Leonard Calabrese, DO: Immunology for the Rheumatologist

Rheumatology Network interviewed Leonard Calabrese, DO, to discuss his Congress of Clinical Rheumatology (CCR) East Conference presentations “Interferon History Immunology and Beyond,” “Immunology for the Rheumatology Provider Adjourns,” and “COVID Immunology and the Rheumatologist COVID-19: Autoimmune & Inflammatory Manifestations.” Calabrese is Professor of Medicine at the Cleveland Clinic.

Rheumatology Network: Why is it important for rheumatologists to take immunology into account when treating their patients?

Leonard Calabrese, DO: Rheumatologists, by definition, are clinical immunologists, which means that that is anyone who applies the principles of basic, translational, and clinical immunology to patient care. We do that every day in virtually almost all our patients. So, it's very important. And given how dynamic this field is, it's challenging to keep up, particularly if you're not doing work in research in this area or are associated with an academic center where it's constantly being discussed. So, we take this as an opportunity.

RN: What is the history of utilizing interferons in rheumatology?

LC: The history of interferon in rheumatology goes back a long way from their discovery in the mid 60s and the struggle to purify these compounds. It took almost 20 years to make these initial observations that interferon, particularly type 1 interferon, were present in excessive amounts in certain immune-mediated diseases, such as lupus, juvenile rheumatoid, and Sjogren’s. And over the ensuing 40 years, the field now has developed robustly to recognizing it's not only a biomarker but probably driving immunopathogenesis, in particular in lupus, and possibly in other diseases. It's been a long road.

RN: What do you believe the future holds for interferons in this field?

LC: I think that the centrality of interferon and driving a number of these diseases, in particular certain end organ manifestations, is very promising. We're also finding that this interferon signature is present in diseases outside of the centrality of rheumatology, and particularly the devastating syndrome of long COVID-19, where 8 months after recovery people who are persistently symptomatic develop regulations of multiple types of interferon, could be a treatable target.

RN: Speaking of COVID, how does COVID-19 affect immunology in patients with rheumatic disease?

LC: It's a complicated question. I think at first, patients with rheumatic diseases, by and large, respond somewhat similar to healthy patients when you control for comorbidities. So, if you're not on any therapy, and your diseases is inactive even though you have baseline rheumatoid arthritis, or mild lupus, or other conditions, and you don't have diabetes, obesity, or other traditional risk factors, patients do fairly comparably. But since our patients often have end organ damage, kidney damage, lung damage, etc, they are more frequently vulnerable to the sequelae of COVID-19. And finally, the biggest issue for our patients is therapy. The therapies that we use are immunosuppressive or immunomodulatory. We're now learning that not all these therapies are equal. As a matter of fact, they're not even close to being equal. Certain patients are highly immunocompromised, and others are not.

RN: What are some of the inflammatory and autoimmune manifestations that you discussed in your presentation?

LC: On one level, COVID-19 itself is an immunologically driven viral illness. So, the mere natural history of COVID-19 is immune-mediated. Most patients get over COVID with what we call phase 1 and phase 2. They acquire the virus and trigger an innate immune response. In the second week, you make some antibodies and cell-mediated immunity and you're better. However, a small population progressed to this hyper-inflammatory phase 3, which is characterized by elevated cytokines, acute phase reactants, clotting, and activation. That is a devastating sequela. For patients with rheumatic disease, there are also other questions. Can COVID activate their underlying rheumatic disease? We’re just starting to learn that it can occur. Most of the time, it does not, and usually it's modest. But can it manifest new autoimmune manifestations? Again, it’s a work in progress because there's compelling evidence that COVID-19 drives autoimmunity, even in healthy people. What that's doing to them right now is not totally clear.

RN: In your opinion, what are some of the biggest challenges that are facing rheumatologists and immunologists today?

LC: Rheumatologists, in particular, are challenged to keep pace with both their declarative knowledge about immunology. The field is like tsunami in terms of developments. What you learned in medical school and training is out of date if you've been out of school for more than a couple of years. And if you are keeping pace with declarative knowledge, you need to know the procedural knowledge of how to use it. What is the state-of-the-art in terms of diagnostics and biomarkers? How should we be using our targeted therapies? The landscape changes constantly and diseases, like COVID 19, have challenged all of us. This is a disease that 2 years ago didn't exist and now affects our patients. We need to master yet another disorder that is immunologically driven.

RN: Is there anything else that you would like our audience to know before we wrap up?

LC: The last thing I'd like to remind rheumatologists is that we are part of the next phase of the epidemic, which will be the continued exposure and vulnerability of our patients to endemic SARS-CoV-2 infection, and we need to be forthrightly involved in managing COVID-19 in the immunocompromised. That means educating our patients, educating ourselves, knowing where the care pathways are, and how to access antivirals and monoclonal antibodies in keeping our patients from severe sequelae of COVID-19. That's going to be an ongoing challenge and I hope everyone is buying into that.