody

CDR

Infliximab

Human

recombinant

antibodies

Adalimumab

Humanized Fab’ fragment

Etanercept

Human recombinant

receptor/Fc fusion

protein

Fc

Receptor

Constant 2

Constant 3

PEG PEG

Certolizumab

VL VH

CL

CH1

Golimumab

TNFα Inhibitors

Adapted from Tracey D et al. Pharmacol Ther. 2008;117:244-279

Other Biologic Agents

Woodrick RS and Ruderman EM Nature Rev Rheumatol. 7:639-52 (2011)

vs

Risks of RA • Extra-articular disease

• Deformity/Disability

• Comorbidities

• Infections

• Mortality

Risks of Biologics • Injection site/infusion reactions

• Serious infections

• Opportunistic infections

• Lymphoma/neoplasia

• Autoimmune/lupus/MS

• Exacerbation of CHF

Making Sense of Safety

Summary from Product Label

Doubling of SIE* Rate With Biologic Use

SIE Rates (PI) Biologic Placebo

Anakinra 2% 1%

Adalimumab 2% 1%

Etanercept 1% 1%

Infliximab 5.3% 3.4%

Golimumab 1.9% 2.2%

Certolizumab 3% 1%

Abatacept 3% 1.9%

Rituximab 2% 1%

Tocilizumab 3.6 / 100py 1.5 / 100py SIE: Serious Infectious Event

HUMIRA (adalimumab) [package insert]. Chicago, IL; Abbott Laboratories; 2008; ENBREL (etanercept) [package insert]. Thousand Oaks, CA;

Immunex Corporation; 2006; REMICADE (infliximab) [package insert]. Malvern, PA; Centocor, Inc; 2007.

Rate

occu

rrin

g i

n R

A

po

pu

lati

on

6,7

Seri

ou

s i

nfe

cti

on

s (

even

ts/1

00 P

Y)

2

4

6

8

0

ETA4

4.2

IFX1

6

RTX5

4.7

ABA6

3.9

MTX7,8

3.8

ADA3

4.65

TCZ2

5.2

Rheumatoid Arthritis:

Serious Infections (RA Clinical Trials)

1. FDA Safety Review (online). 2. Smolen JS et al. Lancet. 2008;371:987-97. 3. Burmester G et al. Arthritis Rheum. 2008;59:32-41. 4. Zeichner JA et al. JAAD. 2006;54:S120-1. 5. Emery P et al. Arthritis Rheum. 2006;54:1390-400. 6. BMS document for abatacept (BMS-188667) Biological License Application 125118; 7. Singh G et al. Arthritis Rheum. 2002;46;2287-93; 8. Doran M et al. Arthritis Rheum. 2002;46:2287-93;

Biologic Comparative risks per 1000

(95%CI)

Control assumed risk = 26

Relative effect

OR (95% CI)

NNTH

(95% CI)

Abatacept 15 (8 - 28) 0.57 (0.30-1.08) NS

Adalimumab 29 (19 – 43) 1.12 (0.73-1.70) NS

Anakinra 28 (12 – 63) 1.08 (0.47-2.50) NS

Certolizumab 86 (41 – 172) 3.51 (1.59-7.79) 17 (7-68)

Etanercept 28 (19 – 39) 1.06 (0.74-1.51) NS

Golimumab 33 (19 – 59) 1.29 (0.71-2.35) NS

Infliximab 37 (26 – 54) 1.45 (0.99-2.13) NS

Rituximab 25 (17 – 38) 0.97 (0.64-1.48) NS

Tocilizumab 40 (22 – 73) 1.58 (0.85-2.94) NS

All biologics 31 (24 – 39) 1.19 (0.94-1.52) NS

Serious Infections with Biologics

Singh JA, et al. Cochrane Database Syst Rev. 2011 Feb 16;(2):CD008794.

Serious Infections With Anti-TNF Treatment

Frequency of Serious Infections in Anti-TNF-treated Patients

Observational RA Population N Rate/100

Pt-Yrs

Adjusted

Relative

Rate*

RABBIT: Listing et al., Arthritis Rheum 2005

64(9):1274–9 858 6.3 2.2

BSRBR: Dixon et al., Arthritis Rheum 2007;

56(9): 2896–2904 8659 5.5 1.2

ARTIS: Askling et al., Ann Rheum Dis 2007;

66:1339–44 4167 5.4* 1.4

Curtis JR, et al., Arthritis Rheum 2007;

56:1125–33 2393 2.9** 1.9

Schneeweiss S, et al., Arthritis Rheum

2007; 56(6):1754-64 469 2.2 1.0

* Compared with MTX- or DMARD-treated patients with RA

RCTs of TNF inhibitors in High Risk Patients#

SIE Outcomes

Study, yr Drug No. Wks DMARD

+Placebo

DMARD +

TNFi

STAR

2003 Adalimumab 636 24 1.3% 1.9%

START

2006 Infliximab 1084 22 1.7%

1.7% 3mg

(5% 10mg)

Weisman

2007 Etanercept 535* 16 3.9% 3.0%

# must have >1 comorbidity (eg, DM, COPD) *1000 pt study closed enrollment after 3.5 yrs for slow accrual

Usual doses did not increase the risk of SIE in patients w/ comorbidities.

Higher dose infliximab significantly increased SIE events

Furst, J Rheumatol. 2003 Dec;30(12):2563-71 Westhovens, Arthritis Rheum. 2006 Apr;54(4):1075-86 Weisman ME, et al. Rheumatology 2007:46:1122

Do TNF Inhibitors / Hospitalizations?

Wolfe, Arthritis Rheum. 2006;54:628-34. Curtis, Arthritis Rheum. 2007 56:1125-33.

Schneeweiss. Arthritis Rheum. 2007 56:1754-64. Suissa, Pulm Pharmacol Ther. 2008;21:234.

Grijalva CJ et al. JAMA. 2011 Nov 6

Author Type of

Hospitalization N RR 95%CI

Wolfe Pneumonia 16,788

1.2

0.8

1.1

0.9-1.4

0.6-1.0

0.6-1.8

Curtis Bacterial infx 5326 1.9 1.3-2.8

Schneweiss Bacterial infx 15,597 1.0 0.6-1.7

Suissa COPD 15,771 0.62 0.43-0.89

Grijalva SIE 10,484 1.05 0.91-1.21

SIE w/ Rituximab, Abatacept and Anakinra in RCTs

Source Biologic SIE Biologic(%) SIE Placebo(%) ORs (95% CI)

Edwards et al, 2004

RTX

6/121 (4.9) 1/40 (2.5)

1.45

(0.56 - 3.73)

Emery et al, 2006 4/316 (1.2) 2/149 (1.3)

Cohen et al, 2006 7/308 (2.3) 3/209 (1.4)

Total 17/745 (2.3) 6/398 (1.5)

Moreland et al, 2002

ABAT

1/90 (1.11) 0/32 (0)

1.35

(0.78 - 2.32)

Kremer et al, 2005 1/220 (0.45) 2/119 (1.7)

Genovese et al, 2005 6/258 (2.3) 3/133 (2.2)

Kremer et al, 2006 13/433 (3.0) 5/219 (2.3)

Weinblatt et al, 2006 28/959 (2.9) 8/482 (1.6)

Total 49/1960 (2.5) 18/985 (1.8)

Bresnihan et al, 1998

ANAK

5/351 (1.42) 1/121 (0.82)

2.75

(0.90 - 8.35)

Cohen et al, 2002 0/345 (0) 0/74 (0)

Cohen et al, 2004 2/250 (0.80) 2/251 (0.8)

Schiff et al, 2004 23/1116 (2.0) 1/283 (0.3)

Total 30/2062 (1.4) 4/729 (0.5)

Salliott C Ann Rheum Dis. 2009 January; 68(1): 25–32.

