Clinical Issues in Rheumatoid Arthritis: Debates & Discussions on the Evolving Role of JAK Inhibitor

Debates & Discussions on the Evolving Role of JAK Inhibitors

Joel Kremer, MD Moderator

Pfaff Family Professor of Medicine Albany Medical College Director of Research, The Center for Rheumatology Founder, Corrona, LLC Albany, New York

Dr. Joel Kremer is the Pfaff Family Professor of Medicine at Albany Medical College and Director of Research at The Center for Rheumatology, a private practice in Albany, New York. In 2000 he transitioned from full-time academic medicine and Head of the Division of Rheumatology at Albany Medical College to the position of Director of Research. He still trains fellows and residents on a weekly basis. He was also privileged to spend 13 years (1997-2010) at the Veterans Affairs Medical Center on a part-time basis as Director of their outpatient rheumatology clinic. He is a graduate of Temple University School of Medicine, where he was elected to Alpha Omega Alpha honorary medical society.

Dr. Kremer has been involved with clinical research for 38 years, starting with intensive study of methotrexate (MTX) in the early 1980s through the mid-late 1990s and has published approximately 50 manuscripts on MTX and given invited lectures at the annual meetings of the American College of Rheumatology (ACR). He received the Virginia P. Engalitcheff Award of the Arthritis Foundation in 1998 for his work on MTX that has “contributed substantially to the welfare of patients with arthritis in the last decade.�

Beginning in the late 1990s through the present he has participated in and led many studies on biologic agents and small molecules (Janus kinase inhibitors).

Dr. Kremer is the Founder and Chief Medical Officer of the Corrona registry. Corrona has become the only registry in the United States that collects real-world evidence on safety and effectiveness of drugs in patients with rheumatic diseases including rheumatoid arthritis (RA), psoriatic arthritis, spondyloarthritis, and, starting last year, Inflammatory bowel disease. Corrona has contributed >100 peer-reviewed manuscripts to the scientific literature including comparative effectiveness, cardiovascular safety, and scrupulous profiles of the activity of many newer agents in the United States. He has contributed >265 peer-reviewed manuscripts and >450 published abstracts and has also edited 4 books and 12 chapters in texts. He serves as the President of the Corrona Research Foundation, a not-for-profit organization founded for the purpose of connecting academic researchers with the Corrona data. He is a Master of the ACR and is also an avid skier and swimmer.

Roy Fleischmann, MD, MACR Co-Medical Director Metroplex Clinical Research Center Clinical Professor of Medicine University of Texas Southwestern Medical Center Dallas, Texas

Dr. Roy Fleischmann is Clinical Professor of Medicine at the University of Texas Southwestern Medical Center, Co-Medical Director of the Metroplex Clinical Research Center, and in private rheumatology practice, all in Dallas.

Educated in New York City, Dr. Fleischmann graduated from Stuyvesant High School and Columbia College, received his medical degree from the State University of New York, Downstate Medical Center, completed his residency in Internal Medicine at Mount Sinai Medical Center, and completed his fellowship in rheumatology at the College of Physicians and Surgeons of Columbia University under the mentoring of Carwile Leroy.

Following his fellowship, he joined the faculty of the College of Physicians and Surgeons of Columbia University before being recruited in 1975 to join the Division of Rheumatology at the University of Texas Southwestern Medical Center, Dallas, by Professor Morris Ziff. While remaining active in the teaching program, he started a private practice in rheumatology on campus in 1978 and in 1984 established the Metroplex Clinical Research Center, which has conducted more than 1000 trials, particularly phase 1-3, focusing on the development of new drugs for the treatment of RA, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, scleroderma, gout, and osteoarthritis. His group of private practitioners specializing in rheumatology currently includes 19 board-certified rheumatologists and 6 mid-level practitioners, making it the largest group of rheumatology private practitioners in the State of Texas, with multiple offices throughout the Dallas-Fort Worth Metroplex. He has been recognized as an outstanding clinician by D magazine of Texas Monthly and has been selected as one of America’s Best Physicians numerous times.

Dr. Fleischmann has authored over 225 articles published in peer-reviewed journals on the management of RA and over 400 abstracts presented at rheumatology meetings worldwide. He has helped design, implement, and report the results of studies on virtually every medication approved for use in the treatment of RA. An early proponent of the aggressive treatment of RA and the importance of measuring disease activity to help guide treatment decisions, he has been an invited speaker on the diagnosis and management of RA at many international rheumatology meetings and symposia worldwide, presenting frequently at ACR and European League Against Rheumatism annual meetings and conducting Meet the Expert sessions.

