My life as a rheumatologist changed significantly just before the turn of the century. The FDA announced on November 2, 1998 that it had approved Enbrel (etanercept) for treatment of rheumatoid arthritis. Because it and similar compounds that followed were made in a living system rather than a test tube, they were dubbed “biologics”. This particular stuff was engineered to block the interaction of tumor necrosis factor (TNF) with its receptor. TNF has little to do with killing cancer, something it seemed to do in the test tube when first isolated in the 60s. But it has a major role in signalling it’s time to kick up the inflammatory response. So my poor rheumatoids finally had something that actually worked. Visits turned away from which joints to inject this time and how’s your Vicodin holding up towards more pleasant conversations about what are you doing with your newly won mobility, urging more, even exercise! Granted, it was hugely effective in only about 20% who got it, they did better if they kept on methotrexate, too and it was hard to get the steroids totally out of the mix. It did dampen response to infections, particularly weird old ones, so we had to stay vigilant for TB and histoplasmosis (mostly from pigeons). Enbrel was joined by other compounds with a similar mechanism of action: Humira (adalimumab) and Remicade (infliximab). Remicade is an i.v. infusion and the others you inject yourself every one or two weeks. The guys and gals in the lab kept at the exercise of blocking molecules that drove rheumatoid inflammation and today’s rheumatologist has a host of arrows in his quiver, with several different types of poison on their tip. Of those 1.3 million RA patients and the 1 million with psoriatic arthritis, most who take a biologic are on Enbrel, Humira or Remicade. TNF blockade helps in some other autoimmune diseases, like Crohn’s, ulcerative colitis, and plain old psoriasis, and a smattering of other oddball skin and eye conditions. But most of it goes to arthritis patients. U.S. sales for the trio in 2019 were $5.05 billion, $19.9 billion, and $3.2 billion, respectively. These numbers are expected to decline steadily now that it’s been over 20 years since their release. The FDA figured out several years ago how to certify that some other company’s off-patent version is just as good, calling such winners “biosimilars”. And they’re appearing.
So treating immune mediated arthritis is much more satisfying than it was in the bad old 20th century. Just keep that eye out for infection, dontcha know. Then, whether it was the Wuhan Lab or some bat at the wet market, a Mr. Corona emerged just slightly different from his ancestors, and here we are nearly 6 months later stuck at home, wearing masks and keeping 6 feet from each other, still piling up bodies, blessedly less all the time. As the thing started to rev up in February, my colleagues who are still practicing got spooked. Some of our patients were landing on the COVID ward. We were being asked how to use one of our potent biologics, the interleukin 6 inhibitor Actemra (tocilizumab), in COVID patients with the most horrible lung disease, as the Chinese had reported it to be helpful. Those who could recollect the 1918 flu pandemic, or had read about it, knew that what killed the lungs in these viral infections was the exuberant immune response of the patient, not the virus itself.
So that eye out for infection was getting nearly blinded by Mr. Corona’s light. Many of my colleagues worked to taper patients off their biologics. Realizing this was entirely new and very scary ground, rheumatologists around the world began carefully cataloguing the particulars of each of “our” patients who contracted COVID-19. The COVID-19 Global Rheumatology Alliance https://rheum-covid.org/ has collected over 1800 cases as of last week and at last week’s “State of the Art”(SOTA) meeting, they reported some of their findings. I’ve pasted in the Rheumatology News synopsis below.
The biggest shock was that patients on anti-TNF agents were 60% less likely to be hospitalized after contracting COVID, compared to others not receiving such agents. The drug that used to be the biggest gun against RA, prednisone, cut the other way. Patients on the equivalent of 10 mg/day of prednisone or more were at a 105% increased risk for hospitalization, compared with those not on corticosteroids after adjustment for age, comorbid conditions, and rheumatic disease severity.
I expect that there will be more than a few rheumatologists quickly contacting their patients currently kept away from biologics. It’ll be interesting to see what else emerges as this registry grows and continues to be mined for associations and correlations.
