Long-term eltrombopag in children with chronic immune thrombocytopenia: A single-centre extended real-life observational study in China.

We have previously confirmed the efficacy and safety of eltrombopag (ELT) in children with chronic immune thrombocytopenia (cITP). However, data on both long-term exposure and early use of TPO-RAs are lacking, so further 'field-practice' evidence on treatment is required. Here, we report the long-term follow-up results (between September 2018 and June 2023) of our previous study. The main objective of this study was to retrospectively review our large institutional experience with ITP patients previously enrolled in our paediatric cITP study. We had more than 3 years of follow-up by June 2023 for treatment patterns and outcomes. A total of 65 patients (28 males) were enrolled, with a median age at ELT initiation of 6.34 (range 1.65, 14.13) years and a follow-up of 47.07 (36.00, 57.00) months, with 40.36 (10.53, 56.83) months of ELT therapy at the time of analysis. In total, 29.23% (19/65) of patients discontinued ELT due to stable response, and 18.46% (12/65) of patients switched to other ITP therapies due to loss of response (LOR) after 19.13 (14.53, 26.37) months. Of the 19 patients who discontinued ELT due to a stable response, 24.62% (16/65) achieved a 12 m sustained response off-treatment (SRoT); the last recorded platelet count ranged from 56 to 166 × 109 /L (median 107 × 109/L); and 4.62% (3/65) patients relapsed at 5, 6 and 9 months after discontinuation. Of the 12 patients who LOR to ELT after 19.13 (14.53, 26.37) months of therapy, four switched to avatrombopag, three switched to hetrombopag, two switched to traditional Chinese medicine (TCM), one underwent splenectomy and two received additional prednisolone under ELT treatment. Thirty-four patients who tapered and maintained a durable response. The patients with LOR and the patients with tapering were compared; the platelet count at the start of ELT is lower, and the time to response is longer in the patients with LOR. The platelet count at the start of ELT and the time to response may be the predictive factors for LOR during ELT treatment. We report more than 3 years of long-term clinical data on children with cITP using ELT. These data do not raise any new safety concerns regarding the long-term use of ELT in children with cITP.

Sufficient vitamin D is favorable for children with persistent and chronic immune thrombocytopenia.

Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia in the absence of other disorders. Vitamin D (VD) has been shown to modulate the immune system and its deficiency is linked to many immunological disorders. Supplementation with VD in ITP has promising results. This work aims at evaluating VD values in children with persistent and chronic ITP and the effect of its deficiency on disease severity and treatment response. A case-control study including 50 persistent and chronic ITP patients and 50 healthy controls was conducted. 25 OH vitamin D level was determined using ELISA technique. VD median value was significantly higher among the control group than that of the patients' group (28 vs 21.5 and p = 0.002). Severe deficiency was detected significantly more among the patients' group than the control group (12 (24%) vs 3 (6%), p = 0.048) respectively. Forty-four percent of complete responders belong to sufficient VD category ((15/34) ~ 44% (p = 0.005)) representing all patients with sufficient VD status (n = 15). Also, a positive correlation between serum level of vitamin D and mean PLT count was observed (r = 0.316, p value = 0.025). Sufficient vitamin D was associated with better treatment response and less disease severity. Vitamin D supplementation may be a new therapeutic option for chronic ITP.

Investigation of the Active Compounds and Important Pathways of Huaiqihuang Granule for the Treatment of Immune Thrombocytopenia Using Network Pharmacology and Molecular Docking.

Materials and Methods: Compounds of HQHG were scanned by LC-MS/MS, and the target profiles of compounds were identified based on SwissTarget Prediction. ITP target proteins were collected from various databases. Then, KEGG pathway and GO enrichment analyses were performed to explore the signaling pathways related to HQHG for ITP. The PPI and drug-herbs-compounds-targets-pathways network were constructed using Cytoscape 3.7.2. Finally, Discovery studio software was used to confirm the key targets and active compounds from HQHG. Results: A total of 187 interacting targets of 19 potentially active compounds in HQHG and 3837 ITP-related targets were collected. Then, 187 intersection targets were obtained. A total of 20 key targets including EGFR, CASP3, TNF, STAT3, and ERBB2 were identified through PPI network analysis. These targets were mainly focused on the biological processes of positive regulation of protein phosphorylation, cellular response to organonitrogen compound, and cellular response to nitrogen compound. 20 possible pathways of HQHG in the treatment of ITP were identified through KEGG enrichment. EGFR, CASP3, TNF, and STAT3 are the four most important target proteins, while adenosine, caffeic acid, ferulic acid, quercetin-3ß-D-glucoside, rutin, scopoletin, and tianshic acid are the most important active compounds, which were validated by molecular docking simulation. Conclusion: This study demonstrated that HQHG produced relief effects against ITP by regulating multitargets and multipathways with multicompounds. And the combined data provide novel insight of drug developing for ITP.

