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Consent for publication | Not applicable. | PMC10403909 |
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Competing interests | NB | NT has received honoraria from Taiho. HH has received honoraria form Eli Lilly and Taiho, and research grant from Taiho. KN has received a consulting fee (paid to the university) from Eli Lilly. KH has received research grant from Taiho. TM (Toshiki Masuishi) have no conflicts of interest to declare. TM (Toshihiko Matsumoto) has received honoraria from Eli Lilly and Taiho. HK has received consulting fees from Eli Lilly and Taiho, and research funding from Taiho. KY has received research grant from Taiho, and received honoraria from Taiho and Eli Lilly. SH has received honoraria from Eli Lilly and Taiho. NB has received honoraria from Eli Lilly and Taiho. KM has received research grant from Taiho, and received honoraria from Taiho and Eli Lilly. | PMC10403909 |
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References | PMC10403909 |
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Background | neuroinflammation, inflammation, schizophrenia experience cognitive impairment, herpes virus infection, schizophrenic | HERPES VIRUS INFECTION, INFLAMMATION | Patients with schizophrenia experience cognitive impairment, which could be related to neuroinflammation in the hippocampus. The cause for such hippocampal inflammation is still unknown, but it has been suggested that herpes virus infection is involved. This study therefore aimed to determine whether add-on treatment of schizophrenic patients with the anti- viral drug valaciclovir would reduce hippocampal neuroinflammation and consequently improve cognitive symptoms. | PMC10719624 |
Methods | schizophrenia, Neuroinflammation, active psychotic symptoms | We performed a double-blind monocenter study in 24 male and female patients with schizophrenia, experiencing active psychotic symptoms. Patients were orally treated with the anti-viral drug valaciclovir for seven consecutive days (8 g/day). Neuroinflammation was measured with Positron Emission Tomography using the translocator protein ligand [ | PMC10719624 |
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Results | TSPO | Valaciclovir treatment resulted in reduced TSPO binding (39%) in the hippocampus, as well as in the brainstem, frontal lobe, temporal lobe, parahippocampal gyrus, amygdala, parietal lobe, occipital lobe, insula and cingulate gyri, nucleus accumbens and thalamus (31–40%) when using binding potential (BPND) as an outcome. With total distribution volume (VT) as outcome we found essentially the same results, but associations only approached statistical significance ( | PMC10719624 |
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Conclusion | psychotic, schizophrenia, neuroinflammation | We found a decreased TSPO binding following antiviral treatment, which could suggest a viral underpinning of neuroinflammation in psychotic patients. Whether this reduced neuroinflammation by treatment with valaciclovir has clinical implications and is specific for schizophrenia warrants further research. | PMC10719624 |
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Keywords | PMC10719624 |
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Introduction | neuroinflammation, cognitive decline, herpes, psychosis, Schizophrenia, schizophrenia | DISORDER, HERPES VIRUS INFECTION, HERPES | Schizophrenia is a disabling disorder that often has a chronic intermittent course (van Os & Kapur, One factor that is suggested to be relevant in schizophrenia is neuroinflammation (Najjar & Pearlman, While findings on neuroinflammation in schizophrenia are inconsistent (Marques et al., The association between herpes viruses and schizophrenia has led to the initiation of anti-viral treatment studies. Studies with medication that specifically disrupt DNA replication of herpes viruses did not reduce overall symptoms and cognition in schizophrenia (Bhatia et al., Based on the possible role in schizophrenia, we hypothesize that a herpes virus infection in the hippocampus contributes to the development of neuroinflammation, and consequently cognitive decline, in patients with schizophrenia. The aim of this study is to determine whether the antiviral drug valaciclovir can reduce hippocampal neuroinflammation, thereby moderating psychosis and improving cognitive performance. | PMC10719624 |
Methods and materials | PMC10719624 |
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Design | psychotic symptoms, psychiatric, neuroinflammation, schizophrenia spectrum disorder | BLIND | The study was a randomized, double blind, placebo controlled, mono-center study in which patients fulfilling the DSM-IV criteria for a schizophrenia spectrum disorder and experiencing active psychotic symptoms were treated with valaciclovir for seven days. Participants underwent two (Participants were randomly assigned to treatment with either valaciclovir or placebo for seven days, starting after the pre-treatment PET scan. Participants were admitted to the psychiatric department of the University Medical Center in Groningen during treatment, either for 24/7 or only during daytime. Their medication was taken under supervision of a psychiatric nurse and side effects were monitored. There was a valaciclovir free period of seven days after treatment, which ensured absence of direct (confounding) pharmacological effects, such as temporarily increase in neuroinflammation.A graphical overview of the study design is shown in Overview of the study design. *Intervention lasted for 7 days, so day 2–9 of the study protocol.This study was approved by the Medical Ethics Committee (institutional review board) of the University Medical Center Groningen (METc2009/105) and was registered before start of inclusion in the clinicaltrials.gov database with identifier NCT01364792 on 2 June 2011. All participants provided written informed consent and Good Clinical Practice guidelines were followed. | PMC10719624 |
Participants | Participants ( | PMC10719624 |
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Intervention | herpes encephalitis | HERPES ENCEPHALITIS, BLIND | Acyclovir is an antiviral drug that is specifically phosphorylated by herpes virus thymidine kinase and incorporated into the DNA, leading to cessation of DNA synthesis of the infected cell. In case of herpes encephalitis caused by HSV-1, intravenous therapy with a dose of approximately 2 g of acyclovir per day, depending on body weight, is applied for ten days (VanLandingham, Marsteller, Ross, & Hayden, The participants were treated for 7 consecutive days, in the dosage of 4 times 2 g per day. Encapsulation and randomization of the study medication was outsourced to the pharmacy department of PRA Health Sciences (Groningen, the Netherlands), and quality control, blinding and de-blinding were done by the Department of Clinical Pharmacy and Pharmacology of the UMCG. All participants, researchers and health care practitioners were blind for the treatment until after the study was closed and all measurements were done. | PMC10719624 |
Outcome measures | The primary outcome measure of the study was the [The sample size needed was estimated using the [ | PMC10719624 |
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Assessment of [ | PMC10719624 |
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PET procedure | A catheter was inserted in the radial artery for arterial blood sampling after testing for collateral blood flow and injection of 1% lidocaïne. A venous catheter was placed in the antebrachial vein of the other arm, for injection of [T1-weighted MRI scans of the brain were made using a 3 T Intera MRI scanner (Philips, The Netherlands), and were examined for abnormalities by an experienced neuroradiologist. | PMC10719624 |
