New and Emerging Treatments and

Management Approaches in RA

Supported by an independent educational

grant from Gilead Sciences Medical Affairs
This activity is provided in collaboration with Rush University Medical Center and Practice Point Communications.

Simply Speaking® Rheumatoid Arthritis “New and Emerging Treatments and Management Approaches in RA” is
Copyrighted 2020 by Practice Point Communications, unless otherwise noted. All rights reserved.
Educator

Arthur Kavanaugh, MD
Professor of Medicine
University of California at San Diego
Director, Center for Innovative Therapy
Division of Rheumatology, Allergy, and Immunology

• Disclosures
– Research Grant: None
– Royalty: None
– Stockholder: None
– Member, Speakers Bureau: None
– Consultant: Gilead, Abbvie, Pfizer, Eli Lilly
– Salary: None
– Other Financial or Material Support: None
– Plan to discuss investigational/off-label uses of drugs or devices? N

2
Learning Objectives
(CME/CNE/CPE)

• Upon completion of this educational activity, participants should be better able to:
– Identify immediate clinical needs/limitations of current rheumatoid arthritis therapy

– Discuss clinical considerations impacting individualized therapy for patients with rheumatoid arthritis

– Discuss clinical trial results of agents in late-stage clinical development and how such agents may impact
future management of patients with rheumatoid arthritis

3
Commonly Used DMARDs That Are FDA-Approved for RA

Synthetic DMARDS Biologic DMARDs

• Conventional • Biologic originator
– Hydroxychloroquine (chloroquine) – TNF
– Methotrexate, leflunomide, sulfasalazine • Etanercept, infliximab, adalimumab, certolizumab,
golimumab
• “Targeted”
– IL‑6 receptor
– JAK3/JAK1, JAK2
• Tocilizumab, sarilumab
• Tofacitinib
– IL-1
– JAK1/JAK2
• Anakinra
• Baricitinib
– CD28 costimulatory interactions with CD80 and
– JAK1
CD86 on T cells
• Upadacitinib
• Abatacept
– B cells (targets CD20)
• Rituximab
• Biosimilars

Smolen JS, et al. Ann Rheum Dis. 2020;79:685-699.

Abbasi M, et al. J Cell Physiol. 2019;234:10018-10031.
Taylor PC. Rheumatology. 2019;58(suppl 1):i17-i26. 4
Mechanisms of Action of DMARDs

• Tumour necrosis factor inhibitors, IL‑6 receptor

inhibitors, and Janus kinase inhibitors
– Block the action of the pro-inflammatory cytokines
involved in the initiation and progression of RA
• Targeting upstream events with CD80 and CD86
inhibitors, as well as CD-20
– May lead to a downregulation of pro-inflammatory
cytokines

Baricitinib
Tofacitinib
Upadacitinib

APC: antigen-presenting cell; BCR: B-cell receptor; CD: cluster of differentiation;

CD40L: CD40 ligand; GM-CSF: granulocyte-macrophage colony-stimulating factor;
JAK: Janus kinase; MHC: major histocompatibility complex; RANK: receptor activator of
nuclear factor‑κB; RANKL: receptor activator of nuclear factor‑κB ligand; TCR: T-cell
receptor; TFH: T follicular helper cell; TH: T helper cell; TNF: tumor necrosis factor.
Smolen JS, et al. Ann Rheum Dis. 2020;79:685-699.
Smolen JS, et al. Nat Rev Dis Primers. 2018;4(18001):1-23. 5
 Methotrexate-Naïve Patients:
Achieving ACR70 is Improved With DMARDs ± Methotrexate

Methotrexate-Naïve Patients (Week-52 Results)

100 Biologic DMARD
Targeted synthetic DMARD

80
ACR70 (%)

60 51% 53%*
47% (69%) 48% (75%)
43% (80%) (86%) 42%
(76%) 38% (77%)
40 (65%)
40% 29%
(62%)
24% (70%)
(62%) 29% 29%
27% (59%) 25% 28% (57%)
20 (62%) (61%) (67%) 22% 21%
(69%) (59%)
16%
(49%)

0
Abatacept Golimumab Tocilizumab Rituximab Certolizumab Etanercept Tofacitinib Baricitinib Upadacitinib
+ MTX + MTX + MTX + MTX + MTX + MTX (Oral-START) + MTX (SELECT-EARLY)
(AGREE) (GO-BEFORE) (FUNCTION) (IMAGE) (C-EARLY) (COMET) (RA-BEGIN)

*Week 48.
Dotted line: response with methotrexate monotherapy; numbers in parentheses are ACR20 rates.
Individual trials, not head-to-head comparisons.
Smolen JS, et al. Nat Rev Dis Primers. 2018;4(18001):1-23; van Vollenhoven R, et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 928. 6
 Treatment-Experienced Patients:
Achieving ACR70 With DMARDs ± Methotrexate

Prior Insufficient Response Prior Insufficient Response

to Methotrexate (Week-24 Results) to Anti-TNF (Week-24 Results)
100 100
Biologic DMARD Biologic DMARD
Targeted synthetic DMARD Targeted synthetic DMARD

80 80
ACR70 (%)

ACR70 (%)
60 60

40 33%* 40
(71%)
24% 23%†
20% 20% 22% 20% 20% (62%) (56%)
(59%) 17%
(68%) (60%) (54%) (52%)
20 20 12% 12% 16% (46%)
10% 12% (51%)
(34%) (53%) (51%)
(50%)

0 0
Abatacept Golimumab Tocilizumab Rituximab Tofacitinib Baricitinib Upadacitinib Abatacept Golimumab Tocilizumab Rituximab Tofacitinib Baricitinib Upadacitinib
+ MTX + MTX + MTX + MTX + MTX + MTX (SELECT- + MTX + MTX + MTX + MTX + MTX + MTX (SELECT-
(AIM) (GO-FORWARD) (OPTION) (DANCER) (Oral- (RA-BUILD) MONOTHERAPY) (ATTAIN) (GO-AFTER) (RADIATE) (REFLEX) (Oral-STEP) (RA-BEACON) (BEYOND)
STANDARD)

*Week 14; †week 12.

Numbers in parentheses are ACR20 rates. Results Individual trials, not head-to-head comparisons.
Smolen JS, et al. Nat Rev Dis Primers. 2018;4(18001):1-23; Smolen JS, et al. Lancet. 2019;393:2303-2311; Genovese MC, et al. Lancet. 2018;391:2513-2524. 7
RA and Need for New Therapeutic Options

• RA is a chronic progressive disease that, if incompletely treated, can lead to progressive joint
destruction and disability
• The number of treatment options for RA has increased substantially, as have the improvements in
efficacy and safety outcomes
• Limitations with currently available RA treatment options
– Most agents remain partially effective

– Remission is achieved in a minority of patients

– Impact of comorbidities

– Safety considerations

• There remains an unmet need for RA treatments that provide excellent response, safety, and are
cost-effective

8
Potential Future Therapeutics for RA

Biologics Intracellular Signal Inhibitors

• Cytokine inhibitors (eg, targeting IL 6, IL 21, • Janus kinase inhibitors (late stage clinical
interferons, GM-CSF or its receptor) development: filgotinib, peficitinib)
• Cytokine–IgG fusion proteins (eg, interleukin 4–IgG) • Bruton’s tyrosine kinase inhibitors
• Bi-specific antibodies • PI3 kinase inhibitors
• Cell-targeting agents (eg, B-cell depletion, co-
stimulatory blockade)
Miscellaneous Approaches
• Toll-like receptor inhibitors
• PADI4 inhibitors
Extracellular Signal Inhibitors • Epigenetic modifiers (eg, histone deacetylase inhibitors)
• Tolerogenic dendritic cell transfer • GnRH antagonists
• Stem cell transfer • Vagus nerve stimulation
• T-regulatory-cell activation • miRNA targeting

Smolen JS, et al. Ann Rheum Dis. 2020;79(6):685-699.

