Clinical Use Of Intravenous Immunoglobulin Research Articles

Immunoglobulin replacement therapy in chronic lymphocytic leukaemia patients with hypogammaglobulinaemia and infection.

To analyse total national utilisation of immunoglobulin (Ig) replacement therapy (IgRT) for Chronic Lymphocytic Leukaemia patients with acquired hypogammaglobulinaemia and severe and/or recurrent bacterial infections. In 2007, the National Blood Authority first published Criteria for the clinical use of intravenous immunoglobulin in Australia. The Australian Red Cross Lifeblood assessed, approved, and recorded all supply with patient demographics, distribution data, intravenous Ig (IVIg) volumes and treatment episodes. IVIg was the sole product used in Australia from 2008-2013 inclusive. From 2008 to 2013 across Australia, 2734 individual CLL patients received 48,870 treatment episodes using a total 1,324,926g of IVIg therapy. Six IVIg products were available, with domestically manufactured Intragam® P accounting for 89.7% of supply. The average age for first dose was 74years. Males received 60.6% of the total treatment episodes representing 20% more than females. The average pre-treatment IgG level was 4.03±2.03g/L (range 0.30-10.50g/L). A sustained average annual increased IVIg utilisation of 5.5% was observed. There was significant regional variation consistent with differences in prescriber preferences across states and territories. This study provides a globally unique insight into IgRT supply and demand in CLL patients by analysis of total national use in Australia over a 6-year period.

Clinical use of intravenous immunoglobulin in Taiwan: A 10-year population study

Intravenous immunoglobulin (IVIG) is used in the treatment of immunological, inflammatory and neurological conditions. We aimed to describe the trends in IVIG utilization in Taiwan. We identified patients receiving IVIG through the national health insurance (NHI) database. We described the distribution of IVIG use according to main indications. During 2008-2017, IVIG distribution grew 10% per year on average. The population IVIG dose was 8.0g per thousand capita. Among the total distribution, approximately 60% were NHI-reimbursed. Pediatrics (52.3%), rheumatology (14.0%) and hematology/oncology (11.4%) accounted for the top three services in terms of IVIG consumption. Primary and secondary immune deficiency (29.8%), Kawasaki disease (20.5%) and thrombocytopenia (16.8%) were the top three indications. Neurological conditions only accounted for 3%. In brief, unlike countries with high population use, the proportion of reimbursed IVIG used for neurological conditions was low. Further studies on self-paid IVIG use is needed to completely understand utilization in Taiwan.

Pivotal Role of Preexisting Pathogen-Specific Antibodies in the Development of Necrotizing Soft-Tissue Infections.

Necrotizing soft-tissue infections (NSTI) are the most severe form of bacterial-induced tissue pathology. Their unpredictable onset and rapid development into life-threatening conditions considerably complicate patient treatment. Understanding the risk factors for NSTI in individual patients is necessary for selecting the appropriate therapeutic option. We investigated the role of pathogen-specific antibodies in the manifestation of NSTI by performing a comparative serologic approach, using plasma samples and bacterial isolates from patients with clinical NSTIs or nonnecrotizing STIs caused by Streptococcus pyogenes. We also evaluated the potential beneficial effect of intravenous immunoglobulin (IVIG) treatment. We identified a hitherto overlooked state of serologic susceptibility in patients with NSTIs during the earliest stages of the infection that is potentially linked to disease progression. Thus, all patients with NSTIs included in this study exhibited a deficiency in specific antibodies directed against the causative S. pyogenes strains and the majority of their exotoxins during the initial stage of the infection. We also showed that the clinical use of IVIG during the course of infection compensates the observed antibody deficiency but is unable to halt the disease progression, once tissue necrosis has developed. These observations emphasize the requirement of preexisting pathogen-specific antibodies to prevent the irreversible progression of tissue infections into severely spreading NSTIs and urge further investigations on the beneficial effect of IVIG-based early phase intervention strategies to prevent the severe effects of this devastating bacterial infection.

Clinical indications for intravenous immunoglobulin utilization in a tertiary medical center: a 9-year retrospective study.

