Healio Rheuminations

A quick take on one of the little-appreciated engines of the innate immune system.

• Intro :10
• A little about this episode :25
• The inflammasome is a component of the innate immune system 3:12
• Remember NLRP3 4:12
• The toll-like receptors 5:05
• Triggering the inflammasome 7:05
• The proteins 8:04
• A medieval battle and a trebuchet 9:56
• A disclosure 17:00
• I hope you enjoyed this episode 18:06

We'd love to hear from you! Send your comments/questions to [email protected]. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum

References:

Booshehri LM, Hoffman HM. J Clin Immunol. 2019;39:277-286.

Hasudungan A. Immunology – NOD like receptors and the inflammasome [Video]. YouTube. https://www.youtube.com/watch?v=biunM2iD8qM&t=4s. Published March 29, 2015. Accessed September 4, 2019.

"Acute rheumatic fever is proceeded by an infection with Group A strep" is a mantra that all health care workers know. This episode digs through the history of how we came to understand this fact, as well as how our understanding of the pathophysiology and treatment of rheumatic fever developed.

• Intro :10
• Why I made this episode :30
• Outline of this episode 1:55
• Rheumatic fever was really bad 3:10
• The early 1700s 4:10
• A big leap 6:15
• The Jones criteria 11:07
• History of the bacteriology 14:23
• The heroic ASO titre 20:51

Rheuminations is powered by Healio 21:40

• Another breakthrough: penicillin 21:51
• Not all group A strep is the same 25:06
• The decline of rheumatic fever 25:56
• What about the host? 29:30
• The joints 38:56
• Summary 40:28
• Never appreciated how bad rheumatic fever was 42:18

We'd love to hear from you! Send your comments/questions to [email protected]. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum

References:

A History of Medical Bacteriology and Immunology, First Edition, Butterworth-Heinemann, Oxford, 1970.

Aspinall GO, et al. Infect Immun. 1994;62:2122-2125.

Carapetis JR, et al. Nat Rev Dis Primer. 2016;doi:10.1038/nrdp.2015.84.

Cox CJ, et al. J Immunol. 2013;doi:10.4049/jimmunol.1102592.

Engel ME, et al. PLoS One. 2011;6:e25326.

FW Denny, et al. JAMA. 1950;143:151-153.

Gray LA, et al. J Infect Dis. 2017;216:1460-1470.

Kaplan MH, et al. Lancet. 1962;1:706-710.

Karthikeyan G, Guilherme L. Lancet. 2018;392:161-174.

Khandke KM, et al. J Exp Med. 1987;doi:10.1084/jem.166.1.151.

Paul O, et al. Clin Cardiol. 1990;13:367-369.

Quinn A, et al. Infect Immun. 2001;69:4072-4078.

Robertson KA, et al. BMC Cardiovasc Disord. 2005;5:11.

Rojas Manuel, et al. J Autoimmun; 2018;95:100-123.

Tandon R, et al. Nat Rev Cardiol. 2013;10:171-177.

Join me as I explore a case of fever and migratory inflammatory arthritis, then discuss the case with the double-boarded rheumatologist/infectious disease expert, Cassandra Calabrese, DO.

• Intro :10
• My new book :24
• Inside this episode 1:20
• Case presentation 1:38
• Introducing Dr. Cassandra Calabrese 9:22
• The interview 10:40
• Was the patient's presentation typical for rheumatic fever? 10:58
• Do most rheumatic fever cases have migratory arthritis? 13:23
• How different is this from reactive arthritis? 15:42
• What's the deal with aspirin in this condition? 17:26
• What are the skin manifestations? 18:19
• Tell us about Sydenham chorea 20:23
• What's the difference between valvulitis and carditis? 22:07
• Tell us about heart disease and recurrence 23:13
• Can you talk about rheumatic fever recurrence? 24:32
• Continuous prophylaxis 25:41
• Can you walk us through the ASO (antistreptolysin O) titer? 26:20
• How long is this on the differential? 28:38
• Summary of our discussion 29:43
• Thank you, Dr. Calabrese 32:18

We'd love to hear from you! Send your comments/questions to [email protected]. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum

Cassandra Calabrese, DO, is a rheumatologist in the department of rheumatic and immunologic disease and the department of infectious disease at Cleveland Clinic.

John Stone, MD, MPH, is the world leader in the field of IgG4-related disease research. In this episode, he breaks down the histology of IgG4-related disease, important aspects of what is known about the pathophysiology of the disease, as well as future directions in treatment.

• Intro :10
• Inside this episode :13
• IgG4-related disease background :31
• An anecdote 1:15
• The interview 4:09
• History of IgG4-related disease 4:18
• IgG4 pathology and terms 7:48
• What makes IgG4 different from other IgG subclasses? 10:23
• What do we know about the interplay between B and T cells? 12:31
• What is SLAMF7? 16:30
• What happens to T cells during B-cell depletion? 18:22
• Antigens involved in IgG4 21:06
• Future of treatment 23:10
• Thank you, Dr. Stone 24:32

We'd love to hear from you! Send your comments/questions to [email protected]. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum

John Stone, MD, MPH, is director of clinical rheumatology at Massachusetts General Hospital.

In this episode, James Rosenbaum, MD, an expert in inflammatory eye disease, breaks down how systemic autoimmune conditions can affect the eye and highlights pearls that Rheumatologists should know.

