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BACKGROUND: Studies of flares of autoimmune inflammatory rheumatic diseases (AIIRD) after COVID-19 mRNA vaccination are limited by small sample size, short follow up or at risk of selection bias. METHODS: A national retrospective cohort study of consecutive AIIRD patients ≥12 years old, across 8 hospitals who received at least one dose of a COVID-19 mRNA vaccine. Patients were included from the date of 1st vaccine dose and censored at the time of flare or on the date of the clinic visit at least 3 months from cohort entry, whichever came first. Predictors of flare were determined by Cox proportional hazards analysis. FINDINGS: 4627 patients (73% Chinese, 71% female) of median (IQR) age 61 (48, 70) years were included; 42% Rheumatoid arthritis, 14% Systemic lupus erythematosus and 11% Psoriatic arthritis. 47% were in remission, 41% low disease activity, 10% moderate disease activity and 1% in high disease activity. 18% patients flared, of which 11.7% were within the 3-month period of interest. 11.8% patients improved. Median (IQR) time-to-flare was 60 (30, 114) days. 25% flares were self-limiting, 61% mild-moderate and 14% severe. Older patients (53-65 years and >66 years) had a lower risk of flare [HR 0.6 (95% CI 0.5-0.8) and 0.7 (0.6-0.8) respectively]. Patients with inflammatory arthritis and with active disease had a higher risk of flare [HR 1.5 (1.2-2.0) and 1.4 (1.2-1.6), respectively]. Treatment with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), immunosuppression and prednisolone was also associated with an increased risk of flare [HR 1.5 (1.1-2), 1.2 (1.1-1.4) and 1.5 (1.2-1.8) for prednisolone ≤7.5 mg respectively]. INTERPRETATION: There was a moderately high rate of AIIRD flares after mRNA vaccination but also improvement in several patients. Severe flares and hospitalisation were rare. Thus, vaccination remains safe and highly recommended.
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Artrite Reumatoide , Doenças Autoimunes , COVID-19 , Coronavirus , Lúpus Eritematoso Sistêmico , Febre Reumática , Humanos , Feminino , Pessoa de Meia-Idade , Criança , Masculino , Vacinas contra COVID-19/uso terapêutico , Estudos Retrospectivos , Singapura/epidemiologia , COVID-19/epidemiologia , COVID-19/prevenção & controle , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/epidemiologia , Prednisolona/uso terapêutico , Vacinas Sintéticas/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Vacinação , Sistema de Registros , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/epidemiologia , Vacinas de mRNARESUMO
Complement is viewed as a critical serum-operative component of innate immunity, with processing of its key component, C3, into activation fragments C3a and C3b confined to the extracellular space. We report here that C3 activation also occurred intracellularly. We found that the T cell-expressed protease cathepsin L (CTSL) processed C3 into biologically active C3a and C3b. Resting T cells contained stores of endosomal and lysosomal C3 and CTSL and substantial amounts of CTSL-generated C3a. While "tonic" intracellular C3a generation was required for homeostatic T cell survival, shuttling of this intracellular C3-activation-system to the cell surface upon T cell stimulation induced autocrine proinflammatory cytokine production. Furthermore, T cells from patients with autoimmune arthritis demonstrated hyperactive intracellular complement activation and interferon-γ production and CTSL inhibition corrected this deregulated phenotype. Importantly, intracellular C3a was observed in all examined cell populations, suggesting that intracellular complement activation might be of broad physiological significance.
