In Part 1, we look at the original studies that led to the discovery of TNF in two separate labs where researchers were looking for two completely different things. We’ll learn how these discoveries then fueled the use of TNF in the failed trials as an anti-cancer agent, and the eventual development of antibody therapy against TNF in septic shock. Intro :11 The origins of this episode and what we’ll cover here and in Part 2 :18 What Part 1 will cover 2:01 Early cytokine research in general codiscovery of TNF TNF as anticancer agent TNF’s role in cachexia trials of anti-TNF in the setting of septic shock What part 2 will cover 2:59 TNF’s role in rheumatoid arthritis TNF in the late 1800s 3:18 Lipopolysaccharide from gram-negative bacteria is first isolated and discovered 8:16 Fast forward to the 1960s, enter Memorial Sloan Kettering Cancer Center 9:08 Anthony Cerami studies cachexin in his Rockefeller lab 11:10 Focus on cachexia 12:27 Late 1980s: TNF is produced and given to humans using recombinant technology 20:01 Studies of TNF in patients with various types of cancer 20:48 High doses seem to induce shock-like illness 21:38 TNF-secreting tumor is created and tested 25:21 Some take away 26:12 Studying TNF led to the discovery that it’s associated with shock 26:33 Money pours into research on blocking TNF 27:00 A look at studies of TNF in infection 27:22 Study of TNF in sepsis 30:20 Let’s talk about anti-TNF and what it’s doing 34:00 Studies of anti-TNF in humans 36:00 Rat and baboon studies don’t always correlate with humans 40:25 Episode recap 40:45 Stay tuned for Part 2 42:20 Follow us on Twitter @HRheuminations and leave us a review in iTunes 42:50 We’d love to hear from you! Send your comments/questions to rheuminationspodcast@healio.com. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum References: Beutler B, et al. Science. 1985;229:869–871. Blick M, et al. Cancer Research. 1987;47:2986-2989. Carswell E, Williamson B. Cancer Imm. 2012;12:4. Feldman M. Nat Rev Immunol. 2002;2:364-371. Fong Y, et al. J Exp Med. 1989;170:1627-1633. Kawakami M. Mol Med. 2014;doi:10.2119/molmed.2014.00177. Lv S, et al. Int J Clin Pract. 2014;68:520-528. Marks JD, et al. Am Rev Respir Dis. 1990;141:94-97. McCarthy EF. Iowa Orthop J. 2006;26:154-158. Michi HR, et al. N Engl J Med. 1988;318:1481-1486. Oliff A. Cell. 1988;54:141-142. Opal SM, et al. J Infect Dis. 1990;161:1148-1152. Qui P, et al. Expert Opin Investig Drugs. 2011;20:1555-1564. Tracey KJ, et al. Nature. 1987;330:662-4. Waage A, et al. Lancet. 1987;1:355-7.

Take a listen to this medical mystery and learn about a not-so-rare condition — depending on where you live. Hear some interesting historical stories about the physicians who helped establish the diagnosis, as well as an interview with a renowned expert. Intro :11 A 57-year-old woman presents with multiple-week history of joint pain. She also complains of lesions on her forearms. :32 Initial lab results 1:30 She arrives at my office 1:50 Review of her vitals 1:57 Physical exam findings and patient history 2:05 What about the nodules on her skin? 3:20 Tests leading to diagnosis 4:40 What’s the diagnosis? 4:55 A personal anecdote 5:20 Symmetrical polyarticular inflammatory arthritis in the setting of erythema nodosum 6:18 What do we know about Löfgren Syndrome? 7:45 History of this diagnosis 8:35 What we know 100 years later 11:13 Focus on the inflammatory arthritis of Löfgren Syndrome 14:25 Are these different diseases? 18:07 Summary of what we’ve discussed so far 19:13 Unsung heroes who showed sarcoidosis is associated with inflammatory arthritis 20:40 Introduction of Dr. Daniel Culver 28:26 An update on sarcoidosis with Dr. Culver 29:17 Why should we care about staging on X-ray? 29:22 Are there any clues that it may be sarcoid based on histology and morphology of the granuloma itself? 30:56 How does bronchoalveolar lavage help? 32:58 How often do you see remissions in non-Löfgren’s sarcoidosis? 34:41 What are your thoughts on the serum biomarkers? 36:34 Can you comment with your thoughts on the link between the environment and the disease? 38:25 What about infectious triggers? 40:06 Do you think genetic studies will eventually be used for diagnosis or prognosis? 41:18 Where do you think we’ll be with the diagnosis and treatment of sarcoidosis in 10 years? 42:38 Thank you, Dr. Dan Culver 44:28 Episode recap 44:40 Follow us on Twitter @HRheuminations and leave us a review in iTunes 45:18 Daniel Culver, DO, is director of the Interstitial Lung Disease Program at Cleveland Clinic and director of The Sarcoidosis Center of Excellence at Cleveland Clinic. We’d love to hear from you! Send your comments/questions to rheuminationspodcast@healio.com. Follow us on Twitter @AdamJBrownMD @HealioRheum @HRheuminations References: Grunewald J, Eklund A. Am J Respir Crit Care Med. 2009;179:307-312. Le Bras E, et al. Arthritis Care Res (Hoboken). 2014;66:318-322. Lofgren S, Lundback H. Acta medica Scandinavica. 1952;142. Maña J, et al. Am J Med. 1999;107:240-245. Palmer DG, Schumacher HR. Ann Rheum Dis. 1984;43:778–782. Segura BT, et al. Medicina Clinica (Barc). 2014;143:166-9.

