Sarcoidosis-associated small fiber neuropathy in a large cohort: Clinical aspects and response to IVIG and anti-TNF alpha treatment.

OBJECTIVE: Small fiber neuropathy commonly affects patients with sarcoidosis and is often refractory to standard immunosuppressive therapies used for systemic disease. The clinical features of sarcoidosis-associated small fiber neuropathy (SSFN) and its response to medical therapy have not been described in a large population. METHODS: We performed a retrospective review of patients with SSFN seen at the Cleveland Clinic over a 4-year period. RESULTS: SSFN was identified in 143 individuals although other causes of neuropathy were found in 28 cases. Of the remaining 115 patients, 100 (87%) were Caucasian and 72 (63%) were female. Median age at reported neuropathy onset was 46 years (range 19-77 years), while median age of systemic diagnosis was 41 years. Pain and paresthesias were the most common symptoms, of which 54% were nonlength-dependent. Dysautonomia was seen in 61 patients with cardiac symptoms (orthostasis, palpitations) as the most common presentation followed by gastrointestinal and sweating dysfunction. Symptomatic improvement with treatment was seen in 47 of 62 patients that received IVIG, 8 of 12 patients that received anti-TNF and 10 of 14 patients who received combination therapy. Of 27 patients who were untreated, 4 improved. CONCLUSIONS: The most common presentation of SSFN in our series was a painful non-length dependent polyneuropathy with the highest overall incidence in Caucasian females. In most patients, neuropathy symptoms developed within 3 years of systemic sarcoidosis diagnosis. IVIG appeared beneficial in treating SSFN symptoms while nearly 2/3 of subjects also responded favorably to anti-TNF with or without IVIG. Further prospective studies are needed.

Hematologic toxicities associated with intravenous immunoglobulin therapy.

Intravenous immunoglobulin (IVIG) is an immunomodulating agent that induces beneficial therapeutic responses in children and adults. IVIG is not only used for prophylaxis and therapy of infections in patients with primary and secondary immunodeficiencies associated with defective antibody production, but also used for treatment of patients with systemic inflammatory disorders, autoimmune diseases, and neuroimmunologic conditions. IVIG is generally considered a safe and efficacious therapeutic modality. However, it is associated with certain adverse effects including hematologic complications such as hemolytic anemia, leukopenia, neutropenia, monocytopenia, disseminated intravascular coagulation, and changes in blood rheology. Venous and arterial thrombotic complications can also occur following treatment with IVIG in high risk patients. It is very important for clinicians to have the knowledge of those adverse events profiles; and this article summarizes hematologic toxicities associated with IVIG therapy reported in the literature; and describes strategies for their identification and management.

Natural anti-Siglec autoantibodies mediate potential immunoregulatory mechanisms: implications for the clinical use of intravenous immunoglobulins (IVIg).

Human intravenous immunoglobulins (IVIg) contain natural autoantibodies against the inhibitory lectin-receptors Siglec-8 and Siglec-9. These two members of the Siglec family are known to mediate both inhibitory and death signals. Here, we discuss recent findings regarding the cytotoxic effects of natural anti-Siglec autoantibodies on both neutrophils and eosinophils, and present the concept of a novel regulatory mechanism exhibiting anti-inflammatory properties. Consequently, IVIg may amplify this regulatory pathway by increasing the concentration of natural anti-Siglec autoantibodies in blood and tissues.

Efficacy of topical immunoglobulins against experimental adenoviral ocular infection.

PURPOSE: Presently, there is no U.S. Federal Drug Administration (FDA)-approved antiviral therapy for the treatment of adenoviral (Ad) ocular infections. The goal of the present study was to determine the antiviral efficacy of human immunoglobulin (Ig), a preparation of highly purified and concentrated immunoglobulin (IgG) antibodies isolated from a large pool of human plasma donors, in vitro and on acute Ad replication in the Ad5 New Zealand White (NZW) rabbit ocular model. METHODS: The antiviral activity of human Ig against multiple wild-type and human ocular isolates of adenovirus serotypes was investigated in vitro by using neutralizing assays in different human epithelial cell lines. In vivo bilateral topical ocular toxicity and antiviral efficacy were evaluated with established Ad5/NZW rabbit ocular models. In vivo Ig antiviral results were compared with those obtained with topical 0.5% cidofovir and saline. RESULTS: In three different epithelial cell lines,

Intravenous immunoglobulin preparations contain anti-Siglec-8 autoantibodies.

