Onsite Program Pennsylvania Rheumatology Society
September 17 — 1 8 , 2 0 1 6 PA Harrisburg, │ Meeting Scientific 3rd Annual TABLE OF CONTENTS
Accreditation Purpose, Target Audience, & Membership
Agenda Thieves' Market Judging Instructions Faculty Participants
PRS Board and Planning Committee
Meeting Support
CME Disclosure
Notice of Disclaimer Poster Presenters Attendee List CME Evaluation
1/236 ACCREDITATION
FOR PHYSICIANS:
This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education through the joint providership of the Pennsylvania Medical Society and the Pennsylvania Rheumatology Society. The Pennsylvania Medical Society is accredited by the ACCME to provide continuing medical education for physicians.
The Pennsylvania Medical Society designates this live activity for a maximum of 8.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
Faculty and all others who have the ability to control the content of continuing medical education activities sponsored by Pennsylvania Medical Society are expected to disclose to the audience whether they do or do not have any real or apparent conflict(s) of interest or other relationships related to the content of their presentation(s).
PURPOSE & TARGET AUD IENCE
Update Members, Rheumatologists, and non-MD/DO’s who have an interest in Rheumatology with the most current and up-to-date treatments and scientific information regarding the field. Expand knowledge and competence in managing patients seen in daily practice.
WHAT IS THE PENNSYLV A N I A R H EUMATOLOGY SOCIETY?
The Pennsylvania Rheumatology Society is the professional association organized and operated to serve the common professional interests of rheumatologists and their patients in Pennsylvania and the Pennsylvania region.
HOW CAN I B ECOME A PRS MEMBER?
The Pennsylvania Rheumatology Society (PRS) is comprised of three different membership categories. An Active Membership is open to MDs and DOs who live or practice in Pennsylvania with a demonstrated interest in Rheumatology only. These members have the opportunity to vote on important Society issues during the Annual Business Meeting. An Affiliate Membership is open to anyone interested in the practice of Rheumatology. Trainees in general medicine or rheumatology may join for the duration of their training for no fee.
If you would like to become a member of PRS, please visit our website www.parheumatology.org and click on the Membership tab. .
2/236 P R O G R A M AT A G L A N C E D A Y I
Saturday, September 17th
7:00 am – 8:00 am Registration, Continental Breakfast, Exhibit Time, & Poster Viewing
7:50 am – 7:55 am Presidential Welcome Philip L. Cohen, MD Pennsylvania Rheumatology Society President
7:55 am – 8:00 am Meeting Announcements and Introductions Alfred E. Denio, III, MD Pennsylvania Rheumatology Society Program Chair/Secretary/Treasurer
8:00 am – 9:00 am Update on Giant Cell Arteritis and Polymyalgia Rheumatica Carol A. Langford, MD, MHS, FACP 1 AMA PRA Category I CME Credit™
9:00 am – 10:00 am Recent Advances in SLE Therapy: Development of Targeted Therapies Richard A. Furie, MD 1 AMA PRA Category I CME Credit™
10:00 am – 10:30 am Break, Exhibit Time, View Research Posters
10:30 am – 11:30 am Amplified Musculoskeletal Pain Syndrome – Evaluation and Treatment David D. Sherry, MD 1 AMA PRA Category I CME Credit™
11:30 am – 12:30 pm Thieves Market Presentations 1 AMA PRA Category I CME Credit™
11:30 am – 11:40 am Chronic Abdominal Pain, Weight Loss, and Perivascular Inflammation: Is it Vasculitis? Alexis S. Zavitsanos, MD Temple University Hospital
11:45 am – 11:55 am A Pain in the Back Annemarie Schorpion, MD University of Pennsylvania
12:00 pm – 12:10 pm Common Rheumatologic Symptoms Mimicking an Uncommon Disease Erika M. Joyce, DO Allegheny General Hospital
12:15 pm – 12:30 pm Judging* *Please go to page 5 for information about how to judge the presentations
12:30 pm – 1:30 pm Working Lunch Pennsylvania Ballroom 12:40 pm – 12:55 pm ACR Update William F. Harvey, MD, MSc, FACR Chair, ACR Government Affairs Committee
3/236 12:55 pm – 1:30 pm Annual Business Meeting 6:00 pm – 8:00 pm Networking Reception Poolside* *Weather permitting PROGRAM AT A GLANCE D A Y I I Sunday, September 18th
7:00 am – 8:00 am Registration, Continental Breakfast, Exhibit Time, & Poster Viewing
7:50 am – 8:00 am iPad Drawing & Introductions Barbara E. Ostrov, MD Pennsylvania Rheumatology Society Board Councilor
8:00 am – 8:45 am Your Clinic Patient – A “Walking Culture Dish” with Implications for Autoimmunity Martin A. Kriegel, MD, PhD 1 AMA PRA Category I CME Credit™
9:00 am – 9:45 am Psoriatic Arthritis Update Christopher T. Ritchlin, MD, MPH 1 AMA PRA Category I CME Credit™
10:00 am – 10:30 am Break, Exhibit Time, View Research Posters
10:30 am – 11:15 am Management of Raynaud’s Phenomenon and Digital Ischema Laura K. Hummers, MD, ScM 1 AMA PRA Category I CME Credit™
11:30 am – 12:15 pm Blindsided by Arthritis Lisa A. Lerman, MD, PhD, MSCE 1 AMA PRA Category I CME Credit™
12:15 pm Adjournment and Departure
Win an Apple iPad Air 2!
As you visit with exhibitors, remember to thank them for their invaluable support of the Pennsylvania Rheumatology Society and ask them to initial your bingo card to be entered in a raffle for an Apple iPad Air 2*! Drawing will take place on Sunday morning at 7:50 am and you must be present to win.
*PRS program committee is not eligible for the raffle.
4/236
HOW TO JUDGE THE THI EVES’ MARKET
Click on the link below to access the judging poll. You will rate each Thieves’ Market presentation as:
Below Average Average Above Average Superb
Each presentation will be judged on:
Scientific Merit Delivery Novelty Overall Impression
You do not need to create an account or sign in to the complete this poll. Scores will be unknown to other meeting attendees. Please only score the cases once all have been presented. We will announce the results at tonight’s reception. Thank you for your participation! Click Here to Score the Cases Now!
After clicking on the link above, click on the “Start Survey” button to complete the poll. Please only complete this once to ensure fair scoring
5/236 FACU LTY
Alfred E. Denio, III, MD+ Melissa A. Lerman, MD, PhD, MSCE Fellowship Program Director Assistant Professor of Clinical Pediatrics Geisinger Medical Center Perelman School of Medicine Danville, PA University of Pennsylvania Philadelphia, PA Christopher T. Derk, MD, MS+ Associate Professor of Medicine Douglas W. Lienesch, MD+ Fellowship Program Director Assistant Professor of Medicine University of Pennsylvania Fellowship Program Director Philadelphia, PA UPMC Rheumatology Division Chief Joseph L. Enama, MD+ UPMC Mercy Hospital Fellowship Program Director Pittsburgh, PA Penn State College of Medicine Hershey, PA Christopher T. Ritchlin, MD, MPH Chief Richard A. Furie, MD Professor of Medicine Chief Department of Medicine, Allergy/Immunology and Division of Rheumatology Rheumatology Professor of Medicine University of Rochester Hofstra Northwell School of Medicine Canandaigua, NY Manhasset, NY Annemarie Schorpion, MD* Laura K. Hummers, MD, ScM University of Pennsylvania Assistant Professor of Medicine Philadelphia, PA Co-Director Johns Hopkins Scleroderma Center David D. Sherry, MD Baltimore, MD Director Amplified Pain Program Erika M. Joyce, DO* Professor of Pediatrics Allegheny General Hospital Perelman School of Medicine Pittsburgh, PA Attending, Rheumatology University of Pennsylvania Martin A. Kriegel, MD, PhD Philadelphia, PA Assistant Professor of Immunobiology and Medicine Yale University Irene J. Tan, MD, FACR+ New Haven, CT Professor of Medicine Fellowship Program Director Carol A. Langford, MD, MHS, FACP Lewis Katz School of Medicine Associate Professor of Medicine Temple University Cleveland Clinic Learner College of Medicine Philadelphia, PA Case Western Reserve University Director Alexis S. Zavitsanos, MD* Center for Vasculitis Care and Research Temple University Hospital Cleveland, OH Philadelphia, PA
* Designates a Thieves’ Market Presenter + Designated a Thieves’ Market Judge
6/236 BOARD & PLANNING COM MITTEE President Councilor Philip L. Cohen, MD Donald S. Miller, MD Philadelphia, PA Ardmore, PA
Vice President/President Elect Councilor Lawrence H. Brent, MD Barbara Ellen Ostrov, MD Philadelphia, PA Hershey, PA
Secretary/Treasurer Councilor Alfred E. Denio, III, MD Alan D. Roumm, MD Danville, PA Camp Hill, PA
Immediate Past President Councilor Paul J. Killian, MD Terence W. Starz, MD Pittsburgh, PA Pittsburgh, PA
Councilor Councilor Donald P. Goldsmith, MD Irene J. Tan, MD Philadelphia, PA Philadelphia, PA
Councilor Executive Director Bruce I. Hoffman, MD Maria B. Elias Philadelphia, PA Harrisburg, PA
Councilor Program Committee Arthur S. Huppert, MD Philadelphia, PA Alfred E. Denio, MD Program Chair Councilor Warren A. Katz, MD Irene J. Tan, MD Upper Gwynedd, PA Thieves’ Market Facilitator
Councilor Lawrence H. Brent, MD Alan J. Kivitz, MD Committee Member Duncansville, PA Barbara Ellen Ostrov, MD Councilor Committee Member Douglas W. Lienesch, MD Mars, PA Philip L. Cohen, MD Committee Member
7/236 M EETING SUPPORT
The Pennsylvania Rheumatology Society wishes to thank and acknowledge the following organizations for supporting the Society and the 2016 Annual Meeting with a corporate partnership: Abbvie Amgen Bristol Meyers Squibb Genentech Johnson & Johnson Health Care Systems, Inc. Mallinckrodt Pfizer The Pennsylvania Rheumatology Society wishes to thank and acknowledge the following organizations for supporting the Society and the 2016 Annual Meeting with an educational grant: Pfizer The Pennsylvania Rheumatology Society wishes to thank and acknowledge the following organizations for supporting the 2016 Annual Meeting by exhibiting:
Abbvie Alexion Amgen The Arthritis Foundation Bristol Myers Squibb Celgene Crescendo Bioscience Exigent Diagnostics Furring Pharmaceuticals Genentech Gilead Sciences GlaxoSmithKline ImmunArray Johnson & Johnson Health Care Systems, Inc. Lilly Pharmaceuticals, LLC Mallinckrodt Medic Pharma Novartis (2 tables) Oxford Immunities Pfizer Sobi Sound Rheum Diagnostics UCB
8/236 CME DISCLOSURE Financial relationships reported by members of the Pennsylvania Rheumatology Society’s Planning Committee are provided below. During all phases of planning for the Annual Meeting, areas of conflict were managed through a peer-review process and/or through individual recusal when appropriate. The Planning Committee has reviewed all presenter disclosure reports, identified potential conflicts of interest, and implemented strategies to manage those areas of conflict, where they exist.
Name Company Name Nature of Relationship Lawrence H. Brent, MD* AbbVie Speakers Bureau Genentech Speakers Bureau Pfizer Speakers Bureau Mallinckrodt Speakers Bureau Philip L. Cohen, MD* None None Alfred E. Denio, III, MD* Bristol Meyers Squibb Speaker Johnson & Johnson Christopher T. Derk, MD, MS None None Joseph L. Enama, MD Richard A. Furie, MD AstraZeneca Research Grant, Consultant, Investigator Baxalta Consultant BiodenIdec Research Grant, Consultant, Investigator BMS Research Grant, Consultant, Investigator Boehringer-Ingelheim Research Grant, Consultant, Investigator Celgene Research Grant, Consultant, Investigator Eli Lilly Research Grant, Consultant, Investigator EMD Merck Consultant Estrela Consultant GSK Research Grant, Consultant, Investigator Mallinckrodt Research Grant, Consultant, Investigator Medimmune Research Grant, Consultant, Investigator Pfizer Research Grant, Consultant, Investigator Sanofi Research Grant, Consultant, Investigator Takeda Research Grant, Investigator UCB Research Grant, Consultant, Investigator Laura K. Hummers, MD, ScM Boehringer-Ingelheim Research Grant Corbus Pharmaceuticals Research Grant Cyton Therapeutics Research Grant Erika M. Joyce, DO None None Martin A. Kriegel, MD, PhD Abbvie Research Grant BMS Consultant Carol A. Langford, MD, MHS, FACP BMS Research Grant GlaxoSmithKline Research Grant Genentech Research Grant Melissa A. Lerman, MD, PhD, MSCE None None Douglas W. Lienesch, MD None None Barbara E. Ostrov, MD* None None Christopher T. Ritchlin, MD, MPH Amgen Consultant, Research Grant Abbvie Consultant, Research Grant Janssen Consultant Reginyon Consultant Sanofi Consultant Boehringer-Ingelheim Consultant Novartis Consultant Sunovian Consultant
9/236 Annemarie Schorpion, MD None None David D. Sherry, MD None None Irene J. Tan, MD, FACR* None None Alexis S. Zavitsanos, MD None None
* Designates a Pennsylvania Rheumatology Society program committee member
NOTICE OF DISCLAIMER
The information presented is that of the contributing faculty and does not necessarily represent the views of the Pennsylvania Rheumatology Society, the CME accreditor, Pennsylvania Medical Society, and/or any named commercial entity providing financial support.
The Pennsylvania Rheumatology Society makes every effort to ensure that speakers are knowledgeable authorities in their fields. Seminar attendees are nevertheless advised that the statements and opinions expressed by seminar speakers are those of the speakers, not that of Pennsylvania Rheumatology Society. The speakers’ statements and/or opinions should not be construed as Pennsylvania Rheumatology Society policy or recommendations, and Pennsylvania Rheumatology Society disclaims any liability or responsibility for the consequences of any actions taken in reliance upon those statements or opinions.
10/236 PROGRAM OUTCOMES
U P D A T E S O N G I A N T C E L L A RTERITIS AND P OLYMYALGIA R HEUMATICA Identify the clinical features and diagnostic approach to giant cell arteritis and polymyalgia rheumatic. Describe the current treatment approaches for giant cell arteritis and polymyalgia rheumatic. Outline novel findings that have been described in giant cell arteritis and polymyalgia rheumatic.
Y OUR CLINIC PATIENT – A “ WALKING CULTURE DISH ” WITH IMPLICATIONS FO R AUTOIMMUNITY Review the bidirectional host immune-microbiota interactions affecting autoimmunity. Recognize the impact of diet, antibiotics and fecal transplants on the microbiome. Summarize the effect of the microbiota on immunomodulatory drugs and vaccination efficacy.
P S O R I A T I C A R T H R I T I S U PDATE Illustrate the pathophysiology of psoriatic arthritis. Prescribe appropriate therapy for patients with psoriatic arthritis. Evaluate new and evolving therapies for psoriatic arthritis.
N E W T HERAPIES FOR S Y S T E M I C L U P U S E RYTHEMATOSUS Illustrate elements of the pathogenesis of SLE and how they relate to therapy of SLE. Integrate new therapies into the treatment of patients with SLE. Evaluate potential new therapies for SLE.