TNF Inhibitors and Risk of Septic Arthritis

• BSRBR: 191 septic arthritis among 11,881 anti-TNF and 3673

DMARD Rx patients

• Infectious risk greatest early

• Risk Factors: Prior joint replacement

0

0.0

00.0

10

.02

Cu

mu

lative

ha

za

rd f

un

ctio

n

Etanercept

Adalimumab

Follow-up (years)

Infliximab

nbDMARD

1 2 3

Ann Rheum Dis 2011 Oct;70(10):1810-4

0

10

20

30

40

50

60

70

80

90

100

Cum

ula

tive f

req

uen

cy o

f seri

ous in

f

% of severe

infections/

cycle

3 months 6 months 9 months 12 months

Duration between RTX infusion and serious infections

1st Cycle

2nd Cycle

Real World Infections (SIE) w/ Rituximab

• French AIR Registry

• 1303 pts (1.2 yr F/U)

• 82 SIE in 78 pts

• 5.0 SIE/100 pt-yrs

• ~50% w/in 1st 3 mos

• Predictors (OR):

– Chr. Lung Dz (3.0)

– Cardiac Insuff (3.0)

– Xtra-Artic Dz (2.9)

– HypoIgG before RTX (4.9)

Gottenberg JR, et al. Arthritis Rheum 2010

Serious Infection Risk Over Time

Decreased rate of serious infection over time in Japanese cohorts. Perhaps

better patient selection and/or monitoring?

Sakal R et al. Rheumatol Int. Published On-Line 2014

Infection Risk with RA Therapies

• Serious bacterial infections

– Incidence with biologics > DMARDs

– No direct comparisons between biologics agents

– Skin, soft tissue, and joints more common sites of infection

• Combined biologic therapy contraindicated

– Increased serious infectious events (SIEs) with combined use

– SIE etanercept + anakinra, 3.7%–7.4% vs etanercept alone, 0%

– SIE abatacept/biologic, 5.8% vs biologic alone, 1.6%

Furst DE et al. Ann Rheum Dis. 2007;66:2-22.

Genovese MC et al. Arthritis Rheum. 2004;50:1412-1419.

Weinblatt M et al. Arthritis Rheum. 2006;54:2807-2816.

RA and Serious Infections

The best predictors of serious infection

events (SIE) and infectious deaths:

1. RA severity/disease activity

2. Corticosteroid therapy

3. Comorbid diseases: CHF, CRF, IDDM,

COPD, etc.

4. Cutaneous barrier breakdown

(ulcers, wounds)

5. Joint surgery

Kaandorp CJ, Arthritis Rheum 1995;38:1819-25 Doran Fl. Arthritis Rheum 2002;46:2287-93

Community-acquired Pneumonia (CAP) in Elderly

11,241 individuals > 65 yrs, followed 2002 - 2005

CAP/1000 person-yrs

Elderly 14.0

Immunocompromised 30.9

Chronic lung disease 46.5

Long-term steroid Rx 40.1

NDB: 16,788 RA pts 17

Risk factors (HR ~2-4) Age, Pred, DM, MI, Lung Dz

Infectious risk is driven by age, severity, steroids, comorbidity

Vila-Corcoles A,; EPIVAC Study Group. Respir Med. 2008 Wolfe F, et al. Arthritis Rheum 54:628-34, 2006

Treatment Related Risk of SIE in RA

0

1

2

3

4

5

6

TNFi Pred High dose Pred

Hazard

ratio

Penn NDB Tenn

TNF inhibitors and Selected SIE in Elderly RA Medicare and Pharmacy Claims database

Age, gender

Adjusted HR

TN

F

Pneumonia 1.4 (0.7–2.9)

Bacteremia 1.0 (0.5–2.1)

Osteomyelitis 1.0 (0.3–4.3)

ST

ER

OID

Pneumonia 2.4 (1.3–4.2)

Bacteremia 2.9 (1.8–4.5)

Osteomyelitis 1.5 (0.6–4.1)

*HR compared with MTX initiation (alone or in combination)

Conclusions: • No increased risk in infections in patients on anti-TNF compared to MTX • Prednisone use confers significant, dose-related risk of infection

Schneeweiss S, et al. Arthritis Rheum. 2007;56:1754-64 .

Risk of Infection/Hospitalization with TNFi

• Retrospective cohort study: 4 US databases (1998–2007)

• SIE event rate in RA: TNFi 8.17 vs DMARD 7.66 per 100 pt-y; adj. HR 1.09 (95% CI 0.94–1.25)

• TNFi did not ↑ SIE/hospitalization, but IFX did ↑ SIE risk

SIE Hosp HR RA IBD SpA

TNFi 1.05 (0.91–1.21)

1.10 (0.83–1.46)

1.05 (0.76–1.45)

Prednisone 0–4 mg/d 1.32 1.09 1.13

Prednisone 5–10 mg/d 1.78 0.93 2.01

Prednisone >10 mg/d 3.95 1.38 2.77

Overall TNFi use not assoc with increased SIE (but IFX was) Prednisone increases

SIE risk in RA and SpA, but not IBD

NS

Courtesy TREG 2012

NS

Grijalva CJ, et al. ACR 2011, Chicago, #801

Serious Infection and Baseline

Disease Activity

• Data from BSRBR*

– DMARD n=1365

– ETN n=3470

• DAS28 ≤5: IR = 27.1/1000 pt-y

• DAS28 >6 & ≤7:IR=40.5/1000 pt-y

• DAS28 >8: IR = 64.2/1000 pt-y

• For every 1 point DAS28

– HR for SIE 17%

– HR 1.17 (95% CI 1.08–1.27, P<0.001)

– No difference between ETN or DMARD

Disease activity, not medication, determines risk of SIE

Infe

cti

on

rate

per

1000 p

t-y

20

60

≤4 6 7

DAS28

DMARD

ETN

TOTAL

40

≥8

80

70

50

30

10

0

5

BSRBR – British Society for Rheumatology Biologics Registers Emery P, et al. ACR 2011, Chicago, #429

Courtesy TREG 2012

Risk of Infection Augmented by Steroid

Dose, Biologics and Comorbidities

SIE risk augmented by Steroids, TNF inhibitor, comorbidity, prior SIE

Estimated Serious Infections per 100 Patient Years based on Risk Factors

• age >60 years, • chronic lung disease • chronic renal disease • high number of treatment • prior serious infections.

