1
New Goals of Therapy for Psoriatic and Rheumatoid Arthritis:Managing Comorbidities, Preserving Joints, and Pursuing Remission with Biologics
A Virtual Reality Tour
This activity is supported by aneducational grant from Lilly.
Faculty
Jon T. Giles, MD, MPH
Associate Professor of Medicine
Division of Rheumatology
Columbia University College of Physicians and Surgeons
New York, NY
2
Disclosures
• Dr. Giles is a consultant for Lilly, Genentech, Horizon, BMS, UCB, Ironwood, and Abbvie. He also provided grant research for Pfizer.
• Several of the therapies reviewed in this presentation may involve off-label use of medications.
Learning Objectives
• Assess the pathophysiologic differences and similarities between PsA and RA
• Review current guidelines for RA and PsA to drive management decisions and treatment choice
• Review the current pharmacotherapeutic strategies for managing PsA and RA in the rheumatology clinic
• Discuss patient-centric strategies for managing PsA and RA, with a focus on joint preservation, quality of life, and enhanced communication
3
Psoriatic Arthritis: Pathophysiology and Diagnosis
Psoriatic Arthritis: Timing
• Usually skin changes/PsO before arthritis (70%)1
• Subset with skin and joints concurrently (15%)1
• Subset with inflammatory joint symptoms prior to skin changes (15%)1
• Typical lag time of 7–12 years from the onset of psoriasis to diagnosis of PsA1,2
1. Anandarajah AP, Ritchlin CT. Nat Rev Rheumatol. 2009;5:634-641. 2. Mease PJ, Armstrong AW. Drugs. 2014;74:423-441.
PsO = psoriasis; PsA = psoriatic arthritis.
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Audience Response Question
The presence of psoriasis in which of the following areas would be the best predictor of psoriatic arthritis?
A. ScalpB. HandsC. Back/trunkD. Elbows/knees
Predictors of PsA
• Psoriasis at certain body sites– Scalp
– Intergluteal areas (‘inverse/intertriginous’ psoriasis)
• Psoriatic nail lesions– Onycholysis
– Nail pitting
• Younger age of psoriasis onset
• Greater BSA involvement of psoriasis
• Family history of psoriatic arthritis
• All studies had limitations. – Case-control studies, recall bias,
possible misclassification bias (OA)
Wilson FC et al. Arthritis Rheum. 2009;61:233-239. Soltani-Arabshahi R et al. Arch Dermatol. 2010;146:721-726. Tey HL et al. J Dermatol. 2010;37:426-430. Ogdie A, Gelfand JM. Curr Rheumatol Rep. 2015;17:64.
OA = osteoarthritis.BSA = body surface area; OA = osteoarthritis.
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Video 1: PsA Pathophysiology
Examples of Tools Measuring PsA
• Peripheral joints– ACR joint count (TJC, SJC, VAS pain, PtGA,
PGA, HAQ, CRP or ESR)
– PsARC
– DAS
• Spine/axial– BASDAI
– ASAS-N
• Enthesitis– MASES index (Maastricht Ankylosing
Spondylitis Enthesitis Score)– Leeds Enthesitis Index
• Dactylitis– Leeds Dactylitis Index
• QoL– SF36
– PsAQoL– HAQ
– Fatigue: FACIT-F
– Work/WPAI– PsAID
– RAPID3, PtGA of arthritis, etc.
TJC = tender joint count; SJC = swollen joint count; VAS = Visual Analogue Scale; PtGA = patient global assessment of disease activity; PGA = Patient Global disease Activity; HAQ = Health Assessment Questionnaire; PsARC = PsA response criteria; BASDAI = Bath Ankylosing Disease Activity Index; ASAS = Assessment in AS (ankylosing spondylitis); LEI = Leeds Enthesitis Index; LDI = Leeds Dactylitis Index; QoL = quality of life; SF36 = short-form (health survey); FACIT = Functional Assessment of Chronic Illness Therapy-Fatigue; WPAI = Working Productivity and Activity Impairment; PsAID = PsA Impact of Disease.
6
Rheumatoid Arthritis: Pathophysiology and Diagnosis
Rheumatoid Arthritis Pathogenesis
Pianta A et al. Arthritis Rheumatol. 2017;69:964-975. Pelzek AJ et al. Arthritis Rheumatol. 2017;69:1176-1186.
Genetic susceptibility (HLA‐DRB1, etc.)
Adaptive immunity and citrullination (ACPAs) occur due to:• Smoking • Gingivitis
Lymphocyte activationMacrophage activationNeutrophil activationDendritic cell activation
Release of cytokines (TNF/IL‐1/IL‐6/IL‐17)
HLA = human leukocyte antigen; ACPAs = anti-citrullinated protein antibodies.
