Tuberculosis and Biologicscenterfortuberculosis.mayo.edu/uploads/7/1/7/3/71735537/... · ©2014...

©2014 MFMER | slide-1

Tuberculosis and Biologics

Speaker: Leonard H. Calabrese, D.O.


DISCLOSURES

• CONSULTANT Genentech, BMS, Abbvie, Jansen UCB Pfizer Regeneron Crescendo


Tuberculosis and Biologics

• Concept of IMIDS and development of biologics

• TNF inhibitors

• Biology

• Epidemiology of TB

• MOA implications

• Other Biologics

• T cell, B cell, IL1, IL6, IL17, IL12/23

• Jakatinibs

• Screening recommendations and controversies


Damage / Destruction / Symptoms

(RA, SLE, PsA, IBD, AS, MS)

Inflammation

(TNF, IL-1, IL-6, IL-17,

IL-23, IL-18, IL-15, Others)

Immune-Mediated Inflammatory Diseases

Initiation

Susceptibility

Triggers

Accelerants

Immune responses Adaptive Innate

DM, CHF, Alzheimer's, Transplant, Sepsis, Allergy, Vasculitis, ASO, HIV

Slide credit: clinicaloptions.com

http://www.clinicaloptions.com/oncology


Evolution of Biologics for IMIDS

1940s

Gold

Hydroxychloroquine

Corticosteroids

Etanercept

1950s 1960s 1970s 1980s 1990s 2000s

D-Penicillamine

Methotrexate

Auranofin

Azathioprine

Infliximab

Adalimumab

Golimumab

Certolizumab

Anakinra

Leflunomide

Rituximab

Abatacept

Tocilizumab

Ustikinumab

Belimumab

Natalizumab

Canakinumab

Rilonacept

Tofacitinib

Vedolizumab Secukinumab



The History of TNF and the Development of

Anti-TNFs for Inflammatory Diseases

1893 1975

Coley notes

tumor necrosis

1975 Old

characterizes

TNF

1985 1988 1991 1998 1999 2006 2016

Beutler isolates

& sequences

cachectin /

Aggarwal TNF

1982-1988

Analysis of

inflammatory

synovial fluid

TNF, Il-1, IL-6

First TNFR- Ig

fusion protein

developed

1993-1999

Development

of Etanercept

1998 Infliximab

1999

Adalimumab

Over 3.0 Million

treated

Certolizumab

Golimumab

William B. Coley

(1862-1936)

hemorrhagic regression in 25%In vitro:

Molecular: 56 °C stable, ~150 kDa


Tumor Necrosis Factor (TNF-α)

• TNF (alpha) translated as a 233 aa, 26kD pro-protein - initially membrane bound /cleaved by TACE

• Secreted as a 17kD molecule that homotrimerizes to be active

• Present in pico to atomolar concentrations

• Produced by a wide variety of cells in response to variety of danger signals

• Membrane-bound and soluble forms of TNF-α

Effects of Low TNF Concentrations

Low

TNF

Activation, microbicidal activity

Eosinophils

Activation,IL-1, IL-6, IL-8, GM-CSF, microbicidal activity, release from bone marrow

Adhesion molecules

(ICAM-1),

extravasation

T, B lymphocytes

IL-6, TNF, prostaglandins, GM-CSF

chemokines, microbicidal activity

Macrophages

Neutrophils

Ab production, proliferation,

GC formation

Activated B

lymphocytes

Apoptosis, survival

IL-2R, IFNγ, IL-4, IL-5

Activated ThO

Antiviral state, ICOSL Host cell

Apoptosis, survival,

cytotoxicity

Activated CTL

Target cell MHC class I

MHC class II Antigen Presenting Cell

Effects of Moderate TNF Concentrations

Moderate TNF

Bone remodeling

IL-6, IL-8, TNF

GM-CSF, IL-6,

IL-8 proliferation

Endothel., Fibrocytes

Hematopoisis

Smooth muscle

Proliferation, collagen Epithelium

IL-1, IL-6

Macrophages

Fever, prostaglandins Brain

Bone marrow Acute phase

proteins

Hepatic cells

Prostaglandins,

TNF, GM-CSF, collagenase,

proliferation

Stromal cells

Coagulation Blood vessels

Glucocorticoids Adrenal glands

Apoptosis, necrosis due to

blood vessel blockage

Tumor cells

Osteoblasts Alk. phosphatase

Collagenase Osteoclasts

Effects of High TNF Concentrations

High TNF

IL-1, IL-6, TNF

Bone Destruction Fibrosis

Endotoxic

Shock

Osteoclasts Fibroblasts

Multiple Cell Types


Etanercept

(Enbrel®)