Strangfeld A, et al. Ann Rheum Dis. 2011 Nov;70(11):1914-20. Courtesy TREG 2012

RABBIT: Calculating the Risk of Serious

Infection (SIE) in the Next 12 Months

RA patient #1

47 yr. old woman has no

comorbidities, 2 prior DMARD

failures, has 3 tender and 3

swollen joints, HAQ = 0.5, and

takes MTX and prednisone 10

mg qday

SIE Risk = 1.4%

SIE Risk = 2.6% *calculated from http://www.biologika-register.de

RA patient #2

62 yr. old woman with COPD and

prior pneumonia has failed 6 prior

DMARDs/biologics, has 6 tender

and 6 swollen joints and HAQ=1.2

while taking leflunomide and

prednisone15 mg qday

SIE Risk = 28.4%

SIE Risk = 45.2%

Risk Calculated from Risk Factors

Age Pred # priorDMARDs Prior SIE Current Biologic

Cush JJ. ACR Drug Safety Quarterly 2013; 4 (4):1-3 Zinck A, Ann Rheum Dis.2013 Jun 28 Epub

High Risk RA Patients

Patient Profiling: SIE Risk Factors

• Elderly

• Hx of pneumonia

• Hx of septic arthritis

• Hx of smoking

• Hx of comorbidities – esp chronic lung disease

• > 10 mg/day prednisone

• Multiple DMARD failures

• High disease activity

• Those requiring higher TNFi doses

• Cytotoxics, cyclosporine

Serious Infections Are Usually Multifactorial

• RA (inflammation/debility)

• Comorbidities

• Steroid use

• Advanced age

• Biologic use

– small, significant 1-2X risk

– occurs early (1st 6 mos)

• Inflammation augmented;

• Depletion of susceptibles

– higher doses (TNFi)

RA Activity

Comorbid

Diseases

Drugs

(steroids, biologics)

Summary

• Best way to avoid serious infections:

– Employ screening measures (when possible)

– Rigorous Patient selection

– Vaccination where appropriate

– Avoid or lower corticosteroid use

– Maintain optimal disease control

– Monitor signs and symptoms periodically

½ life 5x ½ life

102 hrs 21d

(3wk)

210 hrs 44d

(6wk)

2 wks 70d

(10 wk)

How Long Before Major Planned Surgery

Would You Cease/Hold TNFi?

How long would you

stop before surgery?

etanercept 1.72 wks

infliximab 4.05 wks

adalimumab 2.47 wks

Cush JJ. Ann Rheum Dis 2005;64 Suppl 4:iv18-23.

Perioperative Infectious Risk

• 37,137 patients; 50,359 orthopedic

surgeries over 8 y

• Inflammatory arthritis (IRD) vs other

• 422 perioperative infections

– 2% in IRD vs 0.8% in “other”

– OR: 2.58; 95%CI 1.9, 3.5; P<0.001

• Periop infections higher with TNFi

– OR: 2.6; 1.1, 6.2; P=0.027

• 10x higher risk within 1 dose interval

(OR 10.0) (81% inflix)

Risk in relation to When TNFi D/C

IFX

3–5 mg/kg

BW

-200 0

Time-lag of last dose (days)

-250 -150 -100 -50

Infection

No infection

ADA

40 mg

-200 0 -250 -150 -100 -50

Infection

No infection

ETN

50 mg

-200 0 -250 -150 -100 -50

Infection

No infection

ETN

25 mg

-200 0 -250 -150 -100 -50

Infection

No infection

Orthopedic surgery appears safer

after 1 skipped dose

Scherrer CB, et al. ACR 2012, Washington, # 1669. Courtesy TREG 2012

Surgery - Recommendations

• Surgical site infx risk higher w/ TNF inhib

(OR 5.3-5.7)

• Risk of infection is greatest: after administration

(peak drug levels?) or when TNFi Rx washed-out

(inflammation risk)

1. Do not do surgery at peak drug levels

2. Do not do surgery at nadir of therapy

3. Suspend TNFi for one dosing interval (or 4 wks)

– Etanercept > 1 week

– Adalimumab > 2-4 weeks

– Infliximab > 4-8 weeks * Synthesis of 7 retrospective studies Mornohara M, et al. Mod Rheumatol. 2011 Feb 12. Giles JT, et al. Arthritis Rheum 2006;55(2):333-7.

Den Broeder AA. J Rheumatol. 2007;34(4):689-95. Dixon W, et al EULAR 2007, OP0215

Tuberculosis Risk

TB Risk Augmented by:

• Host factors (HIV, Prison)

• Geography/environment

• Exposure

• Drugs (TNFi > biologics)

• Number needed to Harm

– 681 (95% CI 143,14706)

compared to control

RA

+TNF

Relative Risk

9

2

1

30

Korea Sweden

RA

No TNF

RA

No TNF

RA

+TNF

NL NL

TNFi risk

4-9 x in low

risk populat.

TNFi risk

30 x in high

risk populat.

1. Winthrop K. EULAR 2005, #SP0005; 2. Askling J, et al. Arthritis Rheum 52:1986-92, 2005 3. Seong SS, et al. 2007 Apr;34(4):706-11; 4. Singh JA, et al. Cochrane Reviews 2011

Latent Tuberculosis

Risk Factor LTBI Prevalence

Close TB contact 37%

Homeless 13-32%

IV Drug users 14-28%

Foreign born 19%

Prisoners 2-17%

Progression LTBI to Active TB

Risk Factors RR

HIV 9.9

Close TB Contact 6.1

CXR TB findings 5.2

Pred > 15mg/d 2.8

CRF 2.4

TNF inhibitor 2.0

IDDM (poor control) 1.7

Smoking 1.5

Horsburgh CR, Rubin EJ, NEJM 2011: 364: 15

0

2

4

6

8

10

2 4 6 8 10 12 14 16 18 20 22 24 26 28 >28

Weeks of Infliximab Exposure

Num

ber

of cases

TB Following Infliximab Exposure

*Data reported for 57 patients, most of whom had received monthly infusions of infliximab.

Keane J, et al. N Engl J Med. 2001;345:1098-1104.

TB Screening Before Adalimumab Therapy

in North America and Europe

# cases 7 27

Exposure

(pt-yrs)

534 14,010

1.3

0.19

0.0

0.5

1.0

1.5

2.0

Pre-Screening Post-screening

Eve

nts

pe

r 1

00

-pt-

yrs

# cases 5 22

Exposure

(pt-yrs)

5919 8091

0.08

0.27

0.0

0.5

1.0

1.5

2.0

US/Canada Europe/Australia

Eve

nts

pe

r 1

00

-pt-

yrs

Perez J, et al. EULAR 2005, #OP0093

TB Screening Protocols in Spain

Carmona L, et al. Arthritis Rheum 52:1766-72 (2005)

Patient-years of

exposure to TNF

antagonists

No. of active

TB cases

Active TB rate

per 100,000

(95% Cl)

All TB cases

Pre-OR 6,126 32 522 (369-738)

Post-OR 1,699 2 117 (29-470)

IRR recommendations‡ - - 0.22 (0.03-0.88)

TB cases with RA only

Pre-OR 4,780 27 564 (387-823)

Post-OR 1,049 1 95 (13-676)

IRR recommendations‡ 0.17 (0.004-1.02)

Non-Tuberculous Mycobacterial (NTM) Infections

are More Common than mTB

• 29,500 new users of TNF inhibitors

among 3 databases (2000-07)

• 24 new NTM and 11 TB cases

• NTM Sx: fever cough malaise

• Most common sites: pulm, LN, skin,

soft tissues

• NTM more common than TB among

these RA patients

0

10

20

30

40

50

60

70

80

Rate

pe

r 1

00

,000

pt-

yrs

Rate per 100,000 pt-yrs

US TB TB NTM

Winthrop KL, et al. ACR 2010, Atlanta, #404 Winthrop KL, et al. Emerg Infect Dis. 2009 Oct;15(10):1556-61.

