The association between reproductive history and abdominal adipose tissue among postmenopausal women: results from the Women's Health Initiative.

STUDY QUESTION: What is the association between reproductive health history (e.g. age at menarche, menopause, reproductive lifespan) with abdominal adiposity in postmenopausal women? SUMMARY ANSWER: Higher visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) tissue levels were observed among women with earlier menarche, earlier menopause, and greater parity. WHAT IS KNOWN ALREADY: Postmenopausal women are predisposed to accumulation of VAT and SAT. Reproductive health variables are known predictors of overall obesity status in women, defined by BMI. STUDY DESIGN, SIZE, DURATION: This study is a secondary analysis of data collected from the baseline visit of the Women's Health Initiative (WHI). The WHI is a large prospective study of postmenopausal women, including both a randomized trial and observational study. There were 10 184 women included in this analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data were collected from a reproductive health history questionnaire, dual-energy x-ray absorptiometry scans, and anthropometric measures at WHI baseline. Reproductive history was measured via self-report, and included age at menarche, variables related to pregnancy, and age at menopause. Reproductive lifespan was calculated as age at menopause minus age at menarche. Statistical analyses included descriptive analyses and multivariable linear regression models to examine the association between reproductive history with VAT, SAT, total body fat, and BMI. MAIN RESULTS AND THE ROLE OF CHANCE: Women who reported early menarche (<10 years) or early menopause (<40 years) had the highest levels of VAT. Adjusted multivariable linear regression results demonstrate women who experienced menarche >15 years had 23 cm2 less VAT (95% CI: -31.4, -14.4) and 47 cm2 less SAT (95% CI: -61.8, -33.4) than women who experienced menarche at age 10 years or earlier. A similar pattern was observed for age at menopause: compared to women who experienced menopause <40 years, menopause at 50-55 years was associated with 19.3 cm2 (95% CI: -25.4, -13.3) less VAT and 27.4 cm2 (-29.6, 10.3) less SAT. High parity (>3 pregnancies) was also associated with VAT and SAT. For example, adjusted beta coefficients for VAT were 8.36 (4.33, 12.4) and 17.9 (12.6, 23.2) comparing three to four pregnancies with the referent, one to two pregnancies. LIMITATIONS, REASONS FOR CAUTION: The WHI reproductive health history questionnaire may be subject to poor recall owing to a long look-back window. Residual confounding may be present given lack of data on early life characteristics, such as maternal and pre-menarche characteristics. WIDER IMPLICATIONS OF THE FINDINGS: This study contributes to our understanding of reproductive lifespan, including menarche and menopause, as an important predictor of late-life adiposity in women. Reproductive health has also been recognized as a sentinel marker for chronic disease in late life. Given established links between adiposity and cardiometabolic outcomes, this research has implications for future research, clinical practice, and public health policy that makes use of reproductive health history as an opportunity for chronic disease prevention. STUDY FUNDING/COMPETING INTEREST(S): HRB and AOO are supported by the National Institute of Health National Institute of Aging (R01AG055018-04). JWB reports royalties from 'ACSM'S Body Composition Assessment Book' and consulting fees from the WHI. The remaining authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Factors Associated With an Electronic Health Record-Based Definition of Postacute Sequelae of COVID-19 in Patients With Systemic Autoimmune Rheumatic Disease.

OBJECTIVE: Many individuals with rheumatic disease are at higher risk for severe acute coronavirus disease 2019 (COVID-19). We aimed to evaluate risk factors for postacute sequelae of COVID-19 (PASC) using an electronic health record (EHR)-based definition. METHODS: We identified patients with prevalent rheumatic diseases and COVID-19 within the Mass General Brigham healthcare system. PASC was defined by the International Classification of Diseases, 10th revision (ICD-10) codes, relevant labs, vital signs, and medications at least 30 days following the first COVID-19 infection. Patients were followed until the earliest of incident PASC, repeat COVID-19 infection, 1 year of follow-up, death, or February 19, 2023. We used multivariable Cox regression to estimate the association of baseline characteristics with PASC risk. RESULTS: Among 2459 patients (76.37% female, mean age 57.4 years), the most common incident PASC manifestations were cough (14.56%), dyspnea (12.36%), constipation (11.39%), and fatigue (10.70%). Serious manifestations including acute coronary disease (4.43%), thromboembolism (3.09%), hypoxemia (3.09%), stroke (1.75%), and myocarditis (0.12%) were rare. The Delta wave (adjusted hazard ratio [aHR] 0.63, 95% CI 0.49-0.82) and Omicron era (aHR 0.50, 95% CI 0.41-0.62) were associated with lower risk of PASC than the early pandemic period (March 2020-June 2021). Age, obesity, comorbidity burden, race, and hospitalization for acute COVID-19 infection were associated with greater risk of PASC. Glucocorticoid (GC) use (aHR 1.19, 95% CI 1.05-1.34 compared to no use) was associated with greater risk of PASC. CONCLUSION: Among patients with rheumatic diseases, following their first COVID-19 infection, we found a decreased risk of PASC over calendar time using an EHR-based definition. Aside from GCs, no specific immunomodulatory medications were associated with increased risk, and risk factors were otherwise similar to those seen in the general population.

