5th annual. SCIENTIFIC MEETING September 22-23, 2018 Sheraton Harrisburg/Hershey Hotel ONSITE PROGRAM

Transcription

1 5th annual SCIENTIFIC MEETING September 22-23, 2018 Sheraton Harrisburg/Hershey Hotel ONSITE PROGRAM

2 TABLE OF CONTENTS Pennsylvania Rheumatology Society CME Information Purpose, Target Audience, & Membership Agenda Faculty Participants PRS Board and Planning Committee Poster Presenters Saturday Lectures Thieves' Market Presenters and Judging Instructions Annual Business Meeting Sunday Lectures Meeting Support CME Evaluation PRS 2019 Annual Meeting - Save the Date

3 Pennsylvania Rheumatology Society 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 AUDIENCE 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 PENNSYLVANIA RHEUMATOLOGY 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 BECOME A PRS MEMBER? The Pennsylvania Rheumatology Society (PRS) is comprised of three different membership categories. An Active Membership is open to MD s and DO s only. These members can 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 to submit an application.

4 PROGRAM AT A GLANCE DAY I Pennsylvania Rheumatology Society Saturday, September 22 nd 7:00 am 7:50 am Registration, Continental Breakfast, Exhibit Time, & Poster Viewing 7:50 am 7:55 am Presidential Welcome Lawrence H. Brent, MD Pennsylvania Rheumatology Society President 7:55 am 8:00 am Meeting Announcements and Introductions Moderator: Tanmayee Bichile, MD 8:00 am 9:00 am Heritable Diseases of Connective Tissue Staci Kallish, DO 1 AMA PRA Category I CME Credits 9:00 am 10:00 am Neurological Complications of Rheumatic Disorders: Updates and Future Directions Julius Birnbaum, MD, MHS 1 AMA PRA Category I CME Credits 10:00 am 10:30 am Break, Exhibit Time, & Poster Viewing 10:30 am 11:30 am Addressing Physician Burnout and Stress Jon Shapiro, MD, DABAM 1 AMA PRA Category I CME Credits 11:30 am 12:30 pm Thieves Market Presentations 1 AMA PRA Category I CME Credits Panelists: Humaira Hussain, MD; Sonia Manocha, MD; Barbara Ostrov, MD 11:30 am 11:45 am Kidney Conundrum Daniel Tseytlin, DO 11:45 am 12:00 pm A Unicorn in a World of Horses. A Rare Presentation of a Common Disease Cathy Lee Ching, MD 12:00 pm 12:15 pm The Man with the Nodular Hand Jevon Fragoso, BS 12:15 pm 12:30 pm Thieves' Market Judging, Voting*, and Awards Ceremony *Please see page 6 for judging guidelines. 12:30 pm 1:15 pm Working Lunch Ralph Schumacher, Jr., MD Fellows Research Award (1 st Place) Irene Tan, MD and Barbara Ostrov, MD 12:45 pm 1:00 pm ACR Update Mark Andrejeski, Executive Vice President American College of Rheumatology 1:00 pm 1:15 pm Annual Business Meeting

5 Pennsylvania Rheumatology Society 6:30 pm 8:30 pm Networking Reception Poolside* *Weather Permitting. PROGRAM AT A GLANCE DAY II Sunday, September 23 rd 7:00 am 7:50 am Registration, Continental Breakfast, Exhibit Time, & Poster Viewing 7:50 am 8:00 am Meeting Announcements & Introductions Moderator: Lawrence H. Brent, MD 8:00 am 9:00 am Combined Session Fibromyalgia: Update for Rheumatologists Roland Staud, MD 1 AMA PRA Category I CME Credits 9:00 am 9:10 am Adult Breakout Sessions Introductions Moderator: Lawrence H. Brent, MD 9:10 am 10:10 am Connective Tissue Disorder-Associated Interstitial Lung Disease (CTD-ILD) and Updates Maria Elena Vega-Sanchez, MD 1 AMA PRA Category I CME Credits 10:10 am 10:40 am Break, Exhibit Time, & Poster Viewing 10:40 am 11:40 am Update on the Radiology of Spondyloarthropathies Donald Flemming, MD, FACR 1 AMA PRA Category I CME Credits 9:00 am 9:10 am Pediatric Breakout Sessions Introductions Moderator: Barbara Ostrov, MD Location: Ash/Birch Rooms (lower level) 9:10 am 10:10 am Henoch Schonlein Purpura: Update on Diagnosis and Treatment Pamela Weiss, MD, MSCE 1 AMA PRA Category I CME Credits 10:10 am 10:40 am Break, Exhibit Time, & Poster Viewing 10:40 am 11:40 am Update on Kawasaki Disease Mary Beth Son, MD 1 AMA PRA Category I CME Credits 11:45 am 12:45 pm Combined Session Autoantibodies in Inflammatory Muscle Disease Chester Oddis, MD 1 AMA PRA Category I CME Credits 12:45 pm ipad Raffle, Adjournment and Departure

6 Pennsylvania Rheumatology Society Win an Apple ipad! As you visit with exhibitors, remember to thank them for their invaluable support of the Pennsylvania Rheumatology Society and have them initial your bingo card to be entered in a raffle for an Apple ipad *! Drawing will take place on Sunday afternoon at 12:45 pm and you must be present to win. *PRS program committee is not eligible for the raffle. HOW TO JUDGE THE THIEVES MARKET You may rank each Thieves Market presentation as: Below Average Average Above Average Superb Each presentation will be judged on: Scientific Merit Delivery Novelty Overall Impression We will be taking a hand count at the end of the Thieves Market presentations to determine the Ralph Schumacher, Jr., M.D. Fellows Research Award (1 st place), 2 nd, and 3 rd place winners. We will announce the results at the Saturday working lunch. Thank you for your participation!

7 FACULTY Julius Birnbaum, MD, MHS Assistant Professor Division of Rheumatology and Department of Neurology Johns Hopkins Hospital Baltimore, MD Cathy Lee Ching, MD* Thomas Jefferson University Donald J. Flemming, MD, FACR G. Victor Rohrer Professor of Radiology Education Professor of Orthopedics and Rehabilitation Medicine Vice Chairman for Education Department of Radiology Penn State Hershey Medical Center Hershey, PA Jevon Fragoso, BS* Temple University School of Medicine Staci Kallish, DO Assistant Professor, Medical Genetics Hospital of the University of Pennsylvania Children s Hospital of Philadelphia Philadelphia, PA Humaira H. Khan, MD + Associate Professor Drexel University College of Medicine Sonia Manocha, MD + Pittsburgh, PA Chester V. Oddis, MD Professor of Medicine Director, Myositis Center University of Pittsburgh School of Medicine Associate Director, Fellowship Training Program Division of Rheumatology and Clinical Immunology Pittsburgh, PA Jon Shapiro, MD, DABAM Medical Director Pennsylvania Physicians Health Program Pennsylvania Medical Society Harrisburg, PA Pennsylvania Rheumatology Society Mary Beth Son, MD Director of the Rheumatology Program Boston Children's Hospital Assistant Professor, Harvard Medical School Boston, MA Roland Staud, MD Professor of Medicine Division of Rheumatology and Clinical Immunology University of Florida Gainesville, FL Maria Elena Vega-Sanchez, MD Assistant Professor of Medicine Assistant Program Director, Pulmonary and Critical Care Fellowship Department of Thoracic Medicine and Surgery Lewis Katz School of Medicine at Temple University Philadelphia, PA Pamela F. Weiss, MD, MSCE Associate Professor of Pediatrics and Epidemiology UPENN Perelman School of Medicine Attending and Clinical Research Director Division of Rheumatology Children s Hospital of Philadelphia Philadelphia, PA Lisa Scalzi, MD, MS + Hershey, PA Irene J. Tan, MD, FACR Professor of Medicine Fellowship Program Director Lewis Katz School of Medicine Temple University Philadelphia, PA Daniel Tseytlin, DO* Lehigh Valley Health Network * Designates a Thieves Market Presenter + Designated a Thieves Market Judge

8 Pennsylvania Rheumatology Society BOARD & PLANNING COMMITTEE President Lawrence H. Brent, MD Philadelphia, PA Vice President/President Elect Alfred E. Denio, III, MD Danville, PA Secretary/Treasurer Irene J. Tan, MD Philadelphia, PA Immediate Past President Philip L. Cohen, MD Philadelphia, PA Councilor Douglas W. Lienesch, MD Mars, PA Councilor Chris T. Derk, MD, MS Penn Valley, PA Councilor Lisabeth V. Scalzi, MD, MS Hershey, PA Fellow-In-Training Representative Cathy Lee Ching, MD Philadelphia, PA Western Early Career Representative Tanmayee Bichile, MD Allison Park, PA Executive Director Maria B. Elias Harrisburg, PA Program Committee Alfred E. Denio, MD Program Chair Irene J. Tan, MD, FACR Thieves Market Facilitator Lawrence H. Brent, MD Committee Member Barbara Ellen Ostrov, MD Committee Member Phil Dunn, MD Committee Member Councilor James M. Ross, MD Allentown, PA

9 Pennsylvania Rheumatology Society M EETING SUPPORT The Pennsylvania Rheumatology Society wishes to thank and acknowledge the following organizations for supporting the Society and the 2018 Annual Meeting with a Corporate Partnership: Abbvie Amgen Bristol Myers Squibb Genentech GlaxoSmithKline Horizon Pharma Janssen Pharmaceuticals, Inc. Lilly USA, LLC Pfizer Sanofi Genzyme Regeneron UCB The Pennsylvania Rheumatology Society wishes to thank and acknowledge the following organizations for supporting the 2018 Annual Meeting by exhibiting: Alexion Amgen, Inc. Antares Pharma Arthritis Foundation Celgene Corporation Coalition of State Rheumatology Organizations Crescendo Bioscience Diplomat Gilead Sciences McKesson - intrafusion Medac Pharma Novartis Novartis Sanofi SOBI The Children's Institute of Pittsburgh Wellspan Health

10 Pennsylvania Rheumatology Society 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 Julius Birnbaum, MD, MHS None None Cathy Lee Ching, MD None None Alfred Denio, MD* Bristol Myers Squibb Speaker Abbvie Speaker Philip Dunn, DO* None None Donald J. Flemming, MD, FACR None None Jevon Fragoso, BS None None Staci Kallish, DO None None Humaira H. Khan, MD None None Brent Lawrence, MD* Pfizer Speaker Bureau Johnson and Johnson Stock Sonia Manocha, MD None None Chester V. Oddis, MD Genentech Research/Clinical Mallinckrodt Research/Clinical Bristol Myers Squibb Research/Clinical Barbara Ostrov, MD* None None Lisa Scalzi, MD, MS None None Jon Shapiro, MD, DABAM None None Mary Beth Son, MD None None Roland Staud, MD None None Irene Tan, MD* None None Daniel Tseytlin, DO None None Maria Elena Vega-Sanchez, MD None None Pamela F. Weiss, MD, MSCE 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.

11 Pennsylvania Rheumatology Society PROGRAM OUTCOMES H ERITABLE D ISEASES OF C ONNECTIVE T ISSUES Illustrate the clinical manifestations of the various heritable diseases of connective tissue. Integrate the history, physical, and appropriate genetic testing to make an accurate diagnosis of patients with heritable diseases of connective tissue. Recommend treatments useful in the management of patients with heritable diseases of connective tissue. N EUROLOGICAL C OMPLICATIONS OF R HEUMATIC D ISORDERS: U PDATES AND F UTURE D IRECTIONS Competence outcomes: Learners with improved knowledge base to make prompt diagnosis and treatment of several neurologic complications of rheumatic disorders. Performance outcomes: Learners to order appropriate diagnostic tests; and to make more timely referral to Neurology specialists; earlier and collaborative treatment plans. Patient outcomes: Improved quality of life and survival, preserve functions and independence. A DDRESSING P HYSICIAN B URNOUT AND S TRESS Improved understanding of one s own issues surrounding wellness and burnout. Intent to assess and manage one s own burnout and wellness concerns. Develop a series of strategies that can be implemented to improve personal burnout and wellness. C ONNECTIVE T ISSUE D ISORDER- A SSOCIATED I NTERSTITIAL L UNG D ISEASE (CTD- ILD) AND U PDATES Competence outcomes: Learners with improved knowledge base to make prompt diagnosis and treatment of CTD-ILD. Increased knowledge of the magnitude of ILD in CTD. Performance outcomes: Learners to perform more intentional lung exams; to order appropriate diagnostic tests; and to make more timely referral to Pulmonary specialists; earlier and collaborative treatment plans. Patient outcomes: Improved survival, preserve lung functions and independence. U PDATE ON THE R ADIOLOGY OF S PONDYLOARTHROPATHIES Improved understanding of how best to use various radiographic modalities to diagnosis SpA. Appropriate use of various radiographic modalities to monitor the course and progress of SpA. Implement improved utilization of x-ray versus CT versus MRI to diagnose and monitor SpA. U PDATE ON K AWASAKI D ISEASE Improved promptness of diagnosis and treatment. Know and implement newer treatment approaches for the IVIG failure patients. Improve one s follow up monitoring and treatment planning. H ENOCH S CHONLEIN P URPURA: U PDATE ON D IAGNOSIS AND T REATMENT Improve timeliness and thoroughness of diagnosis of HSP. Know and implement up to date treatment strategies for HSP patients. Improve long-term monitoring planning for patients with HSP. T HIEVES M ARKET 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. F IBROMYALGIA: U PDATE FOR R HEUMATOLOGISTS As a result of this activity, rheumatologists will apply new diagnostic and management strategies for fibromyalgia. A UTOANTIBODIES IN I NFLAMMATORY M USCLE D ISEASE Goal of this lecture is to improve learner s competence of inflammatory muscle disease allowing them to accurately diagnose and determine the prognosis of patients with myositis and prescribe effective therapy. Also, to improve the proper use of specific autoantibodies.

12 Pennsylvania Rheumatology Society POSTER PRESENTERS Tanya Allawh, DO Drexel Internal Medicine It's Not Only Lupus Asana Anderson, MBBS Temple University Hospital An Unusual Union Reema Andrade, MD Jason Bankert, DO Megan Bielawski, MD Rashmi Dhital, MD The Wright Center for Graduate Medical Education Geisinger Medical Center Internal Medicine Geisinger Medical Center Rheumatology Fellowship Reading Hospital What the Mind does not Know the Eye does not See "It's Taking 15 Uncomfortable Minutes to Empty my Bladder..." A Funny Feeling Risk of Venous Thromboembolism among Patients on Bisphosphonates: A Metaanalysis of Observational Studies Nadishani Dissanayaka, DO Temple University Hospital I Can't Breath and my Legs are Weak. Adam Elisha, DO Lauren Freid, MD Jay Ghadiali, MD Timothy Hahn, MD Sarah Sertial, DO University of Pittsburgh Medical Center Hospital of the University of Pennsylvania Temple University Hospital Internal Medicine Penn State Hershey Medical Center The Masquerading Swollen Ankle Are You Kidneying me? A Missed Opportunity An Atypical Approach to an Uncommon Scenario in the Treatment of Juvenile Idiopathic Arthritis Vivek Joseph, MD Drexel College of Medicine A Novel Therapy - A New Challenge Erika Joyce, DO Marissa Karpoff, MD University of Pittsburgh Medical Center University of Pennsylvania Under your Nose? A Young Man with Fever, Vomiting, and a Rash Sayanika Kaur, MD Drexel College of Medicine Mysterious Bumps Kevin Lu, MD Temple University Hospital The Ebb and Flow of Sugar Erik O'Connell, DO Geisinger Medical Center Hitting the Wall Anna Papazoglou, MD University of Pittsburgh Medical Center The Worst Headache of my Life Anand Patel, MD Temple University Hospital "I was Coughing up Blood"

13 Pennsylvania Rheumatology Society Jennifer Reams, DO Geisinger Medical Center What Aren't You Telling Me? Sara Seyedali, MD Cooper University Hospital You KNEE-d to get that checked out Elizabeth Thomas, DO Geisinger Medical Center The Knee That Wouldn't Heal Patrick Webster, MD Richard Zamore, MD Allegheny Health Network (AHN) Medical Education Consortium Hospital of the University of Pennsylvania Making A Rash Decision The Many Faces of Destructive Sinus Disease

14 Pennsylvania Rheumatology Society Saturday, September 22 nd Lectures Heritable Diseases of Connective Tissue Staci Kallish, DO 1 AMA PRA Category I CME Credits Neurological Complications of Rheumatic Disorders: Updates and Future Directions Julius Birnbaum, MD, MHS 1 AMA PRA Category I CME Credits Addressing Physician Burnout and Stress Jon Shapiro, MD, DABAM 1 AMA PRA Category I CME Credits Thieves Market Presentations 1 AMA PRA Category I CME Credits Kidney Conundrum Daniel Tseytlin, DO A Unicorn in a World of Horses. A Rare Presentation of a Common Disease Cathy Lee Ching, MD The Man with the Nodular Hand Jevon Fragoso, BS 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 6 of this program.