• Medwatch: 239 NTM reports, 105

(44%) met NTM disease criteria

• Median age 62 yrs; 65% female, and

70% had RA

• Assoc. w/ inflix (n = 73), etan(n=25),

ADA (n = 7)

• 44% extrapulmonary

• MAI 50%

• 9% died

Who Should Undergo PPD Testing?

Per Product labeling

– All TNF inhibitors

– Abatacept

– Tocilizumab

– Leflunomide

– Tofacitinib

NOT REQUIRED

– MTX

– Anakinra

– Rituximab

– Apremilast

Given likelihood of progression to biologic use, screening at

initiation of MTX therapy may be an efficient approach

Screening for Mycobacterium Tuberculosis Infection

1. Everyone should be screened for LTBI prior to TNFi use (PPD, IGRA)

2. IGRA indicated? When available; when there is a hx of BCG vaccine

3. BCG vaccinated should be tested for LTBI; positive results most likely mean infx

4. Either PPD or IGRA positivity is evidence of infection

5. PPD are good for up to a week (72 hrs is optimal)

6. Concordance between PPD & IGRA is poor (kappa ~0.3)

7. 2 step TST is only rec in health care workers at the time of hire

8. CXR is only helpful in diagnosing active TB (not screening)

9. PPD testing should be repeated or done periodically (twice & when risk changes)

6-10% of patients originally negative will be positive on repeat (anergy vs new?)

10. Pts w/ documented hx of adeq. Rx LTBI or active TB can safely recv TNFi Rx

11. Pts w/ secondary LTBI (PPD or IGRA) should have culture to exclude active TB

12. LTBI: “preventive anti-tuberculous therapy must be initiated before giving TNFi”

13. Surprisingly low frequency of INH hepatitis in our pts (Labs monthly x3)

14. Guidelines do not recommend screening for MTX, DMARDs (PI says yes LEF)

Cush JJ, Winthrop K, Dao K, Chaisson R. ACR Drug Safety Quarterly June 2010

TST vs IFN Gamma Releasing Assays

in Low Risk Populations

TST IGRA

Use Low risk

pop.

↑risk recent infx

BCG hx

Unreliable pt

Sensitivity 90-100% 80-90%

Specificity 29-39% 56-83%

PPV 2.7-3.1% 4-8%

NPV 99-100 99-100

TST+ IGRA+ ++

LTBI Horsburgh CR, Rubin EJ, NEJM 2011: 364: 15

Bartalesi Eur Respir J 2009; 33:586-593

Utility of Repeated TB Testing

• 411 pts on TNFi Rx (11/00 - 6/09)

from LA county hospital

• New PPD positives

– ~10% on annual testing

• Most initially anergic

• Some are new infections

• 7/30 Culture positive

• Conclusion: Repeat testing for

TB appears to be useful

• New TB infection is possible

411 on TNFi

382

Baseline TST

282

TST negative

149 rescreen x 1

74 rescreens x 2

11 rescreens x 3

100

TST+ (INH)

21+

8+

1+

30 Cooray D, et al. ACR 1153, 2009

Serial Quantiferon-TB gold testing: conversions detected over

2 years in the CT-P13 biosimilar development programme

• CT-P13 (IFX) approved by EMA in 17 countries (PLANETAS & PLANETRA RCTs)

• QFT at Week 0, 62 and 110 low risk vs Weeks 14, 30, 54, 62, 110 high-risk nations

• 476 enrolled: 458 were QFT‒ at baseline 16.6% (n=76) conversion to QFT+

• 73% Rx for

LTBI

• 9 neg ReTest

Countries

by risk

TB incidence

per/100,000

Secondary

conversion

Week 62

converts

Week 110

converts

Very low 0‒19 9.3% 9.3% 0

Low 20‒49 11.4% 8.5% 3%

Intermediate 50‒124 21.7% 19.6% 2.1%

High >125 52% 48% 4%

Serial QFT assessments do identify

new cases of LTBI or active RA. The

risk of new conversions depends on

residence and endemic risk

Park W, et al. EULAR 2014, Paris, #FRI0281

New Issues with TB Testing

• Worry about nTM more than mTB

• Everyone gets Tested – TST/PPD or IGRA

• Super Positives always indicate infection

• +Test Sxs + CXR + Culture (if on TNFi)

• Do repeat x 1 and when risk changes

– IGRA not valid as repeat

• “Indeterminant” repeat

– 5%: most due to Steroid use (turn negative w/ Rx)

• Shorter regimens (RIF x 4m) preferred to INH x9

Opportunistic Infections: Case Reports

• Histoplasmosis1

– 10 cases, 9 with infliximab

• Listeriosis2

– 15 cases, 14 with infliximab

• Sporotrichosis3

– Single case report

• Aspergillosis4

– Case report following loading dose of infliximab - Proposed source: construction at medical center

• Pneumocystis5

– 10 cases with infliximab, 3 deaths

• CNS Toxoplasmosis6

– 4 cases

• Coccidiomycosis7

– 13 cases with infliximab 1. Lee et al., A & R, 2002; 2. Slifman et al., A & R, 2003; 3. Gottlieb et al., Clin Infect Dis, 2003; 4. De Rosa et al., IDSA, 2002;

5. Velayos and Sandborn, Inflam Bowel Dis 2004; 6. Lassoued et al., Semin Arthritis Rheum 2007; 7. Bergstrom et al., A & R, 2004

High Death Rates with Opportunistic

Infections and Biologic Use

• Rare events

• Severity of the disease (both RCTs/Practice)

– More comorbidity in Practice

– Contributions of steroids and other agents?

• Severity of SIE/opportunistic infection

– Unusual presentations

• More disseminated & localized infections

– Delays in diagnosis

• SAE & SIE closely monitored/reported in RCTs

Tsiodras S, et al. Mayo Clin Proceed 2008; 83:181

Fungal and Opportunistic Infections

with Biologic Use

• NO Screening measures!!

