New Goals of Therapy for Psoriatic and Rheumatoid ...€¦ · •Review current guidelines for RA...

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

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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


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ACR/NPF Guideline for Treatment of PsAActive PsA Despite TNFi Biologic


ACR/NPF Guideline for Treatment of PsAActive PsA Despite IL-17i or IL12/23i Monotherapy


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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‐


Enthesitis

Corticosteroid in

jections as in

dicated

NSAIDs

DMARDs (MTX, LEF,

SSZ) or PDE4i

Biologics (TNFi,

IL‐12/23i)



Dactylitis

Biologics (TNFi,

IL‐12/23i, IL‐17i) or PDE4i

Topical or procedura

l or DMARDs (CSA, LEF, MTX,

acitretin)



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.

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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

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Anti-TNFα• Etanercept• Adalimumab• Infliximab• Golimumab• Certolizumab Nonpharmacologic

measures• PT and OT• Obesity control• Depression treatment• Cardiovascular





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



Anti-TNFα• Etanercept• Adalimumab• Infliximab• Golimumab• Certolizumab

Nonpharmacologic measures• PT and OT• Obesity control• Depression treatment• Cardiovascular





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

% %

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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.

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Anti-TNFα• Etanercept• Adalimumab• Infliximab• Golimumab• Certolizumab

Nonpharmacologic measures• PT and OT• Obesity control• Depression treatment• Cardiovascular





Rheumatoid Arthritis: Treatment Options

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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.

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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


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


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.


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.

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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.

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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

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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

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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!

New Goals of Therapy for Psoriatic and Rheumatoid ...€¦ · •Review current guidelines for RA...

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