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Management of Psoriatic ArthritisAlexis Ogdie, MD MSCE

Assistant Professor of Medicine and Epidemiology

Director, Penn Psoriatic Arthritis Clinic

Division of Rheumatology

Center for Clinical Epidemiology and Biostatistics

Perelman School of Medicine

University of Pennsylvania

Disclosures

• Consulting: Amgen, Abbvie, BMS, Celgene, Lilly, Novartis, Pfizer, Takeda

• Grants: NIH/NIAMS, RRF, Novartis, Pfizer

• I am a member of the ACR/NPF treatment guidelines team – what I say today is separate from that project and doesn’t reflect that work.

Objectives

• Consider the broader context of disease in management of PsA

• Discuss treatment strategies

• Examine available therapies for PsA, their mechanisms of action, and potential benefits and risks

PsA: A heterogeneous disease

Physical Function and DisabilityFamily Role

Fatigue

Emotional Wellbeing Poor Sleep

Social ParticipationWork Productivity

Orbai et al. Ann Rheum Dis 2017

PsA: A heterogeneous disease Less than 30% of patients with PsA reach remission by any definition

Michelson et al, J Rheumatol 2017

https://secure.www.upenn.edu/webservices/logos/penn_fulllogo.eps.ziphttps://secure.www.upenn.edu/webservices/logos/penn_fulllogo.eps.zip

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Treating PsA = Treating the Whole PatientMSK

DiseaseSkin and Nail

Disease

Treatment Burden

Concomitant Conditions

Work

Family and Friends

Emotionalwellbeing

Fatigue

Sleep

Exercise and muscle balance

Diet

Primary CareScreening for CVD, Diabetes, osteoporosis, IBD, Uveitis, Skin Cancer, etc

Therapy, Psychiatry, Occupational therapy

Physical therapy

Nutritionist

Sleep physician or Sleep psychologist

Dermatologist

Specialty Pharmacist

ClipArt from: https://www.canstockphoto.co.uk/images-photos/3d-character-success_3.html

What do you need to know before choosing a therapy?• Disease manifestations

• Concomitant Conditions • “Extra-articular” manifestations and comorbidities

• Prior therapies• Primary failure vs secondary failure

• Patient preferences

• The target

GRAPPA Guidelines (2015)

Peripheral Arthritis

Axial Disease

Enthesitis Dactylitis SkinNail

Disease

Coates et al, Arthritis Rheum 2016

PsA is associated with several concomitant conditions, particularly metabolic disease

Ogdie A, et al. Curr Opin Rheumatol. 2015

PsA

Cardiovascular Disease

Diabetes

Fatty Liver DiseaseDepression and Anxiety

Inflammatory Bowel Disease

Eye Disease Obesity

Treat to Target

Select Target

Objectively Monitor Disease

Modify treatment to get to target

Follow up on change

Primary target: Remission

Alternative target: LDA

Coates et al. Lancet 2016Smolen et al. Ann Rheum Dis 2017

Treatment Targets in PsA• Minimal Disease Activity

(MDA) defined as 5/7 of the following:• Tender joint count ≤ 1

• Swollen joint count ≤ 1

• PASI ≤ 1 or BSA ≤ 3

• Patient pain VAS ≤15

• Patient global activity VAS ≤ 20

• HAQ ≤ 0.5

• Tender entheseal points ≤ 1

• Disease activity in PsA(DAPSA):

– Tender joint count +

– Swollen joint count +

– Patient pain (1-10) +

– Patient global activity (1-10) +

– CRP

Coates et al. Lancet 2016Smolen et al. Ann Rheum Dis 2017

Coates & Helliwell. Curr Rheum Reports 2015Coates et al. Arthritis Rheum 2017

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The Tight Control in Psoriatic Arthritis (TiCOPA) trial

Coates et al. Lancet 2016

However, must balance increased adverse events

with better efficacy

62 59

44

33

0

10

20

30

40

50

60

70

ACR20 PASI75

Tight Control Standard

Therapies for PsA

Overview of disease pathophysiology

Lories, R. Nature Med. 2012; 18(7):1018

Microbiome

HLA-B27

Biomechanical Stress/Trauma

Infection

SpA Treatment Toolbox

Acupuncture

Occupational therapy

Exercise

Physical therapy

Methotrexate

Leflunomide

Glucocorticoids

NSAIDs

Infliximab

Adalimumab

Etanercept

Golimumab

CertulizimabSocial Support

Sulfasalazine

Local Glucocorticoid Injections

Patient Education

Ustekinimab (IL12/23i)

Omega-3-FA

Apremilast (PDE4i)

CyclosporineWeight Loss

Oral Small Molecules

TNF alpha inhibitors

Adjunct Therapy

In Development/Not Approved

New MOA therapies

Dietary Changes?

Talk Therapy

*Limited evidence

Ixekizumab (IL17i)

Tofacitinb (JAK3)

Brodalumab (IL17R)

Secukinumab (IL17i)

=option for spondylitis

Guselkumab (IL23i)

Tildrakizumab (IL23i)

Rizankizumab (IL23i)

Abatacept (CTLA4 Ig)

PsA: A heterogenous disease

But most clinical trial outcomes are focused on the joints . . . .

