New Treatments for Rheumatoid Arthritis

Professor Ernest ChoyHead of Rheumatology and Translational Research

Institute of Infection and ImmunityDirector of Arthritis Research UK and Health and Care

Research Wales CREATE Centre

EULAR 2016 recommendations

Smolen JS, et al. Ann Rheum Dis 2017;0:1–18.

EULAR 2016 update on Management of RA

Smolen J et al. EULAR 2016 Congress oral presentation

Remission(>0 to <2.8)

ADACTA Trial: Clinical Disease Activity Index (CDAI) Analysis at Week 24 (ITT)

9.317.2*

19.8

30.7

0%

10%

20%

30%

40%

50%

ADA (N = 162) TCZ (N = 163)

Pat

ien

ts, %

Remission + Low Disease Activity (>0 to <10)

47.9%†

29.0%

*P = 0.0389, remission (unadjusted, no control for multiple testing). †P = 0.0003, remission + low disease activity (unadjusted, no control for multiple testing).

Proportions of patients were compared using Cochran-Mantel-Haenzsel (CMH) analysis stratified by region and duration of RA.

Data collected after withdrawal/initiation of escape therapy were set to missing. LOCF was used for missing data.

Gabay C, et al. Lancet. 2013 May 4;381(9877):1541-50.

Therapeutic targeting of IL-6 and its receptor

Hunter CA & Jones SA. Nature Immunology 16, 448–457 (2015)

Tocilizumab and sarilumab are approved for RA treatment

IL-6 inhibitors in rheumatology: At-a-glance

Tocilizumab (Roche) [IL-6]

Sarilumab (Sanofi, Regeneron) [IL-6 ]

Vobarilizumab (Ablynx) [IL-6R]

Sirukumab (GlaxoSmithKline, Johnson & Johnson)[ IL-6 ]

Clazakizumab (Alder, Vitaeris) [IL-6 ]

Phase 3Phase 2Phase 1

Development phase completed (RA):

Olokizumab (R-Pharm) [IL-6 ]

SARIL-RA-MOBILITY: Study Flowchart

7

n=398 placebo qw / q2w

52 weeks

Inadequate response to

MTX therapy

n= 29 sar 100 mg qw

n=28 sar 100 mg q2w

n=400 sarilumab 150 mg q2w

n=27 sar 150 mg qw

n=399 sarilumab 200 mg q2w

Dose selection

Open label extension

R Nonselected doses:

All IMP added to MTX (6-25 mg/week) background treatment; * 3 patients randomised but never treated.

N=1282

N=1197: Efficacy population

Selected doses

Rescue: From Week 16, patients with lack of efficacy defined as less than 20% improvement from baseline in either SJC or TJC for 2 consecutive visits were eligible for rescue with open label sarilumab.

Cohort 1 Cohort 2

Part A1: 12 weeks Part B2: 52 weeks

n=52 placebo qw

n=50 Sar 100 mg qw

n=51 Sar 150 mg q2w

n=51 Sar 100 mg q2w

n=52 Sar 200 mg q2w

n=50 Sar 150 mg qw

n=28

n=30

n=30

(88 – 3 + 1197): Safety population

Sar=sarilumab; SJC=swollen joint count; TJC=total joint count. 1. Huizinga TW et al. Ann Rheum Dis. 2013 Dec 2. doi: 10.1136/annrheumdis-2013-204405. 2. Genovese M et al. Presented at: 15th Annual European Congress of Rheumatology, European League Against Rheumatism; June 11-14, 2014; Paris, France. Oral presentation OP0028.

Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase

III Study

Arthritis & RheumatologyVolume 67, Issue 6, pages 1424-1437, 25 MAY 2015 DOI: 10.1002/art.39093http://onlinelibrary.wiley.com/doi/10.1002/art.39093/full#art39093-fig-0002

Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase

III Study

Arthritis & RheumatologyVolume 67, Issue 6, pages 1424-1437, 25 MAY 2015 DOI: 10.1002/art.39093http://onlinelibrary.wiley.com/doi/10.1002/art.39093/full#art39093-fig-0003

SARILUMAB MONOTHERAPY IS SUPERIOR TO ADALIMUMAB IN

MTX-IR/-INT PATIENTS

Sarilumab was superior to adalimumab in reducing disease activity and improving physical function1,2. aIncludes patients who increased the frequency of dosing of adalimumab 40 mg to qw because of an inadequate response. 1. KEVZARA Summary of Product Characteristics. Sanofi Genzyme/Regeneron Pharmaceuticals, 2017; 2. Burmester GR, et al. Ann Rheum Dis. 2017;76(5):840–7.

MTX-IR/INT patientsMONARCH: Week 241,2

Monotherapy

Week 24Adalimumab40 mg q2wa

(n=185)

Sarilumab200 mg q2w

(n=184)p-value

Change from baseline in DAS28-ESR, mean (SE)

-2.20 (0.106) -3.28 (0.105) <0.0001

DAS28-ESR remission (<2.6), % 7.0 26.6 <0.0001

ACR20 response rate, % 58.4 71.7 0.0074

ACR50 response rate, % 29.7 45.7 0.0017

ACR70 response rate, % 11.9 23.4 0.0036

Change from baseline in HAQ-DI, mean (SE)

-0.43 (0.045) -0.61 (0.045) 0.0037

SAFETY PROFILE OF SARILUMAB IS CONSISTENT WITH IL-6

BLOCKADE AND IS STABLE OVER >5 YEARS OF EXPOSURE

AE, adverse event; csDMARDs, conventional synthetic disease-modifying antirheumatic drugs; nE, number of events; PY, patient-years; TEAE, treatment-emergent adverse events; RA, rheumatoid arthritis

TNF-IR of MTX-IR/INT patientsEXTEND: [DURATION]Combination therapy

Most common AE (≥5%)Raw incidence

raten (%)

Exposure-adjusted incidence rate

nE (nE/100 PYs)a

Neutropenia 527 (18.3) 1090 (14.3)

Upper respiratory tract infection 376 (13.0) 592 (7.8)

Accidental overdoseb 362 (12.5) 518 (6.8)

Urinary tract infection 301 (10.4) 450 (5.9)

Alanine aminotransferase increased

300 (10.4) 396 (5.2)

Viral upper respiratory tract infection

281 (9.7) 393 (5.2)

Bronchitis 238 (8.2) 325 (4.3)

Hypertension 238 (8.2) 255 (3.4)

RA 236 (8.2) 331 (4.4)

Injection-site erythema 216 (7.5) 1071 (14.1)

Diarrhea 161 (5.6) 202 (2.7)

• Many cytokine receptors lack intrinsic kinase activity, instead relying on associated tyrosine kinases, such as JAKs, to transmit signals from the extracellular environment to the nucleus1,2

12

Cytokine receptor signaling through intracellular tyrosine kinases

1. Leonard WJ. Nat Rev Immunol. 2001;1(3):200-208; 2. Mavers M et al. Curr Rheum Rep. 2009;11(5):378-385.

JAK inhibitors in rheumatology: At-a-glance

Tofacitinib (Pfizer) [JAK3, JAK2, JAK1]

Baricitinib (Eli Lilly) [JAK1, JAK2]

VX-509 (Vertex) [JAK3]

Filgotinib (Galapagos, Gilead) [JAK1]

ASP-015K (Astellas) [JAK1, JAK3]

ABT-494 (AbbVie) [JAK1]

Phase 3 and ApprovedPhase 2Phase 1

Development phase completed (RA):

Adapted from Norman et al. Expert Opin Investig Drugs 2014;23(8):1067-77

Tofacitinib and Baricitinib are approved for RA treatment

A subgroup of non-receptor protein tyrosine

kinases: JAK1, JAK2, JAK3, and TYK21,2

Characterised by two adjacent kinase

domains, resembling the face of the

Roman god Janus2

Implicated in cell growth, survival,

development and cell differentiation1

Essential for immune cells and

haematopoietic cells1

Janus family kinases (JAKs)

1. Ghoreschi K et al. Immunol Rev 2009;228:273–87; 2. Thomas SJ et al. Br J Cancer 2015;113:365–71.

Cytokine

Cytokine receptor

JAK

Phosphate ions

Cytokines activate JAK signalling pathways leading to transcription of inflammatory mediators

• Rapid membrane-to-nucleus signalling:

‒ Cytokines bind trans-membrane receptors that are associated with JAKs1

P, phosphate.Coskun M et al. Pharmacol Res 2013;76:1–8.