Smolen JS, et al. Nat Rev Dis Primers. 2018;4(18001):1-23. 9
Overview

• New Therapies
– Recently approved and under review by the FDA
• Jakinibs (upadacitinib and filgotinib)
• Emerging management approaches

10
JAK Signalling by Various Cytokines

• Cytokine-activated JAKs use ATP to phosphorylate each

others’ tyrosine residues as well as the intracellular tail of the
receptor subunits
– Create docking sites that recruit downstream signalling molecules

• Receptor-bound signal transducer and activator of transcription

(STATs) are themselves tyrosine phosphorylated by JAKs
• STAT phosphorylation mediates dimerization and translocation
to the nucleus
– Nuclear accumulation of the STATs allows DNA binding and
activation of gene transcription
• Establishes a direct, evolutionarily conserved membrane-to-nucleus
signalling pathway

Gadina M, et al. Rheumatology. 2019;58(suppl 1):i4-i16.

Serhal L, et al. Expert Rev Clin Immunol. 2019;15:13-25.
Banerjee S, et al. Drugs. 2017;77:521-546. 11
JAK Pathways and Inhibition as a Therapeutic Target

• 4 types of JAKs
(JAK 1, 2, 3, and TYK2) Ɣ c Cytokines gp120 c Cytokines
IL-3, IL-5, GM-CSF,
– Individual JAK protein cannot carry a G-CSF EPO, TPO,
IL-2, IL-4, IL-7, IL-12, INFα,
signal on its own; it must pair with IL-9, IL-15, IL-21 IL-6 IL-23 GH, leptin, prolactin IFN IFNƔ
either 1 or 2 other members of the
JAK family
– Only homodimer is JAK2

• Combinations of different JAK-

receptor subsets contribute to
specific function at the cellular JAK3 JAK2 TYK2 TYK2
TYK2 JAK2 JAK2 JAK2 JAK2
level
JAK1 JAK1 JAK1 JAK1
• JAK inhibitors
Lymphoid cell Acute phase response Th17 Erythropoiesis Antiviral immunity Antiviral & antimicrobial
– JAK1, 2, 3: peficitinib maturation & T cell differentiation differentiation Myelopoiesis NK cell activation immunity
activation Lipid metabolism Thrombopoiesis Th1 differentiation
– JAK 3/1, 2: tofacitinib Bone resorption Growth Macrophage &
Nk cell activation
– JAK1, 2: baricitinib
– JAK1: filgotinib, upadacitinib
– JAK3: decernotinib (RA development
stopped)
Gadina M, et al. Rheumatology. 2019;58(suppl 1):i4-i16.
Serhal L, et al. Expert Rev Clin Immunol. 2019;15:13-25.
Banerjee S, et al. Drugs. 2017;77:521-546. 12
Upadacitinib

• Selective JAK1 inhibitor

• FDA approval: August 16, 2019

– Treatment of adults with moderately-to-severely active RA who have an inadequate response or intolerance
to MTX
– Key phase 3 studies supporting approval
• SELECT-EARLY (MTX-naïve, versus MTX)

• SELECT-MONOTHERAPY (MTX-IR, versus continue MTX)

• SELECT-NEXT (csDMARD-IR, versus placebo)

• SELECT-COMPARE (MTX-IR, versus adalimumab and placebo)

• SELECT-BEYOND (bDMARD-IR, versus placebo)

– Additional phase 3 study

• SELECT-CHOICE (bDMARD-IR, versus abatacept)

13
Upadacitinib Dosage and Administration

• Recommended oral dose: 15-mg once daily

• May be used as monotherapy or in combination with MTX or other nonbiologic DMARDs

• Avoid initiation or interrupt upadacitinib

– If absolute lymphocyte count <500 cells/mm3, absolute neutrophil count <1000 cells/mm3, or hemoglobin
level <8 g/dL

Upadacitinib full prescribing information, August 2019. https://www.rxabbvie.com/pdf/rinvoq_pi.pdf. 14

Upadacitinib (Black Box Warning):
Serious Infections

• Patients treated with upadacitinib are at increased risk for developing serious infections that may lead to
hospitalization or death
– Most cases were taking concomitant immunosuppressants such as methotrexate or corticosteroids

• If a serious infection develops, interrupt upadacitinib until the infection is controlled

• Reported infections
– Active TB

• Test for latent TB before and during upadacitinib (consider treatment for latent infection prior to upadacitinib use)

– Invasive fungal infections (including cryptococcosis and pneumocystosis), bacterial, viral (including herpes zoster), and
other infections due to opportunistic pathogens
• Carefully consider the risks and benefits of upadacitinib prior to initiating therapy in patients with chronic or
recurrent infection
• Closely monitor for signs/symptoms of infection during/after treatment (including TB in patients who tested
negative for latent TB infection prior to initiating therapy)

Upadacitinib full prescribing information, August 2019. https://www.rxabbvie.com/pdf/rinvoq_pi.pdf. 15

Upadacitinib (Black Box Warning):
Malignancies and Thrombosis

• Malignancies
– Lymphoma and other malignancies have been observed in patients treated with upadacitinib

• Thrombosis (including deep venous thrombosis, pulmonary embolism, and arterial thrombosis) have
occurred with Janus kinase inhibitors used to treat inflammatory conditions
– Many of these adverse events were serious and some resulted in death

– Consider the risks and benefits prior to treating patients who may be at increased risk

– Patients with symptoms of thrombosis should be promptly evaluated and treated appropriately

Upadacitinib full prescribing information, August 2019. https://www.rxabbvie.com/pdf/rinvoq_pi.pdf. 16

SELECT-EARLY: Updated
Citation
Upadacitinib Monotherapy in MTX-Naïve RA Patients

Phase 3 (43 countries)

Double-blind
Upadacitinib Monotherapy
Symptoms consistent with RA ≥6 weeks
15 mg qd (n=317)
RF and ACPA positive and/or ≥1 joint erosion
No prior bDMARD or JAK inhibitor Upadacitinib Monotherapy Extension Phase
30 mg qd (n=314) (up to 5 years)
MTX Monotherapy
(n=314)
Week 0 12 24 72 260

Primary Current
Endpoint Analysis

Primary outcomes (week 12):

Proportion achieving ACR20.
Proportion achieving DAS28-CRP <2.6.
Baseline characteristics:
Time since RA diagnosis: 3 years.
RA and/or ACPA positive: 83%.
DAS28-CRP: 5.9.
van Vollenhoven R, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 207. 17
 SELECT-EARLY: Updated
Citation
Response Rates at Week 72 (NRI)

ACR20/50/70 Clinical Remission

100 UPA 15 mg qd (n=317) 100 UPA 15 mg qd (n=317)
UPA 30 mg qd (n=314) UPA 30 mg qd (n=314)
MTX (n=314) MTX (n=314)
80 80
71%* 72%*
67%*
62%* 61%*
Patients (%)

Patients (%)
60 60
54%* 52%*
50%
47%*
44%*
40 39% 40
35%* 33%*
28% 29%*
26%
20 20 17%
13%

76%* 77%* 54% 52%* 56%* 28% 33%* 37%* 14% 36%* 41%* 14% 16%* 21%* 6% 13%* 15%* 6%
0 0
ACR20 ACR50 ACR70 DAS28-CRP <2.6 CDAI ≤2.8 Boolean REM
NRI: Non-responder imputation method.
Numbers in bars are response rates at week 12.
*P<0.001 versus MTX.
van Vollenhoven R, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 207. 18
SELECT-EARLY: Updated
Slide
Safety Outcomes at Week 72

• Upadacitinib was generally well tolerated

Safety Outcomes at Week 72
compared with MTX at week 72
Upadacitinib
– Higher rate of serious adverse events with 15 mg 30 mg MTX
upadacitinib 30 mg monotherapy versus (n=317) (n=314) (n=314)
upadacitinib 15 mg Rate (events per 100 patient-years)
Serious adverse events 14 15 12
– Rate of discontinuations due to adverse events Adverse events leading to 10 11 9
similar across all 3 monotherapy arms discontinuation
Serious infections
– Higher rates of herpes zoster with upadacitinib 30 Opportunistic infection <1 2 0
Herpes zoster virus 6 5 1
versus upadacitinib 15 mg and MTX monotherapy Death 1 2 <1
• No herpes zoster events had CNS or ophthalmic Incidence (%)
involvement Malignancy 1 1 <1
MACE (adjudicated) 1 1 1
VTE (adjudicated) 0 <1 1

*P≤0.0001 versus MTX.

