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UPDATE ON PSORIATIC ARTHRITIS

UPDATE ON PSORIATIC ARTHRITIS. DR KAREN PONT EK CME EVENT FERNIE 5 OCTOBER 2019. I have no disclosures. Learning objectives. 1. Diverse clinical spectrum of psoriatic arthritis ( PsA ) 2.Implications of PsA 3.New treatment approaches to PsA.

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UPDATE ON PSORIATIC ARTHRITIS

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  1. UPDATE ON PSORIATIC ARTHRITIS DR KAREN PONT EK CME EVENT FERNIE 5 OCTOBER 2019 Footer for Disclaimer Text

  2. I have no disclosures Footer for Disclaimer Text

  3. Learning objectives 1. Diverse clinical spectrum of psoriatic arthritis (PsA) 2.Implications of PsA 3.New treatment approaches to PsA

  4. Psoriatic arthritis is a chronic inflammatory disease PSORIATIC ARTHRITIS • Is a chronic systemic inflammatory disease1 • Results from an uncontrolled immune response2,3 • Involves the skin and joints’ and is closely linked to psoriasis1 • Has a significant negative impact on quality of life4 1. Kavanaugh A, et al. RheumatolTher 2016;DOI 10.1007/s40744-016-0029-z; 2. Schafer P. Biochem Pharmacol 2012;83:1583–1590; 3. Gottlieb A, et al. J Am Acad Dermatol 2008;58:851–864; 4. Salaffi F, et al. Health Qual Life Outcomes 2009;7:25.

  5. Worldwide, the prevalence of psoriatic arthritis is <1%1 but many patients remain undiagnosed2 The prevalence of PsA is ~30% among the psoriasis population2,3 Higher rates among white people than other ethnicities4 Often occurs between the ages of 30 and 50 years5 No gender difference in prevalence5 • Up to 41% of PsA patients among the psoriasis population may be undiagnosed3 1. Liu JT, et al. World J Orthop 2014;5:537–543; 2. Zachariae H. Am J ClinDermatol 2003;4:441–447; 3. Mease PJ, et al. J Am AcadDermatol 2013;69:729–735; 4. Kerr GS, et al. ClinRheumatol 2015;34:1753–1759; 5. Gottlieb A, et al. J Am AcadDermatol 2008;58:851–864.

  6. PsoriaticArthritisAffects PatientswithPsoriasis PrevalenceofPsAinpatientswithPSOinEuropeandNorthAmerica UnitedKingdom2 13.8% Denmark1 42.0% U.S Germany1 34.0% Canada118.0% France1 27.0% Hungary1 38.0% Belgium1 18.0% UnitedStates136.0% Italy2 34.0% Spain3 22.9% Asmanyas~40%ofpatientswithPSOwilldevelopPsA4,5 1. MeasePJ etal.JAmAcadDermatol.2013;69:729–735. 2. CatanosoMetal.Reumatismo.2012;64(2):66–70.3. LopezEstebaranzJLetal.EuJDermatol.2015;25:57–63. 4. MeasePJ andArmstrongAW.Drugs.2014;74(4):423–441. 5. GladmanDDetal.AnnRheumDis. 2005;64Suppl 2:ii14–17.

  7. There are several environmental and genetic triggers for psoriatic arthritis PSORIASIS-RELATED GENETICS ENVIRONMENT • Probable genetic basis: family history of PsA is common in patients1,3 • HLA-B27 alleles increase susceptibility to PsA4 • Genetic loci associated with psoriasis and PsA have been identified (PSORS)5 • Infection(e.g. streptococcal throat infection)1,2 • Joint tissue trauma1 – “deep Koebner effect” • Local stress response1 • Psoriasis involving scalp, intergluteal areas or > 3 affected sites6 • Vaccination for rubella6 1. Chimenti MS, et al. Autoimmun Rev 2013;12:599–606; 2. Psoriatic Arthritis. www.aomed.org. Accessed 16.09.16; 3. AlShobaili HA, et al. Int J Health Sci 2010;4:23–29; 4. FitzGerald, et al. Arthritis Research & Therapy 2015;17:115;5. Capon F, et al. J Invest Derm 1999;112:32–35; 6. Ogdie A and Gelfand J. Arch Derm 2010;146(7):785–788.