A M P L I F I E D M USCULOSKELETAL P A I N S Y N D R O M E – E VALUATION AND T REATMENT Differentiate at least two clinical patterns of pain in amplified musculoskeletal pain syndrome. Demonstrate clinical screening for allodynia. Recognize that excessive alpha-delta sleep does not correlate with symptoms or poor sleep. Illustrate the principles behind and the outcome of a therapeutic exercise program. Prescribe the appropriate therapy for amplified musculoskeletal pain.
R AYNAUD ’ S D ISEASE : E VALUATION AND T REATMENT Differentiate primary and secondary Raynaud’s disease. Demonstrate the appropriated evaluation for a patient with Raynaud’s disease. Evaluate therapeutic options for patients with Raynaud’s disease.
U VEITIS FROM THE R HEUMATOLOGISTS ’ P ERSPECTIVE Describe diseases that cause uveitis. Define the classification system for uveitis (location and activity). Describe the morbidities of uveitis. Prescribe appropriate therapy for patients with uveitis. Evaluate new and evolving therapies for uveitis.
T HIEVES ’ M ARKET Broaden their differential diagnostic skills to include rare disorders or rare presentations of common conditions. Apply up-to-date clinical information on the diagnosis and management of patients with rheumatic and immunologic disorders. Describe the most current information regarding the pathophysiology underlying rheumatic disorders. Apply new diagnostic and management strategies.
11/236 POSTER PRESENTERS
Syed Alam, MD Temple University Hospital On Strange Seas of the Brain
University of Pittsburgh Atypical Optic Neuritis in Myo-Pale' Aye, MD Medical Center ANCA-Associated Vasculitis University of Pittsburgh Emily Brunner, MD Gut Instinct Medical Center
Shazdeh Butt, MD Geisinger Medical Center Is it Lupoid Lues or Luetic Lupus?
Sjogren's Syndrome and Neuromyelitis Optica: Courtney Corbeil, MD Geisinger Medical Center A Numbing Diagnosis
Penn State Hershey Hiranda Dodanwala, MD What Could Be Wrong with These Muscles? Medical Center
Necrotic Granulomas in the Setting of Crohn’s Christina Downey, MD Geisinger Medical Center Disease and SAPHO Syndrome
Philip Dunn, MD Geisinger Medical Center “Atypical” Case of Recurrent Acute Renal Failure
Tumor Necrosis Factor (TNF) Blocker Erika Joyce, DO Allegheny Health Network Administration: Compliance with Screening Guidelines Prior to Initiation University of Pittsburgh Amanda Kocoloski, MD But Was It Really Sjogren's Syndrome? Medical Center
UPMC Presbyterian Shadyside A Curious Case of Painless Jaundice Judith Lin, MD Internal Medicine Residency and Muscle Weakness
Hospital of the University Catherine Najem, MD Not a Usual Abdominal Pain! of Pennsylvania Drexel College of Barriers to Adherence to 2011 Guidelines for Christina Payne, MD Medicine/Hahnemann Hospital Hydroxychloroquine Baseline Retinal Screening
Scott Pompa, MD Drexel Rheumatology History of Scrotal Ulcers: A Diagnostic Challenge
29-year-old Postpartum Woman with Pulmonary Shikha Rathi, MD Temple University Hospital Hypertension Revealing Further Mysteries
Jennifer Reams, DO Geisinger Medical Center An Immunity Challenge!
Abraham Tacang, MD Geisinger Medical Center Achy Mary: A Case of Monoarticular Arthritis
Concordance of the Microscopic Analysis of Joint Alexis Zavitsanos, MD Temple University Hospital Aspirate for the diagnosis of gout
12/236 2016 ANNUAL MEETING ATTENDEE LIST
13/236 Syed Alam Joseph Enama PHILADELPHIA, PA 19118 HERSHEY, PA 17033 Myo-Pale' Aye Jean Fioti PITTSBURGH, PA 15261 SHAVERTOWN, PA 18708 William Ayoub Richard Furie SEWICKLEY, PA 15143 MANHASSET, NY Sharon Banks Prateek Gandiga HERSHEY, PA 17033 PHILADELPHIA, PA 19103 Lawrence Brent Michelle Gauntlett PHILADELPHIA, PA 19141 OLD FORGE, PA 18518 Emily Brunner Donald Goldsmith PITTSBURGH, PA 15261 PHILADELPHIA, PENNSYLVANIA 19134 Shazdeh Butt Donald Goldsmith DANVILLE, PA 17822 PHILADELPHIA, PA 19134 Nicole Butteri Rajesh Gopalarathinam MOON TOWNSHIP, PA 15108 PITTSBURGH, PA 15212 Scott Case Bruce Grothen MALVERN, PA 19355 MERRIMACK, NH 03054 Devon Charlton William Harvey MARS, PA 16046 ATLANTA, GA 30328 Kevin Clawson Bruce Hoffman CHAMBERSBURG, PA 17201 BALA CYNWYD, PA 19004 Philip Cohen Laura Hummers PHILADELPHIA, PA 19140 BALTIMORE, MD 21231 Courtney Corbeil Arthur Huppert DANVILLE, PA 17822 DIRECT MAIL FROM AMA, PHILADELPHIA 19107 Teresa Cozza Erika Joyce BRONX, NY 10458 PITTSBURGH, PENNSYLVANIA 15212 Alfred Denio Rayford June DANVILLE, PA 17822 HERSHEY, PENNSYLVANIA 17033 Chris Derk Hiren Kachhia PENN VALLEY, PA 19072 SUMMIT, NJ 07901 Hiranda Dodanwala Arati Karhadkar HERSHEY, PENNSYLVANIA 17033 GLADWYNE, PA 19035 Adam Dore Paul Killin PITTSBURGH, PA 15224 PITTSBURGH, PA 15238 Christina Downey Amanda Kocoloski DANVILLE, PA 17821 PITTSBURGH, PA 15261 Philip Dunn Robyn Koelsch DANVILLE, PA 17821 ALEXANDRIA, VA 22308 Maria Elias Martin Kriegel HARRISBURG, PA 17111 NEW HAVEN, CT 14/236 Ottar Kristinsson Zachary Post HERSHEY, PA 17033 PISCATAWAY, NEW JERSEY 08854 Carol Langford Julio Ramos CLEVELAND, OH SCRANTON, PENNSYLVANIA 18510 Lindsay Ledwich Shikha Rathi ALLISON PARK, PENNSYLVANIA 15101-4223 PHILADELPHIA, PENNSYLVANIA 19140 Melissa Lerman Jennifer Reams PHILADELPHIA, PA 19141 DANVILLE, PA 17821 Douglas Lienesch Christopher Ritchlin MARS, PENNSYLVANIA 16046 CANANDAIGUA, NY Judith Lin Cindy Rodriguez-Silva PITTSBURGH, PA 15206 WYNNEWOOD, PA 19096 Sonia Manocha Alan Roumm WEXFORD, PA 15090 CAMP HILL, PA 17011 Sherilyn McCollum Robert Sanford EASTON, PA 18045 CAMP HILL, PA 17011 Catherine McDermott Marianne J Santioni HERSHEY, PA 17033 OLD FORGE, PA 18518 Saurin Mehta Lisa Scalzi WYOMISSING, PA 19610 HUMMELSTOWN, PA 17036 Denise Mervis Annemarie Schorpion MCDONALD, PA 15057 PHILADELPHIA, PA 19104 Pierre Minerva Mythili Seetharaman BALA CYNWYD, PENNSYLVANIA 19004 ALLENTOWN, PA 18104 Catherine Najem Sucharitha Shanmugam BOOTHWYN, PA 19061 COLLEGEVILLE, PA 19426 Nancy Olsen David Sherry HERSHEY, PENNSYLVANIA 17033 PHILADELPHIA, PA 19141 Barbara Ostrov Savita Singh HERSHEY, PA 17033 PHILADELPHIA, PA 19006 Ramesh Pappu Terence Starz CHERRY HILL, NJ 08003 PITTSBURGH, PA 15232 Ruchika Patel Angela Stupi PHILADELPHIA, PA 19141 WEXFORD, PA 15101 Christina Payne Abraham Tacang PHILADELPHIA, PENNSYLVANIA 19103 DANVILLE, PA 17822 Michael Perilstein Irene Tan POTTSTOWN, PA 19464 PHILADELPHIA, PA 19140 Scott Pompa Nancy Walker PHILADELPHIA, PA 19102 WYOMISSING, PA 19610 Chadler Pool Allison Zamerowski Alexis Zavitsanos TOWNSEND, DE 19734 OLD FORGE, PA 18518 PHILADELPHIA, PENNSYLVANIA15/236 19129 Saturday, September 17th Lectures
Update on Giant Cell Arteritis and Polymyalgia Rheumatica Carol A. Langford, MD, MHS, FACP 1 AMA PRA Category I CME Credits™ Recent Advances in SLE Therapy: Development of Targeted Therapies Richard A. Furie, MD 1 AMA PRA Category I CME Credits™
Complex Regional Pain Syndromes, Fibromyalgia ,and Amplified Pain Syndromes David D. Sherry, MD 1 AMA PRA Category I CME Credits™ Thieves Market Presentations 1 AMA PRA Category I CME Credits™ Chronic Abdominal Pain, Weight Loss, and Perivascular Inflammation: Is it Vasculitis? Alexis S. Zavitsanos, MD Temply University Hospital A Pain in the Back Annemarie Schorpion, MD University of Pennsylvania
Common Rheumatologic Symptoms Mimicking an Uncommon Disease Erika M. Joyce, DO Allegheny General Hospital
Annual Business Meeting
Thieves’ Market Judging will be from 12:15 pm – 12:30 pm Instructions on how to judge the Thieves’ Market can be found on page five of this program.
16/236 UPDATE ON GIANT CELL ARTERITIS & POLYMYALGIA RHEUMATICA Carol A. Langford, MD, MHS, FACP
SATURDAY, SEPTEMBER 17TH 8:00 AM – 9:00 AM
17/236 Update On Giant Cell Arteritis and Polymyalgia Rheumatica
Carol A. Langford, MD, MHS
Harold C. Schott Chair Director, Center for Vasculitis Care and Research Department of Rheumatic and Immunologic Diseases Cleveland Clinic
CME Disclosure Statements Carol A. Langford, MD, MHS
Unlabeled use of commercial products To date, there are no therapeutic agents FDA approved for the treatment of giant cell arteritis or polymyalgia rheumatica
All references to use of a commercial product discussed in this presentation constitute an unlabeled use of the product
Speaker relationship to products discussed in this presentation
Bristol-Myers Squibb provide funding for clinical trials Genentech on which the speaker is an investigator GlaxoSmithKline
18/236 Vasculitis = Inflammation of the Blood Vessel
blood vessel damage
compromise of vessel lumen attenuation of vessel wall
organ ischemia aneurysm formation hemorrhage
Vasculitis Can Affect Any Vessel
Aorta Capillary Vein
Large Vessel Medium Vessel Small Vessel
Takayasu Arteritis Polyarteritis nodosa Microscopic polyangiitis
19/236 Large Vessel Vasculitis: Not Just One Disease
Primary Vasculitis Secondary Vasculitis Unique disease entities in Vasculitis is occurring in the which vasculitis is occurring due to setting of an underlying an as yet unknown cause disease or exposure Giant cell arteritis Infection Takayasu arteritis Syphilis Staphylococcus Cogan syndrome Salmonella Tuberculosis Behçet’s disease Fungus Kawasaki disease Spondyloarthropathies GPA (Wegener’s) Sarcoidosis Microscopic polyangiitis Systemic lupus erythematosus EGPA (Churg-Strauss) Relapsing polychondritis Polyarteritis nodosa Trauma Previous surgery Isolated (focal) aortitis Atherosclerosis
Giant Cell Arteritis Epidemiology
• Has also historically been called temporal arteritis
• The most common form of systemic vasculitis - 26 per 100,000
• Occurs in people over the age of 50 (average age in 70’s)
• 2:1 Female:Male
• Granulomatous vasculitis
Weyand, et al. NEJM 2014;371:50 Buttgereit et al. JAMA 2016;351:2442
20/236 Polymyalgia Rheumatica Cranial Disease
GCA GIANTMany patients CELL will ARTERITIS have features of more than one phenotype
Systemic / Inflammatory Large Vessel Disease Disease
Giant Cell Arteritis Polymyalgia Rheumatica
Clinically characterized by: • Age > 50 years • Bilateral shoulder aching required = 2 points • Increased ESR and/or CRP * = 1 point • Hip girdle pain/aching *PMR = all required + either * • Morning stiffness > 45 minutes - 4 points without ultrasound * • Typical absence of other joint involvement - 5 points with ultrasound * • Absence of RF and anti-CCP * • Prompt response to prednisone 10-20 mg daily
Diagnosis: • No definitive lab or imaging findings • Diagnosis based upon compatible features and ruling out other processes
2012 Classification criteria for PMR (Dasgupta et al. A&R 2012) • Not intended for diagnosis of the individual patient • Based on clinical features + ultrasound findings
21/236 Polymyalgia Rheumatica Utility of Ultrasound for Diagnosis
Ultrasound has long been known to demonstrate findings in PMR
Subacromial / Subdeltoid bursitis (Salvarani et al. Ann Int Med 1997)
Cantini et al. A&R 2001 • Although ultrasound was used in the 2012 Classification criteria for PMR it includes options without ultrasound (Dasgupta et al. A&R 2012)
• Ultrasound does not distinguish between PMR and other causes of bursitis
Role of ultrasound in PMR continues to evolve Ultrasound by itself is not diagnostic for PMR Ultrasound does not need to be routinely performed for possible PMR
Giant Cell Arteritis Polymyalgia Rheumatica
PMR can occur as an isolated entity or as part of GCA
40-60% GCA PMR 10-20%
Hernández-Rodriguez et al. Medicine 2007;86:233 – 73 patients where PMR preceded GCA – 20% developed ischemic complications (16 visual, 3 stroke, 1 large vessel)
Aortitis and cranial arteritis can occur later in patients with PMR
22/236 Giant Cell Arteritis Systemic / Inflammatory Disease
Symptoms and Signs • Fever • Night sweats • Fatigue, malaise • Anorexia, weight loss
Laboratories • CBC: anemia, leukocytosis, thrombocytosis • Increased CRP • Increased ESR
Can accompany PMR, cranial, or large vessel presentations but Can also occur in isolation as a presenting phenotype of GCA
Giant Cell Arteritis Cranial Disease
External carotid
Symptoms and signs • headache • temporal artery abnormalities • jaw and/or tongue claudication From the ACR slide • scalp tenderness and/or ischemia collection
23/236 Giant Cell Arteritis Cranial Disease
Visual Features anterior ischemic optic neuropathy
Ocular muscle ischemia
Internal carotid
Giant Cell Arteritis Cranial Disease
• Most dreaded clinical manifestations of cranial disease:
Cranial ischemic complications (CIC) Ischemia of tissue due to vessel occlusion • visual loss - 14% (6-42%) • stroke - 3-8% • tongue ischemia • scalp ischemia
• Risk factors for permanent CIC – transient CIC (amaurosis fugax, diplopia, TIA) –prior CIC Cid et al. Arth Rheum 1998;41:26 Gonzales-Gay et al. Arth Rheum 1998;41:1497 Nesher et al. Medicine 2004;83:114
24/236 Giant Cell Arteritis Large Vessel Involvement
Subclavian Artery Stenosis Thoracic Aortic Aneurysm
Giant Cell Arteritis Large Vessel Involvement
Evans et al. Arthritis Rheum 1994; 37:1539 Evans et al. Ann Intern Med 1995; 122:502
Thoracic aortic aneurysms (TAA) Abdominal aortic aneurysms (AAA)
• AAA 2.4 x more likely than the general population • TAA 17.3 x more likely than the general population • TAA can occur late and have serious outcomes that may be fatal • In those who had surgery only 50% had active inflammation
25/236 Giant Cell Arteritis Large Vessel Involvement
Nuenninghoff et al. Arthritis Rheum 2003; 48:3522 and 3532
168 GCA patients - 27% had large vessel complications
18% aortic aneurysm (1 out of every 5) subclavian 13% large-artery stenosis (1 out of every 8) carotid/vertebral iliac
No difference in overall mortality rate in those with large-artery involvement Thoracic aortic dissection in GCA is associated with increased mortality
Large vessel disease is not uncommon in GCA Awareness of thoracic aortic aneurysm risk is important
Giant Cell Arteritis – Temporal Artery Biopsy
Positive in only 30-70%
(In large vessel disease positive in < 30%)
26/236 Giant Cell Arteritis What Factors Are Associated with a Positive Biopsy ?
