Intravenous immunoglobulin therapy for children with Stevens-Johnson syndrome

OBJECTIVE: To review the experience with intravenous immunoglobulin (IVIG) therapy in patients with Stevens-Johnson syndrome (SJS) in our institution. METHODS: All charts of patients with SJS admitted to Children's Hospital between November 1988 and June 1998 were reviewed. RESULTS: Twelve patients with SJS were detected. There were 8 males and 4 females, with a mean age 6 years (range 10 mo to 17 yrs). All patients presented with high fever and cutaneous and mucous membrane changes, and the diagnosis SJS was confirmed by a dermatologist. Of the 12 patients with SJS, 7 were treated with IVIG, 2 with corticosteroids, and 3 with supportive care. IVIG was administered in a single infusion at 1.5-2 g/kg, and was given on an average of hospital day 3 (range 1-8 days). The average duration of fever was 8 days (range 3-14) in the IVIG treated patients compared to 14 days (range 6-20) in the non-IVIG treated group (p = 0.06). The mean hospital stay was 12 days (range 4-22) for the patients treated with IVIG and 15 days (range 6-25) for the non-IVIG treated group (p = 0.5). No toxicity was observed with IVIG therapy. CONCLUSION: Duration of fever was shortened in patients treated with IVIG, although statistical significance was marginal. The hospital stay was slightly shortened in patients treated with IVIG; however, statistical significance was not reached. Prospective and controlled, multicenter studies are needed to further investigate these preliminary findings.     

Therapy with immunoglobulin in patients with acute myocarditis and cardiomyopathy: analysis of leukocyte balance

Intravenous immunoglobulin (IVIG) therapy has been used to treat several autoimmune or inflammatory diseases. We conducted a clinical trial of immunoglobulin therapy for acute myocarditis. The study consisted of two projects: (1) a comparison of prognosis between patients treated with and those not treated with IVIG in a multi-center study; (2) analyses of inflammatory cytokines and blood cell profiles in a substudy. In (1), 15 patients were treated with IVIG (1–2 g/kg, over 2 days), whereas 26 were untreated. There was a statistically significant difference between the survival curves of the patients treated with IVIG and the survival curves of those not treated with IVIG. There was no significant difference between the IVIG-treated and untreated groups in terms of clinical parameters of the acute and chronic phases. In (2), 10 patients were treated with IVIG and 6 were untreated. In both groups, all of the data except for changes in the fraction of lymphocytes and the fraction of monocytes decreased due to the treatment or during the course. In patients in the IVIG group, the percentage of peripheral eosinophils was decreased and the percentage of peripheral monocytes was increased by this treatment when they were compared with the pretreatment data. Therefore, therapy with IVIG seems to be a promising treatment for acute myocarditis given that it improves the clinical course, which may be due to modulation of inflammatory cytokines and the peripheral leukocyte balance.     

High-dose intravenous immunoglobulin modifies complement-mediated in vivo clearance

The mechanism of effect of high-dose intravenous immunoglobulin (IVIG) therapy in immune cytopenias is incompletely known. One of the leading theories ascribes the short-term effects of IVIG to the competition of infused IVIG for Fc receptors, thereby inhibiting IgG-mediated clearance. Using a system independent of IgG-Fc receptor interactions, we examined another potential mechanism of IVIG action. Guinea pigs were infused with a human IVIG preparation at 600 mg/kg/day for two consecutive days. Parallel groups of animals were treated with the same volume and/or concentration of saline and albumin. Clearance of IgM- sensitized guinea pig erythrocytes, which is wholly complement dependent, was significantly retarded in animals treated with high-dose IVIG. The effect was specific for IVIG, since human albumin (as a second foreign protein) failed to change the clearance of IgM- sensitized guinea pig erythrocytes. Experiments in which IVIG-treated animals were subjected to pre- and posttreatment clearance studies revealed heterogeneity among individual animals in respect to their response to IVIG infusions. Decrease of available plasma complement components did not account for the effect, since both C3 and CH50 values remained unchanged after IVIG treatment, despite rising levels of IVIG in sera of treated animals. The results of in vitro C3 uptake studies and the effect of IVIG on clearance of preopsonized cells suggest that IVIG produces a kinetic depression of C3 uptake and modifies the process of complement fragment deposition on erythrocytes. A generalized effect on mononuclear phagocytes is less likely but cannot be wholly ruled out. These studies establish another potential mechanism of IVIG action and suggest extension of its use to other complement-mediated diseases.     