Effectiveness of a fourth dose of COVID-19 mRNA vaccine in patients with systemic autoimmune rheumatic diseases using disease-modifying antirheumatic drugs: an emulated target trial.

BACKGROUND: Patients with systemic autoimmune rheumatic diseases using disease-modifying antirheumatic drugs (DMARDs) might have blunted responses to COVID-19 vaccines. The initial mRNA vaccine series is defined as three doses for this population and a fourth booster dose is recommended. The effectiveness of the fourth dose in patients with systemic autoimmune rheumatic diseases using DMARDs is not well established. We aimed to assess the effectiveness of receiving versus not receiving a fourth dose of COVID-19 mRNA vaccine using a target trial framework, in a cohort of patients with systemic autoimmune rheumatic diseases receiving DMARD therapy. METHODS: We conducted an emulated target trial using observational data from the Mass General Brigham health-care system to compare receiving versus not receiving a fourth mRNA vaccine dose. Analysed patients had systemic autoimmune rheumatic diseases, were prescribed DMARDs, and were eligible for a fourth dose of BNT162b2 or mRNA-1273 vaccines between Jan 16 and June 11, 2022. To account for temporal changes, the study period was divided into 1-week intervals. Fourth-dose-exposed patients were included in a 1-week interval if they received a fourth mRNA dose in that interval; fourth-dose-unexposed patients were eligible for but had not received the fourth dose of the vaccine. The primary outcome was a SARS-CoV-2 infection; the secondary outcome was severe SARS-CoV-2 infection (ie, admission to hospital or death within -3 to +14 days of a positive test). We assessed the effectiveness of the fourth dose using time-stratified, overlap propensity score-weighted Cox regression models. FINDINGS: We included 4305 patients, 3126 of whom received a fourth dose of vaccine and 1179 who had not. The median follow-up time was 135 days (IQR 112-154) among patients who had received a fourth dose and 65 days (30-156) among patients who had not received a fourth dose. After overlap weighting in both groups, 1863 (72·7%) of 2563 participants were women, 700 (27·3%) were men, and 2242 (87·5%) were White. Rheumatoid arthritis was present in 1392 (54·3%) of 2563 participants; the most frequent treatments were conventional synthetic DMARDs (1489 [58·1%]) or biological DMARDs (1007 [39·3%]). SARS-CoV-2 infection risk was lower among patients receiving versus not receiving a fourth dose of vaccine (HR 0·59 [95% CI 0·47-0·74]). A fourth dose reduced the risk of admission to hospital or death within -3 to +14 days of SARS-CoV-2 infection (0·35 [0·14-0·85]). INTERPRETATION: In this emulated target trial, a fourth dose of COVID-19 mRNA vaccine reduced the risk of SARS-CoV-2 infection and severe COVID-19 among patients with systemic autoimmune rheumatic diseases using DMARDs during the Omicron era. Patients with systemic autoimmune rheumatic diseases should be encouraged to remain up-to-date with COVID-19 vaccinations. FUNDING: The National Institutes of Health and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

Breakthrough COVID-19 After Tixagevimab/Cilgavimab Among Patients With Systemic Autoimmune Rheumatic Diseases.