Smetana and Shmerling. JAMA 2002;287:92
Meta-analysis of 21 studies from 1966-2000 2680 patients who had a temporal artery biopsy – 39.2% positive
Not discriminatory: • Headache • PMR • Visual symptoms (except diplopia)
Most powerful predictors of (+) biopsy: • Jaw claudication • Diplopia • Abnormal temporal artery by physical exam
Giant Cell Arteritis Does Treatment Influence Biopsy Results ?
Achkar et al. Ann Internal Med 1994;120:992.
535 patients with temporal artery biopsies 1988-1991
• (+) biopsies were found in: – 31% who did receive prednisone before biopsy – 35% who did not receive prednisone before biopsy
• Arteritis could still be detected after 14 or more days of treatment
Provide support that glucocorticoid treatment should not be delayed in patients where there is a high degree of suspicion for GCA
27/236 Giant Cell Arteritis Utility of Ultrasound
Color Duplex Ultrasonography Hypoechoic Echo
Corresponds to a dark area around the lumen of an inflamed artery
Longitudinal section Transverse section Karahaliou et al. Arth Care and Res 2006
Giant Cell Arteritis Utility of Ultrasound
Schmitt et al. NEJM 1997;337:1336 • 73% of GCA and 0% controls had a halo around the lumen of the temporal artery • In patients with typical features and halo, biopsy may not be necessary
Salvarani et al. Ann Internal Med 2002;137:232 • 86 patients with suspected GCA who had ultrasound and biopsy • Halo did not improve diagnostic accuracy beyond physical exam
Karassa et al. Ann Internal Med 2005;142:359 • Meta-analysis of 23 studies examining ultrasound in GCA • Cautious interpretation based on clinical features, pretest probability is imperative
Ultrasound is a very user dependent technique
This together with the available data raises concern about the ability of ultrasound to diagnose GCA in most clinical practices
28/236 Giant Cell Arteritis General Approach to Disease Monitoring History • Cranial, PMR, large vessel, constitutional symptoms Physical Examination • Temporal arteries • 4 extremity BP • Peripheral pulse inequality • Auscultation – cardiac for insufficiency murmurs, vascular for bruits Laboratories • On medications: chemistries, CBC, ESR, CRP every month • On no medications: CBC, ESR, CRP every 1-3 mo Imaging • CXR annually • CTA or MRA for any features of large vessel disease • CTA or MRA for known large vessel disease every year There remains no definitive means of accurately determining active disease
Giant Cell Arteritis Large Vessel Imaging - Arteriography
Catheter–directed dye arteriogram • Central pressure measurements • Intervention • Precise definition of anatomy (distal lesions)
CTA or MRA • Non-invasive • Visualization of whole large vessel tree • Allows imaging of the vessel wall
29/236 MR to Assess the Vessel Wall
Isointense compared to muscle Hyperintense compared to muscle No Edema Edema – (? Inflammation ?)
Giant Cell Arteritis Large Vessel Imaging - MRI
Are vessel wall changes (signal intensity) useful to serially assess disease activity in large vessel vasculitis ?
Tso et al: Arthritis Rheum 2002;46:1634
Study of large vessel changes by MRI in Takayasu arteritis Vessel wall edema seen in: 94% active disease 81% uncertain disease activity 56% apparent clinical remission
55% had vessel wall edema by serial MR without new vascular lesions Absence of edema was also seen in patients who had active disease
Raises doubts about utility of edema on MRI to assess disease activity
30/236 Giant Cell Arteritis Large Vessel Imaging - PET
Positron Emission Tomography (PET) Utilizes radiolabeled fluorodeoxyglucose (FDG) to visualize metabolically active tissue.
Utility of PET for Diagnosis of GCA Blockmans et al. Rheumatol 1999;38:444 • Pre-treatment GCA (n=6), PMR (n=5) and 23 controls • Thoracic aorta uptake: 4/6 GCA, 4/5 PMR, 1/23 control
Prieto-Gonzáles et al. ARD 2014 • 32 patients GCA, prednisone < 3 days, 20 controls • Sensitivity 80%, specificity 79% for GCA
Could PET be useful for monitoring in GCA ? Is PET useful in long-term disease ?
Giant Cell Arteritis Large Vessel Imaging – MRI and PET
Both et al. Ann Rheum Dis 2008;67:1030
• Evaluated MRI/PET for measurement of disease activity in 25 patients
with complicated GCA who had received immunosuppressive therapy
• MRI was only valuable for stenoses or aneurysms (lumenography)
• MRI/PET showed no statistical correlation with ESR/CRP or BVAS
Questions the reliability and utility of MRI/PET as a measure of disease activity in patients who have had long term disease
31/236 Giant Cell Arteritis Relationship with Takayasu Arteritis
Are Takayasu arteritis and Giant cell arteritis related diseases ? Unknown Similarities: • Involvement of large vessels • Histologic evidence of granulomatous inflammation
Differences: • Age of involvement • Distribution of vessel involvement • ? Treatment response
Maksimowicz-McKinnon K et al. Medicine 2009;88:221
Giant Cell Arteritis Treatment Goals
1. Prevent serious morbidity and/or mortality
2. Reduce symptoms that affect quality of life
3. Stop disease relapse
4. Avoid treatment-induced toxicity
32/236 Giant Cell Arteritis Treatment
1950 2016
Prednisone Prednisone + + Aspirin Aspirin
What is the data for their use ? Why have alternatives not yet been identified ?
Giant Cell Arteritis Treatment with Glucocorticoids
Shick et al. 1950 • Mayo Clinic – first report of use and benefit
Birkhead et al. 1957 • B/L blindness went from 17% to 9% after glucocorticoid introduction
Ross Russell 1959 • Visual failure 38% salicylates versus 0% glucocorticoids
Aiello et al. 1993 • 1% probability of visual loss after initiating glucocorticoids
Compelling evidence that glucocorticoids protect vision
33/236 Giant Cell Arteritis Data for Initial Glucocorticoid Dose
Retrospective Series from the 1970-1980’s
st Prednisone (PD) or 1 Author Prednisolone (PN) dose (in mg)
Fauchald PD 40-60 Sorensen PD 30-60 von Knorring PN 30-40 Fernandez-Herlihy PD 40-80 Graham PD 80 Bengtsson PN < 20-60
Formed the basis for initial use of prednisone 40-60 mg daily Prospective trials since have largely used prednisone 40-60 mg daily
Giant Cell Arteritis Data for Initial Glucocorticoid Dose
Use of Low Dose Prednisone (20 mg daily)
• Effective dose for PMR
• Data for use in GCA in retrospective series ? Influence of clinical picture on dosage chosen
• There have been no prospective trials of safety and efficacy
Current data favor initial use of prednisone 40-60 mg daily to prevent visual and vascular complications
34/236 Giant Cell Arteritis Relapse and Duration of Glucocorticoid Treatment
Relapse rate: Estimation of relapse rate has been variable based upon how it is defined From retrospective series Relapse rate 26-90% Recent prospective trials Relapse rate 75-90%
Treatment Duration: From historical series: Duration is typically over 2 years, for many is over 4 Proven et al. Arthritis Rheum 2003;49:703 125 patients, 87 followed to discontinuation of prednisone • Time to discontinuation: median 22 months (range 2.3-122 months)
Glucocorticoids do not prevent disease recurrence and an extended treatment duration is required in most patients
GLUCOCORTICOID TOXICITY
Occurs in 35-86%
35/236 Giant Cell Arteritis Role of Pulse Methylprednisolone (IV MP)
Are there toxicity/relapse benefits to starting all patients on IV MP ? Mazlumzadeh et al. Arthritis Rheum 2006;54:3310 • 27 patients randomized to IV MP or placebo then prednisone 40 mg/d • Higher number taking < 5 mg prednisone at 36 weeks in the IV group (p=0.003) • Higher number of sustained remissions in the IV group • Only 6 of 14 in IV MP group were able to sustain remission without prednisone • IV MP did not reduce frequency of prednisone side effects • Insufficient evidence for IV MP to become standard treatment in all patients
When is IV MP (1 g/day x 3 days) commonly used in practice ? • Vision loss in one eye (to protect vision in the other eye) • Transient vision loss or diplopia • TIA or other fixed or transient cranial ischemic events
Is IV MP more effective than prednisone 40-60 mg/d ? • Unclear – no comparative studies • Risk versus benefit must be weighed in the individual patient
Giant Cell Arteritis Role of Acetylsalicylic Acid (ASA)
Nesher et al. Arthritis Rheum 2004;50:1332 175 patients retrospectively reviewed for cranial ischemic complications (CIC) • ASA treated patients were 5x less likely to have CIC prior or after diagnosis • CIC developed in 3% of ASA-treated patients vs 13% (P=0.02) Only 10 patients would need to be treated with ASA to prevent one CIC
Lee et al. Arthritis Rheum 2006;54:3306 143 patients retrospectively reviewed for ischemic complications • 16% on therapy had an ischemic event compared to 40% not on therapy • No increase in risk of bleeding complications
In patients without contraindications, ASA 81 mg/day appears to provide adjunctive benefit in the treatment of GCA
36/236 Giant Cell Arteritis Methotrexate
Jover et al. Ann Int Med 2001 Hoffman, INSSYS. A & R 2002
48 Patients 98
Single center, RDBPC Design Multi-center, RDBPC
MTX = placebo Disease related MTX = placebo serious morbidity
MTX < placebo (P=0.018) Relapse MTX = placebo (P=0.26)
MTX < placebo (P=0.01) Cumulative GC dose MTX = placebo
MTX = placebo GC toxicity MTX = placebo
Evidence does not suggest that MTX reduces the risk of GC toxicity
Methotrexate (MTX) in Giant Cell Arteritis Mahr et al. Arthritis Rheum 2007; 56:2789
Methods: • Jover et al. Ann Internal Med 2001;134:106 Meta-analysis of: • Hoffman et al. Arthritis Rheum 2002;46:1309 • Spiera et al. Clin Exp Rheumatol 2001;19:495
Results:
• Have to treat 4 patients with MTX to prevent first relapse • Have to treat 11 patients with MTX to prevent a cranial relapse • MTX was associated with a reduction in cumulative steroid dose • MTX did not reduce frequency of prednisone side effects
Absolute reduction in relapse by MTX is at best very modest Decision to use MTX must weigh risk against small margin of benefit
37/236 Potential Disease Mechanisms in Giant Cell Arteritis
NEJM 2003
Evidence of GCA as an antigen driven disease
Macrophages Dendritic cells T lymphocytes
• Brack et al. Mol Med 1997;3:530 • Weyand, Goronzy. NEJM 2003;349:160 • Ma-Krupa et al. J Exp Med 2004;199:173
When TNF inhibitors became available in the late 1990’s There was interest in whether these would be effective in GCA
Infliximab in Giant Cell Arteritis Hoffman et al. Ann Intern Med 2007; 146:621
Enrolled 44 patients with newly diagnosed GCA
• Primary Endpoint: proportion of relapse-free subjects through week 22 • Safety Endpoint: incidence of adverse events
38/236 Infliximab in Giant Cell Arteritis Hoffman et al. Ann Intern Med 2007; 146:621
Efficacy: 100 90 Proportion of Relapse-Free 80 Subjects through Week 22 70 P=0.651 60 50 No difference in cumulative 50 42.9 prednisone dose 40 30 Safety: 20
Infection: Proportion of Patients (%) 10 0 • 71% infliximab Placebo Infliximab • 56% placebo 5 mg/kg
Infliximab does not provide benefit in the treatment of GCA
Also negative GCA trials with other TNF inhibitors: • Etanercept (Martinez-Taboada et al. ARD 2008;67:6254) • Adalimumab (Seror et al. ARD 2013,July)
Infliximab in Polymyalgia Rheumatica (PMR) Salvarani et al. Ann Intern Med 2007; 146:631
Methods: • 51 patients with newly diagnosed PMR • All received prednisone 15 mg/d tapered to 0 mg/day over 16 weeks • Randomized to receive: infliximab 3mg/kg at weeks 0, 2, 6, 14 and 22 vs placebo
Results: No difference in placebo and infliximab: • Relapse/recurrence at 52 weeks P=0.53 • Relapse/recurrence at 22 weeks • Proportion off steroids at week 22 • Total number relapse/recurrence • Duration of prednisone • Dose of prednisone • Adverse events – 8 in each group
Infliximab does not provide benefit in the treatment of PMR
39/236 NEJM 2003 IL-6 in GCA
IL-6 has been of longstanding Interest in GCA
Utility as a acute phase reactant – variable
• Dasgupta et al. Br J Rheum 1990;29:456 • Roche et al. A&R 1993;36:1286 • Weyand et al. A&R 2000;43:1041 • García-Martínez et al. AC&R 2010;62:835
Expression and production in GCA tissue
• Weyand et al. Ann Int Med 1994;121:484 • Hernández-Rodríguez et al. Rheum 2004;43:294
IL-6
Tocilizumab in GCA
Question: Could tocilizumab provide benefit in GCA ?