BACKGROUND: Human intravenous immunoglobulin (IVIg) preparations are used for the treatment of autoimmune and allergic diseases. Natural autoantibodies are believed to contribute to IVIg-mediated anti-inflammatory effects. OBJECTIVE: To address the question of whether IVIg preparations contain anti-sialic acid-binding Ig-like lectin-8 (anti-Siglec-8) autoantibodies. METHODS: The presence of possible anti-Siglec-8 autoantibodies in IVIg preparations was first examined by functional eosinophil death and apoptosis assays. Specificity of IVIg effects was shown by depleting anti-Siglec-8 autoantibodies from IVIg. Binding of purified anti-Siglec-8 autoantibodies to recombinant Siglec-8 was demonstrated by an immunodot assay. RESULTS: IVIg exerts cytotoxic effects on purified human blood eosinophils. Both potency and efficacy of the IVIg-mediated eosinophil killing effect was enhanced by IL-5, granulocyte/macrophage colony-stimulating factor, IFN-gamma, TNF-alpha, and leptin. Similarly, inflammatory eosinophils obtained from patients suffering from the hypereosinophilic syndrome (HES) demonstrated increased Siglec-8 cytotoxic responses when compared with normal blood eosinophils. Pharmacologic blocking experiments indicated that the IVIg-mediated additional eosinophil death in the presence of cytokines is largely caspase-independent, but it depends on reactive oxygen species. Anti-Siglec-8 autoantibody-depleted IVIg failed to induce caspase-independent eosinophil death. CONCLUSION: IVIg preparations contain natural anti-Siglec-8 autoantibodies. CLINICAL IMPLICATIONS: Anti-Siglec-8 autoantibodies present in IVIg preparations may have therapeutic relevance in autoimmune and allergic diseases, respectively, such as Churg-Strauss syndrome.

Superior immunomodulatory effects of intravenous immunoglobulins on human T-cells and dendritic cells: comparison to calcineurin inhibitors.

BACKGROUND: Prophylactic administration of anti-HBs intravenous immunoglobulins (IVIg) in hepatitis B infected-liver transplant patients protects against acute rejection. To explore the suitability of intravenous immunoglobulins (IVIg) as prophylaxis of acute rejection and graft-versus-host disease (GVHD) after allograft transplantation, the effects of IVIg and calcineurin inhibitors (CNI) on human blood-derived T-cells and DC were compared. METHODS: T-cells were stimulated with phytohemagglutinin (PHA) or allogeneic spleen antigen-presenting cells (APC) and T-cell proliferation and cytokine production were determined in presence or absence of IVIg or CNI. Immature blood dendritic cells (DC) were stimulated in presence or absence of IVIg or CNI, and allogeneic T-cell stimulatory capacity, cell death, and phenotypic maturation were established. RESULTS: IVIg and CNI equally inhibited T-cell proliferation and IFN-gamma production after PHA stimulation or allogeneic stimulation. CD8+ T-cells were preferentially affected by both IVIg and CNI after allogeneic stimulation. Like CNI, addition of IVIg at later time points after T-cell activation suppressed mitotic progression of responding T-cells. IVIg-treated DC were suppressed in their capacity to stimulate allogeneic T-cell proliferation by 73+/-12%, whereas DC-function was not affected by CNI. The decreased allogeneic T-cell stimulatory capacity of IVIg-treated DC correlated to induction of cell death in DC and decreased up-regulation of CD40 and CD80. CONCLUSIONS: In vitro IVIg functionally inhibit the two principal immune cell-types involved in rejection and GVHD, i.e. T-cells and DC, whereas CNI only suppress T-cells. By targeting both T-cells and DC, IVIg may be a promising candidate for immunosuppressive treatment after allograft transplantation.

