Systemic therapy of necrobiotic xanthogranuloma: a systematic review
Orphanet journal of rare diseases. 2022;17(1):132
BACKGROUND Even though a plethora of systemic therapies have been proposed for necrobiotic xanthogranuloma (NXG), there is no systematic review on this topic in literature. OBJECTIVE To review all existing literature on the systemic therapy of NXG in order to identify the most effective therapies. METHODS All reported papers in the literature were screened for systemic treatments of NXG. Papers without proper description of the therapies, papers describing topical therapy, and articles without assessment of effectiveness were excluded. Subsequently, we analyzed 79 papers and a total of 175 cases. RESULTS The most effective treatments for NXG are intravenous immunoglobulins (IVIG), corticosteroids, and combination therapies including corticosteroids. CONCLUSIONS Corticosteroids and IVIG should therefore be considered first-line treatments in patients with NXG.
A Multicenter Cross-Sectional Study and Systematic Review of Necrobiotic Xanthogranuloma With Proposed Diagnostic Criteria
JAMA dermatology. 2020
Importance: Necrobiotic xanthogranuloma (NXG) is a non-Langerhans cell histiocytosis classically associated with paraproteinemia attributable to plasma-cell dyscrasias or lymphoproliferative disorders. Despite the morbidity of NXG, the literature is limited to case reports and small studies, and diagnostic criteria are lacking. Objective: To evaluate the characteristics of NXG and propose diagnostic criteria. Design, Setting, and Participants: This multicenter cross-sectional study was conducted at tertiary academic referral centers and followed by a systematic review and a consensus exercise. The multicenter cohort included patients with NXG diagnosed at the Brigham and Women's and Massachusetts General Hospitals (2000-2018), the University of Iowa Hospitals and Clinics (2000-2018), and the University of Pennsylvania Health System (2008-2018). The systematic review was conducted in 2018 and included patients with NXG identified in the Cochrane, Ovid EMBASE, PubMed, and Web of Science databases. The consensus exercise was conducted by 8 board-certified dermatologists to identify diagnostic criteria. Main Outcomes and Measures: Demographic factors, comorbidities, clinical features, and treatment response. Results: Of 235 included patients with NXG (34 from the multicenter cohort and 201 from the systematic review results), the mean (SD) age at presentation was 61.6 (14.2) years; 147 (62.6%) were female. Paraproteinemia was detected in 193 patients (82.1%), most often IgG-kappa (117 patients [50.0%]). A malignant condition was detected in 59 patients (25.1%), most often multiple myeloma (33 patients [14.0%]). The overall rate of paraproteinemia and/or a malignant condition was 83.8% (197 patients). In the multicenter cohort, evolution of paraproteinemia into multiple myeloma was observed up to 5.7 years (median [range], 2.4 [0.1-5.7] years) after NXG presentation. Cutaneous lesions consisted of papules, plaques, and/or nodules, typically yellow or orange in color (113 of 187 [60.4%]) with a periorbital distribution (130 of 219 [59.3%]). The eye was the leading site of extracutaneous involvement (34 of 235 [14.5%]). In the multicenter cohort, intravenous immunoglobulin had the best treatment response rate (9 of 9 patients [100%]), followed by antimalarial drugs (4 of 5 patients [80%]), intralesional triamcinolone (6 of 8 patients [75%]), surgery (3 of 4 patients [75%]), chemotherapy (8 of 12 patients [67%]), and lenalidomide or thalidomide (5 of 8 patients [63%]). The consensus exercise yielded 2 major criteria, which were (1) clinical and (2) histopathological features consistent with NXG, and 2 minor criteria, consisting of (1) paraproteinemia, plasma-cell dyscrasia, and/or other associated lymphoproliferative disorder and (2) periorbital distribution of cutaneous lesions. In the absence of foreign body, infection, or another identifiable cause, fulfillment of both major and at least 1 minor criterion were proposed to establish the diagnosis of NXG. Conclusions and Relevance: Necrobiotic xanthogranuloma is a multisystem disorder associated with paraproteinemia and malignant conditions. The proposed diagnostic criteria may advance clinical research and should be validated.