GCA GCA Christidis et al. 2011 1 Besada et al. 2012 1 Seitz et al. 2011 5 Unizony et al. 2012 7 Beyer et al. 2011 2 Lurati et al. 2012 1 Sciascia et al. 2011 2 Işik et al. 2012 1 Salvarani et al. 2012 2 Ashraf et al. 2013 1 Vinit et al. 2012 1 Loricera et al 2014 22
• Overall a beneficial response was observed
• 1 report of active vascular inflammation seen on histology despite treatment with tocilizumab (Unizony et al. AC&R 2012;64:1720)
• Supported the need for further study
40/236 Tocilizumab (Anti-IL6 Receptor) Villiger PM et al. Lancet 2016; 387:1921-7
• Design – Phase 2 double-blind, newly diagnosed or relapsing GCA – Randomized 2:1 - 20 Tocilizumab/prednisone vs 10 placebo/prednisone – Standardized prednisolone taper – 1mg/kg/day to ~ 7 mg/day week 12 • Results – Week 12 remission: 85% Toc/pred vs 40% placebo/pred (p=0.05) – Week 52 remission: 85% toc/pred vs 20% placebo/pred (p=0.001) – Serious adverse events: 35% toc/pred vs 50% placebo/pred (p=0.46) – GI adverse events: 4 toc/pred (3 serious) vs 1 placebo/pred
• Challenges with tocilizumab in GCA: – Acute phase reactants (ESR and CRP) are suppressed by this agent – Potential for side effects (cytopenias, AST/ALT, lipids, GI perforation) – Not a replacement for prednisone – used together
Efficacy of anti-IL-6 is encouraging Results from a large phase 3 study pending (GiACTA)
Abatacept in Giant Cell Arteritis
T cell activation has been felt to play an important role GCA
Abatacept (CTLA4-Ig)
Intervention with T cell activation
Studies of Abatacept in GCA and TAK (AGATA) • Multicenter, randomized withdrawal design trial • Presented at 2016 ACR late-breaking abstracts (Langford et al. A & R 2016) • Further results to be provided in publication
41/236 Th17 Pathways in Giant Cell Arteritis
Deng et al. Circulation 2010;121:906
Examined Th17 pathways in peripheral blood and temporal artery biopsies
• Circulating Th1 and Th17 cells expanded
• Glucocorticoids (GC) suppressed IL-17 producing cells, spared cells secreting IFN-
• GC inhibited Th17 promoting cytokines and recruitment and survival of Th17 cells
Suggests that 2 distinct T cell subsets promote vascular inflammation in GCA Future avenue for therapeutic investigation ? (GC Sensitive) (GC Resistant)
What About B Cell Depletion in GCA ?
Interest in B cell based therapies was initially limited due to the paucity of evidence supporting their participation in pathogenesis
Hoyer et al. Ann Rheum Dis 2012; 71:75 • 17 TAK patients - observed disturbances of B cell homeostasis in which increased numbers of plasmablasts correlated with disease activity • 3 patients with refractory TAK treated with rituximab achieved remission
Three other case reports of rituximab use in TAK and GCA • Bhatia et al. Ann Rheum Dis 2005; 64:1099 • Galarza et al. Clin Rev All Immunol 2008; 34:124 • Ernst et al. Case Rep Rheum 2012: Epub
Unclear if rituximab warrants further study in GCA No current clinical role for B cell depleting therapies in GCA
42/236 Is Treatment of GCA Large Vessel Disease Different ?
• Unknown • Trials in GCA have almost exclusively involved cranial disease • Might other agents play a greater role in GCA large vessel disease ?
ie: Methotrexate is used in Takayasu arteritis - However -
Even in Takayasu, methotrexate use is based only on open-label trials
Currently, GCA large vessel and cranial disease is treated similarly Potential exists for there to be differences in treatment responsiveness
Giant Cell Arteritis Non-Medical Management of Large Vessel Disease
Surgical treatment for sequelae of aneurysmal disease • Aortic root / valve replacement • Aortic aneurysm thoracic / abdominal
Non-medical management of fixed stenotic lesions causing ischemia • Severe limb claudication affecting quality of life • CNS: TIA / cerebral ischemia / stroke • Renal artery stenosis (hypertension, renal insufficiency) • Angina • Bowel ischemia / infarction
Interventional recommendations: • If possible, avoid intervention during active disease • Base stenosis intervention on symptoms – not just presence of lesion • Avoid arm intervention unless symptoms are severe – collateral potential
43/236 Giant Cell Arteritis Non-Medical Management of Large Vessel Disease stents
Modalities:
• PCTA • Stent • Open surgical bypass
bypass
Limitation of revascularization – occlusion Patency rate has varied between series Long-term series are important to assess efficacy
Giant Cell Arteritis Non-Medical Management of Large Vessel Disease
Liang et al. J Rheumatol 2004; 31:102 Data on 52 revascularization procedures in Takayasu arteritis
Procedure # performed Occlusion # (%) Time to occlusion
PCTA 7 3 (43%) 1-72 months Stent 7 5 (71%) 2-45 months Bypass 31 11 (35%) 1 day -168 months
Endovascular revascularization procedures (PCTA, stent) are associated with: • Good short-term outcome • Favorable safety with low morbidity/mortality • High long-term failure rate in TAK
Surgical bypass grafts have the best long-term outcome TAK Although non specifically studied in GCA – would view this similarly
44/236 Giant Cell Arteritis Outcome Mortality
• GCA does not influence overall patient survival (Matteson et al. A&R 1996) • Large vessel disease does not lower survival (Nuenninghoff et al. A&R 2003) • Increased in 1st 2 years in > 70 years (Mohammad et al. ARD 2014; Jan) • Thoracic aortic dissection in GCA is associated with increased mortality
Morbidity
• Substantial ! • Much is a result of glucocorticoids • Disease related morbidity: Cranial ischemic events: blindness Large vessel events: Stroke, extremity claudication • Appears to be an increased risk of cardiovascular events (MI/CVA/PVD) particularly within 1st month (Tomasson et al. Ann Int Med 2014; 160:73)
Giant Cell Arteritis Summary
• GCA is an important disease of older individuals • GCA - cranial and large vessel disease, PMR, systemic inflammation • Large vessel thoracic aorta aneurysms can occur late and cause mortality • Morbidity occurs as a result of both disease and treatment
• Glucocorticoids prevent blindness and are the foundation of GCA treatment • Patients may require prednisone for over 4 years • Aspirin 81 mg/d should be given with prednisone when possible • To date, there remain no efficacious treatments beyond prednisone+aspirin
Future questions: – how do we better assess disease activity in GCA ? – if GCA is an antigen driven disease - what is the antigen ? – why are certain vessels preferentially affected in GCA ? – are GCA and TAK part of the same spectrum or are they unique diseases ? – how can understanding these lead us to novel treatments ?
45/236 RECENT ADVANCES IN SLE THERAPY: DEVELOPMENT OF TARGETED THERAPIES Richard A. Furie, MD
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Sherry, MD SATURDAY, SEPTEMBER 17TH 10:30 AM – 11:30 AM 81/236 Complex Regional Pain Syndrome, Fibromyalgia & Amplified Pain Syndromes David D. Sherry, MD The Children’s Hospital of Philadelphia DISCLOSURE Relevant Financial Relationships None Off Label Usage None Industry Acknowledgment None 82/236 Learning Objectives 1. Recognize the different clinical patterns of pain in amplified musculoskeletal pain (e.g., with and without overt autonomic changes) 2. Understand how to check for allodynia 3. Understand the principles behind and the outcome of a therapeutic exercise program 4. Identify the characteristic profile of children with amplified musculoskeletal pain Who are these kids? How to establish a diagnosis? How do we explain it? How do we treat it? Does it work? 83/236 PAIN • Definitions are important PAIN • An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage • Pain is always subjective 84/236 PAIN TERMS • ALLODYNIA – pain due to stimulus that does not normally provoke pain • HYPERALGESIA – an increased response to a stimulus that is normally painful • HYPERESTHESIA – allodynia and hyperalgesia 85/236 STORIES • 12 y.o. girl with cold, blue foot, no sock, on crutches and pain spreading up leg/hand • 13 y.o. girl cannot bend her knee or walk and cannot read (can see) • 8 y.o. boy cannot go to school after playing soccer - crawls about home • 12 y.o. girl who cannot sit down for 2 years • 13 y.o. boy with shoulder pain after basketball & traveling pains • 14 y.o. girl with 1 year widespread pain, +ROS, poor sleep, depressed all are suffering Amplified Pain Syndromes Fibro & All can be hypervigilant total Intermittent body No autonomic CRPS1 changes – localized & diffuse 86/236 Sleep • Poor sleep, little sleep, unrested. • Is it a disorder or a complaint? • They do not fall asleep in school. Alpha-delta sleep in fibromyalgia Alpha delta sleep Alpha-delta sleep Total sleep time (minutes) (% of total slow (minutes) wave sleep) Patients, pre- 60 70 397 treatment Patients, post- 56 74 409 treatment Controls 17 22 454 Pre treatment Post treatment P Sleep difficulty 55 21 0.008 (100 worse) Lack of Energy 62 16 0.001 (100 worse) Sleep 2013;36(4):509-516. 87/236 Sleep • Sleep hygiene – No caffeine – soda, tea, coffee – No exercise for 2-3 hours before bedtime – No TV, radio – If don’t get to sleep in 30 minutes, get up and do something non-stimulating • Fix the sleep and you WILL NOT fix the pain – sleep apnea folks do not hurt • Medication does not help but it will make it your problem to fix them Amplified Pain • Females • Mean age 12 years • Mean duration is > 1 year • Most have constant pain • Pain may be in multiple sites 88/236 Sex Race 11% 5% White Black Hispanic-Latino 84% 89/236 Forms of Amplified Pain Localized Pain Location 90/236 Historical Clues • Increasing pain over time • Worse with rest, cast, splint • Failed all prior therapy or side effects Past Medical History Clues • Slow healer • Positive Review of Symptoms • High level athlete or dancer 91/236 Social History Clues • Major life events • Role model for chronic pain • Typical personality – mature – excels – pleaser – perfectionistic Physical Exam Clues • Spokes-mother • Pseudo-mature • Incongruent affect • La belle indifference • Enmeshment – very subjective 92/236 Autonomic Signs • Cold • Cyanotic • Clammy • Decreased pulse • CHECK AFTER EXERCISE • Dystrophic skin 93/236 94/236 95/236 Trigger Points Hard to know what they mean occiput lateral C-spine trapezius 2nd rib scapula epitrochlear gluteal fold posterior greater trochanter medial knee Need 3 months of widespread pain to apply 96/236 Now painful areas shoulder girdle upper arm lower arm buttocks/trochanter upper leg lower leg jaw upper back lower back chest abdomen neck Need 3 months of widespread pain to apply PLUS Symptoms fatigue unrefreshed sleep cognitive irritable bowel abdominal pain hair loss hives urinary frequency numbness chest pain bruising Raynaud blurred vision nervousness dry mouth dizziness etcetera, etcetera, etcetera 97/236 Check for Conversion • Stiffness • Paralyzed • Shaking • Conversion gait • Non epileptic spells • Blind, deaf, memory loss Conversion in Fibromyalgia 45 of 64 (70%) 98/236 After 11 days ketamine coma and 40 boosters Conversion fist 99/236 Post spinal cord stimulator and conversion plantar flexion Pain and conversion 100/236 Conversion symptoms seen Motor, stiffness 29 Memory loss 3 Gait (astasia-abasia) 14 Weakness 3 Dizziness 8 Blindness 2 Motor, paralysis 7 Coma 2 Twitching, shaking 6 Breathing symptoms 1 Loss of voice 5 Inability to eat 1 Numbness 5 Regression 1 Pseudo-seizures 4 (Self mutilation) 5 Could not write: 101/236 Cutting 102/236 Allodynia • Light touch • Gentle pinch of a fold of skin • CHECK BORDERS REPEATEDLY – may vary 4 to 12 cm within seconds Laboratory Studies • Blood studies – normal • Radiographs – normal or osteoporosis • Bone Scan – decreased – can be normal or spotty (adult-like) • MRI – edema – soft tissue & bone 103/236 104/236 MRI – bony edema Working Model of Pain • Makes the pain understandable (real) • They are not faking it • Pain can arise from: – injury – illness – psychological stress 105/236 Treatment • Discontinue medical investigations • Discontinue medications 106/236 <0.001 Professionals seen <0.001 Therapies tried <0.001 Medications tried <0.001 Hospitalizations 0.051 Aids <0.001 Past surgeries <0.001 Procedures done 2008 2009 2010 2011 2012 2013 2014 P Age141514141414140.195 FDI282322232022190.127 Pain score76666660.145 Kaufman KL, et al. Pain Medicine 2016 doi: 10.1093/pm/pnw188 Treatment • MORE EXERCISE THAN YOU CAN IMAGINE • DESENSITAZATION 107/236 Exercise Therapy • 5-6 hours a day of PT/OT • Continuous aerobic activities • Focus on function - real activities • Desensitization – towel and lotion rubs – massage Outcome • Within 1-2 weeks 80% fully functional • Within 1st month 95% fully functional • Within 1st month 75% pain free • ~10% fail - need psychotherapy before they can allow themselves to get better • Clinical Journal of Pain 1999;15:218-23 108/236 Outcome - CRPS 103 Patients • 103 patients treated with exercises – 95 (92%) resolved their pain and function – VAS initially 76 out of 100 maximum • Those in remission (n=77): 1 – 3-20 in 8 children with overuse/mechanical pains • those not in remission (n=7): 58 • 49 followed for over 2 year (mean 5y3m) – 43 (88%) had no symptoms of CRPS • Clinical Journal of Pain 1999;15:218-23 Outcome - CRPS 103 Patients • Relapses – 15 of 49 (31%) had relapses (some without autonomic signs) – median time to relapse was 2 months, 79% were within first 6 months – most resolved quickly with reintroduction of exercise (half at home by self and half at hospital with PT/OT) – Clinical Journal of Pain 1999;15:218-23 109/236 Outcome - CRPS 32 patients • Portland/Pittsburgh – 89 % no pain – 95% full function in 2 months – 7 recurred – 5 treated themselves PMR 2012;4:349-54 Outcome - CRPS 56 Patients • Boston • Old study with drugs 70 patients – 42% significantly better • New study 56 patients – 95% significantly better J Bone Joint Surg AM 1992 74:910-9 Clin J Pain 2012 28:766-74 110/236 After 5 months and 8 blocks 111/236 7 days later with just exercise therapy Fibromyalgia (diffuse) 10 patients - sleep study Baseline post-Rx P FDI 31 4 .004 Pain VAS (100 mm) 65 17 .000 Functional disability inventory 0-12 normal 13-28 moderately disabled 29+ severely disabled Sleep 2013;36(4):509-516. 