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1.
Lancet Rheumatol ; 6(8): e528-e536, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38876129

RESUMO

BACKGROUND: Validation of protective associations of the lupus low disease activity state (LLDAS) against flare, irreversible damage, health-related quality of life, and mortality has enabled the adoption of treat-to-target strategies in patients with systemic lupus erythematosus (SLE). Previous validation studies were of short duration, limiting the ability to detect longer term signals in flare rate and irreversible damage. In addition, previous studies have focused on percent time at target, rather than actual periods of time that are more useful in clinical practice and trials. We assessed long-term protective associations of LLDAS and remission, and specifically examined protective thresholds of sustained LLDAS and remission. METHODS: Patients aged 18 years or older with SLE were followed up from May 1, 2013, to Dec 31, 2020 in a prospective, multinational, longitudinal cohort study. Patients were recruited from 25 centres in 12 countries. Multi-failure time-to-event analyses were used to assess the effect of sustained LLDAS on irreversible damage accrual (primary outcome; measured with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index) and flare (key secondary outcome; measured with the SELENA Flare Index), with dose exposure and threshold effects studied. Sustained LLDAS or remission were defined as two or more consecutive visits over at least 3 months in the respective state. This study is registered with ClinicalTrials.gov, NCT03138941. FINDINGS: 3449 patients were followed up for a median of 2·8 years (IQR 1·1-5·6), totalling 37 662 visits. 3180 (92·2%) patients were women, and 3031 (87·9%) were of Asian ethnicity. 2506 (72·7%) patients had sustained LLDAS at least once. Any duration of sustained LLDAS or remission longer than 3 months was associated with reduced damage accrual (LLDAS: hazard ratio 0·60 [95% CI 0·51-0·71], p<0·0001; remission: 0·66 [0·57-0·76], p<0·0001) and flare (LLDAS: 0·56 [0·51-0·63], p<0·0001; remission: 0·66 [0·60-0·73], p<0·0001), and increasing durations of sustained LLDAS corresponded to increased protective associations. Sustained DORIS remission or steroid-free remission were less attainable than LLDAS. INTERPRETATION: We observed significant protective associations of LLDAS and remission against damage accrual and flare, establish a threshold of 3 months sustained LLDAS or remission as protective, and demonstrate deepening protection with longer durations of sustained LLDAS or remission. FUNDING: The Asia Pacific Lupus Collaboration receives project support grants from AstraZeneca, Bristol Myers Squibb, EMD Sereno, GSK, Janssen, Eli Lilly, and UCB.


Assuntos
Lúpus Eritematoso Sistêmico , Índice de Gravidade de Doença , Humanos , Feminino , Adulto , Masculino , Estudos Prospectivos , Pessoa de Meia-Idade , Estudos Longitudinais , Indução de Remissão , Qualidade de Vida
2.
Drug Saf ; 2024 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-38916712

RESUMO

BACKGROUND: Immunocompromised individuals are at high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent severe or fatal coronavirus disease 2019 (COVID-19), yet they have suboptimal responses to mRNA and inactivated COVID-19 vaccines. The efficacy of tixagevimab-cilgavimab in reducing symptomatic SARS-CoV-2 infection was demonstrated in phase III clinical trials. Nevertheless, real-world data on the effectiveness and safety of tixagevimab-cilgavimab remain limited. OBJECTIVE: The aim was to evaluate the effectiveness and safety of tixagevimab-cilgavimab among immunocompromised individuals. METHODS: Adults who were immunocompromised or receiving immunosuppressive therapies were included in this target trial emulation using territory-wide electronic health records in Hong Kong. A sequential trial emulation approach was adopted to compare effectiveness and safety outcomes between individuals who received tixagevimab-cilgavimab and individuals who did not. RESULTS: A total of 746 tixagevimab-cilgavimab recipients and 2980 controls were included from 1 May 2022 to 30 November 2022. Tixagevimab-cilgavimab significantly reduced the risk of COVID-19 infection (hazard ratio [HR] 0.708, 95% confidence interval [CI] 0.527-0.951) during a median follow-up of 60 days. No significant difference was observed in the risk of COVID-19-related hospitalisation. Zero versus eight COVID-19 mortality cases and zero versus two severe COVID-19 cases were observed in tixagevimab-cilgavimab recipients and controls, respectively. Notably, significant risk reduction in COVID-19 infection was also observed among immunocompromised individuals who had been previously vaccinated with three or more doses of COVID-19 vaccine, or had no prior COVID-19 infection history. CONCLUSIONS: Tixagevimab-cilgavimab was effective in reducing COVID-19 infection among immunocompromised patients during the Omicron wave. Findings were consistent among individuals who previously received three or more doses of COVID-19 vaccine, or had no previous history of COVID-19 infection.