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Joint capsule
Synovial membrane
Joint space
Cartilage
Synoviocytes
Bone
Osteoclast
Fibroblast‐like synoviocyte
Macrophage
Dendritic cell
T cell
Plasma cell
B cell
Mast cell
Pannus
Neutrophils
Synoviocytes
Normal Joint vs Rheumatoid Synovitis
Modified from Strand V et al. Nat Rev Drug Discov. 2007;6:75-92.
RA Pathobiology
Modified from Smolen JS, Steiner G. Nat Rev Drug Discov. 2003;2;473-488 and Choy EH, Panayi GS. N Engl J Med. 2001;344:907-916. Silverman GJ, Carson DA. Arthritis Res Ther. 2003;5(suppl 4):S1-S6.
APC = antigen-presenting cell; RANKL = receptor activator of nuclear factor-κB ligand.
Synoviocytes
B cell
M?
Immune complexesComplement fixationAttract inflammatory
cell infiltrates
IL-2IFN?TNFIL-17
RANKL
Pannus
Articularcartilage
TNF, IL-1, IL-6,Metalloproteinases (MMPs)
IL-4IL-6
IL-10
IL-6, TNF,IFN?, IL-10,
Lymphotoxin
Plasma cell
Antigen-presentingCells– B cells– Dendritic cells– Macrophages
OsteoclastChondrocytes
Production of MMPs and other effector moleculesMigration of polymorphonuclear cells
Erosion of bone and cartilage
Rheumatoid factor,ACPAs
T cellAPC
8
Negative RF AND negative ACPA 0Low-positive RF OR low-positive ACPA 2
3High-positive RF OR high-positive ACPA
(0–1)
<6 weeks 0≥6 weeks 1
Normal CRP AND normal ESR 0
Abnormal CRP OR abnormal ESR 1
Serology (0–3)
Symptom duration (0–1)
Acute-phase reactants
Swollen/tender joints (0–5)
Patients with a score of ≥6 have “definite” RA.
2010 ACR/EULAR RA Classification Criteria
Aletaha D et al. Arthritis Rheum. 2010;62:2569-2581.
1 large joint 02–10 large joints 11–3 small joints 24–10 small joints 3>10 joints 5
ACR = American College of Rheumatology; EULAR = European League Against Rheumatism; RF = rheumatoid factor; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate.
Psoriatic Arthritis: Treatment Options
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Video 2: PsA Treatments
Not disease-modifying• NSAIDs• Corticosteroid injections• Corticosteroids (oral)
Traditional DMARDs• Methotrexate• Leflunomide• Sulfasalazine• Cyclosporine
Anti-TNFα• Etanercept• Adalimumab• Infliximab• Golimumab• Certolizumab Nonpharmacologic measures
• PT and OT• Obesity control• Depression treatment• Cardiovascular
risk factor mod• Smoking cessation• Microbiome modification
Newer therapies• Ustekinumab (IL12/23)• Secukinumab (IL17A)• Abatacept (CTLA4-Ig)• Apremilast (PDE4)• Ixekizumab (IL17)• Tofacitinib (JAK3)
In development• Brodalumab (IL17R)• Guselkumab (IL23)• Risankizumab (IL23)• Tildrakizumab (IL23)• Upadacitinib (JAK1)
PsA Treatment Options
DMARD = disease-modifying antirheumatic drug; NSAID = nonsteroidal antiinflammatory drug; PT = physical therapy; OT = occupational therapy; CTLA = cytotoxic T lymphocyte antigen; PDE = phosphodiesterase; JAK = Janus kinase.
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ACR/NPF Guideline for Treatment of PsATreatment-Naïve Active PsA
Singh J, et al. Arthritis & Rheumatology. 2019;71(1):5-32.
ACR/NPF Guideline for Treatment of PsAActive PsA Despite Oral Small Molecules
Singh J, et al. Arthritis & Rheumatology. 2019;71(1):5-32.
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ACR/NPF Guideline for Treatment of PsAActive PsA Despite TNFi Biologic
Singh J, et al. Arthritis & Rheumatology. 2019;71(1):5-32.
ACR/NPF Guideline for Treatment of PsAActive PsA Despite IL-17i or IL12/23i Monotherapy
Singh J, et al. Arthritis & Rheumatology. 2019;71(1):5-32.
