Psoriatic arthritisNeil McHugh

Royal National Hospital for Rheumatic DiseasesUniversity of Bath

AnkylosingSpondylitis

Psoriatic arthritis

Enteropathicarthritis

Reactivearthritis

• Features• Spondylitis• Uveitis• Enthesitis• Psoriasis• IBD• Familial• B27 related• Th17/IL23

Non-radiographic

SPA

UndifferentiatedSPA

Axial Spondyloarthropathy Peripheral joint arthritis

The Spondyloarthropathies

Topographical association betweennail disease and DIPJ involvement

Psoriasis and ArthritisV WrightAnn Rheum Dis 1956, 15, 348

‘This arthritis was less severe than rheumatoid arthritis, and was characterized by distalinterphalangeal joint involvement, erosion of the terminal phalanges, and a greater incidence of sacro-iliac joint changes.’

Burden of psoriatic arthritis

• Joint damage in 50% within 2 years of disease

• Reduced quality of life similar to rheumatoid arthritis

• Comorbidities – e.g. obesity, cardiovascular disease, uveitis

• One in three unemployed

• High direct health costs (£4832 per patient-year)

Husted Arthritis Rheum 2001

Sokoll J Rheumatol 2001

Lindqvist J Rheumatology 2008

Kane et al Rheumatology 2003

Diagnosis of psoriatic arthritis

Moll and Wright subgroups of psoriatic arthritis

Predominantly DIP Disease

Oligoarthritis

Polyarthritis

Arthritis Mutilans

Spondylitis

Seminar Arthritis Rheum 1973

The CASPAR criteria

To meet the CASPAR criteria a patient must have an inflammatory articular disease (joint, spine or entheseal) and ≥ 3 points from:

1. Current psoriasis 2 points

or Personal history of psoriasis 1 point

or FH of psoriasis 1 point

2. Current psoriatic nail dystrophy 1 point

3. Negative RF 1 point

4. Current or Rheumatologist confirmed dactylitis 1 point

5. Juxta-articular new bone formation 1 point

Taylor et al 2006. Arthritis and Rheum; 54, 2665-2673

Psoriatic arthritis

• Skin psoriasis affects 2-3% of normal population often with nail disease

• About 30% of individuals with psoriasis develop a distinct form of inflammatory arthritis called psoriatic arthritis

• Estimated 400,000 in England

Differential diagnosis from Rheumatoid arthritis

Features Psoriatic arthritis Rheumatoid arthritis

Number of joints involved 30-50% with oligoarthritis Predominantly polyarthritis

Joint involvement Any joint, including distal interphalangeal joints

Spares distal interphalangeal joints

Enthesitis Typical, clinically present in up to 80% Not typical

Dactylitis Present in 30% Not typical

Axial involvement Axial spondyloarthritis phenotype Erosive cervical disease

Skin/nail disease Psoriasis in 80%, nail disease in 60% Background population prevalance

Serology Usually RhF and ACPA negative Usually RhF and/or ACPA positive

Typical radiographic changes Periosteal new bone formation Erosion and osteopenia

Radiographic and MRI features of psoriatic arthritis

McGonagle and Tan Clin Exp Rheum 2015Tillett and McHugh Oxford Textbook PsA 2017

Clinical Practice Research Datalink• Median interval between psoriasis

and PsA 8 years (excluding synchronous

onset 9 years)

• 60% diagnosed within 10 years

RNHRD PsA Database• Median interval between psoriasis

and PsA 7 years (excluding synchronous

onset 13 years)

• 57% diagnosed within 10 years

Time interval from first psoriasis record to first PsA record

comparing CPRD to Bath Psoriatic arthritis cohort

Risk factors for arthritis in psoriasis

Life style Obesity, smoking

Clinical Nail psoriasis, severity or pattern of psoriasis

Imaging Ultrasound evidence of enthesitis

Genetic Biomarkers

HLA-B27, IL13, PTPN22

Other Biomarkers

DC-STAMP. hsCRP, MMP-3, DKK-1, M-CSF, CPII:C2C

Psoriatic Arthritis is Associated with Diagnostic Delay and Worse Outcome at 3 Months when Compared with Rheumatoid Arthritis: Results from the UK National Audit for Inflammatory Arthritis

Median time to diagnosis in weeks

Holland et al EULAR 2017

PsA (n=1016) RA (n=1016)

Symptoms to GP presentation 8.9 6.6

GP presentation to referral 5.4 4

GP presentation to diagnosis 12.1 9.7

Symptoms to diagnosis 28.6 21.6

Adjusted for age, sex, ethnicity and deprivation index; P<0.02 for all between-group comparisons

Psoriatic Arthritis is Associated with Diagnostic Delay and Worse Outcome at 3 Months when Compared with Rheumatoid Arthritis: Results from the UK National Audit for Inflammatory Arthritis

Holland et al EULAR 2017

How important is detection of early psoriatic arthritis?

