Comparison of effectiveness of interventions in reducing mortality in patients of toxic epidermal necrolysis: A network meta-analysis
Indian journal of dermatology, venereology and leprology. 2021;:1-17
BACKGROUND Limited evidence is available about effectiveness and choice of immunomodulating treatment modalities for toxic epidermal necrolysis (TEN). AIMS To compare the effectiveness of interventions to reduce mortality in patients of toxic epidermal necrolysis through network meta-analysis. METHODS Studies were retrieved using PubMed, Google Scholar and Cochrane Database of Systematic Reviews from inception to September 18, 2018. Only English language articles were considered. Observational and randomized controlled studies having ≥ 5 TEN patients in each intervention arm were included. Two investigators independently extracted study characteristics, intervention details and mortality data. Bayesian network meta-analysis was performed using the Markov chain Monte Carlo (MCMC) approach through the random effect model. The ranking analysis was done to provide a hierarchy of interventions. The consistency between direct and indirect evidence was assessed through node spit analysis. The primary outcome was to compare the mortality [Odds ratio OR (95% credibility interval CrI)] among all treatment modalities of TEN. RESULTS Twenty-four studies satisfying the selection criteria were included. The network analysis showed improved survival with cyclosporine as compared to supportive care [OR- 0.19 (95% CrI: 0.05, 0.59)] and intravenous immunoglobulin [OR- 0.21 (95% CrI: 0.05, 0.76)]. The hierarchy of treatments based on "surface under the cumulative ranking curves" (SUCRA) value were cyclosporine (0.93), steroid+intravenous immunoglobulin (0.76), etanercept (0.59), steroids (0.46), intravenous immunoglobulin (0.40), supportive care (0.34) and thalidomide (0.02). No inconsistencies between direct and indirect estimates were observed for any of the treatment pairs. LIMITATIONS Evidence is mainly based on retrospective studies. CONCLUSION The use of cyclosporine can reduce mortality in TEN patients. Other promising immunomodulators could be steroid+intravenous immunoglobulin combination and etanercept.
Delayed Pressure Urticaria: A Systematic Review of Treatment Options
J Allergy Clin Immunol Pract. 2020
BACKGROUND Delayed pressure urticaria (DPU) is characterized by recurrent erythematous and often painful swelling after the skin is exposed to sustained pressure. Treatment is challenging. Antihistamines, the first-line and only approved treatment, are often not effective. OBJECTIVE To systematically review the treatment options for DPU. METHOD A literature search of electronic databases for all relevant articles published until April 29, 2019 was conducted using the search terms "delayed pressure urticaria" and "pressure urticaria". This systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses recommendations. RESULTS Twenty-one studies (8 randomized controlled trials [RCTs], 10 retrospective cohort studies, and 3 open-label prospective studies) were included. Second-generation antihistamines (sgAHs) were effective in 3 RCTs. The combination of sgAHs and montelukast (2 RCTs) or sgAH and theophylline (1 non-RCT) was more effective than the sgAH alone. The disease improved with omalizumab (4 non-RCTs), sulphones (3 non-RCTs), oral prednisolone (1 RCT, 2 non-RCTs), intravenous immunoglobulin, and gluten-free diet (1 non-RCT each). There are no studies on updosing of antihistamines over standard dosage in DPU. CONCLUSION Overall, the quality of studies on DPU is low. Due to the lack of other evidence, antihistamines remain the first-line therapy. Updosing of sgAHs could be considered in patients with uncontrolled symptoms based on the extrapolation of evidence from chronic spontaneous urticaria, even though there is no evidence of its efficacy over standard dosage. Addition of montelukast may be considered. Omalizumab or sulphones may be used in treatment-resistant patients. High-quality DPU studies should be conducted.
Scleromyxedema treatment: a systematic review and update
Int J Dermatol. 2020
IMPORTANCE Scleromyxedema is a chronic disease with high morbidity and mortality and no definitive therapeutic guidelines. OBJECTIVE To review all available data on the efficacy and the safety of the available treatments of scleromyxedema and suggest a possible therapeutic approach. EVIDENCE REVIEW We performed a systematic literature review in Pubmed/Medline, Embase, and Cochrane collaboration databases, searching for all articles since 1990 on the treatments of scleromyxedema, with no limits on participant age, gender, or nationality. FINDINGS Ninety-seven studies were included in this systematic review, of which one prospective, two retrospective, 70 case reports/case series, and 24 letters/correspondence/clinical image. Intravenous immunoglobulin (IVIG) was the most used first-line therapy based on its efficacy and its generally well-tolerated nature; most patients require continued treatment to remain in remission. Thalidomide and systemic glucocorticoids were mostly considered as second-line therapies and were given alone or in association with IVIG. Patients with severe or refractory disease were treated with autologous bone marrow transplantation, melphalan, or bortezomib with dexamethasone. CONCLUSIONS AND RELEVANCE Consideration of patient comorbidities, disease distribution, clinician experience, and treatment accessibility is mandatory in every therapeutic approach of scleromyxedema.