15

Gene transcription

• Binding activates JAKs

• STATs bind DNA and activate or repress transcription of target genes

• JAKs phosphorylate receptors• STATs bind to receptors

• JAKs phosphorylate STATs

• STATs translocate to the nucleus

Activation of the JAK pathway

regulates transcription of genes

involved in many cellular processes1

Cell

membrane

Cytoplasm

Nucleus

Cytokine

The JAK/STAT signalling pathways

γ-chain cytokines2

STAT1, 3, 5, 6

IL-10 IL-22

STAT1, 3, 5

IL-6†

IL-11

STAT1, 3, 5

IFN-γ

STAT1, 3, 5

IL-12IL-23

STAT3, 4

EPO TPO

GM-CSF

STAT5

Example of cytokines that signal through JAK/STAT combinations1

• There are four JAK family members: JAK1, JAK2, JAK3, and TYK2

1. O’Sullivan LA et al. Mol Immunol 2007;44:2497–2506.2. Ghoreschi K et al. Immunol Rev 2009;228:273-287.

EPO, erythropoietin; GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; JAK, Janus kinase; STAT, signal transducer and

activator of transcription; TPO, thrombopoietin; TYK, tyrosine kinase.

In vitro JAK selectivity of JAK inhibitors (IC50, nM; [ATP] = 1 mM)1,2

Tofacitinib(XELJANZ; Pfizer)

Baricitinib(Olumiant; Eli Lilly)

Filgotinib(Galapagos)

JAK1 15 4 363

JAK2 77 7 2400

JAK3 55 787 >10,000

TYK2 489 61 2600

Differences in JAK Inhibitor Selectivity Necessitates Independent

Characterisation of Each Molecule

ATP=adenosine triphosphate; EPO=erythropoietin; IC50=half maximal inhibitory concentration; IL=interleukin; IFN=interferon; JAK=Janus kinase;

STAT=signal transducer and activator of transcription; TPO=thrombopoietin; TYK2=tyrosine kinase 2.

1. Clark JD, et al. J Med Chem. 2014;57(12):5023-5038. 2. O‘Sullivan LA, et al. Mol Immunol. 2007;44(10):2497-2506.

Jak

2

EPO, TPO, IL-3,

GM-CSF

Prolactin

IL-2, IL-4, IL-7, IL-9,

IL-15, IL-21

IL-6, IL-11, IL-27, CNTF,

LIF, OSM

g

cJAK

1

TYK

2JAK

1

IFNγ

JAK

1

IL-12/23

TYK

2

TYK

2JAK

1

IL-22

IL-10IFNα/β

JAK

3

JAK

2 JAK

2

JAK

2 JAK

2

JAK

2

17

In vitro JAK isoform selectivity

Enzyme essay IC50(nM)

Compound JAK1 JAK2 JAK3 TyK2 JAK2:JAK1 JAK3:JAK1 TyK2:JAK1

Tofacitinib 15.1 77.4 55.0 489 5.1 3.6 32.4

Baricitinib 4.0 6.6 787 61 1.5 196.8 15.3

Filgotinib 363 2400 >10,000 2,600 6.6 >27.5 7.2

Upadacitinib 8 600 139 NA 75 17.4 NA

Peficitinib 3.9 5.0 0.7 4.8 1.3 0.2 1.2

Decernotinib 112 619 74.4 >10,000 5.5 0.67 >89

Choy EH. Rheumatology (Oxford). 2019 Jan 28. epub

Common g chaincytokinesIL-2, 4, 7, 9, 13 &15

JAK1 JAK2JAK3

TyK2

gp130 cytokinesIL-6, 11,12, 27Leukemia inhibitory factorOncostatin M

JAK1

Common beta chaincytokines & hormonesIL-3, 5, G-CSF, GM-CSFErythropoietinLeptinThrombopoetinGrowth hormoneProlactin