In this guest episode, Leonard Calabrese, DO, provides the history of systemic lupus erythematosus, with special emphasis on the discovery of the LE cell and the two clinics involved in its detection.   Introduction of Leonard Calabrese, DO :11 In this episode … 1:44 A brief history of systemic lupus erythematosus and the major players 2:15 Laurent-Theodore Biett 2:55 Casanave 3:05 von Hebra 3:24 Moritz Kaposi 4:05 Sir William Osler 5:25 Fast-forward to observations made during WWII era 7:00 The story of two clinics 8:55 The Mayo Clinic 9:00 The Cleveland Clinic 16:24 A race against time 18:29 Lupus is no longer a diagnostic problem 20:02 In a nutshell 20:15 Housekeeping items 20:51 Leonard Calabrese, DO, is head of Cleveland Clinic’s Section of Clinical Immunology, co-director of Center for Vasculitis Care and Research, and chief medical editor of Healio Rheumatology. We’d love to hear from you! Send your comments/questions to rheuminationspodcast@healio.com. Follow us on Twitter @AdamJBrownMD @HealioRheum @HRheuminations @LCalabreseDO

Richard Furie, MD, is chief, division of rheumatology, at Northwell Health, and professor of medicine at Hofstra/Northwell School of Medicine. Join us in this ACR interview, as we discuss the story of interferon, lupus therapeutics — including B cell depletion — and the future of lupus research and treatments. Intro :10 Background on Dr. Furie :16 The interview :56 What advancements in the pathophysiology of lupus are you most excited about? 1:10 The interferon story 1:23 The interferon story is not finished yet 7:18 Dendritic cells in lupus patients 7:41 What is “interferon signature?” 8:07 Do we see different clinical phenotype in patients with high interferon signature? 9:38 What’s your opinion on the role of B cells? 10:07 Any other pathophysiology mechanisms being used to target B cells? 13:15 Are we stretched thin in terms of number of lupus patients in trials? 15:21 How would designating lupus as an orphan disease change the way it’s investigated? 16:40 What is your main concern regarding study design? 17:37 Looking 10 years ahead, do you think what we call “lupus” will still be referred to as such, or will it be decompartmentalized into different diseases? 21:26 What’s the expense of cytokine profiling? 22:40 What excites you the most about the future of lupus research? 23:21 Thank you, Dr. Furie 24:41 Recap 24:43 Shout out to the 7th Annual Basic and Clinical Immunology for the Busy Clinician: What is New and Hot in Immunology bootcamp in Scottsdale, AZ, Feb. 15-16, 2019 25:31 We’d love to hear from you! Send your comments/questions to rheuminationspodcast@healio.com. And be sure to follow us on Twitter @AdamJBrownMD and @HealioRheum. This information is brought to you by Healio and is not sponsored by, nor a part of, the American College of Rheumatology.

