Two-week methotrexate discontinuation in patients with rheumatoid arthritis vaccinated with inactivated SARS-CoV-2 vaccine: a randomised clinical trial.

OBJECTIVE: To evaluate the effect on immunogenicity and safety of 2-week methotrexate (MTX) discontinuation after each dose of the Sinovac-CoronaVac vaccine versus MTX maintenance in patients with rheumatoid arthritis (RA). METHODS: This was a single-centre, prospective, randomised, investigator-blinded, intervention study (NCT04754698, CoronavRheum) including adult patients with RA (stable Clinical Disease Activity Index (CDAI) ≤10, prednisone ≤7.5 mg/day) randomised (1:1) to withdraw MTX (MTX-hold) for 2 weeks after each vaccine dose or maintain MTX (MTX-maintain), evaluated at day 0 (D0), D28 and D69. Coprimary outcomes were anti-SARS-CoV-2 S1/S2 IgG seroconversion (SC) and neutralising antibody (NAb) positivity at D69. Secondary outcomes were geometric mean titres (GMT) and flare rates. For immunogenicity analyses, we excluded patients with baseline positive IgG/NAb, and for safety reasons those who flared at D28 (CDAI >10) and did not withdraw MTX twice. RESULTS: Randomisation included 138 patients with 9 exclusions (5 COVID-19, 4 protocol violations). Safety evaluation included 60 patients in the MTX-hold and 69 patients in the MTX-maintain group. Further exclusions included 27 patients (13 (21.7%) vs 14 (20.3%), p=0.848) with positive baseline IgG/NAb and 10 patients (21.3%) in MTX-hold with CDAI >10 at D28. At D69, the MTX-hold group (n=37) had a higher rate of SC than the MTX-maintain group (n=55) (29 (78.4%) vs 30 (54.5%), p=0.019), with parallel augmentation in GMT (34.2 (25.2-46.4) vs 16.8 (11.9-23.6), p=0.006). No differences were observed for NAb positivity (23 (62.2%) vs 27 (49.1%), p=0.217). At D28 flare, the rates were comparable in both groups (CDAI, p=0.122; Disease Activity Score in 28 joints with C reactive protein, p=0.576), whereas CDAI >10 was more frequent in MTX-hold at D69 (p=0.024). CONCLUSION: We provided novel data that 2-week MTX withdrawal after each dose of the Sinovac-CoronaVac vaccine improves anti-SARS-CoV-2 IgG response. The increased flare rates after the second MTX withdrawal may be attributed to the short-term interval between vaccine doses. This strategy requires close surveillance and shared decision making due to the possibility of flares.

Distinct impact of DMARD combination and monotherapy in immunogenicity of an inactivated SARS-CoV-2 vaccine in rheumatoid arthritis.

OBJECTIVES: To evaluate the distinct impact of disease modifying antirheumatic drugs (DMARD) combination and monotherapy in immune response to an inactivated SARS-CoV-2 vaccine in patients with rheumatoid arthritis (RA). METHODS: This phase 4 prospective study analysed seroconversion (SC) of anti-SARS-CoV-2 immunoglobulin G (IgG) and neutralising antibodies (NAb) induced by the inactivated vaccine (CoronaVac) in patients with RA in comparison to controls (CG). Disease activity and treatment were also assessed. Only participants with baseline negative IgG/NAb were included. RESULTS: Patients with RA (N=260) and CG (N=104) had comparable median ages (59 years (50-65 years) vs 58 years (49.8-64 years), p=0.483). Patients with RA had moderate but lower SC (61.8% vs 94.2%, p<0.001) and NAb positivity (45% vs 78.6%, p<0.001) in comparison to CG after full vaccination. Baseline disease activity did not influence immunogenicity (p>0.05). After multivariate analyses, factors independently related to reduced SC were: older age (OR=0.79 (0.70-0.89) for each 5-year interval, p<0.001), methotrexate (OR=0.54 (0.29-0.98), p=0.044), abatacept (OR=0.37 (0.19-0.73), p=0.004) and number of DMARD (OR=0.55 (0.33-0.90), p=0.018). Regarding NAb, age (OR=0.87 (0.78-0.96) for each 5-year interval, p=0.007) and prednisone >7.5 mg/day (OR=0.38 (0.19-0.74), p=0.004) were negatively related to the presence of NAb. Further comparison of SC/NAb positivity among RA treatment subgroups and CG revealed that methotrexate/tofacitinib/abatacept/tocilizumab use, in monotherapy or in combination, resulted in lower responses (p<0.05), while tumour necrosis factor inhibitor and other conventional synthetic DMARD interfered solely when combined with other therapies. CONCLUSIONS: Patients with RA under DMARD have a moderate immunogenicity to CoronaVac. We identified that nearly all DMARD combinations have a deleterious effect in immunogenicity, whereas a more restricted number of drugs (methotrexate/tofacitinib/abatacept/tocilizumab) also hampered this response as monotherapy. These findings reinforce the need of a broader approach, not limited to specific drugs, to improve vaccine response for this population. TRIAL REGISTRATION DETAILS: NCT04754698.