• Recent meta-analysis suggest between 10-15 % prevalence of undiagnosed PsA in dermatology clinics1

• Delay in diagnosis may be associated with poor outcome

• Most studies are retrospective and have selection and recall bias

• NICE recommends annual screening for patients in primary care on treatment for psoriasis

• At least 40% people with psoriasis not on treatment or not attending healthcare2

1 Vilani et al JAAD 20152 Lebwohl AJCD 2015

Assessment of psoriatic arthritis

Psoriatic arthritis endpoints used in clinical trials

ACR Response Criteria: 20%, 50%, 70%Tender and swollen joint score (modified for PsA to include DIP and CMC joints)3/5: patient global, physician global, patient pain, HAQ, acute phase reactant (ESR, CRP)

Psoriatic Arthritis Response Criteria (PsARC)*Improvement in at least 2 of 4 criteria, including:

Physician global assessment (0-5)

Patient global assessment (0-5)

Tender joint score (>30%)

Swollen joint score (>30%)

Improvement in at least 1 of 2 joint scoresNo worsening in any criteria

Domains of psoriatic disease

CPDAI (composite psoriatic disease activity index)None (0) Mild (1) Moderate (2) Severe (3)

Peripheral

Arthritis

≤ 4 joints; normal

function (HAQ <0.5)

≤ 4 joints but function

impaired; or > 4 joints,

normal function

> 4 joints and function

impaired

Skin Disease PASI ≤ 10 and DLQI

≤ 10

PASI ≤ 10 but DLQI >10;

or PASI > 10 but DLQI ≤

10

PASI > 10 and DLQI > 10

Enthesitis ≤ 3 sites; normal

function (HAQ <0.5)

≤ 3 sites but function

impaired; or >3 sites but

normal function

>3 sites and function

impaired

Dactylitis ≤ 3 digits; normal

function (HAQ <0.5)

≤ 3 digits but function

impaired; or >3 digits but

normal function

>3 digits and has function

impaired

Spinal Disease BASDAI <4; normal

function (ASQol < 6)

BASDAI >4 but normal

function; BASDAI <4 but

function impaired

BASDAI >4 and function

impaired

ACTIVITY

DamageImpact of

Disease

Disease

Severity*

Reversible

Irreversible

*Total effect of disease on organ function

Musculoskeletal

Psychosocial

Cardiovascular

Patient reported outcomes

HAQ

ASQOL

DLQI

SF36

EQ5D

WPAI

ACR 20

PsARC

PASI 75

CPDAI

PASDAS

AMDF

DAPSA

Sharp score

Mortality

66/68 joint

score

BASDAI

PASI score

NAPSI

Enthesitis score

Do we have the correct outcome measures for psoriatic arthritis?

The EULAR Psoriatic Arthritis Impact of DiseaseDomain od Health Relative importance in the PSAID-12

score for clinical practiceRelative importance in the PSAID-9score for clinical trials

Pain 15 17.4

Fatigue 10 13.1

Skin problems 10 12.1

Work and/or leisure activities 10 11.0

Functional capacity 10 10.7

Discomfort 10 9.8

Sleep disturbance 10 8.9

Coping 5 8.7

Anxiety 5 8.5

Embarrassment and/or shame 5 N/A

Social participation 5 N/A

Depression 5 N/A

Gossec et al 2015 Ann Rheum Dis

Ann Rheum Dis 2017

Revised 2016 OMERACT core set domains for psoriatic arthritis

International patient and physician consensus on a psoriatic arthritis core outcome set for clinical trials