Systemic treatments in the management of atopic dermatitis: a systematic review and meta-analysis
BACKGROUND As an evidence resource for the currently planned European Academy of Allergy and Clinical Immunology (EAACI) clinical practice guideline "systemic treatment of atopic dermatitis (AD)" we critically appraised evidence on systemic treatments for moderate-to-severe AD. METHODS We systematically identified randomized controlled trials (RCTs) investigating the safety and efficacy of systemic treatments for AD up to February 2020. Primary efficacy outcomes were clinical signs, AD symptoms and health-related quality of life. Primary safety outcomes included cumulative incidence rates for (serious) adverse events. Trial quality was assessed applying the Cochrane Risk of Bias Tool 2.0. Meta-analyses were conducted where appropriate. RESULTS 50 RCTs totalling 6681 patients were included. Trial evidence was identified for Apremilast, Azathioprine (AZA), Baricitinib, Ciclosporin-A (CSA), corticosteroids, Dupilumab, Interferon-gamma, intravenous immunoglobulins (IVIG), Mepolizumab, Methotrexate (MTX), Omalizumab, Upadacitinib and Ustekinumab. Meta-analyses were indicated for the efficacy of Baricitinib [EASI75 RD 0.16, 95% CI (0.10;0.23)] and Dupilumab [EASI75, RD 0.37, 95% CI (0.32;0.42)] indicating short-term (i.e. 16-week treatment) superiority over placebo. Furthermore efficacy analyses of AZA and CSA indicated short-term superiority over placebo, however non-validated scores were used and can therefore not be compared to EASI. CONCLUSION The most robust, replicated high quality trial evidence is present for the efficacy and safety of Dupilumab for up to 1 year in adults. Robust trial evidence was further revealed for AZA, Baricitinib and CSA. Methodological restrictions led to limited evidence-based conclusions for all other systemic treatments. Head-to-head trials with novel systemic treatments are required to clarify the future role of conventional therapies.
Treating toxic epidermal necrolysis with systemic immunomodulating therapies: a systematic review and network meta-analysis
Journal of the American Academy of Dermatology. 2020
BACKGROUND Various systemic immunomodulating therapies (SITs) have been used to treat toxic epidermal necrolysis (TEN) but their efficacy remains unclear. OBJECTIVE To perform a systematic review and network meta-analysis (NMA) evaluating the effects of SITs on mortality for Stevens-Johnson syndrome (SJS)/TEN overlap and TEN. METHODS A literature search was performed in online databases (from inception to Oct 31, 2019). Outcomes were mortality rates and SCORe of Toxic Epidermal Necrolysis (SCORTEN)-based standardized mortality ratio (SMR). A frequentist random-effects model was adopted. RESULTS Sixty-seven studies involving 2079 patients were included. An NMA of 10 treatments revealed that none was superior to supportive care in reducing mortality rates and that thalidomide was associated with a significantly higher mortality rate (Odds ration [OR], 11.67; 95% confidence interval [CI], 1.42-95.96). For SMR, an NMA of 11 treatment arms demonstrated that corticosteroids and intravenous immunoglobulin (IVIg) combination therapy was the only treatment with significant survival benefits (SMR, 0.53; 95% CI, 0.31-0.93). LIMITATIONS Heterogeneity and a paucity of eligible randomized controlled trials. CONCLUSIONS Combination therapy with corticosteroids and IVIg may reduce mortality risks in patients with SJS/TEN overlap and TEN. Cyclosporine and etanercept are promising therapies but more studies are required to provide clearer evidence.