JAK2 JAK2

Interferon-a/bIL-10 cytokine family:IL-10, 20, 22, 28

JAK1 TyK2 JAK1

Interferon-g

JAK2 JAK2 TyK2

IL12, 23Type III interferon

P P

P

P P P P P P P P

P

P

TofacitinibBaricitinibUpadacitinibFilgotinibPeficitinibDecernotinib

TofacitinibBaricitinibUpadacitinibFilgotinib

TofacitinibBaricitinibUpadacitinibFilgotinib

TofacitinibBaricitinibUpadacitinibFilgotinib

Baricitinib Baricitinib

Choy EH. Rheumatology (Oxford). 2019 Jan 28. epub

Phase 3 Tofacitinib and BaricitinibPrograms

Tofacitinib (N~5,000) Baricitinib (N~3,000)

MTX-naïve / limited ORAL StartMTX-naive5mg BID vs. 10mg BID vs. MTXN=958

BEGINBiologic / DMARD-naïve, ≤3 doses MTX allowed4mg QD + MTX vs 4mg QD vs MTXN=581

MTX-IR, Humira H2H ORAL Standard5mg vs. 10mg vs. ADA vs. pboN=717

ORAL Strategy Phase 4

5mg + MTX vs. 5mg vs. ADAN=1080

BEAMbiologic-naïve4mg vs. 40mg ADA vs. pbo

MTX backgroundN=1304

DMARD-IR ORALScan MTX-IR5mg vs. 10mg vs. pbo (MTX bgrd.)

pbo X to 5/10N=611

ORAL Sync5mg vs. 10mg vs. pbo

DMARD bgrd.N=792

BUILDbiologic-naïve2mg QD vs. 4mg QD vs. pbo

DMARD backgroundN=684

DMARD-IR, monotherapy ORAL SoloDMARD-IR5mg vs. 10mg vs. pbopbo X-over to 5mg/10mg

N=611

ORAL Strategy Phase 4

5mg + MTX vs. 5mg vs. ADAN=1080

Biologic-IR ORAL StepTNF-IR5 mg vs. 10 mg vs. pbo

MTX backgroundN=396

BEACONTNF-IR2mg vs. 4mg vs. pbo

DMARD backgroundN=525

Extension ORAL Sequel10mg / 5mgN=4385

BEYOND2mg vs. 4mg

DMARD background allowed from originating studyN=3073

Source: clinicaltrials.gov, company presentations / publications

MTX/DMARD-IR

28.3

51.5 52.647.2

0

20

40

60

80

100

Pati

en

ts w

ith

res

po

nse (

%)

Tofacitinib – ORAL Standard study

• The study was not powered for

superiority or non-inferiority

between active treatments,

and comparisons should not

be made between tofacitinib

and adalimumab

• Advancement penalty

Placebo Tofacitinib 5 mg BID Tofacitinib 10 mg BID Adalimumab 40 mg sc Q2W

n=30/106 101/196 103/196 94/199

**p<0.001; ***p<0.0001 vs placebo

*** *****

ACR20 (NRI)

JAK inhibitor

van Vollenhoven R, et al. NEJM 2012;367:508–519. van Vollenhoven R, et al. NEJM 2012;367:suppl 1–18.

MTX-IR

RA-BEAM: ACR Response Rate at Weeks 12, 24, and 52

Primary endpoint: ACR20 vs PBO at Wk 12.Data are % patients achieving response (NRI).

***P≤0.001 vs PBO. +P≤0.05 vs ADA. ++P≤0.01 vs ADA; +++P≤0.01 vs ADAACR20/50/70=20%, %50, or 70% improvement in American College of Rheumatology; ADA=adalimumab; MTX=methotrexate; NRI=nonresponder imputation; PBO=placebo;

wk=week.Taylor P et al. N Engl J Med. Supplement. 2017;376(7):652-662. doi:10.1056/NEJMoa1608345.

