Pharmacologic interventions for Kawasaki disease in children: A network meta-analysis of 56 randomized controlled trials
BACKGROUND Although the current consensus recommends a standard treatment of high-dose intravenous immunoglobulin with high-dose aspirin to manage Kawasaki disease (KD), the use of different adjunctive therapies remains controversial. The aim of the current network meta-analysis (NMA) was to compare the efficacy and tolerability of different existing interventions for the initial and refractory stages of KD. METHODS An NMA of randomised controlled trials (RCTs) was conducted using the frequentist model applied after electronic searches in PubMed, Embase, ScienceDirect, ProQuest, ClinicalTrials.gov, ClinicalKey, Cochrane CENTRAL, and Web of Science. The main outcomes were reduced fever duration/diminished severity of fever subsided. The initial stage of KD was defined as the first stage to treat patients with KD; the refractory stage of KD represents KD patients who failed to respond to standard KD treatment. The cut-off points for intravenous immunoglobulin (IVIG) were low (100-400 mg), medium (1 g), and high (at least 2 g). FINDINGS A total of fifty-six RCTs with 6486 participants were included. NMA demonstrated that the medium-dosage IVIG + aspirin + infliximab [mean difference=-1.76 days (95% confidence intervals (95% CIs): -3.65 to 0.13 days) compared to high-dosage IVIG + aspirin] exhibited the shortest fever duration; likewise, the medium-dosage IVIG + aspirin + infliximab [odds ratio (OR)=0.50, 95% CIs: 0.18-1.37 compared to high-dosage IVIG + aspirin] exhibited the smallest incidence of coronary artery lesion (CAL) in the initial-stage KD. In the refractory-stage KD, the high-dosage IVIG + pulse steroid therapy (OR=0.04, 95% CIs: 0.00-0.43 compared to the high-dosage IVIG only) had the best rate of decline of fever; likewise, the high-dosage IVIG + ciclosporin [OR=0.05 (95% CIs: 0.00-1.21) compared to the high-dosage IVIG only] exhibited the smallest incidence of CAL. Infliximab significantly improved resolution compared to the high-dosage IVIG only group (OR=0.20, 95%CIs: 0.07-0.62) in refractory-stage KD. INTERPRETATION The NMA demonstrated that the combination therapy with the standard therapy of IVIG and aspirin might have an additional effect on shortening the duration of fever and lowering the CAL incidence rate in patients with acute KD. Moreover, the combination therapy with high-dose IVIG and pulse steroid therapy or cyclosporine therapy might have an additional effect on improving the rate of decline of fever and lowering the incidence rate of CAL in children with refractory KD. Because some of the findings of this NMA should be considered hypothesis-generating rather than confirmatory, further evidence from de novo randomised trials is needed to support our results. FUNDING None.