  8. Psoriatic arthritis is associated with many comorbidities1 LIFESTYLE • Cardiovascular disease • Type II diabetes • Hypertension • Obesity • Hyperlipidaemia NEUROLOGICALDISORDERS PSYCHIATRIC • Neuropathy • Seizure disorder • Multiple sclerosis • Depression • Anxiety AUTOIMMUNE RESPIRATORY • Thyroid disease • Lupus • Type I diabetes • Asthma • Chronic obstructive lung disease • Sleep apnoea OTHER • Osteoporosis • Liver disease • Cancer • Infection GASTROINTESTINAL • Ulcer • Irritable bowel syndrome 1. Husted J, et al. Arthritis Care Res 2011;63:1729–1735.

  9. Classification, symptoms and clinical presentation

  10. Psoriatic arthritis is part of the spondyloarthritis family1 Psoriatic arthritis Reactive arthritis Ankylosing spondylitis Axial Spondylo-arthritis SPONDYLO -ARTHRITIS Peripheral spondylitis Enteropathic arthritis: associated with CD / UC 1. American College of Rheumatology. Spondyloarthritis (Spondyloarthropathy). https://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Spondylarthritis_(Spondylarthropathy). Accessed 23.01.15.

  11. Patientswith SpAhaveManyOverlappingClinicalFeatures SpAdiseasesmayshareseveralclinicalfeatures,showfamilialclustering,andareassociatedwith HLA-B27positivity1 Extra-articularmanifestations (EAMs) includinguveitis, psoriasisandinflammatory boweldisease(IBD)1,2 Uveitis axSpA3 Psoriasis axSpA3 PsA4 PsA11 15% 7–18% 13% 94% Sacroiliitis axSpA3† IBD axSpA3 Sacroiliitisandspondylitis (inflammationofoneor both sacroiliacjoints)2 PsA12-13** PsA5 86% ~34–78% 5% 4% Dactylitis axSpA3 Peripheral Arthritis PsA14 axSpA3* PsA6–9¥ Peripheralarticular manifestationsincluding peripheralarthritis, enthesitis anddactylitis1,2 5% 16–48% 13% Up to 96% Enthesitis axSpA3 PsA10 13% 35% The prevalenceofEAMsandperipheralarticular manifestationsvariesacrossSpAdiseasesubtypes2 1.GargNetal.BestPractResClinRheumatol.2014;28(5):663–672.7. 2. 3. 4. 5. 6. 12.Battistone MJ etal.SkeletalRadiol. 1999; 28(4):196–201. *Asymmetriclowerlimb arthritis;¥Calculatedfromsymmetricalpolyarthtis,asymmetricalmono-/oligo-arthritis,distalinterphalangealjoint involvement,arthritismutilansandperipheraljoints;†Sacroiliitis onMRI;**Sacroillitisgrade2orhigher. CollantesE etal.Rheumatology.2007;46(8):1309–1315. van den Berg et al.Rheumatology.2013; 52:1492–1499. ChenH andChouC.Curr RheumatolRev. 2008;4:111–14. WilliamsonL etal.J Rheumatol.2004;31:1469–70. Moll JandWrightV.Semin ArthritisRheum.1973;3:55–78. 8.Helliwell PS andTaylor WJ.AnnRheumDis. 2005;64(SupplII):ii3–13.Fernandez-SueiroJ etal.AnnalsRheumDis2013;71:569. Ii8. 9.GladmanD. (2006) AnnRheumDis.65 Suppl3,iii22-iii24 SAT0288. 14.Helliwell P etal.J Rheumatol.2005; 32: 1745–1750. PolachekA etal.ACR/ARHPAnnualMeeting Abstract 1710. KaneD etal.Rheumatology(Oxford)2003; 42(12): 1460-1468.

  12. Psoriatic arthritis consequently has a diverse clinical presentation Uveitis or conjunctivitis: eye inflammation in some patients2 Psoriatic skin lesions1 Enthesitis: inflammation where ligaments/tendons attach to bone, causing tenderness and swelling1 Spinal/pelvic changes: in patients with axial involvement1 Dactylitis; ‘sausage’ fingers/toes1 Finger/toenail symptoms: small indentations, lifting and/or discoloUration1 Pain/swelling in fingers and toes: may also affectshoulders, wrists, knees, ankles and elbows1 1. Gottlieb A, et al. J Am AcadDermatol 2008;58:851–864; 2. Au SC, et al. Psoriasis Forum 2011;17:169–179.