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GRAPPA Treatment Schema for Active PsA
Coates LC et al. Arthritis Rheumatol. 2016;68:1060-1071.Standard therapeutic route Expedited therapeutic route
*Open-label data available.White text identifies conditional recommendations for drugs without current regulatory approvals or where recommendations are based on abstract data only.GRAPPA = Group for Research and Assessment of Psoriasis and Psoriatic Arthritis; IA = intraarticular; MTX = methotrexate; SSZ = sulfasalazine; LEF = leflunomide; TNFi = TNFinhibitor; SpA = spondyloarthritis; PDE4i = PDE4 inhibitor; CSA = cyclosporine A.
NSA
IDs an
d IA
corticosteroids as in
dicated
DMARDs (MTX, SSZ, LEF), TNFi or PDE4i
Biologics (TNFi, IL‐
12/23i, IL‐17i) or PDE4i
Switch biologic (TNFi, IL‐12/23i or IL‐17i)
Peripheral arthritisPhysiotherapy an
d NSA
IDs
NSAIDs only
TNFi, IL‐17i or IL‐12/23i*
Switch biologic (TNFi, IL‐17i orIL‐12/23i*)
No direct evidence for therapies in axial PsA;recommendations based on axial SpA literature
Axial disease
Physiotherapy
NSAIDs
Biologics (TNFi,
IL‐12/23i,IL‐17i) or PDE4i
Corticosteroid injections; consider on individual basis due to potential for serious side effects; no clear evidence for efficacy
Switch biologic (TNFi, IL‐
12/23i, IL‐17i) or PDE4i
Enthesitis
Corticosteroid in
jections as in
dicated
NSAIDs
DMARDs (MTX, LEF,
SSZ) or PDE4i
Biologics (TNFi,
IL‐12/23i)
Switch biologic (TNFi, IL‐
12/23i, IL‐17i) or PDE4i
Dactylitis
Biologics (TNFi,
IL‐12/23i, IL‐17i) or PDE4i
Topical or procedura
l or DMARDs (CSA, LEF, MTX,
acitretin)
Switch biologic (TNFi, IL‐
12/23i, IL‐17i) or PDE4i
Nails
Topicals as in
dicated
Topicals (keratolytics, steroids, vitamin D analogues, emollients, calcineurin)
Phototherapy or DMARDs (MTX, CSA, acitretin, fumaric acid
esters) or PDE4i
Biologics (TNFi, IL‐12/23i, IL‐17i) or
PDE4i
Switch biologics (TNFi, IL‐12/23i, IL‐17i) or PDE4i
Skin
Which domains are involved?
Assess activity, impact, and progn
ostic factors
Traditional DMARDs
• Methotrexate
• Leflunomide
• Sulfasalazine
• Cyclosporine
POSITIVES• Many years of use• Helpful in some cases• Inexpensive• Prevent antibody generation,
increase retention of TNFαI drugs (MTX)
NEGATIVES• Lack of high-quality data• Suboptimal dosing• Not disease modifying
Kumar P, Banik S. Clin Med Insights Arthritis Musculoskelet Disord. 2013;6:35-43. Parida JR et al. World J Orthop. 2015;6:278-283. Eder L et al. Ann Rheum Dis. 2014;73:1007-1011. Finzel S et al. Ann Rheum Dis. 2013;72:1176-1181.
TNF-αI = TNF-alpha inhibitor.
13
Methotrexate vs. Etanercept: SEAM Trial
65%
36%
61%
36%
51%
23%
0%
10%
20%
30%
40%
50%
60%
70%
ACR20 Minimal Disease Activity
24-Week ACR 20 and MDA Response
ETN/MTX ETN MTX
Mease P, et al. Arthritis Rheumatol. 2019; article in press.
Res
pons
e R
ate
(%)
**
* *
*P<0.05 vs MTX monotherapy
• 24-week double-blind study
• 851 pts randomized to:• MTX 20 mg + placebo weekly
• ETN 50 mg + placebo weekly
• ETN 50 mg + MTX 20 mg weekly
• First high-quality trial of MTX against ETN
• MTX may be a reasonable choice for PsA, albeit less efficacious than ETN
Tight Control in PsA Trial (TiCOPA)
Coates LC et al. Lancet. 2015;386:2489-2498.