– RELY ON SUSPICION AND SIGNS AND

SYMPTOMS

• Patients living in endemic areas are at risk

• Opportunistic infection are severe and deadly

– Rare events, unusual presentations & delays in

diagnosis

• More disseminated & localized infections

• FDA : ‘Clinicians should consider initiating empiric

fungal therapy while evaluating at-risk individuals

with undiagnosed systemic illnesses’ Diak P et al., FDA 2008

Tsiodras S, et al. Mayo Clin Proceed 2008; 83:181

Listeriosis and Biologics

• Analysis of FDA AERS 2004 – 2011

• 266 cases or Listeria monocytogenes

– Median Onset time 184 days

– Mortality rates 11.1% (ADA) – 27.3% (RTX)

• Presents w/ fever, fatigue, myalgias, GI symptoms (N/V/D),

meningitis and other CNS symptoms

Drug Use • INFL (77.1%), ETN (11.7%)

• ADA (9.8%), GOL (0.4%)

• Rituximab (4.1 %)

• Abatacept (0.4 %)

• Steroids (56%) MTX (31.6%)

Indications • 47.7 % Rheumatologic

• 38% IBD

• 3.4 % Hematological dz

• 10.5 % Other s

Bodro M, Eur J Clin Microbiol Infect Dis. 2013 Apr 9. [Epub ahead of print]

CDC: Shingles, Zoster Vaccine & RA

• Shingles: 1 million/yr (1/3 life risk)

• Zostavax: since 2006

– 51% reduction in VZV, 67% reduction in PHN (postherpetic neuralgia)

• Indicated in adults > 60 yrs

• OK in on MTX, AZA, pred <20/d

• NOT for acute zoster or PHN

• NOT w/ Recombinant biologics

• Give 2 wks before, 4 wks after anticipated immunosuppression

Cush, Calabrese, Kavanaugh ACR HOTLINE 2008

Herpes Zoster and RA

• Incidence of HZ in seniors with

RA = 6.5 events/1000 pt-y1

– Prednisone increases the risk1

• Anti-TNF increases risk of HZ

infection compared to DMARD2

– HR: 2.2 (1.4–3.6)

• Current DMARD, steroid use and TNFi increase risk of H. zoster infection

• Consider VZV vaccination in all RA patients

≤5 mg/day 1.77 (1.56–2.01)

6–9 mg/day 1.61 (1.26–2.05)

10–19mg/day 2.13 (1.82–2.49)

≥20 mg/day 2.90 (2.44–3.44)

Past use 1.39 (1.27–1.52)

Risk of H. zoster

Infection2

0 1 3 4 5

5

0

2

Follow up (years)

Cu

mu

lative

in

cid

en

ce

p

er

100 p

ts f

ollo

wed u

p

INF

ADA

ETN

DMARD

P=NS

1Widdifield J, et al. ACR 2010, Atlanta, #341; 2Galloway J, ibid, #421. SLIDE COURTESY OF TREG2010

Biologics and Vaccination

• RA patient have lower responses than controls

• Humoral responses to influenza and pneumococcal vaccines are not affected by prednisone, MTX, TNF inhibitors, abatacept

• Blunted vaccine responses with rituximab

– Give vaccination prior to use of rituximab (tocilizumab)

• PDR: says do not vaccinate with live vaccines

• Live vaccine use requires cessation of Biologic for >4 weeks and waiting for 2-4 weeks after vaccination before starting the biologic agent

Fomin I, et al. Ann Rheum Dis 65: 191-4, 2006 Kapetanovic MC, et al. Rheumatol 45:106-11, 2006

Inactive Vaccines* Live Vaccines

Influenza (IM)

Typhoid (IM)

Tetanus/diptheria/pertussis

Pneumococcal (23/7valent)

Human papilloma virus

Hepatitis B

Hepatitis A

Hemophilus influenza B

Meningococcus

Rabies

Influenza (nasal)

Typhoid (po)

Yellow fever

Varicella [Varivax] [Zostavax]

Measles, mumps, rubella (MMR)

BCG (bacillus Calmette-Guerin)

Polio (po)

Smallpox

Anthrax

HPV (Gardisil): approved for use in girls age 9-26 yrs. Not indicated in older Or Pts with active HPV warts or Cervical Cancer H Zoster: recommended for >60 yrs who are immunocompetent, w/ prior H Zoster, “anticipated immunosuppression”. Cautioned against use w/ TNFi (but pre, MTX OK)

* component / toxoids / inactivated / killed) Kavanaugh, A Curr Opin Rheumatol 2009

Can you Treat Resolved HBV w/ TNFi?

(HBsAg-, HBcAb+)

• TNFi Rx pts may not be adequately HBV tested (~25%)

• HBV activation can occur w/ HBsAg+;

• Risk may also occur w/ resolved infx HBsAg-, HBcAb+ (± anti-HBsAb+)

• TNFi can be safely used in pts with resolved HBV infection

• Screening for HBV, HCV and monitoring of LFTs is strongly advised

Reactivation risk in inactive HBV (HBsAg-, HBcAb+)

Author/ year N Reactivation

Charmin 2009 21 0/21

Bobbio 2009 69 0/69

Chung 2009 8 1/8

Vassilopoulous 2010 19 1/19

Caporali 2010 67 0/67

Cassano 2011 62 0/62

= 2/246 had

reactivation w/ TNFi

exposure

Vaughn Inflamm Bowel Dis. 2011 Sep 26; Charpin Arthritis Res Ther. 2009;11:R179 Bobbio-Pallavicini F, et al. ACR 2009; Vassilopoulous ARD 69:1372, 2010; Caporali R. Arth Care Res 62:749, 2010; Cassano J Biol Regul Homeost Agents. 2011;25:285

Indication HBsAg

Status Rx Exposure

HBV reactivation

No Lamivudine Prophylaxis

RA 9

CD 8

SpA 5

18/20 +

(2 NA)

14 INF

5 ETA

1ADA

3 ADA/ETA

6 wks - > 2 yrs 14/22

+ Lamivudine Prophylaxis

RA 3

CD 1

SpA 2

6/6 +

3 INF

1 ETA

2 INF/ADA

7 mos - > 2 yrs 0/6

HBsAg+ and TNF Inhibition

Aliment Pharmacol Ther. 2010 Jan;31(1):20-34..

Risk of Hepatitis B Reactivation

• Abatacept in RA – 8 patients found to

be HBsAg+

– 4 recv etanovir no reactivaton

– 4 recv NO Anti-Viral Rx 4/4

reactivation

• RTX in CD20(+) Diffuse lg B-cell

lymphoma

• Rx w/ CHOP vs R-CHOP.

• 104 pts between 2003-2006

• ?RTX in pts who resolved HBV infx

(neg. HBsAg; postive HB core

• reactivation only in RTX pts (24%)

46 pts HBsAg neg/HBc pos

CHOP R-CHOP

N 25 21

Reactiv-ation 0 5

Caution w/ HBcAb+ and intense

immunosuppression

Avoid biologics or use antiviral

prophylaxis if HBsAg+

Kim PS, et al. ACR 2011, Chicago #2238;

Yeo W, J Clin Oncol. 2009 27:605

Strategy in HBV Infected Patients Requiring

Immunosuppression

• Screen high risk patients

• HBV Screen : (HBsAg, anti-HBc and follow up

with HBV-DNA viral load if appropriate

• HBsAg + CAUTION; Avoid biologics

– TNF inhibitors, RTX, abatacept

– Refer to hepatology for pre-emptive anti-viral Rx

• Resolved HBV infection (HBsAg- and HBcAb+)

may receive biologics w/ caution

• Caution in those w/ most intense forms of

immunosuppression who are HBcAb + patients

Winthrop KL, Calabrese LH. Ann Rheum Dis. 2011;70:1701-3

Patients who should NOT receive

TNF inhibitors!