Increment of immunogenicity after third dose of a homologous inactivated SARS-CoV-2 vaccine in a large population of patients with autoimmune rheumatic diseases.

OBJECTIVE: To determine the immunogenicity of the third dose of CoronaVac vaccine in a large population of patients with autoimmune rheumatic diseases (ARD) and the factors associated with impaired response. METHODS: Adult patients with ARD and age-balanced/sex-balanced controls (control group, CG) previously vaccinated with two doses of CoronaVac received the third dose at D210 (6 months after the second dose). The presence of anti-SARS-CoV-2 S1/S2 IgG and neutralising antibodies (NAb) was evaluated previously to vaccination (D210) and 30 days later (D240). Patients with controlled disease suspended mycophenolate mofetil (MMF) for 7 days or methotrexate (MTX) for 2 weekly doses after vaccination. RESULTS: ARD (n=597) and CG (n=199) had comparable age (p=0.943). Anti-S1/S2 IgG seropositivity rates significantly increased from D210 (60%) to D240 (93%) (p<0.0001) in patients with ARD. NAb positivity also increased: 38% (D210) vs 81.4% (D240) (p<0.0001). The same pattern was observed for CG, with significantly higher frequencies for both parameters at D240 (p<0.05). Multivariate logistic regression analyses in the ARD group revealed that older age (OR=0.98, 95% CI 0.96 to 1.0, p=0.024), vasculitis diagnosis (OR=0.24, 95% CI 0.11 to 0.53, p<0.001), prednisone ≥5 mg/day (OR=0.46, 95% CI 0.27 to 0.77, p=0.003), MMF (OR=0.30, 95% CI 0.15 to 0.61, p<0.001) and biologics (OR=0.27, 95% CI 0.16 to 0.46, p<0.001) were associated with reduced anti-S1/S2 IgG positivity. Similar analyses demonstrated that prednisone ≥5 mg/day (OR=0.63, 95% CI 0.44 to 0.90, p=0.011), abatacept (OR=0.39, 95% CI 0.20 to 0.74, p=0.004), belimumab (OR=0.29, 95% CI 0.13 to 0.67, p=0.004) and rituximab (OR=0.11, 95% CI 0.04 to 0.30, p<0.001) were negatively associated with NAb positivity. Further evaluation of COVID-19 seronegative ARD at D210 demonstrated prominent increases in positivity rates at D240 for anti-S1/S2 IgG (80.5%) and NAb (59.1%) (p<0.0001). CONCLUSIONS: We provide novel data on a robust response to the third dose of CoronaVac in patients with ARD, even in those with prevaccination COVID-19 seronegative status. Drugs implicated in reducing immunogenicity after the regular two-dose regimen were associated with non-responsiveness after the third dose, except for MTX. Trial registration number NCT04754698.

Immunogenicity, safety, and antiphospholipid antibodies after SARS-CoV-2 vaccine in patients with primary antiphospholipid syndrome.