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Subpopulações de Linfócitos B/citologia , Linfócitos T CD4-Positivos/imunologia , Catepsina L/metabolismo , Diferenciação Celular , Ativação do Complemento/fisiologia , Complemento C3/metabolismo , Homeostase/fisiologia , Adulto , Artrite Reumatoide/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linhagem Celular , Sobrevivência Celular/imunologia , Criança , Complemento C3/imunologia , Complemento C3a/metabolismo , Complemento C3b/metabolismo , Regulação da Expressão Gênica/imunologia , HumanosRESUMO
OBJECTIVES: Targeting remission in rheumatoid arthritis (RA) improves health-related quality of life (HRQoL) and disability. However, the impacts of different remission criteria and durations and their frequencies are uncertain. Our observational study assessed these factors. METHODS: We recruited RA patients with disease durations <10 years, stable suppressive therapies and stable disease activity scores for 28 joints using ESR (DAS28-ESR) ≤3.2. Intermittent and sustained remisisons were classified using DAS28ESR, simple disease activity index (SDAI) and ACR/EULAR Boolean criteria. HRQoL, measured using SF-36, fatigue, EuroQol and health assessment questionnaire (HAQ) was compared using time-integrated areas under the curve (AUC). RESULTS: 104 patients were enrolled and followed for 12 months. DAS28-ESR remissions were intermittent in 42%, sustained in 47% and absent in 11%. Boolean remissions were intermittent in 38%, sustained in 10% and absent in 52%. Baseline remissions by all criteria significantly improved HAQ, Euroqol, SF36 and fatigue scores compared with low disease activity (LDAS); AUCs showed significant benefits for all HRQoLs persisted over 12-months. Boolean remissions achieved most benefits. Over time all remission states gave significantly better HRQoL scores than LDAS. Sustained DAS28ESR and SDAI remissions improved HRQoL more than intermittent remissions. Sustained and intermittent Boolean remissions gave similar improvements. Analysis of SF-36 domains showed even sustained Boolean remissions failed to optimise pain and fatigue. CONCLUSIONS: All remissions improve HRQoL but different criteria have variable impacts. Boolean remission had most impact but occurred least. There are trade-off between optimising individual impacts (Boolean remissions) and achieving maximal overall impacts (DAS28-ESR remissions).
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Artrite Reumatoide/psicologia , Qualidade de Vida , Idoso , Sedimentação Sanguínea , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Objectives: RA patients receiving TNF inhibitors (TNFi) usually maintain their initial doses. The aim of the Optimizing Treatment with Tumour Necrosis Factor Inhibitors in Rheumatoid Arthritis trial was to evaluate whether tapering TNFi doses causes loss of clinical response. Methods: We enrolled RA patients receiving etanercept or adalimumab and a DMARD with DAS28 under 3.2 for over 3 months. Initially (months 0-6) patients were randomized to control (constant TNFi) or two experimental groups (tapering TNFi by 33 or 66%). Subsequently (months 6-12) control subjects were randomized to taper TNFi by 33 or 66%. Disease flares (DAS28 increasing ⩾0.6 with at least one additional swollen joint) were the primary outcome. Results: Two hundred and forty-four patients were screened, 103 randomized and 97 treated. In months 0-6 there were 8/50 (16%) flares in controls, 3/26 (12%) with 33% tapering and 6/21 (29%) with 66% tapering. Multivariate Cox analysis showed time to flare was unchanged with 33% tapering but was reduced with 66% tapering compared with controls (adjusted hazard ratio 2.81, 95% CI: 0.99, 7.94; P = 0.051). Analysing all tapered patients after controls were re-randomized (months 6-12) showed differences between groups: there were 6/48 (13%) flares with 33% tapering and 14/39 (36%) with 66% tapering. Multivariate Cox analysis showed 66% tapering reduced time to flare (adjusted hazard ratio 3.47, 95% CI: 1.26, 9.58; P = 0.016). Conclusion: Tapering TNFi by 33% has no impact on disease flares and appears practical in patients in sustained remission and low disease activity states. Trail registration: EudraCT, https://www.clinicaltrialsregister.eu, 2010-020738-24; ISRCTN registry, https://www.isrctn.com, 28955701.
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Adalimumab/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Etanercepte/administração & dosagem , Idoso , Artrite Reumatoide/fisiopatologia , Progressão da Doença , Feminino , Humanos , Quimioterapia de Manutenção , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Indução de Remissão , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
Introduction: Periodontitis as a comorbidity in systemic lupus erythematosus (SLE) is still not well recognized in the dental and rheumatology communities. A meta-analysis and network meta-analysis were thus performed to compare the (i) prevalence of periodontitis in SLE patients compared to those with rheumatoid arthritis (RA) and (ii) odds of developing periodontitis in controls, RA, and SLE. Methods: Pooled prevalence of and odds ratio (OR) for periodontitis were compared using meta-analysis and network meta-analysis (NMA). Results: Forty-three observational studies involving 7,800 SLE patients, 49,388 RA patients, and 766,323 controls were included in this meta-analysis. The pooled prevalence of periodontitis in SLE patients (67.0%, 95% confidence interval [CI] 57.0-77.0%) was comparable to that of RA (65%, 95% CI 55.0-75.0%) (p>0.05). Compared to controls, patients with SLE (OR=2.64, 95% CI 1.24-5.62, p<0.01) and RA (OR=1.81, 95% CI 1.25-2.64, p<0.01) were more likely to have periodontitis. Indirect comparisons through the NMA demonstrated that the odds of having periodontitis in SLE was 1.49 times higher compared to RA (OR=1.49, 95% CI 1.09-2.05, p<0.05). Discussion: Given that RA is the autoimmune disease classically associated with periodontal disease, the higher odds of having periodontitis in SLE are striking. These results highlight the importance of addressing the dental health needs of patients with SLE. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/ identifier CRD42021272876.