MTX+CSA or MTX+LEF
6259
44
33
0
10
20
30
40
50
60
70
ACR20 PASI75
Tight Control Standard
MTX MTX+SSZ
Second TNFα
TNFα
Res
po
nse
at
48 w
eeks
(%
) P=0.0194P=0.0015
14
Not disease-modifying• NSAIDs• Corticosteroid injections• Corticosteroids (oral)
Traditional DMARDs• Methotrexate• Leflunomide• Sulfasalazine• Cyclosporine
Anti-TNFα• Etanercept• Adalimumab• Infliximab• Golimumab• Certolizumab Nonpharmacologic
measures• PT and OT• Obesity control• Depression treatment• Cardiovascular
risk factor mod• Smoking cessation• Microbiome modification
Newer therapies• Ustekinumab (IL12/23)• Secukinumab (IL17A)• Abatacept (CTLA4-Ig)• Apremilast (PDE4)• Ixekizumab (IL17)• Tofacitinib (JAK3)
In development• Brodalumab (IL17R)• Guselkumab (IL23)• Risankizumab (IL23)• Tildrakizumab (IL23)• Upadacitinib (JAK1)
PsA Treatment Options
TNF Inhibitors in PsA
Mease PJ. Rheum Dis Clin North Am. 2015;41:723-738.
59 58 5852
58
1511
148
24
0
10
20
30
40
50
60
70
ETA IFX ADA GOL CER
TNFi Placebo
1115
20 1825
0 1 1 1 30
10
20
30
40
50
60
70
ETA IFX ADA GOL CER
TNFi Placebo
ACR20 ACR70
ETA = etanercept; IFX = infliximab; ADA = adalimumab; GOL = golimumab; CER = certolizumab.
Res
po
nse
(%
)
Res
po
nse
(%
)
15
Not disease-modifying• NSAIDs• Corticosteroid injections• Corticosteroids (oral)
Traditional DMARDs• Methotrexate• Leflunomide• Sulfasalazine• Cyclosporine
Anti-TNFα• Etanercept• Adalimumab• Infliximab• Golimumab• Certolizumab
Nonpharmacologic measures• PT and OT• Obesity control• Depression treatment• Cardiovascular
risk factor mod• Smoking cessation• Microbiome modification
Newer therapies• Ustekinumab (IL12/23)• Secukinumab (IL17A)• Abatacept (CTLA4-Ig)• Apremilast (PDE4)• Ixekizumab (IL17)• Tofacitinib (JAK3)
In development• Brodalumab (IL17R)• Guselkumab (IL23)• Risankizumab (IL23)• Tildrakizumab (IL23)• Upadacitinib (JAK1)
PsA Treatment Options
IL-12 receptor IL-23 receptor
Th1 cell signaling Th17 cell signaling
Ustekinumab: IL-12/23 Inhibitor Targets p40 Subunit
Modified from Koutruba N et al. Ther Clin Risk Manag. 2010;6:123-141.
p40 p40p35 p19
16
Ustekinumab: Efficacy in PsA
McInnes IB et al. Lancet. 2013;382:780-789. Ritchlin C et al. Ann Rheum Dis. 2014;73:990-999.
42.4 43.7
22.8 20.2
0
10
20
30
40
50
60
70
PSUMMIT-1 PSUMMIT-2
ACR20
UST 45mg Placebo
57.251.3
115
0
10
20
30
40
50
60
70
PSUMMIT-1 PSUMMIT-2
PASI 75
UST 45mg Placebo
% %
UST = ustekinumab.
IL-17RA IL17RCIL-17RA IL17RAIL-17RCIL-17RC
IL-17A/IL-17FIL-17FIL-17 A
Anti-IL17
Anti-IL-17
Anti-IL-17RA
SecukinumabIL-17Ai
IxekizumabIL17Ai
BrodalumabIL-17RAi
IL-17 Inhibitors
17
Secukinumab: Efficacy in PsA
Mease PJ et al. N Engl J Med. 2015;373:1329-1339. McInnes IB et al. Lancet. 2015;386:1137-1146.
50.0 51
17.3 15
0
10
20
30
40
50
60
70
FUTURE-1 FUTURE-2
ACR20
SEC 150 Placebo
61.1
48
8.3
16
0
10
20
30
40
50
60
70
FUTURE-1 FUTURE-2
PASI 75
SEC 150 Placebo
SEC = secukinumab.
Res
po
nse
(%
)
Res
po
nse
(%
)
Secukinumab: FUTURE 5
Mease PJ et al. 2017 ACR/ARHP annual meeting: abstract 17L.
LD = with loading dose; mTSS = modified total van der Heijde Sharp score.
88
7983
73
30%
40%
50%
60%
70%
80%
90%
100%
300 mg (LD) 150 mg (LD) 150 mg Placebo
No
wo
rsen
ing
of
join
t d
amag
e o
n m
TS
S (
%)
Reduced progression of joint structural damage
18
Ixekizumab: ACR20/50/70 Response
Mease P, et al. Ann Rheum Dis. 2017;76:79-87. Nash P, et al. Lancet. 2017;389;2317-27.
Res
po
nse
(%
)
IXE = ixekizumab.*P<0.05 vs placebo.
