Epidemiology
each group (breakthrough vs non-breakthrough, respectively) were also similar with the exception of obesity which was more common in those with non-breakthrough infection (25% vs 15%, p=0.04). The median (IQR) comorbidity count was 1 (0, 1) in those with breakthrough infection compared with 1 (0, 2) in those with non-breakthrough infection (p=0.68). The most common SARD category (in those with breakthrough vs non-breakthrough infection, respectively) was inflammatory arthritis (53% vs 63%), followed by connective tissue disease (26% vs 23%), vasculitis (11% vs 8%), other disease (6% vs 3%), or multiple diseases (4% vs 2%) (p=0.33 for difference across categories). The most common conventional synthetic DMARDs used at the time of COVID-19 included hydroxychlo- roquine (29% vs 18%, p=0.04), methotrexate (23% vs 20%, p=0.567) and mycophenolate (12% vs 4%, p=0.02). The most common biologic and targeted synthetic DMARDs at the time of COVID-19 infection included TNF inhibitors (24% vs 21%, p=0.66) followed by anti-CD20 monoclonal antibodies (12% vs 5%, p=0.08) and Janus kinase inhibitors (6% vs 4%, p=0.40). Postacute sequelae according to breakthrough infection status Over 204 days, the mean time spent free from symptoms (time postsymptom resolution), reflected by the area under the cumu- lative incidence curves, was 133.8 days in the breakthrough group and 112.4 days in the non-breakthrough group (table 2; figure 1; Online supplemental file 2). Thus, the breakthrough group was symptom-free for an additional 21.4 days (95% CI 0.95 to 41.91, p=0.04) compared with the non-breakthrough group. The breakthrough group also experienced more symptom-free days over follow-up time when limited to 28 and 90 days (online supplemental figures 2 and 3). Those with breakthrough infection were less likely to have PASC at 28 days (41% vs 54%, p=0.04) and at 90 days (21% vs 41%, p<0.0001) (table 2; figure 2), corresponding to a lower odds of PASC at 28 days (adjusted OR, aOR 0.49, 95% CI 0.29 to 0.83) and 90 days (aOR 0.10, 95% CI 0.04 to 0.22). Our findings remained consistent in sensitivity analyses limiting the sample to those who did not receive nirmatrelvir/ ritonavir or monoclonal antibodies, those who did not receive any COVID-19-related treatment, those who completed the questionnaires within 6 months of COVID-19 infection and those who did not require hospitalisation (online supplemental tables 1–4). Acute COVID-19 symptoms and clinical course according to breakthrough infection status Infection during the period in which the Omicron variants were predominant (17 December 2021 onward) was more common in patients with breakthrough COVID-19 infection (84, 72%) than in patients with non-breakthrough COVID-19 infection (3, 2%) (table 3). Those with breakthrough infection had more nasal congestion/rhinorrhoea (73% vs 46%, p<0.0001) and sore throat (54% vs 37%, p=0.01), and those with non-breakthrough infection had more anosmia (46% vs 22%, p<0.0001), dysgeusia (45% vs 28%, p<0.01) and joint pain (11% vs 4%, p=0.05). Those with breakthrough infection more often received nirma- trelvir/ritonavir (12% vs 1%, p<0.0001) and monoclonal anti- body treatment (34% vs 8%, p<0.0001) compared with those with non-breakthrough infection. Fewer patients with break- through COVID-19 infection required hospitalisation than those with non-breakthrough infection (5% vs 27%, p=0.001).
using a two-sample t-test for continuous normally distributed variables or Wilcoxon test for continuous non-normally distrib- uted variables. Categorical variables were compared by using χ 2 tests. To assess differences in the symptom-free time between those with breakthrough versus non-breakthrough infection, we used restricted mean survival time (RMST). 32–34 The event in this anal- ysis was the number of days to COVID-19 symptom resolution. We compared the areas under the cumulative incidence curves, representing the number of days following symptom resolution (symptom-free days). Thus, the difference between the two groups reflects the difference in the number of symptom-free days between the two groups, with the non-breakthrough group as the reference group. RMST has multiple strengths, including no required assumptions regarding proportional hazards as well as ease of interpretation (effect estimate in difference in number of days as opposed to an HR). Our primary follow-up period was 204 days, given that this was the maximum follow-up period among those with breakthrough infections. We performed secondary analyses assessing these outcomes at 28 and 90 days. We calculated ORs for PASC at 28 and 90 days using unad- justed and multivariable adjusted logistic regression. The first multivariable model adjusted for age, sex and race. The second multivariable model adjusted for age, sex, race, comorbidity count and use of any one of the following medications: anti- CD20 monoclonal antibodies, methotrexate, mycophenolate or glucocorticoids. These medications were chosen because of their impact on SARS-CoV-2 vaccine immunogenicity. To assess the robustness of our findings, we conducted four sensitivity analyses evaluating ORs for PASC as well as differ- ences in other patient-reported outcomes, limiting the popu- lation to: (1) those who did not receive nirmatrelvir/ritonavir or monoclonal antibodies, (2) those who did not receive any COVID-19-related treatment, (3) those who completed the questionnaires within 6 months of COVID-19 infection and (4) those who did not require hospitalisation for acute COVID-19 infection. The level of significance was set as a two-tailed p<0.05, and statistical analyses were completed using SAS statistical software (V.9.4; SAS Institute). Patient and public involvement Patients and the public were not involved in the design, conduct, reporting or dissemination plans of this research. Of 1308 patients invited, 305 completed surveys (23% response rate), and of these, we analysed 280 patients with SARDs who survived COVID-19. One hundred and sixteen (41%) had a breakthrough COVID-19 infection and the remainder (164, 59%) were either unvaccinated or were partially vaccinated at the time of diagnosis and were considered to have non- breakthrough COVID-19 infection. The breakthrough and non- breakthrough groups were similar with respect to age, sex, race, ethnicity, smoking status and SARD category (table 1). The majority in each group were female (80% of those with breakthrough infection vs 79% of those with non-breakthrough infection, p=0.88), and the mean age at the time of survey completion was 53 vs 52 years, respectively (p=0.68). Most patients in each group (breakthrough vs non-breakthrough, respectively) were white (87% vs 79%, p=0.08) and never smokers (75% vs 71%, p=0.65). Common comorbidities in RESULTS Participant characteristics
Patel NJ, et al . Ann Rheum Dis 2023; 82 :565–573. doi:10.1136/ard-2022-223439
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