  13. Psoriatic arthritis is clinically heterogeneous with five distinct subtypes1–3 Asymmetric oligoarticular arthritis 3 • Affects ~35% of PsA cases • Does not affect the same joints on both side of the body at the same time Distal interphalangeal joint-predominant arthritis 2 • Inflammation and stiffness near the ends of the fingers and toes • DIP may indicate recent-onset PsA Symmetric polyarticular arthritis 4 • Affects ~50% of PsA cases • Affects joints on both sides of the body at the same time • Can be hard to differentiate from rheumatoid arthritis • PSORIATIC ARTHRITIS 1 Arthritis mutilans Predominant spondylitic involvement 5 • Rare form of PsA, affecting 5% • Causes deformities in the small joints at the ends of the fingers and toes • Inflammation of the vertebrae 1. Moll JM and Wright V. Semin Arthritis Rheum 1973;3:55–78; 2. Gottlieb A, et al. J Am Acad Dermatol 2008;58:851–64; 3. Arthritis Foundation. http://www.arthritis.org/about-arthritis/types/psoriatic-arthritis/what-is-psoriatic-arthritis.php. Accessed 23.09.16.

  14. Psoriatic arthritis has distinct radiographic and laboratory features Ossifying enthesopathy: Abnormal calcification of the tendon or ligament at the insertion into the bone Erosion Joint space narrowing Pencil-in-cup (osteolysis)1 Bony overgrowth1 1. Johns Hopkins Arthritis Centre. http://www.hopkinsarthritis.org/arthritis-info/psoriatic-arthritis/diagnosis/. Accessed 16.09.16; 2. Huynh D and Kavanaugh A. Rheumatology 2015;54:20–28.

  15. IMAGING Ritchlin CT et al. N Engl J Med ;376:957-970

  16. Diagnosis is typically > 10 years after first signs of psoriasis appear - Psoriasis skin diagnosis: 1st peak at age 16 for females, age 22 for males - PsA onset 10 years later1 10 Years with PsA Years with psoriasis ~30% of psoriasis patients develop PsA2 Joint symptoms of PsA may precede the first signs of psoriasis in some patients1 1. Gladman DD, et al. Ann Rheum Dis 2005;64:ii14–ii17; 2. Zachariae H. Am J ClinDermatol 2003;4:441–447.

  17. Diagnosis is typically > 10 years after first signs of psoriasis appear Radiological damage 2 47% of PsA patients show joint erosions in hands or feet at 2 years1 Years with PsA 1. Kane D, et al. Rheumatology 2003;42:1460–1468.

  18. Diagnosing psoriatic arthritis can be a challenge Symptoms of the disease often mimic those of other rheumatic diseases2 Wide spectrum of clinical disease1 • Skin involvement may be lacking if arthritis symptoms appear first • Targets include the axial skeleton, peripheral joints and peripheral enthuses (each target can be involved in isolation) • PsA shares many common features with rheumatoid arthritis PsAcan be difficult to diagnose Low disease prevalence3 Relapsing and remitting disease course3 No definitive laboratory test for PsA 1. Olivieri L, et al. J Rheumatol 2008;35;3–5; 2. Gottleib A, et al. J Am AcadDermatol 2008;58:851–864; 3. O’Neill T and Silman AJ. BaillieresClinRheumatol 1994;8:245–261.

  19. Evidence shows that psoriatic arthritis and rheumatoid arthritis are clinically and biologically distinct Typical features of PsA1 Dactylitis Enthesitis Spondylitis Asymmetric joint involvement DIP involvement Psoriasis Nail disease Radiographically evident enthesopathic changes Associated with HLA B27, CW6 1:1 female:male Typical features of RA1,2 Rheumatoid nodules Rheumatoid vasculitis Serum rheumatoid factor Symmetric joint involvement Primarily hand and wrist involvement Pannus Associated with HLA DR4 3:1 female:male DIP, distil interphalangeal. 1. Gottlieb A, et al. J Am AcadDermatol 2008;58:851–864; 2. Scutellari P, et al. Eur J Radiol 1998;27(suppl 1):S31–38.