Corticosteroids for the treatment of Kawasaki disease in children
The Cochrane database of systematic reviews. 2022;5:Cd011188
BACKGROUND Kawasaki disease (KD), or mucocutaneous syndrome, is the leading cause of childhood-acquired heart disease in high-income countries. There is much controversy on how best to treat children with KD and in particular who may benefit from additional treatment beyond the standard intravenous immunoglobulin (IVIG) and aspirin, such as the addition of corticosteroids. This is an update of the review first published in 2017. OBJECTIVES To assess the impact of corticosteroid use on the incidence of coronary artery abnormalities in KD as either first-line or second-line treatment. SEARCH METHODS The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register, CENTRAL, MEDLINE, Embase, CINAHL and two trials registers to 8 February 2021. We searched the reference lists of relevant articles for additional studies. SELECTION CRITERIA We selected randomised controlled trials involving children with all severities of KD who were treated with corticosteroids, including different types of corticosteroids, different durations of treatment, and where corticosteroids were used alone or in conjunction with other accepted KD treatments. We included trials using corticosteroids for both first- and second-line treatment. DATA COLLECTION AND ANALYSIS Two review authors independently selected studies, assessed study quality and extracted data using standard Cochrane methods. We performed fixed-effect model meta-analyses with odds ratios (ORs) or mean difference (MD) with 95% confidence intervals (CIs). We used a random-effects model when there was heterogeneity. We assessed the certainty of the evidence using GRADE. The outcomes of interest were incidence of coronary artery abnormalities, serious adverse events, mortality, duration of acute symptoms (such as fever), time for laboratory parameters to normalise, length of hospital stay and longer-term coronary morbidity. MAIN RESULTS This update identified one new study, therefore the analysis included eight trials consisting of 1877 participants. Seven trials investigated the use of corticosteroids in first-line treatment and one investigated second-line treatment. The trials were all of good methodological quality. On pooled analysis, corticosteroid treatment reduced the subsequent occurrence of coronary artery abnormalities (OR 0.32, 95% CI 0.14 to 0.75; 8 studies, 986 participants; moderate-certainty evidence), without resultant serious adverse events (0 events; 6 studies, 737 participants; moderate-certainty) and mortality (0 events; 8 studies, 1075 participants; moderate-certainty evidence). In addition, corticosteroids reduced the duration of fever (MD -1.34 days, 95% CI -2.24 to -0.45; 3 studies, 290 participants; low-certainty evidence), time for laboratory parameters (erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)) to normalise (MD -2.80 days, 95% CI -4.38 to -1.22; 1 study, 178 participants; moderate-certainty evidence), and length of hospital stay (MD -1.01 days, 95% CI -1.72 to -0.30; 2 studies, 119 participants; moderate-certainty evidence). None of the included studies reported long-term (greater than one year after disease onset) coronary morbidity. AUTHORS' CONCLUSIONS Moderate-certainty evidence shows that use of steroids in the acute phase of KD can be associated with reduced coronary artery abnormalities, reduced inflammatory markers and shorter duration of hospital stay when compared to no corticosteroids. There were no serious adverse events or deaths reported with or without corticosteroid use. Low-certainty evidence shows use of corticosteroids can reduce duration of clinical symptoms (fever and rash). None of the included studies reported on long-term (greater than one year after disease onset) coronary morbidity. Evidence presented in this systematic review agrees with current clinical guidelines on the use of corticosteroids in the first-line treatment in KD.
Immunoglobulin for multifocal motor neuropathy
The Cochrane database of systematic reviews. 2022;1(1):Cd004429
