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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.
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Anticorpos Monoclonais , Antirreumáticos , COVID-19 , Doenças Reumáticas , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Estudos Retrospectivos , Antirreumáticos/uso terapêutico , Doenças Reumáticas/complicações , Doenças Reumáticas/tratamento farmacológicoRESUMO
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.
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COVID-19 , Registros Eletrônicos de Saúde , Doenças Reumáticas , Humanos , COVID-19/epidemiologia , COVID-19/complicações , Feminino , Masculino , Pessoa de Meia-Idade , Doenças Reumáticas/epidemiologia , Doenças Reumáticas/complicações , Idoso , Fatores de Risco , SARS-CoV-2 , Adulto , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/complicações , Síndrome de COVID-19 Pós-Aguda , ComorbidadeRESUMO
OBJECTIVE: Vaccination decreases the risk of severe COVID-19 but its impact on postacute sequelae of COVID-19 (PASC) is unclear among patients with systemic autoimmune rheumatic diseases (SARDs) who may have blunted vaccine immunogenicity and be vulnerable to PASC. METHODS: We prospectively enrolled patients with SARD from a large healthcare system who survived acute infection to complete surveys. The symptom-free duration and the odds of PASC (any symptom lasting ≥28 or 90 days) were evaluated using restricted mean survival time and multivariable logistic regression, respectively, among those with and without breakthrough infection (≥14 days after initial vaccine series). RESULTS: Among 280 patients (11% unvaccinated; 48% partially vaccinated; 41% fully vaccinated), the mean age was 53 years, 80% were female and 82% were white. The most common SARDs were inflammatory arthritis (59%) and connective tissue disease (24%). Those with breakthrough infection had more upper respiratory symptoms, and those with non-breakthrough infection had more anosmia, dysgeusia and joint pain. Compared with those with non-breakthrough COVID-19 infection (n=164), those with breakthrough infection (n=116) had significantly more symptom-free days over the follow-up period (+21.4 days, 95% CI 0.95 to 41.91; p=0.04) and lower odds of PASC at 28 and 90 days (adjusted OR, aOR 0.49, 95% CI 0.29 to 0.83 and aOR 0.10, 95% CI 0.04 to 0.22, respectively). CONCLUSION: Vaccinated patients with SARDs were less likely to experience PASC compared with those not fully vaccinated. While we cannot rule out the possibility that findings may be due to intrinsic differences in PASC risk from different SARS-CoV-2 variants, these findings support the benefits of vaccination for patients with SARDs and suggest that the immune response to acute infection is important in the pathogenesis of PASC in patients with SARDs.
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COVID-19 , Doenças Reumáticas , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , COVID-19/complicações , COVID-19/prevenção & controle , SARS-CoV-2 , Doenças Reumáticas/complicações , Síndrome de COVID-19 Pós-Aguda , Vacinação , Infecções Irruptivas , Progressão da DoençaRESUMO
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.
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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.
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Artrite Reumatoide , Doenças Autoimunes , COVID-19 , Doenças Reumáticas , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Doenças Reumáticas/epidemiologia , COVID-19/epidemiologia , Doenças Autoimunes/epidemiologia , Estudos Retrospectivos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologiaRESUMO
Organoids derived from human stem cells are a promising approach for disease modeling, regenerative medicine, and fundamental research. However, organoid variability and limited control over morphological outcomes remain as challenges. One open question is the extent to which engineering control over culture conditions can guide organoids to specific compositions. Here, we extend a DNA "velcro" cell patterning approach, precisely controlling the number and ratio of human induced pluripotent stem cell-derived progenitors contributing to nephron progenitor (NP) organoids and mosaic NP/ureteric bud (UB) tip cell organoids within arrays of microwells. We demonstrate long-term control over organoid size and morphology, decoupled from geometric constraints. We then show emergent trends in organoid tissue proportions that depend on initial progenitor cell composition. These include higher nephron and stromal cell representation in mosaic NP/UB organoids vs. NP-only organoids and a "goldilocks" initial cell ratio in mosaic organoids that optimizes the formation of proximal tubule structures.