大剂量静脉注射免疫球蛋白辅助治疗儿童系统性红斑狼疮

目的　观察大剂量静脉注射免疫球蛋白 (IVIG)治疗儿童系统性红斑狼疮 (SLE)的疗效。方法　 6 9例SLE患儿随机分成两组 ,IVIG组 33例用大剂量IVIG和激素及环磷酰胺 (CTX) ;对照组 36例用激素和CTX治疗。观察大剂量IVIG对SLE疾病活动指数 (SLEDAI)、临床表现和SLE血清学指标的影响。结果　IVIG组治疗 3个月后SLEDAI明显低于对照组 (P <0 0 1) ,在降低蛋白尿、ANA及抗dsDNA抗体以及控制院内感染、病情稳定方面显著优于对照组。结论　大剂量IVIG是治疗儿童SLE有效的辅助措施。     

Intravenous immunoglobulin therapy for juvenile dermatomyositis: efficacy and safety

OBJECTIVE: To assess the efficacy of intravenous immunoglobulin (IVIG) for the treatment of juvenile dermatomyositis (JDM) in patients who were unresponsive to corticosteroids (steroid resistant or steroid dependent) or showed unacceptable toxicity. METHODS: A retrospective chart review of the course of all patients with JDM treated with IVIG who attended the Dermatomyositis Clinic at The Hospital for Sick Children, Toronto, Canada, from August 1986 to December 1996. RESULTS: Eighteen patients with JDM were treated with IVIG. Ten patients were taking additional 2nd line treatments, methotrexate, azathioprine, cyclosporine, and cyclophosphamide. The main indication for starting IVIG was the failure of steroid therapy to induce remission of JDM. Twelve patients showed clinical improvement with IVIG. In these patients, the corticosteroid dose was reduced by > 50% for > 3 months without clinical or biochemical flare. Nine of these 12 patients had IVIG alone as a 2nd line agent, whereas 3 patients were treated with additional agents. Six patients remained steroid dependent; they subsequently required multiple agents to induce remission of JDM. CONCLUSION: Most steroid dependent or steroid resistant patients in our clinic were able to markedly reduce their dose of corticosteroid with the addition of IVIG. Given the retrospective nature of our data and the fact that multiple agents were sometimes used together, it will be important to confirm these findings in a controlled trial.     

Changes in intravenous immunoglobulin prescribing patterns during a period of severe product shortages, 1995-2000

BACKGROUND AND OBJECTIVES: Canadian consumption of intravenous immunoglobulin (IVIG) has increased dramatically since it was first marketed in the early 1980s, and Canada is now the world's largest per capita consumer. During the late 1990s, worldwide product shortages of IVIG occurred. This study was designed to identify the disease conditions for which IVIG was being prescribed in academic hospitals during this period, and to explore the effects that IVIG shortages had on prescribing patterns. MATERIALS AND METHODS: Blood bank and pharmacy records of IVIG distribution were collected retrospectively from four Toronto teaching hospitals for the period 1995-2000. These records were then cross-referenced with patient medical records to determine the indication for IVIG administration. RESULTS: A total of 100,208 g of IVIG was prescribed to 429 patients over a 6-year period. Most of the IVIG consumption was in patients with haematological (22%) or neurological (20%) conditions, in recipients of bone marrow transplants (19%) and in patients with infectious disease-related conditions (including congenital and acquired hypogammoglobulinaemia, 18%). Dermatological conditions (7%) were the most rapidly growing indication for IVIG usage during the 6-year period of review, increasing from 0% of annual IVIG usage in 1995 to 16% in 2000. Over 80% of the diseases treated were supported by published recommendations. After 1997 there was an abrupt decline in the annual number of patients treated, primarily owing to a decline in single-use recipients. Annual consumption of IVIG, however, remained stable. CONCLUSIONS: IVIG shortages were followed by a decrease in the number of single-use recipients, who probably represented empirical use of IVIG; this had little effect on the total amount of IVIG distributed annually. Stricter adherence to currently available published recommendations may not be the optimal means of controlling IVIG use within an academic hospital setting. Rather, emphasis may be better placed on improving the evidence base upon which these recommendations are made, for example by conducting controlled prospective clinical trials.     