5853
4035
23 22
0
10
20
30
40
50
60
70
Anti-TNF Naïve Anti-TNF Experienced
ACR 20 ACR 50 ACR 70
*
*
*
*
*
IXE 80 mg Q4W; 24-week response
*
IL-17A Inhibitor: Ixekizumab in PsAJoint and Skin Endpoints
Mease PJ et al. Ann Rheum Dis. 2017;76:79-87.
Res
po
nd
ers
(%)
Weeks Weeks Weeks
PASI 75 PASI 90 PASI 100100
242016
PBO IXE Q4W IXE Q2W ADA Q2W
12840
80
60
40
20
0
100
24201612840
80
60
40
20
0
100
24201612840
80
60
40
20
0
Significantly greater PASI responses compared with placebo were observed as early as week 4 for PASI 75 and PASI 90, and week 8 for PASI 100 (p≤0.01)
IXEQ4W IXWQ2W ADAQ2W PBO
mTSS Change from Baseline 0.17 0.08 0.10 0.49
% Pts with Change in mTSS at 24 wks (3 thresholds)
< 0 83.0% 83.5% 91.6% 72.0%
< 0.5 89.0% 94.8% 95.8% 77.4%
< 0.95 94.0% 96.9% 95.8% 83.9%
P<0.05 for all comparisons with placebo; mTSS: modified Total Sharp Score
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Apremilast: Phosphodiesterase 4 Inhibitor
Perez-Aso M et al. Arthritis Res Ther. 2015;17:249.
PDE4
Accumulation of cAMP
NF‐BCREB
ATF‐1
Decreases inflammatory cytokines: TNF, IFNɣ, IL-12, IL-17, IL-22, IL-23
PKA
N
NH
HS OO
O
O
O
OO
cAMP = cyclic adenosine monophosphate; PKA = protein kinase A; NF-κB = nuclear factor-kappa B; ATF-1 = activating transcription factor 1; CREB = cAMP responsive element binding (protein).
Apremilast (APR) for PsA: PALACE Trials
Kavanaugh A et al. Ann Rheum Dis. 2014;73:1020-1026. Cutolo M et al. J Rheumatol. 2016;43:1724-1734. Edwards CJ et al. Ann Rheum Dis. 2016;75:1065-1073.
40
32.1
41
19 18.9 18
0
5
10
15
20
25
30
35
40
45
PALACE1 PALACE2 PALACE3
ACR20
APR 30 BID Placebo
P<0.0001
P=0.006
21 21
4.68
0
5
10
15
20
25
30
35
40
45
PALACE1 PALACE3
PASI 75
APR 30 BID Placebo
P<0.05P=0.004
Ability of Apremilast to prevent joint injury is unproven.
P<0.001
% %
20
Abatacept: Phase III Trial(FDA Approved for PsA on 7-6-2017)
Mease PJ et al. Ann Rheum Dis. 2017;76:1550-1558.
39.4
26.722.3
19.6
0
5
10
15
20
25
30
35
40
45
ACR20 PASI50
%
P<0.001
ABA = abatacept.
Note: The population is possibly more refractory, ie, 60% had prior anti-TNF exposure. Benefits (but not equal responses) were seen regardless of exposure.
ABAPBO
50.5
60.6
51.9
33.3
49.647
23.7
0
10
20
30
40
50
60
70
Tofa-5 Tofa-10 ADA Placebo
Tofacitinib for PsA
Mease PJ et al. Arthritis Rheumatol. 2016;68(suppl 10): abstract 2983. Gladman DD et al. Arthritis Rheumatol. 2016;68(suppl 10): abstract 10L.
42.744.3
39
14.6
21.3
43.2
14
0
5
10
15
20
25
30
35
40
45
50
Tofa-5 Tofa-10 ADA Placebo
ACR20 PASI 75TNF naïve
TNF IR
TNF naïve
TNF IR
% %
IR = inadequate response/responder.
21
Not disease-modifying• NSAIDs• Corticosteroid injections• Corticosteroids (oral)
Traditional DMARDs• Methotrexate• Leflunomide• Sulfasalazine• Cyclosporine
Anti-TNFα• Etanercept• Adalimumab• Infliximab• Golimumab• Certolizumab
Nonpharmacologic measures• PT and OT• Obesity control• Depression treatment• Cardiovascular
risk factor mod• Smoking cessation• Microbiome modification
Newer therapies• Ustekinumab (IL12/23)• Secukinumab (IL17A)• Abatacept (CTLA4-Ig)• Apremilast (PDE4)• Ixekizumab (IL17)• Tofacitinib (JAK3)
PsA Treatment Options
In development• Brodalumab (IL17R)• Guselkumab (IL23)• Risankizumab (IL23)• Tildrakizumab (IL23)• Upadacitinib (JAK1)
Rheumatoid Arthritis: Treatment Options
22
Audience Response Question
In RA, the primary target for treatment should be which of the following?