Infliximab

(Remicade®)

Human

recombinant

receptor/Fc fusion

protein

Monoclonal

antibody

Adalimumab (Humira®)

Golimumab (Simponi®)

= murine = human

Three classes of anti-TNF and 5 drugs

Adapted from Hanauer SB. Gastroenterol Disord 2004;4(Suppl. 3):S18-24.

IgG1

Fc IgG1

Fc

Fab

Receptor

PEGylated

humanized

Fab′ fragment

Certolizumab

pegol

(Cimzia™)

PEG


The Role of TNF in Tuberculosis

• TNF is critical in the formation of granulomas and for maintaining their structural integrity

• TNF is a macrophage-activating factor

• Excessive and prolonged inhibition of TNF signaling leads to exacerbation of TB

0 10 20 30 40 50 0

2

4

6

8

10

100 200 300

Wildtype

TNF knockout

Anti-TNF mAb

Days After Infection

Log

10 c

fu/L

ung

Flynn, JL, et al. Immunity. 1995;2:561-572.

Mohan VP, et al. Infect Immun. 2001;69:1847-1855.


TB in infliximab treated patients Keane NEJM 345:1098-1104,2001


RA and Tuberculosis l August 2010 l 15

TNF- Antagonist Therapy and TB

• Atypical clinical presentation

• 50% extrapulmonary

• 15%–20% disseminated

• Median time to onset

• Infliximab (INF)=12 weeks; (range, 1–52 weeks)1

• Etanercept (ETN)=11.5 months; (range, 1–20 months)2

TNF=tumor necrosis factor

1. Keane J et al. N Engl J Med. 2001;345:1098-1104. 2. Mohan AK et al. Clin Infect Dis.

2004;39:295-299.


Hematologic Events

Addition of Warning Information in Anti-TNF Labels Over Time

Infections Sepsis

Hypersensitivity

Neurologic Events

Malignancies

Tuberculosis

1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009

CHF

Hepatotoxicity

HSTCL

HBV

ENBREL® (etanercept) Prescribing Information, Immunex Corporation.

HUMIRA® (adalimumab) Prescribing Information, Abbott Laboratories.

CIMZIA® (certolizumab pegol) Prescribing Information, UCB Inc.

FDA web site. Available at: http://www.fda.gov.

REMICADE® (infliximab) Prescribing Information, Centocor Ortho Biotech, Inc.

SIMPONI™ (golimumab) Prescribing information, Centocor Ortho Biotech, Inc.

Data collected during clinical trials and postmarketing surveillance

Pediatric malignancy

Leukemia

Invasive fungal infections

Nu

mb

er

of

Pa

tie

nts

Ex

po

se

d (

in t

ho

us

an

ds)

400

200

0

800

600

1,000

1,200


Tuberculosis

TB in US

6

TB in US

Crohn Inflix

9

TB in US RA

on Infliximab

41 +

TB in all non US

RA and Crohn’s patients

224

TB in RA

US pts

6

TB in US

high risk groups

>32

Incidence of TB per

100,000 pts years

Dye C et al, JAMA 1999

+Wolfe, Arth & Rheum 2001

*Gomez-Reino Arth Rheum 2003

TB in SPAIN

Infliximab

1,893*


TB Risk

• RA TB risk based on pop. risk2,3

• Swedish RA patients (low risk): RA patients have 2-fold increase of TB2

• Korean RA patients (high risk): have a 9-fold increase in TB3

• TNF inhibitors magnify the risk of TB from 9- to over 30-fold

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

Relative Risk

9

2

1

General population

RA no TNF-antagonist

RA with TNF-antagonist

30

Korea Sweden

No TNF

No TNF

+TNF

+TNF

NL


Anti-TNF and tuberculosis (TB): reactivation of latent TB

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

Infusion Number

% of Patients

0

20

40

60

1 2 3 4 5 6 7 8 9 10

• 70 cases of TB after infliximab

• TB occurs early after treatment


TNF Antagonists and TB Risk

Wallis R., et al., Lancet ID, 2008.