Ana-Maria Orbai, Maarten de Wit, Philip Mease, Judy A Shea, Laure Gossec, Ying Ying Leung, William Tillett, MusaabElmamoun, Kristina Callis Duffin, Willemina Campbell, Robin Christensen, Laura Coates, Emma Dures, Lihi Eder, Oliver FitzGerald, Dafna Gladman, Niti Goel, Suzanne Dolwick Grieb, Sarah Hewlett, Pil Hoejgaard, Umut Kalyoncu, Chris Lindsay, Neil McHugh, Bev Shea, Ingrid Steinkoenig, Vibeke Strand, Alexis Ogdie

Treatment and guidelines

secukinumab,ustekinumab,

apremilast

2015

Authorisations for therapies with alternative MoAs

brodalumab,tofacitinib,

guselkumab,clazakizumab,ixekizumab,

ABT-122

2016 and The Future

More targets and more options

etanercept

The first biological

therapy: TNFi4

2000 2005

infliximab,adalimumab

2009

golimumab

2014

More TNFi

certolizumabpegol

1990s

RA csDMARDs1

Methotrexate,sulfasalazine etc

c.1960s

PsA described as a clinical

entity

Early treatments: NSAIDs,

corticosteroids

Advancing treatments for psoriatic arthritis

Advances in the treatment of psoriatic arthritis

• TNF inhibition

• Other biologicals• IL12/23

• IL17

• Small molecules• PDE4i

• Treatment strategies

Efficacy of traditional DMARDs vs anti-TNF

LFN: . Peter Kaltwasser, et al., ; CSA: Salvarani et al; SSZ: Salvarani et al; MTX: Kinsgley et al.

Anti-TNF treatments: ACR responses at 12/14 weeks

Trial n ACR20% ACR50% ACR70%

Rx P Rx P Rx P

Adalimumab 315 58 14 36 4 20 1

Certolizumab 409 58 24 36 11 25 3

Etanercept 205 59 15 38 4 11 0

Golimumab 405 52 8 32 3.5 18 0.9

Infliximab 200 58 11 36 3 15 1

• Effective for all domains of disease and slow structural damage

• Risk of infection (e.g. mycobacterium)

• Risk of malignancy and safety in pregnancy and heart failure?

Adapted from Mease Rheum Dis Clin N Am 2015

Predictors of response to anti-TNF

• Positive predictors• Male gender

• High CRP

• Younger age

• Concomitant methotrexate

• Negative predictors• Smoking

• Obesity

• High HAQ-DI

Effectiveness of switching anti-TNF-registry data

• South Swedish Arthritis Treatment Group Register

• ACR20 response at 12 weeks falls to 47% for first time switches and and to 22% for second time switches

• Median drug survival time 64 months for first time switches and 14 months for second-time switches

• Higher HAQ predicted premature drug withdrawal

• Results suggest that other therapeutic options should be considered after 2nd course of anti-TNF

Kristensen et al J Rheum 2016:43:81-87

Advances in the treatment of psoriatic arthritis

• TNF inhibition

• Other biologicals• IL12/23

• IL17

• Small molecules• PDE4i

• Treatment strategies

IL-12 and IL-23 cytokines

Teng et al Nature Med 2015:21:719

• TNF inhibition

• Other biologicals• IL12/23

• IL17

• Small molecules• PDE4i

• Treatment strategies

Patel DD and Kuchroo VK Immunity Dec 2015

IL12 and IL23 as targets for therapy

Indications for Ustekinumab

• Recommended by NICE as a possible treatment, alone or with methotrexate, for adults with active psoriatic arthritis, if TNFicontraindicated or failed one or more TNFis

• 90 mg dose at same cost as 45 mg dose for patients > 100 kg

• Stopped after 24 weeks if not working

• Ideal patient• High psoriasis burden

• TNFi refractory, especially primary non-responder

• TNF adverse events ( e.g. lupus-like reaction) or contraindications (recurrent infections?)

