Rheumatologists may be in a unique position to consult and help in the management of patients with severe disease caused by COVID-19, said experts.
"Some of the drugs that appear promising for patients who are severely ill with COVID-19 are those in which rheumatologists have extensive experience, such as hydroxychloroquine or tocilizumab [Actemra]," said Theresa Wampler Muskardin, MD, of NYU Langone Health in New York City.
It appears that in patients who are having the worst outcomes with COVID-19 infections, the immune system itself may be the culprit, with developments similar to hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS), Muskardin explained. In these conditions, the immune system becomes overactive with excessive production of T cells and macrophages, resulting in a "cytokine storm" with a variety of proinflammatory cytokines such as interleukins (IL)-1, 6, 12, and 18 being released. Fatalities are not uncommon.
Patients with certain rheumatic diseases, particularly those with systemic juvenile idiopathic arthritis or adult-onset Still's disease, are most often affected by those potentially catastrophic events. Accordingly, many rheumatologists are experienced in diagnosing and managing HLH and MAS, according to Muskardin, who is a pediatric and adult rheumatologist.
"There is a role for us in educating our colleagues on recognizing impending secondary HLH or MAS and helping to select patients who may benefit from immunologic treatments," she told 鶹ý in an interview.
"This is an opportunity for us to have conversations with our intensivists and people on the front lines of caring for these patients and to educate them on recognizing the subset of patients who may have impending HLH or MAS and those in whom we should be intervening," she said.
Risks and Questions
Patients with rheumatic and autoimmune diseases are at increased risk of developing severe manifestations of COVID-19 coronavirus, according to Mary K. Crow, MD, who is chief of rheumatology at the Hospital for Special Surgery in New York City. "There aren't a lot of data yet, but we are extrapolating that assumption from what we understand both about the rheumatic and immune-mediated diseases as well as the effect of immunosuppressive medications," she said.
"But we really need to capture the data to understand who is at greatest risk," said Muskardin. "There is already an initiative underway by the , an international case reporting registry that will allow rheumatologists to submit dis-identified data about their patients who acquire COVID-19," she said.
Many patients are asking if they should change or stop their immune-modulating treatments if they develop the infection or even to prevent the infection, and experts agree that no changes should be made without consulting a rheumatologist. "There are always opportunities to modify medical regimens -- doctors and patients do that together all the time -- switching one drug for another or adjusting the dose," Crow said.
"Should rheumatic patients get this infection, every aspect of their care, from the COVID-19 point of view and the rheumatic disease point of view, would be up for discussion with the physicians taking care of them," she added.
"Providers should follow their current practice for stopping therapy during an episode of infection. For example, a patient on a medication that primarily affects T cells might warrant stopping treatment during the infection," said Muskardin.
But it also depends on the specific immune-mediated disease, she cautioned. "If that medication is managing what is otherwise a life-threatening condition like a systemic vasculitis, the decision is less straightforward."
With regard to specific drugs, Michael George, MD, of the University of Pennsylvania in Philadelphia, offered this advice: "We do know that Plaquenil [hydroxychloroquine] and chloroquine are not typically associated with an increased risk of infections. Sulfasalazine is also not associated with increased infection risk." Risks with methotrexate are also low, but decisions on stopping during infection are done on a case-by-case basis, he noted.
"Biologics and JAK inhibitors have a somewhat greater risk of infection, and many physicians would recommend stopping these if someone develops COVID-19, although we don't have much data to guide us," he said.
Both Crow and Muskardin emphasized that it's of utmost concern that patients with rheumatic disease follow the general CDC advice on social distancing, handwashing, and working from home. Whenever possible, patients also could rely on telemedicine visits and patient portals, Muskardin noted, adding that patients should have a month's supply of medication on hand and should be up to date on vaccines, particularly for conditions that might confuse the clinical picture such as influenza, pneumonia, and pertussis.