Intravenous immunoglobulins (IVIG) are a biologic product originally developed to treat immunocompromised patients. In the past decades, there has been increased utilization of IVIG in autoimmune conditions. The objectives were to evaluate the clinical use of IVIG in the largest tertiary medical center in Israel and to determine top uses, estimate off-label usage, and assess consumption of this blood product. We conducted an observational, retrospective study involving all patients who received IVIG from 2007 through 2015. Subjects were classified into five groups according to the indication for treatment. A total of 1117 patients were identified. The mean (±SD) ages of adults and children were 55 ± 17 and 8 ± 7 years, respectively. Most common indication for treatment were immune-mediated conditions (54%), followed by secondary immunodeficiency (28%), primary immunodeficiency (10%), infections (4%), and miscellaneous (4%). The main immune-mediated conditions treated were hematologic disorders (305 patients, 27%), neurologic disorders (219 patients, 20%), and rheumatologic conditions (79 patients, 7%). Overall, a significant change in study period was observed in the number of patients (p < 0.001), consumption of IVIG (p < 0.01), and amount of IVIG administered per patient (p < 0.01). Fifty-six percent of the IVIG infusions were given for off-label Food and Drug Administration (FDA) indications. In this study, we demonstrated that immune-mediated conditions represent the majority of indications for treatment with IVIG. We observed a 417% increase in IVIG administration (g) over time, attributed mainly to autoimmune diseases. Many indications are still off-label according to FDA recommendations.

Commercial Intravenous Immunoglobulin Preparations Contain Functional Neutralizing Antibodies against the Staphylococcus aureus Leukocidin LukAB (LukGH)

The pathogenesis of Staphylococcus aureus is mediated by an array of important virulence factors, including the two-component leukocidin family of toxins. LukAB (also known as LukGH), the most recently discovered leukocidin, is potently lethal to phagocytes, produced during invasive human disease, and present in all known clinical isolates of S. aureus Intravenous immunoglobulin (IVIg) is often used clinically in severe S. aureus infections. The primary aim of this study was to assess the binding and neutralization potential of IVIg against LukAB. A secondary aim was to examine the lot-to-lot variability of IVIg in the binding and neutralization of LukAB. We studied 24 distinct lots of IVIg and compared them to serum from children with invasive S. aureus infection (in the acute and convalescent phases) and from healthy, uninfected controls. We found that all lots of IVIg contained functional antibodies targeting LukAB. After adjusting for total antibody content per sample, we found that the amount of anti-LukAB antibody in IVIg was similar to that seen with healthy controls and less than that seen with patients with invasive S. aureus infection. IVIg samples had lower neutralization capacity than samples from healthy controls and children with invasive infection. IVIg had remarkably little lot-to-lot variation in LukAB binding but had significantly more variation in toxin neutralization. These results represent the first report of functional antibodies against the important S. aureus leukocidin LukAB in IVIg. Given the frequent clinical use of IVIg for severe S. aureus infections, improving our understanding of functional antibody properties exhibited by this therapeutic is essential.

Intravenous immunoglobulin in the treatment of neurologic disorders.

Intravenous immunoglobulins (IVIGs) are often used in the treatment of autoimmune disorders and immunodeficiencies, and it has been estimated that neurologic indications can account for up to 43% of IVIG used in clinical practice. In neurologic clinical practice, IVIG is used for acute therapy of newly diagnosed autoimmune disorders or exacerbations of pre-existing conditions, or as long-term maintenance treatment for chronic disorders. IVIG exerts its effects on humoral and cell-based immunity through multiple pathways, without a single dominant mechanism. Clinical use of IVIG has been supported by guidelines from American Academy of Neurology and European Federation of Neurologic Societies. IVIG is generally recommended for the treatment of Guillain-Barre syndrome and chronic inflammatory demyelinating polyneuropathy in adults, multifocal motor neuropathy and myasthenia gravis, and should be considered as a treatment option for dermatomyositis in adults and Lambert-Eaton myasthenic syndrome. Additional potential indications include stiff person syndrome, multiple sclerosis during pregnancy or while breastfeeding, refractory autoimmune epilepsy, and paraneoplastic disorders. Clinical use of IVIG is mostly safe but few adverse effects may still occur with potentially severe complications, including aseptic meningitis and thromboembolism. In addition to intravenous route (IVIG), subcutaneous immunoglobulins have been used as an alternative treatment option, especially in patients with limited intravenous access. Treatment with IVIG is effective in various autoimmune diseases, but its broader use is constrained by limited supply. This review evaluates the use of immunoglobulins in treatment of neurologic diseases.