In this episode, John Stone, MD, MPH, director of clinical rheumatology at Massachusetts General Hospital, sits down to discuss his approach to giant cell arteritis and the results of the GiACTA trial. Learn why Stone believes the most important diagnostic test in GCA is the patient’s history. Intro :10 Background on Dr. Stone :59 The interview 2:10 Differentiating subtle GCA from the “classic case” 2:20 Data from Stone’s recent paper in Rheumatology 5:17 Using bilateral biopsies 9:00 Recommendations for temporal artery biopsy – who, when, where 11:13 Thoughts on imaging for GCA diagnosis 13:14 IL-6 and treatment of GCA 15:16 GiACTA trial – what surprised you most about the efficacy of prednisone alone? 19:05 Findings with tocilizumab 21:29 Inflammatory markers in GCA 24:47 Should we use tocilizumab right off the bat? 26:50 What excites you the most about the future of this field? 29:59 Thank you, Dr. Stone 31:33 Recap 31:38 We’d love to hear from you! Send your comments/questions to rheuminationspodcast@healio.com. And be sure to follow us on Twitter @AdamJBrownMD and @HealioRheum.

John J. O’Shea, MD, is scientific director of the NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases, and chief of their Molecular Immunology and Inflammation Branch. In this ACR interview, he joins me to talk about the JAK/STAT pathway, what we’ve learned from mouse models, current FDA-approved JAK inhibitors and the future of this exciting field. Intro :10 Background on Dr. O’Shea :45 The interview 2:37 How did you start looking into the JAK/STAT pathway? 3:16 What should a clinician understand about this pathway? 5:22 What do these cytokines have in common? 6:37 What have we learned from mouse models? 8:48 GWAS studies in JAK/STAT 11:49 Can we quantify how much a certain cytokine may be using this pathway? 12:39 Can you explain suppressor of cytokine signaling, aka SOCS? 14:15 What do we know about how these different cytokines can have individual signaling controls? 16:40 An explanation of phenocopy 18:01 What evidence do we have that JAK may circumvent STAT, and vice versa? 18:41 An overview of FDA-approved JAK inhibitors and the pipeline 20:52 What excites you the most about the future of this field? 23:26 In a state of wonder over success of biologics 25:50 Thank you, Dr. O’Shea 27:20 Recap 27:30 We’d love to hear from you! Send your comments/questions to rheuminationspodcast@healio.com. And be sure to follow us on Twitter @AdamJBrownMD and @HealioRheum. This information is brought to you by Healio and is not sponsored by, nor a part of, the American College of Rheumatology.

In this ACR interview, the walking encyclopedia of medical history, Eric L. Matteson, MD, of The Mayo Clinic, sits down with me to discuss what excites him about medical history and then takes a deep dive into the history of vasculitis!  Intro :10 Background on Dr. Matteson :28 The interview 2:00 How did you get into history? Why does it mean so much to you? 2:19 Can you tell us about the archives at Mayo Clinic? 6:49 An appreciation of present time and how we take some medications for granted 7:55 Brief history of vasculitis 9:23 Kussmaul and the first failed ophthalmoscope 14:20 Kussmaul’s second failure: gastroscope 15:43 When did we get to the small vessel vasculitis/glomerulonephritis description? 17:25 The discovery of Wegener 20:44 Wegener was not the first to describe granulomatosis with polyangiitis, and the folly of naming diseases for individuals 23:24 Thank you, Dr. Matteson 24:57 Recap 25:05 We’d love to hear from you! Send your comments/questions to rheuminationspodcast@healio.com. This information is brought to you by Healio and is not sponsored by, nor a part of, the American College of Rheumatology.

Martin J. Blaser, MD, is director of the Human Microbiome Program at NYU and author of the book, Missing Microbes. He sat down and spoke with us about how the microbiome plays a role in disease pathogenesis, including autoimmunity, and he also answered the question of whether all of our patients should be on probiotics!   Intro :11 Background on Dr. Blaser :35 The interview 1:20 What is the microbiome? 1:25 How unique are individual microbiomes? 1:49 How does an individual’s microbiome change over time? 2:13 Microbial diversity in different populations 3:12 What’s your concern with the loss of microbiome diversity? 4:20 A bit on Blaser’s research on obesity and antibiotic use 5:21 Is the timing of antibiotic administration important, in terms of the side effects it can produce? 6:43 Worldwide antibiotic prescribing rates 7:54 The microbiome and autoimmunity 9:02 The microbiome and type 1 diabetes, IBD 10:45 Research with IL-17 12:23 Microbiota transplants 13:09 For how long is the microbiome perturbed after giving antibiotics? 13:57 Diet and microbiome findings 14:54 Probiotics, prebiotics and symbiotics 15:33 In 10 years, how will people be investigating/manipulating the microbiome? 18:18 Have we shown with research that introducing certain types of bacteria can be sustainable in the gut? 19:47 Thank you, Dr. Blaser 20:26 Summary 20:33 We’d love to hear from you! Send your comments/questions to rheuminationspodcast@healio.com. This information is brought to you by Healio and is not sponsored by, nor a part of, the American College of Rheumatology.