  20. CASPAR(ClASsificationcriteria forPsoriaticARthritis) TheCASPAR(ClASsificationcriteriaforPsoriaticARthritis)criteriawere formedfromprospective clinicalandradiologicaldatafrom1200patientswitheitherPsAornon-psoriaticarthropathy1 Inflammatoryarticulardisease(joint,spineorentheseal)with≥3pointsfromthe following5categories:2 Points Currentpsoriasis Historyofpsoriasis Familyhistoryofpsoriasis 2 1 1 Psoriasis Psoriaticnaildystrophy Onycholysis, pittingadhyperkeratosis 1 By anymethodexceptlatexbutpreferablybyenzyme- linkedimmunosorbentassay(ELISA)ornephelometry, accordingtothelocallaboratoryreferencerange Anegativetestforrheumatoid factor 1 Swellingofentiredigit or Ahistoryof dactylitisrecordedbyarheumatologist 1 Dactylitis 1 Ill-definedossificationnearjointmargins(butnot excludingosteophyteformation)onplainX-raysof hand or foot Radiologicalevidenceofjuxta- articularnewboneformation 1 Helliwelletal.AnnRheumDis. 2005;64(SupplII):ii3-ii8. Tayloretal.ArthritisRheum.2006;54(8):2665–2673. Specificity0.987,Sensitivity0.914.

  21. Psoriatic arthritis aetiology and pathophysiology

  22. Psoriatic arthritis arises from an uncontrolled immune response1,2 Bone remodelling4 Pain and swelling of joints, enthesitis, dactylitis3 Osteoclasts Inflammation Local inflammation PDE4 cAMP AMP Pro-inflammatory mediators Systemic inflammation Immune cell Immune dysregulation leads to chronic overproduction of pro-inflammatory mediators1,2 1. Schafer P. BiochemPharmacol 2012;83:1583–90; 2. Mease PJ, et al. Drugs 2014;74:423–441. PDE4, Phosphodiesterase 4.

  23. Psoriatic arthritis arises from an uncontrolled immune response1,2 Bone remodelling4 Pain and swelling of joints, enthesitis, dactylitis3 Osteoclasts Inflammation Local inflammation PDE4 cAMP AMP Pro-inflammatory mediators Systemic inflammation Immune cell These stimulate blood vessel growth and permeability, recruit other immune cells, and induce pain and swelling1,3 Immune dysregulation leads to chronic overproduction of pro-inflammatory mediators 1. Schafer P. BiochemPharmacol 2012;83:1583–1590; 2. Mease PJ, et al. Drugs 2014;74:423–441; 3. Gottlieb A, et al. J Am AcadDermatol 2008;58:851–864. PDE4, Phosphodiesterase 4.

  24. Psoriatic arthritis arises from an uncontrolled immune response1,2 Bone remodelling4 Pain and swelling of joints, enthesitis, dactylitis3 Osteoclasts Inflammation Local inflammation PDE4 cAMP AMP Pro-inflammatory mediators Systemic inflammation Immune cell These stimulate blood vessel growth and permeability, recruits other immune cells and induces pain and swelling1,3 Overproduction of pro-inflammatory mediators (TNF-α and other cytokines) alters bone homeostasis, resulting in the joint damage seen in PsA3 Immune dysregulation leads to chronic overproduction of pro-inflammatory mediators 1. Schafer P. BiochemPharmacol 2012;83:1583–1590; 2. Mease PJ, et al. Drugs 2014;74:423–441; 3. Mensah KA, et al. CurrRheumatol Rep 2008;10(4):311–317. PDE4, Phosphodiesterase 4; TNF, Tumour necrosis factor.

  25. Chronic inflammation of the joints and skin drives many of the signs and symptoms of psoriatic arthritis Bone remodeling Osteoblasts/osteoclasts Pain and swelling of joints, enthesitis, dactylitis Bone Innate immune system activation Acquired immune system activation Inflammation PDE4 Systemic inflammation Synovial fluid Overproduction of pro-inflammatory cytokines (e.g. IL17, TNF-, and IL23) Synovial Joint cAMP AMP Bone Cartilage AMP AMP AMP AMP • Overproduction of TNF-α and other cytokines alters bone homeostasis, resulting in joint damage4,5 In PsA, there is overproduction of pro-inflammatory cytokines that initiate and amplify the inflammatory response1 Overproduction of pro-inflammatory cytokines stimulates blood vessel growth, increases the permeability of vessels and recruits other immune cells, resulting in swelling and pain in the joints, as well as enthesitis and dactylitis1−3 Activated immune cells PDE4, phosphodiesterase 4; IL, interleukin; TNF, tumour necrosis factor. 1. Mease PJ, et al. Drugs 2014;74:423–441; 2. McGonagle DJ, et al. Dermatology 2012;225:100−109; 3. Aydin SZ, et al. Ann Rheum Dis 2013;72:992−995; 4. Schett G, et al. Arthritis Res Ther 2011;13(Suppl 1):S4; 5. Xue Y. PLoS One 2012;7:e46740.