Efficacy, Safety, and Immunomodulatory Effect of the Intramuscular Administration of Autologous Total Immunoglobulin G for Atopic Dermatitis: A Randomized Clinical Trial
Allergy, asthma & immunology research. 2020;12(6):949-963
PURPOSE The management of patients with atopic dermatitis (AD) is often difficult. We hypothesized that repeated intramuscular administration of autologous total immunoglobulin G (IgG) could induce clinical improvement in patients with AD through immune modulation. This clinical trial was conducted to evaluate the efficacy, safety, and immunomodulatory effect of the intramuscular administration of autologous total IgG in patients with AD. METHODS In this randomized, double-blind, placebo-controlled trial, 51 adolescent and adult patients with moderate-to-severe AD were randomized to receive 8 weekly intramuscular administrations of autologous total IgG 50 mg (n = 26) or saline (n = 25) over a 7-week period and were followed up to week 16. Changes in the clinical severity score (Eczema Area and Severity Index), affected body surface area, patient-reported Dermatology Life Quality Index (DLQI) score, laboratory biomarkers, and incidence of adverse events from baseline to week 16 were assessed. RESULTS The intramuscular administration of autologous total IgG, compared with saline, decreased the clinical severity score (-64.8% vs. -20.3%, P < 0.001), reduced the affected body surface area (-53.9% vs. -19.1%, P < 0.001), improved the DLQI score (-35.4% vs. -14.4%, P = 0.015), increased serum interleukin-10 and interferon-γ levels (P = 0.011 and P = 0.003, respectively), and reduced the incidence of AD exacerbation (11.5% vs. 48.0%, P = 0.004) from baseline to week 16. No serious adverse events were observed. CONCLUSIONS The intramuscular administration of autologous total IgG provided clinical improvements and a systemic immunomodulatory effect in adolescent and adult patients with moderate-to-severe AD without significant side effects. TRIAL REGISTRATION Clinical Research Information Service Identifier: KCT0001597.
Clinical factors influencing the response to intravenous immunoglobulin treatment in cases of treatment-resistant pyoderma gangrenosum
The Journal of dermatological treatment. 2019;:1-13
BACKGROUND Pyoderma gangrenosum (PG) is a neutrophilic disorder which classically presents as chronic, painful ulcers on the lower extremities. There is evidence supporting a potential role for intravenous immunoglobulin (IVIG) as adjuvant therapy for treatment-resistant cases; however, it is unclear which patients will most benefit from this modality of treatment - an especially important consideration given the cost per infusion ($5,000-$10,000). Thus, we sought to identify the clinical characteristics of patients with refractory PG lesions who demonstrated complete healing when IVIG was incorporated into the therapeutic plan. METHODS We performed a literature search of PubMed/MEDLINE and Embase using the keywords "pyoderma gangrenosum" and "IVIG". We also added four institutional cases. Descriptive statistics were used to analyze the data. Significance was set at p < 0.05. RESULTS We discovered a total of 45 cases. Twenty-three patients with treatment-resistant PG had complete healing, 22 had partial or unhealed PG ulcers. Patients with one ulcer were 4.1 (95% CI: 1.1 to 18.5) times more likely to achieve complete healing than patients with more than one ulcer, when IVIG was added (p = 0.041). CONCLUSION There is increased efficacy of IVIG as a treatment for patients with a solitary treatment-resistant PG lesion compared to patients with multiple refractory lesions.
Treatment of urticarial vasculitis: A systematic review
The Journal of Allergy and Clinical Immunology. 2018
Urticarial vasculitis (UV) is a difficult-to-treat condition characterized by long-lasting urticarial rashes and histopathologic findings of leukocytoclastic vasculitis. Treatment is dictated by severity of skin and systemic involvement and the underlying systemic disease. This is a comprehensive systematic review of the efficacy of current UV treatment options. We searched for relevant studies in seven databases including MEDLINE, Scopus, and Web of Science. In total, 261 eligible studies and 789 unique UV patients were included in the systematic review. Most UV patients are adult females with chronic (≥6 weeks) and systemic disease. UV is mostly idiopathic, but can be associated with drugs, malignancy, autoimmunity and infections. It usually resolves with their withdrawal or cure. Corticosteroids are effective for the treatment of skin symptoms in >80% of UV patients. However, their long-term administration can lead to potentially serious adverse effects. The addition of immunomodulatory or immunosuppressive agents often allows corticosteroids tapering and improves the efficacy of therapy. Biologicals, including omalizumab, as well as corticosteroids, cyclophosphamide, dapsone, mycophenolate mofetil, plasmapheresis, colchicine, hydroxychloroquine, intravenous immunoglobulins, NSAIDs, and cyclosporine can be effective for skin as well as systemic symptoms in UV patients. H1-antihistamines, montelukast, danazol, H2-antihistamines, pentoxifylline, doxepin and tranexamic acid are not effective in most UV patients. As of yet, no drugs have been approved for UV, and management recommendations are based mostly on case reports and retrospective studies. Prospective studies investigating the effects of treatment on the signs and symptoms of UV are needed.