OBJECTIVE: To determine the incidence and baseline factors associated with breakthrough coronavirus disease 2019 (COVID-19) after preexposure prophylaxis (PrEP) with tixagevimab/cilgavimab among patients with systemic autoimmune rheumatic diseases (SARDs). METHODS: We performed a retrospective cohort study among patients with SARDs who received tixagevimab/cilgavimab between January 2, 2022, and November 16, 2022. The primary outcome was breakthrough COVID-19 after tixagevimab/cilgavimab. We performed multivariable Cox regression models adjusted for baseline factors to identify risk factors for breakthrough COVID-19. RESULTS: We identified 444 patients with SARDs who received tixagevimab/cilgavimab (mean age 62.0 years, 78.2% female). There were 83 (18.7%) breakthrough COVID-19 cases (incidence rate 31.5/1000 person-months, 95% CI 24.70-38.24), 7 (1.6%) hospitalizations, and 1 (0.2%) death. Older age was inversely associated with breakthrough COVID-19 (adjusted hazard ratio [aHR] 0.86/10 years, 95% CI 0.75-0.99). Higher baseline spike antibody levels were associated with lower risk of breakthrough COVID-19 (aHR 0.42, 95% CI 0.18-0.99 for spike antibody levels > 200 vs < 0.4 units). CD20 inhibitor users had a similar risk of breakthrough COVID-19 (aHR 1.05, 95% CI 0.44-2.49) compared to conventional synthetic disease-modifying antirheumatic drug (DMARD) users. CONCLUSION: We found that patients with SARDs had frequent breakthrough COVID-19, but the proportion experiencing severe COVID-19 was low. DMARD type, including CD20 inhibitors, did not significantly affect risk of breakthrough COVID-19. Evidence of prior humoral immunity was protective against breakthrough infection, highlighting the continued need for a multimodal approach to prevent severe COVID-19 as novel PrEP therapies are being developed.

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

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/2021-17/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 with 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.

Risk factors and outcomes for repeat COVID-19 infection among patients with systemic autoimmune rheumatic diseases: A case-control study.

OBJECTIVE: To investigate risk factors and outcomes of repeat COVID-19 infections among patients with systemic autoimmune rheumatic diseases (SARDs). METHODS: We performed a case-control study investigating repeat COVID-19 infection within the Mass General Brigham Health Care System. We systematically identified all SARD patients with confirmed COVID-19 (15/Mar/2020 to 17/Oct/2022). Cases had confirmed repeat COVID-19 infections >60 days apart (index date: repeat COVID-19 date). Controls were matched to cases (up to 3:1) by calendar date of first infection and duration between first COVID-19 infection and index dates. We collected demographics, lifestyle, comorbidities, SARD features, and COVID-19 characteristics at initial infection and index date by medical record review. We used conditional logistic regression to identify associations with repeat COVID-19 infection, adjusting for potential confounders. We described the severity of repeat COVID-19 infection among cases. RESULTS: Among 2203 SARD patients with COVID-19, we identified 76 cases with repeat COVID-19 infection (80.3 % female) and matched to 207 matched controls (77.8 % female) with no repeat infection. At first infection, cases were younger (mean 49.5 vs. 60.3 years, p < 0.0001), less likely to have hypertension (32.9 % vs. 45.9 %, p = 0.050), and less likely to have been hospitalized for COVID-19 (13.2 % vs. 24.6 %, p = 0.037) than controls. At index date, cases were more likely than controls to be rituximab users (18.4 % vs. 6.3 %, p = 0.0021). In the multivariable model, younger age (OR 0.67 per 10 years, 95 %CI 0.54-0.82), rituximab use vs. non-use (OR 3.38, 95 %CI 1.26-9.08), and methotrexate use vs. non-use (OR 2.24, 95 %CI 1.08-4.61) were each associated with repeat COVID-19 infection. Among those with repeat COVID-19 infection, 5/76 (6.6 %) were hospitalized and there were no deaths. CONCLUSION: Younger age, rituximab, and methotrexate were each associated with repeat COVID-19 infection risk among patients with SARDs. Reassuringly, there were no deaths, and the hospitalization rate was low among those with repeat COVID-19 infection.

Immunomodulators and risk for breakthrough infection after third COVID-19 mRNA vaccine among patients with rheumatoid arthritis: A cohort study.