Beneficial effect of a multimerized immunoglobulin Fc in an animal model of inflammatory neuropathy (experimental autoimmune neuritis)

Intravenous immunoglobulin (IVIg) is one of the first-line therapies for inflammatory neuropathies. Clinical use of IVIg for these disorders is limited by expense and availability. Here, we investigated a synthetic product alternative to IVIg. The aim of this study was to test the therapeutic efficacy of a novel recombinant polyvalent murine IgG2a Fc compound (stradomer™) in experimental autoimmune neuritis (EAN). Seventy-four Lewis rats were immunized with myelin, randomized into three groups, and were treated with albumin, IVIg, or stradomer at 1% of IVIg dose. Rats were assessed clinically, electrophysiologically, and histologically. The clinical disease severity was evaluated by clinical grading and weight changes. The electrophysiological studies recorded motor conduction velocity (MCV), amplitudes, and latencies of the evoked compound muscle action potential (CMAP) and spinal somatosensory evoked potential. The treatment efficacy of the IVIg and stradomer groups was compared to the albumin (control) group. We demonstrate that stradomer has a similar therapeutic efficacy to human IVIg in EAN. Rats receiving stradomer or IVIg showed significantly lower clinical scores and less prominent weight loss compared with controls. A statistically significant improvement in both MCV and the amplitudes of distal and proximal evoked CMAP was observed in the stradomer and IVIg groups. Finally, treatment with both IVIg and stradomer resulted in statistically less inflammation and demyelinating changes in the sciatic nerve as evidenced by lower histological grade. These results reveal the potential of using fully recombinant multimerized immunoglobulin Fc instead of IVIg for treating inflammatory neuropathies.

Intravenous immunoglobulin treatment recovers the down-regulated levels of Th1 cytokines in the sera and skin of scleroderma patients

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. There is an urgent need to develop new therapeutic approaches against skin fibrosis. Although intravenous immunoglobulin (IVIG) may be one of the promising treatments, the mechanisms by which IVIG improves the fibrosis of SSc remain unknown. To compare the cytokine profile in the sera and skin of SSc patients before and after IVIG administration, and try to clarify the mechanism of the effect of IVIG. Cytokine array revealed that the serum levels of IFN-γ and IL-12, representative Th1 cytokines, were increased by IVIG treatment, but not by placebo. The percentage of IFN-γ- and IL-12-positive cell number/CD4-positive T lymphocyte cell number was also significantly increased by IVIG in SSc skin. Furthermore, mRNA expression of IFN-γ and IL-12 in SSc skin tissue was significantly up-regulated after IVIG treatment. The expression of Th1 cytokine is reported to be decreased in SSc. Our study suggested IVIG recovered the suppressed levels of Th1 cytokines, and that the treatment improves skin fibrosis by correcting the Th1/Th2 balance. In order to facilitate the clinical use of IVIG for SSc, it is necessary to perform a lager study in the future. JSID AbstractsJournal of Dermatological ScienceVol. 69Issue 2Preview Full-Text PDF

Intravenous immunoglobulin treatment recovers the down-regulated levels of Th1 cytokines in the sera and skin of scleroderma patients

BackgroundSystemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of the skin and internal organs. There is an urgent need to develop new therapeutic approaches against skin fibrosis. Although intravenous immunoglobulin (IVIG) may be one of the promising treatments, the mechanisms by which IVIG improves the fibrosis of SSc remain unknown.ObjectivesTo compare the cytokine profile in the sera and skin of SSc patients before and after IVIG administration, and try to clarify the mechanism of the effect of IVIG.MethodsEach three patients received 5-day administration of IVIG, or the same dose of physiologic saline for placebo. Cytokine levels were determined by ELISA array, immunostaining, and real-time PCR.ResultsCytokine array revealed that the serum levels of IFN-γ and IL-12, representative Th1 cytokines, were increased by IVIG treatment, but not by placebo. The percentage of IFN-γ- and IL-12-positive cell number/CD4-positive T lymphocyte cell number was also significantly increased by IVIG in SSc skin. Furthermore, mRNA expression of IFN-γ and IL-12 in SSc skin tissue was significantly up-regulated after IVIG treatment.ConclusionThe expression of Th1 cytokine is reported to be decreased in SSc. Our study suggested IVIG recovered the suppressed levels of Th1 cytokines, and that the treatment improves skin fibrosis by correcting the Th1/Th2 balance. In order to facilitate the clinical use of IVIG for SSc, it is necessary to perform a larger study in the future.

Intravenous immunoglobulins and acquired von Willebrand syndrome

Dear Sir, I read with interest the letter “Are intravenous immunoglobulins really inappropriate in the acquired von Willebrand syndrome?” by Federici et al1. Intravenous immunoglobulin (IVIG) is a fractionated blood product made from pooled human plasma. It was introduced in the late 1970s and rapidly subsumed the use of intramuscular preparations as replacement therapy in primary and secondary immunodeficiencies. It is increasingly important in replacement therapy and as an immunomodulatory agent in autoimmune disease and transplantation. IVIG is the market driver for the plasma industry in the developed world. The literature on this therapeutic agent increases exponentially and the burgeoning interest in therapeutic immunoglobulin is rapidly generating new evidence, both expanding and reducing current therapeutic indications, with varying levels of supportive evidence. In 1998, the effectiveness of IVIG was demonstrated in an open-label crossover study in patients with acquired von Willebrand syndrome associated with monoclonal gammopathy of uncertain significance of the IgG class2. In 2000, an in ternational registry series reported that one-third of the 63 patients treated with high-dose IVIG had a good response1. The currently limited evidence of the probable benefit of IVIG in the very rare bleeding disorder known as autoimmune acquired von Willebrand disease, though mainly coming from case reports and case series and not from large well-designed, prospective, randomised trials, is continuously growing, also thanks to the international registry of the International Society on Thrombosis and Haemostasis. Despite the low level of evidence case reports and case series can provide us with, they are still part of the evidence hierarchy in evidence-based practice and guide an important part of clinical practice. Case series are incorporated in a significant proportion of health technology assessments3. In 2007, the Australian Health Ministers’ Conference issued the “Criteria for the clinical use of intravenous immunoglobulin in Australia” and suggested that the management of autoimmune acquired von Willebrand syndrome includes the treatment of the underlying medical condition and should be undertaken only by or in consultation with haemophilia treatment centres keeping in mind that IVIG constitutes only part of the management of these complex patients4, who also require additional haemostatic support. This very rare and severe bleeding disorder is one of the conditions for which IVIG use is suggested in exceptional circumstances only. These circumstances include the management of bleeding and prior to invasive procedures, except cases associated with IgM paraprotein in which response is unlikely. The use of IVIG is also indicated in cases of failure to respond to chemotherapy/immunosuppressants or when there is insufficient time for chemotherapy/immunosuppressants to be given. In 2011, the guidelines of the United Kingdom Department of Health also recommended that IVIG treatment in this severe bleeding disorder be only undertaken in a comprehensive care centre for haemophilia. In addition, “IVIG is only recommended for patients with acquired von Willebrand syndrome with life- or limb-threatening haemorrhage who have not responded to other treatments, or prior to invasive procedures (grade B recommendation, level IIa evidence)” 5. For the above reasons, although more research is needed, undoubtedly autoimmune acquired von Willebrand syndrome deserves to be included in the rapidly growing list of non-recognised conditions in which IVIG has been utilised with some benefit, as suggested by Federici et al1.