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Data analysis | The list-mode data from the PET scans were reconstructed by filtered back projection into 21 successive frames (6 × 10 s, 2 × 30 s, 3 × 1 min, 2 × 2 min, 2 × 3 min, 3 × 5 min, and 3 × 10 min). Attenuation correction was performed by the separate ellipse algorithm (ECAT EXACT HR + ) or by a low-dose CT (Biograph mCT). PMOD (version 3.8; PMOD Technologies LLC) was used for image processing and pharmacokinetic modeling. The summed PET images of each participant (frames 1–21) were aligned to the MRI scan of the same participant. Hereafter, a 6-tissue probability map normalization of the individual MRI scan into the Montreal Neurological Institute (MNI) space was performed (Ashburner & Friston, Two-tissue compartment modeling was used to calculate binding potential (BPCorrection for the individual delay and an individually fitted whole blood volume was applied. It was assumed that the distribution volume of the non-displaceable compartment ( | PMC10719624 |
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Assessment of clinical functioning | PMC10719624 |
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Symptom severity | The PANSS was used to confirm inclusion criteria and to assess symptom severity before and after treatment. | PMC10719624 |
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Cognitive functioning | schizophrenia | Cognitive functioning was assessed by a trained research physician or a research psychologist, using three cognitive tests, the 15 Word Learning Test (WLT), the Continuous Performance Test (CPT) and the Verbal Fluency Test (VFT). Impairments on these tests were found in schizophrenia patients (Nuechterlein et al., First, the 15 WLT was used to assess memory function (Brand & Jolles, | PMC10719624 |
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Statistical analysis | ± | Statistical analysis was performed in IBM SPSS Statistics 23. Data are reported as mean ± standard deviation. Differences in general information of the participants were assessed using ANOVA (age and duration of illness), Pearson's χ | PMC10719624 |
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Results | PMC10719624 |
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Side effects | ADVERSE EFFECTS, SIDE EFFECTS | No serious adverse effects (SAE) were reported during this study. Side effects related to valaciclovir treatment | PMC10719624 |
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[ | The pre-treatment [Pre- and post-treatment [11C]-PK11195 binding potential in the hippocampus. *The post-treatment hippocampal [Analyses with | PMC10719624 |
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Clinical outcomes | For the PANSS, the 15 WLT and the CPT, no pre-treatment differences were found between the placebo- and valaciclovir-treated groups (Within-group comparisons revealed no differences in the scores on the PANSS and the CPT ( | PMC10719624 |
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Discussion | WLT, neuroinflammation, herpes, psychiatric, HSV-1 infection, psychotic symptoms, schizophrenia, TSPO | SIDE EFFECT, HERPES, CORTEX, INFLAMMATORY RESPONSE | To our knowledge, this is the first study investigating the effect of valaciclovir treatment on neuroinflammation in the hippocampus of patients with schizophrenia. Our main finding is that valaciclovir reduced neuroinflammation in the hippocampus, which could be interpreted as support for the hypothesis that actively replicating herpes viruses are present in the hippocampus and contribute to an inflammatory response. We additionally found significantly reduced neuroinflammation in other included brain regions. Despite the reduction in neuroinflammation, psychotic symptoms and cognitive functioning did not improve in valaciclovir-treated patients. Contrary to what was expected, the score on the 15 WLT decreased over time in valaciclovir-treated patients only, and scores on verbal fluency in both valaciclovir- and placebo-treated patients.We hypothesized the main treatment effects of valaciclovir to be in the hippocampus, because of the affinity of HSV-1 for that region and our earlier finding of neuroinflammation in the hippocampus (Doorduin et al., Following valaciclovir treatment we found reduction in TSPO binding for all brain regions included, which could suggest a global presence of actively replicating herpes viruses, an unknown effect of valaciclovir on TSPO binding or natural variation in neuroinflammation. We found an effect in all tested brain regions, without any clinical effects, which could be an argument for natural variation. TSPO binding was increased in the post-treatment scan, when compared to the pre-treatment scan, in the placebo group. Although this was not statistically significant, it suggests that TSPO binding varies over time. The parietal and occipital cortex that showed a reduced BPA recent meta-analysis reported on the findings of 12 PET imaging studies in schizophrenia (190 schizophrenia patients and 200 healthy controls), using TSPO as a marker of neuroinflammation (Marques et al., There is some discussion on which outcome is the most reliable to determine TSPO binding. The BPWe found a lower performance for the 15 WLT in valaciclovir-treated patients and for the semantic category of the VFT for both treatment groups. This is unusual, as cognitive scores most often improve across a study due to a learning effect. Participation in this study may have been stressful and tiring, affecting concentration in our participants. Impaired concentration could also be a side effect of the high dose valaciclovir, even though we had a wash-out period of 7 days before follow-up measurement. Furthermore, VFT scores decreased in both the valaciclovir and the placebo group. In contrast, the psychiatric condition of patients did not change, as was shown by the pre- and post-treatment PANSS scores.We used [In conclusion, we found a decrease in TSPO binding in the hippocampus of patients with schizophrenia treated with valaciclovir, which was also observed in all other tested brain regions. Although this clearly is not proven by our study, it might suggest that viral activity is responsible for neuroinflammation in patients with schizophrenia. However, other explanations for this association cannot be excluded. Cognitive performance was negatively affected by the treatment, possibly due to study-induced stress. Additional studies are needed to confirm our findings, to find out whether this treatment effect is specific for schizophrenia patients, or for schizophrenia patients that are seropositive for HSV-1 infection, and to understand whether this treatment effect can lead to clinical relevant improvement of symptoms in patients with schizophrenia. | PMC10719624 |
Acknowledgements | psychosis | We very much appreciate the continuous support of the Stanley Medical Research Institute from USA and funding of our study (Trial 08-TGF-1243). The Stanley Medical Research Institute was not involved in study design, data analyses and interpretation or writing of the manuscript. PRA Health Sciences (Groningen, the Netherlands) is acknowledged for the free formulation and blinding of placebo and valaciclovir medication. We are very grateful for the Mental Health practitioners of UCP and Lentis for their inclusion of patient volunteers. We are also grateful for the psychosis ward of the UCP for taking care of our participants. We are especially indebted by the exceptionally motivated patient volunteers. | PMC10719624 |
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Financial support | This study was financed by a grant from The Stanley Medical Research Institute | PMC10719624 |
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Conflict of interest | E.F.J. de Vries declares Institutional financial support for contracted research from Hoffmann-La Roche, Eli Lilly, Bristol Myers Squibb, Ionis Pharmaceutical, Rodin Therapeutics, Lysosomal Therapeutics, Novartis and GlaxoSmithKline. These institutes were not involved in this study. All other authors declare that there is no conflict of interest. | PMC10719624 |
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References | PMC10719624 |
