Bevindingen van de COVID-19 Global Rheumatology Alliance (C19-GRA) suggereren dat patiënten met reumatoïde artritis (RA) die rituximab of JAK-remmers gebruiken, een verhoogd risico hebben op een slechte uitkomst na een SARS-CoV-2-infectie, ten opzichte van patiënten die TNF-remmers gebruiken.
De studie, die werd gepresenteerd op het EULAR 2021 Virtual congres en tevens gepubliceerd in Annals of the Rheumatic Diseases, omvatte 2869 RA-patiënten (gemiddelde leeftijd 57 jaar, 81% vrouw) die werden behandeld met biologische of gerichte synthetische DMARD’s op het moment dat zij COVID-19 kregen en tussen maart 2020 en april 2021 in het C19-GRA-register werden opgenomen. Ongeveer de helft van de patiënten gebruikte gelijktijdig conventionele DMARD’s.
Jeffrey Sparks (Brigham and Women’s Hospital, Boston, Massachusetts, VS) en collega’s gebruikten een ordinale schaal om patiënten te categoriseren op basis van een reeks COVID-19-uitkomsten. Bij de meerderheid (78,6%) was geen ziekenhuisopname nodig; 4,8% werd zonder zuurstoftoediening opgenomen; 11,1% had zuurstof of beademing nodig en 5,5% overleed.
Van de 364 patiënten die rituximab gebruikten, werd 22,0% opgenomen met zuurstof of beademing, ten opzichte van 7,4% van de 1388 patiënten die TNF-remmers gebruikten, terwijl respectievelijk 14,8% en 2,6% overleed. Deze bevindingen vertaalden zich in een significant hoger risico op een ernstiger beloop van COVID-19 bij patiënten die rituximab versus TNF-remmers gebruikten in een multivariabel ordinaal logistisch regressiemodel, met een OR van 4,15.
Ook de 563 patiënten die JAK-remmers gebruikten hadden een significant hoger risico op een ernstiger beloop dan patienten die TNF-remmers gebruikten (OR 2,06). In totaal werd 15,3% van de met een JAK-remmer behandelde personen opgenomen in het ziekenhuis met zuurstof of beademing, terwijl 7,1% overleed.
Jeffrey Sparks en Zachary Wallace bespreken de mogelijkheid dat COVID-19 ernstiger verloopt bij patiënten met RA die worden behandeld met rituximab of JAK-remmers ten opzichte van TNF-remmers (8:06)
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Interview transcript
We performed our study among rheumatoid arthritis patients, all of whom had COVID-19 and all of which were being treated with either biologic or targeted synthetic DMARDs. So the real take home is that the medications patients are on at baseline, if they do develop COVID-19, this seems to affect their disease course. Some of these medications could put patients at increased risk of poor outcomes. In particular, rituximab and also JAK inhibitors, which is a novel finding in the study might put patients at risk for poor outcomes. Conversely, some of these medications might actually confer protective effects for bad outcomes. In particular, things like TNF inhibitors and interleukin 6 inhibitors. I think there were a few reasons why we decided to approach this study designed with what we did. One is that we all know there’s been a lot of data put out there since COVID was first recognized a year ago. And just an incredible amount, which has been really unbelievable. But it still has left a lot of uncertainty, especially in our space with how patients with rheumatic diseases do when they have COVID-19. And so we were in a unique position because of our work with the Global Rheumatology Alliance that we had the ability to use a very large registry with a very large cohort to ask questions that couldn’t necessarily be easily answered using other data sources. So one point was we wanted to address some of the ongoing uncertainty, especially with regard to the medications that Dr. Sparks mentioned, which hadn’t necessarily been well evaluated in other studies. The second is we wanted to expand on some of the prior observations that had been made primarily by focusing on patients with rheumatoid arthritis because a lot of the previous work had been done in more heterogeneous populations of patients with a variety of systemic rheumatic diseases. And so we thought that because we had a larger sample size, we’d be able to really hone in on patients with rheumatoid arthritis who had similar indications for treatment. And that would make some of our analysis a bit more robust. And then I think the third was we really wanted to just generate robust data that could really help inform management guidelines moving forward and strategies for mitigating risks in these patients who might be at higher risk for worse outcomes and are clearly concerned about that risk. So in this study, we used the COVID-19 Global Rheumatology Alliance, which I’m sure most people are familiar with. It’s a voluntary physician registry that really started at the very beginning of the pandemic. And for this study, we used all the data up until mid-April of 2021. So it’s a pretty contemporary data set. And