15 Pennsylvania Rheumatology Society HERITABLE DISEASES OF CONNECTIVE TISSUE STACI KALLISH, DO SATURDAY, SEPTEMBER 22 ND 8:00 AM 9:00 AM

16 Inherited Connective Tissue Disorders Staci Kallish, DO Hospital of the University of Pennsylvania Perelman School of Medicine Department of Medicine Division of Translational Medicine and Human Genetics September 22, 2018 Objectives Understand spectrum of inherited CT disorders Understand common signs suggestive of an inherited CT disorder Be able to recognize more common heritable CT disorders Understand when referral to Clinical Genetics is warranted

17 More than Marfan syndrome More than 35 distinct heritable disorders of connective tissue identified These conditions have overlapping features Some have significant risk of complications The connective tissue problem Connective tissue varies from tissue to tissue Contains a number of cellular types collagen, elastin, fibrillin, others Modified by a number of proteins metalloproteinases, lysyl hydroxylase 3, homocysteine Some proteins glycosylated Genetic defects in a single component of connective tissue may affect many organs (pleiotropy) Overlapping, multi-systemic disorders

18 Overlapping multisystem disorders GIM Marfan syndrome Clinical diagnosis based on characteristic findings, family history Prevalence ~1:5,000-1:10,000 25% de novo, 75% inherited Autosomal dominant Molecular analysis useful in confirming diagnosis in proband, in testing family members before signs appear

19 Multi-system Disease in MFS Eye: myopia, ectopia lentis (~60%), retinal detachment Skeleton: excessive linear growth of long bones, pectus, scoliosis, joint laxity Facial: long face, deep-set eyes, downslanted palpebral fissures, malar hypoplasia, micrognathia, narrow palate Cardiac: aortic dilatation Progressive with predisposition to dissection, MVP Dural ectasia Skin: striae, hernias Pulmonary: bullae, predisposition to spontaneous pneumothorax Multi-system Disease in MFS

20 Ghent criteria Without family history: Aortic z-score 2 + ectopia lentis Aortic z-score 2 + FBN1 mutation Aortic z-score 2 + systemic score 7 Ectopia lentis + FBN1 mutation + enlarged aorta and/or dissection With family history: Ectopia lentis Systemic score 7 Enlarged aorta (Z 2 or 3 depending on age) J Med Genet Marfan Calculator Marfan.org.

21 Pathogenesis of MFS Pathogenesis is complex Dominant negative effect of mutant fibrillin-1 Abnormal fibrillin-1 monomers interfere with function of normal fibrillin-1 Fibrillin is a major building block of microfibrils Serve as substrates for elastin in the aorta and other connective tissues Constitute the structural components of the suspensory ligament of the lens Incorporation of mutant fibrillin-1 into microfibrils disrupts structure, stability, and function Fibrillins ultimately interact with TGF-B signaling pathway Management of MFS ARB or B-blocker to reduce hemodynamic stress on aorta ARB likely also impacts FBN/TGFBR pathway to prevent enlargement of aorta Moderate aerobic exercise is acceptable Limit to 50% aerobic maximum Avoid strenuous static or isometric exercise Increases peripheral blood pressure and proximal aortic wall stress Supportive care for skeletal, ophthalmologic features (surgical correction of severe scoliosis or pectus, eye examinations)

22 Atenolol in MFS NEJM Atenolol vs Losartan in MFS Red Atenolol Blue - Losartan NEJM 2014.

23 Atenolol vs Losartan in MFS Red Atenolol Blue - Losartan NEJM Allelic disorders Ghent criteria distinguished MFS from: MASS phenotype Myopia (but no ectopia lentis) MVP Borderline and non-progressive Aortic enlargement (Z<2) Non-specific Skin and Skeletal findings (systemic score 5) Ectopia lentis syndrome ectopia lentis ± systemic score + FBN1 mutation not associated with aortic involvement or without FBN1 mutation Mitral valve prolapse syndrome MVP + enlarged aorta (Z <2) + systemic score (<5) without ectopia lentis

24 Loeys Dietz syndrome Clinical diagnosis based on findings in 4 major systems Vascular, skeletal, craniofacial, cutaneous Variable spectrum Caused by mutations in TGFBR1, TGFBR2, SMAD3, and TGFB2 Autosomal dominant inheritance LDS Vascular Findings Aortic dissection or dilatation Aggressive dissection Risk of dissection at smaller diameters than seen in MFS Arterial aneurysms and tortuosity 50% aneurysms beyond aortic root, not visible by echocardiogram Tortuosity does not typically cause problems

25 LDS Vascular Findings Marked tortuosity of aorta, aneurysms of aortic root & subclavian artery Aortic root dilatation, severe tortuosity of abdominal arterial branches Nat Genet 2005; Clin Invest Med LDS Vascular Findings Ped Rad 2009.

26 LDS Craniofacial findings Ocular hypertelorism Short, wide, or bifid uvula and/or cleft palate Craniosynostosis Nat Genet LDS Skeletal and Skin findings Skeletal: Pectus deformity Scoliosis Arachnodactyly Joint laxity Congenital talipes equinovarus Skin: Translucent skin Easy bruising Dystrophic scars NEJM 2006.

27 TGFβ receptor-mediated signaling pathway TGFB-1 and -2 receptors activate Smad-dependent and -independent pathways Smads are family of transcription factors critical for transmitting signals from TGFBR to nucleus to regulate expression of: Matrix proteins - collagen (COL1A1, COL3A1), fibronectin Members of fibrinolytic system How have LDS patients presented? 65% with TGFBR2 mutations were first identified because of aortic aneurysm, dissection or sudden death Circulation 2009.

28 LDS Natural History Mean age of death 26 years 67% thoracic aortic aneurysm 22% abdominal aortic aneurysm 7% cerebral bleed 1/3 patients have dissection, surgery for aneurysm, or died from dissection or rupture by 19 years Half of women have complications in pregnancy (aortic dissection, uterine rupture) NEJM Management of LDS Careful monitoring of aorta Surgical correction at smaller size than in MFS (~4cm in adolescents, adults) Treatment with ARB or B-blocker Supportive care for skeletal, craniofacial features (surgical correction of cleft palate, severe scoliosis or pectus)

29 Ehlers Danlos Syndrome - Vascular type Arterial/intestinal/uterine fragility or rupture Hypermobility of small joints Tendon and muscle rupture Extensive bruising, acrogeria Thin, translucent skin Visible veins (chest and abdomen) Characteristic facial appearance Autosomal dominant inheritance May have family history of sudden death Caused by structural defects in pro a 1(III) chain of collagen type III Mutation analysis of COL3A1 gene also recommended AJMG EDS - Vascular type AJMG 1998.

30 EDS Vascular type Outcomes 25% experience a major medical complication by 20 years 80% by 40 years Arterial or organ rupture Median age of death 48 years 12% risk of death in pregnancy Peripartum arterial or uterine rupture NEJM EDS Vascular type Outcomes NEJM 2000.

31 Joint Hypermobility Based on Beighton scale Score of 5/9 or more indicates joint hypermobility Passive dorsiflexion of 5th finger beyond 90 degrees - 1 point each hand Passive apposition of thumb to flexor aspect of forearm - 1 point for each hand Hyperextension of elbow beyond 10 degrees - 1 point for each elbow Hyperextension of the knees beyond 10 degrees - 1 point for each knee Forward flexion of the trunk with knees fully extended so that palms rest flat on floor - 1 point Some suggest score 6/9 significant pre-puberty, 4/9 significant >50 years Beighton score

32 Hypermobility syndromes reclassified 2017 reclassification of Ehlers Danlos syndromes and hypermobility syndromes Specific criteria for each of 13 types of EDS Classical, classic-like, cardiac-valvular, vascular, hypermobile, arthrochalasia, dermatosparaxis, kyphoscoliotic, brittle cornea syndrome, spondylodysplastic, musculocontractural, myopathic, periodontal Further classification of hypermobility into hypermobility spectrum disorders (HSDs) Better classification of those with hypermobility Understanding variability within families, over time Includes hypermobile EDS Hypermobility spectrum disorders AJMG 2017.

33 Hypermobile EDS Generalized joint hypermobility Recurrent subluxations or dislocations Chronic joint/limb pain Most common form of EDS Characterized by skin softness, easy bruising, and/or smooth, velvety skin Autosomal dominant inheritance Diagnosed clinically Molecular testing not available Now part of spectrum of HSDs Complete criteria for heds 1) Generalized joint hypermobility 2) 2 out of 3 of the following: Systemic features Family history Musculoskeletal complications Cannot be used in patients with other autoimmune disease 3) Absence of skin fragility or signs of other inherited CTDs

34 Complete criteria for heds AJMG Complete criteria for heds AJMG 2017.

35 Complete criteria for heds Category C cannot be used in patients with autoimmune disease or other cause for pain AJMG Complete criteria for heds AJMG 2017.

36 Hypermobility spectrum disorders AJMG Classical EDS Generalized joint hypermobility Recurrent subluxations or dislocations Chronic joint/limb pain Characterized by skin hyperextensibility, widened atrophic scars Autosomal dominant inheritance Diagnosed clinically Can evaluate for abnormal electrophoretic mobility of collagen type V Molecular diagnosis by COL5A1 or COL5A2 genes Genetic testing now highly sensitive Utility for such testing unclear

37 EDS Classical and Hypermobility types AJMG HSDs Musculoskeletal Features Joint laxity is an important problem Can cause chronic joint and limb pain Often leads to early osteoarthritis and pain Worsened by excess weight Strengthening the muscle surrounding the joints for stabilization Avoiding body movements that cause undue stress on the joints including high impact activities Physical therapy important for life-long strengthening of the muscles Aquatic therapy and swimming are especially helpful Orthotics provide support for lax joints Pain Management teams

38 HSDs Musculoskeletal Features Low bone density is frequently seen Abnormality in the collagen formation and interaction with bones vs decreased level of activity that in some patients with EDS Calcium and vitamin D supplementation is recommended Headaches Cervical instability, with neck muscle overuse and strain HSDs Skin Features Easy bruising Molluscoid pseudotumors Fleshy lesions associated with scars found over pressure points Subcutaneous spheroids Small spherical hard bodies, frequently mobile and palpable on the forearms and shins May be calcified and detectable radiologically Surgical concerns May require deep sutures as well as superficial sutures in the closure of wounds to allow for better healing Sutures should be left in for twice as long as usual May require the use of mesh with major surgeries to prevent future herniation in the surgical incision site

39 HSDs Cardiac Features Likely does not predispose to mitral valve prolapse, aortic dilatation Screening echocardiogram recommendations unclear New AJMG guidelines conflicting state baseline echo not recommended but include MVP or AoD in dx criteria for heds 2017 study of 325 patients, ~ ½ over 18 years AoD Z-score >2 in 14.2% (46) AoD z-score >3 in 5.5% (18) No significant increases in size of AoD seen over time Recent Penn study of 209 adults with HSDs showing lower rates of AoD, no significant increase in MVP AJMG HSDs Cardiac Features MVP in 13/209 (6.2%) 2 trivial, 5 mild, 1 moderate (5 unspecified) Only 3 patients had AoD 2 had follow up echo with stable diameter AJMG 2018.

40 Dysautonomia in H-EDS Autonomic dysfunction reported as a frequent feature of EDS Non-musculoskeletal complaints are varied Palpitations Syncope Orthostatic hypotension Diarrhea and/or constipation Abnormal temperature regulation Dysautonomia in H-EDS 2014 study of 39 patients with H-EDS All female Resting heart rate higher in H-EDS versus controls Other signs of autonomic dysfunction included abnormal sweating and abnormal responses to Valsalva maneuver Orthostatic intolerance found in 74% patients Seen earlier than in controls More patients prematurely ended tilt testing due to symptoms However, 3 patients ended tilt test due to symptoms despite adequate blood pressure POTS in 41%, gradual orthostatic hypotension in 26% Findings suggestive of reduced sympathetic nervous system reactivity with resting overactivity Semin Arthritis Rheum 2014.

41 Why dysautonomia in H-EDS? Possible mechanisms in H-EDS: Peripheral neuropathy Increased distensibility of blood vessels with increased venous pooling during upright posture Medication use may contribute Opiates cause vasodilatation Trazodone, some blood pressure medications inhibit sympathetic activation Tricyclic antidepressants block sympathetic receptors Depression Deconditioning Pain-induced sympathetic arousal Semin Arthritis Rheum HSDs - Other Features GI Constipation (bowel and abdominal wall may have low tone) or IBS symptoms Diverticula and diverticulitis Gastroesophageal reflux disease (GERD) Dental High-arched palate, tooth crowding TMJ dysfunction with pain and headaches Respiratory Lung blebs or pneumothorax Psychiatric Increased risk of depression due to having a chronic painful disease

42 Pain in heds/hsds AJMG Impact of H-EDS Comparative study looking at 206 patients (all female) 72 with EDS, hypermobility type 69 with fibromyalgia 65 with rheumatoid arthritis Assessed functional impairment with Sickness Impact Profile (SIP) Scale with higher scores indicating more functional impairment Score >10 indicates significant clinical dysfunction Score 0-10 indicates slight dysfunction lacking clinical importance Score = 0 indicates no dysfunction Arth & Rheum 2011.

43 Impact of H-EDS Arth & Rheum Impact of H-EDS All have frequent joint pain, HA Joint dysfunction, dislocation suggests EDS Weakness suggests EDS Stiffness suggests FM or RA Dysautonomia not distinguishing (EDS & FM) Fatigue? (FM > EDS) Cognitive issues suggest FM Arth & Rheum 2011.

44 Common Features Elicited by PT Phys Ther PT Treatment Recommendations Education Education is probably the most important treatment that physical therapists can provide to individuals with HMS. Education about ergonomics and body mechanics may decrease back pain Education about joint protection has been shown to increase function and decrease pain Splints, braces, and taping may be helpful to protect vulnerable joints Exercise Strengthening and proprioceptive exercises are recommended for musculature surrounding affected joints It appears reasonable to advise individuals with HMS to use stretching exercises cautiously, distinguishing between stretching muscles and stretching joints, as the former may be beneficial but the latter may be harmful. Phys Ther 1999.