3.
Int J Infect Dis ; : 107149, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38909928

RESUMO

OBJECTIVES: To evaluate the difference between BNT162b2 and CoronaVac in vaccine effectiveness and safety. METHODS: This target trial emulation study included individuals aged ≥ 12 during 2022. Propensity score matching was applied to ensure group balance. The Cox proportional hazard model was used to compare the effectiveness outcomes including COVID-19 infection, severity, 28-day hospitalization and 28-day mortality after infection. Poisson regression was used for safety outcomes including 32 adverse events of special interests between groups. RESULTS: 639,818 and 1,804,388 individuals were identified for the 2-dose and 3-dose comparison, respectively. In 2-dose and 3-dose comparison, the hazard ratios (HRs) (95% confidence intervals [CI]) were 0.844 [0.833-0.856] and 0.749 [0.743-0.755] for COVID-19 infection, 0.692 [0.656-0.731] and 0.582 [0.559-0.605] for hospitalization, 0.566 [0.417-0.769] and 0.590 [0.458-0.76] for severe COVID-19, and 0.563 [0.456-0.697] and 0.457 [0.372-0.561] for mortality for BNT162b2 recipients versus CoronaVac recipients, respectively. Regarding safety, 2-dose BNT162b2 recipients had a significantly higher incidence of myocarditis (Incidence rate ratio[IRR][95% CI]: 8.999 [1.14-71.017]) versus CoronaVac recipients, but the difference was insignificant in 3-dose comparison (IRR [95% CI]: 2.000 [0.500-7.996]). CONCLUSIONS: BNT162b2 has higher effectiveness among individuals aged ≥ 12 against COVID-19-related outcomes for SARS-CoV-2 omicron compared to CoronaVac, with almost 50% lower mortality risk. (200 words).

4.
JAMA Netw Open ; 7(6): e2418800, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38922614

RESUMO

Importance: Among patients with rheumatoid arthritis (RA) who had an inadequate response to methotrexate, a treatment sequence initiated with biosimilar disease-modifying antirheumatic drugs (DMARDs) provides better clinical efficacy compared with conventional synthetic DMARDs recommended by current treatment guidelines; but its cost-effectiveness evidence remains unclear. Objective: To evaluate the cost-effectiveness of the treatment sequence initiated with biosimilar DMARDs after failure with methotrexate vs leflunomide and inform formulary listing decisions. Design, Setting, and Participants: This economic evaluation's cost-effectiveness analysis was performed at a Hong Kong public institution using the Markov disease transition model to simulate the lifetime disease progression and cost for patients with RA, using monetary value in 2022. Scenario and sensitivity analyses were performed to test the internal validity of the modeling conclusion. Participants included patients diagnosed with RA from 2000 to 2021 who were retrieved retrospectively from local electronic medical records to generate model input parameters. Statistical analysis was performed from January 2023 to March 2024. Interventions: The model assesses 3 competing treatment sequences initiated with biosimilar infliximab (CT-P13), biosimilar adalimumab (ABP-501), and leflunomide; all used in combination with methotrexate. Main Outcomes and Measures: Lifetime health care cost and quality-adjusted life-years (QALYs) of the simulated cohort. Results: In total, 25 099 patients with RA were identified (mean [SD] age, 56 [17] years; 19 469 [72.7%] women). In the base-case analysis, the lifetime health care cost and QALYs for the treatment sequence initiated with leflunomide were US $154 632 and 14.82 QALYs, respectively; for biosimilar infliximab, they were US $152 326 and 15.35 QALYs, respectively; and for biosimilar adalimumab, they were US $145 419 and 15.55 QALYs, respectively. Both biosimilar sequences presented lower costs and greater QALYs than the leflunomide sequence. In the deterministic sensitivity analysis, the incremental cost-effectiveness ratio (US$/QALY) comparing biosimilar infliximab sequence vs leflunomide sequence and biosimilar adalimumab sequence vs leflunomide sequence ranged from -15 797 to -8615 and -9088 to 10 238, respectively, all below the predefined willingness-to-pay threshold (US $48 555/QALY gain). In the probabilistic sensitivity analysis, the probability of treatment sequence initiated with leflunomide, biosimilar infliximab, and biosmilar adalimumab being cost-effective out of 10 000 iterations was 0%, 9%, and 91%, respectively. Conclusions and Relevance: In this economic evaluation study, the treatment sequences initiated with biosimilar DMARDs were cost-effective compared with the treatment sequence initiated with leflunomide in managing patients with RA who experienced failure with the initial methotrexate treatment. These results suggest the need to update clinical treatment guidelines for initiating biosimilars immediately after the failure of methotrexate for patients with RA.


Assuntos
Antirreumáticos , Artrite Reumatoide , Medicamentos Biossimilares , Análise Custo-Benefício , Leflunomida , Humanos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/economia , Leflunomida/uso terapêutico , Leflunomida/economia , Medicamentos Biossimilares/uso terapêutico , Medicamentos Biossimilares/economia , Antirreumáticos/uso terapêutico , Antirreumáticos/economia , Feminino , Masculino , Pessoa de Meia-Idade , Infliximab/uso terapêutico , Infliximab/economia , Adulto , Hong Kong , Estudos Retrospectivos , Anos de Vida Ajustados por Qualidade de Vida , Adalimumab/uso terapêutico , Adalimumab/economia , Idoso
5.
Adv Rheumatol ; 64(1): 38, 2024 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-38720354