Targeting IL-6
Regeneron Pharmaceuticals and Sanofi recently announced that they have embarked on a U.S. clinical program testing sarilumab (Kevzara) as a novel treatment for severe COVID-19 infection.
Sarilumab is an IL-6 receptor antagonist that was approved for use in rheumatoid arthritis in 2017. The rationale for using this agent for COVID-19 coronavirus infection is that IL-6 may play a role in exacerbating the excessive inflammatory response in the lungs of severely ill patients, according to the companies.
The phase II/III double-blind trial has begun enrolling patients from 16 centers and ultimately expects to include 400 patients. The trial will randomize patients to receive high- or low-dose sarilumab or placebo plus usual supportive care. The primary endpoint of the phase II component of the study will be reduction of fever, while a secondary endpoint is the need for supplemental oxygen.
The phase III portion will evaluate longer-term outcomes such as reducing the need for hospitalization and mechanical ventilation, as well as mortality.
Supporting the concept of using IL-6 inhibition in severe COVID-19 infection were the results of an earlier study conducted in China that included 21 patients who were treated with another IL-6 inhibitor, tocilizumab (Actemra).
In that study, which was not peer-reviewed but was published on the ChinaXiv preprint server, 19 of the COVID-19 patients were discharged from the hospital after a mean of 13.5 days and are recovering well, according to Xiaoling Xu, MD, from the respiratory and critical care medicine department at the First Affiliated Hospital of the University of Science and Technology in Anhui, and colleagues.
The authors noted that investigations of the earlier zoonotic coronavirus, referred to as SARS, showed that a cytokine storm occurred, with the release of proinflammatory cytokines IL-6 and IL-12, plus tumor necrosis factor-alpha. Moreover, in another coronavirus infection known as MERS, upregulation of genes regulating IL-6, IL-1β, and IL-8 was observed.
"In our previous research, after analyzing the immune characteristics of patients with COVID-19, we found that aberrant pathogenic T cells and inflammatory monocytes are rapidly activated and then produce a large number of cytokines and induce an inflammatory storm," the researchers wrote. And because IL-6 was clearly implicated, "we suggested that IL-6 might play a key role in the cytokine storm and that interfering with IL-6 might be a potential therapy for severe and critical COVID-19."
The patients enrolled in the trial averaged 56.8 years of age, ranging from 25 to 88, and most were men. Each patient had received a week of standard treatment before receiving tocilizumab. Fever was present in all, dry cough in two-thirds, and fatigue or dyspnea in one-quarter. Twenty patients required oxygen therapy.
All patients had increased levels of C-reactive protein, at a mean of 75 mg/L, and lymphocyte decreases were observed in 85%.
Chest CT scans were abnormal in all patients, typically involving ground-glass opacities and focal consolidation, particularly in the subpleural region.
Within a day of receiving tocilizumab, all patients showed normalization of their temperature. Peripheral oxygen saturation also improved rapidly, and 15 of the patients had a decrease in their requirement for oxygen. Normalization of lymphocyte levels was seen in 10 patients, and C-reactive protein levels also were reduced to normal levels within 5 days. Post-treatment CT scans showed clearance of lesions in 19 patients.
One dose of tocilizumab was given to 18 patients, and an additional dose was given to three patients when fever persisted for 12 hours.
Beginning in early March 2020, China permitted the use of tocilizumab for patients who have potentially serious pulmonary damage and high levels of IL-6, although the drug has not been officially approved by China's National Medical Product Administration.
Other Challenges
Because some treatments such as hydroxychloroquine and the IL-6 inhibitors are showing some promise, there are now shortages of these medications, according to Muskardin. "These are medications that some of our patients rely on to treat their inflammatory disease, so we're considering alternatives whenever possible and urging pharmaceutical companies to continue to provide them to mitigate drug shortages," she said.
"I think that this is an extremely serious situation, not only for our patients but also for healthcare providers, particularly the nurses and doctors who are working in the ER and the ICU. Everyone needs to be extremely careful and protect themselves as much as is feasible," Crow warned.