Infliximab Adalimumab E:I

Wallis et al (AERS) 17 weeks (248) 48 weeks (39) 1:2·8

Wolfe et al (NDB) 21 weeks (4) ~ n/a

Keane et al (AERS) 12 weeks (70) ~ n/a

Askling et al (ARTIS) 19 weeks (11) 32 weeks (6) 1:1·7

Brassard et al (PharMetrics) 17 weeks (19) 79 weeks (32) 1:4·6

Total (weighted mean) 16·2 weeks 59·6 weeks 1:3·7

Data are median time to onset (number of cases). Patients treated for any indication are included.

AERS=US Food and Drug Administration Adverse Event Reporting System. ARTIS=Anti-Rheumatic

Treatment in Sweden. I:E=Infliximab to etanercept ratio. NDB=National Databank for Rheumatic

Diseases. RATIO=Recherche sur Anti-TNF et Infections Opportunistes.

Time to Onset of Tuberculosis After Initiation of TNF

Antagonist Therapy


Differential Risk of TB Between Antibodies and Receptor Constructs

Numerous studies demonstrate differential effect in SIR for granulomatous infections between Abs (INFLX) and receptor (ETN) with lesser data n other molecules

Progression of M tuberculosis infection

Wallis R Lancet ID 2008,

Infliximab Etanercept I:E p value

Aspergillosis 8·63 (17) 6·19 (7) 1·39:1 0.243

Candidiasis 10·15 (20) 5·31 (6) 1·91:1 0.061

Coccidioidomycosis 5·58 (11) 0·88 (1) 6·34:1 0.013

Cryptococcosis 5·08 (10) 7·08 (8) 0·72:1 0.179

Histoplasmosis 18·78 (37) 2·65 (3) 7·09:1 <0.0001

Listeriosis 8·63 (17) 0·88 (1) 9·81:1 0.0006

Non-tuberculosis myocobacterioses 11·17 (22) 6·19 (7) 1·80:1 0.066

Nocardiosis 3·55 (7) 0·88 (1) 4·03:1 0.090

Salmonellosis 0 (0) 1·77 (2) n/a 0.031

Tuberculosis 53·81 (106) 28·32 (32) 1·90:1 <0.0001



Adapted from Dixon WG et al. Ann Rheum Dis. 2010:69:522-528.

UK Biologic Registry Patients On Drug*

DMARD

n=3232

All TNFi

n=10,712

ETN

n=5521

INF

n=3718

ADA

n=4857

Person-y 7345 28,477 12,744 8069 7634

Cases of TB (n) 0 27 5 11 11

Rate/100,000

person-y (95% CI) 0

95

(63–138)

39

(13–92)

136

(68–244)

144

(72–258)

IRR, adjusted for

age, sex, entry year

(95% CI)

-- -- Referent 3.1

(1.0–9.5)

4.2

(1.4–12.4)

*On drug: patient-years and adverse events were attributed to each drug only while the patient was actively receiving that drug.

TB Risk in Anti-TNF Therapy: Numbers and Rates of Incident TB, Including Switchers


RATIO (Research Aligned on Tolerance of bIOtherapies): a French prospective observatory

• Collections of all cases of:

• Opportunistic infections including TB

• Lymphomas

• Occurring on anti-TNF whatever the indication of use from February 2004 to February 2007 all over France

• Number of patients treated with anti-TNF in France during the 3 year 2004–2006 period

• 57,711 patients-year

• Mean age 53.2 (SD 15.8)

• Sex ratio : 49.1 % of males

• Repartition between the drugs during the 3 year 2004–2006 period

• 49% etanercept

• 33% infliximab

• 18% adalimumab

Tubach et al, Arthritis Rheum. 2009;60:1884-1894.


