Abstract

BACKGROUND Population pharmacokinetics (popPK) using the nonlinear mixed-effect (NLME) modeling approach is an essential tool for guiding dose individualization. Several popPK analyses using the NLME have been conducted to characterize the pharmacokinetics of immunoglobulin G (IgG). OBJECTIVE To summarize the current information on popPK of polyclonal IgG therapy. METHOD A systematic search was conducted in the PubMed and Web of Science databases from inception to December 2020. Additional relevant studies were also included by reviewing the reference list of the reviewed articles. All popPK studies that employed the NLME modeling approach were included and data were synthesized descriptively. RESULTS This review included seven studies. Most of the popPK models were developed in patients with primary immunodeficiency (PID). IgG pharmacokinetics was described as a two-compartment model in five studies, while it was described as a one-compartment model in two other studies. Among all tested covariates, weight was consistently identified as a significant predictor for clearance (CL) of IgG. Whereas, weight and disease type were found to be significant predictors for the volume of distribution in central compartment (Vc). In a typical 70 kg adult, the median estimated values of Vc and CL were 4.04 L and 0.144 L/day, respectively. The between subject variability of Vc was considered large. Only two studies evaluated their models using external data. CONCLUSIONS Seven popPK studies of IgG were found and discussed, with only weight being a significant covariate across all studies. Future studies linking pharmacokinetics with pharmacodynamics in PID and other patient populations are required.

Abstract

BACKGROUND Mucous membrane pemphigoid (MMP) is an autoimmune disease, which can lead to fibrosis of mucous membranes and functional impairment. Biologic agents should be explored as alternative treatment options to improve outcomes. OBJECTIVE To conduct a systematic review of biologic treatment outcomes in patients with MMP. METHODS MEDLINE and EMBASE search was conducted on July 23(rd), 2020 to include 63 studies using PRISMA guidelines. RESULTS Use of IVIG (n=154), rituximab (n=112), TNFα inhibitors (n=7), and combination treatments (n=58) were reported in 331 patients with MMP. IVIG led to complete resolution in 61.7% (n=95/154) of patients within 26.0 months, with a recurrence rate of 22.7% (n=35/154) and headache as the most common side effect (8.4%, n=13/154). Rituximab led to complete resolution in 70.5% (n=79/112) of patients within 8.7 months, with a recurrence rate of 35.7% (n=40/112). Most commonly reported side effects were urinary tract infections (4.5%, n=5/112), leukocytopenia (2.7%, n=3/112), death due to severe infections (1.8%, n=2/112). TNFα inhibitors led to complete resolution in 71.4% (n=5/7) of patients within 3.9 months of treatment, without reported adverse events. CONCLUSIONS Randomized clinical trials with long term follow up are required to conclude the promising safety and efficacy of biologic agents in MMP patients.

Abstract

OBJECTIVE To perform a systematic review and meta-analysis on the efficacy and safety of intravenous (IVIg) and subcutaneous (SCIg) immunoglobulin (Ig) therapy in the treatment of idiopathic inflammatory myopathy (IIM) and juvenile dermatomyositis (JDM). METHODS PubMed, Embase and SCOPUS were searched to identify studies on Ig therapy in patients with IIM and/or JDM (2010-2020). Outcome measures were complete response (CR) or partial response (PR) in terms of muscle power and extramuscular disease activity measures on the International Myositis Assessment and Clinical Studies Group (IMACS) core set domains. RESULTS Twenty-nine studies were included (n = 576, 544 IIM, 32 JDM). Muscle power PR with pooled Ig therapy was 88.5% (95% confidence interval (CI): 80.6-93.5, n = 499) and PR with SCIg treatment was 96.61% (95% CI: 87.43-99.15, n = 59). Pooled PR with first-line use of IVIg was 77.07% (95% CI: 61.25-92.89, n = 80). Overall, mean time to response was 2.9 months (95% CI: 1.9-4.1). Relapse was seen in 22.76% (95% CI: 14.9-33). Studies on cutaneous disease activity and dysphagia showed significant treatment responses. Glucocorticoid and immunosuppressant sparing effect was seen in 40.9% (95% CI: 20-61.7) and 42.2% (95% CI: 20.4-64.1) respectively. Ig therapy was generally safe with low risk of infection (1.37%, 95% CI: 0.1-2.6). CONCLUSIONS Add-on Ig therapy improves muscle strength in patients with refractory IIM, but evidence on Ig therapy in new-onset disease and extramuscular disease activity is uncertain.