A Master of the ACR, an Overseas Fellow of the Royal Society of Medicine, a former President of the Texas Rheumatism Association, and a former President of the Dallas–Fort Worth Rheumatism Association, Dr. Fleischmann has served on the finance committee of the ACR and the fund-raising committee of the Research and Education Foundation of the ACR. He is a reviewer for many peer-reviewed journals including the New England Journal of Medicine, The Lancet, Arthritis Rheumatism, the Annals of Rheumatic Disease, and the Journal of Rheumatology as well as editor of Rheumatology and Therapy, former associate editor for Rheumatology (Oxford), member of the editorial boards of the Annals of Rheumatic Disease and RMD Open, and in the top 5% of reviewers for Arthritis and Rheumatology.

Maria Greenwald, MD, FACR Rheumatologist Co-Director Desert Medical Advances Palm Desert, California

Dr. Maria Greenwald graduated summa cum laude from Bryn Mawr College in Pennsylvania with a major in chemistry, and graduated from Yale Medical School with honors (Alpha Omega Alpha). She completed her internship and residency in internal medicine at Yale and was selected national senior scholar for her fellowship in rheumatology at University of California, Los Angeles. She has published extensively with over 100 publications on osteoporosis and rheumatology and is co-director of Desert Medical Advances, a clinical research group.

TARGET AUDIENCE

PHYSICIAN ACCREDITATION STATEMENT

The educational design of this activity addresses the needs of clinical rheumatologists and specialist nurse practitioners (NPs), physician assistants (PAs), and nurses who manage patients with rheumatoid arthritis (RA).

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Global Education Group (Global) and Integritas Communications. Global is accredited by the ACCME to provide continuing medical education for physicians.

This CME/CE activity complies with all requirements of the federal Physician Payment Sunshine Act. If a reportable event is associated with this activity, the accredited provider managing the program will provide the appropriate physician data to the Open Payments database.

STATEMENT OF NEED/PROGRAM OVERVIEW Advances in our understanding of the immunopathologic mechanisms underlying RA have led to the development of disease-modifying antirheumatic drugs (DMARDs) that effectively target relevant pathways. For instance, members of the Janus kinase (JAK) family play a pivotal role in transducing extracellular cytokine signaling, thereby contributing to such processes as cellular proliferation, homeostasis, and host defense against infections.1 In RA, certain JAK-mediated signaling pathways are dysfunctionally active, leading to enhanced transcription of various proinflammatory genes and aberrant immune responses. 2 In this Clinical Issues™ program, a panel of expert rheumatologists will discuss and debate the latest insights into JAK activation in RA immunopathology, recent clinical trial data on the efficacy and safety of current and emerging JAK inhibitors, and the evolving roles of this DMARD class in day-to-day practice. The overall goal is to prepare attendees to translate the latest information on JAK inhibitors into better care for their patients with RA.

REFERENCES 1. Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease. Nat Rev Rheumatol.

2017;13(4):234-243.

2. Malemud C. The role of the JAK/STAT signal pathway in rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2018;10(5-6):117-127.

EDUCATIONAL OBJECTIVES After completing this activity, the participant should be better able to: •• Describe the roles of JAK/signal transducer and activator of transcription (STAT) signaling in immune responses and homeostasis, including contributions to the immunopathogenesis of RA •• Discuss the clinical profiles of current and emerging JAK inhibitors, including implications of enzyme specificity and evidence for efficacy and safety in RA •• Integrate JAK inhibitors into RA-treatment algorithms based on guideline recommendations, current clinical trial data, and patient preferences

PHYSICIAN CREDIT DESIGNATION Global Education Group designates this live activity for a maximum of 1.5 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

DISCLOSURE OF CONFLICTS OF INTEREST Global requires instructors, planners, managers, and other individuals and their spouses/ life partners who are in a position to control the content of this activity to disclose any real or apparent conflicts of interest they may have as related to the content of this activity.

All identified conflicts of interest are thoroughly vetted by Global for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations.

The faculty reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: Roy Fleischmann, MD, MACR Consultant/Independent Contractor: AbbVie Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Pfizer Inc.; Grant/ Research Support: AbbVie Inc., Eli Lilly and Company, Gilead Sciences, Inc., Pfizer Inc. Maria Greenwald, MD, FACR Grant/Research Support: AbbVie Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., Pfizer Inc. Joel M. Kremer, MD, FACP Consultant/Independent Contractor: AbbVie Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Pfizer Inc.; Grant/ Research Support: AbbVie Inc., Eli Lilly and Company, Novartis Pharmaceuticals Corporation, Pfizer Inc.; Stock Shareholder: Corrona

The planners and managers reported the following financial relationships or relationships to products or devices they or their spouses/life partners have with commercial interests related to the content of this CME activity: Lindsay Borvansky Nothing to disclose Andrea Funk Nothing to disclose Ashley Cann Nothing to disclose Celeste Collazo, MD Nothing to disclose Jim Kappler, PhD Nothing to disclose

DISCLOSURE OF UNLABELED USE This educational activity may contain discussion of published and/or investigational uses of agents that are not indicated by the US Food and Drug Administration. Global and Integritas Communications do not recommend the use of any agent outside of the labeled indications.