Clinical Trial Outcomes in PsA• ACR20 – 20% improvement in tender and swollen joint counts plus

20% in at least three of the following• Health Assessment Questionnaire• Patient pain assessment• Patient global assessment• Physician global assessment• Acute Phase Response: C-reactive protein

• PASI75 – 75% improvement in PASI (Psoriasis Area and Severity Index) score (range 0-72)• Head, Trunk, Arms, Legs• %BSA in each area, Erythema, Induration, Desquamation• Weighted score

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Overall limited data for the oral small molecules(“traditional DMARDs”)

• In clinical practice, they do help

• Inexpensive

• Around for a long time

• Really a lack of data; not many studies and studies use relatively low doses

• However, TiCOPA may suggest that we’re just not aggressive enough?

• Existing data does not support a “disease modifying” effect

• MTX helps psoriasis but not SSA; LEF a little but not much

• A major role may be in suppressing antibody formation and prolonging the life of the biologic

Methotrexate in PsA (MIPA) Trial

Kingsley et al. Rheumatology 2012; 51: 1368-77

Target dose of methotrexate = 15 mg weekly

0

2

4

6

8

10

MTX Placebo

Swollen Joints

0

2

4

6

8

10

12

14

16

0 3 6

Tender Joints

Months

0

1

2

3

4

Baseline Follow up

OR (95%CI) p-value

PsARC 1.77 (0.97-3.23) 0.60

ACR20 2.00 (0.65-6.22) 0.23

DAS28 Response 1.70 (0.90-3.17) 0.10

PASI

0

10

20

30

40

50

MTX Placebo

Physician Global

0

10

20

30

40

50

60

Patient Global

MTX

Placebo

Liver disease

Ogdie A, et al. J Invest Derm. 2018

0

1

2

3

4

5

6

Haz

ard

rat

ios

Mild psoriasis

Severepsoriasis

PsA, no DMARD

RA,no DMARD

RA, DMARD

PsA, DMARD

Any liver diseaseCirrhosisNAFLD

TNF inhibitors

Adalimumab & Golimumab Fully human monoclonal anti-TNF antibodies

Human IgG1 Fc

Human variable region Mouse

variable region

Human IgG1 Fc

InfliximabChimeric human (75%)/mouse

(25%) monoclonal anti-TNF antibody

Extracellular domain of

human TNFR2

Human IgG1 Fc

EtanerceptFusion protein

Humanized variable region

PEG

Certolizumab pegolPEGylated Fab1 fragment

Mantravadi et al. Expert Rev Clin Pharmacol 2017

Differentiating Among TNFi:

• Uveitis/Crohn’s/UC• Severity of Psoriasis• Mode (IV vs SQ)• Dosing Intervals

• Insurance Coverage…

To use combination therapy or not?

Apremilast, a phosphodiesterase 4 inhibitor

PDE4

Degradation of cAMP

PKA

NF-B

CREB

ATF-1

Increases inflammatory cytokines: TNF, IFNɣ, IL12, IL23, IL17, IL22

-

--

PDE4

Accumulation of cAMP

PKA

NF-B

CREB

ATF-1

Decreases inflammatory cytokines: TNF, IFNɣ, IL12, IL23, IL17, IL22

- IL-12 receptor IL-23 receptor

TH1 cell signaling TH17 cell signaling

Ustekinumab: p40 subunit, IL12/23 inhibitor

p40 p40p35 p19

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IL17RA IL17RCIL17RA IL17RAIL17RCIL17RC

IL-17A/ IL-17FIL-17FIL-17 A

Anti-IL17Anti-IL17

Anti-IL17RA

IL17 inhibitorsSecukinumab (IL17Ai)

Ixekizumab (IL17Ai)

Brodalumab (IL17RAi)

Tofacitinib

Winthrop. Nature Rev Rheum 2017

Abatacept

Ruderman and Pope Nat Rev Review 2006

Drugs in Development

• Brodalumab (approved for psoriasis)

• Guselkumab (approved for psoriasis)

• Tildrakizumab (approved for psoriasis)

• Rizankizumab (Phase II in PsA complete, Phase III in PsO complete)

• Upadacitinib (phase II)

IL-12 receptor IL-23 receptor

TH1 cell signaling TH17 cell signaling

IL23 Inhibition

p40 p40p35 p19

Guselkumab Phase II for PsA(approved for psoriasis in 2017)

58

78.6

18.412.5

0

10

20

30

40

50

60

70

80

90

ACR20 PASI75

GUS

Placebo

Deodhar et al. ACR Annual Meeting Abstract 4L VOYAGE I Trial: Blauvelt et al. JAAD 2017

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Conclusions• Key considerations in therapy selection:

• Level of disease activity: skin and MSK severity • Disease manifestations• Comorbidities• Patient preference

• Treat to Target • Broader concept than using MDA – just use SOMETHING!

• Many new therapies in PsA and more therapies to come!

• One prescription isn’t going to solve all of the problems• Consider the broader context and impact of the patient’s disease in designing

a management plan.

Acknowledgements

• Kat Bush and Santhi Mantravadi

• PARC Team: Jose Scher, MD, Souyma Reddy, MD, Elaine Husni, MD MPH, Jessica Walsh, MD MBA

• Penn Collaborators: Joel Gelfand, MD MSCE, Andrea Troxel, ScD, Alisa Stephens-Shields, PhD, Joshua Baker, MD MSCE

• OMERACT: Ana-Maria Orbai, MD, Laura Coates, MD, Dafna Gladman, MD, Vibeke Strand, MD, Philip Mease, MD

• Corrona Investigators: Lynn Palmer, PhD Jeff Curtis, MD, MS, MPH, Arthur Kavanaugh, MD, Dan Solomon, MD, MPH, Philip Mease, MD, Joel Kremer, MD, Jeff Greenberg MD

Collaborators Funding