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Organoides , Organoides/citologia , Organoides/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Néfrons/citologia , Diferenciação Celular/fisiologia , Células-Tronco/citologiaRESUMO
The mammalian kidney achieves massive parallelization of function by exponentially duplicating nephron-forming niches during development. Each niche caps a tip of the ureteric bud epithelium (the future urinary collecting duct tree) as it undergoes branching morphogenesis, while nephron progenitors within niches balance self-renewal and differentiation to early nephron cells. Nephron formation rate approximately matches branching rate over a large fraction of mouse gestation, yet the nature of this apparent pace-maker is unknown. Here we correlate spatial transcriptomics data with branching 'life-cycle' to discover rhythmically alternating signatures of nephron progenitor differentiation and renewal across Wnt, Hippo-Yap, retinoic acid (RA), and other pathways. We then find in human stem-cell derived nephron progenitor organoids that Wnt/ß-catenin-induced differentiation is converted to a renewal signal when it temporally overlaps with YAP activation. Similar experiments using RA activation indicate a role in setting nephron progenitor exit from the naive state, the spatial extent of differentiation, and nephron segment bias. Together the data suggest that nephron progenitor interpretation of consistent Wnt/ß-catenin differentiation signaling in the niche may be modified by rhythmic activity in ancillary pathways to set the pace of nephron formation. This would synchronize nephron formation with ureteric bud branching, which creates new sites for nephron condensation. Our data bring temporal resolution to the renewal vs. differentiation balance in the nephrogenic niche and inform new strategies to achieve self-sustaining nephron formation in synthetic human kidney tissues.
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OBJECTIVE: Our aim was to investigate the effectiveness and tolerability of antifibrotics in a real-world cohort of patients with rheumatoid arthritis-associated interstitial lung diseases (RA-ILD). METHODS: In this retrospective cohort study, we identified RA-ILD patients initiating antifibrotics at Mass General Brigham Integrated Health Care System, a large multi-hospital healthcare system in Boston, MA, USA. We used electronic query to identify all patients with at least 2 RA diagnosis codes and a prescription for either nintedanib or pirfenidone (2014-2023). All analyzed patients met 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for RA and had definite RA-ILD according to Bongartz criteria. Data regarding pulmonary function test (PFT) results, adverse events (AEs), tolerability, and clinical data were collected. A linear mixed model with random intercept was used to compare the within-patient trajectory of the percent predicted forced vital capacity (FVCpp) within 18-months before to 18-months after antifibrotic initiation among those with these PFT data. Lung transplant-free survival and drug retention was estimated in a Kaplan-Meier analysis and a Cox regression analysis was performed to identify independent baseline factors associated with lung transplant or mortality. RESULTS: We analyzed 74 patients with RA-ILD that initiated antifibrotics (mean age 67.8 years, 53 % male); 40 patients initiated nintedanib and 34 initiated pirfenidone. Median follow-up was 89 weeks (min 4, max 387). There was a significant improvement in the estimated slope of FVCpp after antifibrotic initiation (-0.3 % per year after initiation compared to -6.2 % per year before antifibrotic initiation, p = 0.03). Nintedanib and pirfenidone had similar FVCpp trajectory. Twenty-six patients (35 %) died and 4 (5 %) had undergone lung transplantation during follow-up. Male sex and heavy smoking were each associated with the composite outcome of lung transplant or mortality. AEs were reported in 41 (55 %) patients, with gastrointestinal (GI) AEs being most common (n = 30). The initial antifibrotic was discontinued in 34 (46 %) patients mostly due to GI AEs (n = 19). The median drug retention time was 142 weeks (95 %CI 56, 262) with no difference between nintedanib and pirfenidone (p = 0.68). CONCLUSION: In this first real-world study of antifibrotic use dedicated to RA-ILD, antifibrotic initiation was associated with a modestly improved trajectory of FVCpp. AEs were frequently reported, particularly GI, and discontinuation was common. However, lung transplant and mortality rates were still high, emphasizing the need for further therapeutic strategies in patients with severe RA-ILD. These real-world data complement previous trial data that investigated efficacy and safety.
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Artrite Reumatoide , Doenças Pulmonares Intersticiais , Transplante de Pulmão , Humanos , Masculino , Idoso , Feminino , Estudos Retrospectivos , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/tratamento farmacológico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , PulmãoRESUMO
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.
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Antirreumáticos , Artrite Reumatoide , Neoplasias Pulmonares , Humanos , Feminino , Idoso , Masculino , Inibidores de Checkpoint Imunológico/uso terapêutico , Estudos Retrospectivos , Artrite Reumatoide/tratamento farmacológico , Fatores de Risco , Antirreumáticos/efeitos adversos , Neoplasias Pulmonares/tratamento farmacológico , Fatores Imunológicos/uso terapêuticoRESUMO
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.
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Antirreumáticos , Artrite Reumatoide , COVID-19 , Feminino , Humanos , Masculino , Antirreumáticos/uso terapêutico , Vacina BNT162 , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Vacinas de mRNA , RNA Mensageiro , SARS-CoV-2 , Estados UnidosRESUMO
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.