MACE: major adverse cardiac event.
VTE: venous thromboembolic event.
van Vollenhoven R, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 207. 19
SELECT-COMPARE: Upadacitinib Versus Adalimumab in Updated
Citation
RA Patients With Inadequate Response to MTX

Phase 3 (44 countries)

Double-blind
Upadacitinib + MTX Extension
Moderate-to-severe active RA ≥3 months
15 mg qd (n=651) Up to 5 Years
IR after MTX for ≥3 months and on
stable dose for ≥4 weeks Adalimumab + MTX (placebo randomized to either
upadacitinib 15 or 30 mg qd)
No IR to bDMARD or prior JAK inhibitor 40 mg EOW (n=327)
Placebo + MTX
(n=651)
Week 0 12 26 48 72 260

Background stable doses of NSAIDs, paracetamol, oral steroids,

or inhaled steroids were allowed. Primary Current
Patients stratified by geographic region. Endpoint
Primary outcomes (week 12): Analysis
Proportion achieving ACR20.
Proportion achieving DAS28-CRP <2.6.
Baseline characteristics:
Age: 54 years.
Time since RA diagnosis: 8 years.
Female: 79%.
RA and/or ACPA positive: 88%.
DAS28-CRP: 5.8.
CDAI: 40.
HAQ-DI: 1.6.
Fleischmann R, et al. Ann Rheum Dis. 2019;71:1788-1800.
Fleischmann R, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 212. 20
 SELECT-COMPARE: Updated
Citation
Response Rates at Week 72 (NRI)

ACR20/50/70 100
Clinical Remission
100 UPA 15 mg qd (n=651)
UPA 15 mg qd (n=651)
ADA 40 mg q2 weeks (n=327) ADA 40 mg q2 weeks (n=327)

80 80

64%‡
Patients (%)

Patients (%)
60 60
53%
51%‡

41%‡
40 38% 38%‡ 40
28%‡
25% 26%
20 20 17%

71%* 63% 45%† 29% 25%† 14% 29%† 18% 13%† 8%

0 0
ACR20 ACR50 ACR70 DAS28-CRP <2.6 CDAI ≤2.8

NRI: Non-responder imputation method. All patients received background MTX.

Numbers in bars are response rates at week 12 (placebo [n=651] ACR20/50/70: 35%/15%/5%; remission: DAS28-CRP <2.6 [6%], CDAI ≤2.8 [3%]).
*P≤0.001 versus placebo and P≤0.05 versus adalimumab; †P≤0.001 versus placebo and adalimumab; and ‡P≤0.01 versus adalimumab.
Fleischmann R, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 212. 21
SELECT-COMPARE: Updated
Citation
Safety Outcomes at Week 72

• No new safety signals for upadacitinib 15 mg

identified through week 72 Safety Outcomes at Week 72
(events per 100 patient-years)
• Rates of serious adverse events and UPA ADA
15 mg 40 mg
discontinuations due to adverse events were (n=651) (n=327)
numerically higher with adalimumab
Serious adverse events 13 16
• Rate of herpes zoster was higher with Adverse events leading to discontinuation 8 11
upadacitinib Serious infections 4 4
Herpes zoster virus 3 1
• Rates of serious infections and adjudicated
Malignancy <1 <1
rates of VTE and MACE were similar between
the 2 arms MACE (adjudicated) <1 <1
VTE (adjudicated) <1 1
Death <1 1

*P≤0.001 versus placebo.

MACE: major adverse cardiac event; VTE: venous thromboembolic event.
All patients received background MTX.
Fleischmann R, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 212. 22
SELECT-CHOICE: Upadacitinib Versus Abatacept in RA Updated
Citation
Patients With Inadequate Response/Intolerant to bDMARDs

Phase 3 (29 countries)

Double-blind
Upadacitinib 15 mg qd Long-Term Extension
Moderate-to-severe active RA ≥3 months
+ csDMARD (n=303) Up to 5 Years
IR bDMARDs (SJC/TJC [66/68]): ≥6 despite
≥3 months with ≥1 bDMARD or intolerance Abatacept Infusion* (Abatacept switched to
upadacitinib 15 mg qd)
to bDMARDs + csDMARD (n=309)
Week 0 12 24 260

Primary Current
Endpoint Analysis
*Infusion at baseline and at weeks 2, 4, 8, 12, 16, and 20.
Primary outcomes (week 12):
Change in DAS28-CRP (non-inferiority margin 0.6).
Secondary outcomes (week 12):
Proportion achieving DAS28-CRP ≤2.6.
Change in DAS28-CRP (superiority).
Baseline characteristics:
Time since RA diagnosis: 11-12 years.
Female: 82%.
Mean age: 56 years.
RF and anti-CCP positive: 64%.
DAS28-CRP: 5.7-5.9.
CDAI: 38-41.
HAQ-DI: 1.7.
Rubbert-Roth A, et al. N Engl J Med. 2020;383:1511-1521. 23
SELECT-CHOICE: Upadacitinib Versus Abatacept in RA Updated
Citation
Patients With Inadequate Response/Intolerant to bDMARDs

• Change in DAS28-CRP at week 12

Week 24 (NRI)
(primary endpoint) 100
UPA 15 mg qd (n=303)
– Upadacitinib met non-inferiority and superiority ABA infusion (n=309)

criteria versus abatacept (P<0.001) 80

• Treatment difference: -0.52 (95% CI -0.69, -0.35)

• Proportion achieving DAS28-CRP remission

Patients (%)
60

– Week 12: upadacitinib was superior to abatacept 46%*

(30% versus 13%; P<0.001) 40

31%
– Week 24: significant difference for upadacitinib was
maintained (46% versus 31%; P<0.001) 21%‡
20
14% 14%
10%

30%* 13% 8%† 3% 6%† 2%

0
DAS28-CRP CDAI Boolean
NRI: Non-responder imputation method.
Numbers in bars are response rates at week 12.
<2.6 ≤2.8 Remission
*P<0.001; †P≤0.01; and ‡P≤0.05 versus adalimumab infusion.
Rubbert-Roth A, et al. N Engl J Med. 2020;383:1511-1521. 24
 SELECT-CHOICE: Updated
Citation
ACR20/50/70 Response Rates at Week 12 and 24 (NRI)

Week 12 Week 24
100 100
UPA 15 mg qd (n=303) UPA 15 mg qd (n=303)
ABA infusion (n=309) ABA infusion (n=309)

80 79%
76%* 80
74%
66%*
Patients (%)

Patients (%)
60 60 59%*

50%
46%†

40 40 37%†
34%
27%
22% †

20 20

14%
0 0
ACR20 ACR50 ACR70 ACR20 ACR50 ACR70

NRI: Non-responder imputation method.

*P<0.05 and †P<0.01 versus abatacept.
Rubbert-Roth A, et al. N Engl J Med. 2020;383:1511-1521. 25
SELECT-CHOICE: Updated
Citation
Safety Outcomes at Week 24

• Upadacitinib was generally well tolerated and

the safety profile was consistent with previously Safety Outcomes at Week 24
reported phase studies UPA
15 mg ABA
– Numerically higher incidence of serious adverse (n=303) (n=309)
events with upadacitinib Serious adverse events (%) 6 3

– Incidence of discontinuations due to adverse Discontinuations due to adverse events (%) 5 3

events was similar between the 2 arms Herpes zoster virus (%) 1 1
Malignancy (%) 0 0
• Numerically higher grade 3 events were MACE (%) <1 0
detected for selected laboratory values in the VTE (%) 1 0
upadacitinib arm Death (%) <1 1
– Elevated AST/ALT, lymphopenia, and elevated Grade 3/4 laboratory abnormalities (%)
AST (3-8x/>8x ULN) 3/<1 <1/0
creatine phosphokinase ALT (3-8x/>8x ULN) 3/0 0/0
Lymphocytes (0.5-1/<0.5 x103) 13/2 8/<1
Creatine phosphokinase (5-10x/>10x ULN) <1/1 0/0
MACE: major adverse cardiac event.
VTE: venous thromboembolic event.
Rubbert-Roth A, et al. N Engl J Med. 2020;383:1511-1521. 26
SELECT-COMPARE: New
Slide
Patient-Reported Outcomes at Week 12

• Post-hoc analysis (n=612)

