Rheumatic Patients Are at Risk for COVID Death Save

Patients with rheumatic diseases who developed COVID-19 were at increased likelihood of death, with risk factors similar to those seen in the general population but also because of factors specific to their underlying disease and its treatment, analysis of data from an international registry found.

Among the 3,729 patients enrolled in the COVID-19 Global Rheumatology Alliance between March and July 2020, 10.5% died. As in the population at large, older age was a major factor in mortality, with 68.7% of those who died being older than 65. The odds ratios for death were 3 (95% CI 2.13-4.22) among those ages 66 to 75, rising to 6.18 (95% CI 4.47-8.53) for those over 75, according to Pedro M. Machado, MD, PhD, of University College London, and colleagues.

In addition, higher disease activity at the time of COVID-19 diagnosis was significantly associated with increased mortality, with an OR 1.87 (95% CI 1.27-2.77) for patients with moderate to high disease activity compared with those in remission or with low disease activity, they reported online in Annals of the Rheumatic Diseases.

That finding confirmed "recent recommendations regarding the importance of disease control in rheumatic diseases in the COVID-19 era," they noted.

Previous studies have suggested that patients with underlying rheumatic disease have similar COVID-19 outcomes as their healthy counterparts, or at least only slightly worse. However, the impact of disease factors and treatments that could alter the functioning of the immune system have not previously been fully addressed.

To provide more data on these questions, the Global Rheumatology Alliance was established on March 24, 2020, with data on COVID-19 being entered by rheumatologists throughout the world.

Patients were classified in three subgroups: having inflammatory joint diseases (not including rheumatoid arthritis), having RA, or having connective tissue diseases such as vasculitis. Both confirmed and presumptive cases of COVID-19 were included.

Mean age of the patients was 57, two-thirds were women, and almost 70% were younger than 65. Specific diagnoses included RA in 37.4%, connective tissue diseases other than lupus in 14.3%, lupus in 10.5%, psoriatic arthritis in 11.8%, and other spondyloarthropathies in 11.6%. Small numbers had other underlying rheumatic diseases such as juvenile idiopathic arthritis and vasculitis.

Most patients were from Europe or North America. A total of 47.5% had minimal or low disease activity before the COVID-19 infection, while 32.4% were in remission.

Half of patients were hospitalized with COVID-19, and while mechanical ventilation was required in 6.2% of patients overall, it was needed in 40.8% of those who died.

The majority of patients reported at least one comorbidity; these included hypertension in 35.3%, chronic pulmonary disease in 19.4%, diabetes in 13.6%, and obesity in 16.1%. Among patients who died, 42.7% had three or more comorbidities.

Variations in death rates were observed across countries, with the highest numbers being in the U.K. and Italy, at 20.9% and 16.8%, respectively. Mortality rates in other countries included 8.5% in Spain, 7.8% in France, 7.6% in Germany, and 7% in the U.S.

In multivariable analyses, factors other than older age that were associated with higher risks of mortality included:

• Male sex: OR 1.46 (95% CI 1.11-1.91)
• Chronic lung disease: OR 1.68 (95% CI 1.26-2.25)
• Cardiovascular disease plus hypertension: OR 1.89 (95% CI 1.31-2.73)
• Smoking among patients with RA: OR 1.45 (95% CI 1.02-2.04)
• Chronic kidney disease in patients with connective tissue disease or vasculitis: OR 2.30 (95% CI 1.37-3.88)

Medication Usage

Treatments at the time of COVID-19 diagnosis included conventional disease-modifying antirheumatic drugs (DMARDs) and/or immunosuppressants in 40.6%, biologic DMARDs in 35.7%, and targeted synthetic DMARDs in 3.9%. No DMARDs or immunosuppressants other than glucocorticoids were being used by 19.8% of patients overall, but by 31.8% of patients who died.

Among patients not receiving DMARDs or immunosuppressants, 39.8% were taking glucocorticoids, and at a mean daily dose above 10 mg in 9.8%. Patients not receiving DMARD therapy had twice the likelihood of death (OR 2.11, 95% CI 1.48-3.01).

And compared with methotrexate monotherapy, the use of rituximab (Rituxan) was associated with a higher risk of death in the overall cohort (OR 4.04, 95% CI 2.32-7.03), as well as in the inflammatory joint disease subgroup (OR 5.42, 95% CI 2.77-10.61), the RA subgroup (OR 4.99, 95% CI 2.43-10.26), and in the connective tissue disease/vasculitis subgroup (OR 3.72, 95% CI 1.21-11.48).

An explanation of the increased risk for treatment with rituximab could relate to that medication's binding to CD20 on the surface of B cells. "B-cell depletion could potentially compromise antiviral immunity, including the development of SARS-CoV-2 antibodies," the researchers suggested.

Higher mortality risks also were observed with treatment with sulfasalazine in the overall group (OR 3.60, 95% CI 1.66-7.78) as well as in the subgroups, and with immunosuppressants such as azathioprine, cyclophosphamide, or mycophenolate (OR 2.22, 95% CI 1.43-3.46).

The association between sulfasalazine and increased mortality was a surprising finding, the authors noted, because of the relatively mild immunosuppressive effects of this drug. However, previous research has suggested that sulfasalazine might influence the immune response to RNA viruses. Nonetheless, "causal interpretation of the association between sulfasalazine and COVID-19 related death should not be made," they cautioned. Sulfasalazine might have been chosen rather than methotrexate by rheumatologists for patients considered to have increased risks, such as those with lung disease.

Greater likelihood of death also was seen with daily doses of prednisone above 10 mg (OR 1.69, 95% CI 1.18-2.41).

"In conclusion, people with rheumatic diseases with higher disease activity have higher odds of COVID-19-related death, highlighting the importance of disease control, preferably by managing DMARDs effectively without increasing glucocorticoids," the researchers concluded.

A limitation of the study was the possibility of selection bias in the registry.

Source Reference: Strangfeld A, et al "Factors associated with COVID-19-related death in people with rheumatic diseases: results from the COVID-19 Global Rheumatology Alliance physician-reported registry" Ann Rheum Dis 2021; DOI: 10.1136/annrheumdis-2020-219498.