OBJECTIVE: Coronavirus disease 19 (COVID-19) has an increased risk of coagulopathy with high frequency of antiphospholipid antibodies (aPL). Recent reports of thrombosis associated with adenovirus-based vaccines raised concern that SARS-CoV-2 immunization in primary antiphospholipid syndrome (PAPS) patients may trigger clotting complications. Our objectives were to assess immunogenicity, safety, and aPL production in PAPS patients, after vaccinating with Sinovac-CoronaVac, an inactivated virus vaccine against COVID-19. METHODS: This prospective controlled phase-4 study of PAPS patients and a control group (CG) consisted of a two-dose Sinovac-CoronaVac (D0/D28) and blood collection before vaccination (D0), at D28 and 6 weeks after second dose (D69) for immunogenicity/aPL levels. Outcomes were seroconversion (SC) rates of anti-SARS-CoV-2 S1/S2 IgG and/or neutralizing antibodies (NAb) at D28/D69 in naïve participants. Safety and aPL production were also assessed. RESULTS: We included 44 PAPS patients (31 naïve) and 132 CG (108 naïve) with comparable age (p=0.982) and sex (p>0.999). At D69, both groups had high and comparable SC (83.9% vs. 93.5%, p=0.092), as well as NAb positivity (77.4% vs. 78.7%, p=0.440), and NAb-activity (64.3% vs. 60.9%, p=0.689). Thrombotic events up to 6 months or other moderate/severe side effects were not observed. PAPS patients remained with stable aPL levels throughout the study at D0 vs. D28 vs. D69: anticardiolipin (aCL) IgG (p=0.058) and IgM (p=0.091); anti-beta-2 glycoprotein I (aß2GPI) IgG (p=0.513) and IgM (p=0.468). CONCLUSION: We provided novel evidence that Sinovac-CoronaVac has high immunogenicity and safety profile in PAPS. Furthermore, Sinovac-CoronaVac did not trigger thrombosis nor induced changes in aPL production.

The influence of obesity on hydroxychloroquine blood levels in lupus nephritis patients.

INTRODUCTION: In 2016 the American Academy of Ophthalmology(2016-AAO) recommended a maximum daily HCQ use of 5.0 mg/kg real body weight(RBW) taking into consideration minimizing eye toxicity. Retinopathy in systemic lupus erythematosus(SLE) patients was recently associated with obesity and this condition is progressively more common in these patients. However, the impact of obesity in HCQ blood levels remains controversial. OBJECTIVE: To determine if the 2016-AAO recommendation based on RBW with and without maximum daily dose restriction results in adequate and safe blood levels in obese lupus nephritis(LN) patients. METHODS: A cross-sectional study was performed with 108 LN patients under the prescribed 2016-AAO dose for at least 3 months. LN patients were assessed for demographic characteristics, body mass index(BMI), disease parameters, HCQ dose, concomitant treatment and HCQ blood levels measured by liquid chromatography-tandem mass spectrometry. Obesity was defined as BMI ≥30kg/m2. RESULTS: Obesity was identified in 35/108(32%) LN patients. The calculation of HCQ daily dosage revealed that obese patients were under a lower prescribed daily dose according to the real body weight (RBW) [4.4(2.9-5.4) vs. 4.9(4-5.5)mg/Kg/day, p < 0.001] due to the maximum limit used. Regardless of that the median of HCQ blood levels was significantly higher in obese compared to non-obese patients (1562 ± 548.6 vs. 1208 ± 448.9 ng/mL, p = 0.002). Further analysis of patients under the 20016-AAO recommendation by RBW without the restriction of maximum daily dose confirmed that in spite of comparable daily dose in 14 obese patients and 61 non-obese patients [4.8 (4.5-5.4) vs. 5.0(4.5-5.5) mg/kg, p = 0.312], the median of HCQ blood levels was significantly higher in obese patients than in non-obese (1734 ± 457.3 vs. 1189 ± 449.4 ng/mL, p < 0.001). CONCLUSION: Obese patients under the 2016-AAO prescribed dose of HCQ based on RBW with and without maximum daily dose restriction have a very high HCQ blood levels compared to non-obese patients, with a potential increased risk of ocular toxicity. The use of 2016-AAO dose of HCQ according to the ideal body weight for this group of patients should be considered.Clinicaltrials.gov #NCT0312243.

One-year prospective nerve conduction study of thalidomide neuropathy in lupus erythematosus: Incidence, coasting effect and drug plasma levels.