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Artrite Reumatoide , Doenças Pulmonares Intersticiais , Transplante de Pulmão , Humanos , Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/complicações , Artrite Reumatoide/complicações , Artrite Reumatoide/cirurgia , Artrite Reumatoide/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Capacidade Vital , Tomografia Computadorizada por Raios X , Estudos RetrospectivosRESUMO
Human organoids are a promising approach for disease modeling and regenerative medicine. However, organoid variability and limited control over morphological outcomes remain significant challenges. Here we extend a DNA 'velcro' cell patterning approach, precisely controlling the number and ratio of human stem cell-derived progenitors contributing to nephron and mosaic nephron/ureteric bud organoids within arrays of microwells. We demonstrate long-term control over organoid size and morphology, decoupled from geometric constraints.
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BACKGROUND: Patients with rheumatic disease may mount a suboptimal serologic response to COVID-19 vaccination. We evaluated predictors of low antibody response in a clinic-based cohort. METHODS: We conducted a cross-sectional study using electronic health record (EHR) data at Brigham and Women's Hospital, Boston, MA. Patients with systemic rheumatic disease that had SARS-CoV-2 spike antibody (Ab) tested using the Roche Elecsys immunoassay, February-August 2021, after 2 doses of mRNA vaccine or 1 dose of adenovirus vector vaccine were identified. Demographics, systemic rheumatic disease, vaccination dates, and disease-modifying antirheumatic drugs (DMARDs) were extracted. The primary outcome was low spike Ab (≤ 200 U/mL). Logistic regression models estimated predictors of low spike Ab. RESULTS: Among 382 patients, the mean age was 57 years, 77% were female, and 37% had low spike Ab. Older age (OR 1.03, 95% CI [1.02, 1.05]), SLE (OR 4.81 [2.08, 8.43], reference: inflammatory arthritis), prednisone (OR 1.67 [1.03, 2.74]), and rituximab (OR 22.91 [9.85, 53.29]) were significantly associated with higher odds of low spike Ab. Use of csDMARD monotherapy (OR 0.12 [0.04, 0.33]) and JAK inhibitors (OR 0.41 [0.18, 0.92]) were associated with significantly lower odds for low spike Ab. After adjusting for systemic rheumatic disease and DMARDs, SLE and rituximab remained significantly associated with low spike Ab. CONCLUSIONS: Over a third of patients with systemic rheumatic disease with spike Ab tested in routine care had low spike Ab after 2 doses of mRNA or 1 dose of adenovirus vector COVID-19 vaccine. SLE and rituximab were significant risk factors for low spike Ab. KEY POINTS: ⢠More than one-third of patients with systemic rheumatic disease that had spike Ab tested in routine care had low spike Ab after 2 doses of mRNA or 1 dose of adenovirus vector COVID-19 vaccine. ⢠Diagnosis of SLE, use of prednisone, and use of rituximab were significantly associated with greater odds of low spike antibodies. ⢠These data underscore the importance of additional doses of COVID-19 vaccine and prophylactic Evusheld in immunosuppressed patients with systemic rheumatic disease as recommended by the US Centers for Disease Control.
