sirolimus and Purpura--Thrombocytopenic--Idiopathic

Autoimmune haemolytic anaemia (AIHA) and autoimmune thrombocytopenia are common complications of childhood-onset lupus, which may be life-threatening. A greater understanding of the pathogenesis of these haematologic manifestations will enhance our understanding of the biology of systemic lupus erythematosus (SLE) and inform the identification of novel treatments.. The mechanisms underlying AIHA and autoimmune thrombocytopenia are incompletely understood and likely multifactorial. Although the development of auto-antibodies is central to the disease process, recent studies have demonstrated the importance of cytokines in the underlying pathologic process. In-vitro and in-vivo evidence points to a role for IL17 in the pathogenesis of AIHA, which involves loss of tolerance to red cell auto-antigens and the development of autoantibodies. Sirolimus, an mTor inhibitor, has benefited patients with primary autoimmune cytopenias, possibly by stimulating T regulatory cells, and may also have efficacy for SLE-associated cytopenias. Similarly, low-dose recombinant human IL-2 therapy has shown promising results for improving platelet counts in patients with autoimmune thrombocytopenia, possibly by restoring the balance between T regulatory, T helper and Th17 cells.. The emergence of new agents directed at restoring immune dysregulation hold promise for the treatment of AIHA and autoimmune thrombocytopenia and should provide better tolerated alternatives to high-dose corticosteroids.

Topics: Anemia, Hemolytic, Autoimmune; Autoantibodies; Humans; Immunologic Factors; Lupus Erythematosus, Systemic; Purpura, Thrombocytopenic, Idiopathic; Receptors, Thrombopoietin; Rituximab; Sirolimus

To investigate the clinical efficacy of calcitriol combined with sirolimus in the treatment of chronic primary immune thrombocytopenia (cITP) patients.. A total of 146 adult cITP patients reated in the First Affiliated Hospital of Hebei North University from March 2017 to March 2020 were randomly divided into observation group (73 cases) and control group (73 cases) according to random number table. The control group was treated with oral sirolimus capsule, the observation group was treated with oral calcitriol capsule combined with sirolimus capsule, and the curative effect of the 2 groups was evaluated after continuous treatment for 6 weeks. The changes of World Health Organization (WHO) bleeding grade, laboratory related index, including peripheral blood regulatory T cell (Treg), serum 1,25-dihydroxy-vitamin D. The overall efficacy of calcitriol combined with sirolimus in the treatment of cITP in adults is satisfactory, which can effectively alleviate patient's condition, improve the quality of life, further increase the platelet level and decrease the expression of VDR in peripheral blood lymphocyte, the mechanism may be related to increasing the level of serum 1,25(OH). 骨化三醇联合西罗莫司治疗成人慢性原发免疫性血小板减少症的临床研究.. 探讨骨化三醇联合西罗莫司治疗成人慢性原发免疫性血小板减少症（cITP）的临床疗效。.. 选取2017年3月-2020年3月河北北方学院附属第一医院收治的146例成人cITP患者，运用随机数字表法将其分成观察组（73例）和对照组（73例）。对照组口服西罗莫司胶囊治疗，观察组在此基础上口服骨化三醇软胶囊治疗，连续治疗6周后评估两组疗效。观察两组治疗前后修订的WHO出血分级、实验室相关指标（外周血调节性T细胞、血清1, 25-二羟维生素D. 应用骨化三醇联合西罗莫司治疗成人cITP的总体疗效满意，可有效缓解患者病情，提高生活质量，进一步提升血小板水平和下调外周血淋巴细胞中维生素D受体表达，其作用机制可能与显著提高血清1, 25-二羟维生素D

Topics: Calcitriol; Humans; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Quality of Life; Sirolimus

Chronic immune thrombocytopenia (ITP) of childhood is still a problem. For treating ITP, several immunosuppressive medications can be considered with various response rates. Our goal was to compare effects of sirolimus and cyclosporine on children with chronic ITP.. This randomized and blinded trial was carried out on 67 children over 5 years old with chronic ITP. Patients were assigned 1:1 to cyclosporine and sirolimus for 6 months. Platelet count was assessed and compared between 2 study groups at different intervals. The clinical trial registry number was IRCT20180501039499N1.. Sixty-one children completed the 6-month treatment. Mean age was 9.3 years with an excess of females. Compared to baseline values, both drugs caused a significant increase in number of platelets over the course of treatment; sirolimus group: 15,800/mcL vs 96,566/mcL, (P < 0.001), cyclosporine group: 14,400/mcL vs 111,266/mcL, P < 0.001,). In addition, differences of platelet number were statistically significant at some treatment intervals (3rd and 6th month, P < 0.05). A quicker response was observed in children receiving cyclosporine. Both drugs had similar rate of response which occurred in 50% of included patients. Finally, sirolimus had a better safety profile.. Our study showed that cyclosporine and sirolimus had an equal rate of response in treating chronic ITP of children. At the same time, the two medications showed significant differences in their side effects.

