How did rheumatology wind up in the cytokine storm?
These are indeed strange and scary times for us all and this month’s cover story takes us into territory we would have found disorienting and completely unrelated to the field of rheumatology only a short generation ago: cytokine storm syndrome. We are indebted to our esteemed faculty, including Randy Q. Cron, MD, PhD, of the University of Alabama at Birmingham, and Maximilian F. Konig, MD, of The Johns Hopkins University School of Medicine, who will discuss the cutting edge of this rapidly evolving field.
Regardless of etiology of these cytokine storms, we as rheumatologists wound up in the eye because of our experience and expertise using immunosuppressive targeted therapies to attack the untoward clinical effects of these inflammatory mediators.
Adding icing to this stormy cake has been the thunderous arrival of the COVID-19 pandemic and the recognition that the most severe form of this illness is driven not by uncontrolled viral replication but the sequelae of progressive immune activation and cytokine release leading to respiratory failure and death. No wonder so many of us are now engaged in the fast-paced research that melds the field of rheumatology and immunology with infectious diseases.
Rheumatology has been at the forefront of the efforts to apply advances in biotechnology for over two decades, starting with the development of biologic therapeutics targeting upstream cytokines such as IL-1 and TNF. We moved into the lead in clinical research after the many failed attempts to use such therapeutics to treat the first cytokine storm, namely sepsis, which almost ended the party before it started as many companies reasonably questioned if these agents would fall short of the high expectations originally proffered.
Following the approval of the first TNF inhibitors for the treatment of rheumatoid arthritis over 20 years ago, we quickly became the stewards for an increasing armamentarium of therapeutics, now referred to as targeted DMARDs (mostly monoclonal antibodies) and now an increasing number of targeted synthetic DMARDs (mostly kinase inhibitors).
The indications have grown from rheumatoid arthritis and spondyloarthritis to inflammatory bowel disease, psoriasis, uveitis and autoinflammatory diseases among many other conditions. We have learned how to use these drugs both effectively and safely. We also know how to use glucocorticoids and are all too familiar with their adverse event profile. Finally, since rheumatology is not limited to a disease of a single organ system, no other specialty has our skill in managing multiorgan immune dysfunction. Essentially, we are now bred to be at the forefront of the rising cytokine storm.
On May 21, I spent an hour or so reviewing (by title) the ongoing trials for COVID-19 on ClinicalTrials.gov. There are now over 1,600 clinical trials registered, 900 of which are therapeutic — a massive leap from only 900 registered trials 10 days before! My perusal of these studies identified many incorporating the approved therapeutics that we use on a regular basis and many others using unapproved agents that we have strong interests in as potential therapies for immune-mediated diseases. Not surprisingly, there are currently 199 trials of hydroxychloroquine.
Further, there are numerous trials examining the utility — either as single therapies or in combination with other modalities in controlled or observational designed trials — of agents targeting IL-1, IL-6 and GM-CSF among other mediators. There are more than a dozen trials using JAK inhibitors, as well as others exploring the utility of BTK inhibitors among other kinase inhibitor candidates. Immune suppressive and immunomodulatory trials using methotrexate, thalidomide, colchicine and vagal nerve stimulation also caught my eye as we use or are studying these therapeutics actively in our field.
At a practical level, what does this mean for rheumatologists? Well for some, such as those on our panel, and many others, they are serving as active participants in this fast-paced area of research. For others across the country and around the world, we will be called upon for our knowledge and experience in the open-label use of these and other treatments on a compassionate basis.
For the rest of us, we are now being called upon to care for our patients, many of whom will be stricken with COVID-19. We will be making the hard decisions on management of their underlying immune disease as well as, if and when, they are drawn into the eye of a cytokine storm. Stay tuned, this is just the beginning. Please send me your thoughts through Twitter at @LCalabreseDO or email me at firstname.lastname@example.org.
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- Leonard H. Calabrese, DO, is the Chief Medical Editor, Healio Rheumatology, and Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, and RJ Fasenmyer Chair of Clinical Immunology at the Cleveland Clinic.