40

17

5

37

19

8

70

45

19

74

51

30

71

56

37

61

35

13

66

45

22

62

47

31

0

20

40

60

80

100

ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70

Res

po

nse

Rat

e (%

)

PBO + MTX (n=488) Baricitinib 4 mg + MTX (n=487) ADA 40 mg + MTX (n=330)

***

++***

+***

***

***

+***

++

+

+***

***

***

***

+***

***

23

Primaryendpoint

Wk 12 Wk 24 Wk 52

BIOLOGIC-IR

Tofacitinib – ORAL Step study

24.4

41.748.1

0

20

40

60

80

100

Pati

en

ts w

ith

resp

on

se (

%)

Burmester GR, et al. Lancet 2013;381:451–60.

n=32/131 55/132 64/133

*p<0.05; ***p<0.0001 vs placebo

***

*

Tofacitinib 5 mg BID Tofacitinib 10 mg BIDPlacebo

ACR20 (Month 3)

JAK inhibitor BIOLOGIC-IR

RA BEACON: ACR Responses at Weeks 12 and 24

27

82

27

13

3

49

2013

45

23

13

55

28

11

46

29

17

0

20

40

60

80

100

ACR20 ACR50 ACR70 ACR20 ACR50 ACR70

PBO Bari 2 mg Bari 4 mg

Week 12 Week 24

Data are % patients achieving response (NRI); *p≤0.05, **p≤0.01, ***p≤0.001 vs. PBO

**

******

******

***

******

***

*******

Pat

ien

ts, %

Genovese MC, et al. EULAR 2015. OP0029.

MONOTHERAPY

Tofacitinib – ORAL Solo study

Month 3

ACR20

***p<0.0001 vs placebo; there are no p values at Month 6 as there is no placebo

Month 6

******

Tofacitinib 5 mg BID Tofacitinib 10 mg BIDPlacebo Placebo 10 mg BIDPlacebo 5 mg BID

JAK inhibitor

Fleischmann R, et al. NEJM 2012;367:495–507. Fleischmann R, et al. NEJM 2012;367:Suppl 1–24.

MTX-IR

ORAL – START6 month

0

10

20

30

40

50

60

70

80

ACR20 ACR50 ACR70

MTX

Tofacitinib 5 mg BID

Tofacitinib 10 mg BID

***p<0.001 vs methotrexate

****

**

**

**

**

Lee EB et al. N Engl J Med 2014;370:2377-86

RA-BEGIN

Fleischmann R et al. Arthritis Rheumatol. 2017 Mar;69(3):506-517

RADIOGRAPHIC OUTCOME

ORAL-SCAN

van der Heijde D, et al. Arthritis Rheum. 2013 Mar;65(3):559-70.

Baricitinib Radiographic Data

RA BUILD:• Significant inhibition of

radiographic progression for both baricitinib 2 and 4 mg vs placebo

RA BUILD1

0.70

0.47

0.23

0.330.30

0.03

0.150.11

0.04

0

0.2

0.4

0.6

0.8

mTSS Erosion JSN

Me

an C

han

ge f

rom

Bas

elin

e

PBO Bari 2 mg Bari 4 mg

*

****

* *

*p≤0.05, **p≤0.01, ***p≤0.001 vs. PBO

RA BEAM2

RA BEAM:• Significant inhibition of

radiographic progression was observed for both baricitinib4 mg and adalimumab vs placebo

0.90

0.61

0.29

1.80

1.23

0.58

0.41

0.29

0.12

0.71

0.51

0.210.330.24

0.10

0.60

0.42

0.19

0

0.5

1

1.5

2

mTSS Erosion JSN mTSS Erosion JSNLS M

ean

Ch

ange

fro

m B

ase

line

PBO Bari 4 mg ADA 40 mg

Week 24 Week 52

***

***

****

******

***

***

***

**

******

*p≤0.05, **p≤0.01, ***p≤0.001 vs. PBO

RA BEGIN3

RA BEGIN:• Significant inhibition of

radiographic progression observed for baricitinib 4 mg + MTX vs MTX

• There was no significant difference in change from baseline in mTSS between baricitnib monotherapy and MTX