The use of intravenous immunoglobulin for treatment of dermatological conditions in Australia: A review

Intravenous immunoglobulin has been used in the treatment of various dermatological conditions, including toxic epidermal necrolysis, bullous pemphigoid and pemphigus vulgaris. From March 2008, the National Blood Authority has implemented the 'Criteria for the clinical use of intravenous immunoglobulins in Australia'. The new criteria have formalized the eligibility requirements for several dermatological conditions. This may increase access to intravenous immunoglobulin for treatment for these conditions. However, there remain stringent eligibility criteria with which dermatologists need to be acquainted. In some conditions, dermatology review is mandated by these criteria while in other conditions with skin manifestations, referral to other specialists is required. The following article provides a summary of the salient points in relation to the clinical use of intravenous immunoglobulin in dermatology, as well as its production and supply in Australia.

Thromboembolic Complications of Intravenous Immunoglobulin (IVIG) in Hypogammaglobulinemic Patients with Chronic Lymphocytic Leukemia (CLL).

Abstract 4416Infectious complications represent a major cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). The etiology is postulated to be secondary to aberrations in cell-mediated immunity, as well as to therapy-related immunosuppression.Hypogammaglobulinemia, which occurs in virtually all patients with CLL, may beprofound and correlates with disease duration and stage. In 1981 during treatment of two children with hypogammaglobulinemia and coincidental idiopathic thrombocytopenic purpura (ITP), physicians in Switzerland observed a reproducible increase in the platelet count following IVIG treatment. This clinical observation and follow up systemic investigations further intensified the widespread clinical use of IVIG as a potential immune modulatory agent. Intravenous immunoglobulin (IVIG) therapy has been used successfully to prevent and treat infections in this cohort of patients.Today, Intravenous immunoglobulin (IVIG) is used in a broad spectrum of autoimmune, inflammatory, and primary and secondary immunodeficiencies. The efficacy has been demonstrated in several control studies. IVIG is a blood product prepared from the serum of between 1,000 and 15,000 donors per batch. The mechanism of action validated by in-vitro models is exerted by a combined effect on autoantibodies, complement activation, cytokines, and saturation of Fc receptors on tissue macrophages.However IVIG administration and treatment is not benign and should be used with caution given the potential manifestations of thromboembolic complications. High concentration and rapid infusion rate of the IVIG, as well as increased dose and osmolarity of the solution are thought to predispose to thrombotic events. Serum viscosity is the implicated mechanism for compromised blood flow and predisposition of high-risk patients to cardiovascular or cerebrovascular infarction.In this retrospective review, we detail IVIG related thromboembolic manifestations in CLL patients, to highlight the importance of risk stratifying patients prior to treatment administration. The current consensus surrounding IVIG is that of a relatively safe treatment, with minor adverse effects such as hypertension, fever and chills, nausea, myalgias, or headache.However our report highlights the importance of proceeding with caution in the application of this therapy, as it's proclivity for thrombotic complications has not been fully elucidated in patients with underlying malignancies. Pre-existing thrombogenic risk factors should be carefully evaluated in patients undergoing treatment with IVIG. Clinical evaluation, with careful attention to vascular history and underlying co-morbidities can potentially unmask the high-risk patient where IVIG could be lethal. Disclosures:No relevant conflicts of interest to declare.

Clinical applications of intravenous immunoglobulins (IVIg) – beyond immunodeficiencies and neurology