Objectives: To investigate COVID-19 breakthrough infection after third mRNA vaccine dose among patients with RA by immunomodulator drug class, and we hypothesized that CD20 inhibitors (CD20i) would have higher risk for breakthrough COVID-19 vs. TNF inhibitors (TNFi). Methods: We performed a retrospective cohort study investigating breakthrough COVID-19 among RA patients at Mass General Brigham in Boston, MA, USA. Patients were followed from the date of 3rd vaccine dose until breakthrough COVID-19, death, or end of follow-up (18/Jan/2023). Covariates included demographics, lifestyle, comorbidities, and prior COVID-19. We used Cox proportional hazards models to estimate breakthrough COVID-19 risk by immunomodulator drug class. We used propensity score (PS) overlap-weighting to compare users of CD20i vs. TNFi. Results: We analyzed 5781 patients with RA that received 3 mRNA vaccine doses (78.8% female, mean age 64.2 years). During mean follow-up of 12.8 months, 1173 (20.2%) had breakthrough COVID_19. Use of CD20i (adjusted HR 1.74, 95%CI 1.30-2.33) and glucocorticoid monotherapy (adjusted HR 1.47, 95%CI 1.09-1.98) were each associated with breakthrough COVID-19 compared to TNFi use. In the PS overlap-weighted analysis, CD20i users also had higher breakthrough COVID-19 risk than TNFi users (HR 1.62, 95%CI 1.02-2.56). A sensitivity analysis excluding patients with cancer or interstitial lung disease yielded similar findings. Conclusions: We identified CD20i and glucocorticoid monotherapy as risk factors for breakthrough COVID-19 among patients with RA after a 3rd vaccine dose. This contemporary study highlights the real-world impact of blunted immune responses in these subgroups and the need for effective risk mitigation strategies.

Humoral immunity to an endemic coronavirus is associated with postacute sequelae of COVID-19 in individuals with rheumatic diseases.

Beyond the acute illness caused by severe acute respiratory coronavirus 2 (SARS-CoV-2) infection, about one-fifth of infections result in long-term persistence of symptoms despite the apparent clearance of infection. Insights into the mechanisms that underlie postacute sequelae of COVID-19 (PASC) will be critical for the prevention and clinical management of long-term complications of COVID-19. Several hypotheses have been proposed that may account for the development of PASC, including persistence of virus and dysregulation of immune responses. Among the immunological changes noted in PASC, alterations in humoral immunity have been observed in some patient subsets. To begin to determine whether SARS-CoV-2- or other pathogen-specific humoral immune responses evolve uniquely in PASC, we performed comprehensive antibody profiling against SARS-CoV-2, a panel of endemic pathogens, and a panel of routine vaccine antigens using systems serology in two cohorts of patients with preexisting systemic autoimmune rheumatic disease (SARD) who either developed or did not develop PASC. A distinct qualitative shift observed in Fcγ receptor (FcγR) binding was observed in individuals with PASC. Specifically, individuals with PASC harbored weaker FcγR-binding anti-SARS-CoV-2 antibodies and stronger FcγR-binding antibody responses against the endemic coronavirus OC43. Individuals with PASC developed an OC43 S2-specific antibody response with stronger FcγR binding, linked to cross-reactivity across SARS-CoV-2 and common coronaviruses. These findings identify previous coronavirus imprinting as a potential marker for the development of PASC in individuals with SARDs.

Outcomes with and without outpatient SARS-CoV-2 treatment for patients with COVID-19 and systemic autoimmune rheumatic diseases: a retrospective cohort study.

Background: Some patients with systemic autoimmune rheumatic disease and immunosuppression might still be at risk of severe COVID-19. The effect of outpatient SARS-CoV-2 treatments on COVID-19 outcomes among patients with systemic autoimmune rheumatic disease is unclear. We aimed to evaluate temporal trends, severe outcomes, and COVID-19 rebound among patients with systemic autoimmune rheumatic disease and COVID-19 who received outpatient SARS-CoV-2 treatment compared with those who did not receive outpatient treatment. Methods: We did a retrospective cohort study at Mass General Brigham Integrated Health Care System, Boston, MA, USA. We included patients aged 18 years or older with a pre-existing systemic autoimmune rheumatic disease, who had COVID-19 onset between Jan 23 and May 30, 2022. We identified COVID-19 by positive PCR or antigen test (index date defined as the date of first positive test) and systemic autoimmune rheumatic diseases using diagnosis codes and immunomodulator prescription. Outpatient SARS-CoV-2 treatments were confirmed by medical record review. The primary outcome was severe COVID-19, defined as hospitalisation or death within 30 days after the index date. COVID-19 rebound was defined as documentation of a negative SARS-CoV-2 test after treatment followed by a newly positive test. The association of outpatient SARS-CoV-2 treatment versus no outpatient treatment with severe COVID-19 outcomes was assessed using multivariable logistic regression. Findings: Between Jan 23 and May 30, 2022, 704 patients were identified and included in our analysis (mean age 58·4 years [SD 15·9]; 536 [76%] were female and 168 [24%] were male, 590 [84%] were White and 39 [6%] were Black, and 347 [49%] had rheumatoid arthritis). Outpatient SARS-CoV-2 treatments increased in frequency over calendar time (p<0·0001). A total of 426 (61%) of 704 patients received outpatient treatment (307 [44%] with nirmatrelvir-ritonavir, 105 [15%] with monoclonal antibodies, five [1%] with molnupiravir, three [<1%] with remdesivir, and six [1%] with combination treatment). There were nine (2·1%) hospitalisations or deaths among 426 patients who received outpatient treatment compared with 49 (17·6%) among 278 who did not receive outpatient treatment (odds ratio [adjusted for age, sex, race, comorbidities, and kidney function] 0·12, 95% CI 0·05-0·25). 25 (7·9%) of 318 patients who received oral outpatient treatment had documented COVID-19 rebound. Interpretation: Outpatient treatment was associated with lower odds of severe COVID-19 outcomes compared with no outpatient treatment. These findings highlight the importance of outpatient SARS-CoV-2 treatment for patients with systemic autoimmune rheumatic disease and COVID-19 and the need for further research on COVID-19 rebound. Funding: None.