Comparison of prophylactic use of intravenous immunoglobulin versus Pentaglobin in pediatric patients after hematopoietic stem cell transplantation
Pediatric Transplantation. 2016;20((2)):276-83.
There are few studies evaluating the use of IgM-enriched IVIG (Pentaglobin() ) in HSCT recipients. This study aimed to compare the efficacy of prophylactic use of IVIG versus prophylactic use of Pentaglobin() within the first 100 days after allogeneic HSCT. We performed a prospective, randomized study of the use of prophylactic IVIG versus prophylactic use of Pentaglobin() in patients after allogeneic HSCT. The first dose of IVIG or Pentaglobin() was given before conditioning regimen and after transplant was given on day +1, +8, +15, and +22. And then, it was given if IgG level was below 400 mg/dL. Twenty-seven patients in IVIG group and 32 patients in Pentaglobin() group were included in the study. There were no significant differences in the duration of neutropenia, hospitalization, fever, and in the number of pyrexial episode, septicemia, bacteremia, local infection, CMV infection, acute GVHD, VOD, and adverse events between the IVIG group and Pentaglobin() group. Randomized placebo-controlled trials are needed to conclude that utilization of IVIG or Pentaglobin() has no beneficial effect in HSCT.Copyright © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Immunoglobulin prophylaxis in chronic lymphocytic leukemia and multiple myeloma: systematic review and meta-analysis
Leukemia & Lymphoma. 2009;50((5):):764-72.
The role of intravenous immunoglobulins (IVIG) prophylaxis in hypogammaglobulinemic patients with lymphoproliferative disorders (LPD) and plasma cell dyscrasias (PCD) has not been established. We performed a systematic review and meta-analysis of randomized-controlled trials comparing prophylaxis with polyvalent IVIG versus control. The primary outcomes were all-cause mortality and major infections. Nine trials, assessing patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM), were included. No survival benefit could be demonstrated, RR 1.36 (95% CI 0.58-3.19, two trials), but there was a significant decrease in the occurrence of major infections, RR 0.45 (95% CI 0.27-0.75, three trials) and a significant reduction in clinically documented infections, RR 0.49 (95% CI 0.39-0.61, three trials). Adverse events, usually not requiring discontinuation of IVIG, occurred significantly more with IVIG. On the basis of the available data, IVIG cannot be recommended routinely for patients with CLL or MM with hypogammaglobulinemia and/or recurrent infections and should be considered on individual basis.
A prospective randomized trial: the influence of intraoperative application of fibrin glue after radical inguinal/iliacal lymph node dissection on postoperative morbidity
European Journal of Surgical Oncology : the Journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2009;35((8):):884-9.
BACKGROUND Effects of intraoperative application of fibrin glue following combined radical inguinal and iliacal lymph node dissection (RILND) on the amount of postoperative lymphatic secretion are discussed controversially. To detect whether fibrin glue application results in a decreased lymphatic secretion following RILND a randomized patient blinded clinical trial was conducted. METHOD Between September 2003 and September 2006 58 patients with stage IV melanoma underwent therapeutic RILND and were randomized into two groups. 29 Patients received 4 cc fibrin glue after RILND whereas 29 patients were only irrigated with saline 0. 9 percent. Postoperatively all patients received two inguinal and one iliacal closed suction drain. The main outcome criteria were the duration of drain placement in the wound. Minor criteria were the total amount of secretion and the length of hospital stay. RESULTS There was no difference between the treatment and the control group in the duration of drain placement (fibrin group: 4 days (1-27); control group 5 days (1-26); p=0. 64). The total amount of fluid was 310 cc (30-6005) in the fibrin group vs. 365 cc (30-3945 cc) in the control group (p=0. 9) and the length of hospital stay 10 days (3-41) (group 1) compared to 11 days (3-41) (p=0. 99) were not different between both groups either. CONCLUSION Intraoperative application of 4 cc fibrin glue does not reduce the length of drain placement, drain output or hospitalisation of patients undergoing RILND with melanoma metastasis to the lymph node basin.
