Expert Conversations on Trials in Rheumatology: IL-6 and Beyond
In this video, Leonard Calabrese, DO, and Cassandra Calabrese, DO, discuss their experiences with the COVID-19 pandemic, including the ongoing drug trials at the Cleveland Clinic.
- Feldman M, Maini RN, Woody JN, et al. Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed [published online April 9, 2020]. Lancet. https://doi.org/10.1016/S0140-6736(20)30858-8
Leonard H. Calabrese, DO, is the head of the Section of Clinical Immunology, manager of the Clinical Immunology Clinic, and co-director of the Center for Vasculitis Care and Research at the Cleveland Clinic in Cleveland, Ohio.
Cassandra Calabrese, DO, holds joint appointments in the rheumatology department and the infectious disease department at the Cleveland Clinic in Cleveland, Ohio.
Len Calabrese: Hi, I'm Dr Len Calabrese from the Cleveland Clinic. I run the RJ Fasenmyer Center for Clinical Immunology, and with me is… Cassandra Calabrese: I'm Dr Cassandra Calabrese, also at the Cleveland Clinic. I am a rheumatologist and have a dual appointment in the infectious disease department. Len Calabrese: So, we're really happy to come at you with some thoughts about COVID-19, because our department bridges infectious disease, as well as autoimmune disease and immune deficiency disease. We've been thrust into the COVID-19 epidemic very vigorously. We are particularly interested in that small population of patients who is progressing, who are critically ill, and who may be candidates for an anti-inflammatory strategy with targeted therapies. So, let me just kind of set this up for a second. I think everyone's well familiar that this disease, while not linear, has varying stages. Early stage of viral acquisition infection, triggering of innate immunity, the development of adaptive immunity where 80% of people will spontaneously resolve within a couple weeks, and about 15% or 20% of people based on comorbidities and features, such as age, get sick. A small percentage of them—2% to 5%— may become critically with hypoxia, progressive pneumonitis, and a small percentage develop this picture of progressive inflammation that is reminiscent of MAS, a secondary HLH, or cytokine storm. We're using this term. Patients who succumb to COVID-19 immunopathology looks like an ARDS, and the biomarker phenotype is one of intense inflammation, with elevated CRPs, elevated ferritin, SIL2Rs. If you look at cytokine profile, it's IL-6, TNF, IL-1, GM CSF, and beyond. As rheumatologists, you know, we're the people in the room that have this armentarium of drugs. In particular, IL-6-targeting agents—tocilizumab, approved for rheumatoid arthritis, systemic JIA, and GCA, is also recently been approved for cytokine storm and now there are two RCTs going on at multiple sites, one phase 3 of tocilizumab, one phase 2 or 3 sarilumab, and we were generating our own experience with it. Cassie, want to give us a thumbnail sketch of, at least at Cleveland Clinic, how we've been approaching this, saying that at this time we are not involved in either of those trials. Cassie Calabrese: Absolutely. We have developed, along with our infectious disease colleagues and infectious disease pharmacy colleagues, an inpatient treatment protocol as many institutions have for sick patients admitted with COVID-19. We are giving IL-6 tocilizumab IV infusion to patients that are mechanically ventilated and have the cytokine-storm-like picture. So far we've given almost 40 patients tocilizumab, with somewhat of a bright outcome in some of these patients able to get off the vent, improving oxygen requirements. Of course, this is just our backup the cuff anecdotal experience. We will be looking at these outcomes formally in the very near future and sharing them with everyone and writing up our early experience. We have a lot of questions that we hope are answered by these large clinical trials, including what time in the disease course is best to administer anti-IL-6, how many doses, what biomarkers are we following, and what are the short-term adverse events of giving anti-IL-6 acutely? We have been giving it to almost 40 patients, and we're certainly limited by the supply and look forward to learning more from the Genentech and Regeneron trials. Len Calabrese: Yeah, just to add to that, we’re talking about IL-6 because it's a biologic possibility, and we have a drug. But there are many other clinical trials moving ahead with inviting targets, or IL-1 is being targeted with several of the currently available agents in several trials. Anti GMC SF by several companies is going into clinical trials, because of background work in ARDS. Then just today, there's a brilliant editorial Op-Ed piece in The Lancet by Marc Feldman, Ravinder Maini, and other colleagues, making a very compelling case for rapidly moving into clinical trials with anti-TNF agents. All of these trials have some logic to them, but as we all know, it will be a balance of risks and benefits. Compromising immune response vs quelling the systemic inflammatory response. There will be no substitute for large medical trials, which I think can generate data within a few months, because they can so rapidly recruit. I just mentioned here, in closing, it's crazy to try to keep up with this. I saw a figure yesterday on Twitter that over the past week, 3800 articles have been published on COVID-19, and it makes you your head spin. We have some we have a special COVID-19 piece coming out the Cleveland Clinic Journal of Medicine. Cassie and I have several articles about targeted therapies there. And then we're both guest editing a special issue of Current Opinions in Rheumatology on COVID-19 in rheumatology. So we look forward to it. Cassie Calabrese: Thanks for having us.