• Intro :10
• Inside this episode :15
• Introducing Dr. Jim Rosenbaum :51
• The interview 1:26
• Some basic terms 1:45
• TEON pneumonic 5:45
• Microbiome work 7:06
• Evaluation of inflammatory eye disease 9:01
• Workup for inflammatory eye disease 10:23
• How do ophthalmologists rule out infection? 18:00
• Is there anatomic overlay between the eye and joints? 23:10
• A pen light and history 25:30
• Treatment algorithm 27:27
• What excites you the most about the future of inflammatory eye disease? 33:31
• Thank you, Dr. Rosenbaum 37:03

We'd love to hear from you! Send your comments/questions to [email protected]. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum

James T. Rosenbaum, MD, is professor of ophthalmology, medicine and cell biology; head of the division of arthritis and rheumatic diseases and Edward E. Rosenbaum Professor of Inflammation Research at Oregon Health and Science University.

We journey into the world of metabolic bone in this episode and explore the varied clinical manifestations of hypophosphatasia. We also interview the head of the center for osteoporosis and metabolic bone disease at the Cleveland Clinic, Chad Deal, MD.

• Intro :10
• The four H's of chondrocalcinosis :18
• What we'll cover in this episode :52
• A general overview 2:33
• The first description of hypophosphatasia 3:39
• History of this condition 13:00
• Two cases 16:00
• The interview 17:55
• Various presentations 18:42
• Laboratory findings 21:13
• Differentiating the terminology 24:55
• The relationship between this and chondrocalcinosis 27:11
• Mechanisms of pain 28:15
• Treatment options 29:30
• Thank you, Dr. Deal 38:00
• Episode recap 38:10

We'd love to hear from you! Send your comments/questions to [email protected]. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum

References:

Linglart A, Biosee-Duplan M. Curr Osteoporos Rep. 2016;14:95-105.

Rathbun JC. Am J Dis Child. 1948;75:822-831.

Robison R. Biochem J. 1923;17:286–293.

Turan S, et al. J Clin Res Pediatr Endocrinol. 2011;3:7-11.

Whyte MP. Bone. 2017;102:15-25.

This ripping yarn delves into the history of tumor necrosis factor in relation to rheumatoid arthritis with emphasis on the original studies that set the stage for the use of TNF inhibition in RA.

• Intro :11
• What we'll cover here :16
• Recap of Part 1 1:25
• What I discovered when doing this episode 1:22
• What this episode won't address 2:40
• Let the tale begin 3:12
• A look at matrix metalloproteinases 3:32
• A breakthrough in understanding RA 6:28
• Two key players: Dr. Mark Feldman and Dr. Ravinder Maini 6:53
• The first cytokine research conducted in RA: IL-1 8:00
• The next cytokine: Tumor necrosis factor 11:16
• What do we know about cytokine production within the joint? 14:33
• IL-6 and TGF-beta 19:16
• A bit about IL-10 23:57

*Visit Healio.com/rheum for daily news and updates*

• How do we choose which cytokines to block to make improvements in RA? 25:16
• What about in vivo data? 29:45
• The history of infliximab 34:00
• Infliximab is approved for RA treatment 45:13
• TNF in RA: from bedside, to bench then back to bedside 46:06
• It's important to recognize the researchers who discovered these pathways 46:18
• Remember the scientists next time you prescribe a TNF inhibitor 47:05
• Read the latest news and commentary on Healio.com/rheumatology and Follow us on Twitter @HealioRheum and @HRheuminations for updates 47:34

We'd love to hear from you! Send your comments/questions to [email protected]. Follow us on Twitter @HRheuminations @AdamJBrownMD @HealioRheum

References:

Brennan FM, et al. J Autoimmun. 1989;2 Suppl:177-186.

Brennan FM, et al. Lancet. 1989;2:244-247.

Butler MD, et al. Eur Cytokine Netw. 1995;6:225-230.

Chu CQ, et al. Arthritis Rheum. 1991;34:1125-1132.

Dayer JM, et al. J Exp Med. 1985;162:2163-2168.

Di Giovine FS, et al. Ann Rheum Dis. 1988;47:768-772.

Feldmann, M. Nat Rev Immunol. 2002;2:364-371.

Feldmann M, Maini SR. Immunol Rev. 2008;223:7-19.

Fontana A, et al. Rheumatol Int. 1982;2:49-53.

Haworth C, et al. Eur J Immunol. 1991;21:2575-9.

Houssiau FA, et al. Arthritis Rheum. 1988;31:784-8.

Keffer J, et al. EMBO J. 1991;10:4025-4031.

Kulkarni AB, Karlsson S. Am J Pathol. 1993;143:3-9.

Kuruvilla AP, et al. PNAS. 1991;88:2918-2921.

Maini RN, et al. Arthritis Rheum. 1998;41:1552-1563.

Malaviya AN, Mehra NK. Indian J Med Res. 2018;148:263–278.

McInnes IB, Schett G. Nat Rev Immunol. 2007;7:429-442.

Mitchison NA, Medawar PB. Proc R Soc Lond [Biol]. 1964;https://doi.org/10.1098/rspb.1964.0093.

Pettipher ER, et al. Proc Natl Acad Sci U S A. 1986;83:8749-8753.

The Beautiful Cure: The Revolution in Immunology and What It Means for Your Health, University of Chicago Press, Chicago, 2018.

Williams RO, et al. Proc Natl Acad Sci U S A. 1992;89:9784-9788.

Xu WD, et al. J Clin Invest. 1989;83:876-882.

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 [email protected]. 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 [email protected]. 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 [email protected]. Follow us on Twitter @AdamJBrownMD @HealioRheum @HRheuminations @LCalabreseDO