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.