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Artrite Reumatoide , Lúpus Eritematoso Sistêmico , Periodontite , Humanos , Artrite Reumatoide/epidemiologia , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/epidemiologia , Metanálise em Rede , Estudos Observacionais como Assunto , Razão de Chances , Periodontite/epidemiologiaRESUMO
BACKGROUND: Immunity to SARS-CoV-2 vaccination and infection differs considerably among individuals. We investigate the critical pathways that influence vaccine-induced cross-variant serological immunity among individuals at high-risk of COVID-19 complications. METHODS: Neutralizing antibodies to the wild-type SARS-CoV-2 virus and its variants (Beta, Gamma, Delta and Omicron) were analyzed in patients with autoimmune diseases, chronic comorbidities (multimorbidity), and healthy controls. Antibody levels were assessed at baseline and at different intervals up to 12 months following primary and booster vaccination with either BNT162b2 or mRNA-1273. Immunity induced by vaccination with and without infection (hybrid immunity) was compared with that of unvaccinated individuals with recent SARS-CoV-2 infection. Plasma cytokines were analyzed to investigate variations in antibody production following vaccination. RESULTS: Patients with autoimmune diseases (n = 137) produced lesser antibodies to the wild-type SARS-CoV-2 virus and its variants compared with those in the multimorbidity (n = 153) and healthy groups (n = 229); antibody levels were significantly lower in patients with neuromyelitis optica and those on prednisolone, mycophenolate or rituximab treatment. Multivariate logistic regression analysis identified neuromyelitis optica (odds ratio 8.20, 95% CI 1.68-39.9) and mycophenolate (13.69, 3.78-49.5) as significant predictors of a poorer antibody response to vaccination (i.e, neutralizing antibody <40%). Infected participants exhibited antibody levels that were 28.7% higher (95% CI 24.7-32.7) compared to non-infected participants six months after receiving a booster vaccination. Individuals infected during the Delta outbreak generated cross-protective neutralizing antibodies against the Omicron variant in quantities comparable to those observed after infection with the Omicron variant itself. In contrast, unvaccinated individuals recently infected with the wild-type (n = 2390) consistently displayed lower levels of neutralizing antibodies against both the wild-type virus and other variants. Pathway analyses suggested an inverse relationship between baseline T cell subsets and antibody production following vaccination. CONCLUSION: Hybrid immunity confers a robust protection against COVID-19 among immunocompromised individuals.
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OBJECTIVE: To determine prevalence and factors associated with flares post Coronavirus disease 2019 (COVID-19) mRNA vaccination in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA). METHODS: A retrospective multi-centre study was conducted (January 2021 to February 2022). Data were collected during index visit, defined as first post-vaccine visit in which the patient had a physician-defined flare, or if at least 3 months had elapsed since first vaccine dose, whichever came first. Factors associated with flares were identified using mixed effects Cox regression and expressed as hazard ratio (HR) and 95% confidence interval (CI). RESULTS: Total of 2377 patients were included (1563 RA, 415 PsA and 399 SpA). Among patients with RA, PsA and SpA, 21.3%, 24.1% and 21.8% experienced a flare respectively. Of those who experienced a flare, only 10.2%, 11.0% and 14.9% were severe in patients with RA, PsA and SpA respectively. Patients with low or moderate/high disease were more likely to flare compared to those in remission in patients with RA only (HR: 1.68, 95% CI 1.22-2.31; HR: 2.28, 95% CI 1.50-3.48, respectively). Receiving the Moderna vaccine was associated with a higher HR of flare compared to the Pfizer vaccine in patients with PsA only (HR: 2.21, 95% CI 1.20-4.08). Patients who had two vaccine doses were found to be less likely to flare (HR: 0.08, 95% CI 0.06-0.10). HRs of flares were not significantly different among RA, PsA and SpA. CONCLUSION: About one-fifth of patients experienced a disease flare post COVID-19 mRNA vaccination, but most flares were non-severe. Patients with active disease prior to vaccination should be monitored closely for disease flares, especially in patients with RA.