BACKGROUND Multifocal motor neuropathy (MMN) is a rare, probably immune-mediated disorder characterised by slowly progressive, asymmetric, distal weakness of one or more limbs with no objective loss of sensation. It may cause prolonged periods of disability. Treatment options for MMN are few. People with MMN do not usually respond to steroids or plasma exchange. Uncontrolled studies have suggested a beneficial effect of intravenous immunoglobulin (IVIg). This is an update of a Cochrane Review first published in 2005, with an amendment in 2007. We updated the review to incorporate new evidence. OBJECTIVES To assess the efficacy and safety of intravenous and subcutaneous immunoglobulin in people with MMN. SEARCH METHODS We searched the following databases on 20 April 2021: the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and WHO ICTRP for randomised controlled trials (RCTs) and quasi-RCTs, and checked the reference lists of included studies. SELECTION CRITERIA We considered RCTs and quasi-RCTs examining the effects of any dose of IVIg and subcutaneous immunoglobulin (SCIg) in people with definite or probable MMN for inclusion in the review. Eligible studies had to have measured at least one of the following outcomes: disability, muscle strength, or electrophysiological conduction block. We used studies that reported the frequency of adverse effects to assess safety. DATA COLLECTION AND ANALYSIS Two review authors independently reviewed the literature searches to identify potentially relevant trials, assessed risk of bias of included studies, and extracted data. We followed standard Cochrane methodology. MAIN RESULTS Six cross-over RCTs including a total of 90 participants were suitable for inclusion in the review. Five RCTs compared IVIg to placebo, and one compared IVIg to SCIg. Four of the trials comparing IVIg versus placebo involved IVIg-naive participants (induction treatment). In the other two trials, participants were known IVIg responders receiving maintencance IVIg at baseline and were then randomised to maintenance treatment with IVIg or placebo in one trial, and IVIg or SCIg in the other. Risk of bias was variable in the included studies, with three studies at high risk of bias in at least one risk of bias domain. IVIg versus placebo (induction treatment): three RCTs including IVIg-naive participants reported a disability measure. Disability improved in seven out of 18 (39%) participants after IVIg treatment and in two out of 18 (11%) participants after placebo (risk ratio (RR) 3.00, 95% confidence interval (CI) 0.89 to 10.12; 3 RCTs, 18 participants; low-certainty evidence). The proportion of participants with an improvement in disability at 12 months was not reported. Strength improved in 21 out of 27 (78%) IVIg-naive participants treated with IVIg and one out of 27 (4%) participants who received placebo (RR 11.00, 95% CI 2.86 to 42.25; 3 RCTs, 27 participants; low-certainty evidence). IVIg treatment may increase the proportion of people with resolution of at least one conduction block; however, the results were also consistent with no effect (RR 7.00, 95% CI 0.95 to 51.70; 4 RCTs, 28 participants; low-certainty evidence). IVIg versus placebo (maintenance treatment): a trial that included participants on maintenance IVIg treatment reported an increase in disability in 17 out of 42 (40%) people switching to placebo and seven out of 42 (17%) remaining on IVIg (RR 2.43, 95% CI 1.13 to 5.24; 1 RCT, 42 participants; moderate-certainty evidence) and a decrease in grip strength in 20 out of 42 (48%) participants after a switch to placebo treatment compared to four out of 42 (10%) remaining on IVIg (RR 0.20, 95% CI 0.07 to 0.54; 1 RCT, 42 participants; moderate-certainty evidence). Adverse events, IVIg versus placebo (induction or maintenance): four trials comparing IVIg and placebo reported adverse events, of which data from two studies could be meta-analysed. Transient side effects were reported in 71% of IVIg-treated participants versus 4.8% of placebo-treated participants in these studies. The pooled RR for the development of side effects was 10.33 (95% CI 2.15 to 49.77; 2 RCTs, 21 participants; very low-certainty evidence). There was only one serious side effect (pulmonary embolism) during IVIg treatment. IVIg versus SCIg (maintenance treatment): the trial that compared continuation of IVIg maintenance versus SCIg maintenance did not measure disability. The evidence was very uncertain for muscle strength (standardised mean difference 0.08, 95% CI -0.84 to 1.00; 1 RCT, 9 participants; very low-certainty evidence). The evidence was very uncertain for the number of people with side effects attributable to treatment (RR 0.50, 95% CI 0.18 to 1.40; 1 RCT, 9 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS Low-certainty evidence from three small RCTs shows that IVIg may improve muscle strength in people with MMN, and low-certainty evidence indicates that it may improve disability; the estimate of the magnitude of improvement of disability has wide CIs and needs further studies to secure its significance. Based on moderate-certainty evidence, it is probable that most IVIg responders deteriorate in disability and muscle strength after IVIg withdrawal. SCIg might be an alternative treatment to IVIg, but the evidence is very uncertain. More research is needed to identify people in whom IVIg withdrawal is possible and to confirm efficacy of SCIg as an alternative maintenance treatment.