Intravenous immunoglobulin as adjunct therapy for refractory pyoderma gangrenosum: systematic review of cases and case series
The British Journal of Dermatology. 2017;178((2):):363-368
Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis. Treatment regimens for refractory cases are non-standardized. Intravenous immunoglobulin (IVIG) is an emerging treatment with reported success, but the efficacy of IVIG for PG is unknown. In this systematic review of cases and case series, we assessed the efficacy of IVIG for treatment of PG, as observed at our institution and reported in the literature. A retrospective chart review at two tertiary care hospitals between 2000-2015, and literature searches in PubMed/MEDLINE, EMBASE, and Web of Science from all years were conducted. There were 49 total patients, including 43 patients from 26 articles and 6 institutional cases. There was complete or partial response in 43 (87.8%) patients and complete response in 26 (53.1%) patients. The mean time to initial response to treatment and treatment length were 3.5 (3.3) weeks and 5.9 (7.8) months, respectively. On average, 2.6 treatments had been trialed before IVIG initiation. IVIG was administered with systemic steroids in 43 (87.8%) cases. Mild adverse events, especially nausea and headache, were reported in 12 (24.5%) patients. Our systematic review suggests a potential role for IVIG as adjuvant therapy for refractory PG. Prospective clinical trials testing the efficacy of IVIG for refractory PG are needed to validate these findings. This article is protected by copyright. All rights reserved.
Systemic immunomodulating therapies for Stevens-Johnson Syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis
Jama Dermatology. 2017;153((6):):514-522
Importance: Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are rare but severe adverse reactions with high mortality. There is no evidence-based treatment, but various systemic immunomodulating therapies are used. Objectives: To provide an overview on possible immunomodulating treatments for SJS/TEN and estimate their effects on mortality compared with supportive care. Data Sources: A literature search was performed in December 2012 for articles published in MEDLINE, MEDLINE Daily, MEDLINE Inprocess, Web of Science, EMBASE, Scopus, and the Cochrane Library (Central) from January 1990 through December 2012, and updated in December 2015, in the English, French, Spanish, and German languages looking for treatment proposals for SJS/TEN. Other sources were screened manually. Study Selection: Initially, 157 randomized and nonrandomized studies on therapies (systemic immunomodulating therapies or supportive care) for SJS/TEN were selected. Data Extraction and Synthesis: Relevant data were extracted from articles. Authors were contacted for further information. Finally, 96 studies with sufficient information regarding eligibility and adequate quality scores were considered in the data synthesis. All steps were performed independently by 2 investigators. Meta-analyses on aggregated study data (random-effects model) and individual patient data (IPD) (logistic regression adjusted for confounders) were performed to assess therapeutic efficacy. In the analysis of IPD, 2 regression models, stratified and unstratified by study, were fitted. Main Outcomes and Measures: Therapy effects on mortality were expressed in terms of odds ratios (ORs) with 95% CIs. Results: Overall, 96 studies (3248 patients) were included. Applied therapies were supportive care or systemic immunomodulating therapies, including glucocorticosteroids, intravenous immunoglobulins, cyclosporine, plasmapheresis, thalidomide, cyclophosphamide, hemoperfusion, tumor necrosis factor inhibitors, and granulocyte colony-stimulating factors. Glucocorticosteroids were associated with a survival benefit for patients in all 3 analyses but were statistically significant in only one (aggregated data: OR, 0.5; 95%% CI, 0.3-1.01; IPD, unstratified: OR, 0.7; 95% CI, 0.5-0.97; IPD, stratified: OR, 0.8; 95% CI, 0.4-1.3). Despite the low patient size, cyclosporine was associated with a promising significant result in the only feasible analysis of IPD (unstratified model) (OR, 0.1; 95% CI, 0.0-0.4). No beneficial findings were observed for other therapies, including intravenous immunoglobulins. Conclusions and Relevance: Although all analyses, including the unstratified model, had limitations, glucocorticosteroids and cyclosporine were the most promising systemic immunomodulating therapies for SJS/TEN. Further evaluation in prospective studies is required. However, this work provides a comprehensive overview on proposed systemic immunomodulating treatments for SJS/TEN, which is of great relevance for treating physicians.