Thrombopoietin receptor agonists for chemotherapy-induced thrombocytopenia: a new solution for an old problem.

Chemotherapy-induced thrombocytopenia (CIT) is common, resulting in increased bleeding risk and chemotherapy delays, dose reduction, and treatment discontinuation, which can negatively affect oncologic outcomes. The only agent approved by the US Food and Drug Administration to manage CIT (oprelvekin) was voluntarily withdrawn from the market by the manufacturer, leaving few options for patients. Therefore, patients experiencing CIT present a significant clinical challenge in daily practice. The availability of thrombopoietin receptor agonists has led to formal clinical trials describing efficacy in CIT as well as a rather extensive body of published observational data from off-label use in this setting but no formal regulatory indications for CIT to date. The accumulated data, however, have affected National Comprehensive Cancer Network guidelines, which now recommend consideration of TPO-RA clinical trials as well as off-label use of romiplostim. This review article details the evidence to date for the management of CIT with thrombopoietin receptor agonists (TPO-RAs), discussing the efficacy data, the specific circumstances when treatment is warranted (and when it is generally unnecessary), and safety considerations. Specific recommendations regarding patient selection, initiation, dosing, titration, and discontinuation for TPO-RA therapy in CIT are given, based on published data and expert opinion where evidence is lacking.

Effectiveness of shengxuexiaoban capsules combined with glucocorticoid therapy for immune thrombocytopenia: A meta-analysis.

OBJECTIVE: To evaluate the effectiveness of the Shengxuexiaoban Capsules combined with glucocorticoid therapy for immune thrombocytopenia (ITP). METHODS: We collected randomized controlled trials (RCTs) using shengxuexiaoban capsules in combination with glucocorticoid to treat ITP by searching major Chinese and English electronic databases. The outcome indicators were the effective rate, recurrence rate, the number of platelets in the blood, recovery time of platelets, and adverse reactions. We used STATA 16.0 and RevMan 5.3 for meta-analysis and GRADE pro. for evidence quality evaluation. RESULTS: A total of 27 RCTs were included in the meta-analysis, and the results showed a significant difference (all p<0.05) in the effective rate, recurrence rate, the number of platelets, and the recovery time of platelets (≥ 100×109) between ITP patients in the control group (who received glucocorticoid therapy alone) and test group (who received glucocorticoid therapy combined with the Shengxuexiaoban Capsules). And that Shengxuexiaoban capsules combined with glucocorticoid therapy were safe. The funnel plot and Egger's test results indicated no obvious publication bias. The GRADE evidence rating showed an intermediate quality of evidence rating for recurrence rate and overall effectiveness. CONCLUSION: Glucocorticoid therapy combined with the Shengxuexiaoban Capsules showed more effectiveness in the treatment of ITP. It can improve the effective rate, reduce the recurrence rate, increase the number of platelets and shorten the recovery time of platelets, and has a good safety profile.

Investigation of the mechanism of action of Shengxuexiaoban Capsules against primary immune thrombocytopenia using network pharmacology and experimental validation.