45 PT Treatment Recommendations Helping patients with HMS understand their disorder may help them cope with the pain they experience. Goldman study found that presence of HMS in patients was associated with increased participation in a treatment regimen Attributed this increase to improved understanding and acceptance patients had for disorder Phys Ther Controlled Trials for HMS First randomized controlled trial for children with HMS 2010 Diagnosed by Beighton score Compared generalized program focusing on muscle strength and fitness to targeted program focusing on correcting motion control in symptomatic joints Improvements were seen in both children s assessment of pain and parents assessment of pain in both groups Rheum 2010.

46 Pain Management in H-EDS Study of 79 patients with EDS, hypermobility type (EDS-H) Diagnosed by Revised Villefranche Criteria Generalized joint hypermobility Skin hyperextensibility or velvety texture without atrophic scars Arch Phys Med Rehabil Self-Reported Complaints in H-EDS Arch Phys Med Rehabil 2011.

47 Treatment Modalities Used Arch Phys Med Rehabil Functional Impairment Using Sickness Impact Profile (SIP) Scores range Higher scores indicate more functional impairment Score >10 indicates clinically significant dysfunction Score 0-10 indicated mild dysfunction lacking clinical importance Score = 0 indicates no dysfunction Arch Phys Med Rehabil 2011.

48 Pain Severity Pain severity was assessed using a visual analog scale (VAS) Score of 0 indicates no pain, 100 indicates unbearable pain Mean VAS scores were: 48.9 for current pain 56.2 for average pain over last week Indicate presence of severe daily pain Arch Phys Med Rehabil Summary from Arch Phys Med Rehab 2011 Pain, joint problems, and muscle problems are omnipresent Large number of non-ms problems are reported Patients with EDS-H use many medications Include analgesics and antidepressants High prevalence of surgery Effect of surgical intervention was favorable in only 33.9% patients Surgical results are often disappointing to both patients and surgeons Physiotherapy (in its various modalities) forms a mainstay of treatment Low dose muscle strength exercises and joint stabilization exercises, including proprioceptive enhancement and re-education of muscle control are likely appropriate Proprioceptive and muscular system play large role in joint stability Muscle strength training also relevant treatment modality Proven physiotherapeutic treatment techniques are absent in EDS-H 63.4% of patients reported a positive effect after physical therapy Arch Phys Med Rehabil 2011.

49 Approach to Patients Diagnosis requires careful history and examination Many disorders diagnosed clinically Patients with CT disorders require multidisciplinary care to manage complications Team approach Physical & Occupational Therapy Orthopedics Physical Medicine & Rehabilitation Pain Management Others based on extra-articular symptoms References Asher S, Chen R, Kallish S. Mitral valve prolapse and aortic root dilation in adults with hypermobile Ehlers-Danlos syndrome and related disorders. Am J Med Genet Attias D, Stheneur C, Roy C, et al. Comparison of clinical presentations and outcomes between patients with TGFBR2 and FBN1 mutations in Marfan syndrome and related disorders. Circ. 2009, 120: Beighton P, DePaepe A, Steinmann B, et al. Ehlers Danlos syndromes: revised nosology, Villefranche, Am J Med Genet. 1998, 77: Carmignac V, Thevenon J, Ades L, et al. In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome. Am J Hum Genet. 2012, 91: Chopra P, Tinkle B, Hamonet C, et al. Pain management in the Ehlers-Danlos syndromes. Amer J Med Genet. 2017, 175: Castori M and Colombi M. Generalized joint hypermobility, joint hypermobility syndrome, and Ehlers-Danlos syndrome hypermobility type. Am J Med Genet. 2015, 196C:1-5. Castori M, Tinkle B, Levy H, et al. A framework for the classification of joint hypermobility and related conditions. Am J Med Genet. 2017, 175C: Chen J, Li B, Yang Y, et al. Mutations of the TGFBR2 gene in Chinese patients with Marfan-related syndrome. Clin Invest Med. 2010, 33(1):E12-E21. De Wandele I, Rombaut L, Leybaert L, et al. Dysautonomia and its underlying mechanisms in the hypermobility type of Ehlers-Danlos syndrome. Sem Arthritis Rheum. 2014, 44: Grahame R et al. The revised (Brighton 1998) criteria for the diagnosis of the benign joint hypermobility syndrome. J Rheum. 2000, 27: Kemp S, Roberts I, Gamble C, et al. Randomized comparative trial of generalized vs targeted physiotherapy in the management of childhood hypermobility. Rheum. 2010, 48: Lacro RV, Dietz HC, Sleeper LA, et al. Atenolol versus losartan in children and young adults with Marfan s syndrome. NEJM. 2014, 371: Loeys BL, Chen J, Neptune ER, et al. A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development cause by mutations in TGFBR1 or TGFBR2. Nat Genet. 2005, 37(3): Loeys BL, Dietz HC, Braverman AC, et al. The revised Ghent nosology for the Marfan syndrome. J Med Genet. 2010, 47:

50 References Loeys BL, Schwarze U, Holm T, et al. Aneurysm syndromes caused by mutations in the TGF-B receptor. NEJM. 2006, 355: Maleszewski JJ, Miller DV, Lu J, et al. Histopathologic findings in ascending aortas from individuals with Loeys-Dietz syndrome (LDS). Am J Surg Pathol. 2009, 33(2): Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Amer J Med Genet. 2017, 175C:8-26. Malhotra A, Per-Lennart W. Loeys-Dietz syndrome. Pediatr Radiol. 2009, 39:1015. Murphy-Ryan M, Psychogios A, Lindor NM et al. Hereditary disorders of connective tissue: A guide to the emerging differential diagnosis. Genet in Med. 2010, 12(6): Pepin M, Schwarze U, Superti-Furga A, Byers P. Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type. NEJM. 2000, 342: Pyeritz RE. Heritable thoracic aortic disorders. Curr Opin Cardiol. 2014, 29: Ritter A, Atzinger C, Hays B, et al. Natural history of aortic root dilation through young adulthood in a hypermobile Ehlers-Danlos syndrome cohort. Amer J Med Genet. 2017, 173A: Rombaut L, Malfait F, De Paepe A, et al. Impairment and impact of pain in female patients with Ehlers-Danlos syndrome. Arth & Rheum. 2011, 63: Rombaut L, Malfait F, De Wandele I, et al. Medication, surgery, and physiotherapy among patients with hypermobility type of Ehlers- Danlos syndrome. Arch Phys Med Rehabil. 2011, 92: Robinson PN, Neumann LM, Demuth S, et al. Shprintzen-Goldberg syndrome: fourteen new patients and a clinical analysis. Am J Med Genet. 2005, 135A: Russek LN. Hypermobility syndrome. Phys Ther.1999, 79: Shores J, Berger KR, Murphy EA, Pyeritz RE. Progression of aortic dilatation and the benefit of Long-term B-adrenergic blockade in Marfan s syndrome. NEJM. 1994, 330: Tinkle B, Castori M, Berglund B, et al. Hypermobile Ehlers-Danlos syndrome (a.k.a. Ehlers Danlos syndrome type III and Ehlers-Danlos syndrome hypermobility type): clinical description and natural history. Amer J Med Genet. 2017, 175: Thank you! Any questions?

51 Pennsylvania Rheumatology Society NEUROLOGICAL COMPLICATIONS OF RHEUMATIC DISORDERS: UPDATES AND FUTURE DIRECTIONS JULIUS BIRNBAUM, MD, MHS SATURDAY, SEPTEMBER 22 ND 9:00 AM 10:00 AM

52 Neurological Complications of Rheumatic Disorders: Updates and Future Directions Julius Birnbaum, MD/MHS Assistant Professor, Department of Neurology and Medicine Johns Hopkins Hospital No Relevant Financial Relationships with Commercial Interests I will not reference an unlabeled or unapproved use of a drug or product in my presentation.

53 Foot drops---how to distinguish between peripheral neuropathies, radiculopathies, and myelopathies Case I A 64 year old gentleman, in the context of weight-lifting, developed electric bolts of pain, radiating down outer part of distal left leg, as well as dorsum of foot, and developed partial left foot drop Six months later, developed chills and anorexia, localized pain between the web of right first and second toe, and then acutely developed right foot drop Quick differential: No increased tone or reflexes, so dealing with disorder of the peripheral nervous system (PNS)

54 How can I localize a lesion in the peripheral nervous system without being overwhelmed by complex lumbar plexus anatomy? Answer: Forget about most of cross-wiring between spinal cord and peripheral nerves (i.e. plexopathies )---concentrate on distinguishing whether lesion is likely due to a radiculopathy, versus a terminal peripheral nerve injury

55 Points to consider when obtaining a nerve biopsy in suspicion of vasculitic neuropathy Nerve biopsy diagnostic in 45% of clinically suspected cases, with muscle biopsy diagnostic in additional 28% of cases Biopsy an electrodiagnostically affected but not a dead nerve Summary: EMG/NCV and biopsy need to be interpreted in context of clinical syndrome, emphasizing the worth and importance of a careful neurological examination! (Said et al, J Neurol, 2005) Characterization of distinct CNS manifestations of NPSLE A simple, 3-step approach for diagnosis and treatment

56

57 Step 1: Broadly consider non-sle causes of an underlying CNS disorder Vast differential diagnosis of competing non-sle causes of neuropsychiatric syndromes is simplified and winnowed down using VITAMIN mnemonic None of these causes reflect disease damage warranting immunosuppressive therapy! Step 2: Consider the specificity of a particular CNS syndrome for NPSLE Is a given CNS syndrome specific for SLE versus non-disease controls? What are limitations of the current ACR NPSLE nomenclature and case definitions for CNS NPSLE?

58 Limitations of the ACR NPSLE case definitions, and implications for diagnostic care The following CNS syndromes included in the ACR case-definitions are non-specific, are seen with similar frequency in non-sle controls, and in most cases can be evaluated and treated as if an SLE patient did not have SLE: Headache Mood disorder Anxiety disorder Mild cognitive impairment

59 Implications of diagnostic step 2: Various neuropsychiatric syndromes included in the ACR NSPLE nomenclature and casedefinitions do not represent the more limited spectrum of NPSLE. Will almost never start immunosuppressive therapy for headaches, mild cognitive impairment, and affective disorders. Step 3: Characterization of distinct NPSLE syndromes Always use VITAMIN mnemonic: To distinguish SLE versus non-sle causes To identify causes of NPSLE syndrome due to damage

60 Cerebrovascular disease Prevalence of 5 to 15 percent of SLE patients. Small-vessel lacunar strokes>embolic strokes>hemorrhagic strokes For embolic strokes, need to particularly consider Liebman-Sacks endocarditis Stringent control of modifiable risk factors The lupus anticoagulant is more strongly associated with increased risk of thrombotic events, compared to anticardiolipin or beta-2-glycoproteins. Mikdashi et al, Stroke, 2007 Use of the VITAMIN mnemonic to detect causes of strokes mediated by disease damage Vascular/Infections: Septic emboli, subarachnoid hemorrhage from mycotic aneurysms, septic thrombophlebitis, atherosclerosis Traumatic: N/A Metabolic: Uncommon. Hyperhomocysteinemia Autoimmune: Other autoimmune or inflammatory syndromes. Iatrogenic complications: Metabolic (corticosteroids), infections (immunosuppressive) therapy Neoplastic: Leptomeningeal disease or lymphomatous infiltration of vasculature NONE OF THESE DISORDERS WARRANT IMMUNOSUPPRESSIVE THERAPY

61 Summary of the CNS neurological complications of SLE Always suspect a non-sle cause Usually CNS syndromes are not an isolated reason to start immunosuppressive therapy At end of this handout, I ve included an addendum which defines spectrum, evaluation, and treatment of other CNS syndromes How are these features highly salient for neurological evaluation of CNS Sjogren s Syndrome (SS)? Neurological Complications of Sjogren s Syndrome

62 Most diffuse and focal CNS syndromes in SS do not display phenotypespecificity for SS The following CNS syndromes are phenotypically non-specific, and are seen with similar frequency in non-ss controls, and in most cases can be evaluated and treated as if a SS patient did not have SS Headache (~60%) Mood disorder and anxiety disorder (~33%) Strokes and seizures (<5 percent) Harboe et al, Ann Rheum Disease, 2009 Tjensvoli et al, European Journal of Neurology, 2013 Implications In a SS patient with headache, anxiety disorder, mood disorder, strokes, and seizures the diagnostic evaluation should proceed as if the patient did not have SS! Patients with these syndromes should not be subjected to immunosuppressive therapy

63 Unlike SLE, studies have not conclusively demonstrated that a CNS vasculopathy exists in SS patients MECHANISMS SLE patients SS Associated with apl antibodies Yes, 40 percent apl antibodies No, <=10 percent with apl antibodies Endothelial activation or arterial Yes Mild, limited surrogate studies stiffness Accelerated atherosclerosis Yes Mild, limited surrogate studies Haga et al, Scand J Rheumatol, 2008 Sabio et al, Arthritis Care & Research, 2014 Vaudo et al, Arthritis & Rheumatism, 2005 Cognitive Impairment

64 Cognitive impairment: Evaluate for impaired subcortical domains Brain fog : A very incisive and illustrative metaphor used by our SS patients Similar to MS, the pattern of cognitive impairment in SS is characterized by impaired subcortical domains These cognitive domains are entirely different than A pattern of cortical domains affected in cortical dementia: Alexia, Agraphia, Acalculia, Aphasia No studies which suggest that cognitive impairment is progressive Blanc et al, ISRN Neurology, 2013 When should I institute immunosuppressive therapy in SS patients with CNS disease?

65 Very infrequently! Demyelinating disorders in SS In the 1980s and 1990s, literature proposed that MS and CNS Sjogren s could be indistinguishable. This engendered mass panic! This largely stemmed from under-appreciation about limits of MRI studies. Can we distinguish between brain lesions in SS versus MS? Most of the time!

66 This pattern of T2 hyperintense, ovoid frontal lesions could potentially be consistent with MS Brain MRI Multiple Sclerosis

67 Periventricular lesions which radiate perpendicularly from the ventricular surface: Dawson s Fingers But in MS, you wouldn t see this pattern of periventricular sparing

68 Non-specific periventricular lesions: Seen commonly in Sjogren s patients, but unfortunately including MS as part of the differential diagnosis. Transverse Myelitis: Can be seen in MS and Sjogren s

69 Devic s Syndrome/Neuromyelitis Optica (NMO) Clinically defined by demyelinating attacks restricted to optic nerve and spinal cord 2006 diagnostic criteria of Devic s syndrome: Attacks of optic neuritis and myelitis, along with two of the following three features: (1) Myelitis which is longitudinally extensive (LETM), spanning three or more vertebral segments (2) Brain MRI which is nondiagnostic of MS (3) Anti-aquaporin antibody positivity (70% sensitive, 94% specific)

70 Dorsal medulla, area postrema, and other brainstem lesions in Neuromyelitis Optica Spectrum Disorders (NMOSD) (Wingerchuk et al, Neurology, 2015) Dorsal medulla, area postrema, and other brainstem lesions in Neuromyelitis Optica Spectrum Disorders (NMOSD) (Wingerchuk et al, Neurology, 2015)

71 Diencephalic and cerebral lesions in NMOSD Diencephalic and cerebral lesions in NMOSD

72 What is relationship between NMOSD is not a CNS manifestation of SS (Birnbaum et al, Arthritis Care Research 2016) Anti-AQP4 is restricted only to SS NMOSD patients, and not seen in any SS patients without NMOSD Such 100 percent syndrome-specificity indicates that NMOSD is a coincidental disorder in SS patients Similar to other CNS neurological disorders, demyelinating syndromes are not a neurological complication of SS Leads to the following provocative but instructive question Another CNS neurological complication falls by the wayside in SS Similar to other CNS neurological disorders, demyelinating syndromes are not a neurological complication of SS Leads to the following provocative but instructive question

73 Does CNS Sjogren s actually exist?

74 Small-fiber neuropathies in SS and SLE Clinical presentation A 44-year old female with SLE complains of the following symptoms: Caterpillars with sharp claws are crawling on my arms and marching up my neck Hot vats of oil being poured on my thighs. My arms and legs ache when I put on any clothes History of a tachy-brady syndrome requiring pacemaker, along with chronic complaints of constipation.