69 TB cases for 3 years: Clinical characteristics

TB cases (n=69)

Age (years) 58.5 ± 15.4 (61.0)

Median time since first anti TNF treatment start 12.0 months

Median time since last anti TNF treatment start 9.9 months

Underlying inflammatory disease

Rheumatoid arthritis

Ankylosing spondylitis

Psoriatic arthritis

Crohn’s disease or UC

Cutaneous psoriasis

Behçet’s disease

40

15

3

9

1

1

Duration of the underlying inflammatory disease before TB

(years)

11.2 ± 8.8 (8.3)

Tubach et al, Arthritis Rheum. 2009 Jul;60(7):1884-94.


Risk factors of TB

• Tuberculin Skin Test result

• > 10 mm: 4

• Between 5 and 10 mm: 11

• < 5 mm: 30

• Unknown or not done: 24

• TST < 5 mm: 30/45 (66%)

• No case in patient with correct previous prophylactic anti-TB

• In France the most common prophylactic regimen is isoniazid + Rifampicin for 3 months

Tubach et al, Arthritis Rheum. 2009 Jul;60(7):1884-94.


RATIO: Anti-TNF therapy and non-TB opportunistic infections

• Median time to occurrence of non-TB OI after start of anti-TNF

• 16.2 (6.0–26.0) months

• Median time since start of last anti-TNF

• 8.7 (3.1–20.4) months

• Underlying disease

• RA – 26

• SpA – 3

• Inflammatory colitis – 8

• Psoriasis – 1

• Other – 5

9.3

23.3

67.4

0

10

20

30

40

50

60

70

80

90

100

Etanercept Adalimumab Infliximab

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Last anti-TNF received

(n=43)

Salmon-Ceron, et al. Ann Rheum Dis. 2011 Apr;70(4):616-623.


Analysis of the Estimation of the Standardized Incidence Ratio (SIR) for the Risk of Tuberculosis

Tubach, et al., Arth Rheum, 2009.

Risk of Tuberculosis in RA (N=40) Risk of Tuberculosis in SPA (N=18)

Risk is lower than in the

French population

Risk is higher than in the

French population

Only Adalimumab or

only infliximab

Only Etanercept

Adalimumab or

infliximab

Etanercept

All anti-TNF

SIR=26.2 [18.4-31.2] p<0.0001 n=31

SIR=24.9 [17.9-34.5] p<0.0001 n=36

n=0

SIR=2.1 [0.8-5.7] p<0.13 n=4

SIR=12.4 [9.1-16.9] p<0.0001 n=40

0 10 20 30 40

STR

Risk is lower than in the

French population

Risk is higher than in the

French population

Adalimumab

or infliximab

Etanercept

All anti-TNF

SIR=15.1

[9.4-24.3]

p<0.0001 n=17

SIR=1.35

[0.2-9.6]

p<0.77 n=1

0 10 20 30 40

STR

SIR=9.7

[6.1-15.4]

p<0.0001 n=18


Risk of TB with Anti-TNF

Tubach, et al., Arth Rheum, 2009.

Time from Onset of Last Anti TNF Treatment and First Symptoms of

Tuberculosis According to the Last Anti TNF Received

Time from onset of last anti TNF treatment (months)

Cum

ula

tive f

requency o

f

tuberc

ulo

sis

0 6 12 18 24 30 36 42 48 54 60 0

10

20

50

60

70

30

40

Total

Infliximab

Adalimumab

Etanercept



Nontuberculous (NTM) Disease

• Environmental mycobacteria

• Lung, skin and soft tissue, disseminated disease

• M. avium, M. kansasii, M. chelonae, M. abscessus

• Surveyed IDSA EIN

• One-fourth of US infectious disease specialists

• Reported 1876 TB or NTM cases

• 49 (2.6%) associated with biologics

• 32 cases NTM vs 17 TB

• Mycobacterium avium complex was most common (n=16)

EIN=Emerging Infections Network; IDSA=Infectious Diseases Society of America


30

*In this case etanercept was used as well, but symptoms worsened while the patient received INF. ND = no data available; NC = no cases identified. Tsiodras S, et al. Mayo Clin Proc. 2008;83(2):181-194.