A. Eventual cessation of medicationB. Clinical remissionC. Use of therapyD. Pain relief
The Principles of Treating to Target
• Treating to target (T2T) by measuring disease activity and adjusting therapy accordingly will result in better patient outcomes.
• The primary target for treatment should be clinical remission, defined as the absence of signs and symptoms of significant inflammatory disease activity.
• In some cases, low disease activity (LDA) may be an acceptable treatment goal, particularly in patients with long-standing established disease.
Smolen JS et al. Ann Rheum Dis. 2010;69:631-637.
23
Oral non-biologicsMethotrexateSulfasalazineHydroxychloroquineLeflunomideAzathioprineCyclosporineTacrolimusCyclophosphamide
Prednisone
Selective cytokine inhibitors
TNF inhibitorsEtanerceptInfliximabAdalimumabCertolizumabGolimumab
IL-1 inhibitorsAnakinra
IL-6 inhibitorsTocilizumabSarilumab
B-cell depletionRituximab
T-cell co-stimulation blockadeAbatacept
JAK inhibitionTofacitinibBaricitinib
Disease-Modifying Pharmacotherapies for RA
Classes of Biologics for RA
Woodrick RS, Ruderman EM. Nat Rev Rheumatol. 2011;7:639-652. Modified from Shuai K, Liu B. Nat Rev Immunol. 2003;3:900-911.
Antigen
MHC
APCB cell
RituximabT‐cell receptor
B‐cell depletionCo‐stimulatory signal
T cell
Abatacept
CD80or CD86
CD28
CD20
Cytokine receptor
Tofacitinib Baricitinib*
JAK inhibitors
JAK JAK
TNF inhibitorsInfliximab
TNFAdalimumab
Etanercept
Certolizumab pegol
Golimumab
Other biologic agentsTocilizumab
IL‐6RIL‐1R
AnakinraIL‐1 IL‐6
IL‐6 signalingIL‐1 signaling
*Baricitinib is not FDA-approved for RA.
TNF
24
2015 ACR RA Treatment Recommendations for Early RA
Singh JA et al. Arthritis Rheumatol. 2016;68:1-26. (Also published in Arthritis Care Res [Hoboken]. 2016;68:1-25.)
DMARD monotherapyb
DMARD monotherapyb
Moderate or high disease
activityb,c
T2Ta
Low disease activity
Moderate or high disease
activity
DMARD-naïve early RA
aTreatment target should ideally be LDA or remission. bConsider using short-term glucocorticoids (GCs) (<3 months) for flares. cConsider adding low-dose GCs (≤10 mg/day of prednisone or equivalent) in patients with moderate or high disease activity when starting DMARDs and in patients with DMARD failure or biologic failure.
2015 ACR RA Treatment Recommendations for Early RA (Continued)
Singh JA et al. Arthritis Rheumatol. 2016;68:1-26. (Also published in Arthritis Care Res [Hoboken]. 2016;68:1-25.)
Combination traditional DMARDsb,c or
TNFi +/– MTXb,c or
non-TNF biologic +/– MTXb,c
See established RA algorithm
T2Ta
Moderate or high disease
activityb,c
aTreatment target should ideally be LDA or remission. bConsider using short-term glucocorticoids (GCs) (<3 months) for flares. cConsider adding low-dose GCs (≤10 mg/day of prednisone or equivalent) in patients with moderate or high disease activity when starting DMARDs and in patients with DMARD failure or biologic failure.
Moderate or high disease
activityb,c
25
100
80
40
20
00
AC
R r
esp
on
se r
ate
(%)
Visit day
60
SC ADASC ABA
64.8%
63.4%ACR20
46.2%
46.0% ACR50
29.2%
26.2%ACR70
85 197 36529 141 253 309
AMPLE Study: Outcomes
Weinblatt ME et al. Arthritis Rheum. 2013;65:28-38.
Estimate of difference (95% CI) between groups was 1.8 (–5.6 to 9.2);intent-to-treat, confirmed with per protocol populations
100
80
40
20
0
ABA SC ADA SC
AC
R20
res
po
nse
rat
e (
%)
64.8 63.4
206/318 208/328
60
Primary endpoint:ABA SC is non-inferior to ADA SC
Comparable efficacy and kinetics of response:ACR scores over 1 year
• No difference in safety• No difference in radiographic progression• ADA was more likely to be discontinued due to adverse events (6.1% vs 3.5%).
