Comparative Efficacy of Rivaroxaban and Immunoglobulin Therapy in the Treatment of Livedoid Vasculopathy: A Systematic Review
Livedoid vasculopathy (LV) is an uncommon chronic coagulation disorder whose underlying etiology is not yet fully understood. It predominantly affects females, especially those in late adolescence. There is currently limited research on treatment options for those with this diagnosis. The present systematic review aims to compare the efficacy of rivaroxaban and intravenous immunoglobulin (IVIG) therapy in the treatment of livedoid vasculopathy. A detailed search was conducted from April 20, 2022, to May 1, 2022, using four databases: Elsevier, Medline Complete, Medline Ovid, and PubMed. Out of these, 20 relevant articles were used, and the data was extracted and analyzed. Both rivaroxaban and IVIG were shown to be effective treatment options with similar treatment response times. However, future large-scale clinical trials are needed to determine an established treatment regimen for these patients.
Biological stratification of clinical disease courses in childhood immune thrombocytopenia
Journal of thrombosis and haemostasis : JTH. 2021
BACKGROUND In childhood immune thrombocytopenia (ITP), an autoimmune bleeding disorder, there is a need for better prediction of individual disease courses and treatment outcomes. OBJECTIVE To predict the response to intravenous Immunoglobulins (IVIg) and ITP disease course using genetic and immune markers. METHODS Children aged below seven years with newly diagnosed ITP (N = 147) from the TIKI study were included, which randomized children to an IVIg or observation group. A total of 46 variables were available: clinical characteristics, targeted genotyping, lymphocyte immune phenotyping, and platelet autoantibodies. RESULTS In the treatment arm, 48/80 children (60%) showed a complete response (platelets ≥100 x 10(9) /L) that lasted for at least one month (complete sustained response; CSR) and 32 exhibited no or a temporary response (absence of a sustained response; ASR). For a biological risk score, five variables were selected by regularized logistic regression that predicted ASR vs CSR: 1) hemoglobin; 2) platelet count; 3) genetic polymorphisms of FcγRIIc; 4) the presence of IgG anti-platelet antibodies; and 5) preceding vaccination. The ASR sensitivity was 0.91 (95% CI, 0.80 - 1.00) and specificity was 0.67 (95% CI, 0.53 - 0.80). In the 67 patients of the observation arm, this biological score was also associated with recovery during one-year follow-up. The addition of the biological score to a predefined clinical score further improved the discrimination of favorable ITP disease courses. CONCLUSIONS The prediction of disease courses and IVIg treatment responses in ITP is improved by using both clinical and biological stratification.
Randomized phase 2 trial of Intravenous Gamma Globulin (IVIG) for the treatment of acute vaso-occlusive crisis in patients with sickle cell disease: Lessons learned from the midpoint analysis
Complementary therapies in medicine. 2020;52:102481
Sickle Cell Disease (SCD) is a chronic hemolytic disorder associated with frequent pain episodes, end organ damage and a shortened lifespan. Currently there exist no disease specific targeted therapies for the treatment of acute vaso-occlusive crisis (VOC) and management with analgesics and hydration is purely supportive. Improvement in understanding of disease pathophysiology has resulted in a great interest in disease modifying novel therapies and many are being evaluated in clinical trials. Here we report the results from the pre-specified mid-point analysis of the Phase 2 study of Intravenous Gamma Globulin (IVIG) for the treatment of acute VOC in patients with SCD and lessons learned.