112/236 Fibromyalgia 64 patients – 1 year outcome Entry Exit 1 year F/U P entry/end P end/1yr FDI 24 7 5 <.001 .12 Pain VAS 66 25 20 <.001 .05 BOT-2 total 24 54 69 <.001 .05 Bruce 9.8 13.4 12.5 <.001 .005 Peds QL 48 66 78 <.001 <.001 Physical health 31 63 78 <.001 <.001 Emotional 50 60 75 <.001 .070 Social 70 85 90 <.001 .140 School 50 55 80 .002 <.001 J Pediatr 2015;167(3):731-737 Mean age 16 years, 94% girls, 95% white Fibromyalgia 64 patients – 1 year outcome Entry Exit 1 year F/U P entry/end P end/1yr FDI 24 7 5 <.001 .12 Pain VAS 66 25 20 <.001 .05 BOT-2 total 24 54 69 <.001 .05 Bruce 9.8 13.4 12.5 <.001 .005 Peds QL 48 66 78 <.001 <.001 Physical health 31 63 78 <.001 <.001 Emotional 50 60 75 <.001 .070 Social 70 85 90 <.001 .140 School 50 55 80 .002 <.001 J Pediatr 2015;167(3):731-737 Mean age 16 years, 94% girls, 95% white 113/236 Fibromyalgia 64 patients – 1 year outcome Entry Exit 1 year F/U P entry/end P end/1yr FDI 24 7 5 <.001 .12 Pain VAS 66 25 20 <.001 .05 BOT-2 total 24 54 69 <.001 .05 Bruce 9.8 13.4 12.5 <.001 .005 Peds QL 48 66 78 <.001 <.001 Physical health 31 63 78 <.001 <.001 Emotional 50 60 75 <.001 .070 Social 70 85 90 <.001 .140 School 50 55 80 .002 <.001 J Pediatr 2015;167(3):731-737 Mean age 16 years, 94% girls, 95% white Fibromyalgia 64 patients – 1 year outcome Entry Exit 1 year F/U P entry/end P end/1yr FDI 24 7 5 <.001 .12 Pain VAS 66 25 20 <.001 .05 BOT-2 total 24 54 69 <.001 .05 Bruce 9.8 13.4 12.5 <.001 .005 Peds QL 48 66 78 <.001 <.001 Physical health 31 63 78 <.001 <.001 Emotional Fun. 50 60 75 <.001 .070 Social Function 70 85 90 <.001 .140 School Function 50 55 80 .002 <.001 J Pediatr 2015;167(3):731-737 Mean age 16 years, 94% girls, 95% white 114/236 Outcome other symptoms • Suicide attempts • Eating disorders • Other body pains –abdomen, head, sinus, eye, teeth • Conversion disorders –paralysis, blind, pseudoseizures Age N patients with suicidal patients with suicidal Total patients with thoughts only attempts suicidality N (%) N (%) N (%) 11 65 10 (15%) 2 (3%) 12 (19%) 12 93 10 (11%) 0 (0%) 10 (11%) 13 85 10 (12%) 1 (1%) 11 (13%) 14 123 14 (11%) 3 (2%) 17 (14%) 15 142 24 (17%) 1 (1%) 25 (18%) 16 152 27 (18%) 4 (3%) 31 (20%) 17 96 15 (16%) 6 (6%) 21 (22%) Total 756 110 (15%) 17 (2%) 127 (17%) 115/236 Stress? • It is Okay to talk about stress • Most parents are very interested in their child’s emotional wellbeing • After discussing it in a straightforward manner, you might learn more than you want to • Need to talk about conversion matter of fact fashion Stresses • Most are issue identification • Family dynamic dysfunction • Martial discord (covert > overt) • School avoidance • Abuse - sexual/physical/emotional • RARELY depressed (10%) 116/236 Counseling • Not traditional pain counseling • People who go to counseling are not dumb or crazy • Counselors are experts in feelings and emotions • What do you tell a counselor? What you really, really DO NOT want to tell him or her 117/236 What is a country doctor to do? • Recognize it • No further investigations unless absolutely indicated • Sympathize and acknowledge the pain as real but resist urge to throw medications at pain and sleep • Work with a physiotherapist to get the child moving – despite pain • Discuss stress and have it addressed • Follow-up in a month Final Analysis • Great kids who are in real need • We can significantly not only address their symptoms (short term benefit) but also address psychological dysfunction (long term benefit) • Very time consuming – for entire team • Very rewarding 118/236 Thank you References in handout StopChildhoodPain.org Free code: painfree 119/236 ANNUAL BUSINESS MEETING SATURDAY, SEPTEMBER 17TH 12:55 PM - 1:30 PM 120/236 Annual Business Meeting September 17, 2016 Agenda • Membership Update • Corporate Partnership Update • Financial Update • Annual Meeting Update • Affiliate Activity & Outreach • Accomplishments • Closing Remarks 121/236 Our Members Current Membership ‐ 116 Active – 91 Affiliate – 5 Trainees/Medical Students – 12 Retired – 8 Members Joined Since October 2015 – 28 Potential Members* – 134 *PA Licensed physicians designating rheumatology as a primary interest Corporate Partnerships 2016 Mallinckrodt Pharmaceuticals Bristol‐Myers Squibb Amgen Pfizer Abbvie Janssen Genentech 122/236 Financial Statement July 31, 2016 ASSETS Cash – Checking ($1,775.00) Cash Management – Fulton 66,425.59 Total Cash 64,650.59 Accounts Receivable 00.00 Prepaid Expenses 00.00 TOTAL ASSETS 64,650.59 LIABILITIES AND NET ASSETS Accounts Payable, General 00.00 Accounts Payable – PAMED 2,586.98 Unearned Revenue 00.00 Total Liabilities 2,586.98 Net Assets, January 1 25,198.87 Change in Net Assets 36,864.74 Net Assets, Year to Date 62,063.61 TOTAL LIAB AND NET ASSETS 64,650.59 Thank you for attending the 3rd Annual Scientific Meeting of the Pennsylvania Rheumatology Society 123/236 Affiliate Activity & Outreach • PAMED Specialty Leadership Cabinet Representative – Dr. Phillip Cohen • ACR Affiliate Society Council Representative – Dr. Paul Killian Biosimilar Substitution, Step Therapy, Prior Authorization, and Specialty Tiers. • Medicare (Novitas) Carrier Advisory Committee – Dr. Alan Roumm Accomplishments • Re‐established The Rheumatology News quarterly e‐newsletter to members • Welcomed 28 new PRS members • Increased Corporate Partners from 5 to 7 124/236 Closing Remarks 125/236 Sunday, September 18th Lectures Your Clinic Patient – A “Walking Culture Dish” with Implications for Autoimmunity Martin A. Kriegel, MD, PhD 1 AMA PRA Category I CME Credits™ Psoriatic Arthritis Update Christopher T. Ritchlin, MD, MPH 1 AMA PRA Category I CME Credits™ Raynaud’s Disease, Evaluation and Treatment Laura K. Hummers, MD, ScM 1 AMA PRA Category I CME Credits™ Uveitis from the Rheumatologists’ Perspective Lisa A. Lerman, MD, PhD, MSCE 1 AMA PRA Category I CME Credits™ iPad Air 2 Drawing iPad drawing will take place on Sunday morning immediately following the am break at 10:30 am. You must be present to win. In the event an attendee is selected and they are not present, we will draw another name to win. PRS program committee not eligible to win. 126/236 YOUR CLINIC PATIENT – A “WALKING CULTURE DISH” WITH IMPLICATIONS FOR AUTOIMMUNITY Martin A. Kriegel, MD, PhD SUNDAY , SEPTEMBER 1 8 TH 8:00 AM – 9:00 AM 127/236 Your Clinic Patient – A “Walking Culture Dish” with Implications for Autoimmunity Pennsylvania Rheumatology Society September 18, 2016 Martin A. Kriegel, MD PhD Assistant Professor of Immunobiology Assistant Professor of Medicine Yale School of Medicine Overview 1. Commensal‐immune interactions and how to study them 2. The role of commensals in rheumatic diseases 3. Diet, drugs, vaccines & the microbiota 4. Emerging therapies in the microbiome field 128/236 Nature 2010 Immunity 2009 129/236 Th17 Treg Cha et al, J Immunol 2010 Smith et al, Science 2013 Brestoff & Artis, Nat Immunol 2013 The Extended Self Treg Atarashi et al, Nature 2013 Lathrop et al, Nature 2011 Cebula et al, Nature 2013 Graphiko.com 130/236 Sulfasalazine Acetaminophen E. lenta Digoxin Science 2012 Drug Metabolism Davila et al, Nat Rev Rheum 2011 131/236 Operational Taxonomic Units Phylogeny versus Function – That is the Question 16S Nature, 2012 132/236 Color Atlas of Immunol (Thieme) 2003 133/236 Dreamstime.com Requirements B27 Peptide Gut Bacteria Arthritis Yes Yes Colitis No Yes Skin/Genital No No Hammer et al, Cell 1990 Taurog et al, J Exp Med 1994 Lesions Taurog et al, Immunol Rev 1999 Color Atlas of Immunol (Thieme) 2003 134/236 Segmented Filamentous Bacteria Induce Th17 Cells Kriegel et al, PNAS 2011 Yurkovetskiy et al, Immunity 2013 Wu et al, Immunity 2010 Lee et al, PNAS 2011 Ruff & Kriegel, Trends Mol Med 2015 SFB‐induced Inflammatory Arthritis Teng et al, Immunity 2016 135/236 Prevotella copri in American vs Chinese Patients with early RA Scher et al, eLife 2013 Zhang et al, Nat Med 2015 P. Copri Drives Experimental Arthritis Maeda et al, A&R 2016 136/236 Citrullination & P. gingivalis •Is P. gingivalis Peptidyl Arginine Deiminase (PPAD) implicated in Periodontal Disease (PD) and RA? • “PPAD autocitrullination is not the underlying mechanism linking PD and RA” • “Anti-PPAD antibodies may have a protective role for the development of PD in patients with RA” • “If P. gingivalis plays a role in RA, it is unlikely to originate from a variation in PPAD gene expression” Konig et al, Ann Rheum Dis 2014 Gabarrini et al, Sci Reports 2015 Native vs Citrullinated Antigens Native Cit. Antigen Early Late RA Mild Aggressive RA Th17 Hajishengallis, Nat Rev Immunol 2015 De Aquino et al, J Immunol 2014 Konig et al, Ann Rheum Dis 2016 137/236 Infections = Most common precipitating factor of CAPS BMJ 2010 Kriegel & Bermas, BWH Expert Approach 2010 Sweiss et al, PLOS One 2011 Murthy et al, Arthritis Rheum 2013 138/236 Antibiotic Depletion of the Gut MicrobiotaPrevention of Thrombotic Events in an APS Model Heart Lung Brain CTRL ABX Single Antibiotics Prevent Systemic Autoimmunity Days Vieira et al, in preparation 139/236 Coriobacteriaceae as Prime Candidates in Mouse and Man Fecal Samples from Patients – Longitudinal Cohort Ruff et al, ACR 2016 Chronic Commensal Cross-reactivity with Autoantigens Abbas; Cell Mol Immunology, 7th Ed. 140/236 Ro60 = Primordial Antigen ‐> Epitope spread Phylogenetic Tree of Ro60 Orthologs Sim & Wolin WIREs RNA, 2011 141/236 Subacute Cutaneous Lupus Erythematosus Courtesy of R.A. Vleugels Koster et al, J Mol Biol 2012 Autoantigen Ro60 T Cell Orthologs within Commensals NCT02394964 Greiling et al, in preparation Anti‐human Ro60 Autoantibodies in MonocolonizedELISA hRo60 monocolonized C57Bl/6 Mice sera 1.5 **** 1 2 3 4 5 6 **** 7 1.0 8 9 10 11 12 *** 13 OD650-450 14 15 0.5 GF 1 GF 2 *** N.S. 0.0 0 00 0 00 :250 1 1:5 :2000 1:10 1 1:40 Serum Dilution Greiling et al, in preparation 142/236 The Microbiota Antigen‐specific memory Diet, Medications, Infections Arbuckle et al, NEJM 2003 Hand et al, Science 2012 Diet: Shaping the Microbiota and the Host Western diet Mixed and • High fat‐high sugar constant • Low fiber Dietary Carnivorous diet • Food excipients diet fiber Vegetarian diet Resistant Vegetarian Starch Carnivorous Increased Mixed diet Bacteroidetes Increased Western diet Firmicutes Increased microbiota Decreased diversity microbiota diversity High‐Amylose Maize Starch Adapted from De Filippo et al. PNAS 2010 143/236 Starch Diets in a Lupus Model Starch #1 Starch #2 Control Diet * Mucosal Immunity Starch Microbiota SLE Systemic Immunity (CRMO) Chronic Recurrent Multifocal Osteomyelitis Lukens et al, Nature 2014 144/236 The Challenge PNAS 2011 Science 2012 IBD as a Paradigm Hecht, NEJM 2008 Garrett et al, Cell Host Microbe 2010 145/236 DMARD Responsiveness in RA Zhang et al, Nat Med 2015 Pneumonitis Colitis Hepatitis Nephritis Thyroiditis Nivolumab Pardoll, Nat Rev Cancer 2012 146/236 Oh et al, Immunity 2014 Novel Therapies on the Horizon? 147/236 Relman, Nat Biotech 2013 including C. scindens Buffie et al, Nature 2014 148/236 H. Pylori Eradication in ITP Importance of Biogeography Response Rate Atlas of Science Frydman et al, Helicobacter 2015 149/236 “Non‐Barrier” Autoimmunity Ruff & Kriegel, Trends Mol Med 2015 http://medicine.yale.edu/lab/kriegel Bill Ruff, Silvio Vieira, Carina Dehner, Teri Greiling, Daniel Zegarra Ruiz, Julia Kline, Christina Kriegel, Rahul Datta, Nina Brodsky, Alonso Iniguez, Xindi Chen Collaborators Andrew Goodman (Yale), Sandra Wolin (Yale), Doruk Erkan (Cornell/HSS) Funding NIH R01, K08 150/236 Tri‐ TMAO Methyl‐ Amine N‐ Oxide Nature, 2011 Predictors of Autoimmunity? Kostic et al, Cell Host Microbe 2015 151/236 Vieira et al, Lupus, 2014 Anti-Ro60 Autoimmunity Originating from Human Ro60+ Commensals UV Ro60 Keratinocyte Apoptosis SCLE Ro60 Anti‐Commensal CD40L and Autoimmune Response B Cell Tfh Cell Homeostatic Anti‐Commensal Response Gut Epithelium Mucus SLE/NLE Layer Ro60 152/236 PSORIATIC ARTHRITIS UPDATE Christopher T. Ritchlin, MD, MPH SUNDAY , SEPTEMBER 1 8 TH 9:00 AM – 10:00 AM 153/236 Psoriatic Arthritis Update Christopherp er Ritchlin,, MD,D, MPH ProfessorProfessoor ofof MedicineM Chief AllergyAllerlerrggygy, IImmunologymmunology & Rheumatology DivisioDivisionn Directorr Translational Immunology Research Center Disclosures Consultant Research AbbottAbbott AmgenAmgen AmgenAmge UCB Lilly Abbvie Janssen NovartisNovartis Sanofi UCB Pfizer 154/236 Evidence Based Medicine 1.Moll J, Wright V. Psoriatic arthritis. Sem Arthritis Rheum 1973; 3(1):55 2. Farth K. Genetic and epigenetic fine mapping of causal autoimmune disease variants. Nature 2015:337. 