RESUMO

BACKGROUND: This study examines the association of standard-of-care systemic lupus erythematosus (SLE) medications with key outcomes such as low disease activity attainment, flares, damage accrual, and steroid-sparing, for which there is current paucity of data. METHODS: The Asia Pacific Lupus Collaboration (APLC) prospectively collects data across numerous sites regarding demographic and disease characteristics, medication use, and lupus outcomes. Using propensity score methods and panel logistic regression models, we determined the association between lupus medications and outcomes. RESULTS: Among 1707 patients followed over 12,689 visits for a median of 2.19 years, 1332 (78.03%) patients achieved the Lupus Low Disease Activity State (LLDAS), 976 (57.18%) experienced flares, and on most visits patients were taking an anti-malarial (69.86%) or immunosuppressive drug (76.37%). Prednisolone, hydroxychloroquine and azathioprine were utilised with similar frequency across all organ domains; methotrexate for musculoskeletal activity. There were differences in medication utilisation between countries, with hydroxychloroquine less frequently, and calcineurin inhibitors more frequently, used in Japan. More patients taking leflunomide, methotrexate, chloroquine/hydroxychloroquine, azathioprine, and mycophenolate mofetil/mycophenolic acid were taking ≤ 7.5 mg/day of prednisolone (compared to > 7.5 mg/day) suggesting a steroid-sparing effect. Patients taking tacrolimus were more likely (Odds Ratio [95% Confidence Interval] 13.58 [2.23-82.78], p = 0.005) to attain LLDAS. Patients taking azathioprine (OR 0.67 [0.53-0.86], p = 0.001) and methotrexate (OR 0.68 [0.47-0.98], p = 0.038) were less likely to attain LLDAS. Patients taking mycophenolate mofetil were less likely to experience a flare (OR 0.79 [0.64-0.97], p = 0.025). None of the drugs was associated with a reduction in damage accrual. CONCLUSIONS: This study suggests a steroid-sparing benefit for most commonly used standard of care immunosuppressants used in SLE treatment, some of which were associated with an increased likelihood of attaining LLDAS, or reduced incidence of flares. It also highlights the unmet need for effective treatments in lupus.


Assuntos
Antimaláricos , Azatioprina , Glucocorticoides , Hidroxicloroquina , Imunossupressores , Lúpus Eritematoso Sistêmico , Metotrexato , Prednisolona , Padrão de Cuidado , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Feminino , Imunossupressores/uso terapêutico , Hidroxicloroquina/uso terapêutico , Masculino , Glucocorticoides/uso terapêutico , Adulto , Azatioprina/uso terapêutico , Prednisolona/uso terapêutico , Metotrexato/uso terapêutico , Antimaláricos/uso terapêutico , Estudos de Coortes , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Leflunomida/uso terapêutico , Inibidores de Calcineurina/uso terapêutico , Modelos Logísticos , Pontuação de Propensão , Índice de Gravidade de Doença , Tacrolimo/uso terapêutico , Exacerbação dos Sintomas , Resultado do Tratamento , Antirreumáticos/uso terapêutico
6.
J Autoimmun ; 146: 103203, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38643729

RESUMO

Lupus erythematosus (LE) is a heterogeneous, antibody-mediated autoimmune disease. Isolate discoid LE (IDLE) and systematic LE (SLE) are traditionally regarded as the two ends of the spectrum, ranging from skin-limited damage to life-threatening multi-organ involvement. Both belong to LE, but IDLE and SLE differ in appearance of skin lesions, autoantibody panels, pathological changes, treatments, and immunopathogenesis. Is discoid lupus truly a form of LE or is it a completely separate entity? This question has not been fully elucidated. We compared the clinical data of IDLE and SLE from our center, applied multi-omics technology, such as immune repertoire sequencing, high-resolution HLA alleles sequencing and multi-spectrum pathological system to explore cellular and molecular phenotypes in skin and peripheral blood from LE patients. Based on the data from 136 LE patients from 8 hospitals in China, we observed higher damage scores and fewer LE specific autoantibodies in IDLE than SLE patients, more uCDR3 sharing between PBMCs and skin lesion from SLE than IDLE patients, elevated diversity of V-J recombination in IDLE skin lesion and SLE PBMCs, increased SHM frequency and class switch ratio in IDLE skin lesion, decreased SHM frequency but increased class switch ratio in SLE PBMCs, HLA-DRB1*03:01:01:01, HLA-B*58:01:01:01, HLA-C*03:02:02:01, and HLA-DQB1*02:01:01:01 positively associated with SLE patients, and expanded Tfh-like cells with ectopic germinal center structures in IDLE skin lesions. These findings suggest a significant difference in the immunopathogenesis of skin lesions between SLE and IDLE patients. SLE is a B cell-predominate systemic immune disorder, while IDLE appears limited to the skin. Our findings provide novel insights into the pathogenesis of IDLE and other types of LE, which may direct more accurate diagnosis and novel therapeutic strategies.


Assuntos
Autoanticorpos , Lúpus Eritematoso Discoide , Lúpus Eritematoso Sistêmico , Pele , Humanos , Lúpus Eritematoso Discoide/imunologia , Lúpus Eritematoso Discoide/patologia , Feminino , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Autoanticorpos/imunologia , Autoanticorpos/sangue , Pele/patologia , Pele/imunologia , Pele/metabolismo , Adulto , Pessoa de Meia-Idade , Alelos , Antígenos HLA/genética , Antígenos HLA/imunologia , Adulto Jovem , Multiômica
7.
Mod Rheumatol ; 34(4): 655-669, 2024 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-38531074

RESUMO

Lupus remains a disease with a low prioritisation in the national agendas of many countries in Latin America, the Middle East, and Asia-Pacific, where there is a dearth of rheumatologists and limited access to new or even standard lupus treatments. There is thus an important need for education, advocacy, and outreach to prioritise lupus in these regions to ensure that patients receive the care they need. This article reviews some of the specific challenges facing the care and management of people with lupus in these regions and suggests strategies for improving patient outcomes. Specifically, we review and discuss (with a focus on the aforementioned regions) the epidemiology of lupus; economic costs, disease burden, and effects on quality of life; barriers to care related to disease assessment; barriers to effective treatment, including limitations of standard treatments, high glucocorticoid use, inadequate access to new treatments, and low adherence to medications; and strategies to improve lupus management and patient outcomes. We hope that this represents a call to action to come together and act now for the lupus community, policymakers, health authorities, and healthcare professionals to improve lupus management and patient outcomes in Latin America, the Middle East, and Asia-Pacific.