BACKGROUND: Shengxuexiaoban Capsules (SC) is a classical prescription in traditional Chinese medicine (TCM) and has been clinically adopted in the treatment of primary immune thrombocytopenia (ITP) in China. However, the underlying mechanisms of the actions of SC on ITP remain clear. METHODS: A network pharmacology approach was adopted to investigate the underlying molecular mechanism of SC in treating ITP, and the effects of SC on the proliferation, differentiation, and apoptosis of megakaryocyte (MK) and on the ITP animal model were investigated. RESULTS: Network pharmacology analysis found 128 active compounds and 268 targets of these compounds in SC, as well as 221 ITP-related targets. The topological analysis found a central network containing 82 genes, which were significantly associated with the regulation of transcription, cell proliferation, apoptosis processes, the PI3K-AKT signaling pathway, the MAPK signaling pathway, and the ERK1 and ERK2 cascades. It showed that SC increased the proliferation and differentiation of MK, but had no significant impact on MK apoptosis in vivo. The addition of SC increased the gene expression of several potential targets, including STAT3, KDR, CASP3, and TGFB1. In addition, SC administration elevated the protein expression of p-AKT and inhibit the protein expression of p-ERK, but has no impact on the protein expression of p-P38. Moreover, SC could improve haemogram parameters, coagulation indicators, and the proliferation and differentiation of MK in the ITP animal model. CONCLUSIONS: The present study systematically elucidated the underlying mechanisms of SC against ITP and provided an efficient strategy to discover the pharmacological mechanism of TCM. It may strengthen the understanding of SC and facilitate more application of this formula in the treatment of ITP.

[Effect of Xijiao Dihuang Combined Prescription on Human Dendritic Cell Function Induced by Lipopolysaccharide].

OBJECTIVE: To observe the effects of drug-containing serum of Xijiao Dihuang combined prescription(XJDH) on the related functions of dendritic cells(DCs) induced in vitro, and to explore the mechanisms underlying the effectiveness of XJDH treatment on primary immune thrombocytopenia(ITP). METHODS: Peripheral blood samples were colle-ted from 6 healthy volunteers. Mononuclear cells were isolated by density gradient centrifugation, and CD14+ mononuclear cells were collected by the magnetic separation technique. CD14+ mononuclear cells were induced into immature DCs by recombinant human granulocyte-macrophage colony stimulating factor (GM-CSF) and recombinant human interleukin 4 (IL-4). Immature DCs were divided into three groups: control group, model group and XJDH group. CCK-8 assay was used to determine the intervention concentration and time of drug-containing serum. Lipopolysaccharide(LPS) with the final concentration of 1 µg/ml was added to model group and XJDH group respectively for 24 h to induce DCs maturation. Normal rat serum was added to control group and model group, and XJDH was added to XJDH group for 24 h. Flow cytometry was used to detect the levels of CD80, CD83 and HLA-DR on the surface of DCs. Western blot was used to detect the expression of TLR4 and NF-κB, and levels of IL-6, IL-12 and TNF-α in cell supernatant was detected by ELISA. RESULTS: Compared with the control group, LPS stimulation increased the expression of CD80, CD83 and HLA-DR, with subsequent increasing expression of TLR4 and NF-κB, as well as IL-6, IL-12 and TNF-α increased(P<0.05). In comparison with model group, the expression of DCs surface molecules CD80, CD83 and HLA-DR, DCs' expression of TLR4 and NF-κB protein, and the levels of IL-6, IL-12 and TNF-α in the cell supernatant of XJDH group decreased after the intervention of XJDH (P<0.05). CONCLUSION: Drug containing serum of Xijiao Dihuang combined prescription can down-regulate TLR4/NF-κB signaling pathway related protein expression, inhibit DCs maturation, and reduce proinflammatory factor secretion, which may be one of the mechanisms of drug-containing serum of Xijiao Dihuang combined prescription in the treatment of immune thrombocytopenia.

Successful phytotherapy for a patient with severe immune thrombocytopenia and failed with corticosteroids, azathioprine, eltrombopag, and platelet transfusion - A case report.

The purpose of this study was to investigate and evaluate the effectiveness of phytotherapy on a severe and complicated Immune Thrombocytopenia (ITP) patient who had failed with conventional treatments. A male patient presented with clinical symptoms of ITP and had been treated with Corticosteroids, Azathioprine, Eltrombopag, and platelet transfusions for over three years. The patient had an initial response but later developed severe complications, including hydrothorax, gastric pain, hematuria, and digestive hemorrhage, and no further response to treatment. The patient then received Phytotherapy for 17 months which significantly improved the clinical symptoms, platelet counts, and laboratory tests. Despite his active lifestyle, the patient was symptom-free with platelet counts ranging from 109 to 132×109/L.

All-trans retinoic acid plus high-dose dexamethasone as first-line treatment for patients with newly diagnosed immune thrombocytopenia: a multicentre, open-label, randomised, controlled, phase 2 trial.