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Methods | DILATION, IOL | This was a randomized controlled trial, conducted over a period of eight months at a monocentric site. Singleton pregnancies in nulliparous and parous patients with cephalic presentation and Bishop score ≥ 6 were enrolled in the study. One hundred participants were randomized into two groups: early amniotomy (initiating IOL with amniotomy followed by oxytocin) versus late amniotomy (initiating IOL with oxytocin followed by amniotomy 4 hours later). The primary endpoint was the time to active phase (cervical dilation ≥ 5 cm) during IOL. Secondary outcomes were time to vaginal delivery, mode of delivery, and maternal and fetal outcomes. | PMC10212086 |
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Results | IOL | Early amniotomy reduced time to active phase by 2 hours and 46 minutes compared to the late amniotomy group (3 h 42 min vs. 6 h 28 min; p<0.0001). It also reduced time to vaginal delivery by 2 hours and 52 minutes (5 h 17 min vs. 8 h 9 min; p = 0.0003). The rate of cesarean section (CS) for failed IOL was significantly lower in the early amniotomy group (31.2% vs. 70.0%; p = 0.02), without any significant difference in the overall rate of cesarean section between the two groups (32.0% vs. 40.8%; p = 0.36). There was no significant difference in maternal or fetal outcomes. | PMC10212086 |
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Conclusions | IOL | Early amniotomy in IOL significantly shortens the time to active phase as well as the overall duration of labor without compromising maternal and neonatal safety. | PMC10212086 |
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Data Availability | Anonymized data were uplaoded. A copy of anonymized uploaded data is now registered on figshare.com (DOI: | PMC10212086 |
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Introduction | APL, IOL | HIGH-RISK PREGNANCIES, IOL | Induction of labor (IOL) is a common practice in obstetrics [In the USA about one in four women undergo IOL. This percentage is expected to rise due to the increasing number of high-risk pregnancies [Oxytocin and amniotomy are two methods used in IOL [There is ongoing debate about the efficacy of amniotomy in cases of IOL, two meta-analysis have suggested that it has the potential to reduce the duration of labor [The purpose of this randomized study was to evaluate the impact of early amniotomy on the time to active phase of labor (APL), duration of labor, as well as maternal and neonatal outcomes during IOL. | PMC10212086 |
Materials and methods | PMC10212086 |
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Ethics statement | IOL | IOL | The study protocol was approved by the ethical committee of Mongi-Slim University Hospital, La Marsa, Tunisia (approval no. 01/2021). This trial was registered on clinical-trials.org (NCT04731896) on January 2021.Women admitted for IOL and who met the inclusion criteria were explained the purpose of the study and were invited to participate. Women gave their written consent to take part in the study. | PMC10212086 |
Study design and participant selection | fetal abnormalities, macrosomia, hyperstimulation, pain, HIV, hepatitis B or C | CHORIOAMNIONITIS, IOL, GROUP B, CONTRACTIONS, COVID-19 INFECTION, CAVITY, FETAL GROWTH RESTRICTION | This is a randomized controlled, non-blind trial. Participants were randomly assigned to two parallel-groups: Group A: Early amniotomy (EA) and Group B: Late amniotomy (LA). The allocation ratio was 1:1.Women admitted for IOL were considered eligible if they met the following criteria: age ≥ 18 years, a full-term (≥ 37 weeks of gestation), singleton, fetus in cephalic presentation and bishop score of ≥ 6.Exclusion criteria were women with history of uterine surgery that breached the uterine cavity, previous cesarean section, ruptured membranes, spontaneous onset of labor, macrosomia, severe fetal growth restriction defined as estimated fetal weight by ultrasound < 3rd centile, major fetal abnormalities, maternal HIV, hepatitis B or C, COVID-19 infection or other contraindications to vaginal delivery.This trial was carried out in the department of obstetrics and gynecology, University Hospital of Mongi Slim La Marsa, Tunis from February 8After inclusion, each woman was assigned randomly to either early amniotomy (EA) or late amniotomy (LA) group.In Group A (EA): women had amniotomy soon after randomization and oxytocin infusion was started 30 minutes later.In Group B (LA): IOL was initiated with oxytocin infusion, and amniotomy was performed 4 hours later unless deemed necessary earlier (e.g. for non-reassuring fetal heart rate on the cardiotocography (CTG).Oxytocin was administered intravenously using a syringe infusion pump. The initial dose was 2mUI/min, with a 2mUI increase every 30 minutes. The target was 3–4 uterine contractions per 10 minutes. Once the target was reached, the infusion rate was not increased and kept constant. The maximum infusion rate was 42 mUI/min. The oxytocin infusion was stopped or reduced if hyperstimulation or abnormal CTG occurred. CTG abnormalities were evaluated according to the International Federation of Gynecology and Obstetrics (FIGO) guidelines [The same protocol of oxytocin administration was used in both groups.Throughout IOL, constant monitoring of fetal heart rate (FHR) and uterine contractions was conducted using an external paper scale CTG and an external tocodynamometer.Epidural was offered as an option of pain management in the labor ward when the contractions become regular and painful. The monitoring of labor relies on a one-to-one care. To minimize the incidence of chorioamnionitis, cervical examinations were performed every 4 hours in the absence of uterine contractions. However, if the patient experienced the onset of labor, the examinations were conducted hourly, and the midwife documented the findings. | PMC10212086 |
Study outcomes | APL, PPH | SECONDARY, POSTPARTUM HEMORRHAGE, POSTPARTUM FEVER | The primary outcome was the time spent between initiating the oxytocin infusion and the start of the active phase of labor (APL) defined as cervical dilatation of 5 cm [The secondary outcome included: time to vaginal delivery (VD), cesarean delivery rate, intrapartum and postpartum fever, postpartum hemorrhage (PPH), Apgar scores at 1 and 5 min, newborn admission to the neonatal intensive care unit (NICU). | PMC10212086 |
Sample size and randomization | IOL | The sample size was calculated using power calculations to detect a significant reduction in the time to APL. Based on the previous IOL performed in the department, the mean time needed to reach APL was 7± 3 hours and 36 minutes. Using an alpha error of 0.05 and 90% power, aiming to decrease by 150 min the time to APL in EA group, a minimum of 44 patients were needed in each arm [A random block allocation sequence was generated with a 1:1 ratio (50 in each group) using a computer-generated randomization program by an independent party, who was not involved in enrolling participants or assigning them to interventions. No stratification was used in this study.The enrollment was conducted by the resident investigator in this study. The resident investigator’s role was to ensure that the eligibility criteria were met and to provide information about the study and verify the written consent. | PMC10212086 |
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Statistical methods | Quantitative variables with are expressed as mean ± standard deviation (SD), Medians [1st Q- 3rd Q]. Qualitative variables are expressed as percentages. The statistical analysis was carried out using “XLSTAT 2022.3.2.1346”. Data were analyzed using Student-test, Mann-Whitney and Chi square. To compare the two groups, per-protocol analysis was employed. Kaplan-Meier survival analysis with a log-rank test was utilized to compare the primary outcome measure. ANCOVA-test analysis was performed to identify independent factors that may influence the time to APL. All statistical tests were two sided and were performed at a significance level of α = 0.05. | PMC10212086 |