Treatment of immune thrombocytopenia (ITP) secondary to malignancy: a systematic review
Immune thrombocytopenia (ITP) can be associated with lymphoproliferative diseases (LPD) or solid tumors. A systematic review of published literature was conducted to evaluate response to treatment of ITP secondary to malignancy. Primary outcome was overall response (complete response+response) to first-line treatments [steroids alone or in combination with intravenous immunoglobulins (IVIg)]. Among secondary outcomes, overall response to second-line treatments [splenectomy, rituximab or thrombopoietin receptor agonists (TPO-RA)] and death were evaluated. Of the retrieved 238 text articles, 108 were analyzable, for a total of 154 patients: 142 in 105 case reports and 12 in 3 observational studies. Thirty-nine patients had solid tumors, 114 LPD, and 1 both. The median follow up was 19 months (IQR, 9-40). The overall response was 50% (62% in solid tumors, 46% in LPD) after steroids and 47% (67% in solid tumors, 36% in LPD) after steroids+IVIg, which are lower than historical responses observed in primary ITP (≈80%). The overall responses to rituximab (used in LPD only), splenectomy and TPO-RA (70%, 73% and 92%, respectively) were similar to those observed in primary ITP. Seven patients (6%) died due to bleeding events. ITP secondary to malignancy appears to be associated with unsatisfactory response to first-line treatments.
IVMP+IVIG raises platelet counts faster than IVIG alone: results of a randomized, blinded trial in childhood ITP
Blood Advances. 2020;4(7):1492-1500
Children with immune thrombocytopenia (ITP) rarely suffer from life-threatening bleeds (eg, intracranial hemorrhage). In such settings, the combination of IV methylprednisolone (IVMP) with IV immune globulin (IVIG) is used to rapidly increase platelet counts (PCs). However, there are no controlled data to support using combination therapy over IVIG alone. We conducted a randomized, double-blind, placebo-controlled study to evaluate the rapidity of the PC increment and associated adverse events (AEs) between 2 regimens: A (IV placebo) and B (IVMP 30 mg/kg), both given over 1 hour, followed in both cases by IVIG (Gamunex 10%) 1 g/kg over 2-3 hours in children 1-17 years old with primary ITP and PCs <20 x 109/L in whom physicians had decided to treat with IVIG. Thirty-two children (ages: median, 8 years; range, 1.2-17.5 years) with a mean baseline PC of 9.2 x 109/L participated. Eighteen were randomized to regimen A and 14 to regimen B. By 8 hours after initiating therapy, 55% of all children had a PC ≥20 x 109/L (no group difference). By 24 hours, mean PCs were 76.9 x 109/L (B) vs 55 x 109/L (A) (P = .06; P = .035 when adjusted for intergroup differences in patient ages). No patient experienced severe bleeding/unexpected severe AEs. There were statistically fewer IVIG-related headaches in the group receiving combination therapy (P = .046). Our findings show a rapid response to IVIG with/without steroids and provide evidence to support the use of IVMP+IVIG in life-threatening situations. This trial was registered at www.clinicaltrials.gov as #NCT00376077.
Children with immune thrombocytopenia (n=32).
IV methylprednisolone (IVMP 30 mg/kg) followed by IVIG (Gamunex 10%) 1 g/kg, (n=14).
IV placebo followed by IVIG (Gamunex 10%) 1 g/kg, (n=18).
By 8 hours after initiating therapy, 55% of all children had a platelet count (PC) >/=20 x 109/L (no group difference). By 24 hours, mean PCs were 76.9 x 109/L (B) vs 55 x 109/L (A). No patient experienced severe bleeding/unexpected severe associated adverse events. There were statistically fewer IVIG-related headaches in the group receiving combination therapy.