BACKGROUND: High-dose dexamethasone is the standard initial treatment for patients with immune thrombocytopenia, but many patients still relapse and require further treatments. All-trans retinoic acid has been shown to exert immunomodulatory effects and promote thrombopoiesis, and so we aimed to assess the activity and safety of all-trans retinoic acid plus high-dose dexamethasone as a first-line treatment for newly diagnosed patients with immune thrombocytopenia. METHODS: This multicentre, open-label, randomised, controlled, phase 2 trial was done at six different tertiary medical centres in China. Eligible participants were adults (aged >18 years) with treatment-naive, newly diagnosed, primary immune thrombocytopenia who had either a platelet count of less than 30 × 109 platelets per L or a platelet count of less than 50 × 109 platelets per L and clinically significant bleeding. We randomly assigned (1:1) participants to receive either all-trans retinoic acid (10 mg orally twice daily for 12 weeks) plus high-dose dexamethasone (40 mg/day intravenously for 4 consecutive days) or high-dose dexamethasone alone using a central, web-based randomisation system. If patients did not respond by day 14, the 4-day course of dexamethasone was repeated. The primary endpoint was 6-month sustained response, defined as the maintenance of a platelet count of at least 30 × 109 platelets per L and at least 2-times higher than the baseline count and the absence of bleeding, with no need for rescue medication at this time. The primary endpoint was analysed by intention-to-treat and safety was assessed in all participants who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT04217148, and is now completed. FINDINGS: Between Jan 1, 2020, and June 30, 2020, 132 patients were randomly assigned to either all-trans retinoic acid plus high-dose dexamethasone (n=66) or high-dose dexamethasone alone (n=66). Three patients did not receive their allocated treatment, leaving 129 in the safety analysis set. At 6 months, a significantly higher proportion of participants in the all-trans retinoic acid plus high-dose dexamethasone group (45 [68%] of 66) than in the high-dose dexamethasone monotherapy group (27 [41%] of 66) had a sustained response (OR 3·095, 95% CI 1·516-6·318; p=0·0017). The most common adverse events were dry skin (31 [48%] of 64 patients), headaches (12 [19%]), and insomnia (12 [19%]) in the combination group, and insomnia (ten [15%] of 65 patients) and anxiety or mood disorders (eight [12%]) in the monotherapy group. Both treatments were well tolerated and no grade 4 or worse adverse events occurred. There were no treatment-related deaths. INTERPRETATION: The combination of all-trans retinoic acid and high-dose dexamethasone was safe and active in newly diagnosed patients with primary immune thrombocytopenia, providing a sustained response. This regimen represents a potential first-line treatment in this setting, but further studies are needed to validate its efficacy and safety. FUNDING: The Beijing Municipal Science and Technology Commission, the National Natural Science Foundation of China, the Beijing Natural Science Foundation, the National Key Research and Development Program of China, and the Foundation for Innovative Research Groups of the National Natural Science Foundation of China.

Megadose Methylprednisolone for Immune Thrombocytopenia in an Infant Positive for SARS-CoV-2: A Case Report.

BACKGROUND Immune thrombocytopenia (ITP) is rare in infants under 1 year old. Bleeding often occurs when the platelet count is <20 000/uL. The disease can progress because of accompanying COVID-19 disease. CASE REPORT A 9-month-old boy, weighing 8.5 kg, came to the hospital with petechiae on the forehead, cheeks, mouth, and extremities. The patient had rhinorrhea for 3 days previously and was febrile, pale, weak, and could not drink. He had the measles-rubella vaccination 19 days prior. Physical examination showed no abnormalities of the eyes, ears, nose, throat, and mouth. Heart and lungs were within normal limits, with no organomegaly, lymphadenopathy, or congenital anomaly of the abdomen. Laboratory examination showed hemoglobin, 12.7 g/dL; leukocytes, 7420/uL; platelet count, 16 000/uL; and hematocrit, 37.9%. Erythrocyte sedimentation rate was 14 mm at 1 h and 21 mm at 2 h. Peripheral blood smear showed normal RBC morphology, normal leukocytes, and few platelets. IgG was reactive and IgM was nonreactive on rapid antibody test. RT-PCR was positive for SARS-COV-2. Chest-X-ray showed pneumonia. The diagnosis was newly diagnosed ITP with COVID-19. Patient was treated with 30 mg/kg body weight/day of IV methylprednisolone for 3 days (250 mg); then 20 mg/kg body weight/day (175 mg) orally for 4 days in 3 divided doses. Azithromycin 100 mg/day, zinc 20 mg/day, and vitamin C 50 mg/day orally were also given. CONCLUSIONS COVID-19 screening is highly recommended during this pandemic to identify it as a potential cause of childhood ITP. Megadose methylprednisolone had an excellent response in alleviating ITP with confirmed COVID-19 in an infant.