SF-36 Domain Improvements ≥ MCID at Week 12
– Baseline PROs were similar between the 2 arms
100 UPA 15 mg qd (n=303)
• Both upadacitinib and abatacept resulted in ABA infusion (n=309)
83%*
clinically meaningful improvements from 80 79%
76%
baseline in PROs at week 12 71%*
66%
63%
• Greater improvement in domains of physical

Patients (%)
60
function, pain, and general health were
observed with upadacitinib compared with
40
abatacept

20

0
*P<0.05 versus abatacept. Physical Bodily Pain General Health
MCID: minimally clinically important differences,
defined as increase of ≥5.0 points for all SF-36 domains. Functioning
Bergman M, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 1728. 27
Safety Profile of Upadacitinib Up to 3 Years in RA: Updated
Citation
Integrated Analysis From the SELECT Phase 3 Trials

UPA 15 mg UPA 30 mg ADA 40 mg MTX

(n=2629) (n=1204) (n=579) (n=314)
Follow-up (patient-years) 4567 2309 769 456
Treatment-emergent adverse events
(per 100 patient-years)
Serious adverse events 12.9 19.8 14.6 12.7
Serious infections 3.2 5.7 3.9 3.1
Herpes zoster 3.4 6.5 1.2 1.1
VTE 0.5 0.3 0.5 0.4
MACE 0.5 0.7 0.4 0.4
Malignancies (minus NMSC) 0.9 1.1 0.7 0.7

Data from 5 randomized phase 3 studies (SELECT-EARLY, SELECT-NEXT, SELECT-MONOTHERAPY, SELECT-COMPARE, AND SELECT-BEYOND).
NMSC: nonmelanoma skin cancer; MACE: major adverse cardiac events; VTE: venous thromboembolic events.
Cohen S, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 237. 28
 Updated
Slide
Filgotinib

• Selective JAK1 inhibitor

• Orally administered, once-daily

• Key phase 3 studies

– FINCH 3 (MTX-naïve, versus MTX)

– FINCH 1 (MTX-IR, versus continue placebo)

– FINCH 2 (bDMARD-IR, versus placebo)

• NDA for RA submitted 12/19/2019

– Filgotinib 100 and 200 mg/day is approved for use in Europe (moderate to severe RA) and Japan (RA in
patients with inadequate response to conventional therapies)

29
FINCH 3: Updated
Citation
Filgotinib ± MTX in MTX-Naïve RA Patients

Phase 3 (31 countries)

Double-blind
Filgotinib 100 mg qd + MTX
Active RA and ACR functional class I-III
(n=207)
SJC/TJC (66/68): ≥6
≥1 joint erosion or positive for either RF Filgotinib 200 mg qd + MTX
or aCCP, or CRP ≥4 mg/L (n=416)
Limited or no prior MTX Filgotinib 200 mg qd Monotherapy
No prior JAK inhibitor (n=210)
MTX Monotherapy
(n=416)
Week 0 24 52

SJC: swollen joint count; TJC: tender joint count; RF: rheumatoid factor;
aCCP: anti-cyclic citrullinated peptide antibody. Primary Endpoint Current
Baseline characteristics: Proportion achieving ACR20 Analysis
Time since RA diagnosis: 2.2 years.
DAS28-CRP: 5.7.
HAQ-DI score: 1.6.
SF-36:
PCS/MCS: 34/43-45.
FACIT-fatigue: 27-28.
VAS pain assessment: (mm): 64-67.

Westhovens R, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 217. 30

 FINCH 3: Updated
Slide
Response Rates at Week 52 (NRI)

ACR20/50/70 Clinical Remission

100 100 FIL 100 mg qd + MTX (n=207)
FIL 100 mg qd + MTX (n=207)
FIL 200 mg qd + MTX (n=416) FIL 200 mg qd + MTX (n=416)
FIL 200 mg qd monotherapy (n=210) FIL 200 mg qd monotherapy (n=210)
80 75%† 75%† MTX monotherapy (n=416) 80 MTX monotherapy (n=416)
73%‡

62% 62%† 61%‡

59%‡

Patients (%)
Patients (%)

60 60
53%*
48% 48% †
46%*
45%† 44%†
40%*
40 40 38%*
35%†
32%
30% 30%*
27%†
22%†
20 20 18%
13%
11%

80%* 81%† 78% 71% 57%‡ 62%† 58%‡ 46% 40%† 44%† 40%† 26% 43%* 54%* 42%* 29% 27%* 26%* 21%† 13% 21%* 23%* 18%† 11%
0 0
ACR20 ACR50 ACR70 DAS28-CRP CDAI Boolean
<2.6 ≤2.8 Remission
NRI: Non-responder imputation method. Numbers in bars are response rates at week 24.
*P<0.05, †P<0.001, and ‡P<0.01 versus methotrexate monotherapy.
Westhovens R, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 217. 31
FINCH 3: Updated
Citation
Safety Outcomes at Week 52

• Overall safety of filgotinib was similar to

MTX monotherapy Safety Outcomes at Week 52
(exposure-adjusted events per 100 patient-years)
• Filgotinib 200 mg qd ± MTX Filgotinib + MTX Monotherapy
Filgotinib
– Higher frequencies of serious adverse 100 mg 200 mg 200 mg MTX
events versus filgotinib 100 mg qd + MTX (n=207) (n=416) (n=210) (n=416)
and MTX monotherapy
Serious adverse events 13 26 17 28
Discontinuations due to 11 27 5 23
adverse events
Serious infections 3 5 5 8
Herpes zoster virus
Malignancy 0 1 0 4
MACE (adjudicated) 1 4 2 2
VTE (adjudicated) 0 0 0 2
*P<0.05; †P<0.001; and ‡P<0.01 versus MTX monotherapy. Deaths 1 2 0 0
mTSS: modified total Sharp score; MACE: major adverse cardiac event;
VTE: venous thromboembolic event.
Westhovens R, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 217. 32
FINCH 1: Filgotinib + MTX in RA Patients With InadequateUpdated
Citation
Response to MTX

Phase 3 (30 countries)

Double-blind
Filgotinib 100 mg qd + MTX
Active- and placebo-controlled
(n=480)
SJC/TJC (66/68) ≥6
≥1 joint erosion and positive for either RF Filgotinib 200 mg qd + MTX
or aCCP, ≥3 joint erosion if RF and aCCP (n=477)
negative, or CRP ≥6 mg/L Adalimumab 40 mg sc q2 weeks + MTX
IR after MTX for ≥12 weeks and stable (n=325)
dose ≥4 weeks
No prior JAK inhibitor Placebo Patients randomized to receive either
(n=475) filgotinib 100 or 200 mg + MTX

SJC: swollen joint count; TJC: tender joint count; RF: rheumatoid factor; Week 0 12 24 52
aCCP: anti-cyclic citrullinated peptide antibody.
Background stable doses of NSAIDs, paracetamol, oral steroids,
or inhaled steroids were allowed.
Baseline characteristics: Primary Endpoint Current
Time since RA diagnosis: 8 years. Proportion Achieving ACR20 Analysis
Female: 82%. (filgotinib versus placebo)
DAS28-CRP: 5.7.
HAQ-DI score: 1.6.
SF-36:
PCS/MCS: 33/44-46.
FACIT-fatigue: 27-28.
VAS pain assessment: (mm): 64-66.