Comparative Effectiveness of BNT162b2 and mRNA-1273 Vaccines Against COVID-19 Infection Among Patients With Systemic Autoimmune Rheumatic Diseases on Immunomodulatory Medications.

OBJECTIVE: To compare the effectiveness of mRNA vaccines (BNT162b2 vs mRNA-1273) against coronavirus disease 2019 (COVID-19) infection among patients with systemic autoimmune rheumatic diseases (SARDs) on immunomodulatory medications. METHODS: We identified patients with SARDs being treated with disease-modifying antirheumatic drugs (DMARDs) and/or glucocorticoids in the Mass General Brigham healthcare system who received either BNT162b2 or mRNA-1273 as their initial vaccine series. Patients were followed until positive SARS-CoV-2 test, death, or February 22, 2022. We compared the risk of breakthrough infection between BNT162b2 and mRNA-1273 vaccine recipients using time-stratified, overlap propensity score (PS)-weighted Cox proportional hazard models. RESULTS: We identified 9838 patients with SARDs who received BNT162b2 or mRNA-1273. Demographic and clinical characteristics were similar in both groups after overlap weighting: mean age 61 years, 75% female, 52% with rheumatoid arthritis, 74% receiving conventional synthetic DMARDs, and 43% receiving biologic DMARDs. Of 5516 BNT162b2 and 4322 mRNA-1273 recipients, 446 and 329 had a breakthrough infection, respectively. The corresponding time-stratified PS-weighted rate difference of breakthrough infection was 0.71 (95% CI -0.70 to 2.12) per 1000 person-months with a weighted hazard ratio (HR) of 1.12 (95% CI 0.90 to 1.39). When follow-up was censored prior to the Omicron wave, there was a trend toward higher breakthrough risk with BNT162b2 vs mRNA-1273 (weighted HR 1.34, 95% CI 0.91 to 1.98). CONCLUSION: Among patients with SARDs, the risk of breakthrough COVID-19 infection is similar after receiving either BNT162b2 or mRNA-1273. Patients with SARDs initiating the vaccine series should be encouraged to receive whichever mRNA vaccine is available.

Outcomes with and without outpatient SARS-CoV-2 treatment for patients with COVID-19 and systemic autoimmune rheumatic diseases: A retrospective cohort study.