Intravenous Immune Globulin (IVIG) for Treatment of Autoimmune Heparin-Induced Thrombocytopenia: A Systematic Review
Ann Pharmacother. 2020;:1060028020943542
Objective: To evaluate intravenous immune globulin (IVIG) for autoimmune heparin-induced thrombocytopenia (aHIT), including platelet recovery, IVIG dose, dosing weight, IVIG product used, and complications reported. Data Sources: PubMed and EMBASE were searched from inception through June 21, 2020. Search terms included heparin-induced thrombocytopenia, HIT, intravenous immune globulin, IVIG, autoimmune HIT, aHIT, and immune globulin. Study Selection and Data Extraction: Patients administered IVIG for HIT and diagnosed by immunoassay (optical density ≥2) or positive activation assay were included. Data Synthesis: Twenty-four cases were reviewed; 92% had persistent aHIT. Time to IVIG administration post-nonheparin anticoagulant initiation was 9 days (median). Most common IVIG cumulative dose was 2 g/kg (dosed as 1 g/kg/d for 2 consecutive days); 75% had a favorable platelet increase (≥50 × 10(9)/L) within 5 days of initial IVIG dosing. Relevance to Patient Care and Clinical Practice: aHIT is characterized by critically low platelets, thrombosis, and a persistent delay in platelet recovery despite treatment with a nonheparin anticoagulant. An immunoassay and subsequent confirmatory activation assay (at low, high, and 0 IU/mL unfractionated heparin levels) is recommended to confirm diagnosis. Patients nonresponsive to nonheparin anticoagulants within 5 days of initiation should be evaluated for IVIG treatment (2 g/kg cumulative dose). More data are needed to clarify appropriate IVIG dosing weight, although based on current published literature, it is recommended to use actual body weight. Conclusions: Data reported support use of IVIG as adjunctive therapy for patients with aHIT. Judicious IVIG use based on key clinical and laboratory findings is critical.
Effectiveness of intravenous immunoglobulin use in heparin-induced thrombocytopenia
Blood Coagul Fibrinolysis. 2020
: Heparin-induced thrombocytopenia (HIT) syndrome is an immune-mediated disorder producing thrombocytopenia and thrombosis, with or without prior exposure to heparin. Although avoidance of heparin products and nonheparin anticoagulants are used, immune-based therapies including intravenous immunoglobulin (IVIg) have been tried when the thrombocytopenia persists or there is breakthrough thrombosis. We sought to systematically review and analyze the published literature on use of IVIg in the treatment of HIT. A systematic search of PubMed, Google Scholar, EMBASE and SCOPUS for all study designs and reports were carried out from inception until April 2019. Statistical analysis was done using Microsoft Excel and Stata version 13. In 34 patients with HIT, the mean age was 60 years. About 70% cases were by unfractionated heparin exposure and 30% by low-molecular weight heparin. The most common precipitant in the patients without heparin exposure was recent surgery. Average nadir platelet count for which IVIg was used was 28 000/mul. Time from resolution of the thrombocytopenia after IVIg treatment was 3 days with average platelet count recovery to 159 000/mul. Mean time from diagnosis to administration of IVIg was day 18. Thrombosis was identified in 32% of patients. About 77% patients improved (platelet count >100 000/mul or cessation of thrombosis) following use of IVIg. Logistic regression did not identify any factors that predicted IVIg response (P > 0.05). No thrombotic events or other adverse events were noted with use of IVIg. IVIg appears to be a safe and effective treatment option for HIT-related thrombocytopenia and for refractory thrombosis.
Anti-Platelet Antibodies in Childhood Immune Thrombocytopenia: Prevalence and Prognostic Implications
Journal of thrombosis and haemostasis : JTH. 2020
BACKGROUND Anti-platelet antibody testing may be useful for the diagnosis and management of childhood immune thrombocytopenia (ITP). OBJECTIVES Here we aimed to assess the prevalence and prognostic significance of anti-platelet glycoprotein-specific IgM and IgG antibodies. METHODS Children with newly diagnosed ITP were included at diagnosis and randomized to an intravenous immunoglobulins (IVIg) or careful observation group (TIKI trial). In this well-defined and longitudinally followed cohort (N = 179), anti-platelet glycoprotein-specific IgM and IgG antibodies were determined by MAIPA. RESULTS The dominant circulating anti-platelet antibody class in childhood ITP was IgM (62% of patients); but IgG antibodies were also found (10%). Children without IgM platelet antibodies were older and more often female. There was weak evidence for an association between IgM anti-GP IIb/IIIa antibodies and an increased bleeding severity (P=0.03). The IgM and IgG anti-platelet responses partially overlapped, and reactivity was frequently directed against multiple glycoproteins. During one year follow-up, children with IgM antibodies in the observation group displayed a faster platelet recovery compared to children without IgM, also after adjustment for age and preceding infections (P=7.1x10(-5) ). The small group of patients with detectable IgG anti-platelet antibodies exhibited an almost complete response to IVIg treatment (N=12; P=0.02), suggesting that IVIg was particularly efficacious in these children. CONCLUSIONS Testing for circulating anti-platelet antibodies may be helpful for the clinical prognostication and the guidance of treatment decisions in newly diagnosed childhood ITP. Our data suggest that the development of even more sensitive tests may further improve the clinical value of antibody testing.