Topics: Adolescent; Child; Child, Preschool; Cyclosporine; Female; Humans; Immunosuppressive Agents; Male; Platelet Count; Purpura, Thrombocytopenic, Idiopathic; Single-Blind Method; Sirolimus

We conducted this randomized trial to investigate the efficacy and safety of rapamycin treatment in adults with chronic immune thrombocytopenia (ITP). Eighty-eight patients were separated into the control (cyclosporine A plus prednisone) and experimental (rapamycin plus prednisone) groups. The CD4⁺CD25⁺CD127(low) regulatory T (Treg) cells level, Foxp3 mRNA expression, and the relevant cytokines levels were measured before and after treatment. The overall response (OR) was similar in both groups (experimental group versus control group: 58% versus 62%, P = 0.70). However, sustained response (SR) was more pronounced in the experimental group than in the control group (68% versus 39%, P < 0.05). Both groups showed similar incidence of adverse events (7% versus 11%, P = 0.51). As expected, the low pretreatment baseline level of Treg cells was seen in all patients (P < 0.001); however, the experimental group experienced a significant rise in Treg cell level, and there was a strong correlation between the levels of Treg cells and TGF-beta after the treatment. In addition, the upregulation maintained a stable level during the follow-up phase. Thus, rapamycin plus low dose prednisone could provide a new promising option for therapy of ITP.

Topics: Adolescent; Adult; Aged; Chronic Disease; Cytokines; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Male; Middle Aged; Prednisone; Prognosis; Purpura, Thrombocytopenic, Idiopathic; Sirolimus; T-Lymphocytes, Regulatory; Treatment Outcome; Young Adult

B cell hyper-function plays an important role in the pathogenesis of immune thrombocytopenia (ITP), but the molecular mechanisms underlying such changes remain unclear. We sought to identify regulators of B cell dysfunction in ITP patients through transcriptome sequencing and the use of inhibitors. B cells were isolated from PBMC of 25 ITP patients for B cell function test and transcriptome sequencing. For the potential regulatory factors identified by transcriptome sequencing, the corresponding protein inhibitors were used to explore the regulatory effect of the regulatory factors on B cell dysfunction in vitro. In this study, increased antibody production, enhanced terminal differentiation and highly expressed costimulatory molecules CD80 and CD86 were found in B cells of patients with ITP. In addition, RNA sequencing revealed highly activated mTOR pathway in these pathogenic B cells, indicating that the mTOR pathway may be involved in B cell hyper-function. Furthermore, mTOR inhibitors rapamycin or Torin1 effectively blocked the activation of mTORC1 in B cells, resulting in reduce antibody secretion, impaired differentiation of B cells into plasmablasts and downregulation of costimulatory molecules. Interestingly, as an unspecific inhibitor of mTORC2 besides mTORC1, Torin1 did not show a stronger capacity to modulate B cell function than rapamycin, suggesting that the regulation of B cells by Torin1 may depend on blockade of mTORC1 rather than mTORC2 pathway. These results indicated that the activation of mTORC1 pathway is involved in B cell dysfunction in patients with ITP, and inhibition of mTORC1 pathway might be a potential therapeutic approach for ITP.

Topics: Humans; Leukocytes, Mononuclear; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Purpura, Thrombocytopenic, Idiopathic; Signal Transduction; Sirolimus; Thrombocytopenia; TOR Serine-Threonine Kinases; Transcription Factors

Although sirolimus (SRL) has been proven to be an effective alternative agent for refractory/relapsed immune thrombocytopenia (R/R ITP), there is currently no recommended optimal blood concentration during its administration. We collected data on SRL drug concentration, platelet response, and drug side effects in ITP patients, constructed ROC curves to evaluate the relationship between the SRL concentration and both efficacy and side effects, and finally suggested a most appropriate SRL blood concentration (8–12ng/ml). This concentration window ensured optimal efficacy of SRL in the treatment of ITP while maintaining tolerable side effects. Additionally, we conducted a multivariate analysis to explore factors that may influence SRL blood concentration. The present study made an important contribution to the precision therapy of ITP with sirolimus by clarifying the optimal blood concentration range.