BACKGROUND: Few prospective studies in cutaneous and systemic lupus erythematosus (CLE/SLE) assessed thalidomide-induced peripheral neuropathy (TiPN) incidence/reversibility, and most have not excluded confounding causes neither monitored thalidomide plasma levels. OBJECTIVES: To evaluate TiPN incidence/reversibility, coasting effect and its association with thalidomide plasma levels in CLE/SLE. METHODS: One-year prospective study of thalidomide in 20 CLE/SLE patients without pregnancy potential, with normal nerve conduction study (NCS), and excluded other PN causes. Thalidomide levels were determined by high-performance liquid chromatography/tandem mass spectrometry. RESULTS: Twelve patients (60%) developed TiPN: 33.3% were symptomatic and 66.6% asymptomatic. Half of this latter group developed coasting effect (TiPN symptoms 1-3 months after drug withdrawal). The main predictive factors for TiPN were treatment duration ≥6 months (p = 0.025) and cumulative dose (p = 0.023). No difference in plasma thalidomide levels between patients with/without TiPN was observed (p = 0.464). After drug withdrawal, 75% symptomatic TiPN patients improved their symptoms. Seven TiPN patients underwent an additional NCS after drug withdrawal: 42.8% worsened NCS, 14.2% was stable, and 42.8% had improved NCS. CONCLUSION: Our data provides novel evidence of coasting effect in half of asymptomatic patients with TiPN. The irreversible nature of this lesion in 25% of TiPN patients reinforces the relevance of early NCS monitoring, and suggests thalidomide use solely as a bridge for other effective therapy for refractory cutaneous lupus patients.

No Associations Between Physical Activity and Immunogenicity in SARS-CoV-2 Seropositive Patients With Autoimmune Rheumatic Diseases Prior to and After Vaccination.

AIM: To investigate the association between physical activity and immunogenicity among SARS-CoV-2 seropositive patients with autoimmune rheumatic diseases prior to and following a 2-dose schedule of CoronaVac (Sinovac inactivated vaccine). METHODS: This was a prospective cohort study within an open-label, single-arm, phase 4 vaccination trial conducted in Sao Paulo, Brazil. In this substudy, only SARS-CoV-2 seropositive patients were included. Immunogenicity was assessed by seroconversion rates of total anti-SARS-CoV-2 S1/S2 immunoglobulin G (IgG), geometric mean titers of anti-S1/S2 IgG, frequency of positive neutralizing antibodies, and neutralizing activity before and after vaccination. Physical activity was assessed through a questionnaire. Model-based analyses were performed controlling for age (<60 or ≥60 y), sex, body mass index (<25, 25-30, and >30 kg/m2), and use of prednisone, immunosuppressants, and biologics. RESULTS: A total of 180 seropositive autoimmune rheumatic disease patients were included. There was no association between physical activity and immunogenicity before and after vaccination. CONCLUSIONS: This study suggests that the positive association between physical activity and greater antibody responses seen in immunocompromised individuals following vaccination is overridden by previous SARS-CoV-2 infection, and does not extend to natural immunity.

Hydroquinone exposure worsens the symptomatology of rheumatoid arthritis.

The genesis of rheumatoid arthritis (RA) is complex and dependent on genetic background and exposure to environmental xenobiotic. Indeed, smoking is associated to developing and worsening pre-existing RA. Nevertheless, the mechanisms and cigarette compounds involved in the harmful processes have not been elucidated. Here, we investigated if the exposure to hydroquinone (HQ), an abundant pro-oxidative compound of cigarette and benzene metabolite, could worsen the ongoing RA. Hence, collagen-induced arthritis (CIA) was induced in male Wistar rats by s.c. injection of 400 µg (200 µL) of bovine collagen type II emulsified in complete Freund's adjuvant on day 1, and a booster injection was performed on day 7. Exposures to nebulized HQ (25 ppm), saline solution or HQ vehicle solution (5% ethanol in saline) were carried out for 1 h, once a day, on days 21-27 after CIA induction. On day 27, animals were euthanized and samples were collected for further analyses. Exposure to HQ caused loss of weight, intensified paw edema, enhanced levels of tumor necrosis factor-α (TNF-α) and anti-citrullinated protein antibody (ACPA) in the serum; augmented synoviocyte proliferation and influx of aril hydrocarbon receptor (AhR) positive cells into the synovial membrane, altered collagen fibre rearrangement in the synovia, and synoviocytes isolated from HQ exposed rats secreted higher levels of pro-inflammatory cytokines, TNF-α and interleukin-1ß. Associated, we point out HQ as an environmental pollutant that aggravates RA, suggesting its participation on worsening RA in smoking patients.