0.61

0.47

0.14

1.02

0.81

0.21

0.390.33

0.06

0.80

0.55

0.250.29 0.26

0.03

0.400.34

0.06

0

0.5

1

1.5

mTSS Erosion JSN mTSS Erosion JSNLS M

ean

Ch

ange

fro

mB

ase

line

MTX Bari 4 mg Bari 4 mg + MTX

Week 24 Week 52

**

****

*p≤0.05, **p≤0.01, ***p≤0.001 vs. MTX

Safety of JAKi

Meta-analysis of Serious Infections in Tofacitinib, Baricitinib, and Biologic DMARDs

Agent Trial types Number of trials

Incidence rate (95% CI),per 100 PY

Patients (N)

Tofacitinib 5 mg bid RCT† 15 2989

Tofacitinib 10 mg bid RCT† 15 3152

Tofacitinib (all doses) RCT+LTE 17 6194

Baricitinib 2 mg qd RCT 6 1657

Baricitinib 4 mg qd RCT 6 3546

TNF inhibitors RCT+LTE 57 26,492

Adalimumab RCT+LTE 18 6570

Certolizumab pegol RCT+LTE 5 3212

Etanercept RCT+LTE 17 7141

Golimumab RCT+LTE 6 2820

Infliximab RCT+LTE 11 4592

Non-TNF bDMARDs

Abatacept RCT+LTE 11 5953

Rituximab RCT+LTE 8 2926

Tocilizumab RCT+LTE 13 5547

0 2 4 6 8 10

2.71

2.72

2.74

4.75

4.90

5.04

7.59

4.06

5.31

6.11

3.04

3.72

5.45

Patients with events per 100 PY (95% CI)

. 3.67

Tofacitinib LTE data as of March 2015. Bars indicate 95% CIs.†Estimate from pooled patient-level data. bid=twice daily; CI=confidence interval; bDMARD=biologic disease-modifying antirheumatic drug; LTE=long-term extension; PY=patient year; qd=once daily; RCT=randomized controlled trial; TNF=tumour necrosis factor.Strand V et al. Poster presentation at EULAR 2017. Abstract THU0211.

3.63 3.48 3.43

2.112.64

0.69

3.73

0

1

2

3

4

5

6

7

8

Overalltofacitinib

5 mg 5 mg Placebo ±csDMARDs

ADA MTX Overalltofacitinib

Incidence Rates of Serious and Nonserious Herpes Zoster

Phase II, III LTE studiesPhase I, II, III and LTE

Inc

ide

nc

e r

ate

pe

r 1

00

PY

(95

% C

I)

Patients 7061 3066 3995 1849 2024 1079 257 223 4967

Total PY 21,519 7735 13,784 1777 1903 285 189 290 16,441

Patients with events 782 269 513 61 79 6 5 2 621

Data as of March 2017. Incidence rate of patients per 100 PY. Bars indicate 95% CI.ADA=adalimumab; CI=confidence interval; csDMARDs=conventional synthetic disease-modifying antirheumatic drugs; LTE=long-term

extension; MTX=methotrexate; PY=patient-years.Data on file. Pfizer Inc.

Tofacitinib Tofacitinib

Incidence Rate of Serious and Non-serious Herpes Zoster with Tofacitinib by Region

Data from Phase I, II, III and LTE studies for tofacitinib all doses, as of March 2017. CI=confiden,ce interval; HZ=Herpes zoster; PY=patient-years; RA=rheumatoid arthritis.

1. Cohen SB, et al. Ann Rheum Dis. 2017;76(7):1253-1262. 2. Supplement to: Cohen SB, et al. Ann Rheum Dis. 2017;76(7):1253-1262. 3. XELJANZ/XELJANZ XR [prescribing information]. New York, NY: Pfizer Inc; 2017.