Combe B, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 208. 33

 FINCH 1: Updated
Citation
Response Rates at Week 52 (NRI)

ACR20/50/70 Clinical Remission

100 100
FIL 100 mg qd + MTX (n=480) FIL 100 mg qd + MTX (n=480)
FIL 200 mg qd + MTX (n=475) FIL 200 mg qd + MTX (n=475)
ADA 40 mg sc q2 weeks + MTX (n=325) ADA 40 mg sc q2 weeks + MTX (n=325)
80 78% 78%
75%
80

60% 62% 60%

Patients (%)
Patients (%)

60 60
54%§

46%
43% 43%
40% 40%
40 40
29%§
24% 24% 22%§
20 20 19% 17%

70%* 77%* 71% 36%* 47%* 35% 19%* 26%* 14% 24%* 34%† 24%* 11%‡ 12%† 6% 6%* 9%† 5%¶
0 0
ACR20 ACR50 ACR70 DAS28-CRP <2.6 CDAI ≤2.8 Boolean Remission
Placebo (n=475) ACR20/50/70 at week 12: 50%/20%/7%. Placebo (n=475) at week 12: 9%/3%/2%.
*P<0.001 versus placebo. *P<0.001 versus placebo; †P<0.001 versus placebo and P<0.01 versus ADA;
‡
P<0.001 versus placebo and P<0.05 versus ADA; ¶P<0.001 versus placebo
NRI: Non-responder imputation method. Numbers in bars are response rates at week 12. and P<0.05 versus ADA; §P<0.05 versus ADA.
Combe B, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 208. 34
FINCH 1: Updated
Citation
Safety Outcomes at Week 24 and 52

• Overall safety of filgotinib + MTX was

Safety Outcomes at Week 24
similar to adalimumab + MTX and
Filgotinib + MTX
placebo ADA 40 mg
100 mg 200 mg + MTX Placebo
• Low frequencies of venous (n=480) (n=475) (n=325) (n=475)
thromboembolic events, serious Radiographic progression
infections, and other adverse events of Mean change in mTSS score 0.17* 0.13* 0.16 0.38
interest with filgotinib + MTX Physical function
Mean change in HAQ-DI -0.8* -0.8* -0.8 -0.6
• Safety profile of filgotinib + MTX through
Serious adverse events (%) 5 4 4 4
week 52 was consistent with week 24
Serious infections (%) 2 2 3 <1
Herpes zoster virus <1 <1 <1 <1
MACE (%) <1 0 <1 <1
VTE (%) 0 <1 0 <1
Malignancies (%) <1 0 <1 <1
Deaths (%) <1 <1 0 <1
*P<0.001 versus placebo.
mTSS: modified total Sharp score; MACE: major adverse cardiac event;
VTE: venous thromboembolic event.
Combe B, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 208. 35
FINCH 2: Filgotinib + csDMARDs in RA Patients With Updated
Citation
Inadequate Response/Intolerant to bDMARDs

Phase 3 (15 countries)

Double-blind, placebo-controlled
Filgotinib 100 mg qd + csDMARDs
Active RA and ACR functional class I-III
(n=153)
On 1 or 2 stable csDMARDs
IR/intolerance after bDMARDs Filgotinib 200 mg qd + csDMARDs
No prior JAK inhibitor (n=147)
Placebo
(n=148)
Week 0 12 24

Primary Endpoint Current

Proportion Achieving ACR20 Analysis

Baseline characteristics:
Time since RA diagnosis: 12 years.
DAS28-CRP: 5.9.
Genovese MC, et al. JAMA. 2019;322:315-325.
Gottenberg J, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 216. 36
 FINCH 2: Updated
Slide
Response Rates at Week 24 by Number of Prior bDMARDs

ACR20/50/70 Clinical Remission (DAS28-CRP <2.6)

100 Number in parentheses: overall ACR20 100 Number in parentheses: overall remission
FIL 100 mg qd + csDMARDs (55%*) FIL 100 mg qd + csDMARDs (26%*)
FIL 200 mg qd + csDMARDs (69%*) FIL 200 mg qd + csDMARDs (31%†)
80 Placebo (35%) 80 Placebo (12%)
70%*
68%†
Patients (%)

Patients (%)
60 56%† 60
50%

40 40
35% 34%*
32%
27%†
24%
21%
20 20
15%

6%
57%* 65%* 36% 59%* 68%* 18% 40%* 52%* 25% 29* 38% † 9%
0 0
<3 Prior bDMARDs ≥3 Prior bDMARDs <3 Prior bDMARDs ≥3 Prior bDMARDs
(n=119/110/114) (n=34/38/34) (n=119/110/114) (n=34/37/34)
Numbers in bars are response rates at week 12.
*P<0.001 and †P<0.01 versus placebo.
Genovese MC, et al. JAMA. 2019;322:315-325; Gottenberg J, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 216. 37
FINCH 2: Updated
Citation
Safety Outcomes at Week 24

• Filgotinib ± csDMARDs was generally well

tolerated compared with placebo at week 24 Safety Outcomes at Week 24
Filgotinib + csDMARDs

100 mg 200 mg Placebo

(n=153) (n=147) (n=148)
Serious adverse events (%) 5 4 5
Discontinuations due to 4 3 4
adverse events (%)
Serious infections (%) 3 <1 2
Opportunistic infection 0 0 0
Herpes zoster virus 1 1 1
Active TB 0 0 0
Malignancy (%) 0 0 0
MACE (%) <1 0 <1

*P≤0.0001 and †P≤0.01 versus placebo.

VTE (%) 0 <1 0
MACE: major adverse cardiac event.
VTE: venous thromboembolic event.
Genovese MC, et al. JAMA. 2019;322:315-325.
Gottenberg J, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 216. 38
Peficitinib

• Inhibits JAK3 and JAK1

• Orally administered, once-daily

• Key phase 3 studies

– MTX-IR (versus continue placebo)

– csDMARD-IR (versus etanercept and placebo)

• Regulatory approval in Japan (March 2019)

– Treatment of RA in patients with inadequate response to conventional therapies

• FDA NDA submission status uncertain

39
New and Emerging Therapies for Rheumatoid Arthritis:
Summary of Focus on Jakinibs

• Jakinibs can achieve rapid improvements in disease

activity, functional status, patient-reported outcomes, JAK Development
Target(s) Stage
and structural integrity in patients with RA
Tofacitinib 3/1, 2 FDA approved
• Jakinibs can be effective in other rheumatic (2012)
diseases, such as psoriatic arthritis
Baricitinib 1/2 FDA approved
• Adverse events of special interest with Jakinibs (2017)
include infections, serious infections, and herpes
Filgotinib 1 NDA submitted
zoster
– Possible associations with VTE and MACE events are
Upadacitinib 1 FDA approved
(8/2019)
being assessed
Peficitinib 3, 1 Approved in Japan

Jegatheesaren J, et al. Immunotherapy. 2019;11:737-754.

Harigai M. Rheumatology. 2019;58:i34-i42.
Westhovens R. Rheumatology. 2019;58:i27-i33. 40
Overview
• New Therapies

• Emerging management approaches

– Prevention of RA and treatment of early RA

41
Prevention of RA and Treatment of Early RA

• Despite significantly improved outcomes in RA with earlier diagnosis and advances in

treatment, there is no cure and disease prevention remains an area of active research
– Studies examining different treatment regimens in varied subsets of patients with pre-clinical RA
have been able in some cases to delay, but not prevent the onset of RA
• A significant challenge is to identify the right time for treatment initiation during the
transition from pre-clinical/early RA to clinical RA
– Factors triggering, contributing to, or accelerating this transition are not fully understood

– There is no risk stratification method to reliably estimate the risk of progressing to RA for
individual persons

Alpizar-Rodriguez D, et al. Clin Rheumatol. 2020;39:1383-1389.

Mahler M, et al. Autoimmun Rev. 2020;19(5):102506.
Greenblatt HK, et al. Curr Opin Rheumatol. 2020;32:289-296.
Drosos AA, et al. Clin Rheumatol. 2020;39:1363-1368.
van der Helm-van Mil A, et al. Ann Rheum Dis. 2020;79:312-315.
Mankia K, et al. J Autoimmun. 2020;110:102399. 42
Mechanisms Involved in Initiation and Progression of RA

• Neo-epitopes may be created by post-translational Neo-epitopes

modifications, and can be recognized by the immune
system
– Presented by APCs and elicit autoantibody formation

– APCs and macrophages can be activated locally and produce

a range of inflammatory mediators
• Autoimmune response triggers and sustains inflammation
– Actions of cytokines and other mediation can drive persistent
inflammatory and immune responses, perpetuating the
disease and ultimately leading to cartilage and bone
destruction

APC: antigen-presenting cell; BCR: B-cell receptor; CD: cluster of differentiation;

CD40L: CD40 ligand; GM-CSF: granulocyte-macrophage colony-stimulating factor;
JAK: Janus kinase; MHC: major histocompatibility complex; RANK: receptor activator of
nuclear factor‑κB; RANKL: receptor activator of nuclear factor‑κB ligand; TCR: T-cell
receptor; TFH: T follicular helper cell; TH: T helper cell; TNF: tumor necrosis factor.
Lin Y-J, et al. Cells. 2020;Apr 3;9(4):880.
Smolen JS, et al. Nat Rev Dis Primers. 2018;4(18001):1-23. 43
Identifying Persons With Preclinical RA