3. Fitzgerald O. Concepts of pathogenesis in psoriatic arthritis: genotype determines clinical phenotype. Arthritis Res Ther. 2015;17:115. 4. Ritchlin, CT. Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. J Clin Invest. 2003;111(6):821. Overview Psoriatic arthritis and Axial SpA Updates Pathogenesis Clinical Perspectives Emerging therapies Treatment Recommendations Treatment horizons 155/236 Accelerated Drug Development in PsA 1973-2003 2003-2012 2013 2014 2015 2016- Gold TNFi UST APR Sec* Ixe Sulfa Brod MTX Combo HCQ IL-23 LEF IL-22 TNFi therapy in PsA: Phase III trials 90 ACR 20/50/70 PASI 50/75/90 80 70 60 50 40 Patients (%) Patients 30 20 10 0 IFX GLM ETN ADA CZP 200 mg CZP 400 mg 156/236 Pathogenesis Genetic Risk Factors in PsA HLA-B IL-23R PsA specific PTPN22 CD8+ memory T cells O’Reilly. Nature Rev Rheum 2011. Bowes J. Nature Comm. 2015157/236 Genotype predicts phenotype Joint deformities and ankylosis B*08:01-C*07:01:01 Dactylitis B*08-B*27 Enthesitis B82705-C:01:07 Fitzgerald O. Arthritis Res Therapy 2015 Farth NK. Nature Feb 19 2015 158/236 T Cell Subsets in SpA Lymphocyte populations in PsA synovial fluid Menon B. Arthritis Rheum 2014 Leijten E. A & R 2015 online159/236 Innate and adaptive lymphocyte subsets GasteigerGasteiger G. NatNat RRevev ImmImmunouno 20142014 IL-23 and resident T cells promote enthesitis and osteoproliferation Sherlock J. Nature Med. 2012; 18(7):1018 160/236 IL-23/Th17 pathways in murine models Model Manipulation Skin/Nails Joint Enthesitis Dactylitis Ref DBA/1 Male/trauma +++ +1,2 ZAP 70 Curdlan inj + + + 2-4 K749 KI Cross with +++ +5 K5.Stat.3C B10Q Mannan inj + + + + 6 1. Braem K, Biological procedures online. 2012;14(1):10. 2. Ebihara S. Autoimmunity. 2014:1-8. 3. Benham H, Arthritis Rheum. 2014;66(7):1755-67. 4. Rehaume LM Arthritis Rheum. 2014;66(10):2780-92. 5. Ruutu M, Arthritis Rheum. 2012;64(7):2211-22. 6. Khmaladze I, PNAS 2014;111(35):E3669-78. Synovial Histopathology of PsA SpA tissues (PsA, AS, USpA): more vascularity, neutrophil and CD 163+ macrophage infiltration No citrullinated proteins in polyarticular PsA Synovial histopathology of PsA (either oligo or poly) resembles other SpA subtypes more than RA. Both groups can be differentiated from RA KruitofKruitof E AArth.rth. RReses TheTherr 2005 Canete J. Ann Rheum Dis 2007 161/236 What are the defining histopathologic features of RA and PsA? • Power Doppler ultrasound biopsies performed on 32 PsA and 23 RA treatment naïve patients with arthritis for <12 months duration • Patients were well matched on BL characteristics • Gene expression of pro-inflammatory cytokines (TNFα, IL-1B, IL-6, IL-23, IL- 17A, IL-12A ) was comparable between PsA and RA PsA RA Histologic parameter (n=30) (n=20) Synovitis score, mean (SD) 3 (2) 5 (2)† Aggregational score, 0.9 (1) 1.9 (1)† mean (SD) Histopathotype, n (%) Lymphoid 23 (7) 57 (13)* Myeloid 37 (11) 30 (7)* PsA synovial tissue has less T cell Fibroid 40 (12) 13 (3)* infiltration, lower synovitis scores, CD3 score, mean (SD) 0.8 (0.8) 1.9 (1.3)‡ and a more fibroid pathotype than CD20 score, mean (SD) 0.7 (1.1) 1.7 (1.6)* RA despite similar levels of cytokine CD68SL score, mean (SD) 1.8 (1.1) 2.8 (1.2)† gene expression, suggesting CD138 score, mean (SD) 0.9 (1.2) 1.9 (1.6)† divergent disease pathways *P≤0.05,α†P≤0.01,α‡P≤0.001αvsαPsA Nerviani A et al. EULAR 2016, London, #FRI0442 Copyright 2016 TREG Consultants LLC Gene expression in PsA closer to psoriasisriasis tthanhan ootherther fformsorms ofof aarthritisrthri 162/236 Belasco J. Arthritis Rheum 2015;67(4):934.2015;67(4):93 Clinical Perspectives RAPID3 as a disease outcome measure in PsA • Sub-analysis of Tight Control of Psoriatic Arthritis (TICOPA) • RAPID3 was highly correlated Baseline 10.00 12 weeks with PASDAS (Pearson 24 weeks correlation 0.794, P<0.01)), 36 weeks 8.00 48 weeks responsive to change, and discriminated well between 6.00 treatment groups • Little added value with inclusion 4.00 of skin VAS (RAPIDPs) RAPID3 score (Pearson correlation 0.831) 2.00 0.00 -2.00 0.00 2.00 4.00 6.00 8.00 10.00 PASDAS RAPID3 is a potentially valuable clinical response measure in PsA 163/236 Coates LC et al. EULAR 2016, London, #THU0419 Copyright 2016 TREG Consultants LLC Patient Perspectives: MAPP Survey Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) in US, Canada,, Europep 3426 patients surveyedd 21% psoriasis Lebwohl M. JAAD 2014; May 2014 Undiagnosed Psoriatic Arthritis 164/236 Vallani AP JADD 2015;73(2):243 Delay in Diagnosis >6 months Erosive Deformed Arthritis Disease Joints Mutilans OR 4.6 OR 2.3 OR 10.6 Functional Drug Free Sacroiliitis Disability Remission OR 2.3 OR 2.2 OR 0.4 Courtesy of Laura Coates Haroon M, et al. ARD 2014 Low correlation between psoriasis and PsA activity Wittkowski K. PLoS One 2011 165/236 New Therapies Tight control of early PsA (TICOPA) • 48 week UK multicenter, open-label RCT – 206 pts with early DMARD naive PsA (<24 months symptoms) • Median age 45, 52% male, 71% polyarthritis • 1° outcome: ACR20 at 48 weeks 70 62 59 • Tight control (TC): 101 pts, q4 wk visits; 60 MTX escalation to 25 mg targeting 51 MDA, then combo DMARDs, then TNFi 50 45 40 38 at 24 wks if ≥ 3 active joints (or 33 alternative DMARD if not MDA but <3 30 25 active joints) 20 17 • Usual care: 105 pts, q12 Wk visits – no % patients set protocol, limitations 10 • SAEs in 20 patients (14 TC, 6 usual 0 care) ACR20 ACR50 ACR70 PASI75 TC Usual care Tight control of PsA disease activity using a treat-to-target approach significantly improves joint and skin outcomes for newly diagnosed PsA pts 166/236 Coates L, Lancet 2015 TICOPA: Prescribed therapy at 12 and 48 weeks 100 4.2 7.6 12 N=206 37 80 43.4 Biologic 60 Combination DMARD 77.9 22.8 LEF 40 55.4 SSZ Patients (%) 51.5 MTX 20 29.3 No treatment 14.7 14.1 6.5 0 3 Tight Standard Tight Standard control care control care 12 weeks 48 weeks Tight control: more combination therapy at 12 wks, more biologics by 48 wks Coates L. Lancet online; Oct 2015 Copyright 2013 TREG Consultants LLC APR: 3-year results PALACE 4, safety PALACE 1-3 ACR20 • 527 patients randomized to placebo, APR 30 mg BID, APR 20 mg BID1 • 1o endpoint: ACR20, Wk 16: – PBO 17%, APR20 29%, APR30 32% • Most common AEs: URTI (3%) and nasopharyngitis (4%) • SAEs in 5.2% ACR50 • 3-year integrated safety analysis of PALACE 1-3 – no new safety signals2 • 1 withdrawal during Year 3 for diarrhea in APR20, none in APR30 ACR70 • Sustained response in DMARD-naïve pts • No new safety signals 1. Wells AF et al. EULAR 2016, London, #THU0422; 167/236 2. Mease PJ et al. Ibid, #THU0470 Copyright 2016 TREG Consultants LLC Targeting the IL-17 Pathway Patel D Immunity 2015 43:1040 SEC subcutaneous only in PsA: FUTURE 2 1,2,3 TNFi-naïve (65% of pts) TNFi-IR (35% of pts)1,2,3 • 397 adadults, active PsA, injections at baseline, Weeks 1, 2, 3, 4, then q4w 70 64 58 70 60 60 ‡ SEC 300 (n=100) 50 44 50 46 SEC 150 (n=100) 37 38 SEC 75 (n=99) 40 40 ‡ 27 30 27 PBO (n=98) 30 25 22 30 19 16 15 15 20 20 14 11 6 6 669 10 2 10 0 Responders (%) Responders 0 0 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 100 Dactylitis resolution2,5 100 Enthesitis resolution2,5 100 PASI 754,5,6 80 § 80 80 * § § 63 § 57 ‡ 60 50 60 48 60 48 42 40 30 40 32 40 28 22 Patients (%) Patients 16 20 15 20 20 0 0 0 Both doses effective. Consider 300 mg in TNFi-IR? *P<0.0001; †P<0.001; §P<0.01; ‡P<0.05 at Week 24 McInnes I Lancet 2015 386;9999:1137 168/236 SEC inhibits structural damage: FUTURE 1 Change from baseline to Week 24 • 606 adults with active PsA SEC 150 mg (n=202) • Higher rates of 0.7 SEC 75 mg (n=202) 0.57 PBO (n=202) non-progression with SEC 0.5 vs PBO 0.35 0.3 0.23 0.13 – 75 mg, 92.3% 0.08 0.10 0.1 0.02 0.04 – 150 mg, 82.3% Radiographic scores -0.1 -0.06 – PBO, 75.7% mTSS Erosion JSN • Rate of non-progression Change from Week 24 to Week 52 maintained up to Week 52 0.7 SEC 150 mg (n=175) SEC 75 mg (n=169) and increased to 86.8% after 0.5 Original PBO (n=152) rescue in PBO patients 0.23 0.3 0.20 0.18 0.12 0.08 0.1 0.01 0.05 Radiographic scores Radiographic -0.1 -0.03 -0.03 mTSS Erosion JSN SEC inhibits structural damage progression in PsA Van Der Heijde D et al. EULAR 2015, Rome, #THU0414 Copyright 2015 TREG Consultants LLC 32 SEC safety in PsA • Integrated safety data from FUTURE 1 and 2, 974 patients – Mean exposure to SEC 358 days Safety outcomes PBO-controlled phase (16 weeks) Entire safety period (n/100 Pt-Y) Any SEC, n=703 PBO, n=300 Any SEC, n=974* PBO, n=300 Patients, n (%) Cases/100 patient-years, n (95% CI) AEs 414 (59) 175 (58) 210 320 Candida 5 (0.7) 0 1.6 0.0 Neutropenia 9 (1.3) 7 (2.3) 1.7 6.7 SAEs 24 (3.4) 12 (4.0) 9.0 13.6 SIEs 2.5 2.9 *Includes patients from the PBO group re-randomized to SEC • Anti-drug antibodies in 1 patient – no apparent loss of efficacy • No signal of MACE or malignancy • 1 new onset Crohn’s in SEC, 1 in PBO Long-term safety and tolerability consistent with blinded data 169/236 Mease P et al. EULAR 2015, Rome, #SAT0579 Copyright 2015 TREG Consultants LLC 33 Ixekizumab (IXE) in active PsA: 52-week results (NRI analysis) ACR responders at Week 52 PASI responders at Week 52 IXE 80 mg q4w (N=191) IXE 80 mg q2w (N=190) IXE 80 mg q4w (N=131) IXE 80 mg q2w (N=117) 100 100 71 74 67 67 59 67 53 49 49 56 50 34 35 50 Patients (%) Patients 0 (%) Patients 0 ACR20 ACR50 ACR70 PASI 75 PASI 90 PASI 100 IXE q4w IXE q2w 100 81 75 AEs 51 43 (n=191) (n=190) 50 Any infection 53 (28) 53 (28) Serious infection 1 (0.5) 0 0 Complete Complete Any Candida infection 3 (2) 5 (3) Patients (%) Patients resolution of resolution of Depression 01 (0.5) enthesitis dactylitis Cytopenias 6 (3) 4 (2) Neutropenia 3 (2) 1 (0.5) N 115 101 53 48 Cerebro-cardiovascular event 4 (2) 3 (2) Baseline 2.8 3.0 84 74 Malignancy 1 (0.5) 0 Change 1.8 1.6 82 62 – – – – CD or UC 1 (0.5) 0 Mease PJ et al. EULAR 2016, London, #OP0109 Copyright 2016 TREG Consultants LLC IXE: Secondary outcomes at Week 52 Patients meeting MDA criteria at Week 52 • MDA results similar whether using PGA or PASI for skin1 100 IXE 80 mg q4w IXE 80 mg q2w 80 • Improvements in function, 60 QoL, work productivity2 38 42 40 29 30 Patients (%) Patients 20 • IXE efficacy was not 0 significantly affected by MDAsPGA MDAPASI background DMARD use3 Results sustained through 52 weeks, no apparent difference between doses 1. Coates LC et al. EULAR 2016, London, #THU0440; 2. Gottlieb A et al. Ibid, #THU0430; 170/236 3. Coates LC et al. Ibid, #THU0441 Copyright 2015 TREG Consultants LLC Bimekizumab proof-of-concept study in PsA • Monoclonal antibody directed against both IL-17A and IL-17F – in vitro human assay showed additive effects of IL-17A and IL-17F inhibition • 4 doses at 0, 3, 6 weeks c/w placebo, primary endpoint ACR-N at Week 8 – 40, 80, 160, 320 mg iv, with double dose at baseline ACR20, ACR50, and ACR70 through Week 8 100 Week 8: ACR20=80% 100 100 PBO (n=12) 80 80 80 Bimekizumab (n=30)* 60 60 60 *Top 3 doses 40 40 40 20 20 20 ACR (95% CI) CI) (95% ACR response rate (%) rate response 0 0 0 0 1 2 3 4 6 8 0 1 2 3 4 6 8 0 1 2 3 4 6 8 Weeks Weeks Weeks • 100% PASI 75 at Week 8 • No significant safety signals. 