5/4/2018. Disclosures. PsA: A heterogeneous disease. Objectives. PsA: A heterogeneous disease Fatigue

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1 5//18 Disclosures Management of Psoriatic Arthritis Alexis 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 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 PsA: A heterogeneous disease 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 Fatigue Work Productivity Social Participation Less than 3% of patients with PsA reach remission by any definition Physical Function and Disability Family Role Emotional Wellbeing Poor Sleep Orbai et al. Ann Rheum Dis 17 Michelson et al, J Rheumatol 17 1

2 5//18 Treating PsA = Treating the Whole Patient Physical therapy Sleep physician or Sleep psychologist Exercise and muscle balance Sleep Fatigue Nutritionist Diet MSK Emotional wellbeing Dermatologist Skin and Nail Family and Friends Specialty Pharmacist Treatment Burden Work Concomitant Conditions Primary Care Screening for CVD, Diabetes, osteoporosis, IBD, Uveitis, Skin Cancer, etc Therapy, Psychiatry, Occupational therapy What do you need to know before choosing a therapy? manifestations Concomitant Conditions Extraarticular manifestations and comorbidities Prior therapies Primary failure vs secondary failure Patient preferences The target Peripheral Arthritis Axial Enthesitis Dactylitis Skin Nail PsA is associated with several concomitant conditions, particularly metabolic disease GRAPPA Guidelines (15) Inflammatory Bowel Cardiovascular Eye PsA Obesity Diabetes Coates et al, Arthritis Rheum 1 Depression and Anxiety Fatty Liver Ogdie A, et al. Curr Opin Rheumatol. 15 Treat to Target Follow up on change Select Target Modify treatment to get to target Objectively Monitor Primary target: Remission Alternative target: LDA Coates et al. Lancet 1 Smolen et al. Ann Rheum Dis 17 Treatment Targets in PsA Minimal 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 HAQ.5 Tender entheseal points 1 activity in PsA (DAPSA): Tender joint count + Swollen joint count + Patient pain (11) + Patient global activity (11) + CRP Coates et al. Lancet 1 Smolen et al. Ann Rheum Dis 17 Coates & Helliwell. Curr Rheum Reports 15 Coates et al. Arthritis Rheum 17

3 5//18 The Tight Control in Psoriatic Arthritis (TiCOPA) trial ACR Tight Control PASI75 Standard Therapies for PsA However, must balance increased adverse events with better efficacy Coates et al. Lancet 1 Overview of disease pathophysiology Microbiome HLAB7 Biomechanical Stress/Trauma Infection Lories, R. Nature Med. 1; 18(7):118 SpA Treatment Toolbox NSAIDs Glucocorticoids Oral Small Molecules Methotrexate Leflunomide Sulfasalazine Cyclosporine TNF alpha inhibitors Etanercept Adalimumab Infliximab Certulizimab Golimumab Local Glucocorticoid Injections New MOA therapies Ustekinimab (IL1/3i) Apremilast (PDEi) Secukinumab (IL17i) Abatacept (CTLA Ig) Ixekizumab (IL17i) Tofacitinb (JAK3) In Development/Not Approved Brodalumab (IL17R) Guselkumab (IL3i) Tildrakizumab (IL3i) Rizankizumab (IL3i) =option for spondylitis Adjunct Therapy *Limited evidence Physical therapy Occupational therapy Exercise Weight Loss Dietary Changes? Acupuncture Omega3FA Patient Education Social Support Talk Therapy PsA: A heterogenous disease But most clinical trial outcomes are focused on the joints.... Clinical Trial Outcomes in PsA ACR % improvement in tender and swollen joint counts plus % in at least three of the following Health Assessment Questionnaire Patient pain assessment Patient global assessment Physician global assessment Acute Phase Response: Creactive protein PASI75 75% improvement in PASI (Psoriasis Area and Severity Index) score (range 7) Head, Trunk, Arms, Legs %BSA in each area, Erythema, Induration, Desquamation Weighted score 3

4 Hazard ratios 5//18 Overall limited data for the oral small molecules ( traditional DMARDs ) Methotrexate in PsA (MIPA) Trial Target dose of methotrexate = 15 mg weekly MTX Placebo 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 OR (95%CI) pvalue PsARC 1.77 (.973.3). ACR. (.5.).3 DAS8 Response 1.7 (.93.17).1 PASI Swollen Joints MTX Placebo Tender Joints Physician Global MTX Placebo Patient Global Baseline Follow up 3 Months Kingsley et al. Rheumatology 1; 51: Liver disease Mild psoriasis Severe psoriasis PsA, no DMARD PsA, DMARD RA, no DMARD Any liver disease Cirrhosis NAFLD RA, DMARD Ogdie A, et al. J Invest Derm. 18 TNF inhibitors Human variable region Human IgG1 Fc Adalimumab & Golimumab Fully human monoclonal antitnf antibodies Extracellular domain of human TNFR Human IgG1 Fc Etanercept Fusion protein Mouse variable region Infliximab Chimeric human (75%)/mouse (5%) monoclonal antitnf antibody Humanized variable region Certolizumab pegol PEGylated Fab 1 fragment Human IgG1 Fc PEG Differentiating Among TNFi: Uveitis/Crohn s/uc Severity of Psoriasis Mode (IV vs SQ) Dosing Intervals Insurance Coverage To use combination therapy or not? Mantravadi et al. Expert Rev Clin Pharmacol 17 Apremilast, a phosphodiesterase inhibitor Ustekinumab: p subunit, IL1/3 inhibitor PDE PDE p p35 p p19 Degradation of camp PKA Accumulation of camp PKA NF B CREB Increases inflammatory cytokines: TNF, IFNɣ, IL1, IL3, IL17, IL ATF1 NF B ATF1 IL1 receptor IL3 receptor CREB Decreases inflammatory cytokines: TNF, IFNɣ, IL1, IL3, IL17, IL T H 1 cell signaling T H 17 cell signaling

5 5//18 Secukinumab (IL17Ai) IL17 inhibitors Ixekizumab (IL17Ai) Tofacitinib AntiIL17 AntiIL17 IL17 A IL17F IL17A/ IL17F IL17RA IL17RC IL17RA IL17RC IL17RA IL17RC AntiIL17RA Brodalumab (IL17RAi) Winthrop. Nature Rev Rheum 17 Abatacept 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) Ruderman and Pope Nat Rev Review IL3 Inhibition p p35 IL1 receptor T H 1 cell signaling p p19 IL3 receptor T H 17 cell signaling Guselkumab Phase II for PsA (approved for psoriasis in 17) ACR PASI75 GUS Placebo Deodhar et al. ACR Annual Meeting Abstract L VOYAGE I Trial: Blauvelt et al. JAAD 17 5

6 5//18 Conclusions Key considerations in therapy selection: Level of disease activity: skin and MSK severity 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 Collaborators 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 StephensShields, PhD, Joshua Baker, MD MSCE OMERACT: AnaMaria 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 Funding