SC = subcutaneous.
Last observation carried forward (LOCF) used for TJC and SJC. ESR and patient's global assessment of disease activity VAS, if ESR = 0, then ESR = 1 is substituted into the DAS28 calculation to enable a nonmissing DAS28.
ADACTA DAS28: Mean DAS28 over Time
Gabay C et al. Lancet. 2013;381:1541-1550.
8
7
6
4
2
1
0
DA
S28 5
3
Baseline 4 8 12 16 20 24
Week
TZC 8 mg/kg (IV) + PBO (SC) (N =163)ADT 40 mg (SC) + PBO (IV) (N = 162)
Head-to-head comparison
26
γc family
IL-2, etc.
GH, Epo,
GM-CSFIL-6
family
IL-12,
IL-23INF-γ
Tofacitinib + + +Baricitinib + + + + +
• JAK-independent cytokine signaling: IL-1, IL-17, IL-18, TGF-β, TNF• Tofacitinib in vitro selectivity JAK3, JAK1>JAK2>>Tyk2• Baricitinib in vitro selectivity JAK1, JAK2 >Tyk2>>JAK3
JAK Inhibitors and Signaling by Type I/II Cytokine Receptors (Tofacitinib and Baricitinib)
Furumoto Y, Gadina M. BioDrugs. 2013;27:431-438.
TYK = tyrosine kinase; GH = growth hormone; Epo = erythropoietin; GM-CSF = granulocyte macrophage colony-stimulating factor.
ORAL STANDARD: Outcomes
van Vollenhoven RF et al. N Engl J Med. 2012;367:508-519.
DAS28-4 (ESR) at month 6
11/177 13/178
16
12
8
4
0
INR (without advancement penalty)
6.2 7.3
HAQ-DI improvementat month 3
–0.8
Placebo
ADA 40 mgTFA 5 mg
1/92DA
S28
-4(E
SR
) <
2.6
(% o
f p
atie
nts
) 16
12
8
4
0
INR (with advancement penalty)
6.2 6.7
11/177 12/178
1.1
Ch
ang
e in
HA
Q-D
I sc
ore
fro
m b
asel
ine
(po
ints
)
–0.24
–0.55–0.49
0.0
–0.2
–0.4
–0.6
Head-to-head comparison
TFA = tofacitinib; INR = imputation of no response.
27
RA-BEAM: Efficacy
Taylor PC et al. Arthritis Rheumatol. 2015;67(suppl 10):abstract 2L.
PBOBaricitinib 4 mgADA
Week 12 Week 24
Pat
ien
ts (
NR
I)(%
)
***P≤0.001, **P≤0.01, *P≤0.05 vs placebo; ++P≤0.01; +P≤0.05 vs adalimumab.
ACR20 ACR50 ACR70 ACR20 ACR50 ACR70
80
60
40
20
0
+***70
+***74
+***30
+***19
++***45
***61
***66
***35
***50 ***
46
***22
***13
5
17
4037
19
8
Non-TNF Options for MTX-IR: Summary
• With MTX– ABA vs ADA is neutral (AMPLE)1
– Phase III—TFA 5 mg BID over ADA (ORAL STANDARD)2
• ACR20 response rates were 51.5% with tofacitinib 5 mg, 47.2% with ADA, and 28.3% with placebo.
• No significant differences in DAS remission
– Phase III—BARI*over ADA (RA-BEAM)3
• Without MTX– TCZ vs ADA favored TCZ (ADACTA)4
• ACR50 of 47.2 vs 27.8%
– Sarilumab* vs ADA favored sarilumab (MONARCH)5
• ACR20/50/70 response rates were 58.4%/29.7%/11.9% for ADA vs 71.7%/45.7%/23.4% for sarilumab (all P≤0.0074).
1. Schiff M et al. Ann Rheum Dis. 2014;73:86-94. 2. van Vollenhoven RF et al. N Engl J Med. 2012;367:508-519. 3. Taylor PC et al. Arthritis Rheumatol. 2015;67(suppl 10):abstract 2L. 4. Gabay C et al. Lancet. 2013;381:1541-1550. 5. Burmester GR et al. Ann Rheum Dis. 2017;76:840-847.
*Baricitinib and sarilumab are not FDA-approved for RA.BID = twice daily; BARI = baricitinib; TCZ = tocilizumab.
