Tofacitinib as a Steroid-Sparing Therapy in Pulmonary Sarcoidosis, an Open-Label Prospective Proof-of-Concept Study.
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SUBMITTER: Friedman MA
PROVIDER: S-EPMC8092019 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Agents that target pro-inflammatory cytokines may be useful in pulmonary sarcoidosis. OBJECTIVE:To determine effectiveness of a non-selective cyclic nucleotide phosphodiesterase (PDE) inhibitor, pentoxifylline (POF). DESIGN:Randomized, double-blind, placebo-controlled trial, SETTING:Clinical Research Center, National Institutes of Health. PATIENTS:27 patients with biopsy-confirmed pulmonary sarcoidosis receiving prednisone. INTERVENTION:Placebo or POF (1200-2000 mg/day) for 10 months, as prednisone was tapered. MEASUREMENTS:Primary endpoints: sustained improvement in two or more pulmonary function parameters, or a combination of one pulmonary function parameter and dyspnea. RESULTS:Except for one patient, primary endpoints were not reached in POF-treated patients. Therefore, a post hoc analysis was performed. The observed relative risk reduction for flares associated with POF treatment was 54.9% (95% CI 0.21, 0.89) and the absolute risk reduction was 50.6% (95% CI 0.22, 0.80). Compared to placebo treatment, in the POF group, the mean prednisone dose was lower at 8 and 10 months (p = 0.007 and 0.01 respectively), and there was a trend towards less prednisone usage over the entire study period (p = 0.053), as determined by cumulative change analysis. CONCLUSIONS:Although our exploratory post hoc analysis suggested that POF reduced flares and had steroid-sparing effects, given the study limitations, definitive conclusions cannot be drawn regarding the efficacy of POF in pulmonary sarcoidosis. In addition, gastrointestinal side-effects, at the doses used, would seem to limit the use of POF in treating pulmonary sarcoidosis. Overall, however, this trial may provide a basis for using more specific, better-tolerated, PDE inhibitors in future clinical trials.
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Project description:PurposeInfluenza-associated pulmonary aspergillosis (IAPA) is a frequent complication in critically ill influenza patients, associated with significant mortality. We investigated whether antifungal prophylaxis reduces the incidence of IAPA.MethodsWe compared 7 days of intravenous posaconazole (POS) prophylaxis with no prophylaxis (standard-of-care only, SOC) in a randomised, open-label, proof-of-concept trial in patients admitted to an intensive care unit (ICU) with respiratory failure due to influenza (ClinicalTrials.gov, NCT03378479). Adult patients with PCR-confirmed influenza were block randomised (1:1) within 10 days of symptoms onset and 48 h of ICU admission. The primary endpoint was the incidence of IAPA during ICU stay in patients who did not have IAPA within 48 h of ICU admission (modified intention-to-treat (MITT) population).ResultsEighty-eight critically ill influenza patients were randomly allocated to POS or SOC. IAPA occurred in 21 cases (24%), the majority of which (71%, 15/21) were diagnosed within 48 h of ICU admission, excluding them from the MITT population. The incidence of IAPA was not significantly reduced in the POS arm (5.4%, 2/37) compared with SOC (11.1%, 4/36; between-group difference 5.7%; 95% CI - 10.8 to 21.7; p = 0.32). ICU mortality of early IAPA was high (53%), despite rapid antifungal treatment.ConclusionThe higher than expected incidence of early IAPA precludes any definite conclusion on POS prophylaxis. High mortality of early IAPA, despite timely antifungal therapy, indicates that alternative management strategies are required. After 48 h, still 11% of patients developed IAPA. As these could benefit from prophylaxis, differentiated strategies are likely needed to manage IAPA in the ICU.
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Project description:Cellular therapy is an emerging therapeutic modality with a great potential for the treatment of autism. Recent findings show that the major underlying pathogenetic mechanisms of autism are hypoperfusion and immune alterations in the brain. So conceptually, cellular therapy which facilitates counteractive processes of improving perfusion by angiogenesis and balancing inflammation by immune regulation would exhibit beneficial clinical effects in patients with autism. This is an open label proof of concept study of autologous bone marrow mononuclear cells (BMMNCs) intrathecal transplantation in 32 patients with autism followed by multidisciplinary therapies. All patients were followed up for 26 months (mean 12.7). Outcome measures used were ISAA, CGI, and FIM/Wee-FIM scales. Positron Emission Tomography-Computed Tomography (PET-CT) scan recorded objective changes. Out of 32 patients, a total of 29 (91%) patients improved on total ISAA scores and 20 patients (62%) showed decreased severity on CGI-I. The difference between pre- and postscores was statistically significant (P < 0.001) on Wilcoxon matched-pairs signed rank test. On CGI-II 96% of patients showed global improvement. The efficacy was measured on CGI-III efficacy index. Few adverse events including seizures in three patients were controlled with medications. The encouraging results of this leading clinical study provide future directions for application of cellular therapy in autism.