• Genetic variables
Duration of Pre-Diagnosis
– >100 genetic risk variants identified RF and Anti-CCP Antibody Positivity
10
– Genetic-based scoring systems remains limited Anti-RF positive 9.2
Anti-CCP positive 8.6
8.4
• Serologic biomarkers
8

RA Diagnosis (years)
– ~66% of patients diagnosed with RA were ACPA-

Duration Before
6.4
positive 6 to 10 years before their diagnosis
6 5.5
• Population prevalence (pre-test probability) of RA is low
(positive predictive value: ~70%)
4.1
4
• ACPA positive healthy individuals: 2% to 5% or more 3.3
2.8
• Probability of developing RA in an unselected ACPA-
positive population: ~50% 2

• Post-test probability might increase with very high titers of

ACPAs or by combining RF and ACPAs, but with lower
0
sensitivity 20-29 30-39 40-49 ≥50
(n=11/12) (n=16/14) (n=14/17) (n=6/8)
Acosta-Herrera M, et al. J Clin Med. 2019;8(6):826.
Aletaha D, et al. Arthritis Rheum. 2011;63:3702-3711. Age at Diagnosis of RA
Smolen JS, et al. Nat Rev Dis Primers. 2018;4(18001):1-23. (years)
Majka DS, et al. Ann Rheum Dis. 2008;67:801-807. 44
Selected Pharmacologic Trials Focused on RA Prevention
Completed
Duration (months) Population Key Results
PROMPT (n=110) 12 Undifferentiated RA RA development (MTX versus placebo): 40% versus 53% (P<0.005)
PRAIRI (n=81) 24 Arthralgias + ACPAs ± Rituximab versus placebo
RF + increased ACPAs RA development: 34% versus 40% (P>0.05)
or synovitis (MRI) Time to diagnosis in 25% of patients: 24 versus 12 months (P>0.05)
ADJUST (n=24) 12 Undifferentiated RA RA development was delayed but not prevented with abatacept

Ongoing (completion 2020-2021)

Drug Population
APIPPRA Abatacept Arthralgia considered to be inflammatory related, ACPA and RF positive, or high ACPA titer
STAPRA Atorvastatin RF IgM and ACPA positivity or high ACPA titer (>3x ULN), ± current joint pain, no current clinical synovitis
StopRA Hydroxychloroquine Elevation of anti-CCP3 ≥40 units, no current or history of synovitis
TREAT Methylprednisolone No clinically detectable arthritis but with arthralgia of small hand or feet joints of recent-onset (<1 year)
EARLIER suspected to be an early presentation of RA (clinically suspected arthralgia)

MTX: methotrexate; ACPA: anti-citrullinated protein antibody; RF: rheumatoid factor.

Alpizar-Rodriguez D, et al. Clin Rheumatol. 2020;39:1383-1389.
Mahler M, et al. Autoimmun Rev. 2020;19(5):102506.
Drosos AA, et al. J Clin Med. 2019;8(8):1237. 45
 Updated
Citation
Prevention of RA

• Prevention programs are mainly aimed at individuals with undifferentiated arthritis and encompass
risk factor modification and pharmacologic strategies
– No evidence is available to support the use of DMARDs in patients without clinical arthritis

– Prevention trials are needed to evaluate effectiveness of risk factor modification

• Challenges/opportunities in RA prevention research

– Accurately classify individuals in each stage of RA development

– Precisely predicting risk of progression to the next “worse” stage of disease

– Understanding the biology of disease in each stage on an individual level so that optimal intervention may be
applied

Chaichian Y, et al. Clin Rheumatol. 2020;39:1379-1381.

Wintrop KL, et al. Ann Rheum Dis. 2019;78:872-878.
Alpizar-Rodriguez D, et al. Clin Rheumatol. 2020;39:1383-1389.
Mahler M, et al. Autoimmun Rev. 2020;19(5):102506.
Greenblatt HK, et al. Curr Opin Rheumatol. 2020;32:289-296.
Drosos AA, et al. Clin Rheumatol. 2020;39:1363-1368.
van der Helm-van Mil A, et al. Ann Rheum Dis. 2020;79:312-315.
Mankia K, et al. J Autoimmun. 2020;110:102399. 46
NORD-STAR Trial: Active Conventional Therapy
Versus 3 Biologic Treatments in Early RA

Phase 4 (n=812)
Open-label, non-inferiority
Adults with early, treatment-naïve RA Conventional Therapy
(MTX + Prednisolone or Triple Therapy + IA Corticosteroids)
ACR/EULAR 2010 criteria
DAS28-CRP >3.2
Certolizumab-Pegol
SJC/TJC (66/68): ≥2
+ MTX
<24 months symptom duration
RF or ACPA positive or CRP >10 mg/L Abatacept
+ MTX

Tocilizumab
+ MTX
Week 0 12 24

Primary endpoint: CDAI remission (ITT, noninferiority margin: 15%). Primary

Baseline characteristics: Endpoint
Mean age: 54 years.
Female: 69%.
Time since RA diagnosis: 7 days.
ACPA/RF positive: 82%/75%.
CDAI: 29.
DAS28-CRP: 5.0.
Hetland ML, et al. Ann Rheum Dis. 2020;79(suppl 1):13-14. Abstract OP0018. 47
NORD-STAR Trial: Outcomes With Active Conventional
Therapy Versus 3 Biologic Treatments in Early RA

• High remission rates were achieved across all 4

treatment arms CDAI Remission Rates (ITT, Week 24)
100
– Higher CDAI remission rate with abatacept + MTX Treatment Difference (%):
versus conventional therapy Reference +4 +9 -1
1.0 (-5 to 13) (0.1 to 19) (-10 to 9)
80
• Active conventional therapy was non-inferior to
certolizumab and tocilizumab, but not to abatacept

Patients (%)
60
• Key secondary outcomes* were generally similar
51%
across treatment arms 46%
42% 41%
40

20

0 Conventional Certolizumab- Abatacept Tocilizumab

Therapy Pegol + MTX + MTX + MTX
*ACR/EULAR Boolean remission, DAS28 remission, SDAI remission, (n=200) (n=203) (n=204) (n=188)
and EULAR good response.
Hetland ML, et al. Ann Rheum Dis. 2020;79(suppl 1):13-14. Abstract OP0018. 48
BeSt Cohort: Mortality in Patients With RA, Treat-to-Target
at Low Disease Activity

• Ongoing cohort study of patients with early RA

Survival
– Symptoms <2 years, mean DAS 4.4
100
• Treatment arms (median duration: 17 years)
– Sequential monotherapy
80
– Step-up combination therapy

– Initial combination therapy with prednisone

Log-rank P=0.76

Patients (%)
60
– Initial combination therapy with infliximab

• Excess mortality was observed in patients with RA after

17 years of treatment compared with the general Dutch 40
population (observed versus expected deaths: 28%
General population
versus 21%; SMR: 1.36 [95% CI 1.16-1.61])
Sequential monotherapy
20
– No significant differences between the 4 treatment strategies Step-up combination therapy
Initial combination therapy with prednisone
– Analyses ongoing to determine contributing factors and
Initial combination therapy with infliximab
causes of death 0
0 5 10 15
Time (years)
BeSt: Behandel Strategieen (Treatment Strategies in Rheumatoid Arthritis).
Maassen JM, et al. Ann Rheum Dis. 2020;79(suppl 1):136-137. Abstract OP0219. 49
 Updated
Citation
Early RA

• Lack of consensus on the definition of early RA; evolution over recent years
– <2 years from onset of symptoms (NICE, 2009)

– <6 months from onset of symptoms (ACR, 2016)

– <3 months from onset of symptoms (EULAR, 2020)

• Early RA and high disease activity

– Unmet need: 21% of patients did not achieve sustained low disease activity using all csDMARDs and/or bDMARDs and
current guideline recommendations (observational, single-center study, <1 year RA duration; median 8.3 years follow-up)
• More comprehensive research into treatment of early RA population is needed
– Lack of studies in early RA with many therapeutic options/classes

Deighton C, et al. BMJ. 2009;338:b702.