Abstract

The two main objectives of this analysis were to (i) characterise the relationship between immunoglobulin (Ig) exposure and chronic inflammatory demyelinating polyneuropathy (CIDP) disease severity using data from 171 patients with CIDP who received either subcutaneous Ig (IgPro20; Hizentra®) or placebo (PATH study), and to (ii) simulate and compare exposure coverage with various dosing approaches considering weekly dosing to be the reference dose. IgG PK parameters including those from a previous population PK model were used to predict individual IgG profile and exposure metrics. Treatment-related changes in inflammatory neuropathy cause and treatment (INCAT) scores were best described by an E(max) model as a function of ΔIgG (total serum IgG at INCAT score assessment minus baseline IgG levels before intravenous Ig restabilisation). Simulations indicate that flexible dosing from daily to biweekly (every other week) provide an exposure coverage equivalent to that of a weekly Ig dose.

Abstract

Pilonidal sinus is an acquired condition caused by irritation to the hair follicles at the natal cleft, presenting with an abscess or chronic infection. It is prevalent in young adults affecting their productive lifestyle with morbidities. There are varieties of treatment options; however, there is no consensus yet for the ideal procedure. Less invasive procedures have evolved to replace the traditional surgical techniques, which cannot significantly reduce the risks of recurrence and wound complications despite extensive surgeries. We aimed to assess the effect of fibrin glue as a primary treatment after cleaning the sinus in pilonidal sinus disease. We searched for articles from PubMed®, Ovid MEDLINE®, Ovid EMBASE®, and Cochrane CENTRAL. Six studies that included 336 patients in total were analyzed. Fibrin glue treatment in these studies reported a quicker return to normal activities postoperatively, a low rate of infection, and an acceptable rate of recurrence. Thus, fibrin glue seems beneficial in the management of pilonidal disease. However, further high-quality studies are essential to support and confirm this evidence. Future research should also evaluate its cost and implications in the ambulatory service.

Abstract

BACKGROUND Standard first-step therapy for Kawasaki disease consists of Intravenous immunoglobulin and high dose Aspirin (80-100 mg/kg/day). The standard dose of Intravenous immunoglobulin (2gr/kg) is strongly effective in reducing the risk of coronary arteries abnormalities. So, the proper dose and efficacy of Aspirin to decrease the risk of coronary arteries abnormalities is a controversial issue. In this study, it is tried to assess the result of eliminating high-dose Aspirin in the treatment of the acute phase of Kawasaki and observe the incidence rate of coronary arteries abnormalities when only Intravenous immunoglobulin was administered. METHODS This study is a prospective randomized, open-label, blinded end-points clinical trial performed in Afzalipour hospital in Kerman University of Medical Sciences from September 2017 to September 2018 in 62 patients with typical and atypical Kawasaki disease. The study group received Intravenous immunoglobulin (2 g/kg) and the control group get the same dose of Intravenous immunoglobulin plus Aspirin with the dose of 80-100 mg/Kg/day until they were afebrile for 48 hours. Afterward, both groups received a daily single dose (3-5 mg/kg) of Aspirin for six weeks. Echocardiography was done after two weeks, six weeks, and six months. Internal diameter of the left and right main coronary arteries was measured and then the corresponding Z-score was calculated. RESULTS In the study group, coronary arteries abnormalities decreased from 38.7% in the 2nd week to 16.1% in the 6th month. In the control group, it declined from 54.8% to 22.6%. There was no statistically significant difference between the groups in term of frequency of abnormal coronary arteries at the study period (P=0.151). CONCLUSIONS We concluded that high dose Aspirin does not have a significant role in preventing coronary arteries abnormalities in Kawasaki disease and giving standard 2 gr/kg/day Intravenous immunoglobulin without high-dose Aspirin in acute-phases therapy does not increase the risk of coronary arteries abnormality.

Abstract

INTRODUCTION This systematic review provides supporting evidence for the accompanying clinical practice guideline on the treatment of central disorders of hypersomnolence in adults and children. The review focuses on prescription medications with U.S. Food & Drug Administration approval and nonpharmacologic interventions studied for the treatment of symptoms caused by central disorders of hypersomnolence. METHODS The American Academy of Sleep Medicine commissioned a task force of experts in sleep medicine to perform a systematic review. Randomized controlled trials and observational studies addressing pharmacological and nonpharmacological interventions for central disorders of hypersomnolence were identified. Statistical analyses were performed to determine the clinical significance of all outcomes. Finally, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) process was used to assess the evidence for the purpose of making specific treatment recommendations. RESULTS The literature search identified 678 studies; 144 met the inclusion criteria and 108 provided data suitable for statistical analyses. Evidence for the following interventions is presented: armodafinil, clarithromycin, clomipramine, dextroamphetamine, flumazenil, intravenous immune globulin (IVIG), light therapy, lithium, l-carnitine, liraglutide, methylphenidate, methylprednisolone, modafinil, naps, pitolisant, selegiline, sodium oxybate, solriamfetol, and triazolam. The task force provided a detailed summary of the evidence along with the quality of evidence, the balance of benefits and harms, patient values and preferences, and resource use considerations. CITATION Maski K, Trotti LM, Kotagal S, et al. Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine systematic review, meta-analysis, and GRADE assessment. J Clin Sleep Med. 2021;17(9):1895-1945.