Sherlock et al Nature Med 2012Lories RJ & IMcInnes IB Nature Medicine 2012

IL23R resident T cells present at the enthesis

Advances in the treatment of psoriatic arthritis

• TNF inhibition

• Other biologicals• IL12/23

• IL17

• Small molecules• PDE4i

• Treatment strategies

IL-17 as a target for treatment in psoriatic arthritis

• Interleukin-17A producing cells increased in circulation, joints and skin plaques of patients with PsA

• Synovium of PsA enriched with IL-17 producing CD4+ effector memory T cells, CD4-CD8+ T cells and functionally active IL-17RA

Patel DD et al ARD 2013, Raychaudhuri SP et al Mol Cell Biochem 2012, Menon et al Arthritis Rheum 2014

Patel DD and Kuchroo VK Immunity Dec 2015

IL-17 isoforms as targets for treatment

Busa S & Kavanaugh A Expert Opin. Drug Saf 2015

Apremilast: Mechanism of action

• TNF inhibition

• Other biologicals• IL12/23

• IL17

• Small molecules• PDE4i

• Treatment strategies

Summary of recent findings of new agentsN ACR20 wk16 ACR20 wk24 PASI75 wk24 Delta HAQ

Rx P Rx P Rx P Rx P

PSUMMIT 1 UST 45mg 205 42 23 57 11 -0.25 0

UST 90mg 204 50 23 62 11 -0.25 0

PSUMMIT 2 UST 45mg 103 44 20 51 5 -0.13 0

UST 90 mg 105 44 20 56 5 -0.25 0

PALACE 1 APREM 30mg bd 163 36 12 37 13 21 5 -0.24 -0.09

PALACE 2 APREM 30mg bd 162 34 19 22 2.7

PALACE 3 APREM 30mg bd 159 43 19 42 NA 21 8 -0.20 -0.07

PALACE 4 APREM 30mg bd 139 32 17

FUTURE 1 SECU 150 mg 202 50 17 65 8.3 -0.40 -0.17

FUTURE 2 SECU 150 mg 100 52 15 48 16 -0.48 -0.31

Advances in the treatment of psoriatic arthritis

• TNF inhibition

• Other biologicals• IL12/23

• IL17

• Small molecules• PDE4i

• Treatment strategies

• Minimal disease activity (MDA) achieved in tight control arm if 5 of the following criteria are met:

• Tender joint count (0-68): ≤1• Swollen joint count (0-66): ≤1• Patient global activity VAS (0-100): ≤20• Patient pain VAS (0-100): ≤15• HAQ-DI (0-3): ≤0.5• Tender entheseal points (0-13): ≤1• PASI (0-72): ≤1 or BSA(0-100): ≤3%

Lancet. 2015 December 19; 386(10012): 2489–2498.

A treat-to-target strategy has effectiveness in PsAand current guidelines support this approach

• In TICOPA, a tight control strategy leads to better outcomes (although greater incidence of AEs) with more patients at MDA and potential associated cost effectiveness in the long-term.

• 2016 GRAPPA recommendations• An ultimate goal of therapy is to achieve the lowest possible level of disease

activity in all domains…

• The treat-to-target approach has also become the first recommendation in 2016 EULAR guidelines

Coates L. C, et al. Lancet. 2015;386:2489─98Coates L. C, et al. Arthritis Rheum. 2016 May;68(5):1060-71 Gossec L, et al. Ann Rheum Dis. 2016 Mar;75(3):499-510.

2016 EULAR guidelines for psoriatic arthritis: management of peripheral joint disease

Gossec et al Nat Rev Rheum 2016

2016 EULAR guidelines for psoriatic arthritis: management of predominant entheseal disease

Gossec et al Nat Rev Rheum 2016

2016 EULAR guidelines for psoriatic arthritis: management of predominant axial disease

Gossec et al Nat Rev Rheum 2016

• Osteolysis

• Inhibition of• TNFi (etanecept, infliximab, adalimumab,

golimumab, certilizumab)

• IL23 (ustekinumab)

• IL17 (sekukinumab)

• PDE4 (Apremilast

• Jak/Stat inhibitors (tofacitinib)

• Anti-RANKL (denosumab)

• New bone formation• NSAIDs

• Wnt anatagonists

• BNP antagonists

• Anti-IL22

Potential therapies to inhibit osteolysis and new bone formation

vs

Key messages

• Psoriatic arthritis is not uncommon but is frequently undiagnosed

• In addition to skin psoriasis other important risk factors are obesity, nail disease and HLA-B27

• Significant comorbidities include obesity, uveitis, Crohn’s, and cardiovascular disease

• Newer treatments (e.g. anti-TNF, anti-IL23, anti-IL17) are more effective than traditional DMARDS ( e.g. methotrexate) and small molecule inhibitors are becoming available

• Psoriatic arthritis is not a benign disease