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.

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.

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.

Disease-modifying antirheumatic drugs and risk of incident interstitial lung disease among patients with rheumatoid arthritis: A systematic review and meta-analysis.

OBJECTIVE: To investigate the association of disease-modifying antirheumatic drugs (DMARDs) and risk of incident interstitial lung disease (ILD) among patients with rheumatoid arthritis (RA) using a systematic literature review and meta-analysis. METHODS: We performed a systematic literature review and meta-analysis of studies examining the association of DMARDs with incident RA-ILD. PubMed, Embase, Web of Science, and Cochrane Library were searched from inception to November 2023 for randomized controlled trials (RCTs), observational studies, and post-marketing surveillance studies that investigated adults with RA and compared DMARDs of interest with placebo, no DMARDs, or other DMARDs. The outcome was incident ILD. We summarized the literature on DMARDs and incident RA-ILD risk. Among studies with sufficient quality, we performed meta-analyses to obtain odds ratios (OR) and 95 % confidence intervals (95 %CI) using the Mantel-Haenszel method. RESULTS: Among 3,612 studies, we identified a total of 40 papers that encompassed 486,465 patients with RA and 3,928 incident ILD outcomes that were included in the final systematic review and meta-analysis. Among the studies, 24 were RCTs, 4 were prospective cohort studies, 9 were retrospective cohort studies, 2 were case-control studies, and 1 was a post-marketing surveillance study. The pooled analysis from RCTs revealed no statistically significant difference in the odds of ILD development for any specific DMARD across all comparisons examined. The largest identified RCT (Oral Surveillance trial) of tofacitinib (n = 2,911) vs. tumor necrosis factor inhibitor (TNFi, n = 1,451) found no relationship with incident ILD (OR 0.94, 95 %CI 0.52 to 1.69, p = 0.828). In 7 observational studies, the use of methotrexate (MTX) yielded a pooled OR for ILD of 0.49 (95 %CI 0.32 to 0.76, p < 0.001) compared to those not using MTX. In a single observational study, tofacitinib users had an OR for ILD of 0.36 (95 %CI 0.15 to 0.87, p = 0.024) compared to TNFi users. CONCLUSION: Observational data suggest no increased risk for any DMARD for incident RA-ILD risk, and perhaps a potential protective role of MTX and tofacitinib. However, these studies may be susceptible to bias, and no specific DMARD showed associations with incident RA-ILD in RCTs. Further well-designed prospective studies are warranted for definitive conclusions on the potential relationship between DMARDs and RA-ILD risk.

Immunomodulator use, risk factors and management of flares, and mortality for patients with pre-existing rheumatoid arthritis after immune checkpoint inhibitors for cancer.

OBJECTIVE: To investigate immunomodulator use, risk factors and management for rheumatoid arthritis (RA) flares, and mortality for patients with pre-existing RA initiating immune checkpoint inhibitors (ICI) for cancer. METHODS: We performed a retrospective cohort study of all patients with RA meeting 2010 ACR/EULAR criteria that initiated ICI for cancer at Mass General Brigham or Dana-Farber Cancer Institute in Boston, MA (2011-2022). We described immunomodulator use and changes at baseline of ICI initiation. We identified RA flares after baseline, categorized the severity, and described the management. Baseline factors were examined for RA flare risk using Fine and Gray competing risk models. We performed a landmark analysis to limit the potential for immortal time bias, where the analysis started 3 months after ICI initiation. Among those who survived at least 3 months, we examined whether RA flare within 3 months after ICI initiation was associated with mortality using Cox regression. RESULTS: Among 11,901 patients who initiated ICI for cancer treatment, we analyzed 100 pre-existing RA patients (mean age 70.3 years, 63 % female, 89 % on PD-1 monotherapy, 50 % lung cancer). At ICI initiation, 71 % were seropositive, 82 % had remission/low RA disease activity, 24 % were on glucocorticoids, 35 % were on conventional synthetic disease-modifying antirheumatic drugs (DMARDs), and 10 % were on biologic or targeted synthetic DMARDs. None discontinued glucocorticoids and 3/35 (9 %) discontinued DMARDs in anticipation of starting ICI. RA flares occurred in 46 % (incidence rate 1.84 per 1000 person-months, 95 % CI 1.30, 2.37); 31/100 flared within 3 months of baseline. RA flares were grade 1 in 16/46 (35 %), grade 2 in 25/46 (54 %), and grade 3 in 5/46 (11 %); 2/46 (4 %) required hospitalization for RA flare. Concomitant immune-related adverse events occurred in 15/46 (33 %) that flared. A total of 72/100 died during follow-up; 21 died within 3 months of baseline. Seropositivity had an age-adjusted sdHR of 1.95 (95 % CI 1.02, 3.71) for RA flare compared to seronegativity, accounting for competing risk of death. Otherwise, no baseline factors were associated with RA flare, including cancer type, disease activity, RA duration, and deformities. 9/46 (20 %) patients had their ICI discontinued/paused due to RA flares. In the landmark analysis among 79 patients who survived at least 3 months, RA flare in the first 3 months was not associated with lower mortality (adjusted HR 1.24, 95 % CI 0.71, 2.16) compared to no RA flare. CONCLUSION: Among patients with pre-existing RA, few changed immunomodulator medications in anticipation of starting ICI, but RA flares occurred in nearly half. RA flares were mostly mild and treated with typical therapies. Seropositivity was associated with RA flare risk. A minority had severe RA flares requiring disruption of ICI, and RA flares were not associated with mortality.

