Study Title

Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance Physician Registry

Original paper: Associations of baseline use of biologic or targeted synthetic DMARDs with COVID-19 severity in rheumatoid arthritis: Results from the COVID-19 Global Rheumatology Alliance physician registry

Authors of original paper

Jeffrey A Sparks MD MMSc, Zachary S Wallace MD MSc, Philip C Robinson MBChB PhD, Pedro M Machado MD PhD, Jinoos Yazdany MD MPH, et al.

Lay summary contributors

Nadine Lalonde, Richard Howard, Tarin T Moni, Mithu Maheswaranathan, Jeffrey Sparks, Zachary Wallace, and Jean Liew

Preamble/Background

The ongoing pandemic has had a significant impact on people suffering from rheumatic diseases. The novel coronavirus has challenged the scientific community to determine appropriate treatment, control, and prevention strategies. Initial research focused on the general population, leaving those suffering from rheumatic diseases to question how all aspects of the coronavirus pandemic affects them and their health. This study observes COVID-19 illness outcomes related to use of five classes of medications, or disease-modifying anti-rheumatic drugs (DMARDs), in patients with Rheumatoid Arthritis. This study also tries to determine if DMARDs may be effective as potential treatments for COVID-19.

Why is this important?

Research regarding COVID-19 has mainly been focused on the general population. Rheumatology patients and their caregivers need to understand their vulnerability with COVID-19 to help with treatment and prevention efforts. 

b/tsDMARDs is an abbreviation for biologic or targeted synthetic Disease-Modifying Anti-Rheumatic Drugs. They are produced from living organisms or contain components of living organisms and include vaccines, blood, blood components, cells, allergens, genes, tissues, and recombinant proteins. They are used in RA to help reduce inflammation and tissue damage.

Examples of b/tsDMARDs used for RA: Adalimumab (Humira), Tocilizumab (Actemra), Tofacitinib (Xeljanz), Rituximab (Rituxan), Abatacept (Orencia)

Objective

To investigate the association of the severity of COVID-19 illness outcomes in patients with RA, who were using different b/tsDMARDs at the time of COVID-19 diagnosis.

What was done?

The study collected information for 2,869 RA patients who were taking medications from five b/tsDMARD classes at the time of COVID-19 diagnosis (confirmed and presumptive cases). The five classes reviewed were: (1) Rituximab (RTX), (2) Abatacept (ABA), (3) Interleukin-6 inhibitors (IL-6), (4) Janus kinase inhibitors (JAKi), and (5) Tumor necrosis factor inhibitor (TNFi).

The study reported various patient statistics for the five b/tsDMARD classes and also compared four DMARD classes to a reference class, Tumor necrosis factor inhibitors [TNFi]. TNFi users were selected as the reference group since TNF inhibitors are the most frequently used class of b/tsDMARDs in RA. The purpose was to evaluate and understand the relative risk for severe COVID-19 illness outcomes (i.e., better or worse than TNFi). Various statistical analyses calculated the association between variables and the reliability of the results. 

*At the time of the study, NO participants had received COVID-19 vaccination. 

The severity scale for COVID-19 illness was categorized as requiring: 

1. No hospitalization, 
2. Hospitalization without oxygenation, 
3. Hospitalization with any oxygenation or mechanical ventilation, and 
4. Death. 

*Patients with multiple outcomes were counted according to the worst outcome experienced.

What was found?

The main findings of the study include:

1. 78.6% of RA patients taking b/tsDMARDs at the time of COVID-19 diagnosis required NO hospitalization.
2. Patients had significantly worse COVID-19 illness outcomes if they were taking Rituximab (RTX) or Janus kinase inhibitors (JAKi) as compared to those taking Tumor necrosis factor inhibitors (TNFi). Those taking Abatacept (ABA) or Interleukin-6 inhibitors (IL-6i) showed NO worse outcomes than those using TNFi.

What does this mean?

1. This study, using the largest sample of individuals with RA and COVID-19 to date, confirmed findings from prior studies suggesting an association between the use of B cell depleting therapies (RTX) and worse COVID-19 outcomes. 
2. These results inform physicians regarding extra risk factors for people taking b/tsDMARDs when diagnosed with COVID-19 assisting physicians to provide improved treatment plans.
3. The association between RTX and JAKi with poor COVID-19 outcomes, indicates that priority for vaccination efforts should include consideration for people taking RTX and JAKi.
4. Other risk-mitigating practices (i.e., mask wearing, hand and surface washing, social distancing) remain critical for COVID-19 control for people taking b/tsDMARDs, especially RTX and JAKi. 
5. IL-6 inhibitors (including tocilizumab) have been used as a COVID-19 treatment but in this study, there was no association found for improved COVID-19 illness outcomes compared to TNFi. 

 

The following factors were not able to be considered in this study and may have affected the results

1. Based on clinical trial data, Tofacitinib and Baricitinib, both JAKi treatments, may have some benefit for time to recovery in patients with more severe COVID-19. In this study, worse outcomes were associated in RA patients using JAKi at the time of COVID-19 diagnosis. The timing of exposure to JAKi before and during the COVID-19 disease course (early vs later in disease course) may be responsible for the differences between this study and the clinical trials for COVID-19 treatment. 
2. There may be relevant differences in COVID-19 outcomes depending on the type of JAKi used given that JAK inhibitors target different JAKs. 
3. While the overall analysis found no association of Abatacept with increased COVID-19 illness outcome severity, there was a statistically significant association seen using one of the statistical analyses. Further research is required, such as a study that had a larger number of people taking Abatacept.
4. While the data results were validated using various statistical analyses to confirm the results, it is possible that results were affected by factors not known at the time or considered in this study.