75 What are clinical features suggestive of a small-fiber neuropathy? A painful neuropathy which targets thinly-myelinated A-delta or unmyelinated C-fiber nerves Quality of pain: Burning, paroxysmal, and allodynic Small-fiber deficits on physical examination Electrodiagnostic studies are normal! Require further diagnostic studies Differential diagnosis of potential small-fiber neuropathies VITAMIN mnemonic Vasculitis Infection: HIV, hepatitis B, hepatitis C, mycobacterial, fungal Autoimmune/Inflammatory Disorders: Celiac disease, sarcoidosis, Metabolic Disorders: Diabetes and impaired glucose tolerance (Need to order a 2-hour GGT!), Vitamin B12 deficiency, hypothyroidism, hyperlipidemia Neoplastic Disorders: Paraneoplastic disorders Structural mimics : Syringomyelia, myeloradiculopathies

76 Punch skin biopsy as a diagnostic marker of SFN Decreased intra-epidermal nerve-fiber density (IENFD) of unmyelinated nerves Easy and quick to perform (Sommer et al, Lancet Neurol, 2007) Taken from two standardized sites (proximal thigh and distal leg) Highly diagnostic, efficient and reliable ~90 percent Can identify clinico-pathological subsets that can highlight mechanisms There are two subtypes of small-fiber neuropathies in SLE

77 The role of skin biopsy in evaluation of small-fiber neuropathies

78 Length-dependent (LD) versus non-length-dependent (NLD) small-fiber neuropathies (Chai et al, Medicine, Sept 2005) Discriminating features LD-small-fiber neuropathies NLD-small-fiber neuropathies Distribution of pain Distal Proximal Intra-epidermal nerve Distal<Proximal Proximal Distal fiber density (IENFD) Anatomic target Distal-most axons Proximal-most dorsal root ganglia (DRG) Mechanisms Diverse CD8 T-cell toxicity Small-fiber neuropathies are an under-recognized PNS disorder of many different inflammatory disorders Rheumatoid arthritis (Gemignani et al, J Periph Nerv Syst, 2012) TNF-inhibitors (Birnbaum et al, Semin Arthritis Rheum, 2014) Inflammatory bowel disease (Gondim et al, Inflamm Bowel Dis, 2015) MPA (Birnbaum et al, Arthritis Care Res, 2009) Scleroderma (neuropathic itch)

79 Treatment of SFN in rheumatic diseases Aggressive poly-symptomatic approaches Small case-series suggest a role for IVIG in refractory disease Larger studies are definitely warranted IVIG may have preferential efficacy because it turns off pain pathways as well as autoimmunity Oaklander, Neurotherapeutics, 2016 On the horizon: Autoimmune pain Several autoantibodies have been identified as a biomarker of chronic pain, even in the absence of tissue or peripheral nerve injury Nascent appreciation that in certain contexts, pain itself may be an autoimmune disease Further studies should evaluate in rheumatic disease the applicability of these as well as novel antibodies. For example, can we identify antibodies in patients having neuropathic-type pain without a neuropathy?

80 Conclusions A neurological evaluation and boldly and powerfully disclose diagnostic strategies, mechanisms and treatment The spectrum of CNS disease directly attributable to SLE and SS is considerably narrower than expected Use the VITAMIN mnemonic to formulate a differential diagnosis SFN is an overlooked PNS manifestation of rheumatic diseases Addendum slides on other CNS manifestations of SLE

81 Seizures Occurs in 5 to 20 percent of patients. Seizures are attributable to SLE in approximately 85 percent of cases However, it is particularly important to consider vascular, infectious, metabolic, and structural causes in the VITAMIN mnemonic! Use of the VITAMIN mnemonic to detect causes of seizures mediated by disease damage Vascular/Infections: Septic emboli, subarachnoid hemorrhage from mycotic aneurysms, septic thrombophlebitis: reflects cortical irritation. Traumatic: Rare, subdural or intraparenchymal hemorrhage from a coagulopathy Metabolic (multiplicity): Hypo/hyernatremia, hyper/hypocalcemia, uremia, PRES Autoimmune: Other autoimmune or inflammatory syndromes Iatrogenic complications: infections (immunosuppressive) therapy Neoplastic: Leptomeningeal disease, paraneoplastic syndromes (causative antibodies can also be seen in non-paraneoplastic syndromes) MOST THESE DISORDERS WARRANT IMMUNOSUPPRESSIVE THERAPY

82 Characteristics of seizures in SLE Clinical characteristics: 70 percent generalized, 30 percent focal, long-term anti-epileptic therapy in only 1/3 of patients 1 Demographic: Younger age 2, African-Americans 1,2, and presents early, in less than 1.5 to 5 years of disease onset 1,2 SLE: Increased with disease activity 1,2,3, disease damage 1,3, apl, 3 presence of other NPSLE syndromes 2,-4, but lower risk with plaquenil 1,2 1 Hanly et al, 2 Andrade et al, Ann Rheum Dis, Mikdashi et al, Neurology Petri et al, J Rheumatol, 2016 Defining patients who are at higher risk of developing seizures and requiring anti-epileptic therapy Neuroimaging: Patients with macroscopic lesions involving the cortex EEG: Focal electrophysiological lesions

83 Cognitive impairment in SLE Screen for potentially modifiable causes, including hypothyroidism, mood disorders, sleep disorders, and pain syndromes However, SLE cognitive impairment is not associated with disease activity Emerging theme: Similar to strokes and seizure, there is no role for sustained immunosuppressive therapy Mechanisms and treatment of focal CNS NPSLE Vasculopathy stems from many causes, including endothelial upregulation, accelerated atherosclerosis, and antiphospholipid antibodies (Seltzer F, et al, Arthritis Rheum, 2004) In most cases, this reflects chronic injury to the vasculature, and in focal NPSLE does not usually warrant sustained therapy with immunosuppressive therapy. For demyelinating syndromes, review slides on spectrum of demyelinating disease in Sjogren s syndrome

84 Pennsylvania Rheumatology Society ADDRESSING PHYSICIAN BURNOUT AND STRESS JON SHAPIRO, MD, DABAM SATURDAY, SEPTEMBER 22 ND 10:30 AM 11:30 AM

85 Addressing Physician Burnout & Stress Pennsylvania Rheumatology Society Jon Clifford Shapiro, Lyons, MD, MD DABAM, MRO PHP PHP Medical Medical Director Director

86 Physician Burnout Educational Goals Participants will identify and implement practical approaches and utilize available resources to effectively recognize and address concerns related to physician impairment, specifically burnout and stress, in the workplace. 866-PHP-CALL

87 Definition of Burnout A pathological syndrome in which emotional depletion and maladaptive detachment develops in response to prolonged occupational stress JAMA (23) Exhaustion, cynicism/detachment, sense of ineffectiveness Adapted from Kearney MK. Self-Care of Physicians Caring for Patients at the End Of Life. JAMA. 2009;301: PHP-CALL Exhaustion Feelings of emotional overextension and exhaustion by work Burnout causes the physician to feel the demands of the job are insurmountable 866-PHP-CALL

88 Cynicism Callous and impersonal reaction to patients, in the case of a physician The passion the physician once felt for his/her work is replaced by cynicism and depersonalization 866-PHP-CALL Loss of Professional Effectiveness Feelings of incompetence, poor achievement and low motivation Burnout causes the physician to doubt his/her self-worth and professional effectiveness 866-PHP-CALL

89 Stress Stress very subjective term as we use it today, usually with negative connotations. Originally stemmed from the work of Hans Selye in 1936 and simply referred to the non-specific responses of the body to any demand for change. Good stress vs. bad stress winning the lottery vs. getting a divorce 866-PHP-CALL

90 Productivity and Stress Productivity Flow 5 0 Daniel Goleman: Emotional Intelligence Stress

91 Pressure Sores Sense of being de-valued by society Can doctors in your country can be trusted? U.S.=25th/30 Blendon, R. et al. NEJM 371;17, 1571, Oct 23, 2014 Some physicians see themselves not as the pillars of any community but as technicians on an assembly line or pawns in a money making game. Sandeep Jauhar from Doctored: the disillusionment of an American Physician. 866-PHP-CALL Pressure Sores Market forces shifting power to: Employers, Payers, Patients, Owners Inadequate information Sleep deprivation Dangerous workplace environment Malpractice Maintenance of Certification 866-PHP-CALL

92 Dangerous Workplace Workplace Violence against Health Care Workers in the United States James P. Phillips, M.D. N Engl J Med 2016; 374: April 28, 2016DOI: /NEJMra PHP-CALL Pressure Sores Malpractice Personal Consequences of Malpractice Lawsuits on American Surgeons, Balch, CM et al, jamcollsurg Higher burnout, depression and thoughts of suicide. Physicianlitigationstress.org 866-PHP-CALL

93 2012 The ABIM took in $55 million for certifications Many physicians are waking up to the fact that our profession is increasingly controlled by people not directly involved in patient care who have lost contact with the realities of day-to-day clinical practice. Paul Teirstein, MD Boarded to Death Why Maintenance of Certification Is Bad for Doctors and Patients n engl j med 372;2, jan 8, PHP-CALL Adverse Events A Piece of My Mind- What I learned about adverse events from Captain Sully: It s not what you think. MP Stiegler, JAMA 313(4) Jan 27,2015. No one considered asking them to head back to La Guardia and fly another leg. Yet in medicine, physicians are generally expected to continue caring for patients, without even a brief period of time to reflect or regroup. 866-PHP-CALL

94 Pressure Sores Intermediate level practitioners No reward for responsible change Lack of Control over work environment Too much work - Too little time Electronic Medical Record 866-PHP-CALL Let Doctors Be Doctors Video: PHP-CALL

95 Inherent conflicts? Satisfying Physicians Increased incomes Restricted physician access Few locations Low overhead Flexible scheduling Daytime hours Reduce Overbooking Physician decision making Satisfying Patients Low premium rates Open physician access Several locations Increased service Set appointments Extended hours Short wait times Patient autonomy 866-PHP-CALL

96

97 The fault is not in our stars, but in ourselves Burnout results not just from where we work but from who we are 866-PHP-CALL

98 some level of impairment to residents is a common and predictable sequel to the time they spend at traditionally catastrophic levels of stress... Levey RE: Acad Med 76:142, PHP-CALL

99 Medical Education: A Neglectful & Abusive Family System Difficulty setting limits Excessive demands of self (and others) Deny needs & criticize others for expressing their needs Deny mistakes to avoid punishment Learn to appear self-sufficient-perfectionism Medical Education: A Neglectful and Abusive Family System; McKegney, Catherine P, Family Medicine, 21:450, PHP-CALL Things I wish they taught me in Medical School Pfifferling JH: Res and Staff Phys, 36:85, 1990 Setting life priorities (Values) The importance of vacations Being your own Best Friend Dealing with loss & failure Expressing feelings How to say I Don t Know How to say No Inevitability of ambiguity & uncertainty 866-PHP-CALL

100 Character Drives Physician Burnout High achievement orientation Difficulty setting boundaries Intellectualization Delayed gratification Perfectionism 866-PHP-CALL Perils of perfectionism The desire to excel must be differentiated from the desire to be perfect Myers M and Gabbard G

101 Steve Adelman, MD NY CPH Medical Director We work in a zero defect environment. Physicians are expected to deliver excellent and cost effective care in a fashion that delights every single patient. This unrealistic goal sets us up for failure. 866-PHP-CALL

102 Personal & Professional Consequences of Burnout Recognizing Burnout Consequences Question: Which of the following causes of death among young physicians is most common? A. Substance abuse B. Drunk driving C. Suicide 866-PHP-CALL

103 Recognizing Burnout Consequences Answer: C. Suicide More than 400 physicians are lost to suicide in the U.S. annually (2-4x rate of general population) 26% of all young physician deaths are due to suicide Acad Med Mar;70(3):242-4 Problems with work were 3x more likely to have contributed to suicide vs. non-physician 866-PHP-CALL Physician Suicide (cont.) Suicide accounts for: 3% of the yearly male physician deaths 6.5% of the yearly female physician deaths 35% of premature deaths among physicians 866-PHP-CALL

104 Burnout among US medical students, residents and early career physicians relative to the general US population Dyrbye, LN, CP West, D Satele, et al., Academic Medicine, (3): p PHP-CALL

105 JAMA Guidelines for Suicide Prevention, 2003 The culture of medicine accords low priority to physician mental health despite evidence of untreated mood disorders and an increased burden of suicide. 866-PHP-CALL Burnout & Satisfaction with Work-Life Balance Among US Physicians Relative to the General US Population Tait D. Shanafelt, MD; Sonja Boone, MD; Litjen Tan, PhD; Lotte N. Dyrbye, MD, MHPE; Wayne Sotile, PhD; Daniel Satele, BS; Colin P. West, MD, PhD; Jeff Sloan, PhD; Michael R. Oreskovich, MD Online First, August 20,2012, Arch Intern Med 866-PHP-CALL

106 What do we know? Burnout may be a natural consequence of our professional indoctrination coupled with a stressful ever changing medical profession High prevalence in physician Contributes to physician dissatisfaction Physician turnover Erodes patient care Contributes to mental health and substance abuse problems. 866-PHP-CALL What do we KNOW On an individual level burnout is recognizable, reversible, treatable Institutional involvement is key in reengaging physicians and reversing the trend in burnout 866-PHP-CALL

107 Identifying Burnout - 2 Item MBI The Maslach burnout index scale has 22 questions. Researchers at Mayo determined that you can actually do an accurate screen with just two items: 1. I feel depleted and burned out from my work. 2. I have become more callous toward people since I started this job - treating patients as objects instead of humans. Arch Intern Med. 2012;172(18): PHP-CALL How many physicians suffer from symptoms of burnout on any given day? A. One in every ten physicians B. One half of all physicians C. We really don t know because physicians never bother to respond to surveys 866-PHP-CALL

108 Answer: Answer: B According to a recent study in the Archives of Internal Medicine, almost half of U.S. physicians report at least one symptom of burnout a much higher rate than that reported by individuals employed in other occupations. It also appears that burnout rates are increasing among U.S. physicians. 866-PHP-CALL Recognizing Burnout Warning Signs Sleep problems, including nightmares Social withdrawal Professional and personal boundary violations Poor judgment Perfectionism and rigidity Questioning the meaning of life Kearney,MK. Self-care of Physicians Caring for Patients at the End of life. JAMA 2009;301: PHP-CALL