In vivo exposure to hydroquinone during the early phase of collagen-induced arthritis aggravates the disease.

Robust correlation between the severity of rheumatoid arthritis (RA) and cigarette smoking has been clinically demonstrated. Nevertheless, cigarette compounds responsible for this toxic effect and their mechanisms have not been described. Considering that hydroquinone (HQ) is an abundant, pro-oxidative compound of the matter particle phase of cigarette smoke, we investigated whether HQ exposure during the initial phase of collagen-induced arthritis (CIA) could aggravate the disease. For this purpose, male Wistar rats were exposed to aerosolized HQ (25 ppm), saline or 5% ethanol solution (HQ vehicle) for 1 h per day during 14 days. CIA was induced through s.c. injection of bovine collagen Type II (0.4 mg/100 µL) at days seven and 14 of exposure. Clinical signs of disease and the cell profile and chemical mediators in the synovial fluid and membrane were analysed at day 35 after the beginning of exposure. HQ exposure aggravated CIA-related paw edema and increased the cell infiltrate and interleukin-6 (IL-6) levels in the synovial fluid, promoted intense tissue collagen deposition and enhanced synoviocyte proliferation and higher frequency of aryl hydrocarbon receptor (AhR+) and interleukin (IL-17+) neutrophils in the synovial membrane. in vitro data also highlighted that neutrophils expressed increased levels of AhR, IL-17 and reactive oxygen species (ROS) generation. However, only AhR expression and ROS generation were blocked by in vitro treatment with AhR antagonist. Therefore, we conclude that in vivo HQ exposure at the early phase of AR onset worsens RA, leading to high frequency of AhR/IL-17+ neutrophils into the joint.

Post-acute COVID-19 in three doses vaccinated autoimmune rheumatic diseases patients: frequency and pattern of this condition

Abstract Background Data on post-acute COVID-19 in autoimmune rheumatic diseases (ARD) are scarce, focusing on a single disease, with variable definitions of this condition and time of vaccination. The aim of this study was to evaluate the frequency and pattern of post-acute COVID-19 in vaccinated patients with ARD using established diagnosis criteria. Methods Retrospective evaluation of a prospective cohort of 108 ARD patients and 32 non-ARD controls, diagnosed with SARS-CoV-2 infection (RT-PCR/antigen test) after the third dose of the CoronaVac vaccine. Post-acute COVID-19 (≥ 4 weeks and > 12 weeks of SARS-CoV-2 symptoms) were registered according to the established international criteria. Results ARD patients and non-ARD controls, balanced for age and sex, had high and comparable frequencies of ≥ 4 weeks post-acute COVID-19 (58.3% vs. 53.1%, p = 0.6854) and > 12 weeks post-acute COVID-19 (39.8% vs. 46.9%, p = 0.5419). Regarding ≥ 4 weeks post-acute COVID-19, frequencies of ≥ 3 symptoms were similar in ARD and non-ARD controls (54% vs. 41.2%, p = 0.7886), and this was also similar in > 12 weeks post-acute COVID-19 (68.3% vs. 88.2%, p = 0.1322). Further analysis of the risk factors for ≥ 4 weeks post-acute COVID-19 in ARD patients revealed that age, sex, clinical severity of COVID-19, reinfection, and autoimmune diseases were not associated with this condition (p > 0.05). The clinical manifestations of post-acute COVID-19 were similar in both groups (p > 0.05), with fatigue and memory loss being the most frequent manifestations. Conclusion We provide novel data demonstrating that immune/inflammatory ARD disturbances after third dose vaccination do not seem to be a major determinant of post-acute COVID-19 since its pattern is very similar to that of the general population. Clinical Trials platform (NCT04754698).