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Results | A total of 521 women was screened, 100 were eligible and agreed to participate in the study. They were randomized equally into two groups: EA or LA. In LA group, in one occasion, the amniotomy was impossible. As we performed a per-protocol analysis, the patient was excluded after randomization. Ninety-nine patients were included in the analysis. The CONSORT flowchart is shown in ( | PMC10212086 |
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CONSORT 2010 flow diagram. | HIGH-RISK PREGNANCY | The baseline characteristics, high-risk pregnancy rate, and the mean gestational age are represented in | PMC10212086 |
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Independent factors affecting duration of active labor: ANCOVA analysis. | The results of the Kaplan-Meier survival analysis with log-rank test revealed that the duration of both the time to APL and the time to VD were significantly shorter in the EA group; p = 0.001 ( | PMC10212086 |
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Kaplan Meier analysis results. | PPH, Cord prolapse | IOL | There was a significative lower rate of CS for failed IOL in EA compared to LA group (31.2% vs. 70.0%; p = 0.02). However, no significant difference between both groups regarding the overall rate of CS was observed. The main indication of CS in both groups was failed IOL.Although the difference was not statistically significant, the EA group exhibited a lower incidence of PPH compared to the LA group (4.0% versus 12.2%; p = 0.06). Cord prolapse occurred in only one case in the EA group. The fetal outcomes between the two groups were found to be comparable ( | PMC10212086 |
Discussion | APL, IOL | DILATION, IOL | The main objective of this study was to evaluate the impact of EA on the time to active phase and the duration of labor, maternal and neonatal outcomes during IOL.We observed a significant reduction in the time to APL and the overall duration of labor with EA as compared to LA in IOL. Moreover, the rate of caesareans section for failed IOL was significantly lower in the early amniotomy group, without any significant difference in the overall rate of CS between the two groups. These benefits were associated with no significant difference between both groups regarding maternal and neonatal outcomes.Our study presents several strengths including randomization, the implementation of the CONSORT recommendation, the classification by parity, a well codified oxytocin administration protocol, and a clear description of early and late amniotomy.However, this study has its limitations. The primary outcome measure of our study was the time to the APL, as successful IOL is defined as achieving this phase after oxytocin and unsuccessful IOL is defined as the inability to reach it, even though the aim of IOL is natural childbirth. Nevertheless, there is no consensus on the definition of the APL among international societies, leading to conflicting interpretations of successful IOL. For instance, the American college of obstetricians and gynecologists (ACOG) defines it as cervical dilation greater than 6 cm [Two meta-analyses, focused on the comparison between LA and EA [The assessment of cervical ripeness using the BISHOP score is a crucial aspect in achieving successful IOL. In this study, our aim was to investigate the impact of amniotomy on IOL success by defining a BISHOP score greater than six. By doing so, we could obtain a more precise evaluation of the actual effect of amniotomy on the success of IOL. The use of a specific BISHOP score in our study provided valuable insights into the effectiveness of amniotomy, which could facilitate better interpretation and comparability of results, leading to more robust conclusions.In previous clinical trials, a shorter duration of labor was observed in the EA group in comparison to LA group (5–10), except for the studies conducted by Levy et al and Lee et al which did not demonstrate a significant difference in the duration of labor between the two groups [ | PMC10212086 |
Comparison of studies regarding early or late amniotomy during induction of labor. | PPH, IOL, labor, prolonged labor | POSTPARTUM HEMORRHAGE, IOL, PROLONGED LABOR | *: Time to active phase of laborThe question arises whether EA has an impact on the CS rate compared to late amniotomy in cases of IOL. In their meta-analysis, Kim et al reported no significant difference in the rate of CS between early and late amniotomy groups (RR, 1.09; 95% CI, 0.80–1.49) [Induction of labor (IOL) has been associated with postpartum hemorrhage (PPH), primarily caused by oxytocin infusion and prolonged labor [In the context of labor induction, it is crucial to prioritize maternal and fetal safety over a shorter duration of labor. Our trial confirms the safety and effectiveness of early amniotomy compared to late amniotomy during IOL. Early amniotomy decreases the time to APL and VD, and reduces the cesarean delivery rate due to failed IOL, without increasing the overall cesarean delivery rate or causing any significant difference in maternal or fetal outcomes. The use of this procedure can reduce the mobilization time of medical staff assigned to monitor patients in the delivery room and better organize work in light of the increasing indications for labor induction. However, further studies are needed to evaluate patient satisfaction. | PMC10212086 |
Conclusion | In women with a favorable cervix, Early amniotomy following induction of labor has been shown to reduce the time to active phase and the total duration of labor, as well as decrease the incidence of cesareans section due to failed Induction of labor. These benefits are observed without any significant difference in maternal or fetal outcomes, when compared to late amniotomy performed 4 hours after initiating induction of labor with oxytocin. | PMC10212086 |
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Supporting information | PMC10212086 |
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Ethical approval. | (PDF)Click here for additional data file. | PMC10212086 |
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Study protocol. | (DOCX)Click here for additional data file. | PMC10212086 |
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CONSORT 2010 checklist. | (DOC)Click here for additional data file. | PMC10212086 |
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Tables and figures. | (PDF)Click here for additional data file. | PMC10212086 |
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References | PMC10212086 |
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Abstract | PMC9875607 |
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Background | ANAPLASTIC THYROID CANCER, THYROID CANCER | Anaplastic thyroid cancer (ATC) is considered the most lethal thyroid cancer, with an overall 5‐year survival rate below 10%. The FDA approved a BRAF/MEK inhibitor combination for the treatment of patients with BRAF‐mutated ATC. However, effective therapeutic options for patients with wild‐type BRAF are lacking. | PMC9875607 |
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Case | ATCs, advanced/metastatic | In our phase II study, patients having advanced/metastatic solid ATCs were treated with famitinib and camrelizumab, a combination therapy involving a multi‐targeted kinase inhibitor and an anti‐PD‐1 antibody. We report a case of a patient with locally advanced unresectable ATC who underwent this combination therapy, allowing us to perform complete surgical resection followed by post‐operative radiation therapy. | PMC9875607 |
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Conclision | To the best of our knowledge, this is the first report describing the use of famitinib and camrelizumab as a neoadjuvant treatment for ATC with wild‐type BRAF. Clinical trial for a novel neoadjuvant approach for ATC are currently open for enrollment.