Efficacy, safety and tolerability of a new 10% liquid intravenous immune globulin [IGIV 10%] in patients with primary immunodeficiency.

The present clinical study was designed to evaluate the efficacy, pharmacokinetics and safety of a new 10% liquid intravenous immune globulin in patients with primary immunodeficiency diseases. Sixty-one adults and children with primary immuno-deficiency diseases received doses of 300-600 mg/kg body weight every 21-28 days for 12 months. No validated acute serious bacterial infections were reported. The 95% confidence interval for the annualized rate of acute serious bacterial infections (primary endpoint) was 0-0.060. A total of four predefined validated other bacterial infections commonly occurring in primary immunodeficiency disease subjects were observed; none were serious, severe or resulted in hospitalization. The median elimination half-life of IgG was 35 days. Median total IgG trough levels varied from 9.6 to 11.2 g/L. Temporally associated adverse experiences were determined for 72 h after each infusion and the most common adverse experience was headache, which was associated with 6.9% of infusions. The study met the primary endpoint for efficacy and demonstrated excellent tolerability of the new 10% liquid intravenous imunoglobulin preparation.

IVIg therapy in brain inflammation: etiology-dependent differential effects on leucocyte recruitment.

Several studies have reported beneficial effects of intravenous immunoglobulin (IVIg) in diseases of the neuroaxis. However, IVIg effects on leucocyte recruitment, a hallmark feature of autoimmunity and acute inflammation, remain largely unexplored. Using intravital microscopy, we studied the effects of IVIg on leucocyte recruitment in experimental autoimmune encephalomyelitis, a model of multiple sclerosis. In IVIg-treated mice, a significant decrease in recruitment (rolling and adhesion) was observed prior to and following disease onset, and this was concomitant with improved clinical score. Since much of the recruitment is dependent upon alpha4-integrin (ligand for VCAM-1) we used an in vitro flow chamber system and demonstrated a 60% decrease in alpha4-integrin-dependent leucocyte adhesion to immobilized VCAM-1. Finally, we used leucocytes from multiple sclerosis patients and demonstrated that IVIg treatment decreased recruitment by 60% on human endothelium. However, when we visualized the role of IVIg in a second model of brain inflammation, cerebral ischaemia-reperfusion, IVIg actually promoted the formation of platelet-leucocyte aggregates in post-ischaemic cerebral vessels. In conclusion, we report a new mechanism of action of IVIg through interference of alpha4-integrin-dependent leucocyte recruitment in both an animal model and human multiple sclerosis. We also report that IVIg will not be beneficial in all types of pro-adhesive states and may in fact be detrimental in a situation such as stroke.

IGIV-C, a novel intravenous immunoglobulin: evaluation of safety, efficacy, mechanisms of action, and impact on quality of life.

The general safety and efficacy of intravenous immunoglobulin (IGIV) as treatment for idiopathic thrombocytopenic purpura (ITP) has been well-studied. The current study compares the safety and efficacy of a novel IGIV (IGIV-C; Gamunex, 10%) with a licensed solvent/detergent-treated product (IGIV-S/D; GamimuneN, 10%) in treatment of ITP. Ninety-seven pediatric and adult patients with acute and chronic ITP were treated in a multi-center, prospective, randomized, double-blind parallel group, non-inferiority trial at 26 international sites. Baseline data (age, duration of ITP, platelet counts, previous treatment) were comparable between groups. Patients were treated with 1 g/kg/day of IGIV-C or IGIV-S/D for 2 days. The primary end-point, proportion of patients whose platelet counts increased from >/=20 x 10(9)/L to >/=50 x 10(9)/L within 7 days after dosing, was achieved by 35/39 (90%) and 35/42 (83%) of patients treated with IGIV-C and IGIV-S/D, respectively. A secondary endpoint, maintaining platelet counts >/=50 x 10(9)/L for >/=7 days, was achieved by 29/39 (74%) of IGIV-C and 25/42 (60%) IGIV-S/D treated patients. Compared with IGIV-S/D, fewer patients treated with IGIV-C received corticosteroids beyond day 7 (p = 0.02). Efficacy was independent of the presence of isoantibodies or blood type, supporting mechanisms of effect different from anti-D treatments. Adverse events were generally mild and occurred with similar frequency in each group. Viral safety monitoring for HIV, HCV, HBV and Parvovirus B19 showed no seroconversions on study. In conclusion, IGIV-C is as safe and efficacious as IGIV-S/D in treatment of ITP.