Abstract

BACKGROUND Primary cytomegalovirus (CMV) infection during pregnancy carries a risk of congenital infection and possible severe sequelae. There is no established intervention for preventing congenital CMV infection. METHODS In this multicenter, double-blind trial, pregnant women with primary CMV infection diagnosed before 24 weeks' gestation were randomly assigned to receive a monthly infusion of CMV hyperimmune globulin (at a dose of 100 mg per kilogram of body weight) or matching placebo until delivery. The primary outcome was a composite of congenital CMV infection or fetal or neonatal death if CMV testing of the fetus or neonate was not performed. RESULTS From 2012 to 2018, a total of 206,082 pregnant women were screened for primary CMV infection before 23 weeks of gestation; of the 712 participants (0.35%) who tested positive, 399 (56%) underwent randomization. The trial was stopped early for futility. Data on the primary outcome were available for 394 participants; a primary outcome event occurred in the fetus or neonate of 46 of 203 women (22.7%) in the group that received hyperimmune globulin and of 37 of 191 women (19.4%) in the placebo group (relative risk, 1.17; 95% confidence interval [CI] 0.80 to 1.72; P = 0.42). Death occurred in 4.9% of fetuses or neonates in the hyperimmune globulin group and in 2.6% in the placebo group (relative risk, 1.88; 95% CI, 0.66 to 5.41), preterm birth occurred in 12.2% and 8.3%, respectively (relative risk, 1.47; 95% CI, 0.81 to 2.67), and birth weight below the 5th percentile occurred in 10.3% and 5.4% (relative risk, 1.92; 95% CI, 0.92 to 3.99). One participant in the hyperimmune globulin group had a severe allergic reaction to the first infusion. Participants who received hyperimmune globulin had a higher incidence of headaches and shaking chills while receiving infusions than participants who received placebo. CONCLUSIONS Among pregnant women, administration of CMV hyperimmune globulin starting before 24 weeks' gestation did not result in a lower incidence of a composite of congenital CMV infection or perinatal death than placebo. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Center for Advancing Translational Sciences; ClinicalTrials.gov number, NCT01376778.).

Abstract

OBJECTIVES Enterovirus (EV) is a frequent cause of encephalitis. The optimal therapeutic approach remains a matter of debate. We present the case of an immunosuppressed patient with EV encephalitis successfully treated with IVIG and conduct a systematic review on the characteristics of EV encephalitis as well as the safety and efficacy of IVIG-therapy. METHODS We conducted a systematic review assessing PubMed, Cochrane Database, Biosis Previews and the ClinicalTrials.gov website to identify all reports on patients with EV encephalitis as of December 31, 2020. Main outcomes assessed were efficacy and safety of the respective therapeutic approach. RESULTS We included a total of 73 papers: one prospective trial, one retro- and prospective case series, one purely retrospective case series, and 70 case reports. The case reports cover a total of 101 patients. The immunosuppressed were at higher risk of contracting EV encephalitis and experiencing lethal courses. Hypogammaglobulinaemia particularly predisposes for EV disease, even with moderate reduction of serum IgG levels. IVIG therapy in the immunosuppressed may confer a survival advantage. CONCLUSIONS IVIG therapy is rarely associated with severe adverse events and may be considered in immunosuppressed patients with EV encephalitis. Future trials should investigate optimal IVIG dosing and route of application, the benefit of antibody-enriched IVIG preparations and the serum immunoglobulin level that should trigger prophylactic replacement.

Abstract

BACKGROUND For most viral encephalitides, therapy is merely supportive. Intravenous immunoglobulins (IVIG) have been used as a prophylactic and therapeutic approach. We conduct a systematic review on the safety and efficacy of IVIG in viral encephalitis. METHODS We conducted a systematic review assessing PubMed, Cochrane Database, Biosis Previews and the ClinicalTrials.gov website to identify all reports on patients with viral encephalitis treated with IVIG as of May 31, 2019. The main outcomes assessed were therapeutic efficacy and safety. For an increased homogeneity of the population, atypical viral infections were excluded, as were reports on prophylactic IVIG use, intrathecal application of immunoglobulins, or use of antibody-enriched IVIG-preparations. Data were extracted from published studies. Descriptive statistics were used. RESULTS We included a total of 44 studies (39 case reports). The case reports cover a total of 53 patients. Our search retrieved two prospective and three retrospective studies. These show heterogeneous results as to the efficacy of IVIG therapy. Only one study reports a significant association between IVIG-use and death (odds ratio 0.032; 95% confidence interval 0.0033-0.3024; p = 0.0027). None of the studies report significant differences in the number of serious adverse events. CONCLUSION Data on the efficacy of IVIG-therapy is heterogeneous. While it seems generally safe, evident superiority compared to supportive treatment has not been demonstrated so far. Future trials should also investigate the optimal dosing and timing of IVIG and their benefit in the immunosuppressed.