Shuwen Yang, Dongmei Ji, Fen Xue are co‐first authors. | PMC9875607 |
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INTRODUCTION | ATCs, Thyroid cancer, aggressive disease, thyroid cancer | THYROID CANCER, ANAPLASTIC THYROID CANCER, THYROID CANCER | Anaplastic thyroid cancer (ATC) is an extremely aggressive disease. It originates from follicular thyroid cells. It is the most dedifferentiated subtype of thyroid cancer and does not retain any biological characteristics of the follicular cells. Thyroid cancer stem cells can also play a role in the initiation and growth of ATCs. BRAF V600E mutation occurs in 25%–45% of the ATCs.Anaplastic thyroid cancer has an overall survival of 6 months following diagnosisHowever, effective therapeutic options for patients with wild‐type BRAF are lacking. Immunotherapy with anti‐PD‐L1 antibodies, alone or in combination with BRAF inhibitors, has shown promising result for the treatment of ATC.We report a case of a patient with locally advanced, unresectable ATC who was treated with famitinib and camrelizumab, allowing us to perform complete surgical resection, followed by postoperative radiation therapy. | PMC9875607 |
CASE DESCRIPTION | tumor, isodose, dyspnea, Tumor, calcification, Necrosis, pain, Tumors, NCT04521348, thyroid cancer, Cancer | THYROID CARCINOMA, TUMOR, DEGENERATION, METASTASIS, TUMOR, HYPERTENSION, DISEASE, NECROSIS, TUMORS, MAY, INFLAMMATORY INFILTRATION, CERVICAL MASS, ONCOLOGY, THYROID CANCER, DESMOPLASIA, CANCER | A 51‐year‐old man inadvertently noticed a cervical mass that had been growing rapidly for 1 month. On May 26, 2020, the patient went to the outpatient department of Fudan University Shanghai Cancer Center. He had no dyspnea and was in good clinical condition with an Eastern Cooperative Oncology Group performance status score of 0. However, he complained of pain on touching the mass. Therefore, cervical ultrasound (US) and thyroid computed tomography (CT) were performed in May 2020. Imaging results showed calcified masses on both the lobes and isthmus of the thyroid, suggesting the possibility of thyroid carcinoma. The trachea was shifted to the right and invasion of the internal jugular vein and common carotid artery was observed (Figure The effects of the therapy on the disease. Tumor size and cervical nodes size change from (A) and (B) baseline; (C) and (D) after three cycles of famitinib and camrelizumab treatment; (E) and (F) then after surgery and external radiation therapy.Core needle biopsy on left lobe: (A) and (B) the touch imprint cytology show the neoplastic tumor cells with obvious pleomorphism and nucleoli in some cells. (A) is hematoxylin and eosin histology section at 400× and (B) is Liu's stain at 400×. (C) the epithelioid tumor cells show solid growth cells which are obviously heteromorphic (hematoxylin and eosin histology section at 100×). (D) the nuclei of tumor are large, nucleoli are apparent and mitosis is easy to see (hematoxylin and eosin histology section at 400×).Immunohistochemically stained slides of core needle biopsy revealed the tumor cells to be positive for AE1/AE3, TTF‐1, PAX8, P53 (70%) at 200×.In June 2020, the patient was recruited for a clinical trial that combined multiple‐target kinase inhibitors and anti‐PD‐1 antibodies in patients with advanced thyroid cancer (NCT04521348). He was administered three cycles of famitinib (20 mg/qd) and camrelizumab (200 mg/q3w). The patient exhibited a good clinical status, but suffered from famitinib‐induced grade 3 hypertension, which was controlled with nifedipine and valsartan. Famitinib was discontinued for 3 days during the second cycle.After three cycles of treatment, CT showed partial response (PR) of the lesion according to the Response Evaluation Criteria in Solid Tumors (version 1.1) (Figure Total thyroidectomy with removal of lymph node group VI and left radical neck dissection (groups II, III, IV, and V) were performed in July 2020. Postoperative pathological examination identified a 35‐mm (maximum diameter) lesion in the left thyroid lobe (Figure (A) and (B) show a surgical gross specimen; (C) and (D) show some foci poorly differentiated tumor nests were observed, with degeneration. Necrosis, desmoplasia, calcification, chronic inflammatory infiltration, and foamy histiocytes aggregates were found in surrounding areas, cholesterol crystals occasionally appeared (hematoxylin and eosin histology section at 40× and 100×).Postoperative therapy included L‐thyroxine (125 μg/d). Positron emission tomography CT showed no masses in the thyroid or neck lymph nodes and no distant metastasis. By August 2020, the patient had recovered well and received intensity‐modulated radiation therapy (IMRT) with a dose of 60 Gy (in 30 fractions) to the thyroid bed and cervical nodal regions and 54 Gy to the mediastinal nodes (Figure A coronal and a sagittal view of the post‐operative radiation planning CT scan. The blue and yellow lines represent the 60 Gy and 54 Gy isodose lines, respectively and the staining areas within these lines represent clinical targets specified at 60 and 54 Gy, respectively.Surveys of patient‐reported outcomes were obtained approximately 24 months after the diagnosis. They showed a very good quality of life, including continuation of normal activities such as jogging. | PMC9875607 |
DISCUSSION | dysphagia, aggressive thyroid cancers, tumor, dyspnea, pembrolizumab, hoarseness, neutropenia, toxicities, Anaplastic thyroid cancer, airway distress, deaths, hypertension, thyroid cancer | DYSPHAGIA, LEUKOCYTOPENIA, TUMOR, NEUTROPENIA, HYPERTENSION, THYROID, DISEASE, ANAPLASTIC THYROID CANCER, SOLID TUMORS, THYROID NODULE, THROMBOCYTOPENIA, MALIGNANCIES, THYROID CANCER, THYROID CANCERS | Anaplastic thyroid cancer is considered the most lethal thyroid cancer, accounting for 38%–50% of all deaths related to thyroid cancers. The overall 5‐year survival rate for ATC is below 10%Anaplastic thyroid cancer often presents with severe symptoms including airway distress, hoarseness, dyspnea, and dysphagia due to a fast‐growing neck mass. A definitive diagnosis is usually made using fine‐needle aspiration biopsy and/or high‐resolution US. The patient in the present case underwent CNB of the prevailing thyroid nodule, which was diagnosed as ATC.According to American Thyroid Association guidelines, a combination of surgery, chemotherapy, and radiotherapy should be used to manage and control local and metastatic ATCs.We attempted experimental therapy involving a combination of famitinib (a tyrosine kinase inhibitor [TKI]) and camrelizumab (an immune checkpoint inhibitor [ICI]). TKIs are currently used to treat aggressive thyroid cancers, as they induce clinical responses and stabilizes the disease. The role of TKIs in the treatment of thyroid cancer is limited to cases wherein progression continues after primary therapy (surgery and radioiodine therapy) and local ablation therapies. Careful evaluation of the risk/efficacy ratio is recommended in such cases. Testing each patient's sensitivity to different TKIs could pave the way for personalized treatment.Famitinib, a sunitinib analog, is a novel and highly potent multi‐target receptor tyrosine kinase inhibitor against c‐Kit, vascular endothelial growth factor receptor, and platelet‐derived growth factor receptor; with antitumor activity in the range of solid tumors.In the present case, the primary thyroid lesion as well as cervical lymph nodes had shrunk following a combination therapy with a TKI and an ICI, which enabled us to perform complete surgical resection. After