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.

Forced vital capacity trajectories and risk of lung transplant and ILD-related mortality among patients with rheumatoid arthritis-associated interstitial lung disease.

We aimed to determine the prevalence and outcomes for forced vital capacity percent predicted (FVCpp) decline among patients with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). We identified patients with RA-ILD in the Mass General Brigham Healthcare system. RA-ILD diagnosis was determined by review of high-resolution computed tomography (HRCT) imaging by up to three thoracic radiologists. We abstracted FVCpp measurements, covariates, lung transplant, and ILD-related death from the medical record. We employed a relative FVCpp decline cutoff of > 10% within 24 months. We also used a group-based trajectory model to obtain patterns of change from RA-ILD diagnosis. We then assessed for associations of each FVC decline definition with risk of lung transplant or ILD-related death using multivariable logistic regression. We analyzed 172 patients with RA-ILD with a median of 6 FVCpp measurements per patient over 6.5 years of follow-up (mean age 62.2 years, 36% male). There were seven (4%) lung transplants and 44 (26%) ILD-related deaths. Ninety-eight (57%) patients had relative decline of FVCpp by > 10% in 24 months. We identified three trajectory groups of FVCpp change: rapidly declining (n = 24/168 [14%]), slowly declining (n = 90/168 [54%]), and stable/improving (n = 54/168 [32%]). The rapidly declining group and FVCpp > 10% had adjusted odds ratios (aOR) for lung transplant/ILD-related death of 19.2 (95%CI 4.9 to 75.5) and 2.8 (95%CI 1.3 to 6.1) respectively. Over half of patients with RA-ILD had declining FVCpp. The different trajectory patterns demonstrate the importance of FVC monitoring for identifying patients at the highest risk of poor outcomes. Key Points • Over half of patients with RA-ILD had declining FVCpp over a median of 6.5 years of follow-up. • The rapidly declining FVCpp trajectory group had stronger associations with lung transplant and ILD-related death compared to those with FVCpp decline by > 10%. • Clinicians can employ FVC monitoring to proactively treat patients who are at risk of poor outcomes.

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.

Mortality and immune-related adverse events after immune checkpoint inhibitor initiation for cancer among patients with pre-existing rheumatoid arthritis: a retrospective, comparative, cohort study.