Objective: To investigate temporal trends, severe outcomes, and rebound among systemic autoimmune rheumatic disease (SARD) patients according to outpatient SARS-CoV-2 treatment. Methods: We performed a retrospective cohort study investigating outpatient SARS-CoV-2 treatments among SARD patients at Mass General Brigham (23/Jan/2022-30/May/2022). We identified SARS-CoV-2 infection by positive PCR or antigen test (index date=first positive test) and SARDs using diagnosis codes and immunomodulator prescription. Outpatient treatments were confirmed by medical record review. The primary outcome was hospitalization or death within 30 days following the index date. COVID-19 rebound was defined as documentation of negative then newly-positive SARS-CoV-2 tests. The association of any vs. no outpatient treatment with hospitalization/death was assessed using multivariable logistic regression. Results: We analyzed 704 SARD patients with COVID-19 (mean age 58.4 years, 76% female, 49% with rheumatoid arthritis). Treatment as outpatient increased over calendar time (p<0.001). A total of 426(61%) received outpatient treatment: 307(44%) with nirmatrelvir/ritonavir, 105(15%) with monoclonal antibodies, 5(0.7%) with molnupiravir, 3(0.4%) with outpatient remdesivir, and 6(0.9%) with combinations. There were 9/426 (2.1%) hospitalizations/deaths among those treated as outpatient compared to 49/278 (17.6%) among those with no outpatient treatment (adjusted odds ratio [aOR] 0.12, 0.05 to 0.25). 25/318 (8%) of patients who received oral outpatient treatment had documented COVID-19 rebound. Conclusion: Outpatient treatment was strongly associated with lower odds of severe COVID-19 compared to no outpatient treatment. At least 8% of SARD patients experienced COVID-19 rebound. These findings highlight the importance of outpatient COVID-19 treatment for SARD patients and the need for further research on rebound. What is already known on this topic?: Previous studies suggest that monoclonal antibodies are an effective outpatient treatment option for patients at high-risk of severe COVID-19, including those with systemic autoimmune rheumatic diseases (SARDs).Nirmatrelvir/ritonavir and molnupiravir are recently-authorized effective oral outpatient SARS-CoV-2 treatment options, but clinical trials were performed among the general population, mostly among unvaccinated and prior to Omicron viral variants.Oral outpatient SARS-CoV-2 treatments may result in COVID-19 rebound, characterized by newly-positive COVID-19 testing and recurrent symptoms, but no studies have investigated rebound prevalence among SARD patients. What this study adds?: This is one of the first studies investigating outpatient SARS-CoV-2 treatments among SARD patients that includes oral options and quantifies the prevalence of COVID-19 rebound.Outpatient treatment was associated with 88% reduced odds of severe COVID-19 compared to no treatment.At least 8% of SARDs receiving oral outpatient treatment experienced COVID-19 rebound. How this study might affect research practice or policy?: These results should encourage clinicians to prescribe and SARD patients to seek prompt outpatient COVID-19 treatment.This research provides an early estimate of the prevalence of COVID-19 rebound after oral outpatient treatment to quantify this risk to clinicians and SARD patients and encourage future research.

Impact of cross-coronavirus immunity in post-acute sequelae of COVID-19.

Beyond the unpredictable acute illness caused by SARS-CoV-2, one-fifth of infections unpredictably result in long-term persistence of symptoms despite the apparent clearance of infection. Insights into the mechanisms that underlie post-acute sequelae of COVID-19 (PASC) will be critical for the prevention and clinical management of long-term complications of COVID-19. Several hypotheses have been proposed that may account for the development of PASC, including persistence of virus or the dysregulation of immunity. Among the immunological changes noted in PASC, alterations in humoral immunity have been observed in some patient subsets. To begin to determine whether SARS-CoV-2 or other pathogen specific humoral immune responses evolve uniquely in PASC, we performed comprehensive antibody profiling against SARS-CoV-2 and a panel of endemic pathogens or routine vaccine antigens using Systems Serology in a cohort of patients with pre-existing rheumatic disease who either developed or did not develop PASC. A distinct humoral immune response was observed in individuals with PASC. Specifically, individuals with PASC harbored less inflamed and weaker Fcγ receptor binding anti-SARS-CoV-2 antibodies and a significantly expanded and more inflamed antibody response against endemic Coronavirus OC43. Individuals with PASC, further, generated more avid IgM responses and developed an expanded inflammatory OC43 S2-specific Fc-receptor binding response, linked to cross reactivity across SARS-CoV-2 and common coronaviruses. These findings implicate previous common Coronavirus imprinting as a marker for the development of PASC.

Temporal trends in COVID-19 outcomes among patients with systemic autoimmune rheumatic diseases: from the first wave through the initial Omicron wave.

OBJECTIVES: To investigate temporal trends in incidence and severity of COVID-19 among patients with systemic autoimmune rheumatic diseases (SARDs) from the first wave through the initial Omicron wave. METHODS: We conducted a retrospective cohort study investigating COVID-19 outcomes among patientswith SARD systematically identified to have confirmed COVID-19 from 1 March 2020 to 31 January 2022 at Mass General Brigham. We tabulated COVID-19 counts of total and severe cases (hospitalisations or deaths) and compared the proportion with severe COVID-19 by calendar period and by vaccination status. We used logistic regression to estimate the ORs for severe COVID-19 for each period compared with the early COVID-19 period (reference group). RESULTS: We identified 1449 patients with SARD with COVID-19 (mean age 58.4 years, 75.2% female, 33.9% rheumatoid arthritis). There were 399 (28%) cases of severe COVID-19. The proportion of severe COVID-19 outcomes declined over calendar time (p for trend <0.001); 46% of cases were severe in the early COVID-19 period (1 March 2020-30 June 2020) vs 15% in the initial Omicron wave (17 December 2021-31 January 2022; adjusted OR 0.29, 95% CI 0.19 to 0.43). A higher proportion of those unvaccinated were severe compared with not severe cases (78% vs 60%). CONCLUSIONS: The proportion of patients with SARD with severe COVID-19 has diminished since early in the pandemic, particularly during the most recent time periods, including the initial Omicron wave. Advances in prevention, diagnosis and treatment of COVID-19 may have improved outcomes among patients with SARD.