Assuntos
Lúpus Eritematoso Sistêmico , Humanos , América Latina/epidemiologia , Lúpus Eritematoso Sistêmico/terapia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/epidemiologia , Oriente Médio/epidemiologia , Ásia/epidemiologia , Acessibilidade aos Serviços de Saúde , Qualidade de Vida , Efeitos Psicossociais da Doença , Gerenciamento Clínico
8.
J Rheumatol ; 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38490668

RESUMO

OBJECTIVE: To assess whether Lupus Low Disease Activity State (LLDAS) attainment is associated with favorable outcomes in patients with recent onset systemic lupus erythematosus (SLE). METHODS: Data from a 13-country longitudinal SLE cohort were collected prospectively between 2013 and 2020. An inception cohort was defined based on disease duration < 1 year at enrollment. Patient characteristics between inception and noninception cohorts were compared. Survival analyses were performed to examine the association between LLDAS attainment and damage accrual and flare. RESULTS: Of the total 4106 patients, 680 (16.6%) were recruited within 1 year of SLE diagnosis (inception cohort). Compared to the noninception cohort, inception cohort patients were significantly younger, had higher disease activity, and used more glucocorticoids, but had less organ damage at enrollment. Significantly fewer inception cohort patients were in LLDAS at enrollment than the noninception cohort (29.6% vs 52.3%, P < 0.001), but three-quarters of both groups achieved LLDAS at least once during follow-up. Limiting analysis only to patients not in LLDAS at enrollment, inception cohort patients were 60% more likely to attain LLDAS (hazard ratio 1.37, 95% CI 1.16-1.61, P < 0.001) than noninception cohort patients and attained LLDAS significantly faster. LLDAS attainment was significantly protective against flare in both the inception and noninception cohorts. A total of 88 (13.6%) inception cohort patients accrued organ damage during a median 2.2 years of follow-up. CONCLUSION: LLDAS attainment is protective from flare in recent onset SLE. Significant protection from damage accrual was not observed because of low rates of damage accrual in the first years after SLE diagnosis. (ClinicalTrials.gov: NCT03138941).

9.
Ann Rheum Dis ; 83(8): 998-1005, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38423757

RESUMO

OBJECTIVES: To assess the risk of flare and damage accrual after tapering glucocorticoids (GCs) in modified serologically active clinically quiescent (mSACQ) patients with systemic lupus erythematosus (SLE). METHODS: Data from a 12-country longitudinal SLE cohort, collected prospectively between 2013 and 2020, were analysed. SLE patients with mSACQ defined as the state with serological activity (increased anti-dsDNA and/or hypocomplementemia) but without clinical activity, treated with ≤7.5 mg/day of prednisolone-equivalent GCs and not-considering duration, were studied. The risk of subsequent flare or damage accrual per 1 mg decrease of prednisolone was assessed using Cox proportional hazard models while adjusting for confounders. Observation periods were 2 years and censored if each event occurred. RESULTS: Data from 1850 mSACQ patients were analysed: 742, 271 and 180 patients experienced overall flare, severe flare and damage accrual, respectively. Tapering GCs by 1 mg/day of prednisolone was not associated with increased risk of overall or severe flare: adjusted HRs 1.02 (95% CI, 0.99 to 1.05) and 0.98 (95% CI, 0.96 to 1.004), respectively. Antimalarial use was associated with decreased flare risk. Tapering GCs was associated with decreased risk of damage accrual (adjusted HR 0.96, 95% CI, 0.93 to 0.99) in the patients whose initial prednisolone dosages were >5 mg/day. CONCLUSIONS: In mSACQ patients, tapering GCs was not associated with increased flare risk. Antimalarial use was associated with decreased flare risk. Tapering GCs protected mSACQ patients treated with >5 mg/day of prednisolone against damage accrual. These findings suggest that cautious GC tapering is feasible and can reduce GC use in mSACQ patients.


Assuntos
Glucocorticoides , Lúpus Eritematoso Sistêmico , Prednisolona , Exacerbação dos Sintomas , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/complicações , Feminino , Masculino , Glucocorticoides/administração & dosagem , Glucocorticoides/uso terapêutico , Adulto , Pessoa de Meia-Idade , Prednisolona/administração & dosagem , Prednisolona/uso terapêutico , Redução da Medicação/métodos , Estudos Longitudinais , Progressão da Doença , Estudos de Coortes , Modelos de Riscos Proporcionais , Estudos Prospectivos
10.
Nat Commun ; 15(1): 1716, 2024 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-38403654