109 What can the individual clinician do? 866-PHP-CALL

110 Make healthy lifestyle choices that increase resilience to & recovery from burnout Concentrate on the wonderful core of medicine-the doctor-patient relationship Get an appropriate amount of sleep Build physical activity into your daily routine exercise can increase energy and improve your mood Eat healthful food, avoid excessive alcohol and caffeine 866-PHP-CALL

111 The opposition s response about exercise 1. If exercise made you live longer then mailmen would be immortal 2. Whales only eat fish, swim all day and they are still obese 3. Rabbits run all the time and only live five years 4. Tortoises never run and they can live a century 866-PHP-CALL

112 Make healthy lifestyle choices that increase resilience to & recovery from burnout (cont.) Relaxation yoga, meditation and deep breathing may work for one person while participating in a favorite hobby may work for another Attend to your health and do not self-treat Cultivate interests outside of medicine (e.g., hobbies, service organizations, second careers, or reading non-medical materials) 866-PHP-CALL Make healthy lifestyle choices that increase resilience to & recovery from burnout (cont.) Protect your time with family and friends Formulate realistic financial goals Set aside time to do nothing (i.e., schedule nothing on your calendar; avoid the temptation to fill the space with activities) Support humanistic values in medical education! Organized medicine 866-PHP-CALL

113 Organizational Burnout Maslach, C.; Schaufeli, W. B.; Leiter, M. P. (2001). S. T. Fiske; D. L. Schacter; C. Zahn-Waxler, eds. "Job burnout". Annual Review of Psychology. 52: Burnout occurs when there is a disconnect between the organization and the individual with regard to what they called the six areas of work life: Workload reasonable expectations Control - autonomy Reward -acknowledgement/compensation Community- positive work place environment Fairness treated with respect Values integrity is encouraged 7 Drivers of Burnout and Engagement

114 Shanafelt et al. Executive Leadership and Physician Well-being: Nine Organizational Strategies to Promote Engagement and Reduce Burnout. Mayo Clin.Proc. What can Institutions do? Administrative Strategies Physician wellness committees. Make clinician satisfaction and well being quality indicators Schedule regular meetings for physicians to discuss stressful situations, difficult patients and challenging diagnoses Build time into schedules for stress-relieving activities Incorporate mindfulness and teamwork into practice. Schedule retreats that focus on team building and selfawareness. 866-PHP-CALL

115 Administrative Strategies Preserve physician career fit with protected time for meaningful activities. Promote part-time careers and job sharing Mentor programs for junior clinicians Promote physician control of the work environment 866-PHP-CALL Stress and medical malpractice: organizational risk assessment and intervention Jones JW, Barge BN, Steffy BD, Fay LM, Kunz LK, Wuebker LJ.. J Appl Psychol.1988;73(4): Large medical malpractice insurer developed and tested a stress reduction program for hospital employees that focused on individual training in stress management and organizational control of factors that produced stress. A pilot study found a reduction in medication errors. 866-PHP-CALL

116 Code Lavender Through the program, a provider who summons emotional support is met by a team of holistic nurses within 30 minutes of a call. The team provides Reiki and massage, health snacks and water, and lavender arm bands to remind the individual to relax for the rest of the day. The Holistic Services Team also offers a variety of other methods, including spiritual support, mindfulness training, counseling and yoga. 866-PHP-CALL Stanford Physicians Wellness 866-PHP-CALL

117 Stanford center research and promotion of physician wellness Doctors who take care of themselves Are better role models for their patients. Are better role models for their children. Have higher patient satisfaction and safety scores. Experience less stress and burnout. Live longer.(?) 866-PHP-CALL Intervention to Promote Physician Well-being, Job Satisfaction and Professionalism - A randomized Clinical Trial Randomized study Control Group: 1h every 2 weeks protected time Intervention group: Structured meetings 1h every 2 weeks Based on: Reflective practice Facilitated small group learning (8 to 10 modules) Themes centered on self, patient, balance between both (medical errors, difficult patients, work-life balance, etc.) The intervention improved meaning and engagement in work and reduced depersonalization with sustained results at 12 months. West C Intervention to Promote Physician Well-being, Job Satisfaction, and Professionalism. A randomized Clinical Trial JAMA Intern Med 2014

118 Examples of Hospital projects for MD wellness Patient schedule changes for work-life balance e.g. no complex patients in the last slots of the day. Environmental changes. Involve people in designing their own work space. Art, rugs etc. Rush Memorial- Guided mindfulness meditation UCSF Finding meaning in medicine. Facilitated topics about remembering the heart of medicine 866-PHP-CALL Pa Medical Society advocacy priorities for employed physicians Assuring Physician s clinical autonomy. Keeping physicians in charge of medical decision making Resolving complaints when a physician reports concerns about clinical interference Due process protections for clinical privileges Eliminating restrictive covenants 866-PHP-CALL

119 Winding down now Burnout may be a natural consequence of our professional indoctrination coupled with a stressful ever changing medical profession High prevalence in physician Those with burnout are more likely to abuse substances, become depressed and suicidal and make medical errors Burnout is recognizable, reversible, treatable 866-PHP-CALL

120 Healthy Doctors Give Better Care Decreased medical errors Increased patient satisfaction Better treatment recommendations Increased treatment adherence Lower malpractice risk Better attitudes toward work Higher team functioning Lower turnover Online Burnout Resources Steps Forward offers modules on preventing physician burnout in practice, preventing resident and fellow burnout and improving physician resiliency. Executive Leadership and Physician Well-being:Nine Organizational Strategies to Promote Engagement and Reduce Burnout. Shanafelt, TD and Noseworthy, jhhttp://dx.doi.org/ /j.mayocp AMA online education Malpractice resourcesphysicianlitigationstress.org Stanford physicians wellness site Rap video about EHR letdoctorsbedoctors

121 Physicians Health Program

122 Any Questions? Atul Gawande M.D. from Being Mortal Despite our virtuosic surgical capacities, our cutting-edge technology and our pharmaceutical advances, the patientdoctor relationship is still the heart of medicine. 866-PHP-CALL

123 Pennsylvania Rheumatology Society ANNUAL BUSINESS MEETING SATURDAY, SEPTEMBER 22 ND 1:00 PM 1:15 PM

124 Annual Business Meeting September 22, 2018 Agenda o Call to Order o Approval of Minutes 9/22/17 o Membership Report o Council Appointments o Approval of Bylaws Change o Corporate Partnership Update o Financial Update o Annual Meeting Update o New Business/Closing Remarks 1

125 PRS Annual Business Meeting Minutes 9/16/17 Sheraton Harrisburg, PA The meeting was called to order by President Dr. Philip Cohen at 1:05 PM. Dr. Cohen shared the strong financial position of the organization and a few of the new initiatives planned, including the funding of FIT travel to the ACR meeting. The minutes from the September 17, 2016, Annual Business Meeting were approved as presented. Dr. Cohen reviewed the membership report and mentioned the increase in PRS members to 156. The nominating report and 2017 ballot were approved as presented. Dr. Cohen noted the restructuring of the board to include 4 officers and 4 councilors with 3 additional FIT and Early Career appointees for a total of of 3 PRS Annual Business Meeting Minutes 9/16/17 Sheraton Harrisburg, PA Dr. Cohen reviewed the Governance Task Force Report which included the bylaws revisions previously provided to all members via . There was a motion to approve the bylaws changes. Motion carried. Dr. Cohen acknowledged and thanked the 2017 Corporate Partners: AbbVie, Bristol Myers Squibb, Genentech, Janssen, Pfizer, Sanofi and UCB. Dr. Cohen reviewed the July 2017 financial statement with total liability and net assets at $162,900. He noted that the society is in a much stronger position than the prior year. 2 of 3 2

126 PRS Annual Business Meeting Minutes 9/16/17 Sheraton Harrisburg, PA Dr. Cohen commented on the 4th Annual Meeting s increased attendance numbers, excellent program and speakers and important industry support. He thanked the program planning committee, board members and staff. He then introduced, Dr. Larry Brent, who gave a few words as incoming President. The meeting was adjourned at 1:09 PM Respectfully submitted, Maria Elias PRS Executive Director 3 of 3 MOTION TO APPROVE Membership Report Current Membership 192 Active 96 Affiliate 6 Trainees/Medical Students 80 Retired 10 Members Joined Since January Potential Members* 177 *PA Licensed physicians designating rheumatology as a primary interest 3

127 Appointments for Councilor Replacement: Lisabeth Scalzi, MD Central Council Appointment: Cathy Lee Ching, MD FIT Representative Bylaws Changes The PRS board discussed and approved the suggested bylaws changes that were ed to all PRS members on 8/22/18. Need a Motion to Approve the Changes as Presented: SECTION 3. SECTION 4. Early Career Representatives. There shall be two Early Career representatives appointed by the council the President to the Board. Nominees must be five years, or less, out of training. These positions will serve two-year terms, with the opportunity to be elected to an officer or councilor position after the term has ended. Fellow in Training Representatives. There shall be one two Fellow in Training representatives appointed by the President to the Board. Nominations by Program Directors will be reviewed with a final appointment by the council. This These positions will serve a July-June appointment with a one-year term. Reappointment opportunities will be available for first year fellows in training. ARTICLE III. SECTION 1. THE COUNCIL The Council shall consist of the immediate Past-President, President, Vice President (President-Elect), Secretary-Treasurer, four councilors, two early career representatives and one two fellow in training representatives. It shall be the duty of the Council to supervise the affairs of the Society, to elect new members and to help the President arrange for the annual business meeting. All members of the Council will have voting privileges. Six Seven members shall constitute a quorum. 4

128 Corporate Partnerships 2018 AbbVie Amgen Bristol Myers Squibb Eli Lilly Genentech GSK Horizon Pharma Janssen Pfizer Sanofi UCB Financial Statement YEAR END DECEMBER 2017 PRIOR YEAR TO DATE YEAR TO DATE ASSETS Cash Checking ($85.60) ($0.00) Cash Management Fulton 112, , Long Term Investment, Fulton Financial Advisors 50, Total Cash 162, , Accounts Receivable Prepaid Expenses TOTAL ASSETS 163, , LIABILITIES AND NET ASSETS Accounts Payable General Accounts Payable PAMED 2, , Unearned Revenue , Total Liabilities 3, , Net Assets, January 1 95, , Change in Net Assets 64, , Net Assets, Year to Date 159, , TOTAL LIAB AND NET ASSETS 163, ,

129 Thank you for attending the 5th Annual Scientific Meeting of the Pennsylvania Rheumatology Society Any New Business? Adjournment 6

130 Pennsylvania Rheumatology Society Sunday, September 23 rd Lectures Combined Session: Fibromyalgia: Update for Rheumatologists Roland Staud, MD 1 AMA PRA Category I CME Credits Adult Breakout Sessions: Connective Tissue Disorder-Associated Interstitial Lung Disease (CTD-ILD) and Updates Maria Elena Vega-Sanchez, MD 1 AMA PRA Category I CME Credits Update on the Radiology of Spondyloarthropathies Donald Flemming, MD, FACR 1 AMA PRA Category I CME Credits Pediatric Breakout Session: Henoch Schonlein Purpura: Update on Diagnosis and Treatment Pamela Weiss, MD, MSCE 1 AMA PRA Category I CME Credits Update on Kawasaki Disease Mary Beth Son, MD 1 AMA PRA Category I CME Credits Combined Session: Autoantibodies in Inflammatory Muscle Disease Chester Oddis, MD 1 AMA PRA Category I CME Credits ipad Drawing ipad drawing will take place on Sunday afternoon at 12:45 pm. 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.

131 Pennsylvania Rheumatology Society COMBINED SESSION: FIBROMYALGIA: UPDATE FOR RHEUMATOLOGISTS ROLAND STAUD, MD SUNDAY, SEPTEMBER 23 RD 8:00 AM 9:00 AM Slides not provided by speaker.

132 Pennsylvania Rheumatology Society ADULT BREAKOUT SESSION: CONNECTIVE TISSUE DISORDER- ASSOCIATED INTERSTITIAL LUNG DISEASE (CTD-ILD) AND UPDATES MARIA ELENA VEGA-SANCHEZ, MD SUNDAY, SEPTEMBER 23 RD 9:10 AM 10:10 AM

133 Connective Tissue Disorder- Associated Interstitial Lung Disease (CTD-ILD) and Updates Maria Elena Vega, M.D Assistant Professor of Medicine Lewis Katz School of Medicine at Temple University Nothing to disclose Disclosures

134 Objectives Describe the magnitude of ILD in CTD. Define CTD-ILD. Appraise the utility of PFT, 6-minute walk test and high resolution chest CT in diagnosing CTD-ILD. Review updates and treatment of CTD-ILD. Pulmonary involvement in CTD The lung is a common site of complication of systemic CTD. Can involve: The respiratory muscles, the pleura, the conducting airways, the lung parenchyma and the pulmonary vessels.

135 Lung Involvement in CTD Lung Involvement SS RA Sjogren s Syndrome MCTD PM/DM SLE ILD Likely Common Possible Common Likely Unusual Pulmonary Hypertension Airways Disease Likely Unusual Unusual Likely Unusual Unusual Unusual Common Common Possible Unusual Possible Pleural Unusual Common Possible Possible Unusual Likely Diffuse Alveolar Hemorrhage Unusual Unusual Unusual Unusual Unusual Common ILD in CTD IDL is one of the most common and clinically important manifestations of CTD. It can also be the first and only manifestation of previously unrecognized CTD. ILD can also occur as a complication of treatment for CTD.

136 Definition of CTD-ILD The ILDs are a group of diffuse parenchymal lung disorders that are classified according to specific clinical, radiological and histopathological features. ILD has no identifiable cause = Idiopathic Associated with an underlying CTD. Incident Cases of ILD Coultas AJRCCM 1994;150:

137 Epidemiology The overall incidence of CTD-ILD is estimated at 15%. Radiographic prevalence on high resolution computerized tomography (HRCT): RA 19% PM/DM 23-38% SLE 30% MCTD 52-85% SS 75% SSc % Epidemiology ILD is the leading cause of morbidity and mortality in CTD. CTD-ILD is associated with a more favorable prognosis than is idiopathic interstitial pneumonia of equivalent severity.

138 Histopathology NSIP (Non-Specific Interstitial Pneumonia) - most Cellular Fibrotic - Scleroderma / Systemic Sclerosis, PM /DM UIP (Usual Interstitial Pneumonia) RA LIP (Lymphocytic Interstitial Pneumonia) Sjogren s Syndrome OP (Organizing Pneumonia) RA, PM/DM Diagnosis PFT and 6 min walk Pulmonary Function Test Spirometry decreased FVC Lung volumes decreased TLC Diffusion capacity reduced Six minute walk test Evaluate for resting or exertional hypoxemia

139 Diagnosis - HRCT High-resolution computed tomography (HRCT) of the lung provides detailed visualization of the lung parenchyma. More sensitive than chest X ray and PFT. The technique of HRCT involves use of 1-2-mmthick collimation scans with a high spatial frequency algorithm. NSIP pattern The predominant finding is ground glass opacity (GGO). NSIP is by far the most common ILD in patients with connective tissue disease.

140 UIP pattern Honeycombing consisting of multilayered thick-walled cysts. Architectural distortion with traction bronchiectasis due to fibrosis. Predominance in basal and subpleural region. Organizing Pneumonia Bilateral peripheral consolidations, sharply demarcated. Consolidations may be migratory.

141 Lymphocytic Interstitial Pneumonia CT findings are nonspecific but include mixed alveolar interstitial infiltrates and thin-walled cysts. Treatment Decisions to treat depend on spirometry data and symptom decline. Debate over treating patients if they have radiographic pattern of UIP. Treatment if obvious GGOs. Vary by underlying CTD.