  26. Tissue-specific inflammation is thought to underlie psoriatic arthritis pathogenesis: proposed models Alternative model of psoriasis and PsA pathogenesis2 Traditional model of psoriasis and PsA pathogenesis1 Enthesis Enthesis Associated bone Adjacent soft tissue T cells Autoimmunity High mechanical stress Skin/synovial antigen Microdamage A proposed new model embraces the concept of autoinflammation, in which tissue-specific factors, including microtrauma, lead to regional innate immune activation and persistent inflammation, rather than primary T-and B-cell-driven immunopathology.2,3 The traditional model for psoriasis and PsA is that autoimmunity directed against a common skin and joint autoantigen leads to chronic autoreactive T-cell-driven inflammation1 T cells Inflammation Inflammation 1. McGonagle D, et al. Ann Rheum Dis 2008;67:1–4; 2. McGonagle D, et al. JEADV 2009;23(Suppl. 1):9–13; 3. Fitzgerald O, et al. Arthritis Res Ther 2015;17:115.

  27. Enthesitis is key to the pathophysiology of psoriatic arthritis 1 Positive feedback between the innate and adaptive immune system via the IL23–IL17 axis1 Lymphoid stress surveillance Innate immune response TNF IL17A IL22 … NKT ILC γδ T cell IL23R Neutrophils DC The enthesis MHC-I Adaptive immune response TNF IL17A IL22 … Cytotoxic T cells (Tc17) 1.McGonagle D, et al. Nat Rev Rheumatol 2015;11(12):731–740. DC, dendritic cell; ILC, innate lymphoid cell; IL, interleukin; MHC, major histocompatibility complex; NKT, natural killer T cell; TNF, tumour necrosis factor.

  28. The molecular pathogenesis of psoriatic arthritis is driven by the IL23/IL17 axis at the enthesis HLA, human leukocyte antigen; IL, interleukin; ROR, RAR-related orphan receptor; TNF, tumour necrosis factor; UPR, unfolded protein response. 1. Lories R and McInnes I. Nat Med 2012;18(7):1018-1019; 2. Sherlock J, et al. Nat Med 2012;18:1069–1076. • The enthesis has been identified as a site for immune surveillance1 • In ankylosing spondylitis, a disease process commonly associated with enthesitis, or inflammation localised to the enthesis, has been attributed to elevated IL23 levels acting on specialised resident entheseal T cells2 • These cells produce cytokines and subsequently drive bone remodelling2

  29. Nail disease and enthesitis are a link between psoriasis and psoriatic arthritis • Nail lesions are a clinical feature of PsA and not RA1 • Nail dystrophy in psoriasis patients may indicate enthesitis around the DIP joint and is therefore associated with an increased risk OF PsA2 Subungual hyperkeratosis Oil drop discolouration Superficial lamina Extensortendon Nail Midline sagittal Collagen fibres Deeplamina Flexor tendon Extensortendon Nail Lateral sagittal Laterallamina Flexortendon Splinter haemorrhages Onycholysis Image reproduced with permission from: McGonagle D, et al. JEADV 2009;23(Suppl. 1):9–13. 1. Gottlieb A, et al. J Am AcadDermatol 2008;58:851–864; 2. Wilson F, et al. Arthritis Rheum 2009;61(2):233-239. DIP, distal interphalangeal; RA, rheumatoid arthritis