Topics: Humans; Immunosuppressive Agents; Kidney Transplantation; Purpura, Thrombocytopenic, Idiopathic; Retrospective Studies; Sirolimus; Thrombocytopenia

The complex pathogenesis of relapsed and refractory (R/R) immune thrombocytopenia (ITP) contributes to the varied efficacy and tolerability of current treatment regimens. Rapamycin, an immunomodulatory agent, was originally used in the prevention of organ rejection after organ transplantation. Additional evidence now shows that rapamycin can successfully treat R/R ITP. Here, we summarize recent clinical progress on the role and potential mechanism of rapamycin in the treatment of ITP.. PubMed, Web of Science and CNKI database were searched to identify eligible studies, and the clinical data and preclinical studies on the use of mTOR inhibitors in ITP treatment were reviewed. The key results (efficacy and safety) of the most recent clinical reports were summarized.. Case series provide evidence of the effectiveness and tolerable safety profile of rapamycin in ITP, including primary and some secondary ITP. Mechanistic explorations indicate that rapamycin can regulate immune cell subsets (Th1, Th2, Th17, Treg, Breg, MDSC, etc.), modulate cytokine secretion (IL-6, IL-10, TGF-β, BAFF, etc.) and promote platelet autophagy.. Emerging clinical data and basic studies suggest that rapamycin, as a multifaceted regulator, could provide a new promising option for the therapy of ITP. Additional research is needed to identify those patients which may benefit the most, as well as therapeutic regimens with which rapamycin may be combined.

Topics: Humans; Purpura, Thrombocytopenic, Idiopathic; Sirolimus; T-Lymphocytes, Regulatory; Th17 Cells; Thrombocytopenia

Topics: Adolescent; Aminopeptidases; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Female; Humans; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Mutation; Phenotype; Purpura, Thrombocytopenic, Idiopathic; Serine Endopeptidases; Sirolimus; T-Lymphocytes

Autoimmune cytopenia includes autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and Evans syndrome (ES) caused by abnormal activation of autoimmunity and has a considerable refractory/relapse rate. To evaluate the efficacy and toxicity of sirolimus of primary relapsed/refractory autoimmune cytopenia, records of 45 patients with primary relapsed/refractory AIHA, ES, or ITP from October 2016 to January 2019 in two institutions, were collected; there were 3 pediatric patients and 42 adult patients. The median age at diagnosis was 31 (1-84) years. Patients were treated for a median of 14 (6-39) months and followed-up for a median of 18 (10-40) months. Thirty-eight patients responded to sirolimus, with 28 complete responses (CRs) and a median of 2 (2-5) months to response. Five patients had mucositis; the incidences of other adverse events were all less than 5%. Four patients relapsed, making the CR and overall response rate 46.7% and 75.6% at the end of follow-up. There were no differences in patient age, sex, time from diagnosis to sirolimus, serum sirolimus concentration, and disease distribution between CR and non-CR patients, or between responders and nonresponders, though AIHA patients were likely to relapse less and respond better. In conclusion, sirolimus is effective for patients with primary relapsed/refractory autoimmune cytopenia with a low relapse rate and good tolerance.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia, Hemolytic, Autoimmune; Autoimmunity; Child; Child, Preschool; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Male; Middle Aged; Mucositis; Patient Safety; Purpura, Thrombocytopenic, Idiopathic; Recurrence; Retrospective Studies; Sirolimus; T-Lymphocytes, Regulatory; Thrombocytopenia; Treatment Outcome

Topics: Adolescent; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Infant; Male; Mycophenolic Acid; Purpura, Thrombocytopenic, Idiopathic; Retrospective Studies; Salvage Therapy; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

Autoimmune cytopenias are characterized by immune-mediated destruction of hematopoietic cell lines with immune thrombocytopenia (ITP) affecting platelets and Evans syndrome (ES) affecting platelets and red blood cells. For patients with persistent disease, limited options for effective and well-tolerated therapies exist.. Our aim is to describe our institution's experience with sirolimus as therapy for pediatric patients with persistent ITP and ES.. A retrospective analysis was performed in patients with persistent ITP and ES treated with sirolimus. Responses were categorized as complete response (CR), partial response, modest response, or no response.. Of the 17 patients treated, 12 had ITP and 5 had ES. Seventy-three percent of ITP patients achieved a CR, 78% of them by 3 months. Only 2 patients did not achieve a durable response. Eighty percent of ES patients had a response, with 50% of them achieving CR and the other 50% an asymptomatic partial response. One patient with ES achieved modest response, but discontinued therapy due to an adverse effect. Of the patients that achieved CR, 90% remain off all therapy for a median of 2 years.. Our data suggest that sirolimus is a safe and effective steroid-sparing agent in the treatment of persistent ITP and ES.

Topics: Adolescent; Anemia, Hemolytic, Autoimmune; Child; Female; Humans; Infant; Male; Purpura, Thrombocytopenic, Idiopathic; Remission Induction; Retrospective Studies; Sirolimus; Thrombocytopenia; Treatment Outcome; Young Adult