Background: Patients with pre-existing rheumatoid arthritis initiating immune checkpoint inhibitors for cancer might be at risk of increased mortality, rheumatoid arthritis flares, and other immune-related adverse events (AEs). We aimed to determine whether pre-existing rheumatoid arthritis was associated with higher mortality and immune-related AE risk in patients treated with immune checkpoint inhibitors. Methods: This retrospective, comparative cohort study was conducted at the Mass General Brigham Integrated Health Care System and the Dana-Farber Cancer Institute in Boston (MA, USA). We searched data repositories to identify all individuals who initiated immune checkpoint inhibitors from April 1, 2011, to April 21, 2021. Patients with pre-existing rheumatoid arthritis had to meet the 2010 American College of Rheumatology-European Alliance of Associations for Rheumatology (ACR-EULAR) criteria. For each pre-existing rheumatoid arthritis case, we matched up to three non-rheumatoid arthritis comparators at the index date of immune checkpoint inhibitor initiation by sex (recorded as male or female), calendar year, immune checkpoint inhibitor target, and cancer type and stage. The coprimary outcomes were time from index date to death and time to the first immune-related AE, measured using an adjusted Cox proportional hazards model. Deaths were identified by medical record and obituary review. Rheumatoid arthritis flares and immune-related AE presence, type, and severity were determined by medical record review. Findings: We identified 11 901 patients who initiated immune checkpoint inhibitors for cancer treatment between April 1, 2011, and April 21, 2021; of those, 101 met the 2010 ACR-EULAR criteria for rheumatoid arthritis. We successfully matched 87 patients with pre-existing rheumatoid arthritis to 203 non-rheumatoid arthritis comparators. The median age was 71·2 years (IQR 63·2-77·1). 178 (61%) of 290 participants were female, 112 (39%) were male and 268 (92%) participants were White. PD-1 was the most common immune checkpoint inhibitor target (80 [92%] of 87 patients with rheumatoid arthritis vs 188 [93%] of 203 comparators). Lung cancer was the most common cancer type (43 [49%] vs 114 [56%]), followed by melanoma (21 [24%] vs 50 [25%]). 60 (69%) patients with rheumatoid arthritis versus 127 (63%) comparators died (adjusted hazard ratio [HR] of 1·16 [95% CI 0·86-1·57]; p=0·34). 53 (61%) patients with rheumatoid arthritis versus 99 (49%) comparators had any all-grade immune-related AE (adjusted HR 1·72 [95% CI 1·20-2·47]; p=0·0032). There were two (1%) grade 5 immune-related AEs (deaths) due to myocarditis, both in the comparator group. Rheumatoid arthritis flares occurred in 42 (48%) patients with rheumatoid arthritis, and inflammatory arthritis occurred in 14 (7%) comparators (p<0·0001). Those with rheumatoid arthritis were less likely to have rash or dermatitis (five [6%] vs 28 [14%]; p=0·048), endocrinopathy (two [2%] vs 22 [11%]; p=0·0078), colitis or enteritis (six [7%] vs 28 [14%] comparators; p=0·094), and hepatitis (three [3%] vs 19 [9%]; p=0·043). Interpretation: Patients with pre-existing rheumatoid arthritis initiating immune checkpoint inhibitors had similar risk of mortality and severe immune-related AEs as matched comparators. Although patients with pre-existing rheumatoid arthritis were more likely to have immune-related AEs, this finding was mostly due to mild rheumatoid arthritis flares. These results suggest that this patient population can safely receive immune checkpoint inhibitors for cancer treatment. Funding: None.

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.

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.

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.

A Roadmap for Investigating Preclinical Autoimmunity Using Patient-Oriented and Epidemiologic Study Designs: Example of Rheumatoid Arthritis.

Background & Aims: Rheumatoid arthritis (RA) is a prototypic autoimmune disease causing inflammatory polyarthritis that affects nearly 1% of the population. RA can lead to joint destruction and disability along with increased morbidity and mortality. Similar to other autoimmune diseases, RA has distinct preclinical phases corresponding to genetic risk, lifestyle risk factors, autoantibody development, and non-specific symptoms prior to clinical diagnosis. This narrative review will detail observational studies for RA risk and clinical trials for RA prevention as a roadmap to investigating preclinical autoimmunity that could be applied to other diseases. Methods: In this narrative review, we summarized previous and ongoing research studies investigating RA risk and prevention, categorizing them related to their design and preclinical phases. Results: We detailed the following types of studies investigating RA risk and prevention: retrospective population-based and administrative datasets; prospective studies (case-control and cohort; some enrolling based on genetics, first-degree relative status, elevated biomarkers, or early symptoms/arthritis); and randomized clinical trials. These correspond to all preclinical RA phases (genetic, lifestyle, autoimmunity, early signs/symptoms). Previous and ongoing randomized controlled trials have enrolled individuals at very elevated risk for RA based on biomarkers, symptoms, imaging abnormalities, or early signs/symptoms. Conclusion: We detailed the rich variety of study designs that is necessary to investigate distinct preclinical phases of an autoimmune disease such as RA. However, further progress is needed to fully elucidate the pathogenesis of RA that may ultimately lead to prevention or delay of disease onset.

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 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.

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.