The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of any organization associated with this activity. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings.

DISCLAIMER Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management.

Any procedures, medications, or other courses of diagnosis or treatment discussed in this activity should not be used by clinicians without evaluation of patient conditions and possible contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

INSTRUCTIONS TO RECEIVE CREDIT In order to receive credit for this activity, the participant must attend the program and complete the program evaluation.

FEE INFORMATION & REFUND/CANCELLATION POLICY There is no fee for this educational activity.

GLOBAL CONTACT INFORMATION For information about the accreditation of this program, please contact Global at 303-395-1782 or cme@globaleducationgroup.com.

PROGRAM AGENDA 5:30 pm – 6:00 pm

Registration and Dinner

6:00 pm – 6:10 pm

Introductions and Preactivity Questionnaire

6:10 pm – 6:30 pm

RA Pathophysiology: The Mechanistic Rationale for JAK Inhibition

6:30 pm – 6:55 pm

Current and Emerging JAK Inhibitors: What Is the Evidence in RA?

6:55 pm – 7:15 pm

Integrating JAK Inhibitors Into RA Treatment Algorithms

7:15 pm – 7:30 pm

Postactivity Questionnaire and Question & Answer Session

GUIDELINES

Efficacy and safety of tofacitinib monotherapy, tofacitinib with methotrexate, and adalimumab with methotrexate in patients with rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, randomized controlled trial.

Singh JA, et al. Arthritis Rheumatol. 2016;68(1):1-26.

Fleischmann R, et al. Lancet. 2017;390(10093):457-468.

EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update.

Baricitinib versus placebo or adalimumab in rheumatoid arthritis.

Smolen JS, et al. Ann Rheum Dis. 2017;76(6):960-977.

Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease modifying antirheumatic drug treatment.

2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis.

PATIENT, CAREGIVER, AND PROVIDER RESOURCES

American College of Rheumatology: Patient and Caregiver Resources

Taylor PC, et al. N Engl J Med. 2017;376(7):652-662.

Fleischmann R, et al. Arthritis Rheumatol. 2017;69(3):506-517.

The ACR has produced a library of videos about the impact of rheumatic disease, what to do when diagnosed with rheumatic disease, when to see a rheumatologist, and what patients have to say about their experiences of living with rheumatic disease.

A phase 3, randomized, controlled trial comparing upadacitinib monotherapy to MTX monotherapy in MTX-naïve patients with active rheumatoid arthritis.

Arthritis Foundation

A phase 3, randomized, double-blind study comparing upadacitinib to placebo and to adalimumab, in patients with active rheumatoid arthritis with inadequate response to methotrexate.

The Arthritis Foundation provides self-care tools and resources covering treatment options, pain management, diet and exercise, and common comorbidities associated with many different arthritic conditions.

European League Against Rheumatism

van Vollenhoven R, et al. Arthritis Rheumatol. 2018;70(suppl 10). Abstract 891.

Fleischmann R, et al. Arthritis Rheumatol. 2018;70 (suppl 10). Abstract 890.

EULAR is an organization that represents people with arthritis/rheumatism, health professionals, and scientific societies of rheumatology of all the European nations.

Safety and efficacy of filgotinib in a phase 3 trial of patients with active rheumatoid arthritis and inadequate response or intolerance to biologic DMARDs.

NIH Health Topics: Rheumatoid Arthritis

Genovese MC, et al. Arthritis Rheumatol. 2018;70(suppl 10). Abstract L06.

A resource from the National Institute of Arthritis and Musculoskeletal and Skin Diseases for people who have rheumatoid arthritis, as well as for their family members, friends, and others who want to find out more about rheumatoid arthritis.

Thromboembolism with Janus kinase (JAK) inhibitors for rheumatoid arthritis: how real is the risk?

SUGGESTED READING

JAK inhibition as a therapeutic strategy for immune and inflammatory diseases.

Schwartz DM, et al. Nat Rev Drug Discov. 2017;17(1):78.

Clinical efficacy of new JAK inhibitors under development.

Just more of the same?

Westhovens R. Rheumatology (Oxford). 2019;58(suppl 1):i27-i33.

Scott IC, et al. Drug Saf. 2018;41(7):645-653.

Pregnancy outcomes in the tofacitinib safety databases for rheumatoid arthritis and psoriasis.

Clowse ME, et al. Drug Saf. 2016;39(8):755-762.

Additional abstracts from the 2018 American College of Rheumatology/ Association of Rheumatology Health Professionals Annual Meeting.

October 2018; Chicago, IL.

Please visit our clinical resource center for the full list of resources: www.ExchangeCME.com/RAResources19