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Since the start of the COVID-19 pandemic early this year, there have been a number of studies published to test the effectiveness of hydroxychloroquine as a possible treatment. In today’s edition of Overdrive, the podcast from Rheumatology Network, Dr. Daniel Solomon, editor-in-chief of Arthritis and Rheumatology, helps us make sense of the science.
Since the start of the COVID-19 pandemic early this year, there have been a number of studies published to test the effectiveness of hydroxychloroquine as a possible treatment. Observational studies have been published, case reports were published and randomized controlled trials were published showing that this tried and true treatment for some rheumatic conditions doesn’t work for COVID-19.
Dr. Daniel Solomon, who is editor in chief of Arthritis and Rheumatology and chief of clinical sciences for rheumatology at Brigham and Women’s Hospital in Boston, describes the abundance of new research on hydroxychloroquine and cytokine storm syndrome as an infodemic.
In today’s edition of Overdrive, Dr. Solomon helps us make sense of the science.
Daniel H. Solomon, M.D., MPH, professor of medicine at Harvard Medical School and chief of clinical sciences in the Division of Rheumatology at Brigham and Women’s Hospital in Boston. He currently serves as the editor in chief of Arthritis and Rheumatology, which is where our editorial and commentary was published that we’re talking about today.
This was a commentary that we wrote myself and the deputy editors of Arthritis and Rheumatology. We felt compelled to write about what we described as an “infodemic” and others have described it that way as well. Because there is so much information regarding all aspects of the pandemic from diagnostics to treatments to prevention. And, in the rheumatology world because COVID affects the immune system and often presents with extremes in inflammation many treatments that we have used in rheumatology have been considered as possible treatments for COVID. This includes hydroxychloroquine as well as some of the anticytokine therapies against IL-6 and IL-1, as well as a drug as simple as steroids (dexamethasone).
So, as rheumatologists we’re very knowledgeable and aware of these drugs and aware of things like cytokine storm syndrome. And, so listening to how misrepresentations in the lay press and on TV and in social media have impacted the pandemic, the public health efforts and even our patients because of difficulty of getting access to routine drugs like hydroxychloroquine. So, I think we all felt very compelled and moved to speak about this issue. And, we talk about two specific examples in this commentary. One is hydroxychloroquine and the second one is the cytokine storm syndrome. I think they’re both really compelling examples of this misinformation.
I look at hydroxychloroquine as a typical example of how our optimism and reality sets in with any therapeutic. There’s kind of a similar arc. This arc has been compressed to several months---three to six months---as opposed to years that we typically see with different compounds. Initially there was the observation, or the recognition that hydroxychloroquine had some activity against coronaviruses. They were not large studies or necessarily studies particularly done in people with COVID. These were other coronaviruses. But there was biologic plausibility to the notion that hydroxychloroquine might have some action against COVID. We didn’t know which patients, whether it was preventive, whether it was early, whether it was mild or severe. But there was some biologic plausibility. And, then people made observations in small case series where they saw that patients who received hydroxychloroquine often with other antibiotics. Hydroxychloroquine is an antimalarial. It was some immunomodulatory effects as well so it seems like an interesting drug. It has been on the market for decades so people felt comfortable using an approved drug. It wasn’t a new investigational drug. And, in these small case series, there was some suggestion that it might work. But we all know that a case series is an uncontrolled experiment. You look at three, four, five patients, but you don’t look at the counterfactual:What would have happened if they didn’t get this. You don’t have the randomized control arm. And, so a small case series is just that. It’s just a small case series. They sometimes give us some insight of ‘yeah maybe there’s something going on here.’ And, then we would go to more formal observational studies. We look at group of patients who did or did not receive the drugs so now we have a contrasts and we try to match them up in certain ways and we adjust for differences and regression analyses. These are typical observational studies. And, maybe the first one looked like there might be some benefit. But quickly as people did larger and better designed observational studies, those too found no benefit and at the same time people were organizing randomized controlled trials which is our goal standard and is how we prove how a drug works or doesn’t work.
We think about a hierarchy of evidence from biologic plausibility to case series to poorly done observational to better done observational to randomized controlled trials to very large randomized trials or meta-analyses randomized trials. So, we worked our way through the hierarchy just over weeks---if not two or three months. And, as we got to the randomized trials (there’s been three or four randomized trials that have shown no benefit. Have these trials tried the drug at every dosage and in every subgroup of patient? No, but now we have a lot of data to suggest it doesn’t work.
So, in reality, the onus of proof of still on the people who still believe it works because all of the data---the best data---show that it doesn’t work. So, might it work? It’s possible. I wouldn’t say very possible. I’d say there’s a slim possibility that in certain subgroups at certain dosages, it’s possible it could work, but all of the best data is suggesting that it doesn’t work.
So, observational studies can be very useful. They kind of pointed us in a direction, but then as larger and better designed studies were conducted, it really argued against it. It’s an example of how kind of the information got out behind the science.
I think we point out in the commentary, that science is somewhat self-correcting. We look at something, we make some best guess. Initially, we weren’t sure masks were useful. But, overtime, we realized masks (are useful) and now, in our health system, the recommendation is to wear eye protection.
So, opinions evolve as the science evolves. We have to understand that. The infodemic has kind of gotten beyond the science and many points along the way---whether it’s about hydroxychloroquine or other therapeutics and just other observations.
Solomon, D.H., Bucala, R., Kaplan, M.J. and Nigrovic, P.A. (2020), The “Infodemic” of COVID‐19. Arthritis Rheumatol. Accepted Author Manuscript. doi:10.1002/art.41468