Neil McHugh Royal National Hospital for Rheumatic Diseases University of Bath

Transcription

1 Psoriatic arthritis Neil McHugh Royal National Hospital for Rheumatic Diseases University of Bath

2 The Spondyloarthropathies Axial Spondyloarthropathy Peripheral joint arthritis Features Spondylitis Uveitis Enthesitis Psoriasis IBD Familial B27 related Th17/IL23 Nonradiographic SPA Ankylosing Spondylitis Psoriatic arthritis Reactive arthritis Undifferentiated SPA Enteropathic arthritis

3 Psoriasis and Arthritis V Wright Ann Rheum Dis 1956, 15, 348 Topographical association between nail disease and DIPJ involvement This arthritis was less severe than rheumatoid arthritis, and was characterized by distal interphalangeal joint involvement, erosion of the terminal phalanges, and a greater incidence of sacro-iliac joint changes.

4 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

5 Diagnosis of psoriatic arthritis

6 Moll and Wright subgroups of psoriatic arthritis Predominantly DIP Disease Arthritis Mutilans Polyarthritis Oligoarthritis Spondylitis Seminar Arthritis Rheum 1973

7 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 Arthritis and Rheum; 54,

8 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

9 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

10 Radiographic and MRI features of psoriatic arthritis Tillett and McHugh Oxford Textbook PsA 2017 McGonagle and Tan Clin Exp Rheum 2015

11 Time interval from first psoriasis record to first PsA record comparing CPRD to Bath Psoriatic arthritis cohort 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

12 Risk factors for arthritis in psoriasis Life style Clinical Imaging Genetic Biomarkers Other Biomarkers Obesity, smoking Nail psoriasis, severity or pattern of psoriasis Ultrasound evidence of enthesitis HLA-B27, IL13, PTPN22 DC-STAMP. hscrp, MMP-3, DKK-1, M-CSF, CPII:C2C

13 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 PsA (n=1016) RA (n=1016) Symptoms to GP presentation GP presentation to referral GP presentation to diagnosis Symptoms to diagnosis Adjusted for age, sex, ethnicity and deprivation index; P<0.02 for all between-group comparisons Holland et al EULAR 2017

14 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

15 How important is detection of early psoriatic arthritis? Recent meta-analysis suggest between % prevalence of undiagnosed PsA in dermatology clinics 1 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 healthcare 2 1 Vilani et al JAAD Lebwohl AJCD 2015

16 Assessment of psoriatic arthritis

17 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 scores No worsening in any criteria

18 Domains of psoriatic disease

19 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

20 ACR 20 PsARC PASI 75 CPDAI PASDAS AMDF DAPSA Sharp score Mortality ACTIVITY Disease Severity* Reversible 66/68 joint score BASDAI PASI score NAPSI Enthesitis score HAQ ASQOL DLQI SF36 EQ5D WPAI Patient reported outcomes Damage Musculoskeletal Psychosocial Cardiovascular Irreversible Impact of Disease *Total effect of disease on organ function

21 Do we have the correct outcome measures for psoriatic arthritis?

22 The EULAR Psoriatic Arthritis Impact of Disease Domain od Health Relative importance in the PSAID-12 score for clinical practice Pain Fatigue Skin problems Work and/or leisure activities Functional capacity Discomfort Sleep disturbance Coping Anxiety Embarrassment and/or shame 5 N/A Social participation 5 N/A Depression 5 N/A Relative importance in the PSAID-9 score for clinical trials Gossec et al 2015 Ann Rheum Dis

23 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, Musaab Elmamoun, 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 Revised 2016 OMERACT core set domains for psoriatic arthritis Ann Rheum Dis 2017

24 Treatment and guidelines

25 Advancing treatments for psoriatic arthritis PsA described as a clinical entity c.1960s Early treatments: NSAIDs, corticosteroids Methotrexate, sulfasalazine etc RA csdmards s etanercept The first biological therapy: TNFi 4 infliximab, adalimumab golimumab More TNFi 2009 secukinumab, ustekinumab, apremilast Authorisations for therapies with alternative MoAs certolizumab pegol brodalumab, tofacitinib, guselkumab, clazakizumab, ixekizumab, ABT-122 More targets and more options 2016 and The Future

26 Advances in the treatment of psoriatic arthritis TNF inhibition Other biologicals IL12/23 IL17 Small molecules PDE4i Treatment strategies

27 Efficacy of traditional DMARDs vs anti-tnf LFN:. Peter Kaltwasser, et al., ; CSA: Salvarani et al; SSZ: Salvarani et al; MTX: Kinsgley et al.

28 Anti-TNF treatments: ACR responses at 12/14 weeks Trial n ACR20% ACR50% ACR70% Rx P Rx P Rx P Adalimumab Certolizumab Etanercept Golimumab Infliximab 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

29 Predictors of response to anti-tnf Positive predictors Male gender High CRP Younger age Concomitant methotrexate Negative predictors Smoking Obesity High HAQ-DI

30 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

31 Advances in the treatment of psoriatic arthritis TNF inhibition Other biologicals IL12/23 IL17 Small molecules PDE4i Treatment strategies

32 IL-12 and IL-23 cytokines TNF inhibition Other biologicals IL12/23 IL17 Small molecules PDE4i Treatment strategies Teng et al Nature Med 2015:21:719

33 IL12 and IL23 as targets for therapy Patel DD and Kuchroo VK Immunity Dec 2015

34 Indications for Ustekinumab Recommended by NICE as a possible treatment, alone or with methotrexate, for adults with active psoriatic arthritis, if TNFi contraindicated 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?)

35 IL23R resident T cells present at the enthesis Sherlock et al Nature Med 2012 Lories RJ & IMcInnes IB Nature Medicine 2012

36 Advances in the treatment of psoriatic arthritis TNF inhibition Other biologicals IL12/23 IL17 Small molecules PDE4i Treatment strategies

37 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

38 IL-17 isoforms as targets for treatment Patel DD and Kuchroo VK Immunity Dec 2015

39 Apremilast: Mechanism of action TNF inhibition Other biologicals IL12/23 IL17 Small molecules PDE4i Treatment strategies Busa S & Kavanaugh A Expert Opin. Drug Saf 2015

40 Summary of recent findings of new agents N ACR20 wk16 ACR20 wk24 PASI75 wk24 Delta HAQ Rx P Rx P Rx P Rx P PSUMMIT 1 UST 45mg UST 90mg PSUMMIT 2 UST 45mg UST 90 mg PALACE 1 APREM 30mg bd PALACE 2 APREM 30mg bd PALACE 3 APREM 30mg bd NA PALACE 4 APREM 30mg bd FUTURE 1 SECU 150 mg FUTURE 2 SECU 150 mg

41 Advances in the treatment of psoriatic arthritis TNF inhibition Other biologicals IL12/23 IL17 Small molecules PDE4i Treatment strategies

42 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 December 19; 386(10012):

43 A treat-to-target strategy has effectiveness in PsA and 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 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: Coates L. C, et al. Arthritis Rheum May;68(5): Gossec L, et al. Ann Rheum Dis Mar;75(3):

44 2016 EULAR guidelines for psoriatic arthritis: management of peripheral joint disease Gossec et al Nat Rev Rheum 2016

45 2016 EULAR guidelines for psoriatic arthritis: management of predominant entheseal disease Gossec et al Nat Rev Rheum 2016

46 2016 EULAR guidelines for psoriatic arthritis: management of predominant axial disease Gossec et al Nat Rev Rheum 2016

47 Potential therapies to inhibit osteolysis and new bone formation 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 vs

48 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