Temporal trends in COVID-19 outcomes among patients with systemic autoimmune rheumatic diseases: From the first wave to Omicron.

Objectives: To investigate temporal trends in incidence and severity of COVID-19 among patients with systemic autoimmune rheumatic diseases (SARDs) from the first wave through the Omicron wave. Methods: We conducted a retrospective cohort study investigating COVID-19 outcomes among SARD patients systematically identified to have confirmed COVID-19 from March 1, 2020 to January 31, 2022 at a large healthcare system in Massachusetts. We tabulated COVID-19 counts of total and severe cases (hospitalizations or deaths) and compared the proportion with severe COVID-19 by calendar period and by vaccination status. We used logistic regression to estimate the ORs for severe COVID-19 for each period compared to the early COVID-19 period (reference group). Results: We identified 1449 SARD patients with COVID-19 (mean age 58.4 years, 75.2% female, 33.9% rheumatoid arthritis). There were 399 (27.5%) cases of severe COVID-19. The proportion of severe COVID-19 outcomes declined over calendar time (p for trend <0.001); 45.6% of cases were severe in the early COVID-19 period (March 1-June 30, 2020) vs. 14.7% in the Omicron wave (December 17, 2021-January 31, 2022; adjusted odds ratio 0.29, 95%CI 0.19-0.43). A higher proportion of those unvaccinated were severe compared to not severe cases (78.4% vs. 59.5%). Conclusions: The proportion of SARD patients with severe COVID-19 has diminished since early in the pandemic, particularly during the most recent time periods, including the Omicron wave. Advances in prevention, diagnosis, and treatment of COVID-19 may have improved outcomes among SARD patients. KEY MESSAGES: What is already known about this subject?: Patients with systemic autoimmune rheumatic diseases (SARDs) may be at increased risk for severe COVID-19, defined as hospitalization or death.Previous studies of SARD patients suggested improving COVID-19 outcomes over calendar time, but most were performed prior to the wide availability of COVID-19 vaccines or the Omicron wave that was characterized by high infectivity.What does this study add?: The proportion of SARD patients with severe COVID-19 outcomes was lower over calendar timeThe adjusted odds ratio of severe COVID-19 in the Omicron wave was 0.29 (95%CI 0.19-0.43) compared to early COVID-19 period.The absolute number of severe COVID-19 cases during the peak of the Omicron variant wave was similar to the peaks of other waves.SARD patients with severe vs. not severe COVID-19 were more likely to be unvaccinated.How might this impact on clinical practice or future developments?: These findings suggest that advances in COVID-19 prevention, diagnosis, and treatment have contributed to improved outcomes among SARD patients over calendar time.Future studies should extend findings into future viral variants and consider the roles of waning immunity after vaccination or natural infection among SARD patients who may still be vulnerable to severe COVID-19.

DMARD disruption, rheumatic disease flare, and prolonged COVID-19 symptom duration after acute COVID-19 among patients with rheumatic disease: A prospective study.

OBJECTIVE: To describe disease-modifying antirheumatic drug (DMARD) disruption, rheumatic disease flare/activity, and prolonged COVID-19 symptom duration among COVID-19 survivors with systemic autoimmune rheumatic diseases (SARDs). METHODS: We surveyed people with pre-existing SARDs who had confirmed COVID-19 at Mass General Brigham to investigate post-acute sequelae of COVID-19. We obtained data on demographics, clinical characteristics, COVID-19 symptoms/course, and patient-reported measures. We examined baseline predictors of prolonged COVID-19 symptom duration (defined as lasting ≥28 days) using logistic regression. RESULTS: We analyzed surveys from 174 COVID-19 survivors (mean age 52 years, 81% female, 80% White, 50% rheumatoid arthritis) between March 2021 and January 2022. Fifty-one percent of 127 respondents on any DMARD reported a disruption to their regimen after COVID-19 onset. For individual DMARDs, 56-77% had any change, except for hydroxychloroquine (23%) and rituximab (46%). SARD flare after COVID-19 was reported by 41%. Global patient-reported disease activity was worse at the time of survey than before COVID-19 (mean 6.6±2.9 vs. 7.6±2.3, p<0.001). Median time to COVID-19 symptom resolution was 25 days (IQR 11, 160). Prolonged symptom duration of ≥28 days occurred in 45%. Hospitalization for COVID-19 (OR 3.54, 95%CI 1.27-9.87) and initial COVID-19 symptom count (OR 1.38 per symptom, 95%CI 1.17-1.63) were associated with prolonged symptom duration. Respondents experiencing prolonged symptom duration had higher RAPID3 scores (p=0.007) and more pain (p<0.001) and fatigue (p=0.03) compared to those without prolonged symptoms. CONCLUSION: DMARD disruption, SARD flare, and prolonged COVID-19 symptom duration were common in this prospective study of COVID-19 survivors, suggesting substantial impact on SARDs after acute COVID-19.