28
When a TNFi Fails
Options After TNF Inhibitor Failure (Partial List)
• Triple therapy (TT)– RACAT (ETA ↔ TT [MTX, SSZ, hydroxychloroquine])1
• Second TNF– EXXELLERATE (ADA ↔ CZP in nonresponders)2
– GO-FORWARD (golimumab + MTX superior to MTX)3
– OPPOSITE (numerical trend favoring infliximab over continuing ETA in ETA IR patients)4
• Change MOA– REFLEX (rituximab + MTX superior to MTX)5
– RADIATE (TCZ + MTX superior to MTX)6
– ATTAIN (ABA superior to PBO)7
– ORAL Step (TFA + MTX superior to MTX)8
– BEACON (BARI superior to PBO)9
• Multiple options– French Rotation of anti-TNF Or Change of Class of Biologic (ROC)10
• Note: Use of non-TNFi biologics is NOT limited to TNFi non responders
1. O’Dell JR et al. N Engl J Med. 2013;369:307-318. 2. Smolen JS et al. Lancet. 2016;388:2763-2774. 3. Keystone EC et al. J Rheumatol. 2016;43:298-306. 4. Furst DE et al. Ann Rheum Dis. 2007;66:893-899. 5. Cohen SB et al. Arthritis Rheum. 2006;54:2793-2806. 6. Emery P et al. Ann Rheum Dis. 2008;67:1516-1523. 7. Genovese MC et al. N Engl J Med. 2005;353:1114-1123. 8. Burmester GR et al. Lancet. 2013;381:451-460. 9. Genovese MC et al. N Engl J Med. 2016;374:1243-1252. 10. Gottenberg J et al. Arthritis Rheumatol. 2015;67(suppl 10): abstract 3110.
29
2015 ACR/2016 EULAR GuidelinesKey Principles
• Perform disease activity measurements and functional assessments frequently.
• Simplification of therapy in patients with LDA or remission at the physician’s discretion
• Arbitrary switching based on payer/insurance is not recommended.
• Patients at risk of persistent arthritis should start DMARDs within 3 months, even if classification criteria are not fulfilled.
• Oral GCs can be added at the lowest effective dose and tapered.
• Aim for remission within 3 months.
• Maximize non-pharmacologic interventions (eg, PT/OT, smoking cessation, dental care, weight control, vaccination updates) patient education.
Singh JA et al. Arthritis Rheumatol. 2016;68:1-26. (Also published in Arthritis Care Res [Hoboken]. 2016;68:1-25.). Combe B et al. Ann Rheum Dis. 2017;76:948-959.
Patient Satisfaction
30
Patient Satisfaction
• Patient satisfaction is seldom studied or incorporated into practice guidelines.
• Studies rely on clinician-centered measures to determine treatment adequacy.
• Patient satisfaction remains an important consideration, correlated with: – Patient adherence to therapy – Treatment outcomes
• Satisfaction contributes to responses in HRQoL indices (eg, DLQI, etc.)
Mercy KM et al. JAMA. 2014;312:2676-2677.
HRQoL = health-related QoL; DLQI = Dermatology Life Quality Index.
PsA and Quality of Life
Alten R, et al. Clin Rheumatol. 2019; Article in Press.
• Patients failing immunomodulator therapies had poorer HRQoL vs treatment success:
– SF-36 – EQ-5D-3L – MCS
• Also impaired:– Physical functioning– Activity– Work productivity
31
Extra‐Articular Organ Systems Affected by RA
Brain
Cervical Spine
Lungs
Larynx
Heart and Blood Vessels
Kidneys
OropharynxEyes
Skin
Skeletal Muscle
Spleen/Hematologic
Adipose Tissue
GI system
Peripheral Nerves
Bone
PsA and RA Comorbidities
Sinnathurai P, et al. Intern Med J. 2018;48:1360-8. Haddad A. Rambam Maimonides Med J. 2017;8:e0004. Jeong H, et al. PLoS One. 2017;12:e0176260. Dougados M. Curr Opin Rheumatol. 2016;28:282-8.
• PsA comorbidities include:– Diabetes mellitus, obesity, metabolic syndrome, cardiovascular diseases,
osteoporosis, inflammatory bowel disease, autoimmune eye disease, non-alcoholic fatty liver disease, depression, and fibromyalgia
• RA comorbidities include:– Myocardial infarction, angina, CVD, osteoporosis, pulmonary TB, asthma,
thyroid disease, depression, hepatitis and certain cancers
• Comorbidities impact patient care, management, treatment decisions, quality of life, and mortality.
• Recognize and monitor comorbidities• Understand their effect on patient management to ensure an
optimal outcomes
32
Communication in Practice
• Maintain patient motivation and engagement in care.
• Understand/explore reasons for declines in adherence.
• Set up realistic expectations.
• Take a health-literate approach to prescribing and educating patients.
Building a trusting one-on-one relationship with the patientis essential for long-term management.
Thank You!
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