Singh JA, et al. Arthritis Rheumatol. 2016;68:1-26.
Smolen JS, et al. Ann Rheum Dis. 2020;79:685-699.
Kaltsonoudis E, et al. Semin Arthritis Rheum. 2019;48:597-602.
Paul D, et al. Clin Exp Rheumatol. 2020;38:1008-1015.
Poppelaars PB, et al. Ann Rheum Dis. 2019;78:586-589. 50
Overview
• New Therapies

• Emerging management approaches

– Clinical considerations impacting individualized therapy

51
Recognition of the Role of Individualized Therapy for RA

• Therapeutics are not delivered via a pathogenetically coherent protocol that takes account of early
dominant autoimmunity and later damage-related effector pathways
– Predictors to permit precision medicine approaches in rheumatology are lacking

• Treatment decisions should be based on safety, tolerability, disease activity, and other patient
factors, such as comorbidities and progression of structural damage
– Shared decision between the patient and the rheumatologist

• Although stringent remission (or at least low disease activity) is today’s therapeutic goal, many
patients do not reach/achieve this target but remain dependent on medication
– Pathogenesis of RA non-responders remains unidentified

– More research is needed to tie the epigenetic, environmental, and therapeutic factors together to optimize
treatment response
Smolen JS, et al. Ann Rheum Dis. 2020;79:685-699.
Kerschbaumer A, et al. Ann Rheum Dis. 2020;79:744-759.
Mahler M, et al. Autoimmun Rev. 2020;19(5):102506.
Greenblatt HK, et al. Curr Opin Rheumatol. 2020;32:289-296.
Drosos AA, et al. Clin Rheumatol. 2020;39:1363-1368.
Drosos AA, et al. J Clin Med. 2019;8:1237.
Singh JA, et al. Arthritis Care Res. 2016;68:1-26. 52
Comorbidities in Patients With RA

• Comorbid conditions have been shown to be

present in ~54% of patients with RA
– Inflammatory mediators, including cytokines,
immune complexes, and altered lipid
metabolism, circulate to promote several
coexisting conditions

McInnes IB, et al. N Engl J Med. 2011;365:2205-2219.

Moreland LW, et al. UpToDate. 2020. 53
Evolving Treatment Guidance

• Treatment decisions are based on disease activity, safety issues, EULAR 2019 Update
and other patient factors, such as comorbidities and progression
of structural damage
• Recommendations (although evidence-driven) are aspirational in
nature, reflecting ‘best practice’ provided in an ideal world
– Assume awareness of various safety issues, patient adherence, and
costs are not limiting
• Safety from randomized controlled trials may not necessarily
represent real-world practice
– Safety signals inform future research

Smolen JS, et al. Ann Rheum Dis. 2020;79:685-699.

Kerschbaumer A, et al. Ann Rheum Dis. 2020;79:744-759.
Sepriano A, et al. Ann Rheum Dis. 2020;79:760-770. 54
One Published Example of Monitoring Strategies
for RA Drug Treatments
Ongoing Monitoring Via System Review and Physical Examination Ongoing Monitoring Via Laboratory Tests and Other Tests
NSAIDs Dyspepsia, nausea/vomiting, abdominal pain, edema, hypertension CBC and complete metabolic panel q6-12 months
Glucocorticoids Mood, weight gain, visual changes, weakness, polyuria, polydipsia, edema, infection Diabetes screening, lipids, BMD testing
Hydroxychloroquine Visual changes Ophthalmologic screening
Sulfasalazine Rash, nausea, diarrhea, photosensitivity, hepatotoxicity CBC, aminotransferases and creatinine q2-4 weeks for 1st 3 months or after increasing
dose, q8-12 weeks for 3-6 months, then q12 weeks
Methotrexate Stomatitis, alopecia, diarrhea, nausea/vomiting, flu-like symptoms, hepatotoxicity, CBC, aminotransferases and creatinine q2-4 weeks for 1st 3 months or after increasing
infection, pregnancy dose, q8-12 weeks for 3-6 months, then q12 weeks
Leflunomide Nausea/vomiting, diarrhea, paresthesia, hepatotoxicity, weight loss, hypertension CBC, aminotransferases and creatinine q2-4 weeks for 1st 3 months or after increasing
dose, q8-12 weeks for 3-6 months, then q12 weeks
Minocycline Hyperpigmentation, dizziness, headache None after baseline
Azathioprine Diarrhea, nausea/vomiting, symptoms of myelosuppression, infection CBC, aminotransferases and creatinine q2-4 weeks for 1st 3 months or after increasing
dose, q8-12 weeks for 3-6 months, then q12 weeks
Anti-TNF biologics Infection, demyelination, congestive heart failure, autoimmune phenomenon Repeat TB testing in those at increased risk of or with known exposure
Tocilizumab Infection, hepatotoxicity, gastrointestinal perforations CBC with differential and LFTs monthly until stable, then q3 months; lipids q6 months
Rituximab Infection, PML, symptoms of neutropenia CBC q2-4 months
Abatacept Infection CBC q3 months
Tofacitinib Infection, zoster, hepatotoxicity CBC with differential, creatinine, LFTs monthly for 3 months, then q3 months; lipids
q6 weeks after drug start

Table not meant to be comprehensive.

Moreland LW, et al. UpToDate. 2020. 55
 Updated
Citation
Safety Considerations With Clinically Available DMARDs

• Serious infections
– Moderate increased risk with bDMARDs versus csDMARDs (adjusted RR 3.1-3.9), with no clear difference
across bDMARDs
• Tuberculosis: increased risk with TNF inhibitors (adjusted RR 1.9-2.5) (especially with monoclonal antibodies, also
occurred with tsDMARDs)
• Herpes zoster: increased risk with tofacitinib and upadacitinib versus abatacept (class effect, especially in certain
ethnicities), but no increase with bDMARDs

• Malignancies (except NMSC) and MACE

– No increase in overall risk with bDMARDs or tsDMARDs

• Lower intestinal perforations

– Increased risk with IL-6 inhibitors versus other bDMARDs and csDMARDS

– More data needed on risk with JAKinibs (tofacitinib)

Smolen JS, et al. Ann Rheum Dis. 2020;79:685-699.
Kerschbaumer A, et al. Ann Rheum Dis. 2020;79:744-759.
Sepriano A, et al. Ann Rheum Dis. 2020;79:760-770.
Cohen S, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 237. 56
Venous Thromboembolism in Patients With RA Receiving Updated
Citation
tsDMARD Therapy

• Number of VTE events in patients participating in registrational trials of tsDMARDs is low

– Additional well-designed long-term observational studies are needed

• Tofacitinib and baricitinib

– FDA and EMA warning to use tofacitinib and baricitinib with caution in RA patients with risk factors for VTE

• Upadacitinib
– Integrated safety analysis of phase 3 trials (monotherapy and in combination with csDMARDs) found no
increase in the incidence of VTE with upadacitinib (0.3-0.6/100 person years) versus adalimumab (1.1/100
person-years), MTX (0.5/100 person-years), and placebo (0.4/100 person years)

Smolen JS, et al. Ann Rheum Dis. 2020;79:685-699.