radiotherapy, the patient received camrelizumab for maintenance. Effective choices for systemic treatment of patients having ATC with wild‐type BRAF are still lacking. The present case report suggests that ATC with wild‐type BRAF could exhibit a substantial response to treatment with a combination of a TKI and an ICI. In a phase II cohort study, 42 patients were enrolled. The overall response rate was 19%, with complete response in 3 patients and partial response (PR) in 5 patients. This shows the reactivity of ATC to PD‐1 blockade.Although we cannot exclude the possibility that the patient might have responded to famitinib or camrelizumab monotherapy, the similarity of famitinib with sunitinib and the course of the disease suggest that the combination of famitinib and camrelizumab is more than just an addition of the two drugs. For patients already resistant to TKI therapy, the addition of pembrolizumab is partially effective with a PFS of only 2.96 months,After neoadjuvant therapy, the patient underwent major surgery including total thyroidectomy, bilateral central compartment dissection, and left neck dissection. The surgery successfully preserved critical functional organs such as the trachea, esophagus, parathyroids, and larynx/recurrent laryngeal nerves. Uruno et al. documented their clinical experience with neoadjuvant chemotherapy for ATC.In the neoadjuvant phase, toxicities related to famitinib were classified as grade I–II and the present study noted a lower incidence of side effects such as thrombocytopenia, leukocytopenia, neutropenia, and hypertension when compared with previous reports involving advanced solid malignancies refractory to standard treatment.In conclusion, ATC is associated with high mortality rates. Exploring new strategies is still needed to improve the survival of ATC patients. In this case, we chose a multidisciplinary method to treat this staging IVB ATC patient, which included the systemic treatment of famitinib and camrelizumab as the inducing therapy, and after the shrinkage of the tumor, surgery was performed and then adjuvant radiotherapy with subsequent maintenance immunotherapy was given. This approach is expected to be an effective therapeutic modality and should be explored prospectively in future clinical trials. Trials exploring combination immunotherapy and targeted therapy are currently ongoing (NCT04521348). | PMC9875607 |
AUTHOR CONTRIBUTIONS | PMC9875607 |
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CONFLICT OF INTEREST | The authors have stated explicitly that there are no conflicts of interest in connection with this article. | PMC9875607 |
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ETHICS STATEMENT | Cancer | CANCER | All experiments were approved by Fudan University Shanghai Cancer Center institutional ethics committee (1910208‐17). Written informed consent was obtained from the patient for publication of this case report and any accompanying images. | PMC9875607 |
ACKNOWLEDGMENTS | Not applicable. | PMC9875607 |
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DATA AVAILABILITY STATEMENT | Not applicable. | PMC9875607 |
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REFERENCES | PMC9875607 |
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Key Points | PMC10311390 |
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Question | rheumatoid arthritis | RHEUMATOID ARTHRITIS | What is the effectiveness of adalimumab (ADA) compared with tofacitinib (TOF) for treatment of rheumatoid arthritis in routine clinical practice? | PMC10311390 |
Findings | rheumatoid arthritis | RHEUMATOID ARTHRITIS | In this comparative effectiveness study of 842 patients with rheumatoid arthritis in Australia, TOF was favored slightly at 3 months vs ADA, but there was no difference in scores between patients receiving TOF and those receiving ADA at 9 months. | PMC10311390 |
Meaning | This study showed similar treatment effects for TOF and ADA, which is consistent with data from a randomized trial and current European Alliance of Associations for Rheumatology treatment guidelines. | PMC10311390 |
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Importance | rheumatoid arthritis, RA | RHEUMATOID ARTHRITIS | There is a need for observational studies to supplement evidence from clinical trials, and the target trial emulation (TTE) framework can help avoid biases that can be introduced when treatments are compared crudely using observational data by applying design principles for randomized clinical trials. Adalimumab (ADA) and tofacitinib (TOF) were shown to be equivalent in patients with rheumatoid arthritis (RA) in a randomized clinical trial, but to our knowledge, these drugs have not been compared head-to-head using routinely collected clinical data and the TTE framework. | PMC10311390 |
Objective | RA | To emulate a randomized clinical trial comparing ADA vs TOF in patients with RA who were new users of a biologic or targeted synthetic disease-modifying antirheumatic drug (b/tsDMARD). | PMC10311390 |
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Design, Setting, and Participants | RA | DISEASE | This comparative effectiveness study emulating a randomized clinical trial of ADA vs TOF included Australian adults aged 18 years or older with RA in the Optimising Patient Outcomes in Australian Rheumatology (OPAL) data set. Patients were included if they initiated ADA or TOF between October 1, 2015, and April 1, 2021; were new b/tsDMARD users; and had at least 1 component of the disease activity score in 28 joints using C-reactive protein (DAS28-CRP) recorded at baseline or during follow-up. | PMC10311390 |
Intervention | Treatment with either ADA (40 mg every 14 days) or TOF (10 mg daily). | PMC10311390 |
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Main Outcomes and Measures | The main outcome was the estimated average treatment effect, defined as the difference in mean DAS28-CRP among patients receiving TOF compared with those receiving ADA at 3 and 9 months after initiating treatment. Missing DAS28-CRP data were multiply imputed. Stable balancing weights were used to account for nonrandomized treatment assignment. | PMC10311390 |
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Results | A total of 842 patients were identified, including 569 treated with ADA (387 [68.0%] female; median age, 56 years [IQR, 47-66 years]) and 273 treated with TOF (201 [73.6%] female; median age, 59 years [IQR, 51-68 years]). After applying stable balancing weights, mean DAS28-CRP in the ADA group was 5.3 (95% CI, 5.2-5.4) at baseline, 2.6 (95% CI, 2.5-2.7) at 3 months, and 2.3 (95% CI, 2.2-2.4) at 9 months; in the TOF group, it was 5.3 (95% CI, 5.2-5.4) at baseline, 2.4 (95% CI, 2.2-2.5) at 3 months, and 2.3 (95% CI, 2.1-2.4) at 9 months. The estimated average treatment effect was −0.2 (95% CI, −0.4 to −0.03; | PMC10311390 |
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Conclusions and Relevance | REMISSION | In this study, there was a modest but statistically significant reduction in DAS28-CRP at 3 months for patients receiving TOF compared with those receiving ADA and no difference between treatment groups at 9 months. Three months of treatment with either drug led to clinically relevant average reductions in mean DAS28-CRP, consistent with remission. | PMC10311390 |