Differential effects of Huaier aqueous extract on human CD4+T lymphocytes from patients with primary immune thrombocytopenia.

Huaier, a traditional Chinese medicine, is currently used to treat certain types of cancer in the clinic and is also regarded as an immune-modulating and immune-enhancing agent that regulates immune cells. Emerging evidence indicates that an imbalance of immune cells, such as CD4+ T helper (Th) lymphocytes, contributes to the progression of immune thrombocytopenia (ITP), but the effects of Huaier on the regulation of CD4+ T cells are not yet fully elucidated. In the present study, Jurkat cells and peripheral blood mononuclear cells (PBMCs) from patients with ITP and healthy volunteers were treated with Huaier aqueous extract (HR). The CCK-8 assay revealed that HR suppressed the proliferation of Jurkat cells in a dose-dependent manner, whereas 3 mg/mL could decrease cell viability by 50%. At the latter concentration, the activation of CD4+ T cells from patients with ITP was partially attenuated. In addition, HR could correct the unbalanced Th1/Th2 polarization and inhibit the secretion of pro-inflammatory factors interleukin (IL)-2, tumor necrosis factor-α, and interferon-γ. It also suppressed Treg and facilitated Th17 differentiation, but did not change the levels of IL-10 and transforming growth factor-ß. Thus, this study provides more information on how Huaier regulates cellular immunity and improves our understanding of the use of Huaier in ITP.

Vaccine-Induced Immune Thrombotic Thrombocytopenia (VITT): Targeting Pathomechanisms with Bruton Tyrosine Kinase Inhibitors.

A series of cases with rare thromboembolic incidents including cerebral sinus vein thrombosis (some of them fatal) and concomitant thrombocytopenia occurring shortly after vaccination with the coronavirus disease 2019 (COVID-19) vaccine AZD1222 (Vaxzevria) have caused significant concern and led to its temporary suspension in many countries. Immediate laboratory efforts in four of these patients have identified a tentative pathomechanism underlying this syndrome termed initially vaccine-induced prothrombotic immune thrombocytopenia (VIPIT) and renamed recently vaccine-induced immune thrombotic thrombocytopenia (VITT). It encompasses the presence of platelet-activating antibodies to platelet factor-4/heparin complexes, possibly emulated by polyanionic constituents of AZD1222, and thus resembles heparin-induced thrombocytopenia (HIT). Because these immune complexes bind and activate platelets via Fcγ receptor IIA (FcγRIIA), high-dose intravenous immunoglobulin G has been suggested for treatment of VITT in addition to non-heparin anticoagulants. Here we propose inhibitors of Bruton tyrosine kinase (Btk) approved for B cell malignancies (e.g., ibrutinib) as another therapeutic option in VITT, as they are expected to pleiotropically target multiple pathways downstream of FcγRIIA-mediated Btk activation, for example, as demonstrated for the effective inhibition of platelet aggregation, dense granule secretion, P-selectin expression and platelet-neutrophil aggregate formation stimulated by FcγRIIA cross-linking. Moreover, C-type lectin-like receptor CLEC-2- and GPIb-mediated platelet activation, the interactions and activation of monocytes and the release of neutrophil extracellular traps, as encountered in HIT, could be attenuated by Btk inhibitors. As a paradigm for emergency repurposing of approved drugs in COVID-19, off-label use of Btk inhibitors in a low-dose range not affecting haemostatic functions could thus be considered a sufficiently safe option to treat VITT.

The treatment of integrated traditional Chinese and Western medicine to cure severe immune thrombocytopenia in a patient in a minimally conscious state: a case report.