Effects of maintenance treatment after high-dose intravenous gamma-globulin for idiopathic thrombocytopenic purpura]

High-dose intravenous immunoglobulin (IVIG) for idiopathic thrombocytopenic purpura (ITP) produces a dramatic and substantial increase in platelet count, but the increased count tends to return rapidly to its pretreatment level. We studied the effects of immunosuppressive treatment aimed at the maintenance of platelet counts following the IVIG administration in ITP. Thirty-five patients with ITP were treated with IVIG, and then thirty-two of them with an immunosuppressant (azathioprine) and a glucocorticoid (prednisolone). After IVIG, the platelet count increased significantly. With immunosuppressive therapy after IVIG, most patients had a tendency to maintain the counts. In particular, this maintaining effect was remarkable in those patients who had been responsive to the standard prednisolone therapy while non-responders to the prior prednisolone failed to maintain the counts. When prednisolone was given after IVIG, the effect of maintaining platelet counts was dose-dependent. The treatment with azathioprine and prednisolone after IVIG appears to be effective in maintenance of platelet counts.     

Inefficacy of intravenous immunoglobulin in patients with low-risk thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome.

OBJECTIVE: To assess the efficacy of intravenous immunoglobulin (IVIG), in comparison with plasma exchange (PE), in the treatment of patients with thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome (TTP/HUS). DESIGN: Prospective, nonrandomized comparative study. SETTING: Hematology department in a general hospital. PATIENTS: 17 consecutive adult patients, six of them pregnant, with diagnosis of TTP/HUS. Three had a severity score at diagnosis less than or equal to 4 and were treated with IVIG and 14 had a severity score of greater than or equal to 5 and/or were pregnant and received PE. The response was evaluated after 5 days of therapy. RESULTS: Complete remission was obtained in 0/3 cases treated with IVIG and 10/14 (71%) with PE (Fisher's exact test P = 0.05). Three patients died for widespread TTP-HUS, and four had persistent disease. In three of the four resistant patients, complete remission was obtained by further PE but not by further IVIG. The overall remission rate was 76% (13/17). CONCLUSIONS: Our study does not confirm the utility of IVIG in the management of TTP-HUS, as suggested by earlier single case reports.     

Intravenous immunoglobulin treatment for pregnancy-associated dermatomyositis

Pregnancy-associated dermatomyositis (DM) is a rare disorder, until recently treated only with corticosteroids due to the toxicity of other immunosuppressive agents for the fetus. We present a pregnant woman with DM treated successfully with intravenous immunoglobulin (IVIG) and medium dose corticosteroids. A 42-year-old woman presented with a rash, muscle weakness and increased muscle enzymes on the 15th week of her first pregnancy. After the diagnosis of DM she was treated with the combination of medium dose corticosteroids and IVIG. The patients’ symptoms resolved rapidly. No complications were noted for either her or the fetus. Both she and her son remain disease-free after 6 years follow-up. In conclusion, IVIG treatment is a safe and effective alternative for pregnancy-associated DM.     

The Effectiveness of Intravenous Human Immunoglobulin Treatment After Plasmapheresis in Restoring Serum Immunoglobulin Levels: A Preliminary Study

Abstract: This study was performed to examine the effects of intravenous human immunoglobulin (IVIG) on the level of serum immunoglobulin G (IgG) and its subclasses after plasmapheresis in patients with autoimmune disorders. Twenty‐nine patients with predominantly rheumatoid arthritis were enrolled in this study. The plasmapheresis was performed by the use of double‐filtration plasmapheresis (DFPP). Immediately after DFPP, IVIG (2.5 g, 50 ml) was intravenously administered. The treatment with IVIG had almost no effect on subjective and objective symptoms. Immediately after DFPP, the total of serum IgG was decreased by approximately 40%. After 24 h, the total of serum IgG recovered to 16% reduction in IVIG‐treated patients whereas it remained at 32% reduction in nontreated patients. The beneficial effect of IVIG was significantly observed in patients who had shown 1,000–1,800 mg/dl IgG in their sera. After DFPP, IgG subclasses were decreased without change in the ratio of subclasses. Twenty percent to 30% of IgG subclasses were supplemented by the treatment with IVIG without change in the ratio of subclasses. These results suggested that the treatment with IVIG at minimal amount was safe and effective to supplement IgG for hypogammaglobulinemia after DFPP.     

Effect of revision of Japanese diagnostic criterion for fever in Kawasaki disease on treatment and cardiovascular outcome.