Oh, and all those patients of ours on Plaquenil? No difference one way or the other. But there’s no way with the data as collected to tell whether Plaquenil is effective as prophylaxis, as our President is taking it (https://wordpress.com/block-editor/post/theviewfromharbal.com/509). If you’re a patient who happens to be on Plaquenil, you get exposed to Mr. Corona and he doesn’t set up shop, you don’t even show up in the registry, as that’s only for infected patients. That’ll take a different sort of study. I’m still taking it, with a zinc chaser, if I’m ever thrown into the COVID wars,
Heres the story:
TNF inhibitors may dampen COVID-19 severity
Publish date: May 19, 2020 By Bruce Jancin
REPORTING FROM SOTA 2020
Patients on a tumor necrosis factor inhibitor for their rheumatic disease when they became infected with COVID-19 were markedly less likely to subsequently require hospitalization, according to intriguing early evidence from the COVID-19 Global Rheumatology Alliance Registry
Dr. Jinoos Yazdany
On the other hand, those registry patients who were on 10 mg of prednisone or more daily when they got infected were more than twice as likely to be hospitalized than were those who were not on corticosteroids, even after controlling for the severity of their rheumatic disease and other potential confounders, Jinoos Yazdany, MD <https://profiles.ucsf.edu/jinoos.yazdany> , reported at the virtual edition of the American College of Rheumatology’s 2020 State-of-the-Art Clinical Symposium.
“We saw a signal with moderate to high-dose steroids. I think it’s something we’re going to have to keep an eye out on as more data come in,” said Dr. Yazdany, professor of medicine at the University of California, San Francisco, and chief of rheumatology at San Francisco General Hospital.
The global registry launched on March 24, 2020, and was quickly embraced by rheumatologists from around the world. By May 12, the registry included more than 1,300 patients with a range of rheumatic diseases, all with confirmed COVID-19 infection as a requisite for enrollment; the cases were submitted by more than 300 rheumatologists in 40 countries. The registry is supported by the ACR and European League Against Rheumatism.
Dr. Yazdany, a member of the registry steering committee, described the project’s two main goals: To learn the outcomes of COVID-19–infected patients with various rheumatic diseases and to make inferences regarding the impact of the immunosuppressive and antimalarial medications widely prescribed by rheumatologists.
She presented soon-to-be-published data on the characteristics and disposition of the first 600 patients, 46% of whom were hospitalized and 9% died. A caveat regarding the registry, she noted, is that these are observational data and thus potentially subject to unrecognized confounders. Also, the registry population is skewed toward the sicker end of the COVID-19 disease spectrum because while all participants have confirmed infection, testing for the infection has been notoriously uneven. Many people are infected asymptomatically and thus may not undergo testing even where readily available.
Early key findings from registry
The risk factors for more severe infection resulting in hospitalization in patients with rheumatic diseases are by and large the same drivers described in the general population: older age and comorbid conditions including diabetes, hypertension, cardiovascular disease, obesity, chronic kidney disease, and lung disease. Notably, however, patients on the equivalent of 10 mg/day of prednisone or more were at a 105% increased risk for hospitalization, compared with those not on corticosteroids after adjustment for age, comorbid conditions, and rheumatic disease severity.
Patients on a background tumor necrosis factor (TNF) inhibitor had an adjusted 60% reduction in risk of hospitalization. This apparent protective effect against more severe COVID-19 disease is mechanistically plausible: In animal studies, being on a TNF inhibitor has been associated with less severe infection following exposure to influenza virus, Dr. Yazdany observed.
COVID-infected patients on any biologic disease-modifying antirheumatic drug had a 54% decreased risk of hospitalization. However, in this early analysis, the study was sufficiently powered only to specifically assess the impact of TNF inhibitors, since those agents were by far the most commonly used biologics. As the registry grows, it will be possible to analyze the impact of other antirheumatic medications.
Being on hydroxychloroquine or other antimalarials at the time of COVID-19 infection had no impact on hospitalization.
The only rheumatic disease diagnosis with an odds of hospitalization significantly different from that of RA patients was systemic lupus erythematosus (SLE). Lupus patients were at 80% increased risk of hospitalization. Although this was a statistically significant difference, Dr. Yazdany cautioned against making too much of it because of the strong potential for unmeasured confounding. In particular, lupus patients as a group are known to rate on the lower end of measures of social determinants of health, a status that is an established major risk factor for COVID-19 disease.
“A strength of the global registry has been that it provides timely data that’s been very helpful for rheumatologists to rapidly dispel misinformation that has been spread about hydroxychloroquine, especially statements about lupus patients not getting COVID-19. We know from these data that’s not true,” she said.
Being on background NSAIDs at the time of SARS-CoV-2 infection was not associated with increased risk of hospitalization; in fact, NSAID users were 36% less likely to be hospitalized for their COVID-19 disease, although this difference didn’t reach statistical significance.
Dr. Yazdany urged her fellow rheumatologists to enter their cases on the registry website: rheum- covid.org <https://rheum-covid.org/> . There they can also join the registry mailing list and receive weekly updates.