The Therapeutic Efficacy and Safety of Intravenous Immunoglobulin in Dermatomyositis and Polymyositis: A Systematic Review and Meta-Analysis
Modern rheumatology. 2022
OBJECTIVES To evaluate the efficacy and safety of intravenous immunoglobulin (IVIG) in the treatment of dermatomyositis (DM) and polymyositis (PM). METHODS A comprehensive systematic review was conducted in accordance with the guidelines of PRISMA (Preferred Reporting Items for Systematic Reviews And Meta-analyses). PubMed, Embase, and China National Knowledge Infrastructure (CNKI) were searched to find articles published between July 1919 and May 2021 concerning IVIG therapy in PM/DM. We analyzed continuum data through mean difference and the estimated pooled improvement rate through Log transformation. We calculated all the effect measures with a 95% confidence interval. The I²statistic was calculated to assess statistical heterogeneity across the studies. I²values of 25%, 50% and 75% were defined as low, moderate and high, respectively. All analyses were conducted using R Studio, Version 3.6.3. RESULTS Seventeen papers pertinent to our questions were found: three case-control studies, fourteen non-randomized studies. We evaluated the efficacy of IVIG in DM/PM by the indicators of creatine kinase (CK), Manual Muscle Test (MMT) scores, Medical Research Council (MRC) scale, the Activities of Daily Living (ADL) scale and the pooled improvement rate. In a meta-analysis, we found that IVIG significantly improved the level of CK (SMD -0.69, 95%CI -0.93, -0.46; P<0.0001), MMT (SMD 1.12; 95%CI 0.77, 1.47; P<0.00001), MRC (SMD 1.59; 95%CI 0.86, 2.33; P<0.00001), ADL (SMD 1.07; 95%CI 0.59, 1.56; P<0.0001). The CK levels in DM and PM were also significantly improved after IVIG (SMD = -0.73, 95%CI -1.12, -0.34; P=0.0002; and SMD = -3.29, 95%CI -5.82, -0.76; P < 0.0001, respectively). The meta-analysis of three RCTs showed that there was a statistically significant improvement after IVIG (SMD 0.63; 95%CI 0.22, 1.03; P=0.002). In a random effects model pooled muscle power improvement rate was 77% (95% CI: 66.0-87.0%). Meta-analyses of IVIG as first-line therapy showed a significant improvement of CK level (SMD -0.71; 95%CI -1.12, -0.30; P=0.0007). In three studies, the polled improvement rate of esophageal disorders was 88% (95% CI: 80.0-95.0%). There was no statistically significant difference in the rate of improvement between the number of courses < 2 and ≥ 2 (0.80 vs. 0.80 %, P = 0.9). The corticosteroid-sparing effect of IVIG was also well demonstrated, with the proportion of corticosteroid-sparing success reaching 81.8% (72/88). Adverse reactions included headache, fever, Hypotension and dizzy and so on. Mild cortical stroke, staphylococcal septicaemia, asymptomatic myocardial infarction, cerebral infarction, deep vein thrombosis and subendocardial ischemia as severe adverse events were found in seven cases. CONCLUSION IVIG seems to be an effective drug for DM\PM, improving muscle strength, CK levels and esophageal involvement, and it is well tolerated by patients.
On the use of intravenous immunoglobulins for the treatment of the antiphospholipid syndrome - A systematic review and meta-analysis
Autoimmunity reviews. 2021;:102828
The effectiveness of infliximab for Kawasaki disease in children: systematic review and meta-analysis
Translational pediatrics. 2021;10(5):1294-1306
BACKGROUND Kawasaki disease (KD) is a self-limited illness that results in coronary artery aneurysms (CAAs) and threatens children's health and lives. The therapeutic effects of single intravenous immunoglobulin gamma (IVIG) vs. infliximab (IFX) (with or without IVIG) in young children with KD remain unclear. Thus, we made a meta-analysis and systematic review, including all of the studies which have evaluated the effectiveness and safety of IFX and IVIG KD patients. METHODS The databases of the Cochrane Library, PubMed and Embase websites were searched for articles appearing from inception until December 31, 2020. Clinical studies that compared IFX either as initial therapy plus IVIG or rescue therapy after IVIG (IFX group) failure compared with IVIG treatment alone (IVIG group) in treating KD patients were included. RESULTS The meta-analysis included nine studies characterizing 712 patients. The treatment response was significantly higher in the adjunctive IFX therapy group than in the IVIG therapy group [odds ratio (OR) 2.64; 95% CI: 1.52-4.59; P=0.0005]. Subgroup analysis, the effect of IFX therapy on treatment response is more effectiveness in the group of the high-risk KD patients than IVIG therapy (OR 6.07; 95% CI: 2.30-16.04; P=0.0003; random-effects model). Further analysis showed no difference in the improvement of CAAs in short-term follow-up between the two groups. However, adding IFX either as initial therapy or as additional therapy all showed an advantageous effect regarding the ∆Z score of the left anterior descending (LAD) (MD =0.29; 95% CI: 0.27-0.31; P<0.00001) and right coronary artery (RCA) (MD =0.24; 95% CI: 0.22-0.26; P<0.00001). Further, IFX exhibited significant effect on the treatment response compared with IVIG therapy in the Asian group (OR, 2.84; 95% CI: 1.51-5.36; P=0.001; random-effects model), and the beneficial effects of IFX were given without increasing the risk of AEs. CONCLUSIONS This meta-analysis emphasizes the importance of IFX on the treatment response in the high-risk KD patients. IFX may play a role in the Asian KD patients and prevention of progressive CAA, and does not increase the risk of AEs in KD patients.