RESUMO

The persisting risk of long-term health consequences of SARS-CoV-2 infection and the protection against such risk conferred by COVID-19 vaccination remains unclear. Here we conducted a retrospective territory-wide cohort study on 1,175,277 patients with SARS-CoV-2 infection stratified by their vaccination status and non-infected controls to evaluate the risk of clinical sequelae, cardiovascular and all-cause mortality using a territory-wide public healthcare database with population-based vaccination records in Hong Kong. A progressive reduction in risk of all-cause mortality was observed over one year between patients with SARS-CoV-2 infection and controls. Patients with complete vaccination or have received booster dose incurred a lower risk of health consequences including major cardiovascular diseases, and all-cause mortality than unvaccinated or patients with incomplete vaccination 30-90 days after infection. Completely vaccinated and patients with booster dose of vaccines did not incur significant higher risk of health consequences from 271 and 91 days of infection onwards, respectively, whilst un-vaccinated and incompletely vaccinated patients continued to incur a greater risk of clinical sequelae for up to a year following SARS-CoV-2 infection. This study provided real-world evidence supporting the effectiveness of COVID-19 vaccines in reducing the risk of long-term health consequences of SARS-CoV-2 infection and its persistence following infection.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Humanos , Estudos de Coortes , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Progressão da Doença , Estudos Retrospectivos , SARS-CoV-2 , Vacinação
11.
Rheumatology (Oxford) ; 63(2): 525-533, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-37208196

RESUMO

OBJECTIVE: Disease activity monitoring in SLE includes serial measurement of anti-double stranded-DNA (dsDNA) antibodies, but in patients who are persistently anti-dsDNA positive, the utility of repeated measurement is unclear. We investigated the usefulness of serial anti-dsDNA testing in predicting flare in SLE patients who are persistently anti-dsDNA positive. METHODS: Data were analysed from patients in a multinational longitudinal cohort with known anti-dsDNA results from 2013 to 2021. Patients were categorized based on their anti-dsDNA results as persistently negative, fluctuating or persistently positive. Cox regression models were used to examine longitudinal associations of anti-dsDNA results with flare. RESULTS: Data from 37 582 visits of 3484 patients were analysed. Of the patients 1029 (29.5%) had persistently positive anti-dsDNA and 1195 (34.3%) had fluctuating results. Anti-dsDNA expressed as a ratio to the normal cut-off was associated with the risk of subsequent flare, including in the persistently positive cohort (adjusted hazard ratio [HR] 1.56; 95% CI: 1.30, 1.87; P < 0.001) and fluctuating cohort (adjusted HR 1.46; 95% CI: 1.28, 1.66), both for a ratio >3. Both increases and decreases in anti-dsDNA more than 2-fold compared with the previous visit were associated with increased risk of flare in the fluctuating cohort (adjusted HR 1.33; 95% CI: 1.08, 1.65; P = 0.008) and the persistently positive cohort (adjusted HR 1.36; 95% CI: 1.08, 1.71; P = 0.009). CONCLUSION: Absolute value and change in anti-dsDNA titres predict flares, including in persistently anti-dsDNA positive patients. This indicates that repeat monitoring of dsDNA has value in routine testing.


Assuntos
Anticorpos Antinucleares , Lúpus Eritematoso Sistêmico , Humanos , DNA , Coleta de Dados , Testes Hematológicos
12.
J Allergy Clin Immunol ; 153(4): 1125-1139, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38072195

RESUMO

BACKGROUND: Inborn errors of immunity (IEI) often lack specific disease models and personalized management. Signal transducer and activator of transcription (STAT)-1 gain of function (GoF) is such example of an IEI with diverse clinical phenotype with unclear pathomechanisms and unpredictable response to therapy. Limitations in obtaining fresh samples for functional testing and research further highlights the need for patient-specific ex vivo platforms. OBJECTIVE: Using STAT1-GoF as an example IEI, we investigated the potential of patient-derived expanded potential stem cells (EPSC) as an ex vivo platform for disease modeling and personalized treatment. METHODS: We generated EPSC derived from individual STAT1-GoF patients. STAT1 mutations were confirmed with Sanger sequencing. Functional testing including STAT1 phosphorylation/dephosphorylation and gene expression with or without Janus activating kinase inhibitors were performed. Functional tests were repeated on EPSC lines with GoF mutations repaired by CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) editing. RESULTS: EPSC were successfully reprogrammed from STAT1-GoF patients and expressed the same pluripotent makers as controls, with distinct morphologic differences. Patient-derived EPSC recapitulated the functional abnormalities of index STAT1-GoF patients with STAT1 hyperphosphorylation and increased expression of STAT1 and its downstream genes (IRF1, APOL6, and OAS1) after IFN-γ stimulation. Addition of ruxolitinib and baricitinib inhibited STAT1 hyperactivation in STAT1-GoF EPSC in a dose-dependent manner, which was not observed with tofacitinib. Corrected STAT1 phosphorylation and downstream gene expression were observed among repaired STAT1-GoF EPSC cell lines. CONCLUSION: This proof-of-concept study demonstrates the potential of our patient-derived EPSC platform to model STAT1-GoF. We propose this platform when researching, recapitulating, and repairing other IEI in the future.