Infectious Scenario Comment

1. Active Hepatitis* HBsAg+ at greatest risk

2. Nontuberculous

mycobacterial (NTM)

infection*

Despite anti-mycobact. Rx,

never fully eradicate NTM

3. Invasive fungal infection* Difficult to fully eradicate,

reactivation common

4. Intravesicular BCG

treatment

TNF inhibitor use may

potentially lead to

mycobacterial infection

* if absolutely necessary, consider chronic prophylaxis w/ biologic

TNF Inhibitor Use

Difficult Situations

Not Safe to Use Probably Safe to Use

Hepatitis B*

Atypical mycobacterial

infx*

Invasive fungal infection*

Pts receiving BCG therapy

Resolved HBV

(HBcAb+)

Prior treated

LTBI/mTB

Hepatitis C

HIV+

* If absolutely necessary, consider chronic prophylaxis with TNFi

Progressive Multifocal

Leukoencephalopathy (PML)

• Rare fatal demyelinating disorder JC polyomavirus

• PML Sxs: hemiparesis, cognitive/AMS, discoordination, apathy. – Dx: MRI lesions, PCR of CSF

• @risk: conditions that affect cell-mediated immunity – AIDS, Leukemia/ lymphoma , organ transplants, chemotherapy

– FDA Warns of Rituximab, Efalizumab, Natalizumab, Mycophenolate

• Autoimmune pts (noHIV/Cancer), incidence = 0.2 per 100,000 – Rheumatoid arthritis

= 0.4 per 100,000

– SLE = 4.0 per 100,000

• Role testing for JC virus?

Exposed N Rx Death

Biologics 15 14 RTX (4 mono)

6 TNF inhib* 7/10

DMARDs 19 14 Alkylating Rx

14/34 AZA 6/34MMF 10/19

* 5 prior to RTX use FDA Drug S afety Newsletter Fall 2007 Molloy, Calabrese. Arthritis Rheum. 2012 Sep;64(9):3043-51

Multifocal Leukoencephalopathy

With Selected Rheumatic Diseases

• Incidence & risk factors for PML in pts RA, PsA, PSO, JIA, IBD, AS

• Claims data from Medicare and Medicaid Services from 2000–2009.

• 53 PML cases were identified among 2,030,578 patients with

autoimmune diseases

– Prevalence of 2.6 per 100,000 patients.

– Most PML cases HIV and/or Cancer.

– Nine PML cases had received biologic prior to PML hosp.

• 6 had HIV or Cancer

• 3 were previously exposed to rituximab or 6 infliximab

– Autoimmune pts without HIV/Cancer, incidence = 0.2 per 100,000

• Rheumatoid arthritis = 0.4 per 100,000

• SLE = 4.0 per 100,000

• FDA Warnings: Rituximab, Efalizumab, Natalizumab, Mycophenolate

Bharat A, et al. Arthritis Care Res 2012; 64:612–615 Molloy E, et al Arthritis Rheum. 2009;60:3761-5.

Cancer & Biologic Therapies

What is the Concern?

• Prior Hx of Lymphoma

• Prior Hx of Any Cancer

• Family Hx of Cancer

• Cancer onset while on biologic Rx

• Does continued biologic use alter

cancer mortality

TNF Inhibitor Package Inserts

• More malignancies (lymphomas) where noted in TNFi treated patients compared to placebo treated patients.

• Lymphoma & other malignancies, some fatal, have been reported in children/adolescent pts treated with TNFi.

• Risks and benefits of TNFi should be considered prior to initiating therapy in pts with a known malignancy (other than successfully treated non-melanoma skin CA) or when continuing a TNFi in pts who develop a malignancy.

• Acute & chronic leukemia has been reported w/ post-marketing TNFi use; RA pts may be at higher risk (~2-fold) for leukemia.

• Role of TNF blocker in developing malignancies is not known.

• Pts on chronic immunosuppressives or Pso pt w/ Hx PUVA should be examined for presence of NMSC before/during Rx...

HUMIRA [package insert]. Abbott Laboratories; 2011; ENBREL Amgen 2011; REMICADE and SIMPONI Centocor, Inc; 2011; CIMZIA, UCB,

2011;

Other Biologics Package Inserts

• Rituximab: is indicated for Rx of CD20+ NHL

– PI does not discuss further neoplastic risk w/ RTX

• Abatacept: in PCT overall malignancies were similar b/w ABA

& placebo pts (1.3 vs 1.1%).

– But more cases of lung CA ABA (4) vs Placebo (0)

– Lymphoma SIR = 3.5

• Tocilizumab:

– In PCT overall malignancies were similar b/w TCZ & placebo pts

(1.32 vs 1.37/100 pt yrs)

• Tofacitinib:

– 11 solid tumors and 1 lymphoma in 3328 pts, 0 in 809 placebo pts

– Post-viral lymphoproliferative disorders seen in transplant studies

RITUXAN, Genentech 2011; ORENCIA BMS 2011; ACTEMRA, Roche 2011; XELJANZ Pfizer 2014

Lung

Lymphoma

Melanoma

NMSC

Colon

Breast

RA

Rheumatoid Arthritis and Neoplasia

• Cancer Not Increased in RA – Decreased rates of adenocarcinoma

(colon), Breast cancer

– Increased rates of lung cancer,

melanoma and nonmelanomatous

skin cancers

• Increased lymphoma risk: – Long-standing, active RA

– Older

– Rx w/ immunosuppressive therapy

– Patients receiving TNF inhibitors

Lymphoma Risk Rises w/ Increasing Activity

181

65

OR

(9

5%

CI)

6055504540353025201510

9 / 11 / 34 7 / 38 14 / 36 16 / 39

Case / Controls* Odds ratio (OR) and 95% confidence interval (CI)

9 / 36 18 / 38 27 / 36 35 / 37 226 / 37

50

Re

lative

Ris

k

Years

Lymphona

Cancer

overall

3.5

4

3

2.5

2

1.5

1

0.5

0

≥10 4-<10 0-<3 0-<3 3-<6 6-10y

Lymphoma Risk Begins After RA Onset

RA onset

Smedby KE, et al. J Intern Med. 2008 Dec;264(6):514-27. Hellgren Arthritis Rheum. 2010 May;62(5):1252-8

Solid Tumor Risk with TNF Inhibitors

Cush, Dao, Kay. Drug Safety Quarterly. 2012.

Lymphoma with TNF Antagonists

Clinical Trials

Etanercept Infliximab Adalimumab

N

Pt-Yrs

3389

(8336)

1298*

(2458)

2468

(4870)

Lymphoma (N) 9 4 10

Hodgkin's/

Non-Hodgkin's† 3/6 1/3 1/9

SIR Lymphoma

(95% CI) 3.47

(1.6–6.59)

6.4

(1.7–16.3)

4.35

(2.6–10.0)

*Rheumatoid arthritis only. †Majority diffuse large B cell.

FDA 2003

Cases, no.

(%)

Controls, no.