Invasive Fungal Infections with TNF Inhibitor Therapy

• MEDLINE and PubMed database search from 1966-2007 (N = 281)

• Median time until onset of invasive fungal infection:

• INF: 55 days

• ETN: 144 days

• Median age of patient when developing invasive fungal infection was 58 years

• Histoplasmosis most prevalent invasive fungal infection (30%)

• Pneumonia was the most common pattern of infection (32%)

• 29 fatalities (32%) among the 90 cases for which outcome information was available of the total 281 cases

11 44 226 Total

2 1 3 Tinea or pityriasis

versicolor (n=6)

NC NC 1 Prototheca species (n=1)

NC NC 1* Sporothrix species (n=1)

4 8 72 Histoplasma species (n=84)

NC 2 27 Coccidioides species (n=29)

ND ND ND Blastomyces species (n=2)

1 10 17 Cryptococcus species (n=28)

1 9 54 Candida species (n=64)

1 NC 3 Zygomycetes (n=4)

2 14 48 Aspergillus species (n=64)

ADA ETN INF Infectious Agents

Fungal Infections Associated with TNF Inhibitor Therapy



More TB Risk With Monoclonals?

• Drug mechanisms differ

• Greater TNF- binding

• Transmembrane and soluble TNF-

• Forms stable complex

• Longer half-life

• Apoptosis of monocytes and T lymphocytes

• Interferon-gamma downregulation

• Differential granuloma penetration


Differential Effects on TNF Blockers on TB Immunity - Results

Infliximab and adalimumab block T cell activation, whereas etanercept does not

T cell activation (CD69 expression)

Infliximab and adalimumab reduced the proportion of TB-reactive T cells by 50 to

70%, and of PHA-reactive T cells, by 30 to 47% (P<0.05). Etanercept had no

effect.

Wallis R., et al., J. Inf. Dis 194:486-92, 2006.

Stimulus M.tb CF

Cell type CD4 CD4 CD8

PHA

No TNF blocker 0.73% 14.4% 11.1%

Etanercept 0.60% 15.1% 9.1%

Adalimumab 0.37% 10.5% 7.8%

Infliximab 0.22% 10.1% 5.9%

% CD69 + cells at 24 hrs



Interferon- Downregulation

Adapted from Saliu OY et al. J Infect Dis. 2006;194:486-492.

Drug Level

IFN

-γ, %

Co

ntr

ol V

alu

e

ETN

ADA

INF

70

90

None Trough Peak Supra

20

30

40

50

60

80

100


TNF necessary for granuloma homeostasis and especially

membrane TNF on monocytes and lymphocytes

Why a difference of effects on granuloma between Mc Abs and the soluble receptor ?


CFP10

Activation of specific anti-TB T cells on anti-TNF

• In patients with latent TB, addition of anti-TNF to a culture of specific anti-TB T cells

• more important of specific T-cell activation with monoclonal antibodies

200

160

120

80

40

0

0 0.4 1 4 10 40 mg/ml

Pro

life

rati

on

(S

I)

CFP10

40

30

20

10

0

0 0.4 1 4 10 40 mg/ml

IFN

gam

ma

(n

g/m

l)

Ifx

Ada

Eta

In vitro effects of TNF antagonists on anti-mycobacterial immune responses

PBS

Hamdi, Mariette et al, ART 2006, Saliu et al, JID 2006



Granuloma Penetration

• Acute TB infection (mouse)

• Large bacillary load and death

• No difference between anti-TNFs

• Chronic TB infection (mouse)

• Monoclonal antibodies=death (1 month)

• Etanercept=60% alive at 6 months

• Lung path: etanercept with less penetration of granulomas

Plessner HL et al. J Infect Dis. 2007;195:1643-1650.


Evolution of Biologics for IMIDS

1940s

Gold

Hydroxychloroquine

Corticosteroids

Etanercept

1950s 1960s 1970s 1980s 1990s 2000s

D-Penicillamine

Methotrexate

Auranofin

Azathioprine

Infliximab

Adalimumab

Golimumab

Certolizumab

Anakinra

Leflunomide

Rituximab

Abatacept

Tocilizumab

Ustikinumab

Belimumab

Natalizumab

Canakinumab

Rilonacept

Tofacitinib

Vedolizumab Secukinumab




Immunocompetence With New and Emerging Biologic Therapies

• Immunocompetence is defined as the capacity of the integrated immune response to defend against infections and malignancies

• An increased rate of infections is the gold standard, but:

• Clinical trials are generally underpowered for rare events

• Data collected across clinical trials and databases of such events are not uniform

• Diseases such as RA,CD are confounded by an increased baseline risk of SIEs

RA, rheumatoid arthritis; SIE, serious infectious event.