Role of Translocator 18 KDa Ligands in the Activation of Leukotriene B4 Activated G-Protein Coupled Receptor and Toll Like Receptor-4 Pathways in Neutrophils.

TSPO (Translocator 18 KDa; tryptophan-rich sensory protein oxygen sensor) is a constitutive outer mitochondrial membrane protein overexpressed in inflammatory cells during local or systemic processes. Despite its expression is characterized, role of TSPO in inflammation remains elusive. For this study, we investigated the role of TSPO ligands on neutrophil functions elicited by two different inflammatory pathways. Peritoneal neutrophils were isolated from male Balb-C mice, treated with TSPO ligand diazepam, Ro5-4864 or PK11195 (1,100 or 1000 nM; 2 h) and further stimulated with lipopolysaccharide from Escherichia coli (LPS), a binding for Toll-Like Receptor-4 (TLR4), or leukotriene B4 (LTB4), a G-protein coupled receptor (GPCR) ligand. LPS treatment did not lead to overexpression of TSPO on neutrophils, and pre-treatment with any TSPO ligand did not alter cytokine expression, adhesion molecule expression, or the production of reactive oxygen and nitrogen species caused by LPS stimulation. Conversely, all TSPO ligands impaired LTB4's actions, as visualized by reductions in L-selectin shedding, ß2 integrin overexpression, neutrophil chemotaxis, and actin filament assembly. TSPO ligands showed distinct intracellular effects on LTB4-induced neutrophil locomotion, with diazepam enhancing cofilin but not modifying Arp2/3 expression, and Ro5-4864 and PK11195 reducing both cofilin and Arp2/3 expression. Taken together, our data exclude a direct role of TSPO ligands in TLR4-elicited pathways, and indicate that TSPO activation inhibits GPCR inflammatory pathways in neutrophils, with a relevant role in neutrophil influx into inflammatory sites.

In vivo exposure to hydroquinone during the early phase of collagen-induced arthritis aggravates the disease

Robust correlation between the severity of rheumatoid arthritis (RA) and cigarette smoking has been clinically demonstrated. Nevertheless, cigarette compounds responsible for this toxic effect and their mechanisms have not been described. Considering that hydroquinone (HQ) is an abundant, pro-oxidative compound of the matter particle phase of cigarette smoke, we investigated whether HQ exposure during the initial phase of collagen-induced arthritis (CIA) could aggravate the disease. For this purpose, male Wistar rats were exposed to aerosolized HQ (25 ppm), saline or 5% ethanol solution (HQ vehicle) for 1 h per day during 14 days. CIA was induced through s.c. injection of bovine collagen Type II (0.4 mg/100 µL) at days seven and 14 of exposure. Clinical signs of disease and the cell profile and chemical mediators in the synovial fluid and membrane were analysed at day 35 after the beginning of exposure. HQ exposure aggravated CIA-related paw edema and increased the cell infiltrate and interleukin-6 (IL-6) levels in the synovial fluid, promoted intense tissue collagen deposition and enhanced synoviocyte proliferation and higher frequency of aryl hydrocarbon receptor (AhR+) and interleukin (IL-17+) neutrophils in the synovial membrane. in vitro data also highlighted that neutrophils expressed increased levels of AhR, IL-17 and reactive oxygen species (ROS) generation. However, only AhR expression and ROS generation were blocked by in vitro treatment with AhR antagonist. Therefore, we conclude that in vivo HQ exposure at the early phase of AR onset worsens RA, leading to high frequency of AhR/IL-17+ neutrophils into the joint.