Incidence rate per 100 PY (95% CI) Unique patients with

HZ events, n

Total number of

patients, N

Global RA program1 782 7061

By Region2

US/Canada 190 1745

Europe 192 2382

Latin America 123 1221

Asia 277 1673

Japan 120 556

Korea 63 316

India 16 197

Thailand/Malaysia/Philippines 27 208

China/Taiwan 26 260

Australia/New Zealand 25 136

3.6

4.1

2.33.4

5.6

7.87.4

2.9

4.3

2.9

5.5

0 4 8 12

Incidence Rate of Serious and Non-serious Herpes Zoster with Tofacitinib Monotherapy or Combination ± GCs

Crude incidence rates (patients with events per 100 PY) were calculated to examine if differences exist.bid=twice daily; CI=confidence interval; GC=glucocorticoid; HZ=Herpes zoster; nbDMARD=non-biologic disease-modifying antirheumatic

drug; PY=patient-years.1. Winthrop K, et al. [abstract]. Arthritis Rheumatol. 2015;67(suppl 10). http://acrabstracts.org/abstract/herpes-zoster-and-tofacitinib-

the-risk-of-concomitant-nonbiologic-therapy/. Accessed March 28, 2017. 2. Kivitz AJ et al. Presented at: American College of Rheumatology Annual Meeting; November 6-11, 2015; San Francisco, CA. Poster 2143.

Patients 579 394 320 296

PY 603 412 367 361

Patients with events 28 15 12 2

4.8

3.73.4

0.60

2

4

6

8

Cru

de in

cid

en

ce r

ate

per

100 P

Y

(95%

CI)

+nbDMARD

+GCs

+nbDMARD

-GCs-nbDMARD

+GCs

-nbDMARD

-GCs

Tofacitinib 5 mg bid

There are four JAK family members: JAK1, JAK2, JAK3, and TYK2

IL-2, IL-4, IL-6,

IL-10, IL-11,

IFN-β, IFN-γ

IL-2, IL-4, IL-6,

IL-10, IL-11,

IFN-β, IFN-γ

IL-2, IL-4, IL-3, IL-5, IL-6,

IL-10, IL-11, IL-12, IL-23,

IFN-α, IFN-β, IFN-γ

IL-2, IL-4, IL-5,

IL-6, IL-10, IL-11,

IFN-β, IFN-γ,

GM-CSF

IL-3, IL-5, IL-6,

IL-10, IL-11, IL-

12, IL-23, IFN-

α,

IFN-β, IFN-γ

IL-12, IL-23,

EPO, TPO, GM-

CSF, IFN-γ

Key cytokines that signal through JAK/STAT combinations

The JAK/STAT signalling pathways

EPO, erythropoietin; GM-CSF, granulocyte-macrophage

colony-stimulating factor; TPO, thrombopoietin.

1. O’Sullivan LA, et al. Mol Immunol 2007;44:2497–506; 2. Ghoreschi K, et al. Immunol

Rev 2009;228:273–87; 3. Sanjabi S, et al. Curr Opin Pharmacol 2009;9:447–53.

STAT phosphorylation and translocation to the nucleus

Gene transcription and production of inflammatory factors

Changes in Laboratory Tests with JAKi

Tofacitinib (5mg)(JAK, JAK3)

Baricitinib (4mg)(JAK1, JAK2)

Haemoglobin (g/dl) +0.47+0.05 -0.17

Neutrophil (x103/mm3) -1.09+0.1 -1.08 +0.07

Lymphocyte count (x103/mm3) -0.24+0.03 -0.05

Platelets -30% Increase

Choy EH. Rheumatology (Oxford). 2019 Jan 28. epub

Conclusions

• Recent approved therapeutic agents in Europe for the treatment of RA in 2017:– IL-6 inhibitor: sarlimumab– Janus Kinase inhibitors: Tofacitinib and Baricitinib

• Sarlimumab has similar efficacy and safety profile as Tocilizumab

• JAKi selectively is relative and not absolute.• Current approved JAKi and those in development

significantly inhibit JAK1 isoform. • JAK1 is an effective target in RA although zoster reactivation

is a class effect.• The balance of benefit and risk of inhibiting JAK2, JAK3 and

TYK2 is uncertain and should be evaluated in the future.