Immune thrombocytopenia is a common complication in patients in a minimally conscious state (MCS). MCS patients are prone to pulmonary infection for the reasons of long-term bed rest and tracheotomy etc., which leads to frequent immune thrombocytopenia. At present, there is no specific treatment for immune thrombocytopenia. Moreover, the cost of routine treatment is high, and clinicians need to consider different drug combinations, side effects, and the risk of drug dependence when selecting treatments. Here, we report a case of a patient in a MCS who developed immune thrombocytopenia after tracheotomy and long-term bed laying in October 2015. The patient's platelet count declined continuously, and by December 2015, she was in a critical condition, with a platelet count of less than 20×109/L. The patient firstly received routine treatment, however, this could only temporarily prevent the drop in platelets. Following a series of explorations, the patient was treated with a combination of traditional Chinese and Western medicine, which included treatment and preventive measures. For treatment, the patient was given roxithromycin dispersible administration tablets and a self-made preparation of peanut red skin, which could quickly cure the immune thrombocytopenia. Preventive measures included the addition of ursodeoxycholic acid capsules, silybin capsules, and a traditional Chinese medicine preparation. As shown by laboratory examination results, the patient's platelet count has stayed around a normal level since March 2016, and she now has normal liver and kidney function. This outcome evidence that combined traditional Chinese and Western medicine could effectively cure immune thrombocytopenia and prevent its recurrence. Moreover, the cost of the treatment was lower and there were fewer side effects than routine treatment, and at the same time, the method of treatment was simple and convenient. Our practical experience may provide a valuable clue for the treatment of immune thrombocytopenia.

Different Chinese herbal medicine therapy for idiopathic thrombocytopenic purpura: A protocol for systematic review and Bayesian network meta-analysis.

BACKGROUND: Idiopathic thrombocytopenic purpura (ITP) is a common immune system and blood system disease in clinical practice, and it is a hemorrhagic disease caused by immune factors causing platelet destruction and decreasing number of platelets. There is currently no effective treatment plan for ITP. At this stage, glucocorticoid and gamma globulin are mostly used in the treatment of ITP, and some patients use splenectomy to achieve therapeutic purposes, but the various treatment methods are inadequate. At this stage, a large number of randomized controlled studies have reported that Chinese herbal medicine has achieved good curative effect in the treatment of ITP. However, due to the variety of Chinese herbal medicine, there has been no evidence of the effectiveness and safety of Chinese herbal medicine in the treatment of ITP. Because of the above reasons, this study uses the network meta-analysis method based on Bayesian method to compare the clinical efficacy and safety of different kinds of Chinese herbal medicine in the treatment of ITP through direct and indirect comparison, in order to provide evidence-based medical support for the treatment of ITP with Chinese herbal medicine. METHODS: This study uses the method of combining free words with theme words, and using computer to retrieve PubMed, EMbase, The Cochrane Library, WANFANG Database, CNKI, and VIP Database, etc, to collect the randomized control studies on Chinese herbal medicine in the treatment of ITP. The retrieval time is from the establishment of each database to January 2021, and the retrieval languages are Chinese and English. Two researchers independently read the title, abstract and full text of the article to determine whether it is included in the literature; In the event of a disagreement, a third researcher will join the discussion to resolve the disagreement; For the literature that lacks information, trying to contact the original author of the document to supplement it. The literature quality evaluation carried out by using the Stata 14.0 software to draw network and funnel plots, in accordance with the quality evaluation criteria of version 5.1.0 of the Cochrane System Evaluation Manual. Statistical analysis is performed by using ADDIS 1.16.8 software based on the Bayesian model. RESULTS: This study will compare the clinical efficacy and safety of different types of Chinese herbal medicine in the treatment of idiopathic thrombocytopenic purpura through the method of network meta-analysis, and rank the different types of Chinese herbal medicine according to their effectiveness, and the results will be published in a peer-reviewed, high-quality academic journal. CONCLUSION: This study will find effective and safe Chinese herbal medicine for clinical treatment of ITP from the perspective of evidence-based medicine, and benefit more ITP patients.

Preclinical Efficacy and Anti-Inflammatory Mechanisms of Action of the Bruton Tyrosine Kinase Inhibitor Rilzabrutinib for Immune-Mediated Disease.