Looney RJ et al. Clin Immunol. 2007;123:235-243.


BLACK BOX INHERITENCE

Serious Infection Risk

weigh tx benefit vs. risk in pts w/ chronic or recurrent infection;

pulmonary and extrapulmonary tuberculosis (TB), invasive fungal

infections, and other opportunistic infections observed, incl. fatal;

most infections occur in combo w/ other immunosuppressants;

evaluate for TB risk factors and screen for latent TB infection before

and during tocilizumab tx; initiate anti-TB tx before tocilizumab tx;

monitor for infection s/sx during and after tocilizumab tx; since active

TB has developed in pts w/ negative tuberculin skin test, monitor all

pts for active TB s/sx; D/C tocilizumab tx if serious infection occurs

COMPLEX SINCE BIOLOGICS IN IMIDS ARE GENERALLY USED IN

COMBINATION WITH GC AND NB-DMARDS ( MTX etc)


J Rheum 2014


Other New Agents

• Ustikinumab IL12/23 inhibitor

• ?

• Secukinumab anti-IL17

• ?

• Others

• Vedolizumab

• Anti-IL23

• others


• JAK inhibitor

Blocks innate and adaptive immunity

• Cellular selectivity for JAKs

Jak3, Jak1 > Jak2 >> Tyk2

• Effective in variety of preclinical models

• Investigated in a large clinical trial

program in humans

Tofacitinib a Jakatinib

O'Shea JJ, et al. Nat Rev Rheumatol. 2013;9(3):173-182.


Tofacitinib: JAK Usage by Cytokines

JAK3 JAK1>>Jak2

Cytokines in the

Pathogenesis of RA

IL-7 IL-23

IL-15 IL-1

IL-21 IL-17

IL-6 IL-18

IFNα and IFNβ TGF-β

IL-10 TNF

IL-12

• Common gamma chain

IL2,IL7,IL9,IL15,IL21

• Blocks Th1

• Blocks Th17

• Decreased NK cells

NK = natural killer; TGF = transforming growth factor. O'Shea JJ, et al. Nat Rev Rheumatol. 2013;9(3):173-182.


SCREENING for TB in IMIDS

• Anergy

• Recommendations

• IGRA vrs TST

• Retesting


Anergy in Rheumatoid Arthritis: Assessment of Reactivity to Multiple Antigens

0

10

20

30

40

0 1 2 3 4 5 6

Controls (n=67) RA Patients (n=104)

%

RA

Patients

or

Contr

ols

Emery et al, Annals Rheum Dis 43: 430-434, 1984

Reagents: tuberculin, tetanus toxoid, diphtheria toxoid,

streptococcus, candida, trichophyton, proteus

# of individual antigens with positive reaction


Number of TB Reports per Month vs. Patient Exposure (US) With Infliximab

# o

f R

eport

ed T

B C

ases

(4 m

onth

movin

g a

vg)

Feb 2000 - August 2002

0

5

10

15

20

25

30

0 20000 40000 60000 80000 100000 120000 140000 160000 180000

# o

f Patie

nts

Tre

ate

d

Du

ring

Pre

vio

us 6

Mo

nth

s

TB Cases PSUR Period Exposure

Post-Approval

TB Education Program Initiated

Centecor, Data on file


3 IR Therapy


Re-test?

• No formal recommendations

• Complex issues with IGRA given adjunctive immunosuppression, effects of disease activity etc

• Most C level data suggests re-test only on the basis of clinical risk


Conclusions

• Biologic therapies for IMIDS increase the risk of TB reactivation as well as inhibit the defense against newly acquired granulomatous infections

• The preponderance of data are for TNFi and much our current practice is based on extrapolation

• Current screening has been effective at reducing the occurrence of active TB

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