The Power of the Negative Study

“If I have seen further, it is because I stand on the shoulders of giants” Sir Isaac Newton famously stated in a letter to polymath scientist, Robert Hooke back in 1675. Today, Dr. Mary Crow, MD, aides Arthritis & Rheumatology launch a series on immunology, for rheumatologists. She is the co-author of the article Standing on Shoulders: Interferon Research, from Viral Interference to Lupus Pathogenesis and Treatment. In this episode, we stand with Dr. Crow to look back at the achievements made by brilliant minds in interferon research and analyze the unbroken line their advancements in rheumatology have led to today’s discoveries, with more to com

Is there an increased risk of cancer once a patient has Scleroderma? If so, what is the risk and how does one go about showing this? Dr. Ami A Shah, Director of the Division of Rheumatology at Johns Hopkins sits down with us to explain those answers. We go over the methods, results and conclusions of the recent study Distinct Scleroderma Autoantibody Profiles Stratify Patients for Cancer Risk at Scleroderma Onset and During the Disease Course published in Arthritis & Rheumatology. Afterward, Dr. Shah shares with us her journey to becoming a physician-scientist and mentoring others in Scleroderma research through a K24 grant. 

Welcome back to “Journals”! Our topic of discussion today comes from the manuscript Anti-Gephyrin Antibodies: A Novel Specificity in Patients With Systemic Sclerosis and Lower Bowel Dysfunction and our guest today is the study’s first author, Dr. Zsuzsanna McMahan. The study recognizes that the enteric nervous system (ENS) regulates the gastrointestinal (GI) function, which is commonly impaired in those who suffer from systemic sclerosis (SSc). Dr. McMahan and her team’s objective for this study was “to identify novel anti-ENS autoantibodies with an aim to clinically phenotype SSc GI dysfunction”. We sit down with Dr. McMahan and discuss the study’s methods and discoveries. Plus, her experience transitioning from a junior to an independent investigator and what advice she can offer our young listeners for the journey along the way. 

Dr. Tobit Steinmetz is our guest this week, author of the manuscript recently published in “Arthritis and Rheumatology” titled: "Association of Circulating Antibody-Secreting Cell Maturity with Disease Features in Primary Sjogren's Syndrome." Dr. Steinmetz and his team endeavored to better understand the hyperactivity observed among B cells, which play a major role in Primary Sjogren’s Syndrome (SS). To do this, he and the team examined the quantity, maturity and inflammatory properties of Antibody Secreting Cells (ASCs) in the B cell effector branch, which became the focus of the study. Tune in to hear how this was done, what their observations and conclusions were plus, Dr. Steinmetz’s insights for those looking to enter a postdoctoral position! 

After a major event, it’s important to take stock of the causes of such an event, but just as important, on the reactions to it. No other event has challenged humanity in recent memory like COVID-19. Today we discuss the pandemic in relationship to its impact on those who suffer with rheumatic disease and examine the global response. Our guest is Dr. Evelyn Hsieh, MD, PhD, the first author of the paper: Global Perspective on the Impact of the COVID-19 Pandemic on Rheumatology and Health Equity , which was recently published in Arthritis Care & Research. 

Sometimes, we learn more from what isn’t achieved than when we achieve an expected result. Such is the case for our next guest, Dr. David R. Jayne, who is the first author of Clinical and Biomarker Responses to BI 655064, an Antagonistic Anti-CD40 Antibody, in Patients With Active Lupus Nephritis: A Randomized, Double-Blind, Placebo-Controlled, Phase II Trial , a study designed to characterize a dose-response relationship between an anti-CD40 monoclonal antibody known as Bi 655064 and complete renal response (CRR) in patients with active lupus nephritis (LN). Dr. Jayne and his research team’s study may not have shown this dose-response relationship, but what was gained along the way surely shows the power of the negative study! 

Knowing that glucocorticoids significantly increase the risk of fractures and is the most common cause of secondary osteoporosis, the use of the steroid has always been viewed as a doubled edged sword and “Bad for the Bones”. This week, we welcome Dr. Giovanni Adami, first author of Bone Loss in Inflammatory Rheumatic Musculoskeletal Disease Patients Treated with Low-Dose Glucocorticoids and Prevention by Anti-Osteoporosis Medications , whose goal for this study was to assess if a “safe” dose of glucocorticoids exists, with an attention focus on those with inflammatory rheumatic musculoskeletal diseases (iRMDs) to determine if a low enough dose of glucocorticoids can still reduce inflammatory burden and yet significantly reduce expected risk of fracture. 

The pandemic has changed much in our world—from the way we work, to the way we shop, and even the way we learn. Rheumatology wasn’t immune from such changes and when medical institutions needed to adjust their practices to accommodate a changing world around them, the process by which fellowship interviews were conducted needed to change as well. Thus, a shift to the video communication platform Zoom was made. Now, as the pioneering cohorts of the new Zoom matching process graduate, we are joined by Bharat Kumar, MD, MME, FACP, RhMSUS. Dr. Kumar has been doing a lot of research on what went well, what didn’t, and what merits rethinking. Dr. Kumar is the first author of the manuscript Reimagining the Rheumatology Fellowship Interview: Using Participatory Design-Thinking Process to Create a More Applicant-Centered Experience.

Our next guest, Dr. Paul Monach, reviews “Complement”, focusing on its application in the clinical setting. In his work, Dr. Monach presents a typical case with a broad differential diagnosis, then provides an overview of the complement system along with clinical diseases with complement-driven mechanisms. Dr. Shanmugam reviews this manuscript published in Arthritis & Rheumatology plus an analysis of the laboratory tests. Later in the show, Dr. Monach gives us his insights on how he combines his clinical work with his translational work in immunology and acts Chief of Immunology at the VA in Boston, Massachusetts! 

End-stage renal disease is a dangerous reality for those who suffer from Lupus Nephritis (LN), despite improvements in immunosuppressive therapy in the last 20 years. Our next guest, Dr. Brad H Rovin, MD, FACP, FASN, is the first author of the manuscript “Kidney-Related Outcomes and Steroid-Sparing Effects in Patients with Active Lupus Nephritis Treated with Obinutuzumab: A Post Hoc Analysis of a Phase 2 Trial.” which was recently published in Arthritis & Rheumatology. This study was a post hoc analysis of the NOBILITY trial and was conducted to assess kidney-related outcomes in patients using Obinutuzumab.