Bruton tyrosine kinase (BTK) is expressed in B cells and innate immune cells, acting as an essential signaling element in multiple immune cell pathways. Selective BTK inhibition has the potential to target multiple immune-mediated disease pathways. Rilzabrutinib is an oral, reversible, covalent BTK inhibitor designed for immune-mediated diseases. We examined the pharmacodynamic profile of rilzabrutinib and its preclinical mechanisms of action. In addition to potent and selective BTK enzyme and cellular activity, rilzabrutinib inhibited activation and inflammatory activities of B cells and innate cells such as macrophages, basophils, mast cells, and neutrophils, without cell death (in human and rodent assay systems). Rilzabrutinib demonstrated dose-dependent improvement of clinical scores and joint pathology in a rat model of collagen-induced arthritis and demonstrated reductions in autoantibody-mediated FcγR signaling in vitro and in vivo, with blockade of rat Arthus reaction, kidney protection in mouse Ab-induced nephritis, and reduction in platelet loss in mouse immune thrombocytopenia. Additionally, rilzabrutinib inhibited IgE-mediated, FcεR-dependent immune mechanisms in human basophils and mast cell-dependent mouse models. In canines with naturally occurring pemphigus, rilzabrutinib treatment resulted in rapid clinical improvement demonstrated by anti-inflammatory effects visible within 2 wk and all animals proceeding to complete or substantial disease control. Rilzabrutinib is characterized by reversible covalent BTK binding, long BTK residence time with low systemic exposure, and multiple mechanistic and biological effects on immune cells. Rilzabrutinib's unique characteristics and promising efficacy and safety profile support clinical development of rilzabrutinib for a broad array of immune-mediated diseases.

iTRAQ-based quantitative proteomics analysis of immune thrombocytopenia patients before and after Qishunbaolier treatment.

RATIONALE: Treatment of immune thrombocytopenia (ITP) usually involves long-term use of immunosuppressive corticosteroids and splenectomy. However, these treatments often have side effects in patients. The Mongolian medicine Qishunbaolier (QSBLE) has a high curative effect, reduces the chances of relapse, and has no obvious side effects. This study was designed to identify potential therapeutic targets of QSBLE for treating ITP. METHODS: To reveal differences in protein expression between ITP patients (ITPs) before and after QSBLE treatment, comparative proteomics studies were performed using isobaric tags for relative and absolute quantification (iTRAQ). The analysis used nanospray liquid chromatography/tandem mass spectrometry (nano-LC/MS/MS) in positive ion electrospray ionization mode. Key proteins relevant to ITP were revealed by the Kyoto Encyclopedia of Genes and Genomes (KEGG) and other bioinformatics tools. Real-time polymerase chain reaction (RT-PCR) analysis was carried out for confirmation of differentially expressed proteins. RESULTS: A total of 982 differentially expressed proteins were identified in ITPs compared with the controls. Compared with the pre-QSBLE treatment group, 61 differentially expressed proteins were identified in the post-QSBLE treatment group, with 48 proteins being significantly upregulated and 13 downregulated. Twenty-nine pathways were significantly enriched. Q6N030 and other proteins were the key players in the protein-pathway network. Twenty proteins that may play important roles in the treatment of ITP were further filtered. RT-PCR and Western blot analyses further confirmed that MIF, PGK1 and IGHM were upregulated in ITPs after QSBLE treatment, in accordance with the proteomics data. CONCLUSIONS: It is believed that the identified proteins and the results of bioinformatics analysis will provide a potential therapeutic target site for QSBLE for ITP therapy and biomarkers.

Research Progress on Chinese Medicine Immunomodulatory Intervention for Chronic Primary Immune Thrombocytopenia: Targeting Cellular Immunity.

Chronic primary immune thrombocytopenia (CITP) is the most common acquired autoimmune disease that seriously threaten the physical and mental health of patients. Compared with Western medicine treatment, the intervention and treatment of Chinese medicine (CM) has shown certain therapeutic advantages. This paper reviewed the new pathogenesis progress on T cell immune abnormality in CITP, and CM studies on interferes effects of cellular immune regulation of CITP in recent years. Qi deficiency failing to control blood and internal obstruction of blood stasis are the two common types of CM syndromes in CITP patients, the corresponding treatments include invigorating Pi (Spleen), supplementing qi, activating blood, as well as tonifying qi and activating yang, regulating Gan (Liver) to invigorate Pi. The authors also mentioned the problems in the research field of CM for CTIP treatment, and put forward new ideas for the research in the future.