Hypotension with intravenous immunoglobulin therapy: importance of pH and dimer formation.

Therapy with intravenous immunoglobulin preparations has been used effectively in a wide range of conditions. Although generally well tolerated, intravenous immunoglobulin preparations may be associated with transient hypotension in some patients. This study examined the role of different immunoglobulin G fractions in the development of intravenous immunoglobulin-induced hypotension in an anaesthetized rat model and assessed the effects of a new liquid immunoglobulin prepared at a low pH on both the formation of immunoglobulin G dimers and the development of hypotension. The effects of this new preparation in an experimental autoimmune encephalomyelitis model were also evaluated. Results from the haemodynamic studies indicated that immunoglobulin G dimers in polyclonal immunoglobulin G are responsible for the hypotensive events associated with some immunoglobulin preparations. They also showed that adjustment to an acidic pH results in the rapid dissociation of immunoglobulin G dimers and prevents the development of hypotension. Additional experiments demonstrated that only immunoglobulin G dimers with a functional Fc fragment can bind to Fcgamma receptors on macrophages to induce the release of blood pressure-lowering mediators. Moreover, essentially monomeric Fc fragments can block the blood pressure-lowering effects of immunoglobulin G dimers. Preparation of a new liquid intravenous immunoglobulin with the pH adjusted to 4.3 prevents the formation of immunoglobulin G dimers even over long-term storage and does not significantly affect blood pressure in a rat model. This preparation is as effective as other intravenous immunoglobulin preparations in ameliorating symptoms of experimental autoimmune encephalomyelitis. These results, like those from previous studies, indicate that preparation of intravenous immunoglobulin at a low pH substantially reduces immunoglobulin G dimerization; this effect significantly decreases the potential for intravenous immunoglobulin to induce hypotension without reducing its clinically relevant biological activity.

Pharmacokinetics and tolerability of a new intravenous immunoglobulin preparation, IGIV-C, 10% (Gamunex, 10%).

BACKGROUND AND OBJECTIVES: A new intravenous immunoglobulin (IGIV) process has been developed that integrates efficient inactivation of enveloped virus, using caprylate, with immunoglobulin G (IgG) purification and caprylate removal by column chromatography. Two clinical studies were conducted to compare the pharmacokinetics of the new product, IGIV-C, 10% (Gamunex, 10%), formulated with glycine, with the licensed solvent-detergent (SD)-treated intravenous immunoglobulin IGIV-SD, 10% (Gamimune N, 10%), formulated with glycine, and IGIV-C, 5%, formulated with 10% maltose. MATERIALS AND METHODS: Both studies were randomized, multicentre crossover trials of 18 and 20 (respectively) adult patients with primary humoral immune deficiency in which patients received one IGIV product for three consecutive periods (3-4 weeks) before crossing over to the other product. Pharmacokinetic parameters were determined after the third infusion of each product. RESULTS: IGIV-C, 10% was bioequivalent to IGIV-SD, 10%, with half-lives (t1/2) of 35 and 34 days, respectively. IGIV-C, 5%, was bioequivalent to IGIV-C, 10%, with t1/2 of 35 and 36 days, respectively. The products had comparable safety profiles. CONCLUSIONS: The pharmacokinetic profiles observed in these trials indicate that IGIV-C, 10% may replace, and be administered in a manner similar to, IGIV-SD, 10%.