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Artrite Psoriásica , Artrite Reumatoide , COVID-19 , Espondilartrite , Humanos , Artrite Psoriásica/epidemiologia , Estudos de Coortes , Prevalência , COVID-19/epidemiologia , COVID-19/prevenção & controle , Artrite Reumatoide/epidemiologia , Espondilartrite/epidemiologia , VacinaçãoRESUMO
We recently reported that messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccination was associated with flares in 9% of patients with systemic lupus erythematosus (SLE). Herein, we focused our analysis on patients from a multi-ethnic Southeast Asian lupus cohort with the intention of identifying distinct phenotypes associated with increased flares after mRNA COVID-19 vaccination. METHODS: Six hundred and thirty-three SLE patients from eight public healthcare institutions were divided into test and validation cohorts based on healthcare clusters. Latent class analysis was performed based on age, ethnicity, gender, vaccine type, past COVID-19 infection, interruption of immunomodulatory/immunosuppressive treatment for vaccination, disease activity and background immunomodulatory/immunosuppressive treatment as input variables. Data from both cohorts were then combined for mixed effect Cox regression to determine which phenotypic cluster had a higher risk for time to first SLE flare, adjusted for the number of vaccine doses. RESULTS: Two clusters were identified in the test (C1 vs. C2), validation (C1' vs. C2') and combined (C1â³ vs. C2â³) cohorts, with corresponding clusters sharing similar characteristics. Of 633 SLE patients, 88.6% were female and there was multi-ethnic representation with 74.9% Chinese, 14.2% Malay and 4.6% Indian. The second cluster (C2, C2' and C2â³) was smaller compared to the first. SLE patients in the second cluster (C2 and C2') were more likely to be male, non-Chinese and younger, with higher baseline disease activity. The second cluster (C2â³) had more incident flares (hazard ratio = 1.4, 95% confidence interval 1.1-1.9, p = 0.014) after vaccination. A higher proportion of patients in C2â³ had immunomodulatory/immunosuppressive treatment interruption for vaccination as compared to patients in C1â³ (6.6% vs. 0.2%) (p < 0.001). CONCLUSION: We identified two distinct phenotypic clusters of SLE with different patterns of flares following mRNA COVID-19 vaccination. Caution has to be exercised in monitoring for post-vaccination flares in patients with risk factors for flares such as non-Chinese ethnicity, young age, male gender and suboptimal disease control at the time of vaccination.
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BACKGROUND: Pain is the main concern of patients with rheumatoid arthritis (RA) while reducing disease activity dominates specialist management. Disease activity assessments like the disease activity score for 28 joints with the erythrocyte sedimentation rate (DAS28-ESR) omit pain creating an apparent paradox between patients' concerns and specialists' treatment goals. We evaluated the relationship of pain intensity and disease activity in RA with three aims: defining associations between pain intensity and disease activity and its components, evaluating discordance between pain intensity and disease activity, and assessing temporal changes in pain intensity and disease activity. METHODS: We undertook secondary analyses of five trials and one observational study of RA patients followed for 12 months. The patients had early and established active disease or sustained low disease activity or remission. Pain was measured using 100-mm visual analogue scales. Individual patient data was pooled across all studies and by types of patients (early active, established active and established remission). Associations of pain intensity and disease activity were evaluated by correlations (Spearman's), linear regression methods and Bland-Altman plots. Discordance was assessed by Kappa statistics (for patients grouped into high and low pain intensity and disease activity). Temporal changes were assessed 6 monthly in different patient groups. RESULTS: A total of 1132 patients were studied: 490 had early active RA, 469 had established active RA and 173 were in remission/low disease activity. Our analyses showed, firstly, that pain intensity is associated with disease activity in general, and particularly with patient global assessments, across all patient groups. Patient global assessments were a reasonable proxy for pain intensity. Secondly, there was some discordance between pain intensity and disease activity across all disease activity levels, reflecting similar discrepancies in patient global assessments. Thirdly, there were strong temporal relationships between changes in disease activity and pain intensity. When mean disease activity fell, mean pain intensity scores also fell; when mean disease activity increased, there were comparable increases in pain intensity. CONCLUSIONS: These findings show pain intensity is an integral part of disease activity, though it is not measured directly in DAS28-ESR. Reducing disease activity is crucial for reducing pain intensity in RA.