Immunoglobulin prophylaxis in hematological malignancies and hematopoietic stem cell transplantation
Cochrane Database of Systematic Reviews. 2008;((4):):CD006501.
IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock: a randomized, controlled, multiple-center trial
Critical Care Medicine. 2006;34((5):):1319-25.
OBJECTIVE To evaluate the effect of intravenous IgMA-enriched immunoglobulin (ivIGMA) therapy on mortality in neutropenic patients with hematologic malignancies and sepsis syndrome or septic shock. DESIGN Multiple-center, prospective randomized, controlled study. SETTING Six university hospitals in Germany. PATIENTS Patients were 211 neutropenic patients with sepsis syndrome or septic shock after chemotherapy for severe hematologic disorders between 1992 and 1999. INTERVENTIONS Patients received 1300 mL of ivIGMA (7. 8 g IgM, 7. 8 g IgA, and 49. 4 g IgG) infused intravenously within a period of 72 hrs or human albumin according to the same schedule as ivIGMA. MEASUREMENTS AND MAIN RESULTS All-cause mortality at 28 days, sepsis-related mortality at 28 days, all-cause mortality at 60 days, mortality from septic shock, and mortality from microbiologically proven Gram-negative sepsis and septic shock were recorded. Immunoglobulin had no benefit over human albumin. The 28-day mortality rate was 26. 2% and 28. 2% in the ivIGMA and control patients, respectively (difference, 2. 0% [95% confidence interval, -10. 2 to 14. 2 percentage points]). Likewise, the 60-day mortality rate did not differ between both arms (29. 6% vs. 34. 7% in the ivIGMA and control patients, respectively). Mortality rates in patients with sepsis syndrome (17. 1% vs. 16. 7%) and septic shock (51. 9% vs. 54. 8%) were also found to be similar between both groups. CONCLUSIONS Intravenous ivIGMA had no beneficial effects in neutropenic patients with hematologic malignancies and sepsis syndrome and septic shock.
Should immunoglobulin therapy be used in allogeneic stem-cell transplantation? A randomized, double-blind, dose effect, placebo-controlled, multicenter trial
Annals of Internal Medicine. 2003;139((1):):8-18.
BACKGROUND The universal use of prophylactic immunoglobulin in stem-cell transplantation has not been supported by strong evidence of benefit. Results of most trials were reported before effective drugs for cytomegalovirus infection and disease were available, and no trial was placebo controlled. OBJECTIVE To assess the role and the dose-effect relationship of immunoglobulin in the prophylaxis of complications after allogeneic stem-cell transplantation. DESIGN Multicenter randomized, double-blind, dose effect placebo-controlled study. SETTING 19 stem-cell transplantation centers in France. PATIENTS 200 patients who had allogeneic stem-cell transplantation from HLA-identical sibling donors between 1998 and 2000. INTERVENTION Immunoglobulin at doses of 50 mg/kg of body weight, 250 mg/kg, or 500 mg/kg weekly from day -7 to day 100 after transplantation or placebo. MEASUREMENTS Cumulative incidence of infection, graft-versus-host disease, veno-occlusive disease, interstitial pneumonia, and transplantation-related mortality at 6 months; overall survival at 2 years after transplantation. RESULTS Immunoglobulin had no benefit over placebo; 92% of patients in the pooled immunoglobulin group and 90% of patients in the placebo group had one or more infections (difference, 2 percentage points [95% CI, -8 to 12 percentage points]). Cumulative incidences of interstitial pneumonia, graft-versus-host disease, transplantation-related mortality, and overall survival were similar in patients receiving placebo and those receiving immunoglobulin; no dose-effect relationships were evident. Grade 3 (severe) veno-occlusive disease occurred more frequently as the immunoglobulin dose increased (P = 0. 01). CONCLUSIONS Use of prophylactic immunoglobulin in allogeneic recipients of stem-cell transplant from HLA-identical sibling donors is not recommended.
A multicenter, randomized, double-blind comparison of different doses of intravenous immunoglobulin for prevention of graft-versus-host disease and infection after allogeneic bone marrow transplantation
Bone Marrow Transplantation. 2001;28((2):):187-96.