142 Treatment - Cyclophosphamide There are few adequately powered randomized controlled trials in patients with CTD ILD. Utility of cyclophosphamide in the treatment of scleroderma associated ILD. Scleroderma Lung Study I: oral cyclophosphamide vs placebo for 1 year improvement in FVC N Engl J Med 2006; 354: Treatment - Cyclophosphamide Initial combination therapy with low dose steroids and cyclophosphamide IV every month for 6 months followed by maintenance with Azathioprine vs placebo Non significant trend towards improvement in FVC. Suggests that the effect wanes over time. Arthritis Rheum. 2006;54(12):

143 Mycophenolate Mofetil (MMF) Has been studied in various CTD-ILD populations with generally favorable results. Case series of 125 patients Scleroderma (n=44), PM/DM (n=32), RA (n=19) Sustained improvement in FVC and reduced steroid requirement J Rheumatol 2013; 40:640-6 Mycophenolate Mofetil Scleroderma Lung Study II: Randomized, double-blind, parallel group trial. MMF for 24 months or oral cyclophosphamide for 12 months followed by placebo for 12 months. MMF was better tolerated and associated with less toxicity FVC did not differ significantly between the two treatment groups Lancet Respir Med. 2016;4(9):

144 Scleroderma Lung Study III Combining Pirfenidone With Mycophenolate (SLSIII) Double-blind, randomized and placebocontrolled. Scleroderma-related Interstitial Lung Disease. Oral MMF and a placebo or combination of oral MMF and oral pirfenidone. Antifibrotic Agents Agents that had been shown to have efficacy in the treatment of idiopathic pulmonary fibrosis (IPF): Pirfenidone: antifibrotic agent that inhibits transforming growth factor beta (TGF-b)-stimulated collagen synthesis, decreases the extracellular matrix, and blocks fibroblast proliferation in vitro. Nintedanib: a receptor blocker for multiple tyrosine kinases

145 Nintedanib (Ofev) The main benefits are a reduction in the rate of decline in lung function and a longer time to first exacerbation. Side effects: diarrhea (62 %), nausea (24%), vomiting (12%), and elevation in LFT. N Engl J Med. 2014;370(22):2071 / N Engl J Med. 2011;365(12):1079 Pirfenidone (Esbriet) Significant reduction in the one-year rate of decline in FVC compared to placebo. Pirfenidone reduced the decline in the 6 MWD, improved progression-free survival. Side effects: rash, photosensitivity, nausea, diarrhea, abdominal discomfort, anorexia and fatigue. N Engl J Med. 2014;370(22):2083

146 Biologic agents RA Rituximab refractory scleroderma (case series) stability or inc in FVC at 6-12 months. Rituximab Versus Cyclophosphamide in Connective Tissue Disease-ILD (RECITAL) Scleroderma, IIM, MCTD Calcineurin Inhibitors Case studies and case series in patients with DM/PM ILD and IIM ILD Retrospective studies PM/DM and IIM ILD Tacrolimus 1-3 mg / day Cyclosporine 2-5 mg /kg/ day

147 Lung transplantation Lung transplantation may be an option for carefully selected patients with CTD-ILD that are not responsive to pharmacologic interventions Bob 70 year old former smoker man Seronegative RA, GERD, CAD, carotid stenting. 6/2016 RA saturation 86%, ambulated 304 meters, required 4 L. 7/2017 RA saturation 96%, ambulated 270 meters, did not require oxygen.

148 Initial HRCT Chest After treatment

149 Iona 70 year old woman with a past 35 pack-year smoking history, undifferentiated connective tissue disease, ILD and emphysema. On MMF since FVC TLC DLCO Room air saturation Distance (meters) Oxygen with ambulation % 62% 50% 97% 305 none % 66% 52% 98% 361 none % 74% 48% 96% 335 none % 54% 46% 98% 305 none % 63% 47% 98% 290 none

150 Lydia ILD diagnosed by a lung biopsy in Puerto Rico in 2010 (biopsy most consistent with UIP) Anti Synthetase Syndrome FVC TLC DLCO Room air saturation % 37% Distance (meters) Oxygen with ambulation % 58% 32% 98% 342 none % 43% 21% 84% liters

151 Interstitial Pneumonia with Autoinmmune Features Patients with idiopathic interstitial pneumonia (IIP) with clinical features that suggest an underlying autoimmune process. Do not meet established criteria for connective tissue disease. The European Respiratory Society/American thoracic Society Task Force on undifferentiated forms of connective tissue disease associated interstitial lung disease (May 2015). Interstitial pneumonia with autoimmune features (IPAF) Classification Clinical domain Specific extrathoracic features Serologic domain Specific circulating autoantibodies Morphologic domain Specific chest imaging features, histopathologic features or pulmonary physiologic features

152 IPAF Prospective studies are needed to determine the natural history and clinical implications of this classification and to allow for an evidence-based approach to the management of this cohort of patients.

153 Multidisciplinary discussion The multidisciplinary approach is to goal standard for diagnosing and treating patients with CTD-ILD. Pulmonologists, Rheumatologists, Radiologists, and Pathologists. Conclusions Patients with CDT-ILD should be followed regularly with a six minute walk test, PFT and HRCT of the chest. Multidisciplinary approach is to goal standard for diagnosing and treating patients with CTD-ILD. Immunosuppression is the mainstay of treatment for ILD. Clinical trials of novel therapies are needed to inform best treatment strategies.

154 References Tashkin DP at al. Cyclophosphamide versus Placebo in Scleroderma Lung Disease. N Engl J Med 2006; 354: Hoyles RK at al. A multicenter, prospective, randomized, double-blind, placebo-controlled trial of corticosteroids and intravenous cyclophosphamide followed by oral azathioprine for the treatment of pulmonary fibrosis in scleroderma. Arthritis Rheum. 2006;54(12): Fisher A at al. Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol 2013; 40: Tashkin DP at al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med Sep;4(9): References Richeldi L at al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071. Richeldi L at al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011;365(12):1079. King TE Jr. at al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083. Fisher at al. An official European Respiratory Society/ American Thoracic Society research statement: interstitial pneumonia with autoimmune features. Eur Respir J. 2015; 46:

155 Pennsylvania Rheumatology Society ADULT BREAKOUT SESSION: UPDATE ON THE RADIOLOGY OF SPONDYLOARTHROPATHIES DONALD FLEMMING, MD, FACR SUNDAY, SEPTEMBER 23 RD 10:40 AM 11:4 0 AM

156 Update - Imaging of the Spondyloarthropathies Donald J. Flemming, M.D. Dept of Radiology Penn State Hershey Medical Center Spondyloarthropathies Family of inflammatory arthritides of synovium and entheses Axial and asymmetric peripheral arthritis Genetic predisposition - HLA B27 Infectious etiology Spondyloarthropathies psoriasis sacroiliitis carditis gut inflammation spondylitis arthritis HLA B27 enthesopathy conjunctivitis genital inflammation Enteropathic arthritis Psoriasis Reactive arthritis Ankylosing spondylitis

157 HLA B27 Normal population -USA ~0-8% Ankylosing spondylitis - >90% Reactive arthritis % Psoriasis - not increased without arthritis with peripheral arthritis - 20% with axial arthritis - 50% IBD with axial arthritis - 50% Spondyloarthropathy (SpA) Peripheral SpA With psoriasis With IBD With preceding infection Without any above Axial SpA With radiographic SI disease Without radiographic SI disease Abnormal MRI HLA-B27+ and clinical findings Spondyloarthopathies Role of Imaging Demonstrate manifestations Characterize activity and extent of disease Appropriate imaging Understand limitations of techniques Differentiate arthropathies

158 Modalities Radiography Inexpensive; skill to interpret Specific but not sensitive; late findings CT Expensive, radiation Disease activity not studied Spectral CT?? Modalities Ultrasound Inexpensive, widely available More sensitive than x-ray Disease activity assessed Operator dependent MRI Expensive; time consuming Sensitive; too sensitive? Experience matters Nonaxial SpA - Psoriatic Arthritis Peak ages years M:F -1:1 Arthritis in 5-8% of patients with psoriasis Enthesitis hallmark of the disease Dactylitis

159 ASAS Criteria Peripheral SpA Ann Rheum Dis 2011;70:25 31 Non-axial SpA Radiographic Manifestations Fusiform soft tissue swelling Dactylitis Maintenance of mineralization Dramatic joint space loss Bone proliferation Marginal erosions predominate Pencil-in-cup erosions Bilateral asymmetric dz Sausage Digit 16-49% Pts with PsA Low sensitivity but high specificity

160 Sagittal T1 second toe Sagittal T1 first toe J Rheumatol 1997;24: MIP

161 Bone Production Reparative Response Whiskering / brush stroke erosions Osteitis Enthesopathy Periostitis Ankylosis

162 Enthesis Organ Tendon/ligament insertion Fibrocartilage Bursa Fat pad Cancellous bone Investing fascia Enthesitis Enthesitis triggers joint synovitis More peripheral joint damage Joint ankylosis Arthritis mutilans Poorer sleep/functional status Early detection critical MRI vs US

163 Enthesitis - MRI Thickening of tendon with T2 Insertional BME Not specific!! No BME? Not sensitive!! Field of view and cost Enthesitis-MRI New Techniques WBMRI Long scan time 61 min No reimbursement Inter/intraobserver reliability??? Ann Rheum Dis 2015;74: Enthesitis-US Patient comfort and low cost High spatial resolution Power doppler inflammation Operator dependent BMI>30 Lower specificity Seminars in Arthritis and Rheumatism 48(2018)35 43

164 Axial SpA Inflammatory Back Pain Age at onset <45 yr Duration > 3 mos Insidious onset Morning stiffness >30 min Improvement with exercise No improvement with rest Awaking from pain Alternating buttock pain 70-80% - Sens ASAS Criteria Axial SpA Ann Rheum Dis 2011;70:25 31 Imaging of Sacroiliitis Radiography initial evaluation Cross sectional imaging CT better for erosions MRI better for active disease high sensitivity/lower specificity Non-specific findings Older patients > 40 years Post partum females

165 AS-Radiographic Manifestations AP pelvis sufficient No benefit from 3 view sacral series Sacroiliac disease bilateral symmetric - same as enteropathic erosions predominate iliac vs sacrum sclerosis Ankylosis

166 SI Joint Anatomy

167 Sacroiliitis Differential Diagnosis Axial SpA Hyperparathyroidism Osteiitis Condensans Infection Osteoarthritis DISH

168 Radiography - Limitations Low sensitivity 30% vs MRI Very hard to read Poor inter/intraobserver reliability Experience matters FP rate 28-60% for local vs central read 1 Training may not improve results 2 1. Ann Rheum Dis 2018;77:e1. 2. Ann Rheum Dis 2003;62:

169 Sacroiliitis - CT Gold standard for erosions Radiation in young patients Low dose techniques on horizon No assessment of BME, synovitis, capsulitis, enthesitis Spectral CT New technique quantify BME MRI still superior Br J Radiol :

170 MRI of Sacroiliitis T1 structural abnormality Erosion, fat metaplasia, sclerosis T2 BME Disease activity, enthesitis Coronal/ Axial Oblique T1 and STIR Other sequences DWI Contrast not required MRI of Sacroiliitis Erosions better seen on T1 Active = BME or SC enhancement Single lesion on two or more slices Multiple lesions on single slice Capsulitis or enthesitis not sufficient Sclerosis - >5mm deep to SC bone Periarticular fat deposition Ankylosis 38M Active Sacroiliitis

171 Fat Deposition=Chronic 33M Active and Chronic 74M with OA

172 74M with OA MRI sacroiliac (SI) joints Osteitis Condensans Ilii (OCI). Osteochondral Injury 28F Postpartum Robert G W Lambert et al. Ann Rheum Dis 2016;75: by BMJ Publishing Group Ltd and European League Against Rheumatism Sacroiliitis-MRI New Techniques Dynamic contrast enhancement (DCE) Quantitative assessment of dz activity Requires contrast and software Necessary?? Rheumatology International /s

173 Sacroiliitis-MRI New Techniques Diffusion weighted imaging (DWI) Quantitative assessment of dz activity Necessary?? Rheumatology International /s AS-Radiographic Manifestations Spine Disease - ascends from lumbar to cervical Discovertebral destruction Romanus and Andersson lesions Shiny corner sign Squaring of vertebral body Syndesmophyte Bamboo spine Late findings

174 Normal Ank Spon

175 DISH Diffuse Idiopathic Skeletal Hyperostosis Common disease - 12% of elderly population Flowing bulky paravertebral ossification Four contiguous vertebral bodies Thoracic>lumbar>cervical Enthesophytes - particularly pelvis Absence of erosions/ joint abnormality DISH Ank S

176 DISH Ank Spon

177 Summary Imaging has significant role in SpA Enthesitis Probably best assessed by US Sacroiliitis AP pelvis avoid 3 view SI joint MRI for equivocal cases or disease assessment Contrast not required Hard to interpret - Sens but Spec Spine disease MRI for early disease Sens but Spec Hard to interpret

178 Pennsylvania Rheumatology Society PEDIATRIC BREAKOUT SESSION: HENOCH SCHONLEIN PURPURA: UPDATE ON DIAGNOSIS AND TREATMENT PAMELA WEISS, MD, MSCE SUNDAY, SEPTEMBER 23 RD 9 :10 AM 10:10 AM Slides not provided by speaker.

179 Pennsylvania Rheumatology Society PEDIATRIC BREAKOUT SESSION: UPDATE ON KAWASAKI DISEASE MARY BETH SON, MD SUNDAY, SEPTEMBER 23 RD 1 0 :40 AM 11:40 AM

180 Kawasaki Disease: An Update Mary Beth Son, MD Boston Children s Hospital September 23 rd, 2018 No disclosures relevant to this talk

181 Outline of Talk Signs and Symptoms of KD Diagnosis Treatment knowns and unknowns Long Term Prognosis/Outcomes History: Kawasaki Disease 1967: Dr. Tomisako Kawasaki, a Japanese pediatrician, describes mucocutaneous lymph node syndrome Thought that the illness self-resolved without intervention and had no sequelae Rapid increase in incidence of KD form 1960 s-1080 s with continued increasing prevalence

182 Original Diagnostic Criteria Fever of > F persisting at least 5 days AND 4/5 following criteria: Bilateral conjunctival injection Erythema & cracking of lips; strawberry tongue & erythema of pharynx Erythema & edema of hands and feet; later peeling Polymorphous exanthem Cervical lymphadenopathy (> 1.5 cm.), usually unilateral Epidemiologic Case Definition In the presence of fever and 4 principal criteria, the diagnosis of KD can be made on Day 4 of illness. Patients with fever and < 4 principal criteria can be diagnosed with KD when coronary artery abnormalities are detected on imaging (usually echocardiogram).