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Artrite Reumatoide , Artrite Reumatoide/complicações , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/terapia , Sedimentação Sanguínea , Humanos , Dor/etiologia , Medição da Dor/métodos , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To evaluate attitudes and behaviors of patients with rheumatic diseases during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: An online survey delivered by text message to 4695 patients on follow-up at a tertiary rheumatology center. Latent class analysis was performed on the survey variables. RESULTS: There were 2239 (47.7%) who responded to the survey and 3 clusters were identified. Cluster 3 (C3) was defined by patients who were most worried about COVID-19, more likely to wear face masks, and more likely to alter or stop their medications. Patients in C3 were more likely to be female, Malay, and unemployed. CONCLUSION: We identified 3 clusters with different healthcare beliefs and distinct sociodemographics.
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COVID-19/psicologia , Conhecimentos, Atitudes e Prática em Saúde , Doenças Reumáticas/psicologia , Adulto , Idoso , Surtos de Doenças , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Inquéritos e Questionários , ViagemRESUMO
OBJECTIVE: We examined how combination DMARD therapies and TNF inhibitors therapies plus MTX (TNF/MTX) affect clinical and radiological outcomes compared with MTX monotherapy in early RA. METHODS: We systematically searched EMBASE, PubMed and Ovid Medline for randomized controlled trials (RCTs) of combination therapy in early RA. We evaluated ACR responses, withdrawals for inefficacy and toxicity, HAQ and radiographic progression. Meta-analysis using Review Manager evaluated random effects odds ratios (ORs) and random effects weighted mean differences (WMDs) between treatments. RESULTS: A preliminary search identified 2029 citations; 15 were relevant RCTs (4200 randomized patients). Patients with active disease were enrolled. Compared with MTX monotherapy, both combination DMARDs and TNF/MTX increased ACR20-70 responses (OR 1.64-2.02 and 2.03-2.30, respectively), reduced withdrawals for inefficacy (OR 0.52 and 0.29), reduced HAQ (WMD -0.17 and -0.16) and reduced annual X-ray progression (WMD -1.20 and -0.84%). DMARD combinations increased withdrawals for toxicity (OR 2.69; there was no difference with TNF/MTX). The only head-to-head RCT showed comparable efficacy for combination DMARDs and TNF/MTX combinations. CONCLUSIONS: In early active RA, both combination DMARDs and TNF/MTX are more effective than MTX monotherapy. DMARD and TNF/MTX combinations had equal efficacy on ACR response, withdrawals for inefficacy, disability and erosive progression. There is an apparent advantage for TNF/MTX combinations in the effect on toxicity with fewer consequent patients. We conclude that there is strong evidence in favour of combination treatment for RA but there is still uncertainty about which regimen is preferable.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Idoso , Antirreumáticos/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
OBJECTIVE: To investigate predictors of flare in rheumatoid arthritis (RA) patients with low disease activity (LDA) and to evaluate the effect of flare on 12-month clinical outcomes. METHODS: Patients with RA who were taking disease-modifying antirheumatic drugs and had a stable 28-joint count Disease Activity Score (DAS28) < 3.2 were eligible for inclusion. At baseline and every 3 months, clinical (DAS28), functional [Health Assessment Questionnaire-Disability Index (HAQ-DI), EQ-5D, Functional Assessment of Chronic Illness Therapy Fatigue scale (FACIT-F), Medical Outcomes Study Short Form-36 (SF-36)], serum biomarkers [multibiomarker disease activity (MBDA) score, calprotectin, CXCL10], and imaging data were collected. Flare was defined as an increase in DAS28 compared with baseline of > 1.2, or > 0.6 if concurrent DAS28 ≥ 3.2. Cox regression analyses were used to identify baseline predictors of flare. Biomarkers were cross-sectionally correlated at time of flare. Linear regressions were performed to compare clinical outcomes after 1 year. RESULTS: Of 152 patients, 46 (30%) experienced a flare. Functional disability at baseline was associated with flare: HAQ-DI had an unadjusted HR 1.82 (95% CI 1.20-2.72) and EQ-5D had HR 0.20 (95% CI 0.07-0.57). In multivariate analyses, only HAQ-DI remained a significant independent predictor of flare (HR 1.76, 95% CI 1.05-2.93). At time of flare, DAS28 and its components significantly correlated with MBDA and calprotectin, but correlation coefficients were low at 0.52 and 0.49, respectively. Two-thirds of flares were not associated with a rise in biomarkers. Patients who flared had significantly worse outcomes at 12 months (HAQ-DI, EQ-5D, FACIT-F, SF-36, and radiographic progression). CONCLUSION: Flares occur frequently in RA patients with LDA and are associated with worse disease activity, quality of life, and radiographic progression. Higher baseline HAQ-DI was modestly predictive of flare, while biomarker correlation at the time of flare suggests a noninflammatory component in a majority of events.