Assuntos
Mutação com Ganho de Função , Fator de Transcrição STAT1 , Células-Tronco , Humanos , Mutação , Fosforilação , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Células-Tronco/imunologia , Células-Tronco/metabolismo
13.
Cell Rep Med ; 4(10): 101195, 2023 10 17.
Artigo em Inglês | MEDLINE | ID: mdl-37716352

RESUMO

It is unknown if vaccination affects the risk of post-COVID-19 cardiovascular diseases (CVDs). Therefore, this retrospective cohort study examines the short-term and long-term risks of post-infection CVD among COVID-19 patients with different vaccination status utilizing data from electronic health databases in Hong Kong. Cox proportional hazards regression adjusted with inverse probability of treatment weighting is used to evaluate the risks of incident CVD (coronary heart disease, stroke, heart failure) and all-cause mortality in COVID-19 patients. Compared with unvaccinated patients, vaccinated patients have a lower risk of CVD and all-cause mortality, and the lowest risk is observed in those who completed three doses of vaccine. Similar patterns in the subgroups of different vaccine platforms, age, gender, Charlson comorbidity index, and disease severity are observed. These findings highlight a positive dose-response relationship between overall CVD risk reduction and the number of vaccine doses received.


Assuntos
COVID-19 , Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/epidemiologia , Vacina BNT162 , Estudos de Coortes , Estudos Retrospectivos , COVID-19/epidemiologia , COVID-19/prevenção & controle , Vacinação
14.
EClinicalMedicine ; 64: 102225, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37753272

RESUMO

Background: Molnupiravir and nirmatrelvir-ritonavir have emerged as promising options for COVID-19 treatment, but direct comparisons of their effectiveness have been limited. This study aimed to compare the effectiveness of these two oral antiviral drugs in non-hospitalised and hospitalised patients with COVID-19. Methods: In this target trial emulation study, we used data from a territory-wide electronic health records database on eligible patients aged ≥18 years infected with COVID-19 who were prescribed either molnupiravir or nirmatrelvir-ritonavir within five days of infection between 16 March 2022 and 31 December 2022 in the non-hospitalised and hospitalised settings in Hong Kong. A sequence trial approach and 1:1 propensity score matching was applied based on age, sex, number of COVID-19 vaccine doses received, Charlson comorbidity index, comorbidities, and drug use within past 90 days. Cox regression adjusted with patients' characteristics was used to compare the risk of effectiveness outcomes (all-cause mortality, intensive care unit (ICU) admission or ventilatory support and hospitalisation) between groups. Subgroup analyses included age (<70; ≥70 years); sex, Charlson comorbidity index (<4; ≥4), and number of COVID-19 vaccine doses received (0-1; ≥2 doses). Findings: A total of 63,522 non-hospitalised (nirmatrelvir-ritonavir: 31,761; molnupiravir: 31,761) and 11,784 hospitalised (nirmatrelvir-ritonavir: 5892; molnupiravir: 5892) patients were included. In non-hospitalised setting, 336 events of all-cause mortality (nirmatrelvir-ritonavir: 71, 0.22%; molnupiravir: 265, 0.83%), 162 events of ICU admission or ventilatory support (nirmatrelvir-ritonavir: 71, 0.22%; molnupiravir: 91, 0.29%), and 4890 events of hospitalisation (nirmatrelvir-ritonavir: 1853, 5.83%; molnupiravir: 3037, 9.56%) were observed. Lower risks of all-cause mortality (absolute risk reduction (ARR) at 28 days: 0.61%, 95% CI: 0.50-0.72; HR: 0.43, 95% CI: 0.33-0.56) and hospital admission (ARR at 28 days: 3.73%, 95% CI: 3.31-4.14; HR: 0.72, 95% CI: 0.67-0.76) were observed in nirmatrelvir-ritonavir users compared to molnupiravir users. In hospitalised setting, 509 events of all-cause mortality (nirmatrelvir-ritonavir: 176, 2.99%; molnupiravir: 333, 5.65%), and 50 events of ICU admission or ventilatory support (nirmatrelvir-ritonavir: 26, 0.44%; molnupiravir: 24, 0.41%) were observed. Risk of all-cause mortality was lower for nirmatrelvir-ritonavir users than for molnupiravir users (ARR at 28 days: 2.66%, 95% CI: 1.93-3.40; HR: 0.59, 95% CI: 0.49-0.71). In both settings, there was no difference in the risk of intensive care unit admission or ventilatory support between groups. The findings were consistent across all subgroup's analyses. Interpretation: Our analyses suggest that nirmatrelvir-ritonavir was more effective than molnupiravir in reducing the risk of all-cause mortality in both non-hospitalised and hospitalised patients. When neither drug is contraindicated, nirmatrelvir-ritonavir may be considered the more effective option. Funding: HMRF Research on COVID-19, The Hong Kong Special Administrative Region (HKSAR) Government; Collaborative Research Fund, University Grants Committee, the HKSAR Government; and Research Grant from the Food and Health Bureau, the HKSAR Government; the Laboratory of Data Discovery for Health (D24H) funded by the AIR@InnoHK administered by Innovation and Technology Commission.