183 Hospitalizations for Kawasaki Syndrome Among Children in the United States, Holman, Robert; Belay, Ermias; Christensen, Krista; Folkema, Arianne; Steiner, Claudia; MD, MPH; Schonberger, Lawrence; MD, MPH. Pediatric Infectious Disease Journal. 29(6): , June DOI: /INF.0b013e3181cf8705 National Survey of pediatric hospitalizations due to Kawasaki disease and coronary artery aneurysms in the USA. Yusuke Okubo, Kotaro Nochioka, Hiroshi Sakakibara, Marcia Testa, Robert P. Sundel Clinical Rheumatology. 36: , February DOI: /s Recurrent KD? Japan: ~3% recurrence rate, highest risk in the 2 years following index case Higher risk of developing coronary artery sequelae with recurrence. US: Overall rate of recurrence is 1.7% with 3.5% in Asians and Pacific Islanders Maddox et al. Pediatrics International (2015) 57, doi: /ped.12733

184 Signs of Kawasaki Disease Other Clinical Manifestations Respiratory Peribronchial/Interstitial Infiltrates Pulmonary nodules Musculoskeletal Arthritis/Arthralgia Gastrointestinal Diarrhea, vomiting, abdominal pain Hepatitis Hydrops of the gallbladder Pancreatitis

185 Other Clinical Manifestations Neurologic Irritability Aseptic meningitis Facial nerve paresis Sensorineural hearing loss Genitourinary Urethritis Hydrocele Differential Diagnosis Measles Adenovirus/Enterovirus Staph/Strep toxin mediated diseases Drug hypersensitivity reaction Systemic onset juvenile idiopathic arthritis Rocky mountain spotted fever (rickettsial) Leptospirosis

186 Characteristics Suggesting Disease Other Than KD Exudative conjunctivitis Exudative pharyngitis Discrete intraoral lesions Bullous or vesicular rash Generalized adenopathy

187 The Thing To Remember: Infants 6 Months Old Have highest incidence of Coronary aneurysms. Atypical or incomplete disease. Echo if fever 7 days without other explanation and with laboratory measures of inflammation, even in the absence of any principal clinical criteria.

188 Number of Clinical Criteria Among Patients with Coronary Artery Aneurysms Performance of 2004 American Heart Association Recommendations for Treatment of Kawasaki Disease. Yellen et al. Pediatrics, 2010; 125; e234. DOI: /peds What Causes Kawasaki Disease? ipcconsulting.eu

189 Race-Specific Incidence Estimates (per 100,000 children age < 5 years) Japanese (in Japan) 264 Asian/Pacific Islanders 33 Blacks 17 Hispanic 11 Caucasians 9 *Nakamura, J 2015; זּ Holman et al, 2003

190 Evidence from Japan that KD has a Genetic Component Siblings have an ~ 10-fold relative risk Emerging recognition of KD in successive generations Signaling Pathways Participating in KD Pathogenesis Calcineurin-NFAT (ITPKC), contributes to susceptibility to KD and to CAL Treatment with calcineurin inhibitors? TGFβ - SNPs in TGFβ2, TGFβR2, and SMAD3 contribute to risks of CAL Treatment with statins? FCGR2A (encoding FcγRIIa), contributes to disease susceptibility

191 Tropospheric Wind Patterns Are Associated with Incidence of KD KD and surface winds in Japan (a) San Diego (b) and Hawaii (c). Rodo X et al., Sci Rep 2011 Tropospheric Winds Are aerosolized particles from Central Asia the culprit of KD? Deep sequencing of the trophospheric biome has disclosed Candida species

192 Goals for Therapy in the Acute Phase Reduce the systemic inflammatory response Prevent coronary aneurysms- ideal If aneurysms already present: Minimize peak dimension reached Prevent coronary thrombosis

193 Recommendations for Initial Treatment with IVIG and ASA IVIG (2g/kg) as a single infusion within 10 th day of illness, as soon as possible after diagnosis It is reasonable to treat after the 10 th day of illness with persistence of fever or coronary artery abnormalities with elevation of ESR or CRP (>3.0 mg/dl) Administer moderate (30-50mg/kg/d) to highdose (80-100mg/kg/d) ASA until patient is afebrile McCrindle et al. Circulation. 2017;135(17) Rescue Therapy After First IVIG Given to high risk patients: IVIG resistance/fever Defined as recrudescent or persistent fever 36 hours after end of IVIG Evolving coronary aneurysms Options: 2 nd dose of IVIG, steroids, infliximab

194 IVIG can be associated with antibody-mediated hemolytic anemia especially patients with non- 0 blood groups who have: High doses of IVIG High degree of inflammation. Intravenous immunoglobulin-related hemolysis in patients treated for Kawasaki disease. Luban NL, Wong EC, Henrich Lobo R, Pary P, Duke S. Children's National Medical Center, Washington, DC. George Washington University School of Medicine and Health Sciences, Washington, DC. Courtesy of JC Burns

195 Consider Primary Adjunctive Treatment In High-Risk Patients High Kobayashi score in Japanese children Dilated coronary arteries at baseline Baseline zmax 2.0 has C statistic of 0.77, sensitivity = 80%, and negative PV = 98% Age <6 mo: Among those dxed 10 days 43% with CAA or dilation at baseline 19% with normal CAs at baseline develop CAA Son JAHA 2017; Tremoulet J Pediatr 2017

196 Primary Outcome: largest z score (LAD or RCA) at Week 5 Secondary Outcomes: Hospital days, days of fever, IVIG resistance NEGATIVE STUDY Primary Outcome: incidence of coronary artery abnormalities during study period (through Week 4 of illness; measurements at Weeks 1,2 and 4) Secondary Outcomes: Incidence of CAA at Week 4, z scores, need for rescue treatment, days of fever, CRP at Weeks 1 and 2, and SAE MET ALL OUTCOMES

197 Generalizability of RAISE? Well established risk score utilized in study Early diagnosis Fairly long hospitalizations for IV prednisolone treatment Questions remain regarding duration/dose/type of steroid

198 High risk patients with KD benefit greatly from a timely and potent adjunctive corticosteroid therapy. Criticisms: 6 studies, 383 patients and only 167 treated with steroids and in varying regimens, not applicable to all populations Infliximab 1 Treatment Trial Tremoulet et al., Lancet patients randomized to infliximab vs. placebo, plus conventional therapy. No measurable effect on treatment resistance (11% in both groups) Infliximab group had significantly better Laboratory measures of inflammation Fewer days of fever after treatment LAD z at 2 weeks (borderline) No significant difference in CAA or coronary z scores at 5 weeks.

199 Classification of Coronary Artery Abnormalities Classification Size of Coronary Artery Abnormality No coronary involvement Z-score always < 2 Dilation only Z-score 2 to <2.5 Small aneurysm Z score 2.5 to <5 Medium aneurysm Z score 5 to <10 Large or giant aneurysm Z score 10 or absolute dimension of 8 mm What happens to aneurysms? Kato et al followed a cohort of nearly 600 consecutively diagnosed children with KD between , followed for years All had coronary angiography, 146 patients had aneurysms (25%) Nearly 50% had regression at 1-2 years Ischemic heart disease in ~5%, MI in ~2% Kato et al, Circulation 1996 Sept 15; 94 (6):

200 Regressed Aneurysms Luminal myofibroblastic proliferation Abnormal coronary reactivity to nitrates Abnormal endothelial cell function Decreased myocardial blood flow and coronary flow reserve 30 Myocardial Infarction in Kawasaki Disease Interval from the onset of KD Asymptomatic Symptomatic n=73 n= <1mon yrs < (Kato H, Ichinose E: J Pediatr, 1985)

201 Survival After Myocardial Infarction Tsuda et al. Pediatric Cardiology 2011 Kaplan-Meier survival curve of the entire cohort of patients with giant coronary aneurysms. Suda K et al. Circulation 2011;123:

202 Survival and Cardiac Event Free Rates Tsuda E, American Heart Journal, 2014 VT-Free Survival After Myocardial Infarction Tsuda et al. Pediatric Cardiology 2011

203 Cardiac Event-Free Survival After CABG Kitamura, Circulation, 2009 Most Data Are Reassuring for the KD Patient Whose Coronary Arteries Were Always Normal No late clinical manifestations with ~40 years of follow-up, and no increase in standardized mortality ratio. Nakamura, et al. Mortality Among Japanese with a History of Kawasaki Disease: Results at the end of 2009.J Epidemiology doi: /jea.je

204 Adults < 40 who underwent coronary angiograms for suspected myocardial ischemia at 4 San Diego hospitals (n=261) Of 261, 16 had coronary artery aneurysms 4 had a known history of KD, 9 had presumed KD Paucity of traditional CAD risk factors, younger age, higher risk race for KD ~5% of young adults evaluated by angiography had coronary sequelae of KD. Lesions are different from typical atherosclerotic disease Summary: Acute Management Reduce systemic and tissue level inflammation as rapidly as possible Treatment with IVIG should be given to All patients on Day 10 of illness Patients > Day 10 with fever or coronary enlargement with persistent inflammation. Rescue therapy should be given to patients with fever 36 h post completion of IVIG infusion, without other explanation. IVIG-hemolysis in non-blood group O patients

205 Summary: Acute Management First choice for rescue therapies are IVIG ±steroids (RAISE regimen) or infliximab Rescue therapy with CSA and cytotoxic agents is generally used in patients in whom CAA are developing High-risk cases identified at baseline can be treated with primary adjunctive therapies in addition to IVIG. Summary: Long-Term Management Pts without CA dilation during first weeks of illness have normal cardiovascular status. Remodeling of aneurysms is accompanied by luminal myofibroblastic proliferation and abnormal arterial function. Those with past or current aneurysms have life-long risk of progressive CA stenosis or occlusion and worsening ischemia. Long-term cardiovascular surveillance tailored to initial severity of disease and current coronary status

206 Pennsylvania Rheumatology Society COMBINED SESSION: AUTOANTIBODIES IN INFLAMMATORY MUSCLE DISEASE CHESTER ODDIS, MD SUNDAY, SEPTEMBER 23 RD 11:45 AM 12:4 5 PM

207 Autoantibodies in Myositis Pennsylvania Rheumatology Society Annual Meeting September 23, 2018 Chester V. Oddis, MD Director, Myositis Center University of Pittsburgh Disclosures Genentech: Clinical trial support Bristol Myers Squibb: Clinical trial support Mallinckrodt: Clinical trial support Octapharma: Clinical trial support

208 Lecture Objectives Discuss clinical features of myositis classification Discuss spectrum of autoantibodies seen in patients with myositis Classification of Myositis Adult polymyositis Adult dermatomyositis Juvenile myositis (DM >> PM) Malignancy associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM)

209 IIM: Diagnostic Criteria Bohan and Peter (1975) Symmetric proximal muscle weakness Elevation of serum muscle enzymes: CK, aldolase, AST, ALT, LDH Myopathic electromyographic abnormalities: sharp waves, fibrillations, polyphasic motor units, high frequency repetitive discharges Characteristic muscle pathology: myofiber degeneration/regeneration, MNC infiltrates, perifascicular atrophy Cutaneous features (heliotrope, Gottron sign/papules) IIM: Diagnostic Criteria Bohan and Peter (1975) Symmetric proximal muscle weakness Elevation of serum muscle enzymes: CK, aldolase, AST, ALT, LDH Myopathic electromyographic abnormalities: sharp waves, fibrillations, polyphasic motor units, high frequency repetitive discharges Characteristic muscle pathology: myofiber degeneration/regeneration, MNC infiltrates, perifascicular atrophy Cutaneous features (heliotrope, Gottron sign/papules) Problems with B&P Criteria No good way to exclude other myopathies Misclassification of IBM as PM Each criterion not explicitly defined

210 Lundberg et al, Ann RD, 2018 Candidate variables assembled from published criteria/expert opinion Data collected from rheum/derm/neuro/peds clinics worldwide New criteria were derived and each item was assigned a weighted score Total score corresponds to a probability of having IIM Lundberg et al, Ann RD, 2018

211 Lundberg et al, Ann RD, 2018 For patients without classic DM rashes, do a muscle biopsy. For DM patients without muscle involvement do a skin biopsy. These criteria provide a score and probability for having IIM (for clinical trial purposes) Dermatomyositis Rashes Rashes of Dermatomyositis

212 Classification of Myositis Adult polymyositis Adult dermatomyositis Juvenile myositis (DM >> PM) Malignancy associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM) Classification of Myositis Adult polymyositis Adult dermatomyositis Juvenile myositis (DM >> PM) Malignancy associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM)

213 Polymyositis Mimics Endocrine myopathies hyper/hypothyroid Drug or toxic myopathies Metabolic myopathies Mitochondrial myopathies Muscular dystrophies Infectious myositis Neuropathies/neurologic syndromes Paraneoplastic syndromes Other connective tissue disorders Miscellaneous amyloid, sarcoid Muscle Biopsy is a Must in Polymyositis (unlike classic DM)

214 Muscle Biopsy is a Must in Polymyositis (unlike classic DM) And maybe pathologic classification may even be better than clinical classification Pathologic Myositis Classification Pestronk, Curr Opin Rheum, 2011

215 Pathologic Myositis Classification Pestronk, Curr Opin Rheum, 2011 Myovasculopathy DM Pestronk, Curr Opin Rheum, 2011

216 Muscle Biopsy is a Must in Polymyositis (unlike classic DM) Distinguishing Histologic Features: PM vs. DM Polymyositis Lymphocytic invasion of nonnecrotic myofiber perimysial/perivascular CD4+ T helper cell Dermatomyositis perifascicular atrophy perivascular B cells and C 5 C 9 (MAC) deposition endomysial CD8+ T cells perimysial CD4+ T helper cells Classification of Myositis Adult polymyositis Adult dermatomyositis Juvenile myositis (DM >> PM) Malignancy associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM) Necrotizing myopathy (NM) What we called PM before, in some cases, is now called NM

217 Classification of Myositis Adult polymyositis Adult dermatomyositis Juvenile myositis (DM >> PM) Malignancy associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM) Necrotizing myopathy (NM) What we called PM before, in some cases, is now called NM Neurology, 2003

218 Medicine, 2005 Classification of Myositis Adult polymyositis Adult dermatomyositis Juvenile myositis (DM >> PM) Malignancy associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM) Necrotizing myopathy (NM) What we called PM before, in some cases, is now called NM

219 Case One 67 year old Caucasian female with HTN, hyperlipidemia, uterine cancer (1997) July, 2004: atorvastatin June, 2008: lower extremity weakness Spring, 2009: difficulty walking up steps and lifting arms overhead June, 2009: stops atorvastatin on her own but no improvement in weakness September, 2009: CK 6473, repeat 9375; ANA 1:320 (H) Admitted to hospital; muscle biopsy: myonecrosis, no inflammation or vasculitis Necrotizing Myopathy Kassardjian, JAMA Neurol, 2015

220 Case One 67 year old Caucasian female with HTN, hyperlipidemia, uterine cancer (1997) July, 2004: atorvastatin June, 2008: lower extremity weakness Spring, 2009: difficulty walking up steps and lifting arms overhead June, 2009: stops atorvastatin on her own but no improvement in weakness September, 2009: CK 6473, repeat 9375; ANA 1:320 (H) Admitted to hospital; muscle biopsy: myonecrosis, no inflammation or vasculitis Treated with prednisone (60mg/day) and CK and weakness improve Case One March, 2010 (1 st UPMC visit) CK 5800 (increasing as prednisone tapered) No other autoimmune manifestations; no FH of autoimmune diseases No rashes of dermatomyositis Deltoids 4+/5; neck flexors 4/5; iliopsoas 3+/5 Statin myopathy Pt hesitant to increase prednisone

221 Immune Mediated Necrotizing Myopathy Associated with Statins Proximal weakness during or after statin use Elevated CK Persistent weakness and elevated CK despite stopping the statin Improvement with IS agents Muscle biopsy showing necrotizing myopathy without significant inflammation 25 patients from 2 centers Grable Esposito, Muscle & Nerve, 2010 Anti 200/100 kd AutoAb Defines Subgroup of Necrotizing Myopathy (NM) 16/38 patient sera with NM had the doublet All were weak with high CK 63% had statin exposure prior to weakness 83% >age 50 exposed to statins All responded to IS therapy and many relapsed Controls in lanes 5 and 10 Christopher Stine, Arth Rheum, 2010