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Antirreumáticos/uso terapêutico , Artrite Reumatoide/diagnóstico por imagem , Articulações do Pé/diagnóstico por imagem , Articulação da Mão/diagnóstico por imagem , Qualidade de Vida , Adulto , Idoso , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/fisiopatologia , Avaliação da Deficiência , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Radiografia , Índice de Gravidade de Doença , UltrassonografiaRESUMO
Abstract Objective To determine prevalence and factors associated with flares post Coronavirus disease 2019 (COVID-19) mRNA vaccination in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and spondyloarthritis (SpA). Methods A retrospective multi-centre study was conducted (January 2021 to February 2022). Data were collected during index visit, defined as first post-vaccine visit in which the patient had a physician-defined flare, or if at least 3 months had elapsed since first vaccine dose, whichever came first. Factors associated with flares were identified using mixed effects Cox regression and expressed as hazard ratio (HR) and 95% confidence interval (CI). Results Total of 2377 patients were included (1563 RA, 415 PsA and 399 SpA). Among patients with RA, PsA and SpA, 21.3%, 24.1% and 21.8% experienced a flare respectively. Of those who experienced a flare, only 10.2%, 11.0% and 14.9% were severe in patients with RA, PsA and SpA respectively. Patients with low or moderate/high disease were more likely to flare compared to those in remission in patients with RA only (HR: 1.68, 95% CI 1.22-2.31; HR: 2.28, 95% CI 1.50-3.48, respectively). Receiving the Moderna vaccine was associated with a higher HR of flare compared to the Pfizer vaccine in patients with PsA only (HR: 2.21, 95% CI 1.20-4.08). Patients who had two vaccine doses were found to be less likely to flare (HR: 0.08, 95% CI 0.06-0.10). HRs of flares were not significantly different among RA, PsA and SpA. Conclusion About one-fifth of patients experienced a disease flare post COVID-19 mRNA vaccination, but most flares were non-severe. Patients with active disease prior to vaccination should be monitored closely for disease flares, especially in patients with RA.
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Protein transduction domains (PTDs) offer an exciting therapeutic opportunity for the treatment of many diseases. An 11-amino acid fragment of human immunodeficiency type 1 (HIV-1) TAT-protein can transduce large, biologically active proteins into mammalian cells; recent evidence has shown an in vivo PTD for the 116 kDa beta-galactosidase protein. However, there is little information on the in vivo distribution of the TAT fusion protein to define the viability of PTDs for human studies. In this study we examined the tissue kinetics and tissue distribution of the PTD-transduced TAT fusion protein in mice. Low (100 microg) or high (500 microg) doses of TAT-beta-galactosidase fusion protein were administrated to mice through four routes (portal vein, i.v., i.p., and oral). Tissues were harvested 15 min, 1h, 6h, 10h, and 24h after treatment. Distribution of beta-galactosidase in various tissues was analysed by in situ staining, enzymatic activity assay, and Western blot analysis. Beta-galactosidase enzyme activity was observed in all tissues (liver, kidney, spleen, lung, bowel, and brain). Beta-galactosidase activity peaked at 15 min in most tissues after portal vein, i.v., and i.p. administration and at 1h after oral dosing in all tissues. Beta-galactosidase activity in the liver at 15 min after portal vein injection (67 milliunits [mU]/mg) was higher than after i.v. (9.8 mU/mg), i.p. (4.4 mU/mg), and oral (0.3 mU/mg) dosing. In situ staining and Western blot results correlated closely with beta-galactosidase enzyme activity assay. The median initial half-life for activity was 2.2h, ranging from 1.2h to 3.4h (coefficient of variation=28.9%). The bioavailability of beta-galactosidase activity after an orally administered PTD was 24%. This study details the kinetics and tissue distribution of delivering of a model TAT fusion protein into the mouse via PTD. These data allow rational selection of delivery route and schedules for therapeutic PTD and will aid the use of TAT fusion protein transduction in the development of protein therapies.