3 SAEs in 1 pt related to a fall Bimekizumab demonstrated high efficacy for skin and joints in and no major safety signals in this early proof-of-concept study in PsA Glatt S et al. EULAR 2016, London, #OP0108 Copyright 2016 TREG Consultants LLC Brodalumab in PsA: 2-year results • 156/168 patients (93%) entered 96-week open-label extension – Brodalumab 140 mg, 280 mg, or PBO in 12-week DB phase – Planned 280 mg dose reduced to 210 mg after protocol amendment • Week 108: Efficacy at Week 108 – 23 (15%) reported SAE BRO 140 mg BRO 210/280 mg • Most frequent SAEs (≥2 60 57 57 patients): coronary artery 52 PBO 43 disease, cholelithiasis, 40 cellulitis 26 24 – AEs of special interest: 11 oral 20 candidiasis, 1 neutropenia, Responders (%) 0 1 suicidal ideation ACR20 ACR50 – No deaths Brodalumab remains effective at 2 years. Brodalumab was pulled from clinical trials due to reports of suicidal ideation and completed suicides 171/236 Mease P et al. EULAR 2015, Rome, #OP0175 Copyright 2015 TREG Consultants LLC 37 Divergent tissue responses with IL-17i Psoriasis PASI75 PsA ACR20 Papp K. NEJM 2014; 366(13):1181 Mease P. NEJM 2014;370(24):2295 In vitro data and In vivo models may not predict response in disease Antagonism of IL-23/Th17 not effective in RA IL-22 mAb not effective in psoriasis IL-17 mAb worsened Crohn’s colitis IL-17 null mice show increased periosteal bone formation http://clinicaltrials.gov/show/NCT01645280 Kreuger JG Nature Med. 2012;18(12):1751 Heuber W. Gut 2012;61(12):1693 172/236 Treatment Recommendations GRADE process for generating recommandations 173/236 GRAPPA Treatment Recommendations for Psoriatic Arthritis 2015 Methods -Updated systematic literature reviews performed based on data publicly available through November 2014. -Six separate literature reviews completed covering Rx for key PsA clinical domains: Arthritis, Spondylitis, Enthesitis, Dactylitis, Skin and nail disease. -Evidence assessed from the published literature reviews and formally evaluated with the GRADE system to provide treatment recommendations. Coates L et al. Arthritis Rheum 2016 CopyrightCopyright 2015 TRETREGG CConsultantsonsultants LLCLLC GRAPPA PsA Rx Recommendations 2015 174/236 Coates L et al. ACR 2015 San Francisco # Late Breaker Poster Copyright 2015 TREG Consultants LLC Treatment Horizons Targeting IL-12 and lL-23 175/236 Patel D. Immunity 43, December 15, 2015 SpA therapy: Novel strategies Systemic therapies for psoriasis patients with arthritis markers Early dx of PsA Stratification biomarkers Antibody to IL-17A and F Innate lymphocytes? IL-23 as a target Combination therapies: biologics (TNF, IL-17, IL-23) Bitypical antibodies Life-style modification IL-17R blockade- next steps?? Take Home Points 1. PsA: Shared disease pathways and mechanisms with psorias 2. IL-23/IL-17 and TNF pathways of critical importance 3. Targeting IL-17 is an effective strategy in psoriasis and PsA 4. New therapies targeting IL-17 A/F & IL-23 promising 176/236 Center for MSK Research Allergy, Immunology & Rheumatology Divison E Schwarz Dongee Li G Chiu Anatole Kleiner B Boyce Debbie Campbell R Thiele S Moorehead S Haas-Smith B Marston R Barrett NIH A1078907, AR54041, RRF, Amgen 177/236 MANAGEMENT OF RAYNAUD'S PHENOMENON AND DIGITAL ISCHEMA Laura K. Hummers, MD, ScM SUNDAY , SEPTEMBER 1 8 TH 10:30 AM – 11:30 AM 178/236 Management of Raynaud’s Phenomenon and Digital Ischemia Laura K. Hummers, MD, ScM Associate Professor of Medicine Co-Director, Johns Hopkins Scleroderma Center September, 2016 Disclosures • No relevant financial disclosures for this presentation • I receive research funding from o Cytori Therapeutics o Corbus Pharmacueticals o Boehringer Ingelheim o CSL Behring • All of the medications in this presentation are discussed for use for non FDA-approved indications 179/236 Goals • Review the factors that increase risk for CTD among those with RP • Briefly discuss the relevant pathophysiology of Raynaud phenomenon and digital ischemia in scleroderma • Review unique situations in scleroderma • Discuss established therapies and those currently in trial • Review possible treatment algorithms Raynaud’s Phenomenon 180/236 What is and is not Raynaud’s • Temperature Sensitive NOT: •Palmar •Mottling (non‐specific) •Symmetric •Fingernails only •Sharp Demarcation •Unilateral Blood Vessel Structure 181/236 Peripheral Vascular Disease Secondary Raynaud’s Phenomenon/Mimics-Differential Diagnosis • Immune: Autoimmune Disease (Scleroderma, Lupus, Myositis, UCTD) • Trauma: Hand-Arm Vibration Syndrome • Mechanical: Thoracic Outlet Syndrome • Proteins: Cryoglobulins; Cryofibrinogens • Neurogenic: Carpal Tunnel Syndrome • Hormones: Estrogens • Toxins/Drugs/Vasoconstrictors: Smoking (TAO), sympathomimetics, chemotherapy, polyvinyl chloride, cocaine (levamisole) • Vascular disease: Diabetes, Vasculitis, etc. 182/236 Physical Exam Findings Predictors of Development of CTD/Scleroderma • Abnormal nailfold capillaries o Nailfold dilatation/Dropout (avascular areas) o HR 14-18 for development of SSc • Autoantibodies o 30% risk of CTD if just ANA positive o HR 10-23 for SSc with just ANA positivity • Both abnormal NFC and SSc antibody o HR 60 • Negative ANA, normal nailfold capillaries have high NPV (>95%) Moinzadeh P et al. Clinic Rev Allerg Immunol (2012) 43:249-55 Zeigler S. Scand J Rheumatol (2003) 32(6): 343-47 Ingegnoli F et al. (2010) Rheumatol (Oxford) 49(4):797–805 Koenig et al. (2008) Arthritis Rheum 58 (12):3902–3912 183/236 Classification of Systemic Sclerosis van den Hoogen et al. Arthritis Rheum. 2013 Oct 3. Nailfold Capillary changes Method: Drop of Immersion Oil on Nailfold Ophthalmoscope at +40 diopters (10x magnification) OR Dermatoscope 184/236 Complications Digital Ischemic Ulcers 185/236 Risk Factors of Digital Ulcerations • Digital loss (10%) o Anti-centromere antibody o Multiple prior digital ulcerations o Large vessel involvement (ulnar artery) o Older age, long disease duration, PAD, HLD • Ulcers (50%) o Centromere and topo (not Pol III) o Smoking? Caramaschi P et al. J Rheumatol. 2012 Aug; 39(8): 1648-53 Steen V et al. Rheumatology 2009; 48:iii19-24= Acute digital ischemia • Ischemic? – Severe pain – Location – Surrounding hyperemia • Therefore: – At risk for further tissue loss and continued pain – Pain triggers sympathetic response – At risk for further ischemia 58% of scleroderma patients with digital ulcerations 11% with severe disease (gangrene, amputation) 186/236 Non (or less) Ischemic Ulcers Management 187/236 Behavior Modification • Avoid• coldLayers • Stress• reductionAmbient temperature • Hand warmers • ?Biofeedback Local Care Cleansing • Warm soapy water soaks a few times per day Protection • Covering with bandage, wrap if going to be using hands Infection • Antibacterial ointment (mupirocin) Pain • Topical Anesthetics (lidocaine) 188/236 Targets for Therapy Autonomic nervous system Adventitia α2c-adrenergic Media (smooth muscle cells) blockers Intim a CCB Endothelium estrogens NO PDE inhibitors W hite blood cells PGI2 CGRP ACE inhibitors SP NK-A NPY 5-HT SSRI SOM Ach Platelets TXA aspirin VIP NE ET-1 ET-1 inhibitors Rho kinase inhibitors Calcium Channel Blockers All calcium channel blockers vs. placebo o (6 trials): Reduction of frequency of attacks in a 2-week period of -8.31 (95% CI: -15.71, -0.91) o (3 trials): Reduction in severity of ischemic attacks of -0.69 (95% CI: -1.21,-0.17) Thompson et al., 2001 189/236 Symptoms of the 16 study patients with secondary Raynaud's phenomenon while taking sildenafil and placebo Fries, R. et al. Circulation 2005;112:2980-2985 Copyright ©2005 American Heart Association Oral Tadalafil (Cialis) • Scleroderma patients off all treatment for Raynauds (N=39) • 20 mg of tadalafil daily for 4 weeks compared with placebo • Medication was found to be well tolerated Baseline Tadalafil Placebo Difference RCS 3.76 2.43 2.53 NS Raynauds 2.93 2.08 2.1 NS Frequency Raynauds 53.4 40.6 47 NS Duration Schiopu E et al. J Rheum. 2009 190/236 Tadalafil – ACR 2010 • Randomized controlled trial, tadalfil vs. placebo • 53 scleroderma patients treated for 8 weeks • Baseline treatments remained the same • Improvements seen in duration and frequency of Raynaud and in RCS • 14/18 had healing of digital ulcers compared with 5/13 in placebo arm • Fewer new ulcers in tadalafil group than placebo (1 vs. 9) Agarwal et al. Plenary session III, ACR national meeting October, 2010 Bosentan (Tracleer) • Dual endothelin receptor antagonist, FDA approved to treat pulmonary hypertension • 2 Large, Phase III studies in patients with digital ulcers secondary to scleroderma (RAPIDS1, RAPIDS2, open label extension) • 312 patients total • Fixed dose titration 62.5 BID to 125 BID • Primary outcome: # new digital ulcers; time to healing (RAPIDS2) • RAPIDS 1: 2.7 vs. 1.4 new ulcers at 16 weeks (p=0.178); 2 post hoc analyses (p=<0.01) • RAPIDS2: 2.7 vs. 1.9 new ulcers at 24 weeks (p=0.04) Seibold JR, Matucci-Cerinic M, Denton CP et al.. Ann Rheum Dis2006;65(Suppl II):9 Korn JH, Mayes M, Matucci-Cerinic M et al. Arthritis Rheum 2004;50:3985–93. 191/236 Digital Ulcers prevention with mAcitentan in systemic scLerosis • 285 patients, 75 centers, 30 countries • 2 active doses vs. placebo (1:1:1); parallel • Macintentan is a dual, tissue targeting ERA • Inclusion: – Baseline ulcer + history of ulcers in past 6-12 months • Outcomes: – # of new digital ulcers at 16 weeks • Trial ended early due to lack of efficacy • No adverse safety signals Oral Treprostenil • Long acting, chemically stable, prostacyclin analogue • Phase I/IIb study A. Shah; poster presentation at EULAR 2010; Rome, Italy 192/236 Oral Treprostenil • 148 scleroderma patients at 27 centers • Randomized 1:1 to oral treprostenil vs. placebo for 20 weeks • At 20 weeks there was no change in net ulcer burden • Other outcomes did improve including: physician and patient impression of improvement, Raynaud symptoms, hand function Seibold J et al; Digital Ischemic Ulcers in Scleroderma Treated with Oral Treprostinil Diethanolamine: A Randomized, Double- Blind, Placebo-Controlled, Multicenter Study. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :2483 Why the discrepancies? • How to evaluate an ulcer? • Is this an ulcer? • Is it “active”? • Is it healing? 193/236 Summary of Agents • Calcium Channel blockers: Nifedipine, amlodipine, felodipine • Nitric oxide: Nitrates (?topical) • Phosphodiesterase inhibitors: – Sildenafil, Tadalafil, Udenafil, Vardenafil • Selective Serotonin Reuptake inhibitors: Fluoxetine • Angiotensin receptor inhibitor: Lorsartan • Endothelin-1 inhibitor: Bosentan, Ambrisentan, Macintentan • Prostacyclins: epoprostenol, treprostinil, iloprost • sGC stimulators: Riociguat • Other: Statins, ASA, pentoxyphyline, Botulium toxin A Treatment Algorithm‐ RP Symptomatic Raynaud Behavior Modification/Cold and Stress Reduction Initiate CCB therapy and titrate to effect/intolerance Consider addition of losartan, fluoxetine, sildenafil if CCB alone ineffective 194/236 Management for Raynaud/Digital Ischemia: Evidence Agent Class Type of Evidence Positive outcomes Calcium channel RCT Raynaud frequency and blockers duration Endothelin receptor RCT Reduction in new digital antagonists ulcerations IV prostaglandins RCT Raynaud frequency, duration, severity; healing of ulcers Phosphodiesterase RCT/conflicting Raynaud frequency, inhibitors duration, Raynaud condition score, ulcer healing Surgical Case reports/series Ulcer healing sympathectomy Huisstede BM, et al. Arch Phys Med Rehabil. 2011 Jul;92(7):1166-80. Shenoy PD et al. Rheumatology 2010; 49; 2420-8 Galluccio F, Matucci-Cerinic, Autoimmunity Reviews. 10 (20110 241-3. Schiopu E et al. J Rheumatol 2009; 36:2264-8 Thompson et al. Rheumatology. 2005; 44:145-50. Wigley FM et al. Ann Int Med 1994; 120:199-206 Digital Ischemia/Ulcers • Acute Management • Chronic Management o Pain control (narcotics) o Topical antibiotics o Aspirin • With lidocaine o Epoprostenol o Soaking • Peripheral IV o Pain control • 0.5-2 ng/kg/min o Adjust chronic meds • 6 hours daily • Titrate CCB • 3-5 days • Add second line agent • Inpatient/outpatient o ERA o Consider digital sympathectomy o PDE5 o Watch for additive side effects 195/236 Secondary Causes? Gemcitabine Carboplatin Cisplatin Bleomycin Vincristine Conclusions • Raynaud is a common phenomenon • History/exam can help distinguish primary vs. secondary and you can identify those at risk for early scleroderma • Patients with CTD have more severe phenotype due to combination of vasospasm and intrinsic vessel disease • Numerous potential targets for therapy 196/236 BLINDSIDED BY ARTHRITIS Lisa A. Lerman, MD, PhD, MSCE SUNDAY, SEPTEMBER 1 8TH 11:30 AM – 12:30 PM 197/236 Blindsided by Arthritis Melissa A. Lerman, MD, PhD, MSCE Division of Rheumatology The Children’s Hospital of Philadelphia No financial disclosures. 198/236 Case 1 2.5 yo female with altered gait, intermittently, for 2 months. She moves less well in the morning and after naps. She does not complain of pain. Synechiae – sign of eye inflammation 199/236 Uveal Tract Uvea = grape (Greek) Iris, ciliary body, choroid Uve – “it is” Other names: iritis Causes of Uveitis Trauma Infection Genetic Leukemia Idiopathic (unknown) Autoimmune/rheumatic disease 200/236 Infectious Causes Bartonella Lyme Brucella Syphilis CMV Toxocara EBV Toxoplasma Histoplasmosis Tuberculosis HIV HSV Uveitis in Rheumatic Disease Juvenile idiopathic arthritis Tubulo‐interstitial nephritis and uveitis (TINU) Sarcoidosis/Blau Syndrome Inflammatory Bowel Disease‐associated Behçet Disease Vasculitides Systemic Lupus Erythematosus 201/236 Juvenile Idiopathic Arthritis Arthritis > 6 weeks Subtypes Oligoarticular ≤ 4 joints first 6 mo (40%) Polyarticular ≥ 5 joints first 6 mo (20% RF‐, 5% RF+) Enthesitis Related (ERA)(5‐10%) Psoriatic (5‐10%) Systemic (10%) Undifferentiated (5‐10%) ILAR Classifications (1997, 2001) (Intl League of Associations for Rheum) Uveitis in JIA 13‐23% of JIA Anterior, chronic, bilateral Bilateral over time 65% asymptomatic* F>M (4.4:4)* 30% Oligo> 15% Poly RFneg >10% PsA * exceptions 202/236 Case 5 yo girl with oligoJIA since she was 22 mo is in the office. She is growing well, has no active arthritis, and feels great. When did you last see the eye doctor? “We’ve been busy, so it has been probably about a year.” Vision 20/80 Timing of Uveitis Activity Joint ≠ eye Uveitis can develop at any time 12% ‐ incidentally on eye exam JIA diagnosis Can be present at the diagnosis of JIA Can develop years after the JIA Regular SCREENING eye exams are crucial (more detail later) 203/236 Risk Factors for JIA‐U Female, young age, ANA positive, subtype (oligo)1,2 Age of onset and ANA 3,4 Screening guidelines depend on: age onset, ANA, subtype Highest risk 1st 2 years (up to 5‐7 years) 2,4 1. Saurenmann, RK et al. Arthritis Rheum. 