ACR: Suspend immunosuppressants, select DMARDs in rheumatic patients with COVID-19
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Patients with rheumatic diseases who test positive for COVID-19 should temporarily discontinue all treatments with sulfasalazine, methotrexate, leflunomide, immunosuppressants, non-IL-6 biologics and JAK inhibitors, according to new recommendations released by the American College of Rheumatology’s COVID-19 Clinical Guidance Task Force.
Approved by the ACR Board of Directors on April 11, the “COVID-19 Clinical Guidance for Patients with Rheumatic Diseases” draft summary states that patients with rheumatic diseases who have been confirmed to have COVID-19 may continue with anti-malarial therapies — namely hydroxychloroquine and chloroquine — and, in select circumstances, IL-6 inhibitors. The organization’s full manuscript is pending journal peer review.
“[Our] Task Force is comprised of experts in infectious disease and in biologic and non-biologic therapies for rheumatic disease,” ACR President Ellen M. Gravallese, MD, told Healio Rheumatology. “Members reviewed and analyzed the existing literature to develop this ‘living document’ using a well-established method of consensus building.”
“However, research into the treatment of patients who are taking medications for rheumatic disease and who contract COVID-19 is ongoing in many institutions and other settings,” she added. “Task Force members will continue to evaluate new data as results of this research becomes available and we will be posting updated versions of this guidance document with date and time stamps as critical new data emerges.”
The draft guidance was developed by a North American task force of 10 rheumatologists and four infectious disease specialists who convened on March 26, 2020. Members collated clinical questions and produced an evidence report based on current knowledge.
According to the ACR, there were two rounds of asynchronous, anonymous voting via email and two webinars attended by the entire panel. Members voted on agreement with draft statements, with the results used to determine “low,” “medium” and “high” consensus for each item. Only items determined to have moderate or high levels of consensus were included in the draft guidance.
The draft’s statements and guidelines include the following general recommendations for patients with rheumatic disease:
- Patients with rheumatic disease appear to be at risk for poor outcomes from COVID-19, primarily due to general risk factors such as age and comorbidity.
- In addition to following all general COVID-19 preventive measures, patients with rheumatic disease and their providers should discuss ways to reduce the number of health care encounters and potential exposure to coronavirus, including monitoring blood work less frequently, using telehealth and increasing the time between doses of intravenous medications.
- For ongoing treatment of stable patients with no coronavirus exposure or infection, hydroxychloroquine or chloroquine, sulfasalazine, methotrexate, leflunomide, immunosuppressants — such as tacrolimus, cyclosporine, mycophenolate mofetil and azathioprine — biologics, JAK inhibitors and NSAIDs may be continued.
- Stable patients without COVID-19 exposure or infection may still receive denosumab for osteoporosis, but the time between doses may be extended to as long as 8 months, to minimize health care encounters and, if necessary, due to limited access to infusions.
- Patients with stable disease who have been exposed to coronavirus but do not have a known infection may continue with hydroxychloroquine, sulfasalazine and NSAIDs, but immunosuppressants, non-IL-6 biologics and JAK inhibitors should be discontinued temporarily, pending a negative test result COVID-19 or after 2 weeks without infection symptoms.
- IL-6 inhibitors may also be continued, in select circumstances, among patients with stable rheumatic disease who have been exposed to coronavirus but have not yet tested positive for COVID-19.
The full list of guidance statements can be found here.
“These statements are not intended to replace clinical judgment,” noted the guideline document. “Modifications made to treatment plans, particularly in complex rheumatic disease patients, are highly disease-, patient-, geography- and time-specific and, therefore, must be individualized as part of a shared decision-making process. This guidance is provided as part of a ‘living document’, recognizing rapidly evolving evidence and the anticipated need for frequent updates as such evidence becomes available.” – by Jason Laday
Perspective
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David A. McLain, MD, FACP, FACR
The ACR’s North American Task Force recently provided guidance to rheumatologists during the COVID-19 crisis, recommending that we continue to treat rheumatic diseases as we had treated them prior to the COVID-19 pandemic, including the use of immunosuppressants.
Following COVID-19 exposure, the panel recommended continuing hydroxychloroquine, sulfasalazine and NSAIDs and perhaps IL-6 biologics; however, they recommended holding immunosuppressants, non-IL-6 biologics, and JAKs until the COVID-19 test is negative or after two asymptomatic weeks, if no test is available.
The panel was uncertain about temporarily stopping methotrexate and leflunomide. As we know, leflunomide has a long half-life and would require cholestyramine elimination over 11 days to clear it out of the system. For patients who test positive, all medications (minus NSAIDs and IL-6 inhibitors) are to be stopped with the exception of HCQ, per the panel. NSAIDs are to be stopped only if there are severe symptoms, and IL-6 inhibitors could be continued with shared decision-making.
Hydroxychloroquine and chloroquine have been drugs of contention, with positive signals from China, Japan, France and the U.S., yet negative signals from the U.S. and Brazil. No clinical have yet been published, however, a recent retrospective, non-randomized analysis of Veterans Affairs patients reported an increased risk of death with the HCQ and HCQ/azithromycin treatments than with usual supportive care. Critics noted that more HCQ and HCQ/azithromycin patients were intubated and exhibited lymphopenia than the non-treated group, which has been linked to higher mortality risk.
Additionally, critics say this is too late to expect an effect, as a recent Nature article reported, HCQ works on endocytosis of the virus into the cell. Surprisingly, the 30% of untreated group (usual care) received azithromycin alone, which has been postulated to have antiviral effects. The authors of the VA study noted that more severe patients were likely to be in one of the HCQ groups and selection bias could not be ruled out.
On the other hand, unlike doses used in rheumatology, the COVID-19 patients received higher doses and usually a loading dose. Antiviral effects of HCQ have been found to be in the 4.5 μM to 17μM range in vitro. Rheumatology patients have much lower peak serum HCQ drug concentrations (~1μM). This markedly higher serum concentration would likely lead to increased adverse effects. A clinical trial in Brazil testing a high-dose of chloroquine (1200 mg/d) to treat hospitalized patients with COVID-19 was halted prematurely due to increased deaths in the high-dose group.
Another recent finding has been the discovery of myocarditis and cardiomyopathy in COVID-19 patients, making a drug that can increase Q-T intervals and has been itself associated with cardiomyopathy, an even bigger concern. The FDA has issued a warning with regard to the cardiac effects of HCQ and chloroquine and their use in COVID-19. There is an obvious need to wait for ongoing prospective, randomized, controlled trials before widespread use of HCQ or chloroquine in COVID-19 patients, particularly those who are critically ill.
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