(%)

Unadjusted OR

(95% CI)*

Inflammatory

activity

Low 94 (25) 278 (74) 1 (referent)

Medium 196 (52) 94 (25) 7.7 (4.8-12.3)

High 86 (23) 4 (1) 71.3 (24.1-211.4)

Functional class

I 34 (9) 138 (37) 1 (referent)

II 185 (49) 204 (54) 3.9 (2.4-6.3)

III 105 (28) 31 (8) 13.8 (7.2-26.2)

IV 52 (14) 3 (1) 67.5 (18.9-239.8)

Lymphoma Risk in RA Associated with

Disease Activity and Functional Class

Baecklund E, Arthritis Rheum 2006;54:692-701

BSRBR –

Incident Cancers from >14,000 RA pts C

um

ula

tive

In

cid

en

ce

16%

14%

12%

10%

8%

6%

4%

2%

0%

0 1Years since registration

2 3 4

DMARD

Anti-TNF

10735 pts TNF exposed

WG Dixon et al. Arthritis Care & Research 2010;62:755-763.

0

10

20

30

40

50

60

70

80

90

100

TNFi DMARD

Cru

de

Recu

rre

nce

rate

/10

00

pt-

yrs

RABBIT: Risk of Incident and Recurrent CA

• 2001-06: 5279 pts enrolled

• No increase in cancer on TNFi in

nested case control study

• Prior malignancy in 122 pts

– 67 received biologic

• 9 recurrence of tumor (13.4%)

– 55 received DMARD

• 5 recurrence of tumor (9.1%)

• CA risk w/ age, activity, COPD

Strangfeld A, et al. Arthritis Res Ther. 2010;12(1):R5.

ARTIS Registry: TNF Inhibitor Therapy in RA and Overall Malignancy Risk

• 66,995 Swedish RA 1998 - 2006

• 6,403 treated with TNF inhibitor

• Followed for up to 8 years for a

primary cancer

• Conclusions

– Lower mortality risk among patients

treated with TNF inhibitor therapy

compared to biologic-naïve patients

– Lack of trend in overall cancer risk

following TNF therapy, either from

time since initiation or with cumulative

exposure

Time since Start of First TNF Inhibitor (years)

0

0.2

0.6

0.4

1.0

1.2

1.4

1.6

Mortality Risk in TNF Inhibitor–treated vs. Biologic-naïve Patients

RR

0

0.2

0.6

0.4

0.8

1.0

1.2

Cancer Risk from Start of TNF Inhibitor Therapy

RR

<1 1-2 2-3 3-4 4-5 5+ 0

0.2

0.6

0.4

0.8

1.0

1.2

Cancer Risk from TNF Inhibitor Cumulative Exposure

RR

0.8

J Askling et al. Ann Rheum Dis 2008;67(Suppl II):52;

LTH Jacobsson. Ann Rheum Dis 2008;67(Suppl II): 183.

Risk of Lymphoma

• 3 cohorts of patients

– Swedish nationwide inpatient registry (prevalence cohort)

– Incident cohort of early RA

– TNF-related cohort

• All cohorts were linked to nationwide cancer registry

RA cohort n RA patient type RR vs general

population

Adjusted RR vs

prevalent RA

In-patient

registry 53,067 Prevalent 1.9 (1.7–2.1) 1.0

Early RA 3703 Incident 2.0 (1.0–3.5) 0.8 (0.4–1.4)

ARTIS* 4160 Anti-TNF

treated 2.9 (1.3–5.5) 1.1 (0.6–2.1)

ARTIS = TNF inhibitor-treated cohort, identified within framework of a structured

monitoring program for biologics in RA

Askling J, et al. Ann Rheum Dis, 2005.

Hepatosplenic T Cell Lymphoma

• HSTCL: very rare, aggressive, often fatal NHL

– Affects kids and young adults (<30yrs) - usually fatal

– <200 documented cases in literature

– Common w/ transplant, AZA, cyclosporine (not MTX)

– Sxs: HSmegaly, fever, purpura, cytopenia, LFTs (-LN)

– Associated with AZA, 6MP

• Infliximab: 6 cases; 5 deaths (all post-marketing)

– All with Crohn’s disease; all on AZA, 6MP

– Ages 12 – 31 years; 5 Male, 1 Female

• Adalimumab: 8 cases, 4 deaths

– 2 RA: 61 & 70 yrs age

http://www.fda.gov/Drugs/DrugSafety/ucm250913.htm

Cancer Outcome in RA Pts

Rx w/ TNF Inhib.

RA 78,483

TNFi+ 8,562 TNF- 69921

1st CA 314 1st CA 4650

Dead 113

(37%)

Dead 256

(44%)

TNFi+ RR 95% CI

All death 1.1 0.8-1.6

Colon 0.7 0.34-1.58

Breast 0.7 0.05-10.2

Prostate 0.6 0.11-2.96

Lung 0.8 0.54-2.39

Melanoma 1.3 0.31-5.29

• Swedish biologics register 1999-2007

• 3 RA Registries: Swedish RA registry,

ARTIS biologics register, Swedish

Cancer register

• TNFi RR of death = 1.1 (95 CI: 0.8-1.6)

– 0.8 (95%CI, 0.5-1.2)

Raaschou P, Askling J. Arthritis Rheum. 2011 Jul;63(7):1773-5.

Tofacitinib and Lung Cancer Risk

FDA Advisory Committee Meeting, 2013

Tofacitinib Overall Cancer Risk

FDA Advisory Committee Meeting, 2013

Tofacitinib: Malignancy Analysis

• RCTs of tofacitinib (previous slide)

• 107 malignancies (excluding non-

melanoma skin cancer [NMSC])

• Most common: lung breast cancer

• 10 lymphomas

• Overall IR for all malignancies

(excluding NMSC): 0.85 (95% CI

0.70–1.02); lymphomas: 0.08

(0.04–0.14)

• Standardized IR (SIR) lung cancer:

1.91 (1.22–2.84), breast cancer: 0.77

(0.46–1.20)

• SIR vs SEER

– All malignancies: 1.08 (0.89, 1.31)

– Lymphomas: 2.58 (1.24, 4.74)

0.5

1.0

1.5

0-6

0.0

2.0

6-12 12-18

Time period (months)

Rate

/10

0 p

t-y o

f observ

ation

(95%

CI)

18-24 24-30 30-36 36-42 >42

UPDATE 2014

Mariette X, et al. EULAR 2014, Paris, #THU0147

Is there a Cancer Risk w/ Biologics?

Cancer Risk

From Rheumatoid From TNFi

Cancer overall None None

Lung,Skin,Lymphoma Increased Increased

Melanoma, Leukemia Possibly increased Possibly increased

Breast, Colon Decreased Decreased

Recurrence rates ??? Unchanged

Is it RA or the Drug ?

Arthritis Res Ther. 2010 Jan 8;12(1):R5 Smitten A, et al. Arthritis Res Ther. 2008;10:R45., Askling J, et al EULAR 2007, Barcelona, #OP0013 Dixon WG, et al. ACR 2008, San Francisco #1264 Hawkins-Holt,Hochberg, Cohen, Michaud,Wolfe ACR 2003 Abstr 806

Reducing Risk of Neoplasia

Neoplasia Measures to Risk/Monitor

Cancer Screening Health maintenance

Skin Cancers Hx, skin examinations

Lymphoma Pt. selection: age, activity, hx

Breast cancer Self exams, mammography

Prior Cancer Time, Oncologic F/U, Screens

Rheums should treat RA; Leave cancer to the oncologist

(can the oncologist manage RA?)