Intravenous immunoglobulin versus observation in childhood immune thrombocytopenia: a randomized controlled trial
Management of children with newly diagnosed immune thrombocytopenia (ITP) consists of careful observation or immunomodulatory treatment. Observational studies suggest a lower risk of chronic ITP in children after intravenous immunoglobulin (IVIg) treatment. In this multicenter randomized trial, children aged 3 months-16 years with newly diagnosed ITP, platelet counts ≤20 x 10(9)/L and mild to moderate bleeding were randomly assigned to receive either a single infusion of 0.8 g/kg IVIg or careful observation. Primary outcome was development of chronic ITP, at time of study initiation defined as a platelet count < 150 x 10(9)/L after 6 months. Two hundred and six children were allocated to receive IVIg (n=102) or careful observation (n=104). Chronic ITP occurred in 18.6% in the IVIg group and in 28.9% in the observation group (relative risk [RR] 0.64; 95% confidence interval [CI] 0.38-1.08). Platelet counts < 100 x 10(9)/L at 12 months (current definition of chronic ITP) were observed in 10% children in the IVIg group and in 12% in the observation group (RR 0.83; 95% CI 0.38-1.84). Complete response rates in the first three months were significantly higher in the IVIg group. IgG- Fc receptor IIb genetic variations were associated with early complete response in both groups. Grade 4-5 bleeding occurred in 9% in the observation group versus 1% in the IVIg group. IVIg treatment at diagnosis in children with ITP did not result in a lower rate of chronic ITP. In the IVIg group higher early complete response rates and less bleeding events were observed. This trial was registered at www.trialregister.nl as NTR 1563.
What Is the Burden of Immunoglobulin Replacement Therapy in Adult Patients With Primary Immunodeficiencies? A Systematic Review
Frontiers in Immunology. 2018;9:1308
Background: Primary immunodeficiency disorders (PIDs) are a group of heterogeneous rare disorders, whereby the immune system is missing or not functioning adequately. For patients requiring treatment, the most common option is immunoglobulin replacement therapy (Ig). Treatment of PIDs is simultaneously associated with both improvements in health-related quality of life (HRQoL) and increased treatment burden. Objectives: This review sought to review studies investigating the burden of Ig treatment, synthesize evidence in relation to administration routes (subcutaneous or intravenous) and instruments used, as well as make recommendations for clinical and research applications in this area for patients aged 16 years and older. Methods: We searched Medline, EMBASE, and The Cochrane Library. Sifting of titles was performed by two reviewers, and the assessment of full-text articles by three. From a database which contained 3,770 unique results, 67 full texts were reviewed. Eventually, 17 studies were found to meet the inclusion criteria, and included in this review. Due to data heterogeneity, a narrative, descriptive synthesis of the evidence was undertaken. Results: Most studies were carried out in the USA/North America, used a prospective observational design and involved patients with common variable immune deficiency. Four studies measured the burden of receiving IVIg therapy and 13 measured SCIg therapy. A wide range of measures, primarily designed to measure aspects of treatment satisfaction (e.g., life quality index or a slightly modified version) and HRQoL (e.g., The Short Form-36) had been used. Conclusion: Lack of a parallel control group in most studies meant that changes in outcomes could be due to factors other than changes in the treatment regimen. However, overall, PID patients appeared to report little Ig treatment burden and were satisfied with either modality. However, patient preference appeared to be the delivery of the Ig treatment in the patient's home and SCIg was preferred after switching from IVIg therapy. Individual differences appeared to affect treatment preference and therefore understanding the decision support needs of PID patients facing IG treatment choices would be valuable. Using a questionnaire specifically designed to measure the burden of Ig treatment from the patient's perspective is recommended in future research.