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Sistemas de Liberação de Medicamentos , Produtos do Gene tat/farmacocinética , Fragmentos de Peptídeos/farmacocinética , Proteínas Recombinantes de Fusão/biossíntese , Proteínas Recombinantes de Fusão/farmacocinética , beta-Galactosidase/farmacocinética , Administração Oral , Animais , Disponibilidade Biológica , Produtos do Gene tat/administração & dosagem , Produtos do Gene tat/genética , Meia-Vida , Humanos , Injeções Intraperitoneais , Injeções Intravenosas , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/genética , Proteínas Recombinantes de Fusão/administração & dosagem , Distribuição Tecidual , Transdução Genética , beta-Galactosidase/administração & dosagem , beta-Galactosidase/genética , Produtos do Gene tat do Vírus da Imunodeficiência HumanaRESUMO
The prodrug irinotecan is an active agent for the treatment of advanced colorectal cancer and a number of other solid tumors. Irinotecan is converted in vivo to SN-38 (7-ethyl-10-hydroxy-camptothecin), the active metabolite that causes cell death, by human liver carboxylesterases. Previous studies suggest that human carboxylesterase 2 (CES2) is the key activating isoform. Although conversion of irinotecan to SN-38 by liver carboxylesterase is an inefficient process, clinical data indicate that irinotecan has significant antitumor activity. This scenario raises the possibility that local conversion of irinotecan to SN-38 by CES2 in tumor tissues might occur. The expression profile of CES2 protein in human tumor tissues was evaluated in a tissue array of 18 different types of human cancer and in a panel of normal human liver samples by immunohistochemistry and Western blot, respectively. Cytosolic CES2 expression was observed in 101 of 154 tumors (66%) and 55 of 60 normal tissues (92%). Among the 18 types of tumors analyzed, 2 types (gallbladder tumor and lymphoma) did not express CES2, 5 types expressed weak CES2, and 11 types expressed moderate to intense CES2. In functional studies, CES2 protein was highly variable among liver samples, with a 15-fold range in cytosol and a 3-fold range in microsome fractions. Liver microsomal CES2 protein expression was significantly correlated with irinotecan activation to SN-38 (R(s) = 0.70; P = 0.007). This study confirms that CES2 is a key enzyme for irinotecan activation. Tumor CES2 expression may contribute to variable response to irinotecan chemotherapy for solid tumors.
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Camptotecina/análogos & derivados , Camptotecina/farmacologia , Hidrolases de Éster Carboxílico/biossíntese , Neoplasias/metabolismo , Western Blotting , Carboxilesterase , Citosol/metabolismo , Relação Dose-Resposta a Droga , Eletroforese em Gel de Poliacrilamida , Humanos , Imuno-Histoquímica , Irinotecano , Cinética , Fígado/patologia , Microssomos Hepáticos/metabolismo , Neoplasias/tratamento farmacológico , Isoformas de Proteínas , Células Tumorais CultivadasRESUMO
Although the mouse has great potential for pharmacogenomic discovery, little is known about variation in drug response or genetic variation in pharmacologically relevant genes between inbred mouse strains. We therefore assessed variation in gene sequence, mRNA expression and protein activity of thiopurine methyltransferase (TPMT) in multiple inbred mouse strains. TPMT activity was measured by high-performance liquid chromatography detection of 6-MMP produced by incubation of liver homogenates with 6-MP. Genetic variation was assessed by resequencing and single nucleotide polymorphism (SNP) genotyping using pyrosequencing technology. mRNA expression was measured by real-time polymerase chain reaction. We observed an almost five-fold variation in TPMT activity, with strains falling into distinct low and high activity groups. This pattern of TPMT activity was highly correlated with expression of TPMT mRNA among strains, and high TPMT expression is dominant in F1 hybrids. To correlate genotype with phenotype, 29 SNPs and one insertion/deletion were genotyped throughout the TPMT gene and upstream 10 kb. Only two haplotypes were observed across all 30 polymorphisms, corresponding to the low and high activity groups. These results suggest that differential mouse TPMT activity is due to variation in mRNA expression. In addition, the identified pattern of low haplotype diversity suggests that the mouse is likely to be useful for pharmacogenomic discovery by associating haplotype blocks with drug response phenotypes among inbred strains.
Assuntos
Metiltransferases/genética , Sequência de Aminoácidos , Animais , Sequência de Bases , Primers do DNA , Genótipo , Humanos , Fígado/enzimologia , Metiltransferases/química , Metiltransferases/metabolismo , Camundongos , Camundongos Endogâmicos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , RNA Mensageiro/genética , Homologia de Sequência de AminoácidosRESUMO
The pharmacokinetics of valspodar (PSC 833), a selective second-generation P-glycoprotein modulator, was evaluated as part of a Phase I study to modulate paclitaxel therapy in 15 patients with refractory malignancies. Valspodar was given intravenously at 1.42 mg/kg/h for 2 hours, followed by a 27-hour continuous infusion at 0.42 mg/kg/h. Serial blood samples were obtained after intravenous infusion of valspodar and paclitaxel. Valspodar disposition was best described by a linear two-compartment model. The median (range) valspodar clearance was 0.40 ml/min/kg (0.07-1.40 ml/min/kg). The 20-fold interpatient variability in valspodar clearance was not correlated with age, body weight, orgender but might be associated with coadministered medications that were metabolized via cytochrome P450 3A-mediated elimination. Valspodar whole-blood concentrations were maintained above the target threshold of 1000 ng/ml for a median of 32 hours. The pharmacokinetic model generated from this study allows for application in future studies to optimize the use of valspodar.