SIE Risk Reduction with Biologic Rx

Patients @ Risk Screening Measure Prevention

Pneumonia

Elderly, hx of

pneumonia, tobacco,

comorbidity, steroid use

Patient history,

Physical Exam, CXR

if Signs/Sxs

Pneumovax

Smoking

cessation,

steroid, COPD

Rx

Tuberculosis High risk groups, +PPD PPD,

IFN releasing assay

Prophylax or Rx

TB; steroid

Opportunistic

infections

High risk groups

(Endemic, Prior OI)

CXR if Signs/Sxs or

endemic

Avoid biologic or

use chronic

prophylaxis;

Empiric Rx

TNF Inhibitors and Serious Skin

Reactions Following anti-TNF Use

FDA data – 1998-2006 (2002-2006 for adalimumab)

EM SJS TEN Death

– Etanercept: 22 pts 13 4 5 1

– Infliximab: 21 pts 15 5 1 1

– Adalimumab: 8 pts 5 2 - -

• Most pts (>2/3) took TNFi for treatment of RA

• ~50% of etan/inflix pts needed hospitalization

• Median onset since 1st dose: 28 to 60 days

EM – erythema multiforme; SJS – Stevens-Johnson syndrome;

TEN – toxic epidermal necrolysis

US Food and Drug Administration. FDA Drug Safety Newsletter. Winter 2008;1(2).

Psoriasis as a Complication of

TNF Inhibitor Use

• Hundreds of case reports have shown psoriasis to be an adverse

event associated with anti-TNF therapy

– Occurs w/ all marketed TNF agents

– Reported in RA, IBD, SpA, PSO

• ~1 per 1000 pt-years TNFi exposure

• 50% pustular

• 40% plaque

• scalp, erythrodermic variants

• Majority improve psoriasis w/ TNFi D/C

– 1/3 improve w/ continued therapy

or change in TNF blocker

Harrison, et al. Ann Rheum Dis. 2009;68:209-15.; FDA Bulletin 2009.;

Cullen. Aliment Pharmacol Ther. 2011; 34:1318-27. Ko. J Dermatolog Treat. 2009;20:100-8

TNF Inhibitors and CHF

Study Name RENAISSANCE RECOVER ATTACH

TNF Inhib Etanercept Etanercept Infliximab

N=

(NYHA)

925

(NYHC 2-4)

1123

(NYHC 2-4)

150

(NYHC 3-4)

Rx Placebo,

25 mg BIW,TIW

Placebo

25 mg qwk,BIW

Placebo, 5 or 10 mg/kg

@ wk 0, 2 & 6

Duration Med 12.7 mos. Median 5.7mos 28 weeks

Death Rates

Placebo 14.2%

ETANBIW 17.9%

ETANTIW 19.8%

Placebo 8.8%

ETANQWK 5.9%

ETANBIW 7.2%

Placbo 5 mg/kg 10 mg/kg

wk28 0 2.0% 5.9%

wk54 8.2% 8.0% 15.7%

CHF Hosp NA NA Placebo 5 mg/kg 10 mg/kg

wk28 10.2% 6.0% 21.6%

Concerns? TIW dose group more problems.

NYHA Class II are NOT at lower risk 10 mg/kg @ higher risk

New Onset CHF in Clinical Trials

Etanercept

(3389)

Infliximab

(>1600)

Adalimumab

(2045)

Active Drug 2 0.2% 0.1 %

Placebo

Controls 2 2.1% 0.5%

Reduced CV Risk with MTX + TNF Blockade

• 1829 RA pts w/o CAD (1/01–3/08)

• MTX users (n=1119) vs nonusers

(710) vs TNFi users (588) or TNFi

nonusers (n=1241)

Incident CAD (events/1000 pt-y)

Nonuser User 1-y HR 2-y HR

MTX 37.5 17.6 0.54* 0.33*

TNFi 32.1 11.8 0.54# 0.24*

HR user vs nonuser : * P<0.001; #P=0.03

MTX + TNFi independently associated with 46% reduction in CAD; longer use (>2 y)

associated with greater (67–76%) benefit

1.0

0.20

0.30

0.0

0.05

0.15

0.25

20 40 60 100 80 0 120

Time (mo)

Pro

bab

ilit

y o

f

develo

pin

g C

AD

1.0

0.20

0.30

0.0

0.05

0.15

0.25

20 40 60 100 80 0 120

Time (mo)

MTX never use

MTX use 22 mo

MTX use >22 mo

TNFi never use

TNFi use 17 mo

TNFi use >17 mo

Bozaite-Gluosniene R, et al. ACR 2011, Chicago, #719

Tofacitinib: Integrated safety in RA

clinical trials

• Phase 2, Phase 3, and LTE studies according to duration of Tofa exposure

• 5671 patients, 12,664 pt-y of cumulative Tofa exposure (all doses); median

exposure 2.4 years

IR events/

100 pt-y IR

Discrete 6-month period of exposure to Tofa (month)

0–6 6–12 12–18 18–24 24–30 30–36 36–42 >42

SAE 10.27 10.77 10.44 12.08 10.42 10.02 8.45 7.34 8.82

SI 2.93 2.57 3.42 3.16 3.19 2.93 2.86 2.81 1.89

Herpes

zoster 4.22 4.20 4.69 4.23 4.38 3.99 5.07 3.88 2.11

Malignancy 0.85 0.70 0.66 0.94 1.04 0.83 1.00 0.79 1.04

Lymphoma/

LPD 0.06 0.04 0.09 0.00 0.06 0.14 0.08 0.00 0.12

MACE 0.46 0.58 0.36 0.59 0.62 0.41 0.13 0.00 0.00

Cohen S, et al. EULAR 2014, Paris, #OP0154

Safety Issues With Biologic DMARDs

• Serious infections

• Opportunistic infections (TB)

• Autoantibodies and autoimmune

reactions, including lupus-like syndromes

• Malignancies

TNFi: Pregnancy is a

Relative Contraindication

1. Preg NOT a boxed warning

2. Preg NOT a contraindication

3. Pregnancy Category B – There are no adequate and well-

controlled studies of SIMPONI in pregnant women. Because

animal reproduction and developmental studies are not

always predictive of human response, it is not known whether

SIMPONI can cause fetal harm when administered to a

pregnant woman or can affect reproduction capacity.

SIMPONI should be used during pregnancy only if clearly

needed.

4. Encouraged to enroll such pts with OTIS pregnancy registry

1-877-311-8972

Package insert on TNFi

Other Safety Issues in TNF Inhibitor Use

• Hematologic events

– There have been rare reports of pancytopenia, leukopenia,

thrombocytopenia and neutropenia – including aplastic anemia

– Some cases have been fatal

• Autoimmunity

– Formation of autoantibodies has occurred with anti-TNF therapy

– Rarely, lupus-like syndrome may develop

• Data showed that 2 pts out of 3046 pts treated with adalimumab

developed signs suggestive of new-onset lupus-like condition

• Pts improved after discontinuation of therapy

ENBREL (etanercept) package insert. REMICADE (infliximab) package insert. HUMIRA (adalimumab) package insert.