Kerschbaumer A, et al. Ann Rheum Dis. 2020;79:744-759.
Sepriano A, et al. Ann Rheum Dis. 2020;79:760-770.
Mease P, et al. Ann Rheum Dis. 2020;79:1400-1413.
Cohen S, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 237. 57
WHO VigiBase: Updated
Citation
Thromboembolic Safety Profile of Tofacitinib and Baricitinib

• Global database of individual case safety

Population Characteristics
reports (2012-2019)
Tofacitinib Baricitinib
– Europe and United States (n=40,017) (n=2138)
Baseline 28 16
• Events of interest Age >65 years (%)

– DVT Female (%) 79 81

Region reporting (%)
– PT/PE USA 80 0
Europe 3 97
• Disproportionality analysis Other 17 3
Comedication (%)
– Observed versus expected reporting ratio 1 <1
Contraceptives/estrogens/progestogens 6 3
• Reporting odds ratio and IC025 Antidepressants 4 4
Antithrombotic agents

Thromboembolic events during follow-up

DVT (number) 49 22
DVT: deep vein thrombosis. PT/PE (number) 114 36
PT/PE: pulmonary thrombosis/pulmonary embolism.
Vallejo-Yagüe E, et al. Drug Saf. 2020;43:881-891. 58
WHO VigiBase: Updated
Citation
Thromboembolic Safety Profile of Tofacitinib and Baricitinib

• Results support the recommendation to restrict the use

Disproportionality Analysis of
of tofacitinib in patients at risk of thromboembolism Thromboembolic Events
– Elderly Tofacitinib
Europe United States
– Pre-existing high thromboembolic risk
DVT DVT
• Earlier safety signal detection using PT/PE PT/PE

pharmacovigilance data would have been difficult for PT PT

tofacitinib PE PE

• Potential class effect cannot be ruled out

• Real-world studies for both tofacitinib and baricitinib Baricitinib

Europe
(particularly 4 mg) are needed to fully understand their
DVT
thromboembolic risk
PT/PE
PT

DVT: deep vein thrombosis. PE

PT/PE: pulmonary thrombosis/pulmonary embolism.
Vallejo-Yagüe E, et al. Drug Saf. 2020;43:881-891. 59
Tapering DMARD Therapy in RA:
Key Concepts
• Eligible patients
– Achieve remission state clinical criteria (DAS28 <2.6; DAS44 <1.6; SDAI <3.3; CDAI <2.8)

– Sustained remission for ≥6 months (preferably several visits with continuous state being the goal)

– Stable DMARD treatment over 6 months (ie, type and dose)

– Glucocorticoids not needed to maintain remission state

• Factors associated with higher chance to achieve drug-free remission

– ACPA negative
– Absence of ultrasound synovitis and/or normal serum markers of inflammation

• Mode of DMARD tapering/withdrawal

– Gradual withdrawal with an initial dose tapering phase may be preferable over immediate withdrawal

• Monitoring and relapse management

– Regular monitoring needs to be scheduled to detect early relapses

– Instruct patients on the risks of relapse as well as the way to manage them

– Reintroduction of the former DMARD regimen recaptures remission in virtually all patients relapsing

Schett G, et al. Ann Rheum Dis. 2016;75:1428-1437. 60

Meta-Analysis:
Withdrawal or Tapering Biologics in RA

Withdrawal Meta-Analysis Tapering Meta-Analysis

• 6 randomized, controlled trials (n=1927) • 5 randomized, controlled trials (n=771)
– Low disease activity or in remission – Low disease activity or in remission
– OPTIMA, PRESERVE, PRIZE, DOSERA, ADMIRE,
– DOSERA, PRESERVE, AGREE, KABUKI
POET
• Over 9 to 12 months, continuing biologics (versus • Over 6 to 18 months, no difference between
withdrawing) tapering (versus continuing) in the incidence of
– Increased the probability of – Disease relapse, number of serious adverse events,
withdrawals due to lack of efficacy or toxicity, efficacy
• Low disease activity by 34% (RR: 0.66 [95% CI 0.51-0.84])
outcomes (ACR outcomes, DAS28, CRP, ESR, HAQ,
• Remission by 43% (RR: 0.57 [95% CI 0.44-0.74]) pain visual analogue scale, swollen or tender joint
– Lowered the risk of radiographic progression by 9% counts, progression erosion or joint space narrowing
(RR 0.91 [95% CI 0.85-0.98]) scores)
– No difference in serious adverse event, serious
infection, malignancy, and improved ACR scores of
tender and swollen joints
Galvao TF, et al. Clin Rheumatol. 2016;35:1659-1668.
Jiang M, et al. Clin Exp Rheumatol. 2017;35:152-160. 61
ARTIC-REWIND: Outcomes at Month 12 With Tapering of Slide New
TNF Inhibitors in RA Patients With Sustained Clinical Remission

• Open-label, non-inferiority trial (margin: 20%) of patients

with sustained remission ≥12 months (DAS28) on stable Outcomes at Month 12
TNF inhibitor therapy Continue Half-Dose
– Randomized to continue stable TNF inhibitor therapy or half- TNF Inhibitor TNF Inhibitor
dose TNF inhibitor therapy for 4 months, then withdrawal (n=45) (n=47)

• Primary outcome Experienced a flare (%) 5 63

Remained in DAS remission (%) 80 82
– Preventing flares* with continuing stable TNF inhibitor was
superior to half-dose TNF inhibitor (treatment difference: No progression of radiographic 90 81
57.9% (95% CI 42, 74) joint damage (%)
• Similar proportion of patients remained in remission Safety (%)
Discontinuations due to 2 2
• Continuing stable TNF inhibitor therapy had less frequent adverse events
radiographic joint damage progression (treatment Serious adverse events 4 6
difference: -9% [95% CI -24, 6]) Serious infection 0 2
Cancer 0 0
• Results support the continued use of stable TNF inhibitor Death 0 0
therapy for this patient population
*Flare: DAS28 >1.6 + ≥2 swollen joints (of 44) + change in DAS28 >0.6, or both patient/physician
agree that a clinically significant flare had occurred.
Lillegraven S, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 2010. 62
Tapering of JAK Inhibitors in RA Patients With
Low Disease Activity or Remission

• Ongoing, 10-year extension study (RA-BEYOND)

Preliminary Outcomes (week 48)
– Sustained disease control with baricitinib + MTX
Reduce to Continue
– Continue baricitinib 4 mg or reduce dose to 2 mg daily 2 mg 4 mg
Low disease activity (%) 67 80
• Preliminary results with tapering
Remission (%) 33 40
– Lower LDA, remission, and non-serious infection rates
Non-serious infections (%) 25 31
– Higher relapse and rescue rates
Relapse (%) 37 23
• Among those who lost response, 67% regained LDA or
remission within 24 weeks after rescue with 4 mg daily Rescue (%) 18 10
• Further study is needed to determine the risks and
benefits of tapering Janus kinase inhibitors in patients
with RA who are in a sustained, deep RA remission,
and on combination therapy with traditional DMARD

Singh JA. Ann Rheum Dis. 2019;78:153-154.

Takeuchi T, et al. Ann Rheum Dis. 2019;78:171-178. 63
 New
SEAM-RA: Maintenance of Remission After Withdrawal of Etanercept or
Slide
MTX Following Sustained Remission on Combination Therapy

Phase 3
Double-blind
Etanercept 50 mg sc qw (MTX withdrawal)
SDAI ≤3.3 at screening
(n=101)
“Very good disease control” for ≥6 months
(per investigator) on etanercept + MTX MTX 10-25 mg qw (etanercept withdrawal)
Prednisone ≤5 mg or equivalent allowed (n=101)

Etanercept 50 mg sc qw + MTX 10-25 mg qw (n=51)

Week 0 12 24 48

Rescue Therapy*
Etanercept 50 mg sc qw + Primary Endpoint
MTX 10-25 mg qw SDAI remission
(≤3.3)

*Rescue therapy:
SDAI >11 at any time or SDAI >3.3 and ≤11 on 3 separate visits, or SDAI >3.3 and ≤11
at
2 consecutive visits ≥2 weeks apart.
Baseline characteristics:
Duration of RA: 10-11 years.
Female: 76%.
SDAI remission: 94%. 64
Curtis JR, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 939.
SEAM-RA: New
Slide
Outcomes at Week 48

• Maintained SDAI remission

SDAI Remission Rates
– Significantly more patients on etanercept or 100
*P<0.01 versus MTX monotherapy
combination therapy versus MTX monotherapy
– No difference between etanercept monotherapy 80
and combination arms

Patients (%)
• Time to disease worsening was shorter with 60
53%*
50%*
MTX monotherapy (198 days; P<0.001)
– Versus etanercept monotherapy: 253 days 40
29%
– Versus combination therapy: 336 days
20
• Rescue therapy
– Most patients recaptured SDAI remission (71%- 0
Etanercept MTX Etanercept
80%) or low disease activity (75%-96%) Monotherapy Monotherapy + MTX
(n=101) (n=101) (n=51)

Curtis JR, et al. Arthritis Rheumatol. 2020;72(suppl 10). Abstract 939. 65

CME/CNE/CPE Credit

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