In vivo exposure to hydroquinone during the early phase of collagen-induced arthritis aggravates the disease

Robust correlation between the severity of rheumatoid arthritis (RA) and cigarette smoking has been clinically demonstrated. Nevertheless, cigarette compounds responsible for this toxic effect and their mechanisms have not been described. Considering that hydroquinone (HQ) is an abundant, pro-oxidative compound of the matter particle phase of cigarette smoke, we investigated whether HQ exposure during the initial phase of collagen-induced arthritis (CIA) could aggravate the disease. For this purpose, male Wistar rats were exposed to aerosolized HQ (25 ppm), saline or 5% ethanol solution (HQ vehicle) for 1 h per day during 14 days. CIA was induced through s.c. injection of bovine collagen Type II (0.4 mg/100 µL) at days seven and 14 of exposure. Clinical signs of disease and the cell profile and chemical mediators in the synovial fluid and membrane were analysed at day 35 after the beginning of exposure. HQ exposure aggravated CIA-related paw edema and increased the cell infiltrate and interleukin-6 (IL-6) levels in the synovial fluid, promoted intense tissue collagen deposition and enhanced synoviocyte proliferation and higher frequency of aryl hydrocarbon receptor (AhR+) and interleukin (IL-17+) neutrophils in the synovial membrane. in vitro data also highlighted that neutrophils expressed increased levels of AhR, IL-17 and reactive oxygen species (ROS) generation. However, only AhR expression and ROS generation were blocked by in vitro treatment with AhR antagonist. Therefore, we conclude that in vivo HQ exposure at the early phase of AR onset worsens RA, leading to high frequency of AhR/IL-17+ neutrophils into the joint.

Modelagem PK/PD na terapia antimicrobiana com carbapenêmico em pacientes sépticos críticos grandes queimados. " Estudo da efetividade do meropenem administrado através de infusão intermitente versus estendida " / PK/PD modelling in antimicrobial therapy with carbapenem in critically burn septic patients. " Study of the effectiveness of meropenem administered by intermittent versus extended infusion "

O meropenem é um carbapenêmico de amplo espectro e alta potência, largamente prescrito para tratamento de infecções graves causadas por bactérias sensíveis gram-negativas em pacientes críticos internados em Unidades de Terapia Intensiva. O objetivo do presente estudo foi avaliar a efetividade do antimicrobiano em pacientes grandes queimados, recebendo a dose recomendada 1 g q8h através da infusão intermitente de 0,5 hora que ocorreu até 2014 (grupo 1) comparada a infusão estendida de 3 horas que ocorreu após esse período (grupo 2). Investigaram-se 25 pacientes sépticos de ambos os sexos (6F/19M), 26 (21-34) anos, medianas (interquartil), 70 (60-75) kg, superfície corporal total queimada (SCTQ) 35 (16-42)%, SAPS 3: 55 (45-59) e Clcr 129 (95-152) ml/min que foram distribuídos em dois grupos. Registrou-se trauma térmico pelo fogo em 19/25 e trauma elétrico no restante dos pacientes (6/25), lesão inalatória (17/25), intubação orotraqueal e a necessidade de vasopressores em 18/25 pacientes. Duas amostras de sangue foram coletadas (3ª e 5ª horas) para dosagem sérica do meropenem por cromatografia líquida no período precoce do choque séptico. A farmacocinética foi investigada pela aplicação do modelo aberto de um compartimento e a abordagem PK/PD foi realizada com base no novo índice recomendado 100%fΔT>CIM. Evidenciou-se aumento do PCR 224 (179-286) versus 300 (264-339) mg/L, p=0,0411 e neutrofilia: 12 (8-17) versus 8 (2-15) células/mm3, p=0,1404, respectivamente nos grupos de infusão estendida versus infusão intermitente. Os níveis séricos obtidos mostraram diferença significativa entre grupos (p<0,0001) tanto para o pico 21 (21-22) mg/L versus 44 (42-45) mg/L, como para o vale 7,8 (7,3-9,5) mg/L versus 3,0 (2,6-3,7) mg/L. A farmacocinética mostrou-se alterada nos dois grupos frente aos dados de referência reportados em voluntários sadios. Significativa alteração ocorreu em diferentes proporções pela comparação entre os grupos relativamente à constante de eliminação 0,190 (0,157-0,211) versus 0,349 (0,334-0,382) h-1; meia-vida biológica 3,6 (3,3-4,4) versus 2,0 (1,8-2,1) h; depuração total corporal 8,6 (8,2-8,9) versus 5,3 (5,2-5,4) L/h; volume de distribuição 41,8 (39,9-44,5) versus 15,4 (14,1-16,2) L (p<0,0001). A infecção de ferida foi a mais prevalente nos dois grupos com 47% versus 38% dos isolados, sendo a Klebsiella pneumoniae, a principal enterobactéria. A abordagem PK/PD para patógenos CIM 1 a 4 mg/L mostrou cobertura até CIM 4 mg/L para a infusão estendida e até CIM 2 mg/L para infusão intermitente. Em conclusão, demonstrou-se a superioridade da infusão estendida decorrente de alterações na farmacocinética do meropenem em pacientes grandes queimados. O aumento do volume de distribuição contribuiu para o prolongamento da meia-vida e dos altos níveis de vale registrados, o justifica o impacto na cobertura antimicrobiana após infusão estendida e controle das infecções com cura desses pacientes