as Dr. Wallace pointed out, a lot of the previous studies were performed among basically all rheumatic diseases. In this one we wanted to really hone in on just rheumatoid arthritis to try to make sure that some of the findings that we found were related to the drug and not related to the indication. So for that reason, we really restricted the patient sample to rheumatoid arthritis and to patients who were on biologic or targeted synthetic DMARDs at baseline at the moment they were infected with COVID-19. So I think just the study sample and obviously the large nature of it was a real novelty. The second thing we looked at were the outcomes. And unlike previous studies, we really looked at the entire breadth of outcomes related to COVID-19. A lot of previous studies had only looked at a particular single outcome. So we looked at whether patients were hospitalized, whether they received oxygen or were ventilated in a hospital, and also whether they died. And really came up with this COVID-19 ordinal scale that was modeled after clinical trials scales that were doing similarly. So this way we got to really look at all the granularity of the data and also look at each of these outcomes separately. So in this way we were able to really hone in on whether the drugs might alter the course of COVID-19. I think we have two main findings and that was that patients who receive rituximab especially, have worse outcomes overall. When I say worse outcomes as Dr. Sparks mentioned, we use this ordinal scale. So it’s to say that compared to someone who isn’t on rituximab, who’s on one of these other biologics or targeted synthetic DMARDs that we study, patients on rituximab would be one level higher or one degree worse than the- their comparator patients. And so that was one observation. And the other that was particularly novel was that we observed that patients who use JAK inhibitors at baseline also did worse. This is perhaps a little surprising because there’s also been trials showing that patients who received baricitinib to treat COVID did better in some way. And so it’s a little counterintuitive. But it may be that being on these medications prior to or at the time of infection is different than using this medication like baricitinib once you are sick and you have this sort of hyper inflammatory response that’s characteristic of severe COVID-19. And so I think there are some areas there that deserve further study and clarification. But those arr our two main take-home findings. We certainly wonder about how this finding with rituximab extends to other CD20 inhibitors and other indications. So I would suspect that this would probably affect other patients and obviously, rituximab is used for many other indications and there’s other CD20 inhibitors. So I think that would be a logical next step and really how to mitigate the risk. Now that we know it’s there, what can we do? And the obvious thing is vaccination. And certainly, we encourage that. But unfortunately with rituximab, it does seem that the vaccine is much less likely to work successfully.
Sparks en collega’s vonden geen significante associatie tussen behandeling met abatacept of IL-6-remmers en de ernst van COVID-19.
Ze merken op dat deze bevindingen consistent bleven in sensitiviteitsanalyses waarbij patiënten met interstitiële longziekten of kanker (die mogelijk meer kans hebben om rituximab te krijgen) werden geëxcludeerd, en wanneer de analyse werd beperkt tot patiënten uit de VS en er werd gecorrigeerd voor ras.
“Onze observaties, die gebruik maken van de grootste steekproef van personen met RA en COVID-19 die tot nu toe is verzameld, […] bevestigen bevindingen uit eerdere studies die een verband suggereren tussen B-celdepletie op baseline en slechtere COVID-19-uitkomsten bij mensen met reumatische aandoeningen en multipele sclerose”, schrijven de onderzoekers.
In een gesprek met medwireNews zei mede-onderzoeker Zachary Wallace (Harvard Medical School, Boston, Massachusetts, VS) dat er twee redenen zijn waarom deze associatie tussen rituximab en een slechtere uitkomst mogelijk wordt gezien. Hij legde uit dat rituximab leidt tot depletie van perifere B-cellen, wat kan interfereren met het vermogen om neutraliserende antilichamen te vormen waarvan wordt gedacht dat ze belangrijk zijn voor het verkrijgen van initiële controle over de infectie. Ten tweede: depletie van perifere B-cellen kan ook van invloed zijn op de T-celrespons die een patiënt normaal gesproken zou hebben op COVID-19, omdat B- en T-cellen met elkaar interacteren, aldus Wallace.
De onderzoekers concluderen dat RA-patiënten die rituximab of JAK-remmers gebruiken prioriteit moeten krijgen voor aan COVID-19 gerelateerde risicobeperkende strategieën, waaronder vaccinatie en social distancing.
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