15.
EClinicalMedicine ; 63: 102154, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37637754

RESUMO

Background: Case reports suggest that SARS-CoV-2 infection could lead to immune dysregulation and trigger autoimmunity while COVID-19 vaccination is effective against severe COVID-19 outcomes. We aim to examine the association between COVID-19 and development of autoimmune diseases (ADs), and the potential protective effect of COVID-19 vaccination on such an association. Methods: A retrospective cohort study was conducted in Hong Kong between 1 April 2020 and 15 November 2022. COVID-19 was confirmed by positive polymerase chain reaction or rapid antigen test. Cox proportional hazard regression with inverse probability of treatment weighting was applied to estimate the risk of incident ADs following COVID-19. COVID-19 vaccinated population was compared against COVID-19 unvaccinated population to examine the protective effect of COVID-19 vaccination on new ADs. Findings: The study included 1,028,721 COVID-19 and 3,168,467 non-COVID individuals. Compared with non-COVID controls, patients with COVID-19 presented an increased risk of developing pernicious anaemia [adjusted Hazard Ratio (aHR): 1.72; 95% Confidence Interval (CI): 1.12-2.64]; spondyloarthritis [aHR: 1.32 (95% CI: 1.03-1.69)]; rheumatoid arthritis [aHR: 1.29 (95% CI: 1.09-1.54)]; other autoimmune arthritis [aHR: 1.43 (95% CI: 1.33-1.54)]; psoriasis [aHR: 1.42 (95% CI: 1.13-1.78)]; pemphigoid [aHR: 2.39 (95% CI: 1.83-3.11)]; Graves' disease [aHR: 1.30 (95% CI: 1.10-1.54)]; anti-phospholipid antibody syndrome [aHR: 2.12 (95% CI: 1.47-3.05)]; immune mediated thrombocytopenia [aHR: 2.1 (95% CI: 1.82-2.43)]; multiple sclerosis [aHR: 2.66 (95% CI: 1.17-6.05)]; vasculitis [aHR: 1.46 (95% CI: 1.04-2.04)]. Among COVID-19 patients, completion of two doses of COVID-19 vaccine shows a decreased risk of pemphigoid, Graves' disease, anti-phospholipid antibody syndrome, immune-mediated thrombocytopenia, systemic lupus erythematosus and other autoimmune arthritis. Interpretation: Our findings suggested that COVID-19 is associated with an increased risk of developing various ADs and the risk could be attenuated by COVID-19 vaccination. Future studies investigating pathology and mechanisms would be valuable to interpreting our findings. Funding: Supported by RGC Collaborative Research Fund (C7154-20GF).

16.
Int J Mol Sci ; 24(15)2023 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-37569452

RESUMO

Our skin is the largest organ of the body and the foremost defensive barrier against the external environment [...].


Assuntos
Autoimunidade , Pele
17.
Adv Healthc Mater ; 12(29): e2301394, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37540810

RESUMO

It is challenging to manage inflammatory diseases using traditional anti-inflammatory drugs due to their limited efficacy and systemic side effects, which are a result of their lack of selectivity, poor stability, and low solubility. Herein, it reports the development of a novel nanoparticle system, called ROS-CA-NPs, which is formed using polymer-cinnamaldehyde (CA) conjugates and is responsive to reactive oxygen species (ROS). ROS-CA-NPs exhibit excellent drug stability, tissue selectivity, and controlled drug release upon oxidative stress activation. Using mouse models of chronic rheumatoid arthritis and acute ulcerative colitis, this study demonstrates that the systemic administration of ROS-CA-NPs results in their accumulation at inflamed lesions and leads to greater therapeutic efficacy compared to traditional drugs. Furthermore, ROS-CA-NPs present excellent biocompatibility. The findings suggest that ROS-CA-NPs have the potential to be developed as safe and effective nanotherapeutic agents for a broad range of inflammatory diseases.


Assuntos
Nanopartículas , Pró-Fármacos , Animais , Camundongos , Pró-Fármacos/farmacologia , Pró-Fármacos/uso terapêutico , Espécies Reativas de Oxigênio , Polímeros , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico
18.
Front Immunol ; 14: 1200732, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37398664

RESUMO

Objectives: Lupus nephritis (LN) remains one of the most severe manifestations in patients with systemic lupus erythematosus (SLE). Onset and overall LN risk among SLE patients remains considerably difficult to predict. Utilizing a territory-wide longitudinal cohort of over 10 years serial follow-up data, we developed and validated a risk stratification strategy to predict LN risk among Chinese SLE patients - Risk and Factors associated with disease manifestations in systemic Lupus Erythematosus - Lupus Nephritis (RIFLE-LN). Methods: Demographic and longitudinal data including autoantibody profiles, clinical manifestations, major organ involvement, LN biopsy results and outcomes were documented. Association analysis was performed to identify factors associated with LN. Regression modelling was used to develop a prediction model for 10-year risk of LN and thereafter validated. Results: A total of 1652 patients were recruited: 1382 patients were assigned for training and validation of the RIFLE-LN model; while 270 were assigned for testing. The median follow-up duration was 21 years. In the training and validation cohort, 845 (61%) of SLE patients developed LN. Cox regression and log rank test showed significant positive association between male sex, age of SLE onset and anti-dsDNA positivity. These factors were thereafter used to develop RIFLE-LN. The algorithm was tested in 270 independent patients and showed good performance (AUC = 0·70). Conclusion: By using male sex, anti-dsDNA positivity, age of SLE onset and SLE duration; RIFLE-LN can predict LN among Chinese SLE patients with good performance. We advocate its potential utility in guiding clinical management and disease monitoring. Further validation studies in independent cohorts are required.