In this episode, explore data from the major study proving uric acid crystals are present in the synovial fluid of patients with gout, as well as the tale of two rheumatologists who injected their own knees (while still working in the hospital) with uric acid to prove it is the trigger for inflammation in gout. The episode finishes with some ripping yarns about the history of the medications we use to treat this condition.   Intro :10 Controversy surrounding uric acid’s role in gout :45 “Game changing” paper published in 1961 2:07 The first description of pseudo gout 5:53 How do you prove uric acid triggered the inflammatory response? 6:37 One of my favorite studies 6:43 Faires and McCarty inject themselves with uric acid 7:49 Details of what they experienced 8:22 4 hours later … 8:52 Both patients receive treatment 9:12 Review of what we’ve discussed so far 10:06 Let’s try and answer the question posited in The History of Gout, Part 1 10:35 Colchicine – previously a medicinal plant 10:41 A look at the history of urate-lowering therapy 12:59 Probenecid was developed to reduce the excretion of penicillin 13:18 The history of allopurinol 14:32 Don’t give allopurinol to patients on azathioprine 17:21 The answer to the question posed in Part 1 17:49 Summary 18:12 We’d love to hear from you! Send your comments/questions to rheuminationspodcast@healio.com. References: Barnett R. Lancet. 2018;391:2595. Faires JS, Mccarty DJ. Lancet. 1962;280:682-685.   Kippen I, et al. Ann Rheum Dis. 1974;33:391-396. Marson P, Pasero G. Reumatismo. 2011;63:199-206. McCarty DJ, Hollander JL. Ann Intern Med. 1961;54:452-460. Nuki G, Simkin PA. Arthritis Res Ther. 2006;doi: 10.1186/ar1906. Rundles RW. Arch Intern Med. 1985;145:1492-1503. Shyambhavee, Behera BK. J Pharmacol Clin Toxicol. 2017;5:1098. Storey GD. Rheumatology. 2001;40:1189-1190. West JB. Am J Physiol Lung Cell Mol Physiol. 2014;doi:10.1152/ajplung.00223.2014.

Do you know the etymology of the word “gout,” or how a simple microscope aided in the identification of tophi? Join me as I explore the history of this inflammatory arthritis and highlight the important scientists who shaped the modern era of gout. Intro :10 What to expect in Part 2 :48 A question: Which urate-lowering therapy was made for an expressly different reason than to treat gout? 1:34 The first modern description of gout 1:54 Let’s go back to the Greeks 3:05 Why is it called “gout?” 3:06 An anecdote from medical school 4:13 Hippocrates’ words of wisdom on gout 4:58 First century AD: Gout is linked with excessive eating and drinking 6:01 Things get muddled 6:20 1683: The modern era of gout is described 6:42 “Gout Perspectives” published in The Lancet in 2018 7:06 Self-taught Dutch scientist, Antony van Leeuwenhoek, pioneers the microscope and identifies tophi 8:29 Swedish chemist Carl Wilhelm Scheele discovers uric acid 11:38 William Hyde Wollaston tests tophi and discovers it’s full of uric acid 12:57 Emperor of uric acid, Alfred Baring Garrod, associates elevated serum uric acid with gout 13:48 If anyone knows how the thread test works, please email me 14:58 He theorized that uric acid causes gout 15:37 A look back at what we know 16:09 What we don’t know: What’s in the joints of patients with acute gout? 16:22 Stay tuned for The History of Gout, Part 2 16:34 We’d love to hear from you! Send your comments/questions to rheuminationspodcast@healio.com. References: Barnett R. Lancet. 2018;391:2595. Faires JS, Mccarty DJ. Lancet. 1962;280:682-685.   Kippen I, et al. Ann Rheum Dis. 1974;33:391-396. Marson P, Pasero G. Reumatismo. 2011;63:199-206. Mccarty DJ, Hollander JL. Ann Intern Med. 1961;54:452-460. Nuki G, Simkin PA. Arthritis Res Ther. 2006;doi: 10.1186/ar1906. Rundles RW. Arch Intern Med. 1985;145:1492-1503. Shyambhavee, Behera BK. J Pharmacol Clin Toxicol. 2017;5:1098. Storey GD. Rheumatology. 2001;40:1189-1190. West JB. Am J Physiol Lung Cell Mol Physiol. 2014;doi:10.1152/ajplung.00223.2014.