BACKGROUND: The aim of this study was to investigate the effect of a revision of the fever criterion for initial intravenous immunoglobulin (IVIG) treatment, and cardiovascular sequelae, in the new Japanese diagnostic criteria for Kawasaki disease. METHODS AND RESULTS: Patients who were reported in the 16th and 18th nationwide surveys in Japan were analyzed. New criteria group comprised patients who received the diagnosis of Kawasaki disease in the 18th nationwide survey (n=18,789). Old criteria group was comprised patients who received their diagnosis in the 16(th) nationwide survey (n=15,017). The difference between the new and old criteria for complete cases was only 1%. The proportion of patients who were treated with IVIG within 4 days of illness onset in the new criteria group was significantly lower than in the old criteria group (27.7% vs 30.7%). Multivariate logistic regression analysis identified criteria sex, age, recurrence, diagnosis, last day of initial IVIG and additional IVIG treatment as significant independent factors for cardiovascular sequelae. CONCLUSIONS: The guideline revision improves diagnostic sensitivity somewhat, but reflects the clinical reality of the disease that approximately 30% of patients are treated with IVIG within 4 days of illness onset.     

Treatment of Secondary Immune Thrombocytopenia with Non-Hodgkin Lymphoma: A Case Report and Literature Review

Secondary immune thrombocytopenic purpura (ITP) with non-Hodgkin lymphoma (NHL) is a rare disease. Although some treatment regimens are available for primary ITP, the treatment strategy for secondary ITP remains unconfirmed. We herein report a 79-year-old man who was diagnosed with secondary ITP with mantle cell lymphoma. Although intravenous immunoglobulin (IVIG) has been considered an effective option for secondary ITP, similar to the treatment of primary ITP, our patient did not benefit from IVIG. A literature review including the current report revealed that IVIG was ineffective in all treated patients. Secondary ITP with NHL should be treated differently from primary ITP.     

Successful treatment of new onset Wegener’s granulomatosis with IVIG (intravenous immunoglobulin) during pregnancy: a case report

We describe a patient with limited Wegener’s granulomatosis (WG) presenting during pregnancy with aggressive cutaneous involvement. She was treated with a combination of high-dose corticosteroids and intravenous immunoglobulin (IVIG) during her third trimester. The patient had otherwise uneventful pregnancy and a satisfactory outcome for both herself and her newborn. In the English literature, prior to this report, there have been de novo cases of WG in pregnant women that were diagnosed and treated during pregnancy and three cases of WG treated successfully with IVIG during pregnancy.     

Carboxyhemoglobin Levels in Neonatal Immune Hemolytic Jaundice Treated with Intravenous Gammaglobulin

In order to examine the effect of intravenous immunoglobulin (IVIG) on the rate of hemolysis in immune hemolytic hyperbilirubinemia, we measured the carboxyhemoglobin levels of 5 newborn infants who were subjected to IVIG treatment. The pretreatment rate of hemolysis, in the 5 patients with isoimmune hemolytic jaundice (3 patients with Rh hemolytic disease of the newborn and 2 patients with ABO hemolytic disease of the newborn), as reflected by caboxyhemoglobin levels was higher than the rate of hemolysis in normal newborn infants. In 4 out of the 5 patients treated with IVIG, there was a rapid decline (> 30%) of carboxyhemoglobin levels, a pattern which was different from that observed in normal newborn infants with no hemolytic jaundice and in 3 untreated patients with ABO hemolytic disease of the newborn. None of the treated patients required an exchange transfusion. Our preliminary results support the theory that the attenuation of jaundice observed following IVIG treatment in patients with immune hemolytic hyperbilirubinemia is caused, at least in part, by the reduction in hemolysis.     

Identification of an Fc gamma receptor-independent mechanism by which intravenous immunoglobulin ameliorates antiphospholipid antibody-induced thrombogenic phenotype

OBJECTIVE: Patients with the antiphospholipid antibody syndrome (APS) often experience recurrent arterial and venous thrombosis and pregnancy losses. Intravenous immunoglobulin (IVIG) therapy has prevented pregnancy loss in some women with APS and has reversed fetal resorption rates in murine models of pregnancy loss. Although the basis for these effects is unknown, effector mechanisms of pathogenic antibodies often involve receptors for IgG (Fc gamma receptors [Fc gammaR]). We examined the potential mechanisms of action of WIG in an in vivo murine model of antiphospholipid antibody (aPL)-induced thrombosis and endothelial cell activation. METHODS: Mice infused with IgG containing human anticardiolipin antibodies (aCL) were treated with IVIG (36 microg i.v.), saline, or ovalbumin. Surgically induced thrombus formation and in vivo leukocyte adhesion to endothelial cells were measured. Circulating levels of aCL were measured by enzyme-linked immunosorbent assay. To determine whether Fc gammaR are required for the effects of IVIG, we treated mice deficient in stimulatory Fc gammaR. To examine the effects of IVIG on endogenously generated antibody, we treated mice immunized with beta2-glycoprotein I (beta2GPI). RESULTS: IVIG treatment inhibited aPL-induced endothelial cell activation and enhancement of thrombosis in mice passively infused with human aPL-containing IgG, and this was associated with a decrease in aPL levels. Similarly, IVIG lowered aPL levels and inhibited thrombogenesis in mice immunized with beta2GPI. The thrombophilic effects of aPL were evident in Fc gammaR-deficient mice. CONCLUSION: Treatment with IVIG inhibits the thrombogenic effects of aPL in vivo and reduces the levels of aCL in the circulation. Blockade of stimulatory Fc gammaR on inflammatory cells is not necessary for this effect. The mechanism of action of IVIG is more likely saturation of the IgG transport receptor, leading to accelerated catabolism of pathogenic aPL. These results have implications in the management of thrombosis in APS and may have applications for pregnant patients with a history of APS.     