Intravenous immunoglobulin is approved for use in allogeneic bone marrow transplant recipients for prevention of graft-versus-host disease (GVHD) and infections, but the minimally effective dose has not been established. In this multicenter, randomized, double-blind trial, patients undergoing allogeneic marrow transplantation were randomized to receive 100 mg/kg, 250 mg/kg, or 500 mg/kg doses of intravenous immunoglobulin. Each dose was given weekly for 90 days and then monthly until 1 year after transplant. Six hundred and eighteen patients were evaluated. Acute GVHD (grades 2-4) occurred in 39% of the patients (80 of 206) in the 100 mg/kg group, 42% of the patients (88 of 208) in the 250 mg/kg group, and in 35% of the patients (72 of 204) in the 500 mg/kg group (P = 0.344). Among patients with unrelated marrow donors, a higher dose of intravenous immunoglobulin (500 mg/kg) was associated with less acute GVHD (P = 0.07). The incidences of chronic GVHD, infection and interstitial pneumonia were similar for all three doses of intravenous immunoglobulin. The dose of intravenous immunoglobulin also had no effect on the types of infection, relapse of hematological malignancy or survival. Except for more frequent chills (P = 0.007) and headaches (P = 0.015) in patients given the 500 mg/kg or 250 mg/kg dose of immunoglobulin, adverse events were similar for all three doses. These results suggest that 100 mg/kg, 250 mg/kg, and 500 mg/kg doses of intravenous immunoglobulin are associated with similar incidences of GVHD and infections in most allogeneic marrow transplants. These results should be considered when designing cost-effective strategies for the use of intravenous immunoglobulin in allogeneic marrow transplants receiving other current regimens for prophylaxis of GVHD and infection.
Reduced dose intravenous immunoglobulin does not decrease transplant-related complications in adults given related donor marrow allografts
Biology of Blood & Marrow Transplantation. 1999;5((6):):369-78.
Graft-vs.-host disease (GVHD) and infection are major complications of allogeneic bone marrow transplantation. Intravenous immunoglobulin (IVIg) given at a dose of 500 mg/kg/wk has been shown to decrease the risk of acute GVHD, interstitial pneumonia, and infection in adults early after allogeneic transplantation. The current study is a controlled trial to determine whether a lower total dose of IVIg given with pretransplant loading reduces the incidence of transplant-related complications. In a randomized trial of 241 patients > or =20 years of age who were given related donor marrow allografts, 121 individuals receiving Ig prophylaxis (500 mg/kg/d loading from day -6 to -1 and then 100 mg/kg every 3 days from day 3 to 90) were compared with 120 control patients who did not receive IVIg. Randomization was stratified by human leucocyte antigen-matching, remission status of malignancy, GVHD prophylaxis, and cytomegalovirus (CMV) serology. The study was powered to detect a reduction in acute GVHD by 18% and a decrease in transplant-related mortality by 17%. Pretransplant IVIg loading and posttransplant maintenance achieved median serum IgG levels >1350 mg/dL, which were approximately twofold greater than the untreated controls (p<0.01). White blood cell and platelet recoveries were similar for the two groups, although control patients required fewer units of platelets per day (2.5 vs. 3.3, p = 0.008). No significant differences in the incidence of CMV infection, interstitial pneumonia, or bacteremia were observed. The incidence of acute GVHD did not differ between the two groups; however, acute GVHD was less frequent among IVIg recipients achieving maximum serum IgG levels >3000 mg/dL (60 vs. 79%). Neither transplant-related mortality nor disease-free survival was significantly altered by Ig prophylaxis. However, the cumulative incidence of relapse of malignancy was higher in IVIg recipients than in controls (31 vs. 18%, p = 0.03). Multivariable regression analysis demonstrated a 1.89 increased relative risk of relapse for individuals given IVIg (p = 0.021). We conclude that pretransplant loading and a shorter course and lower total dose of IVIg prophylaxis did not appear to decrease the risk of acute GVHD or mortality among adults receiving related donor marrow transplants. Note, IVIg administration may be associated with an increased risk of recurrent malignancy, a finding that warrants further investigation.