Assuntos
Lúpus Eritematoso Sistêmico , Nefrite Lúpica , Humanos , Masculino , Nefrite Lúpica/diagnóstico , Nefrite Lúpica/epidemiologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/diagnóstico , Lúpus Eritematoso Sistêmico/epidemiologia , Autoanticorpos
19.
J Intern Med ; 294(3): 314-325, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37282790

RESUMO

BACKGROUND: This study aimed to compare the cardiovascular safety of interleukin-6 inhibitors (IL-6i) and Janus Kinase inhibitors (JAKi) to tumour necrosis factor inhibitors (TNFi). METHODS: We conducted a retrospective cohort study using population-based electronic databases from Hong Kong, Taiwan and Korea. We identified newly diagnosed patients with rheumatoid arthritis (RA) who received b/tsDMARDs first time. We followed patients from b/tsDMARD initiation to the earliest outcome (acute coronary heart disease, stroke, heart failure, venous thromboembolism and systemic embolism) or censoring events (death, transformation of b/tsDMARDs on different targets, discontinuation and study end). Using TNFi as reference, we applied generalized linear regression for the incidence rate ratio estimation adjusted by age, sex, disease duration and comorbidities. Random effects meta-analysis was used for pooled analysis. RESULTS: We identified 8689 participants for this study. Median (interquartile range) follow-up years were 1.45 (2.77) in Hong Kong, 1.72 (2.39) in Taiwan and 1.45 (2.46) in Korea. Compared to TNFi, the adjusted incidence rate ratios (aIRRs) (95% confidence interval [CI]) of IL-6i in Hong Kong, Taiwan and Korea are 0.99 (0.25, 3.95), 1.06 (0.57, 1.98) and 1.05 (0.59, 1.86) and corresponding aIRR of JAKi are 1.50 (0.42, 5.41), 0.60 (0.26, 1.41), and 0.81 (0.38, 1.74), respectively. Pooled aIRRs showed no significant risk of cardiovascular events (CVEs) associated with IL-6i (1.05 [0.70, 1.57]) nor JAKi (0.80 [0.48, 1.35]) compared to TNFi. CONCLUSION: There was no difference in the risk of CVE among RA patients initiated with IL-6i, or JAKi compared to TNFi. The finding is consistent in Hong Kong, Taiwan and Korea.


Assuntos
Antirreumáticos , Artrite Reumatoide , Doenças Cardiovasculares , Humanos , Doenças Cardiovasculares/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Fatores de Risco de Doenças Cardíacas , Antirreumáticos/efeitos adversos , Estudos Multicêntricos como Assunto
20.
J Travel Med ; 30(5)2023 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-37310901

RESUMO

INTRODUCTION: Evidence on long-term associations between coronavirus disease 2019 (COVID-19) and risks of multi-organ complications and mortality in older population is limited. This study evaluates these associations. RESEARCH DESIGN AND METHODS: The cohorts included patients aged ≥60 year diagnosed with COVID-19 infection (cases), between 16 March 2020 and 31 May 2021 from the UK Biobank; and between 01 April 2020 and 31 May 2022 from the electronic health records in Hong Kong. Each patient was randomly matched with individuals without COVID-19 infection based on year of birth and sex and were followed for up to 18 months until 31 August 2021 for UKB, and up to 28 months until 15 August 2022 for HK cohort. Patients with COVID-19 infection over 6 months after the date of last dose of vaccination and their corresponding controls were excluded from our study. Characteristics between cohorts were further adjusted with Inverse Probability Treatment Weighting. For evaluating long-term association of COVID-19 with multi-organ disease complications and mortality after 21-days of diagnosis, Cox regression was employed. RESULT: 10,759 (UKB) and 165,259 (HK) older adults with COVID-19 infection with matched 291,077 (UKB) and 1,100,394 (HK) non-COVID-19-diagnosed older adults were recruited. Older adults with COVID-19 were associated with a significantly higher risk of cardiovascular outcomes [major cardiovascular disease (stroke, heart failure and coronary heart disease): hazard ratio(UKB): 1.4 (95% Confidence interval: 1.1,1.6), HK:1.2 (95% CI: 1.1,1.3)]; myocardial infarction: HR(UKB): 1.8 (95% CI: 1.3,2.4), HK:1.2 (95% CI: 1.0,1.4)]; respiratory outcomes [interstitial lung disease: HR(UKB: 3.4 (95% CI: 2.5,4.5), HK: 4.0 (95% CI: 1.3,12.8); chronic pulmonary disease: HR(UKB): 1.7 (95% CI: 1.3,2.2), HK:1.6 (95% CI: 1.3,2.1)]; neuropsychiatric outcomes [seizure: HR(UKB): 2.6 (95% CI: 1.7,4.1), HK: 1.6 (95% CI: 1.2,2.1)]; and renal outcomes [acute kidney disease: HR(UKB): 1.4 (95% CI: 1.1,1.6), HK:1.6 (95% CI: 1.3,2.1)]; and all-cause mortality [HR(UKB): 4.9 (95% CI: 4.4,5.4), HK:2.5 (95% CI: 2.5,2.6)]. CONCLUSION: COVID-19 is associated with long-term risks of multi-organ complications in older adults (aged ≥ 60). Infected patients in this age-group may benefit from appropriate monitoring of signs/symptoms for developing these complications.


Assuntos
COVID-19 , Doenças Cardiovasculares , Idoso , Humanos , Doenças Cardiovasculares/epidemiologia , COVID-19/complicações , Progressão da Doença , Hong Kong/epidemiologia , Pessoa de Meia-Idade , Masculino , Feminino
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