Intravenous immunoglobulins reduce skin thickness in systemic sclerosis: evidence from Systematic Literature Review and from real life experience
Autoimmunity reviews. 2021;:102981
INTRODUCTION Intravenous immunoglobulins (IVIG) are a new therapeutic approach in systemic sclerosis SSc. An immunomodulatory and antifibrotic activity has been postulated. IVIG are generally well tolerated and have only rare side effects. Our retrospective study focused its attention on SSc, an autoimmune connective tissue disease, characterized by several complications which has a significant impact on patient's quality of life. The pathophysiology comprises fibrotic, vascular and immunological aspects. AIM: The aim of this study was to verify the effectiveness of IVIG on SSc skin involvement. Moreover, a systematic review of the literature (SLR) of the results obtained to date on the use of Intravenous immunoglobulin (IVIG) in SSc has been also performed. PATIENTS AND METHODS The data of 24 patients (21 women, 3 male) with refractory diffuse SSc skin involvement were evaluated (mean age was 52.13 years). IVIG infusion at a dosage of 2 g/Kg body weight for 4 consecutive days/month, was started between 2002 and 2019. Skin involvement was evaluated with the modified Rodnan Skin Score (mRSS) before therapy and then again after 6 and 12 months. To perform the SLR, the PubMed, Medline, Embase, and Web of Science database were searched from 1990 to 2020 (keywords: IVIG, systemic sclerosis). Three assessors (E.A., C.B. & M.M.C) identified the criteria to scan all papers. RESULTS From the total SLR (106 results), 17 papers were identified after the separation of the clinical cases from the studies (total number of treated patients 183). The studies were classified according to the organ involvement considered in each study, as well as the prescribed dose (high or low doses), and the therapeutic regimens. In the selected papers, the organs mainly involved were the skin, the gastrointestinal, the joint and the cardiovascular systems. Only in one case, plasmapheresis was associated to IVIG. All papers reported significant reduction of the skin involvement, although generally the strength of the works was limited the lack of control cases or by the low number of patients involved. From the real life experience, a statistically significant reduction of mRSS was obtained at 6 months follow-up (average value of -6.61 ± 5.2, p < 0.001), and it was further maintained with a significant stabilization after 12-months (-11.45 ± 9.63, p < 0.002). DISCUSSION This SLR and the data of the retrospective study suggest that IVIG may improve skin involvement reducing mRSS in particular in those patients that were refractory to other standard of care therapies and represents a therapeutic option in patients with concomitant myositis. The literature review revealed encouraging perspectives on the use of this therapy, given the effectiveness found in the selected works.