Meropenem is a broad-spectrum agent widely prescribed for the treatment of septic shock caused by gram-negative susceptible strains in critically ill patients from the Intensive Care Units. Subject of the present study was to evaluate the drug effectiveness in critically ill septic burn patients in SIRS at the early period of septic shock receiving the recommended dose of Meropenem 1 g q8h by intermittent 0.5 hour infusion or the extended 3 hour infusion. Twenty-five septic patients were: (6F/19M), 26 (21-34) years, medians (quartiles), 70 (60-75) kg, total burn body surface (SCTQ) 35 (16-42) %, SAPS 3: 55 (45-59) and Clcr 129 (95-152) ml/min. Thermal trauma was registered in 19/25 and electrical trauma in the remaining patients (6/25), inhalation injury (17/25), orotracheal intubation and vasopressor requirement in 18/25 patients. Patients were distributed in two groups on the basis of the duration of drug infusion that occurred for the patients of group 1 (1g q8h 0.5 hr) until 2014, December in the hospital. In addition, the extended 3 hours infusion occurred after that period for patients enrolled afterwards (group 2). Pharmacokinetics was investigated after blood sampling at the third (3rd) hour and the fifth (5th) hour of starting the meropenem infusion. Serum drug measurement was done by liquid chromatography. A one compartment open model was applied and kinetic parameters were estimated. PK/PD approach based on the new recommended index of drug effectiveness 100% fΔT>MIC was performed, on the basis on PK parameters and the minimum inhibitory concentration, PD parameter. It was demonstrated a significant difference between groups (p <0.0001) related to the trough levels 7.8 (7.3-9.5) mg/L versus 3.0 (2.6-3.7) mg/L, respectively after extended infusion or intermittent infusion. Concerning the pharmacokinetics, it was shown profound changes on meropenem kinetic parameters in both groups of burn patients by comparison with the reference data reported in healthy volunteers. In addition, it is important to highlight that significant changes occurred also by comparison of PK data between groups of patients related to the parameters: elimination constant 0.190 (0.157-0.211) versus 0.349 (0.334-0.382) h-1; biological half-life 3.6 (3.3-4.4) versus 2.0 (1.8-2.1) hr; total body clearance 8.6 (8.2-8.9) versus 5.3 (5.2-5.4) L/hr; volume of distribution 41.8 (39.9-44.5) versus 15.4 (14.1-16.2) L. Concerning the inflammatory biomarker an increase of C-reactive protein was registered in both groups of septic patients in SIRS: 224 versus 300 mg/L, p = 0.0411, after the extended infusion versus intermittent infusion, respectively. Wound and bone were the most prevalent sites of infection in those patients of both groups. It was shown in the isolates the prevalence of Gram-negative strains 54/83 (65%) that were distributed in Enterobacteriaceae, K. pneumoniae 7/30 (23%), and Non-Enterobacteriaceae, P. aeruginosa 13/54 (24%) followed by Acinetobacter baumannii 11/54 (20%). Drug effectiveness against susceptible strains was demonstrated by PK/PD approach up to 4 mg/L over 2 mg/L, after the extended infusion or after intermittent infusion, respectively. In conclusion, the superiority of the extended infusion in septic burn patients at the earlier period of septic shock was demonstrated, once considerable increases on volume of distribution impacted the drug effectiveness of these patients. Cure was obtained by meropenem monotherapy in 22/25 patients; only three patients (3/25) received meropenem - colistine combined therapy due to Acinetobacter baumannii isolated