Assuntos
Ciclosporinas/administração & dosagem , Ciclosporinas/farmacocinética , Modelos Biológicos , Adulto , Idoso , Ciclosporinas/sangue , Feminino , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Estatísticas não ParamétricasRESUMO
Mean survival after diagnosis of unresectable pulmonary metastases is less than one year. Isolated lung perfusion (ILP) is a technique that delivers chemotherapy into the pulmonary artery via a thoracotomy. Human trials are limited. We report an animal model for endovascular lung perfusion (ELP). Twelve swine were used. Treatment swine (N=6) received 150-mg of cisplatin (CDDP) into the pulmonary artery via a balloon occlusion catheter while nine grams of thiosulfate was given IV. Control swine (N=6) received 50-mg CDDP IV with sham pulmonary artery perfusion. Animals were sacrificed immediately (0 h), 4 or 24 h after infusion. Pulmonary and renal platinum/DNA adducts and serum CDDP levels were measured at all time points. Area under the adduct-time curve (AUA) was determined as a measure of systemic exposure. Pathologic study of the lungs was performed. At 0 h, ELP elevated pulmonary adduct levels by 17.38 times while thiosulfate led to reduction in renal DNA adducts despite the elevated CDDP dose. At all time points, pulmonary adducts were at least 6.9 times higher for ELP compared to IV administration. The AUA was 7 times greater for the ELP group. Serum CDDP levels were significantly higher after ELP (p<0.05). There was no evidence of toxic pulmonary injury from ELP. Direct pulmonary artery infusion of CDDP results in greater DNA adduct formation than would be expected from simple dose escalation. Further study of ELP evaluating the acute and chronic effects of repeated treatment administration is warranted.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Adutos de DNA/efeitos dos fármacos , Pulmão/efeitos dos fármacos , Animais , Antineoplásicos/administração & dosagem , Quimioterapia do Câncer por Perfusão Regional , Cisplatino/administração & dosagem , Cisplatino/sangue , Adutos de DNA/metabolismo , Infusões Intra-Arteriais/métodos , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Pulmão/metabolismo , Pulmão/patologia , Modelos Animais , Artéria Pulmonar , Sus scrofa , Tiossulfatos/administração & dosagemRESUMO
The outcomes for patients with metastatic or recurrent esophageal cancer are dismal, with 1-year survival rates of approximately 20%. In this phase II study, we studied the combination of docetaxel (Taxotere) and irinotecan (CPT-11, Camptosar) in patients with metastatic or recurrent esophageal cancer. Eligible patients included those with histologic or cytologic diagnosis of adenocarcinoma or squamous cancer of the esophagus or gastroesophageal junction who had received no previous chemotherapy for metastatic esophageal cancer. Previous chemotherapy in the neoadjuvant or adjuvant setting was allowed. Patients received irinotecan at 160 mg/m2 over 90 minutes followed by docetaxel at 60 mg/m2 intravenously over 1 hour, with chemotherapy cycles repeated every 21 days. Patients were reevaluated every two cycles. Of a planned 40 patients, 15 were enrolled, with 14 patients evaluable for toxicity and 10 evaluable for response and survival. The combination of docetaxel and irinotecan resulted in a response rate of 30%. An additional 40% achieved stable disease. The median survival was 130 days, with three patients still alive at the time of this analysis. The toxicities included 71% incidence of grade 4 hematologic toxicities, with 43% febrile neutropenia. One patient died of cecal perforation after one cycle. There was no evidence of pharmacokinetic interaction, as systemic clearance of both drugs was similar to that seen after single-agent administration. In conclusion, the regimen of docetaxel and irinotecan is active in metastatic or recurrent esophageal cancer. However, this combination chemotherapy regimen has an unacceptable rate of febrile neutropenia. This regimen needs to be modified to reduce the incidence of febrile neutropenia.