DMARD disruption, disease flare, and prolonged symptom duration after acute COVID-19 among participants with rheumatic disease: A prospective study.

OBJECTIVE: To describe disease-modifying antirheumatic drug (DMARD) disruption, rheumatic disease flare/activity, and prolonged COVID-19 symptom duration among COVID-19 survivors with systemic autoimmune rheumatic diseases (SARDs). METHODS: We surveyed patients with SARDs after confirmed COVID-19 at Mass General Brigham to investigate post-acute sequelae of COVID-19. We obtained data on demographics, clinical characteristics, COVID-19 symptoms/course, and patient-reported measures. We examined baseline predictors of prolonged COVID-19 symptom duration (defined as lasting ≥28 days) using logistic regression. RESULTS: We analyzed surveys from 174 COVID-19 survivors (mean age 52 years, 81% female, 80% White, 50% rheumatoid arthritis) between March 2021 and January 2022. Fifty-one percent of 127 respondents on any DMARD reported a disruption to their regimen after COVID-19 onset. For individual DMARDs, 56-77% had any change, except for hydroxychloroquine (23%) and rituximab (46%). SARD flare after COVID-19 was reported by 41%. Global patient-reported disease activity was worse at the time of survey than before COVID-19 (mean 6.6±2.9 vs. 7.6±2.3, p<0.001). Median time to COVID-19 symptom resolution was 14 days (IQR 9,29). Prolonged symptom duration of ≥28 days occurred in 45%. Hospitalization for COVID-19 (OR 3.54, 95%CI 1.27-9.87) and initial COVID-19 symptom count (OR 1.38 per symptom, 95%CI 1.17-1.63) were associated with prolonged symptom duration. Respondents experiencing prolonged symptom duration had higher RAPID3 scores (p=0.007) and more pain (p<0.001) and fatigue (p=0.03) compared to those without prolonged symptoms. CONCLUSION: DMARD disruption, SARD flare, and prolonged symptom duration were common in this prospective study of COVID-19 survivors, suggesting substantial impact on SARDs after acute COVID-19.

Validation of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis as the Cause of End-Stage Renal Disease in the US Renal Data System.

OBJECTIVE: The objective of this study was to validate the diagnosis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) as the primary cause of end-stage renal disease (ESRD) in the US Renal Data System (USRDS). METHODS: We identified patients with ESRD in the Mass General Brigham (MGB) health care system who were enrolled in the USRDS. The health records of those with AAV listed as the primary cause of ESRD in the USRDS were reviewed to confirm the diagnosis and estimate positive predictive value (PPV). Sensitivity was estimated by evaluating the primary cause of ESRD listed in the USRDS for patients with ESRD due to AAV in the MGB AAV cohort. RESULTS: We identified 89 MGB patients with ESRD due to AAV in the USRDS. Of these, 85 cases were confirmed to be true cases of AAV (PPV = 94%). Among the patients classified as having AAV, 84 (99%) had an ANCA test, which was predominantly myeloperoxidase/P-ANCA (47 [55%]); 36 (42%) had a renal biopsy, and all biopsies were supportive of the diagnosis. The majority (81 [90%]) was identified as AAV by International Classification of Diseases Ninth Revision or International Classification of Diseases 10th Revision codes for granulomatosis with polyangiitis (446.4 or M313.1). Of the 77 MGB AAV cohort patients with ESRD who were linked to the USRDS, 41 (53%) had AAV listed as the cause of ESRD; in the remainder, ESRD was attributed to nonspecific nephritis. CONCLUSION: The diagnosis of AAV as the cause of ESRD in the USRDS has a high PPV; sensitivity was moderate. These findings support the continued use of the USRDS to study ESRD due to AAV.