Management of immune thrombocytopenic purpura in children.

Immune thrombocytopenic purpura (ITP) is the most common acquired bleeding disorder occurring in previously healthy children and can be classified into two major forms. Acute and chronic ITP are benign conditions with a high probability of spontaneous recovery with or without therapy. Rates of 80-90% complete remission can be achieved irrespective of the treatment given. In only 10-20% of children thrombocytopenia persists for more than six months, showing a chronic course, which also has a high probability of remitting over time (up to 80% or more). The variability of the clinical course, and the lack of consistent clinical features, make the decision on whether and how to treat difficult. Most physicians are driven to treat all children with symptoms by concern over life-threatening hemorrhage, although the risk of intracranial hemorrhage (ICH) is only 0.1-0.9%. The commonly used treatment regimens for acute ITP are corticosteroids, intravenous immunoglobulins (IVIgG), or intravenous anti-D immunoglobulin (anti-D). So far, there is no evidence that initial therapy can prevent ICH or a chronic course of the disease. In chronic ITP the same drugs are generally used and it seems that pulses with steroids may be just as effective as IVIgG. Anti-D may also be considered a reliable and cheap alternative for chronic disease. A major problem in the management of chronic ITP is the question of whether repeated infusions of Ig (IVIgG or anti-D) and/or corticosteroids can postpone or ultimately preclude splenectomy, which must be considered only for a small proportion of patients resistant to therapy. In these cases, a laparoscopic approach should be preferred. Children who fail to respond to splenectomy (< 20% of cases) warrant second line treatment with other drugs, like cyclophosphamide or azathioprine and deserve a revisit of diagnosis for exclusion of secondary ITP.

Nonspecific human IgG reduces survival in neonatal rats infected with Escherichia coli.

BACKGROUND: Human intravenous IgG (IVIG) containing specific antibodies protects neonatal rats from septic death. However, IVIG has immunosuppressive properties and clinical trials of IVIG in neonates at risk for sepsis have yielded conflicting results. HYPOTHESIS: This study was designed to test the hypothesis that nonspecific antibodies in IVIG reduce survival in neonatal rats infected with Escherichia coli. METHODS: Specific antibodies were adsorbed from IVIG with E. coli to produce IVIG/anti-E. coli-. After transthoracic administration of E. coli, survival was determined in neonatal rats injected intraperitoneally with phosphate-buffered saline, IVIG/anti-E. coli- (500 mg/kg) or IVIG containing anti-E. coli antibodies (IVIG/anti-E. coli+). Complement-mediated hemolytic activity of neonatal rat serum was quantified using sensitized sheep erythrocytes. RESULTS: Compared with placebo, intraperitoneal IVIG/anti-E. coli- reduced neonatal survival after E. coli infection. In contrast, IVIG/anti-E. coli+ protected infected animals. Both IVIG/anti-E. coli- and IVIG/anti-E. coli+ impaired the complement-mediated hemolytic activity of neonatal rat serum. CONCLUSIONS: IVIG contained (1) nonspecific antibodies that reduced survival in neonatal rats infected with E. coli and (2) protective anti-E. coli antibodies that enhanced survival in neonatal rats infected with E. coli. We speculate that in clinical trials of IVIG to treat or prevent neonatal sepsis, inconsistent results may be caused, in part, by lot-to-lot variations in the ratio of immunosuppressive, nonspecific antibodies to protective, specific antibodies.

Vasoactive side effects of intravenous immunoglobulin preparations in a rat model and their treatment with recombinant platelet-activating factor acetylhydrolase.