Monoclonal antibody and anti-cytokine biologics for Kawasaki disease: A systematic review and meta-analysis
Seminars in arthritis and rheumatism. 2021;51(5):1045-1056
BACKGROUND Kawasaki disease (KD) is a form of self-limiting vasculitis that causes coronary artery abnormalities in children. Although clinical trials of monoclonal antibodies and anti-cytokine biologics that block cytokine cascades have been conducted, the studies have revealed contradictory results. To examine the effectiveness of treatment with monoclonal antibodies and anti-cytokine biologics for KD patients, we conducted this systematic review and meta-analysis. METHODS Relevant randomized controlled trials (RCTs) and observational studies (e.g., cohort studies, case-control studies, case-series, and case-reports) were included to summarize available evidence, both qualitatively and quantitatively. The Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, and ICUSHI were used for systematic research. Meta-analysis of the included studies was conducted using fixed-effect or random-effects models, depending on the degree of between-study heterogeneity. We assessed coronary artery and treatment outcomes of the interventions. The certainty of evidence and risk of bias were assessed using the GRADE and Cochrane risk of bias tool. The protocol of this review is registered with PROSPERO (CRD42016033079). RESULTS Results: Of all searched studies, 183 studies were qualitatively analyzed. We finally included four randomized controlled trials with 456 patients in quantitative syntheses. Monoclonal antibodies and anti-cytokine biologics did not reduce the frequency of CAA (risk ratio [RR], 0.93; 95% confidence interval [95%CI], 0.65 to 1.32, low certainty of evidence), compared with the conventional treatment with IVIG. However, the frequency of treatment resistance (RR, 0.60; 95%CI, 0.38 to 0.95, moderate certainty of evidence) was reduced by the antibodies. We found no statistical differences in either "any adverse event" (RR, 0.92; 95%CI, 0.80 to 1.06, low certainty of evidence) or "adverse events attributable to the administration of the medication" (RR, 1.10; 95%CI, 0.72 to 1.69, low certainty of evidence) between the two groups. CONCLUSION Conclusions: Although monoclonal antibodies and anti-cytokine biologics were not effective in reducing the frequency of CAA in KD patients, the frequency of treatment resistance might be reduced by those agents compared with conventional IVIG therapy alone.
Efficacy and safety of intravenous and subcutaneous immunoglobulin therapy in idiopathic inflammatory myopathy: A systematic review and meta-analysis
Autoimmunity reviews. 2021;:102997
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.
Clinical Features in Children With Kawasaki Disease Shock Syndrome: A Systematic Review and Meta-Analysis
Frontiers in cardiovascular medicine. 2021;8:736352
Objective: This study aimed to identify the clinical features of Kawasaki disease shock syndrome (KDSS) in children. Methods: The case-control studies of KDSS and KD children up until April 30, 2021 were searched in multiple databases. The qualified research were retrieved by manually reviewing the references. Review Manager 5.3 software was used for statistical analysis. Results: The results showed that there was no significant difference in the incidence of male and female in children with KDSS. Children with KDSS compared with non-shocked KD, there were significant difference in age, duration of fever, white blood cell (WBC) count, percentage of neutrophils (NEUT%), platelet count (PLT), c-reactive protein level (CRP), alanine transaminase concentration (ALT), aspartate transaminase concentration (AST), albumin concentration (ALB), sodium concentration (Na), ejection fraction, and length of hospitalization as well as the incidence of coronary artery dilation, coronary artery aneurysm, left ventricular dysfunction, mitral regurgitation, pericardial effusion, initial diagnosis of KD, intravenous immunoglobulin (IVIG) resistance and receiving second dose of IVIG, vasoactive drugs, hormones, and albumin. In contrast, there was no difference in the hemoglobin concentration, erythrocyte sedimentation rate, and the incidence of conjunctival injection, oropharyngeal change, polymorphous rash, extremity change, and incomplete KD. Conclusion: Current evidence suggested that the children with KDSS had more severe indicators of inflammation and more cardiac abnormalities. These patients were resistant to immunoglobulin treatment and required extra anti-inflammatory treatment. Systematic Review Registration: PROSPERO registration number CRD42021241207.