Plain Language Summary of Factors Associated with COVID-19 Related Death for People with Rheumatic Disease

Title: Factors Associated with COVID-19-related Death in People with Rheumatic Diseases: Results from the COVID-19 Global Rheumatology Alliance physician-reported registry

Authors: Strangfeld A, Schäfer M, Gianfrancesco M, et al.

Summary Contributors: Richard Howard, Bruce Miller, Mithu Maheswaranathan, Jinoos Yazdany, Jean Liew, Pedro Machado, on behalf of the lay summaries sub-group

LAY SUMMARY

Preamble:

Information about the outcome of people with COVID-19 who have rheumatic disease is limited, particularly with regards to COVID-19 related death. There is concern that certain characteristics such as the immune dysfunction underlying some rheumatic diseases, the medications used to treat these conditions that can interfere with the immune system, and the potential organ (e.g., kidney, lung, heart) manifestations of some diseases, may put people with rheumatic disease at greater risk for severe outcomes from COVID-19.

This study aimed to look for factors specific to people living with rheumatic diseases that are associated with COVID-19 related death. Type of rheumatic disease, rheumatic disease activity, and medications were analyzed along with age, sex, smoking status, cardiovascular disease, and other comorbidities.

What was done?

The Global Rheumatology Alliance (C19-GRA) physician registry is a survey into which physicians may enter data regarding their rheumatology patients with COVID-19. C19-GRA data from March 24 to July 1, 2020 were extracted and analyzed. The data included 3,729 patients, 390 (10.5%) of whom died. Details of each patient such as age, sex, type of rheumatic disease, rheumatic disease severity, background medical conditions, and medications prior to COVID-19 were identified. Appropriate statistical tests were used to evaluate risk factors. Patient consent was not required for the study.

What was found?

As in the general population, older age, male sex, cardiovascular and chronic lung disease were associated with COVID-19 related death.

Rheumatic disease-specific factors were also associated with COVID-19 related-death. Specifically, moderate or high disease activity was associated with 2-fold increased risk of death.

When compared to taking methotrexate alone, increased risk of death was found with certain medications: immunosuppressants (described below), rituximab, sulfasalazine, and higher doses of glucocorticoids (prednisolone equivalent >= 10mg/day). However, when compared to taking methotrexate alone, no increased risk of death was found with other immunomodulators (described below) — including most commonly used drugs for rheumatic diseases. Methotrexate was chosen as the medication-related comparator group because it is commonly used and considered an “anchor drug” for multiple rheumatic diseases, and it represented the largest medication category in this study. Comparison of rheumatology patients taking antirheumatic treatments to those not taking antirheumatic treatments was not adopted in this study due to the variety of conditions, more complicated histories, and older age of those not on treatments.

Note, immunosuppressants are different from immunomodulators.  Immunomodulators include medications used most frequently to treat rheumatic disease, such as: methotrexate, leflunomide (Arava), antimalarials, Abatacept (Orencia), belimumab (Benlysta), and drugs in the categories of: TNF inhibitors, IL-17/IL-23/IL-12+23 inhibitors, JAK inhibitors, and IL-6 inhibitors. Specific drugs in each category are listed at the end of this article.  The most commonly used disease-modifying antirheumatic drugs (DMARDs) are considered immunomodulatory.  Immunosuppressants, in contrast, are used less frequently in rheumatic disease and include: azathioprine, mycophenolate mofetil (CellCept), cyclosporine, cyclophosphamide (Cytoxan), and tacrolimus.

What does this mean?

People with moderate or high disease activity were more likely to die from COVID-19 than those with low disease activity or people who were in remission. Most medications used by people with rheumatic diseases (including most DMARDS) were not associated with higher death.  Medications associated with higher risk included rituximab, sulfasalazine, prednisone-equivalent dosages >= 10mg/day, and a mixed group of other immunosuppressive drugs. Among rheumatic diseases, the only difference in death rates were mild reductions among non-inflammatory joint diseases/non-connective tissue diseases/non-vasculitis.

Tables:

Any given study can only estimate the risk of death from COVID-19 along a range of possibilities, representing a degree of mathematical fuzziness. When comparing groups in a study, the range’s mathematical fuzziness is affected by the number of study participants in each compared group. Often the mathematics require a group to be chosen as a comparator to which other groups are compared.

This study calculated the range of risk of death from COVID-19 associated with different rheumatic diseases when compared relative to rheumatoid arthritis. Results appear in the table below:

Disease	Estimated COVID-19 Risk of Death Compared to Rheumatoid Arthritis
Rheumatoid arthritis	1.0 (comparator group)
Spondyloarthritis	0.34 – 1.54
Psoriatic arthritis	0.53 – 1.07
Vasculitis	0.60 – 1.08
Systemic lupus erythematosus	0.70 – 2.04
Other connective tissue diseases	0.58 – 0.97
Other inflammatory arthritis or non-systemic juvenile idiopathic arthritis	0.46 – 1.34
Other rheumatic diseases (not inflammatory joint diseases / not connective tissue diseases / not vasculitis)	0.35 – 0.73

 

The range of risk of death from COVID-19 associated with medications used to treat rheumatoid diseases are estimated relative to use of methotrexate alone. Results appear in the table below:

Medication	Estimated COVID-19 Risk of Death Compared to Methotrexate Alone
Methotrexate	1.0 (comparator group)
IL-17/IL-23/IL-12+23 inhibitors**	0.03 – 2.03
Belimumab (Benlysta)	0.19 – 2.68
IL-6 inhibitors**	0.38 – 1.84
TNF inhibitors**	0.52 – 1.36
Antimalarials, e.g., hydroxychloroquine (Plaquenil)	0.66 – 1.48
Abatacept (Orencia)	0.61 – 2.34
Leflunomide (Arava)	0.90 – 2.70
JAK inhibitors**	0.91 – 2.09
No DMARD therapy*	1.48 – 3.01
Immunosuppressants (examples in text)	1.43 – 3.46
Sulfasalazine	1.66 – 7.78
Rituximab (Rituxan)	2.32 – 7.03

• Abbreviations: DMARD = disease-modifying antirheumatic drug, such as methotrexate, leflunomide (Arava), tofacitinib (Xeljanz), apremilast (Otezla).

** Medication Names by Category:

Some medications in this document were referenced by classification, such as “TNF inhibitors.”  A list of examples for each class is given below:

• TNF inhibitors:
  • Adalimumab (Humira)
  • Certolizumab pegol (Cimzia)
  • Etanercept (Enbrel)
  • Golimumab (Simponi)
  • Infliximab (Remicade).
• IL-17/IL-23/IL-12+23 inhibitors:
  • Guselkumab (Tremfya)
  • Ixekizumab (Taltz)
  • Secukinumab (Cosentyx).
• JAK inhibitors:
  • Baricitinib (Olumiant)
  • Tofacitinib (Xeljanz)
  • Upadacitinib (Rinvoq).
• IL-6 inhibitors:
  • Sarilumab (Kevzara)
  • Tocilizumab (Actemra).