Previously, we observed in a rat model that intravenous administration of intramuscular immunoglobulin preparations induced a long-lasting hypotension, which appeared to be associated with the presence of IgG polymers and dimers in the preparations, but unrelated to complement activation. We found evidence that this hypotensive response is mediated by platelet-activating factor (PAF) produced by macrophages. In this study, we compared the vasoactive effects of 16 intravenous immunoglobulin (IVIG) products from 10 different manufacturers, in anesthetized rats. Eight of the IVIG preparations showed no hypotensive effects (less than 15% decrease), whereas the other 8 had relatively strong effects (15%-50% decrease). The hypotensive effects correlated with the IgG dimer content of the preparations. Pretreatment of the rats with recombinant PAF acetylhydrolase completely prevented the hypotensive reaction on IVIG infusion, and administration after the onset of hypotension resulted in normalization of the blood pressure. We also observed PAF production on in vitro incubation of human neutrophils with IVIG, which could be blocked by anti-Fcgamma receptor antibodies. This indicates that induction of PAF generation may also occur in a human system. Our findings support the hypothesis that the clinical side effects of IVIG in patients may be caused by macrophage and neutrophil activation through interaction of IgG dimers with Fcgamma receptors. Because phagocyte activation may also lead to the release of other inflammatory mediators, recombinant PAF acetylhydrolase (rPAF-AH) provides a useful tool to determine whether PAF plays a role in the clinical side effects of IVIG. If so, rPAF-AH can be used for the treatment of those adverse reactions. (Blood. 2000;95:1856-1861)

Clinical experience with a new solvent detergent-treated intravenous immunoglobulin free of hypotensive effects.

OBJECTIVE: To see if modifications to the processing of intravenous immunoglobulin to include a virus inactivation stage alter immunoglobulin G (IgG) resulting in hypotension in patients. METHODS: Clinical trials were done involving extensive patient monitoring during infusion: in vitro - testing for markers of hypotension, and in vivo - an animal model which closely simulates clinical use. RESULTS: No hypotensive response was seen in the animal model or clinical trial. CONCLUSIONS: The production process used does not damage IgG or create vaso-active kinins as the preparation was free of hypotensive effects.

Meningitis and hepatitis complicating intravenous immunoglobulin therapy.

OBJECTIVE: To report a case of concomitant meningitis and hepatitis complicating the use of intravenous immune globulin (IVIG). CASE SUMMARY: A 39-year-old African-American woman with an autoimmune syndrome developed both acute meningitis and hepatitis following administration of IVIG. These resolved over several days and left no sequellae. DISCUSSION: This represents the first case of concomitant acute meningitis and hepatitis associated with IVIG. Thorough microbiologic and serologic evaluation of the patient failed to demonstrate an infectious etiology. We postulate that our patient's syndrome resulted from direct toxicity of IVIG. CONCLUSIONS: Both acute meningitis and hepatitis may simultaneously complicate IVIG therapy. The specific mechanism remains unclear.

Cationized hyperimmune immunoglobulins: pharmacokinetics, toxicity evaluation and treatment of human immunodeficiency virus-infected human-peripheral blood lymphocytes-severe combined immune deficiency mice.

The in vivo pharmacokinetics and efficacy of cationized human immunoglobulins in the human-peripheral blood lymphocytes-severe combined immune deficiency mouse model were evaluated in the present studies using the severe combined immunodeficient mouse transplanted with human lymphocytes and infected with human immunodeficiency virus (HIV)-1. Immunoglobulins from noninfected humans and from HIV-infected individuals were cationized. The pharmacokinetic analysis showed that the cationized immunoglobulins have a markedly reduced mean residence time and a marked increase in organ uptake compared to the native immunoglobulins. The toxicity studies performed with homologous immunoglobulins in BALB/c mice demonstrated cationized homologous immunoglobulins have no tissue toxicity at a daily dose of 7.5 mg/kg. Treatment of HIV-infected severe combined immune deficiency mice that were transplanted with human lymphocytes demonstrated therapeutic efficacy for a 2-week treatment at a dose of 5 mg/kg cationized HIV immune globulin. In conclusion, cationized immunoglobulins are potential antibody-based therapeutics for the treatment of acquired immune deficiency syndrome; cationized antibodies undergo enhanced transport into lymphocytes and when homologous cationized immunoglobulins are administered there is no measurable tissue toxicity.