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Introduction | rheumatoid arthritis, RA, tumor necrosis | RHEUMATOID ARTHRITIS, DISEASE, TUMOR NECROSIS | In the past 20 years, the availability of tumor necrosis factor inhibitors (TNFis) and other biologic disease-modifying antirheumatic drugs (bDMARDs) has transformed treatment for patients with rheumatoid arthritis (RA). More recently, targeted synthetic DMARDs (tsDMARDs), including janus kinase inhibitors (JAKis), have become available and are considered equivalent to bDMARDs for patients with moderate to severe disease refractory to conventional synthetic DMARD (csDMARD) therapy.Although trials directly comparing specific b/tsDMARDs head-to-head are limited, a double-blind phase 3b/4 randomized clinical trialRegistries and real-world data sets (RWDs), which include routinely collected data such as electronic medical records (EMRs) and medical claims data, are a valuable source of information for understanding the effectiveness of treatments. There is increasing recognition of the complementary role for real-world evidence based on analyses of RWDs in health care and regulatory decision-making.Target trial emulation (TTE) is a framework for comparative effectiveness analyses whereby principles from the design of randomized clinical trials (RCTs) are applied to observational research by making explicit the design of the trial that is intended to be emulated. | PMC10311390 |
Methods | Detailed technical methods of this comparative effectiveness study are described in eMethods 1 through 7 and the eAppendix in | PMC10311390 |
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Design | The prespecified protocol for the target trial to be emulated is described in eMethods 1 in | PMC10311390 |
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Participants | RA | Eligible patients in the emulated target trial were adults aged 18 years or older who were diagnosed with RA; whose first visit occurred between April 1, 2015, and January 1, 2021; who had no prior recorded b/tsDMARD; who had at least 6 months from their first recorded visit until baseline; and who had at least 6 months of treatment with a csDMARD immediately prior to baseline. These criteria defined (or enriched for) a cohort of new users who were b/tsDMARD naive based on their EMR and the government criteria for b/tsDMARD reimbursement. Patients were excluded if they did not have at least 1 component of the DAS28-CRP recorded at baseline, 3 months, or 9 months. | PMC10311390 |
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Interventions | ADVERSE EVENT | Patients initiated treatment with either ADA (40 mg every 14 days) or TOF (10 mg daily) and, in the target trial, would be expected to continue treatment during follow-up unless an adverse event or contraindication occurred. The limited duration of availability of the biosimilar for ADA meant that all ADA interventions were the originator and not the biosimilar. | PMC10311390 |
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End Point | DISEASE | The primary outcome was disease activity at 3 and 9 months after initiating treatment. The average treatment effect (ATE) was defined as the difference in mean DAS28-CRP among patients receiving TOF compared with those receiving ADA at 3 and 9 months.These time points were selected because joint counts and pathologic markers are assessed for government reimbursement at 3 and 9 months. American College of Rheumatology response of at least 50% was used in the trial of ADA and TOF. | PMC10311390 |
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Setting and Data Source | fits, RA, rheumatic | DISEASE, PATHOLOGY | This analysis used the multicenter OPAL data set, which includes the EMRs for 216 138 patients with rheumatic conditions treated by 112 rheumatologists across Australia at 43 different clinics since 2004. In Australia, government reimbursement is available for b/tsDMARDs for patients with moderate to severe disease who have not responded to at least 6 months of treatment with csDMARDs, and physicians can prescribe the b/tsDMARD that fits the patient’s clinical need. As such, there are no binding guidelines as to the order in which a b/tsDMARD class can be prescribed. Response to treatment is assessed at 3 months and at 6-month intervals thereafter. Tofacitinib is approved by the Australian Therapeutic Goods Administration for use for RA at a dosage of 5 mg twice daily.The deidentified data in the OPAL data set include demographics, disease history, disease activity measures, comorbidities, pathology, medications, patient-reported outcomes, and characteristics of the treating rheumatologist. Data were collected from April 1, 2015, to June 30, 2021. A more detailed description of the data set and a summary of the characteristics of the variables used in this analysis are given in eMethods 2 in | PMC10311390 |
Safety | ADVERSE REACTIONS, ADVERSE REACTION | Treatment cessations due to an adverse reaction were described for all patients who satisfied the inclusion criteria. Treating physicians have discretion to record an adverse reaction to a medication in the EMR, and there may have been unrecorded adverse reactions. All recorded adverse reactions that were considered more serious than nonserious were described. An adverse reaction recorded using the | PMC10311390 |
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Patient Involvement | Patients were not involved in the design of this study or consulted during selection of outcomes or the interpretation of findings. Patients will be involved in the dissemination of this research. | PMC10311390 |
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Statistical Analysis | DISEASE | A multistep method was developed to address the challenges of missing disease activity data and nonrandomized treatment assignment. Analysis that only uses complete cases could lead to selection bias, and thus, multiple imputation was used instead of complete-case analysis. An overview of the methods is presented in | PMC10311390 |
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Multistep Analytical Procedure Developed to Estimate the Average Treatment Effect (ATE) of Tofacitinib (TOF) Compared With Adalimumab (ADA) | Random forest multiple imputation (RF-MI) was used to impute plausible values for missing data in the original electronic medical record (EMR) data set. Stable balancing weights (SBWs) were used to balance the baseline characteristics of the ADA and TOF treatment groups. Gray squares in the grid that represents EMR indicate complete data items and white squares, missing data items. In the complete data sets generated by RF-MI, colored squares represent the imputed values. The different colors used for the same data item in different data sets indicate that imputed values were slightly different in each data set. The covariate balance plots indicate that after SBWs were applied, the mean standardized difference in baseline characteristics between the treatment groups was close to 0 compared with before weighting. The ATE was then calculated separately in each imputed data set before pooling to generate a final estimate.In brief, multiple imputation by chained equations using the random forest algorithm under the missing-at-random assumption was used to impute missing data for the components of the DAS28-CRP at baseline and follow-up, generating 10 imputed data sets.All analyses were performed using R, version 4.0.2 (R Project for Statistical Computing). Differences in mean DAS28-CRP at follow-up were assessed using a 2-sided test and a significance level of | PMC10311390 |
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Results | PMC10311390 |