Subcutaneous immunoglobulin administration: an alternative to intravenous infusion as adjuvant treatment for dermatomyositis?

Monthly high-dose intravenous administration of human polyclonal immunoglobulins (IVIG) has been shown to be effective as an adjuvant treatment for dermatomyositis. We report a patient with dermatomyositis treated with high doses of immunoglobulins by subcutaneous infusion (SCIG). SCIG was used because of the lack of peripheral and central vein access to continue effective IVIG therapy. The treatment was administered at home, was well tolerated, and was associated to the stabilization of the disease after a 1-year follow-up. Thus, our report suggests that SCIG could be an alternative to IVIG in the treatment of dermatomyositis.     

Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome--a comparative observational study. The Canadian Streptococcal Study Group.

Twenty-one consecutive patients with streptococcal toxic shock syndrome (TSS) between December 1994 and April 1995 were treated with a median dose of 2 g of intravenous immunoglobulin (IVIG)/kg (cases) and were compared with 32 patients with streptococcal TSS between 1992 and 1995 who did not receive IVIG therapy (controls). The outcome measure was 30-day survival. Patient plasma was tested for its ability to inhibit T cell activation induced by the infecting strain. The proportion of cases with 30-day survival was higher than that of the controls with 30-day survival (67% vs. 34%, respectively; P = .02). Multivariate analysis revealed that IVIG administration and a lower Acute Physiology and Chronic Health Evaluation II score were associated with survival; the odds ratio for survival associated with IVIG therapy was 8.1 (95% confidence interval, 1.6-45; P = .009). IVIG therapy enhanced the ability of patient plasma to neutralize bacterial mitogenicity and reduced T cell production of interleukin-6 and tumor necrosis factor alpha. IVIG may be an effective adjunctive therapy for streptococcal TSS, possibly because of its ability to neutralize bacterial exotoxins.     

Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies

OBJECTIVE: To compare the 2 most efficacious therapeutic regimens, intravenous immunoglobulin (IVIG) and anticoagulation with low molecular weight (LMW) heparin plus low-dose aspirin, in women with recurrent pregnancy loss associated with antiphospholipid antibodies (aPL). METHODS: We examined 40 women with recurrent abortion (at least 3 occurrences) and repeatedly positive test results for anticardiolipin or lupus anticoagulant. The subjects were randomly assigned to treatment with IVIG or LMW heparin plus low-dose aspirin. Both therapies were started when the women were pregnant as documented by a positive urine test. IVIG was stopped at the thirty-first week of gestation, aspirin at the thirty-fourth week, and heparin at the thirty-seventh week. The primary outcome of interest was the rate of live births with the 2 treatments. RESULTS: The characteristics of the 2 groups were similar at the time of randomization. The women treated with LMW heparin plus low-dose aspirin had a higher rate of live births (84%) than those treated with IVIG (57%). CONCLUSION: Treatment with LMW heparin plus low-dose aspirin should be considered as the standard therapy for recurrent pregnancy loss due to aPL.     

Intravenous immunoglobulin: another therapeutic application

Intravenous immunoglobulin (IVIG) has immunoregulatory functions. In renal transplant, IVIG has been used as an immunosupressor agent only during short period of time and frequently associated to others immunosupressor drugs. In renal transplant IVIG has been used to treat refractory rejection but not as maintenance immunosupressor treatment. We report a case in which IVIG was used as principal immunosupressor agent close to low doses of iv methylprednisolone. The patient could not receive anything by oral way during three months, so she only could be treated by intravenous way. It is the first time that IVIG is used as maintenance immunosupressortreatment for a long time (three months) without secondary effects.