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Project description:Open Label Clinical Trial
2024-07-09 | GSE271627 | GEO
Project description:Lithium has a narrow therapeutic index with a subtle balance between effectiveness and adverse effects. Current guidelines recommend the use of lithium as a treatment for acute bipolar depression; however, the therapeutic range for the treatment has not been fully defined. Recently, the adjunctive lower lithium dose in bipolar depression has revealed potential efficacy; however, no study has investigated it predominantly in monotherapy. In this open-label, proof-of-concept study, 31 individuals with bipolar disorder during a depressive episode were randomized and 29 were followed up for six weeks with flexible lithium dosing. All subjects had a 21-item Hamilton Rating Scale for Depression (HAM-D) score of ?18 at baseline. Subjects were divided into two groups, with higher (Li ?0.5 mEq/l) or lower (Li <0.5 mEq/l) blood lithium levels. Response and remission rates were evaluated using the HAM-D scores. Following 6 weeks of lithium treatment, the remission rate for all patients was 62.0%. The plasma lithium levels did not impact the clinical response. However, subjects with higher blood lithium levels had an increased prevalence of nausea, restlessness, headaches and cognitive complaints. The results indicate that the lithium dose for the treatment of bipolar depression in an individual should be based on the clinical efficacy and side-effects. In the context of personalized psychiatric treatments, it is necessary to evaluate the therapeutic action of lithium with individual regimens in order to develop more tolerable and effective treatment approaches.
| S-EPMC4151672 | biostudies-literature
Project description:BACKGROUND:The underlying pathophysiology in intellectual disability (ID) involves abnormalities in dendritic branching and connectivity of the neuronal network. This limits the ability of the brain to process information. Conceptually, cellular therapy through its neurorestorative and neuroregenerative properties can counteract these pathogenetic mechanisms and improve neuronal connectivity. This improved networking should exhibit as clinical efficacy in patients with ID. METHODS:To assess the safety and efficacy of cellular therapy in patients with ID, we conducted an open-label proof-of-concept study from October 2011 to December 2015. Patients were divided into two groups: intervention group (n?=?29) and rehabilitation group (n?=?29). The intervention group underwent cellular transplantation consisting of intrathecal administration of autologous bone marrow mononuclear cells and standard neurorehabilitation. The rehabilitation group underwent only standard neurorehabilitation. The results of the symptomatic outcomes were compared between the two groups. In the intervention group analysis, the outcome measures used were the intelligence quotient (IQ) and the Wee Functional Independence Measure (Wee-FIM). To compare the pre-intervention and post-intervention results, statistical analysis was done using Wilcoxon's matched-pairs test for Wee-FIM scores and McNemar's test for symptomatic improvements and IQ. The effect of age and severity of the disorder were assessed for their impact on the outcome of intervention. Positron emission tomography-computed tomography (PET-CT) brain scan was used as a monitoring tool to study effects of the intervention. Adverse events were monitored for the safety of cellular therapy. RESULTS:On symptomatic analysis, greater improvements were seen in the intervention group as compared to the rehabilitation group. In the intervention group, the symptomatic improvements, IQ and Wee-FIM were statistically significant. A significantly better outcome of the intervention was found in the paediatric age group (<18 years) and patients with milder severity of ID. Repeat PET-CT scan in three patients of the intervention group showed improved metabolism in the frontal, parietal cortex, thalamus, mesial temporal structures and cerebellum. No major adverse events were witnessed. CONCLUSIONS:Cellular transplantation with neurorehabilitation is safe and effective for the treatment of underlying brain deficits in ID. TRIAL REGISTRATION:ClinicalTrials.gov NCT02245724. Registered 12 September 2014.
| S-EPMC5793399 | biostudies-literature
Project description:Background:Chronic cough is a distressing symptom for many people with pulmonary sarcoidosis. Continuous treatment with a macrolide antibiotic may improve cough. We aimed to assess the potential efficacy of azithromycin in patients with sarcoidosis and self-reported cough.Methods:We conducted a noncontrolled, open-label clinical trial of azithromycin 250?mg once daily for 3?months in patients with pulmonary sarcoidosis who reported a chronic cough. The primary outcome was number of coughs in 24?h. Secondary outcomes were cough visual analogue scales and quality of life measured using the Leicester Cough Questionnaire and King's Sarcoidosis Questionnaire. Safety outcomes included QTc interval on ECG. Measurements were made at baseline and after 1 and 3?months of treatment.Results:All 21 patients were white, median age 57?years, 9 males, 12 females, median 3 years since diagnosis. Five were taking oral corticosteroids and none were taking other immunosuppressants. Twenty patients completed the trial. The median (range) number of coughs in 24?h was 228 (43-1950) at baseline, 122 (20-704) at 1?month, and 81 (16-414) at 3 months (p=0.002, Friedman's test). The median reduction in cough count at 3?months was 49.6%. There were improvements in all patient-reported outcomes. Azithromycin was well tolerated.Conclusion:In a noncontrolled open-label trial in people with sarcoidosis who reported a chronic cough, 3?months of treatment with azithromycin led to improvements in a range of cough metrics. Azithromycin should be tested as a treatment for sarcoidosis cough in a randomised placebo-controlled trial.