  30. TREATMENT APPROACHES:PSORIATIC ARTHRITIS

  31. IS METHOTREXATE NOT A DMARD In psoriatic arthritis??? • MIPA TRIAL1: double-blind, parallel-group RCT (N=221) • 15mg po/week vs placebo • There was no difference between groups in ESR/CRP, SJC, or TJC at 3 or 6 months • There were significant improvements in patient and physician global assessment and PASI scores • Criticism: insufficient statistical power, wide individual variation, no evaluation of subsets, too low doses • MTX does appear less efficacious in PsA than RA, but may be underestimated in PsA • TICOPA trial2: tight control vs standard care. MTX17.5-25mg/week • Kingsley GH, et al. Rheumatology (Oxford). 2012;51 (8):1368-1377 • Coates L et al. Lancet. 2015;386 (100012):2489-2498 Footer for Disclaimer Text

  32. Targeted therapies are being developed to address all parts of the pathogenic pathway in psoriatic arthritis Biologics targeting cytokines and extracellular signalling1,2 Small molecules targeting intracellularsignalling pathways1 Adaptative immunity Targeting cells1 Innate immunity TNF-α inhibitors IL12/23 inhibitors Th1 Keratinocyte Keratinocyte JAK/STAT inhibitors Adaptative immunity Innate immunity NKT cell TNF- α IFN-γ Th1 Innate immunity IL-1β IL-6 TNF-α PDE4 inhibitors Activation Activation Antimicrobial peptides IL-1β IL-6 TNF- α S100 CXCL8 CXCL9 CXCL10 CXCL11 CCL20 IL-12 Innate immunity Keratinocyte Keratinocyte TNF- α IFN-γ Myeloid dendritic cell Myeloid dendritic cell NKT cell IL-23 TNF- α IFN-α IL-17A IL-17F IL-22 Th17 Intracellular signalling pathways are also believed to play a key role in inflammation and immune homeostasis IL17 inhibitors Plasmacytoid dendritic cell Plasmacytoid dendritic cell Th17 Figures adapted from: 1. Nestle F, et al. N Engl J Med 2009;361:496–509; 2. Gooderham M. Skin therapy letter. 2013. Macrophage Macrophage 1. Elyoussfi S, et al. RheumatolInt 2016;36:603–612; 2. Nograles K, et al. Nat ClinPractRheumatol 2009;5:83–91. IFN, interferon; IL, interleukin; NKT, natural killer T cell; Th, T helper; TNF, tumour necrosis factor; PDE4, phosphodiesterase-4; JAK/STAT, janus kinase/signal transducer and activator of transcription.

  33. Most therapeutic interventions in psoriatic arthritis target pro-inflammatory cytokines: extracellular targets Cytokines, immune cells and extracellular pathways in PsA that are targets for treatment1–5 IL2 IFN-γ TNF IFN-γ Th1 IL12 IL12 (p35/40) Anti-TNF TNFR-Fc DC Anti-p40 T Anti-p19 IL6 IL23 (p40/p19) TGF-β Anti-IL17A Anti-IL17RA IL1 TNF IL17A IL17F IL21 IL22 IL23 Th17 IL21 Adapted from Belge K, et al. 20141 IL6 IL23 1. Belge K, et al. F1000Prime Reports 2014;6:4; 2. Nograles K et al. Nat ClinPractRheumatol. 2009;5:83–91.3.Elyoussfi S, et al. RheumatolInt 2016;36:603–612; 4. ClinicalTrials. https://clinicaltrials.gov/ct2/show/NCT02319759. Accessed 20.09.16; 5. AbGenomics News. http://www.abgenomics.com/news_detail.php?NNo=24. Accessed 20.09.16. DC, dendritic cell; IFN, interferon; IL, interleukin; T, naïve T; Th, T helper T; TNF, tumour necrosis factor.

  34. Most therapeutic interventions in psoriatic arthritis target pro-inflammatory cytokines: intracellular targets Cytokines, immune cells and intracellular pathways in PsA that are targets for treatment1,2 STAT1 IL2 IFN-γ TNF IFN-γ IFN-γR STAT4 JAKi Th1 IL12 PDE4i IL12 (p35/40) PDE4 Anti-TNF TNFR-Fc Anti-p40 T DC GSH Anti-p19 IL6 IL23 (p40/p19) TGF-β Anti-IL17A Anti-IL17RA IL1 TNF IL17A IL17F IL21 IL22 STAT3 IL23 IL6R IL23R IL21R Th17 JAKi Adapted from Belge K, et al. 20141 IL21 IL6 IL23 DC, dendritic cell; DMF, dimethyl fumarate; GSH, glutathione; IFN, interferon; IL, interleukin; JAK, janus kinase; PDE4, phosphodiesterase 4; PDE4i, phosphodiesterase 4 inhibitor; STAT, signal transducers and activators of transcription; T, naïve T; Th, T helper; TNF, tumour necrosis factor. 1. Belge K, et al. F1000Prime Reports.2014;6;2. Elyoussfi S, et al. RheumatolInt 2016;36:603–612.