2007; 56(2):647. 2. Heiligenhaus A, et al. Rheumatology (Oxford). 2007;46:1015‐9. 3. Saurenmann, RK et al. Arthritis Rheum. 2010; 62(6):1824‐8. 4. Calandra, S et al. J Rheumatol. 2014; 41(7): 1416‐25. Case 3 13 year old boy with Enthesitis related arthritis: He wears glasses so he waits until his vision check at the optometrist. He is given antibiotic drops –no improvement. 204/236 Uveitis in ERA Different from other JIA associated uveitis Anterior (same) Unilateral Acute (sudden onset and limited duration) Boys>girls Fewer complications Classification of Uveitis Location Course of uveitis Degree of inflammation Other: granulomatous 205/236 Anterior Intermediate Posterior Iritis Vitirits Optic nerve Iridocyclitis Pars planitis Vasculitis Choroid lesion Pan Classification of Uveitis Location Course of uveitis Onset Course Duration Degree of inflammation 206/236 Standardization of Uveitis Nomenclature (SUN) Working Group Jabs, DA et al. AJO 140(3): 509-16. 2005. Classification of Uveitis Location Course of uveitis Onset Course Duration Degree of inflammation 207/236 SUN Working Group Criteria –AU* * AU: Anterior Uveitis Granulomatous Uveitis Nodules in the iris, “mutton‐fat” KP, large vitreous snowballs, or choroidal granulomas TB Syphilis VKH Sarcoid 208/236 Presentation of Disease Anterior Uveitis (AU) 60% pediatric uveitis Largest percentage of JIA associated uveitis ? Red eye, blurry vision, photophobia JIA often painless What can your rheumatologist see in the office? New scarring of pupil since last visit Otherwise –a slit lamp exam is necessary to see uveitis 209/236 Synechiae Iris Scarring Anterior –to cornea Posterior‐ to lens Glaucoma Treat: Dilating drops if new http://www.southwestequinemedical.com/ What does the ophthalmologist do? 210/236 www.diytrade.com What does the ophthalmologist see? Anterior Chamber (AC) Cells http://www.rootatlas.com 211/236 Hypopyon Flare Blood/aqueous barrier broke down from inflammation Extra protein in the anterior chamber Flare in AC ≠ disease reactivation 212/236 Keratitic Precipitates Clusters of cells on cornea (inferior) Marker of quite active disease Less common with JIA http://www.rootatlas.com Case 4 12 year old girl with bilateral knee pain and swelling for 2 months Moves around like an old man in the morning No signs of pubertal maturation Poor weight gain for 2 years No linear growth for 1 year 213/236 Uveitis in Inflammatory Bowel Disease Posterior uveitis (can be intermediate) Bilateral Insidious in onset Chronic in duration Girls>boys Macular edema More complications Episcleritis, scleritis, and glaucoma (> than ERA) Uveitis Complications Visual deficits (<20/50), blindness (<20/200) Synechiae Cataracts (posterior subcapsular) * Band keratopathy Increased intraocular pressure glaucoma * Cystoid macular edema Surgery 214/236 Cataracts pedsinreview.aappublications.org Band Keratopathy Calcific band across middle of cornea (under epithelium) http://images.rheumatology.org 215/236 Increased Intraocular Pressure Blocked flow: Synechiae, trabecular scarring Corticosteroids Pressure checks at EACH visit Cystoid Macular Edema 216/236 Complications in JIA 45% at initial visit 37‐56% overall 1,2 Cataracts > synechiae > glaucoma Predictors 1 Complication at presentation Uveitis pre arthritis ANA negative 3 1. Heiligenhaus A. Rheumatology (Oxford). 2007; 46:1015-9. 2. Saurenmann, RK. Arthritis Rheum. 2007; 56(2):647. 3. Chalom, E. J Rheumatol 1997;24(10):2031. Cataracts in JIA‐U Incidence 0.04/eye‐yr, prevalence 80% (adult‐JIA)1 Risk factors: Active, ongoing inflammation Posterior synechiae at onset Systemic CS 87% risk reduction risk ≤3 gtt/d vs. ≥4 gtt/d 2 Worse post‐surgery visual outcomes in JIA‐U Control inflammation peri‐op better outcomes 1. Angeles-Han, S. Curr Rheumatol Rep. 2011, Dec 28. 2. Thorne, JE. Ophthalmology. 2010; 117(7): 1436-41. 217/236 Visual Loss in JIA‐U Mean F/u ≤20/50 ≤20/200 Review of 10‐30% 1974‐1993 1 Smith (1984‐ 3 years 30% 24% 2004)2 Germany 5.5 46% 15% (2002)3 Toronto 6.4 3.7% 9% (2002‐2003)4 1. Cabral DA. J Rheumatol. 1994; 21:2370-2375 2. Thorne JE. Am J Ophthalmol. 2007;143:840-6. 3. Heiligenhaus A. Rheumatology (Oxford). 2007;46:1015-9. 4. Saurenmann, RK. Arthritis Rheum. 2007; 56(2):647. What can we do to prevent this? Make sure that your child gets regular screening Provider should be an ophthalmologist Pediatric trained? Uveitis specialist? 218/236 AAP Screening Guidelines Cassidy J, et al . Pediatrics 2006;117(5):1843‐5. German Uveitis Study Group Heiligenhaus A. Rheumatology (Oxford) 2007;46(6):1015‐9. 219/236 Ophthalmologist within 1‐2 weeks Tests to Consider CBC ACE, Lysozyme, UCa/U Cr CMP ANCA ESR, CRP RPR Urinalysis Toxoplasma, Toxocara ELISA ANA CMV Ab (serum, urine) HLA B27 Lyme PPD 220/236 Differential Diagnosis Is it sudden or insidious? Laterality? Which part of the eye is affected? Acute or chronic? Associated symptoms? We’ve identified it –what now? Dilating drops (atropine) Limit development/breakup synechiae Use only in acute phase Anti‐inflammatory drugs 221/236 Anti‐inflammatory Players Conventional immuno‐ Biologic suppression immuno‐ Steroids modulators Steroids Immunomodulators Methotrexate Conventional Mycophenolate Mofetil Biological TNFα Inhibition Azathioprine and others Cyclosporine Effectiveness? Toxicity? 222/236 Corticosteroids Topical (drops, gels) Injections/instillations Intraocular, periocular, long acting depot No role for systemic CS in JIA‐U (anterior) Can same complications as disease itself Goals of uveitis control Decrease inflammation (<0.5+) Shortest possible time to control Maintain control Spare steroid exposure Limit topical steroids (<2 drops/day) Outcome measures vary by study 223/236 Anti‐metabolites Methotrexate Mycophenolate Mofetil 224/236 Methotrexate Mechanism: folate antagonist, limits neutrophil adherence (increase adenosine release) Administration: 0.5‐1 mg/kg or 15 mg/m2 Up to 25 mg weekly (1 ml) Oral or subcutaneous, weekly 2‐3 months to build up and become effective Meta‐analysis: 73% respond (95% CI 66%, 81%) Simonini, G. Rheumatology. 2013; 52: 825-31. Side effects Usually well tolerated Give daily folic acid with it (1 mg) Nausea (day after) vs. anticipatory nausea, fatigue Increased risk infections (small) Precaution: No live virus vaccines, pneumococcal/meningitis boosters. Every 3‐4 mo labs (blood count, liver function) Teratogen 225/236 Other immunosuppressants Mycophenolate mofetil Azathioprine Cyclosporine/tacrolimus Cyclophosphamide “Biologics” Interfere with Signaling www.sciencedirect.com 226/236 TNFα Inhibition Tumor necrosis factor alpha Multi‐faceted role in inflammation To market late 1990’s Used for those failing steroids + methotrexate OR with severe disease at onset Etanercept (Enbrel): Used for JIA, ineffective for uveitis Role for Infliximab (Remicade) and Adalimumab (Humira) ADD do not switch 227/236 TNFα Inhibition Infliximab (Remicade): Intravenous Load 2 doses 2 weeks apart and then every 4‐8 weeks 40‐80% response in those resistant to topical steroids + Methotrexate Adalimumab (Humira): Home self‐injectable (subcutaneous) Every 1‐2 weeks 20‐80% response Time‐to‐treatment success under anti‐TNFα Proportion achieving success within: # mo % (95% CI) 347% (35, 60) 659% (46, 72) 12 75% (62, 87) Median = 3.4 months JIA‐AU most successful Lerman, MA. J Rheumatol. 2013; 40(8) 1394-1403. 228/236 Safety Infections, reactivation TB, low blood counts, site reactions, anaphylaxis, PML 8% treatment episodes discontinued w/in 12 mo for adverse effects 1 8.8% minor adverse reactions (no major) 2 IFX: 18.8/100 pt yr vs. ADA: 4.7/100 pt yr No live virus vaccines FDA black box warning ‐ malignancy 1. Lerman, MA. J Rheumatol. 2013. 2. Zannin, M. J Rheumatol. 2012 Jan;40(1):74-9. Which anti‐TNFα? Effectiveness –still under exploration Higher likelihood achieve remission ADA vs. IFX log‐rank, Mantel‐Cox 2 6.83, P<0.001 1 Other studies do not agree Burden on patient and families Financial burden 1. Simonini, G et al. Arthritis Care Res. 2011;63(4):612-8. 229/236 Reactivation Following Achievement of Quiescence under anti‐TNFα 28% relapse within 12 mo While on anti‐TNF: 21.6% After stop anti‐TNF: 63.8% Relapse higher ADA vs. IFX (HR 13.4, 95% CI: 2.2‐82.5) Vs. At 40 mo still in remission on medication: ADA 9/15 (60%) of vs. 3/16 (18.8%) IFX (p<0.02) 1. Lerman, MA et al. Am J Ophthalmol. 2015; 160(1):193-200. 2. Simonini, G et al. Arthritis Care Res. 2011;63(4):612-8. What if anti‐TNFα is not enough? What if disease if uveitis remains active despite anti‐TNFα? What if disease re‐activates WHILE on anti‐ TNFα? 230/236 JIA‐U Is a Chronic Disease 46‐57% reactivate within 12 mo after d/c MTX Relapse‐free survival associated with: Longer duration disease inactivity before stop (>2 yrs) 1 Lower levels of S100A8/S100A9 (calprotectin) Of those quiet on anti‐TNFα, 28% relapse within 12 mo While on anti‐TNF: 21.6% After stop anti‐TNF: 63.8% 1. Kalinina Ayuso, V et al. Am J Ophthalmol. 2011; 151(2):217. 2. Foell D, et al. JAMA. 2010; 303(13): 1266-73. 3. Lerman, MA et al. Am J Ophthalmol. 2015; 160(1):193-200. 231/236 JIA‐U Reactivate after stop MTX Affected by duration of control? Biomarkers? Study 1: 46% reactivate within 12 mo after d/c1 Factors associated with relapse‐free survival after d/c: Included: inactive uveitis >2 yrs pre‐d/c (p=0.033) Study 2 56‐57% reactivate 6 and 12 mo 2 Reactivation: Higher levels of S100A8/S100A9) 1. Kalinina Ayuso, V et al. Am J Ophthalmol. 2011; 151(2):217. 2. Foell D, et al. JAMA. 2010; 303(13): 1266-73. Other open questions Chronic uveitis often reactivates after stopping drug. Is this driven by duration of disease control on drug –or other biomarkers? Clinical question: How long to treat once uveitis is quiet? 232/236 Key Points High risk of uveitis in JIA Uveitis is often painless BUT vision threatening Regular screening by an ophthalmologist is imperative Uveitis is often chronic –and should not be treated long term with steroids Immunomodulators & biologics helpful and safe Immunization recommendations Uveitis Coordinated Care Clinic at the Children’s Hospital of Philadelphia Ophthalmology: Dr. Stefanie Davidson (215‐590‐2791) Rheumatology: Dr. Melissa Lerman (215‐590‐2547) 233/236 Acknoweldgements Division of Rheumatology David Sherry John Kempen Stefanie Davidson References 1. Angeles‐Han S, Yeh S. Curr Rheumatol Rheumatol 1998, Oct;25(10):1991‐4. Rep 2011, Dec 28. 9. Saurenmann RK, Levin AV, Feldman BM, 2. Cabral DA, Uribe AG, Benseler S, O'Neil Rose JB, Laxer RM, Schneider R, Silverman KM, Hashkes PJ, Higgins G, et al. Arthritis ED. Arthritis Rheum 2007, Feb;56(2):647‐57. Rheum 2009, Nov;60(11):3413‐24. 10. Saurenmann RK, Levin AV, Feldman 3. Calandra S, Gallo MC, Consolaro A, BM, Laxer RM, Schneider R, Silverman ED. Pistorio A, Lattanzi B, Bovis F, et al. J Arthritis Rheum 2010, Feb 22;62(6):1824‐8. Rheumatol 2014, Jul;41(7):1416‐25. 11. Simonini G, Paudyal P, Jones GT, Cimaz 4. Cassidy J, Kivlin J, Lindsley C, Nocton J. R, Macfarlane GJ. Rheumatology (Oxford) Pediatrics 2006, May;117(5):1843‐5. 2013, May;52(5):825‐31. 5. Chalom EC, Goldsmith DP, Koehler MA, 12. Thorne JE, Woreta F, Kedhar SR, Dunn Bittar B, Rose CD, Ostrov BE, Keenan GF. J JP, Jabs DA. Am J Ophthalmol 2007, Rheumatol 1997;24(10):2031. May;143(5):840‐6. 6. Heiligenhaus A, Niewerth M, Ganser G, 13. Thorne JE, Woreta FA, Dunn JP, Jabs DA. Heinz C, Minden K, German Uveitis in Ophthalmology 2010, Jul;117(7):1436‐41. Childhood Study Group. Rheumatology 14. Zannin ME, Birolo C, Gerloni VM, (Oxford) 2007, Jun;46(6):1015‐9. Miserocchi E, Pontikaki I, Paroli MP, et al. J 7. Lerman MA, Burnham JM, Chang PY, Rheumatol 2012, Nov 1. Daniel E, Foster CS, Hennessy S, et al. J Rheumatol 2013, Aug;40(8):1394‐403. 8 Petty RE Southwood TR Baum J 234/236 Black Box warning Food and Drug Administration based decision on review of 48 cases of malignancies (worldwide) in children with IBD, Sarcoid, and JIA Combined different diseases Combined TNF inhibitor classes Combined different co‐treatment profiles (MTX vs AZA) Diak, Pet al. A. administration. Arthritis Rheum 2010;62(8):2517‐24. 235/236 CME EVALUATION & CRE DIT INFORMATION There will be no paper evaluation forms distributed at the course. Instead, you will receive an email with a link to an online evaluation on Monday, September 19th. In order to receive CME credit, you must complete the online evaluation and submit an electronic attestation form. The online evaluation will be available for two weeks following the course. This evaluation is necessary in order to meet CME requirements established by the Pennsylvania Medical Society. If you did not provide an email address when you registered, please stop by the PRS registration desk to provide one. This information will not be shared with outside parties or companies and is for the sole use of CME evaluation purposes. THE EVALUATION WILL BE OPEN FROM: MONDAY, SEPTEMBER 19TH – MONDAY O C T O B E R , 3 RD Keep an eye on your email box for the Save the Date for the 4th Annual Scientific Meeting of the Pennsylvania Rheumatology Society in 2017. Join your colleagues for continuing education & networking opportunities. 236/236