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Antirreumáticos , COVID-19 , Lúpus Eritematoso Sistêmico , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Vacinas contra COVID-19 , Rituximab/uso terapêutico , Formação de Anticorpos , Estudos Transversais , Prednisona , COVID-19/prevenção & controle , SARS-CoV-2 , Vacinação , Antirreumáticos/uso terapêutico , Anticorpos AntiviraisRESUMO
Resident macrophages exist in a variety of tissues, including tendon, and play context-specific roles in their tissue of residence. In this study, we define the spatiotemporal distribution and phenotypic profile of tendon resident macrophages and their crosstalk with neighboring tendon fibroblasts and the extracellular matrix (ECM) during murine tendon development, growth, and homeostasis. Fluorescent imaging of cryosections revealed that F4/80+ tendon resident macrophages reside adjacent to Col1a1-CFP+ Scx-GFP+ fibroblasts within the tendon fascicle from embryonic development (E15.5) into adulthood (P56). Through flow cytometry and qPCR, we found that these tendon resident macrophages express several well-known macrophage markers, including Adgre1 (F4/80), Mrc1 (CD206), Lyve1, and Folr2, but not Ly-6C, and express the Csf1r-EGFP ("MacGreen") reporter. The proportion of Csf1r-EGFP+ resident macrophages in relation to the total cell number increases markedly during early postnatal growth, while the density of macrophages per mm2 remains constant during this same time frame. Interestingly, proliferation of resident macrophages is higher than adjacent fibroblasts, which likely contributes to this increase in macrophage proportion. The expression profile of tendon resident macrophages also changes with age, with increased pro-inflammatory and anti-inflammatory cytokine expression in P56 compared to P14 macrophages. In addition, the expression profile of limb tendon resident macrophages diverges from that of tail tendon resident macrophages, suggesting differential phenotypes across anatomically and functionally different tendons. As macrophages are known to communicate with adjacent fibroblasts in other tissues, we conducted ligand-receptor analysis and found potential two-way signaling between tendon fibroblasts and resident macrophages. Tendon fibroblasts express high levels of Csf1, which encodes macrophage colony stimulating factor (M-CSF) that acts on the CSF1 receptor (CSF1R) on macrophages. Importantly, Csf1r-expressing resident macrophages preferentially localize to Csf1-expressing fibroblasts, supporting the "nurturing scaffold" model for tendon macrophage patterning. Lastly, we found that tendon resident macrophages express high levels of ECM-related genes, including Mrc1 (mannose receptor), Lyve1 (hyaluronan receptor), Lair1 (type I collagen receptor), Ctss (elastase), and Mmp13 (collagenase), and internalize DQ Collagen in explant cultures. Overall, our study provides insights into the potential roles of tendon resident macrophages in regulating fibroblast phenotype and the ECM during tendon growth.
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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.
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Antirreumáticos , Artrite Reumatoide , COVID-19 , Humanos , Feminino , Pessoa de Meia-Idade , Masculino , Vacina BNT162 , Vacina de mRNA-1273 contra 2019-nCoV , Vacinas contra COVID-19 , SARS-CoV-2 , Vacinas de mRNARESUMO
OBJECTIVE: Rheumatic disease patients on certain immunomodulators are at increased risk of impaired humoral response to SARS-CoV-2 vaccines. We aimed to identify factors associated with breakthrough infection among patients with rheumatic diseases. METHODS: We identified patients with rheumatic diseases being treated with immunomodulators in a large healthcare system who received at least two doses of either the mRNA-1273 (Moderna) or BNT162b2 (Pfizer-BioNTech) vaccines or one dose of the Johnson & Johnson-Janssen (J&J) vaccine. We followed patients until SARS-CoV-2 infection, death, or December 15, 2021, when the Omicron variant became dominant in our region. We estimated the association of baseline characteristics with the risk of breakthrough infection using multivariable Cox regression. RESULTS: We analyzed 11,468 patients (75% female, mean age 60 years). Compared to antimalarial monotherapy, multiple immunomodulators were associated with higher risk of infection: anti-CD20 monoclonal antibodies (aHR 5.20, 95% CI: 2.85, 9.48), CTLA-4 Ig (aHR 3.52, 95% CI: 1.90, 6.51), mycophenolate (aHR 2.31, 95% CI: 1.25, 4.27), IL-6 inhibitors (aHR 2.15, 95% CI: 1.09, 4.24), JAK inhibitors (aHR 2.02, 95% CI: 1.01, 4.06), and TNF inhibitors (aHR 1.70, 95% CI: 1.09, 2.66). mRNA-1273 recipients had a lower risk of breakthrough infection compared to BNT162b2 recipients (aHR 0.66, 95% CI: 0.50, 0.86). There was no association of sex, body mass index, smoking status, race, or ethnicity with risk of breakthrough infection. CONCLUSION: Among patients with rheumatic diseases, multiple immunomodulators were associated with increased risk of breakthrough infection. These results highlight the need for additional mitigation strategies in this vulnerable population.
Assuntos
Infecções Irruptivas , Vacinas contra COVID-19 , COVID-19 , Doenças Reumáticas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vacina de mRNA-1273 contra 2019-nCoV , Vacina BNT162 , Infecções Irruptivas/epidemiologia , Estudos de Coortes , COVID-19/epidemiologia , COVID-19/prevenção & controle , SARS-CoV-2 , Doenças Reumáticas/epidemiologiaRESUMO
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.
Assuntos
Doenças Autoimunes , COVID-19 , Doenças Reumáticas , Humanos , Feminino , Criança , Masculino , Estudos de Casos e Controles , Metotrexato , Rituximab , Doenças Reumáticas/complicações , Doenças Reumáticas/tratamento farmacológico , Doenças Reumáticas/epidemiologia , Fatores de Risco , Doenças Autoimunes/complicações , Doenças Autoimunes/epidemiologiaRESUMO
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.
RESUMO
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.