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Project description:We recently reported improved glycemic control with reduced insulin dose in subjects with type 1 diabetes treated with the sodium glucose co-transporter-2 inhibitor empagliflozin. To further characterize the effects, we analyzed diurnal glycemic patterns by continuous glucose monitoring (CGM).In an 8-week single-arm open-label pilot study of empagliflozin, we compared ambulatory glucose profiles produced from CGM data during 2-week intervals in a placebo run-in baseline period, end-of-treatment, and post-treatment. Change in glycemic exposure was evaluated by area under the median curve according to time of day (AUCTOTAL 12:00am-11:55pm; AUCDAY 7:05am-10:55pm, AUCNIGHT 11:00pm-7:00am), as well as glycemic variability, glycemic stability and time-in-target (?70 to ?140mg/dL).The 40 patients (26 on insulin pump) were aged 24±5 years and BMI 24.5±3.2 kg/m2. Consistent with the observed HbA1c decrease (8.0±0.9% to 7.6±0.9%, p<0.0001), normalized AUCTOTAL CGM decreased from 153.7±25.4 to 149.0±30.2mg/dL?h at end-of-treatment (p = 0.31), and significantly increased post-treatment (164.1±29.5mg/dL?h, p = 0.02). The numerical decrease in normalized AUCNIGHT (152.0±36.6 to 141.9±34.4mg/dL?h, p = 0.13) exceeded AUCDAY (154.5±24.5 to 152.6±30.4mg/dL?h, p = 0.65). Trends toward lower glycemic variability (83.1±18.9 to 75.6±28.6mg/dL, p = 0.06) and little change in glycemic stability (10.8±3.6 to 10.3±4.5mg/dL/h, p = 0.51) were observed. When empagliflozin was discontinued, these worsened relative to baseline (89.3±19.3mg/dL, p = 0.04 and 11.8±3.7mg/dL/hr, p = 0.08). Time-in-target numerically increased (40.2±11.9 to 43.1±13.5%, p = 0.69) at end-of-treatment but reversed post-treatment. Findings were similar on stratification of pump and MDI subjects.We observed that empagliflozin was associated with patterns of improved nighttime glycemia more prominent than daytime.Clinicaltrials.gov NCT01392560.
| S-EPMC4636141 | biostudies-literature
Project description:OBJECTIVE:Sarcoidosis is an idiopathic inflammatory disorder that is difficult to treat. There is accumulating evidence that constitutive activation of Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling occurs in sarcoidosis and represents a target for treatment. Here we report the efficacy of tofacitinib, a Janus kinase (JAK) inhibitor, in a single patient with multiorgan sarcoidosis. METHODS:A patient with long-standing multiorgan sarcoidosis who was unresponsive to other commonly used therapies, including methotrexate, prednisone, and tumor necrosis factor α blockade, was treated with tofacitinib. RESULTS:Tofacitinib treatment resulted in clinical remission of cutaneous sarcoidosis lesions and resolution of positron emission tomography avid lesions in internal organs after 6 months. An evaluation of lesional tissue and blood before and during treatment showed resolution of granulomatous inflammation and normalization of disease biomarkers. CONCLUSION:This case illustrates the promise of JAK inhibition as a strategy to treat recalcitrant sarcoidosis and suggests that further study of JAK inhibitors in sarcoidosis is needed.
| S-EPMC7011417 | biostudies-literature
Project description:Necrobiosis Lipoidica (NL) is a rare granulomatous disease. There are few effective treatments for NL. We sought to investigate the efficacy and safety of the JAK 1/2 inhibitor, ruxolitnib, in the treatment of NL and identify biomarkers associated with disease and treatment response. We conducted an open-label, phase 2 study of ruxolitinib in 12 patients with NL. We performed transcriptomic analysis of tissue samples pre- and post-treatment. At week 12, the mean NL lesion score decreased by 58.2% (SD 28.7%, P=0.003). Transcriptomic analysis demonstrated enrichment of type I and type II interferon pathways in baseline disease. Weighted Gene Co-expression Network Analysis (WGCNA) demonstrated post-treatment changes in interferon pathways with key hub genes IFNG and STAT1. Limitations include small sample size and a study group limited to patients with <10% BSA. In conclusion, ruxolitinib is an effective treatment for NL and targets the key pathogenic mediators of disease.
2024-02-19 | GSE255518 | GEO