222 Statin Necrotizing Myopathy HMGCR was identified as the 100 kd autoantigenic target Developed an ELISA for anti HMGCR autoab All 16 doublet positive pts were anti HMGCR (+) 45/750 (6%) of cohort were anti HMGCR (+) Mammen, Arth Rheum, 2011 Case One April June, 2010: worse weakness; CK 6367 July, 2010: prednisone increased (60mg/d) and mtx added Jan, 2011: added imuran/mtx (25mg/week), pred 30mg/d May, 2011: added IVIg; continued other IS agents August, 2011: clearly improved with first normal CK in July November, 2011: 5/5 strength; taper IVIg (never off completely) March, 2012: stopped imuran June, 2012: off prednisone Progressive rise of CK ; went back on mtx and IVIg; CK still elevated Pt is anti HMGCR autoab positive

223 Suggests IVIg as first line therapy for statin associated autoimmune, necrotizing myopathy Mammen, NEJM, 2015 Features of Anti SRP Subset Acute onset of severe weakness with myalgias; high CK Necrotizing myopathy (or PM phenotype) no DM rash; ILD rare Poor response to therapy with variable prognosis Refractory, persistently high CK, dystrophy like

224 Muscle Pathology of SRP Antibody Subset Necrotizing myopathy without inflammation Dimitri, Muscle and Nerve, 2007 Classification of Myositis Adult polymyositis Adult dermatomyositis Juvenile myositis (DM >> PM) Malignancy associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM) Necrotizing myopathy (NM) Anti HMGCR Anti SRP

225 Classification of Myositis Adult polymyositis Adult dermatomyositis Amyopathic Dermatomyositis Juvenile myositis (DM >> PM) Malignancy associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM) Necrotizing myopathy (NM) Anti HMGCR Anti SRP Clinically Amyopathic DM (CADM) A subset of DM patients with cutaneous manifestations of DM for 6 months or longer No proximal muscle weakness May have slightly elevated serum muscle enzymes, mild EMG or biopsy abnormalities CADM = Amyopathic DM (ADM) + Hypomyopathic DM (HDM)

226 Sometimes the skin disease can be the most dominant feature

227 DM Scalp Rash Treatment of DM Cutaneous Disease Sun protective measures; avoid photosensitive meds Topical GC (potency depends on severity) Topical calcineurin inhibitors (tacrolimus, pimecrolimus) Antimalarials (hydroxychloroquine or chloroquine); some dermatologists add quinacrine Oral glucocorticoids (varying doses) No Clinical Response after 1 3 months? Yes 2 nd Line Methotrexate (oral/sq) MMF 3 rd Line IVIG Tacrolimus Cyclophosphamide Rituximab Taper prednisone by 20 25% monthly to minimum effective dose

228 Treatment of DM Cutaneous Disease Sun protective measures; avoid photosensitive meds Topical GC (potency depends on severity) Topical calcineurin inhibitors (tacrolimus, pimecrolimus) Antimalarials (hydroxychloroquine or chloroquine); some dermatologists add quinacrine Oral glucocorticoids (varying doses) No Clinical Response after 1 3 months? Yes 2 nd Line Methotrexate (oral/sq) MMF 3 rd Line IVIG Tacrolimus Cyclophosphamide Rituximab 4 th Line Tofacitinib Apremilast Taper prednisone by 20 25% monthly to minimum effective dose Anti CADM 140 (anti MDA 5) Amyopathic DM with rapidly progressive ILD in Japanese (Sato, Arth Rheum, 2005 and 2009) Acute/subacute interstitial pneumonitis in DM in Chinese (Chen, Rheum Int, 2011) Also described in other Asian populations with similar phenotype Target autoantigen is MDA 5. What is MDA 5? Cytoplasmic protein that senses viral RNA and induces production of type I interferon Involved in innate immune defense against viruses

229 Anti CADM 140 (anti MDA 5) Amyopathic DM with rapidly progressive ILD in Japanese (Sato, Arth Rheum, 2005 and 2009) Acute/subacute interstitial pneumonitis in DM in Chinese (Chen, Rheum Int, 2011) Also described in other Asian populations with similar phenotype Target autoantigen is MDA 5. What is MDA 5? Cytoplasmic protein that senses viral RNA and induces production of type I interferon Involved in innate immune defense against viruses Supports role of a viral trigger Anti MDA 5 Novel cutaneous phenotype of palmar papules and cutaneous ulcerations severe vasculopathy Fiorentino, J Am Acad Derm, 2011

230 Case Two 70 year old WM Double pneumonia in June Rash of DM in September Vasculitic skin changes in Jan No muscle weakness Recommended cyclophosphamide Case Two 70 year old WM Double pneumonia in June Rash of DM in September Vasculitic skin changes in Jan No muscle weakness Recommended cyclophosphamide Anti MDA 5 positive

231 Case Three Summer, 2012: Photosensitive rash in 58 yo WF January, 2013: Polyarthritis; mild muscle weakness; rash of DM nl CK; Jo 1, ANA and SSA/B all negative improves on low dose prednisone/mtx May, 2013: DM rashes worse; faint basilar crackles on exam (no pulmonary sx); mild weakness Recommended 20mg prednisone and MMF HRCT/PFTs June 6

232 Case Three July 1: Presents to local ED feeling very SOB CXR opacified In one day, she is up to 12 liters/min O 2 Contacted by rheumatologist Rash a little different

233 Case Three July 1: Presents to local ED feeling very SOB CXR opacified In one day, she is up to 12 liters/min O 2 Contacted by rheumatologist Rash a little different Recommend pulse steroids, cytoxan and rituximab July 2

234 June 6 July 2 June 6 July 2 Anti MDA 5 positive

235 Anti MDA 5 Positivity is Associated with a Poor Pulmonary Outcome MDA5 ( ) (n=106) MDA5 (+) (n=16) p<0.001 Moghadam Kia, Arth Care Rsch, 2016 MDA 5 Positive Vasculopathy 3 months 2 months

236 Myositis specific autoantibodies Myositis specific autoantibodies Anti synthetase syndrome Fever Raynauds Lung fibrosis +/ DM rash Myositis Arthropathy Mechanics hands X Necrotizing myopathy High CK Clinical phenotypes in adults and children X Amyopathic dermatomyositis Rash sine myositis Hypomyopathic Rash precedes myositis Dermatomyositis Rash Malignancy Calcinosis/vasculitis (children) Jo-1 Anti-SRP Anti-SAE Anti-NXP-2 Zo Anti-synthetases EJ YRS PL-7 Anti-HMGCR Anti-MDA-5 Anti-TIF1g Anti-Mi-2 KS OJ PL-12 Slide courtesy of Drs. Chinoy and Gunawardena Anti synthetase Syndrome Defines a clinically homogeneous patient population: Fever Myositis Arthritis (misdiagnosed as RA) Raynaud phenomenon Mechanic s hands ILD

237 Clinical Features: Anti synthetase Syndrome But the skin rash(es) and the myositis may be subtle and the clinical presentation may be lung dominant

238 Case Four 1/2001: 39 yo WF admitted to hospital with 5 weeks of fever ( ) and myalgias; extensive w/u negative except for low titer ANA and mild basilar fibrosis; leaves hospital with FUO frustrated by lack of diagnosis Case Four 1/2001: 39 yo WF admitted with 5 weeks of fever ( ) and myalgias; extensive w/u negative except for low titer ANA and mild basilar fibrosis; leaves hospital with FUO frustrated by lack of diagnosis 3/2001 (office): worsening myalgias and arthralgias, small pleural effusions, fever, Raynaud phenomenon. Dx as UCTD and given empiric prednisone

239 Case Four 1/2001: 39 yo WF admitted with 5 weeks of fever ( ) and myalgias; extensive w/u negative except for low titer ANA and mild basilar fibrosis; leaves hospital with FUO frustrated by lack of diagnosis 3/2001 (office): worsening myalgias and arthralgias, small pleural effusions, fever, Raynaud phenomenon. Dx as UCTD and given empiric prednisone 4/2001: Increased SOB with more prominent diffuse pulmonary infiltrates; subtle Gottron changes; anti PL 12 autoantibody identified Case Four: Subsequent Course Worsening infiltrates and deteriorating PFTs PFTs: FVC 56%, FEV 1 52%, DLCO 40% Responded to glucocorticoids and tacrolimus Skin rash, joint symptoms and fever never return Never developed myositis Raynaud is mild and most recent PFTs (5/2018) FVC 75%; FEV 1 87%; DLCO 78% Echo with nl PAS (25mmHg) Currently on tacrolimus, no prednisone

240 Making the Diagnosis of Autoimmune ILD Not everyone will present with the classic anti-synthetase syndrome Anti synthetase Autoantibodies Antibody Antigen (trna synthetase) Prevalence in IIM (%) Jo 1 histidyl PL 7 threonyl <5 PL 12 alanyl <5 OJ isoleucyl <5 EJ glycyl <5 KS asparaginyl <1 Tyr tyrosyl <1 Zo phenylalanyl < 1

241 University of Pittsburgh Anti Synthetase Cohort Autoantibody Number (% synthetases) Jo (60%) PL (16%) PL 7 27 (12%) EJ 11 (5) OJ 6 (3) KS 9 (4) Total Synthetases 229 University of Pittsburgh Anti Synthetase Cohort Autoantibody Number (% synthetases) Jo (60%) PL (16%) PL 7 27 (12%) EJ 11 (5) OJ 6 (3) KS 9 (4) Total Synthetases 229

242 Initial CTD Diagnosis in Anti Syn Cohort Jo 1 n=122 DM 24% 17% PM 59% Non Jo 1 n=80 Overlap or UCTD 48% SSc 13% PM 22% DM 17% PM DM Overlap or UCTD SSc Aggarwal, Ann Rheum Dis, 2014 Initial CTD Diagnosis in Anti Syn Cohort Jo 1 n=122 DM 24% 17% PM 59% Non Jo 1 n=80 Overlap or UCTD 48% SSc 13% PM 22% DM 17% PM DM Overlap or UCTD SSc Myositis UCTD/Overlap Scleroderma Jo 1 83% 17% 0% Non Jo 1 39% 48% 13% p<0.001 Aggarwal, Ann Rheum Dis, 2014

243 Survival is worse in non Jo 1 than Jo 1 patients Jo 1 non Jo 1 Aggarwal, Ann Rheum Dis, 2014 Survival is worse in non Jo 1 than Jo 1 patients Jo 1 non Jo 1 Diagnosis delay (years) Jo 1 non Jo 1 p value 0.4 ( ) 1.0 ( ) <0.01 Aggarwal, Ann Rheum Dis, 2014

244 Cause of Death in Anti Synthetase Cohort Infection 6% Cancer 9% CTD kidney 3% CTD heart 5% Atherosclerosis 9% Pulmonary HTN 11% Unknown 6% Pulmonary fibrosis 49% In synthetase (+) pts pulmonary disease was most common cause of death Aggarwal, Ann Rheum Dis, 2014 Synthetase Positive Patients: Jo 1 vs. non Jo 1 Non Jo 1 synthetase (+) patients frequently present with non myositis symptoms and may never manifest them. Diagnosis of a specific CTD is delayed in non Jo 1 synthetase (+) patients perhaps leading to worse survival. Synthetase (+) patients, whether Jo 1 or non Jo 1 have increased pulmonary morbidity and mortality.

245 Myositis Autoantibodies Antibody Target Subset Phenotype CADM-140 MDA-5 DM Amyopathic, ILD Jo-1 and other anti-syn Aminoacyl trna synthetases (ARS) PM/DM Anti-synthetase syndrome Mi-2 NuRD DM Shawl, V-neck, Gottron s Shawl Sign V neck Sign Classification of Myositis Adult polymyositis Adult dermatomyositis Amyopathic Dermatomyositis Juvenile myositis (DM >> PM) Malignancy associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM) Necrotizing myopathy (NM) Anti HMGCR Anti SRP

246 Are there autoantibody markers that identify patients with malignancyassociated myositis? Myositis Autoantibodies Antibody Target Subset Phenotype CADM 140 MDA 5 DM Amyopathic, ILD Jo 1 Other anti Syn ARS PM/DM Anti synthetase syndrome Mi 2 NuRD DM Shawl, V neck, Gottron s p155/140 TIF1 γ DM, JDM Severe skin, malignancy Gunawardena, Rheumatol, 2008

247 Anti p155/140 (anti TIF1 γ) Autoantibody Adults: Associated with severe cutaneous DM and cancer associated myositis JDM: Severe cutaneous involvement including ulceration, edema and calcinosis But cancer associated myositis is not seen in JDM Anti NXP 2 is Another Common JDM Autoantibody Found in 20 25% of JDM cohorts Associated with increased risk of calcinosis across all age groups in JDM Marker of severe disease in JDM Calcinosis Skin ulcerations Contractures Tansley, Rheumatol, 2014

248 Anti NXP 2 is Associated with Cancer in Adult DM Reactivity against NXP 2 or TIF1 γ identified 83% of patients with cancer associated DM Sex stratification revealed anti NXP 2 was associated with cancer in males Fiorentino, Arth Rheum, 2013 Myositis specific autoantibodies Myositis specific autoantibodies Clinical phenotypes in adults and children Anti synthetase syndrome Necrotizing Amyopathic Dermatomyositis Fever Myositis Raynauds Arthropathy Lung fibrosis Mechanics hands +/ DM rash myopathy High CK dermatomyositis Rash sine myositis Hypomyopathic Rash precedes myositis Rash Malignancy Calcinosis/vasculitis (children) Jo-1 Anti-SRP Anti-SAE Anti-NXP-2 Zo Anti-synthetases EJ YRS PL-7 Anti-HMGCR Anti-MDA-5 Anti-TIF1g Anti-Mi-2 KS OJ PL-12 Slide courtesy of Drs. Chinoy and Gunawardena

249 Classification of Myositis Adult polymyositis Adult dermatomyositis Amyopathic Dermatomyositis Juvenile myositis (DM >> PM) Malignancy associated myositis Myositis in overlap with another AI disease Inclusion body myositis (IBM) Necrotizing myopathy (NM) Anti HMGCR Anti SRP Inclusion Body Myositis Most common myopathy in middle aged elderly Consider IBM when confronted with refractory polymyositis patient Male predominance (elderly) Insidious onset of painless muscle weakness with slow progression Distal and asymmetric muscle involvement (foot drop) Characteristic pattern of muscle atrophy (forearm flexors, quadriceps, intrinsic muscles of hands)

250 Inclusion Body Myositis Distinctive histology: endomysial inflammation often called polymyositis rimmed vacuoles Anti Mup44 Autoantibodies in IBM Targets cn1a (Cytosolic 5 nucleotidase) Muscle specific enzyme catalyzing AMP to adenosine and inorganic phosphate Involved in physiologic control of energy balance Detected in 33% of sibm patient sera Low in DM, PM and other NM disorders Specificity needs to be established found in some Sjogren/SLE patients Pluk, Ann Neurol, 2013

251 Summary Clinical key: recognize syndromes or clusters of symptoms to identify autoab associated systemic autoimmune rheumatic diseases Watch for autoimmune ILD AutoAb markers have clinical and prognostic importance How do you order them? RDL laboratories OMRF (Ira Targoff has studied these Abs for years) Thank You