Associations of DMARDs with post-acute sequelae of COVID-19 in patients with systemic autoimmune rheumatic diseases: a prospective study,2023,Venkat+

[SNT Gatchaman]

Associations of DMARDs with post-acute sequelae of COVID-19 in patients with systemic autoimmune rheumatic diseases: a prospective study
Venkat, Rathnam K; Wang, Xiaosong; Patel, Naomi J; Kawano, Yumeko; Schiff, Abigail; Kowalski, Emily N; Cook, Claire E; Vanni, Kathleen M M; Qian, Grace; Bade, Katarina J; Saavedra, Alene; Srivatsan, Shruthi; Williams, Zachary K; Wallace, Zachary S; Sparks, Jeffrey A

Objective: We investigated the baseline disease-modifying antirheumatic drug (DMARD) use and post-acute sequelae of COVID-19 (PASC) risk among patients with systemic autoimmune rheumatic diseases (SARDs).

Methods: Patients with SARDs and confirmed COVID-19 infection at Mass General Brigham completed a survey ≥28 days after positive PCR/Antigen test to prospectively investigate their COVID-19 courses. We investigated DMARD use at COVID-19 onset and PASC risk. PASC was defined as any COVID-19 symptom that persisted for ≥28 days. We used logistic regression to estimate odds ratios (OR) for PASC by DMARD class. We also used restricted mean survival time to determine the difference in symptom-free days by DMARD class in the 28-day period after infection.

Results: We analyzed 510 patients with SARDs and COVID-19 from 11/Mar/2021 to 17/Jun/2023; 202 (40%) developed PASC. CD20 inhibitor (CD20i) users had significantly higher odds of developing PASC vs. csDMARD users (adjusted OR 2.69, 95%CI 1.23-5.88). IL-12/23, IL-17A, or IL-23 inhibitor (IL-12/23i, IL-17Ai, IL-23i) users also had significantly higher odds of PASC (adjusted OR 3.03, 95%CI 1.08-8.49). CD20i users had significantly fewer symptom-free days vs. csDMARD users (adjusted -4.12, 95%CI -7.29 to -0.94).

Conclusion: CD20i users had significantly higher odds of PASC and fewer symptom-free days over the 28 days following COVID-19 diagnosis compared to csDMARD users. Further research is needed to investigate whether PASC risk in CD20i users may be due to prolonged infection or other immune mechanisms. The association of IL-12/23i, IL-17Ai, and IL-23i and PASC calls for additional study.

KEY MESSAGES

• CD20i and IL-12/23i, IL-17Ai, and IL-23i users had significantly higher odds of PASC vs. csDMARD users.

• CD20i users had fewer symptom-free days in the month after COVID-19 diagnosis vs. csDMARD users.

• When possible, providers should exercise caution when prescribing CD20i to patients with SARDs.

Link | Paywall (Rheumatology)

 

[SNT Gatchaman]

Patients with systemic autoimmune rheumatic diseases (SARDs) have a higher risk for more severe outcomes of COVID-19 infection due to underlying altered immunity and immunosuppressive medications. [...] Several studies have investigated specific immunosuppressive disease-modifying antirheumatic drugs (DMARDs) and acute COVID-19 outcomes.

CD20 inhibitors (CD20i) have consistently been associated with severe COVID-19 outcomes even after COVID-19 vaccination potentially due to their impairment of the humoral immune response. Yusof et al. reported a 30% rate of all severity breakthrough infection in SARD patients using rituximab and a similar rate of severe breakthrough COVID-19 infections as other severe infections (e.g. pneumonia). Calabrese et al. found that of SARD patients on B-cell depleting therapy who experienced breakthrough infection, 39% were hospitalized and 8% died.

Therefore, we examined the association of DMARD use and PASC in patients with SARDs. We hypothesized that CD20i would have a significantly higher risk of PASC and lower symptom-free days than conventional synthetic DMARDs (csDMARDs).

 

[SNT Gatchaman]

The primary exposure was baseline DMARD use, defined as DMARD use at the time of COVID-19 infection. DMARDs were categorized in the following classes: no DMARDs, csDMARDs only, tumor necrosis factor inhibitors (TNFi), janus kinase inhibitors (JAKi), CD20i, IL-6 receptor inhibitors (IL-6Ri), IL-12/23, IL-17A, and IL-23 inhibitors (IL-12/23i, IL-17Ai, and IL23i), and other biologic DMARDs (bDMARDs) including abatacept, belimumab, and canakinumab. IL-12/23i, IL-17Ai, and IL-23i were grouped because each individually had small sample size and all three are used to treat spondyloarthritis. DMARD use was assigned in a hierarchy. For example, those on a bDMARD in addition to a csDMARD were only categorized in the bDMARD class.

A total of 21/38 (55%) CD20i users developed PASC compared to 54/142 (38%) csDMARD only users. CD20i users had 2.69-fold higher odds for PASC vs. csDMARD users in the multivariable model (95%CI 1.23 to 5.88).CD20i users also had mean 7.21 (SD 9.26) unadjusted symptom-free days over the 28-day follow-up period after COVID-19 diagnosis compared to 10.36 (SD 10.00) symptom-free days for csDMARD users. CD20i were significantly associated with a mean 4.12 fewer adjusted symptom-free days vs. csDMARDs (95%CI -7.29 to -0.94).

 

[SNT Gatchaman]

The most common symptom leading to a PASC diagnosis was fatigue/malaise, which was reported in 43% of participants with SARDs and 62% of CD20i users that developed PASC. While it may be difficult for some patients to distinguish fatigue from PASC versus from their underlying SARD, 87% of participants with SARDs who reported fatigue as a persistent symptom also reported at least 1 other symptom.

Our finding that CD20i users have higher odds of PASC implicates the humoral immune system in defending against PASC and some patients with PASC may have prolonged viral infection. Our finding that IL-12/23i, IL-17Ai, or IL-23i also have higher odds of PASC implicates T-cell mediated inflammation in reducing PASC risk and may also help explain why prolonged viral infection may be a mechanism for PASC in SARD patients. Ultimately, the pathogenesis of PASC is complex, and only a proportion of those in the general population may develop PASC by these mechanisms.

In conclusion, we found that CD20i users had nearly 3-fold higher odds of PASC and about 4 fewer adjusted symptom-free days compared to csDMARDs users. We also found that IL-12/23i, IL-17Ai, or IL-23i users with spondyloarthritis had higher odds of PASC.