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Patients | RA | Of the 52 338 patients with RA in the OPAL data set, 842 eligible b/tsDMARD-naive patients who were new starters of ADA (n = 569; 387 [68.0%] female; 175 [30.8%] male; median age, 56 years [IQR, 47-66 years]) or TOF (n = 273; 201 [73.6%] female; 72 [26.4%] male; median age, 59 years [IQR, 51-68 years]) were identified ( | PMC10311390 |
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Baseline Data | Before SBWs were applied, there were small differences between the treatment groups ( | PMC10311390 |
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Baseline Characteristics of Patients With RA Treated With ADA or TOF | RHEUMATOID ARTHRITIS, DISEASE | Abbreviations: ADA, adalimumab; b/tsDMARDs, biologic or targeted synthetic disease-modifying antirheumatic drugs; CRP, C-reactive protein; DAS28-CRP, disease activity score in 28 joints using C-reactive protein; EMR, electronic medical record; ESR, erythrocyte sedimentation rate; RA, rheumatoid arthritis; SJC28, swollen joint count based on 28-joint assessment; TJC28, tender joint count based on 28-joint assessment; TOF, tofacitinib.Data are presented as number (percentage) of patients unless otherwise indicated.Data were missing for 7 patients in the ADA group (1.2%) and 0 patients in the TOF group.Data were missing for 1 patient in the ADA group (0.2%) and 1 patient in the TOF group (0.4%).Data were missing for 1 patient in the ADA group (0.2%) and 0 patients in the TOF group.Data were missing for 68 patients in the ADA group (12.0%) and 40 in the TOF group (14.7%).Data were missing for 213 patients in the ADA group (37.4%) and 115 in the TOF group (42.1%).Data were missing for 75 patients in the ADA group (13.2%) and 45 in the TOF group (16.5%).Data were missing for 210 patients in the ADA group (36.9%) and 118 in the TOF group (43.2%).Data were missing for 217 patients in the ADA group (38.1%) and 120 in the TOF group (44.0%).After SBWs were applied, the standardized mean differences in baseline characteristics were between −0.03 and 0.03, within the conventional threshold of 0.1 for propensity score matching ( | PMC10311390 |
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Standardized Mean Difference in Baseline Characteristics of Adalimumab (ADA) and Tofacitinib (TOF) Treatment Groups Before and After Weighting | DISEASE | Error bars for disease activity score in 28 joints using C-reactive protein (DAS28-CRP) represent the minimum and maximum standardized mean difference values across 10 imputed data sets. The standardized mean difference is the difference between treatment groups in the mean for each covariate divided by its SD for the entire sample. The vertical dashed black lines indicate standardized mean differences of −0.03 and 0.03. ACT indicates Australian Capital Territory; NSW, New South Wales; QLD, Queensland and Western Australia; and TAS, Tasmania. | PMC10311390 |
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Estimated Comparative Effectiveness | After weighting, mean DAS28-CRP decreased from 5.3 (95% CI, 5.2-5.4) at baseline to 2.6 (95% CI, 2.5-2.7) at 3 months and 2.3 (95% CI, 2.2-2.4) at 9 months in the ADA group (eResults 5 in The ATE for TOF compared with ADA was −0.2 (95% CI, −0.4 to −0.03; | PMC10311390 |
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Estimated Average Treatment Effect (ATE) for Tofacitinib (TOF) Compared With Adalimumab (ADA) at 3 and 9 Months | Squares represent ATEs, with horizontal lines representing 95% CIs based on bootstrap distributions of the estimates. | PMC10311390 |
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Safety | cancer | ADVERSE REACTIONS, CANCER | Due to recent concerns about MACE and cancer associated with JAKi drugs,There were no adverse reactions recorded using | PMC10311390 |
Discussion | cancer, RA | CANCER, DISEASE | In this comparative effectiveness study using the TTE framework, we found a modest but statistically significant reduction in disease activity associated with TOF compared with ADA at 3 months and no difference between drugs at 9 months in patients with RA who were b/tsDMARD naive. These results may be generalizable to patients with RA who have not responded to csDMARD therapy and are eligible to initiate their first b/tsDMARD, subject to the limitations of the study. Although the outcomes, time points, and superiority design differ, the small effect size in our analysis is consistent with the previous findings of noninferiority in the American College of Rheumatology response of at least 50% at 6 months for these drugs in a clinical trial.Observational studies are an important supplement to RCTs for assessing whether trial findings can be reproduced in everyday practice in a less restricted patient population and for guiding treatment decisions that occur outside the idealized setting of a trial.Safety signals, although typically rare, are important in connection with ADA and TOF, especially in light of the relatively higher risks of MACE and cancer associated with JAKi therapy compared with TNFi therapy. | PMC10311390 |
Limitations | DISEASE | As an analysis of observational data, the challenges of missing outcomes data and nonrandomized treatment assignment were possible limitations to this study that may impact interpretation of the generalizability of the results. Our analysis relied on some assumptions, and violation of these would limit the reliability of the results. We assumed the joint counts, CRP levels, and patient global scores were missing at random (ie, whether an outcome was missing was not related to its value after conditioning on the observed data). Under this assumption, the missing data on joint counts, CRP levels, and patient global scores could be accounted for in the imputation model by the characteristics of the patients, the treating rheumatologists, and the clinics, which were fully observed, and accounting for these variables could produce unbiased results in the analysis. Availability of nursing staff time and other characteristics of the clinics and individual rheumatologists are plausible variables to explain whether a rheumatologist in a busy clinic would be able to prioritize recording complete data on all outcomes during a consultation with a patient. Nevertheless, we acknowledge that there may have been bias that could not be addressed if there were further unmeasured sources of missing data that were not accounted for in the imputation model.The assumptions for inferring a causal treatment effect include that (1) the probability of initiating treatment with ADA or TOF may have depended on the measured baseline characteristics but did not depend on future disease activity at follow-up time points, (2) the probability of treatment assignment did not equal 0, and (3) a patient's observed DAS28-CRP at follow-up was the same as that patient's potential DAS28-CRP at follow-up after they followed the treatment that they were observed to be assigned to. | PMC10311390 |
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Conclusions | REMISSION | In this comparative effectiveness study, DAS28-CRP was significantly lower at 3 months for patients treated with TOF compared with ADA. However, 3 months of treatment with either drug led to substantive reductions in mean DAS28-CRP, consistent with remission. There was no difference in DAS28-CRP between patients receiving TOF or ADA at 9 months. The results of this observational study are consistent with clinical trial data | PMC10311390 |
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