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  39. TOFACITINIB for PsA • ACR 20: • 50.5 TNF-naïve • 49.6 TNF- IR (inadequate responders) • Head-head with HUMIRA ACR-20 51.9 • MeasePJ,et al. ACR Nov 2016 & NEJM 2017;377:1537-1550 Footer for Disclaimer Text

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  42. The broader impact of chronic inflammation and clinical implications

  43. Psoriatic arthritis is associated with higher rates of comorbidity than psoriasis alone Prevalence of comorbidities in patients with PsA1 Patients (%) 42% of patients with PsA have three or more comorbid conditions2 a Rates for comorbidities significantly higher in psoriatic arthritis than in psoriasis alone; b infection without antibiotic treatment. 1. Husted J, et al. Arthritis Care Res 2011;63:1729–1735; 2. Husted J, et al. J Rheumatol 2013;40(8):1349–1356.

  44. ** 28.5 ** 27.8 30 Control PsA 23.7 22.3 Patients (%) 20 ** 11.3 ** 10 7.3 7.3 5.5 * ** ** 3.1 2.9 2.3 1.9 1.9 1.3 1.1 0.8 0 Chronic inflammation is also associated with other systemic conditions: Cardiovascular disease Inflammation is a key element in atherosclerosis1 Individuals with PsA have a significantly higher prevalence of cardiovascular disease and risk factors than matched controls2 *P < 0.05 **P < 0.01 HT HL T2D IHD CVD PVD CHF Athero-sclerosis All values adjusted for age and sex; controls matched by age, sex, geographic region, and length of time in plan.2 1. Kremers HM, et al. J Am AcadDermatol 2007;57:347–354; 2. Han C, et al. J Rheumatol 2006;33:2167–2172. CHF, congestive heart failure; CVD, cerebrovascular disease; HL, hyperlipidaemia; HT, hypertension; IHD, ischAemic heart disease; PVD, peripheral vascular disease; T2D, type 2 diabetes.

  45. PSA and Quality of Life Patients with PsA have worse QoL than those with psoriasis alone1 -HAQ -36-item Short Form Health Survey -EuroQOL-5D • PATIENTS WITH PsA HAVE LOW LEVEL OF HRQoLTHAT IMPROVES WITH TREATMENT • HRQoL=health related quality of life • 1. Rosen CF, et al. Rheumatology (Oxford). 2012;51:571-576.

  46. Summary

  47. Summary PsA is a chronic systemicinflammatory disease involvingthe skin and joints, and is closely related to psoriasis1 It is a clinically heterogeneous disease with five distinct subtypes2,3 Diagnosing PsA is a major challenge; CASPAR classification helps to differentiate PsA from other arthropathies4,5 In PsA overproduction of pro-inflammatory cytokines drives the chronic inflammatory response and results in the clinical hallmarks of the disease, including swelling/pain in the joints, enthesitis and dactylitis6 • Several therapies are in development to target different components of the pathogenic pathways implicated in PsA 7 Because dysregulated inflammation has systemic effects, PsA is associated with a number of serious co-morbidities including cardiovascular disease and metabolic syndrome8,9 1. Kavanaugh A, et al. RheumatolTher 2016; DOI 10.1007/s40744-016-0029-z; 2. Moll JM and Wright V. Semin Arthritis Rheum 1973;3:55–78; 3. Gottlieb A, et al. J Am AcadDermatol 2008;58:851–864; 4. Gottleib A, et al. J Am AcadDermatol 2008;58:851–864; 5. Taylor W, et al. Arthritis Rheum 2006;54:2665–2673; 6. Mease PJ, et al. Drugs 2014;74:423–441; 7. Elyoussfi S, et al. RheumatolInt 2016;36:603–612; 8. Han C, et al. J Rheumatol 2006;33:2167–2172; 9. Raychaudhuri SK, et al. MetabSyndrRelatDisord 2010;8:331–334.

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