The clinical use of intravenous immunoglobulin (IVIg) has expanded beyond its traditional place in the treatment of patients with primary immunodeficiencies. Due to its multiple anti-inflammatory and immunomodulatory properties, IVIg is used successfully in a wide range of autoimmune and inflammatory conditions. Recognized autoimmune indications include idiopathic thrombocytopenic purpura (ITP), Kawasaki disease, Guillain-Barré syndrome and other autoimmune neuropathies, myasthenia gravis, dermatomyositis and several rare diseases. Several other indications are currently under investigation and require additional studies to establish firmly the benefit of IVIg treatment. Increasing attention is being turned to the use of IVIg in combination with other agents, such as immunosuppressive agents or monoclonal antibodies. For example, recent studies suggest that combination therapy with IVIg and rituximab (an anti-CD20 monoclonal antibody) may be effective for treatment of autoimmune mucocutaneous blistering diseases (AMBDs), with sustained clinical remission. The combination of IVIg and rituximab has also been used in the setting of organ transplantation. Firstly, IVIg +/- rituximab has been administered to highly human leucocyte antigen (HLA)-sensitized patients to reduce anti-HLA antibody levels, thereby allowing transplantation in these patients. Secondly, IVIg in combination with rituximab is effective in the treatment of antibody-mediated rejection following transplantation. Treatment with polyclonal IVIg is a promising adjunctive therapy for severe sepsis and septic shock, but its use remains controversial and further study is needed before it can be recommended routinely. This review covers new developments in these fields and highlights the broad range of potential therapeutic areas in which IVIg may have a clinical impact.

Expansion of CD4+CD25+ regulatory T cells by intravenous immunoglobulin: a critical factor in controlling experimental autoimmune encephalomyelitis

The clinical use of intravenous immunoglobulin (IVIg) based on its immunomodulatory and anti-inflammatory potential remains an ongoing challenge. Fcgamma receptor-mediated effects of IVIg, although well elucidated in certain pathologies, cannot entirely account for its proven benefit in several autoimmune disorders mediated by autoreactive T cells. In this study, we show that prophylactic infusion of IVIg prevents the development of experimental autoimmune encephalomyelitis (EAE), an accepted animal model for multiple sclerosis (MS). The protection was associated with peripheral increase in CD4+CD25+Foxp3+ regulatory T cell (Treg) numbers and function. The protection was Treg-mediated because IVIg failed to protect against EAE in mice that were depleted of the Treg population. Rather than inducing de novo generation from conventional T cells, IVIg had a direct effect on proliferation of natural Treg. In conclusion, our results highlight a novel mechanism of action of IVIg and provide a rationale to test the use of IVIg as an immunomodulatory tool to enhance Treg in early onset MS and other autoimmune and inflammatory conditions.

Antibody therapy (IVIG): evaluation of the use of genomics and proteomics for the study of immunomodulation therapeutics

Intravenous immunoglobulin (IVIG) is used for an increasingly diverse number of therapeutic applications as an immunomodulation drug. Although it has demonstrated therapeutic effectiveness, the mechanism of action of IVIG in these disorders is poorly understood; this lack of understanding complicates rational clinical application and reimbursement for 'off-label' use. Selected literature on the clinical use of IVIG as an immunomodulation drug is reviewed. We present a brief description of DNA microarray and protein microarray technology and the application of such technologies to the study of immune system cells. The several studies on the application of DNA microarray technology to study gene expression in response to IVIG are presented. There is increasing data on the use of DNA microarray and protein microarray technology to study gene expression in immune system cells including T cells, B cells, macrophages, and leucocytes. There is less information on the effect of IVIG on gene expression in immune system cells. However, there is sufficient information available to suggest that this is a practical approach with the caveat that such work will require careful experimental design and clear definition of the normal population. DNA and protein microarray assays can be used to (i) provide rational indications for the clinical use of IVIG, (ii) provide for specific analysis of raw material and end product IVIG in screening for content related to immunomodulation, and (iii) accelerate the development of next generation products which would be more focused and/or targeted therapeutics.

Use of Intravenous Immunoglobulin in Patients With Acquired von Willebrand Syndrome

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder with laboratory findings similar to those for congenital von Willebrand disease. Unlike the congenital form, AVWS usually occurs in individuals with no personal or family history of bleeding disorders. According to an international registry, AVWS is mainly associated with lymphomyeloproliferative, immunologic, and cardiovascular disorders, as well as with solid tumors and other miscellaneous conditions; however, the prevalence of AVWS in these underlying disorders is still unknown. von Willebrand factor (VWF) is synthesized normally in most AVWS patients, and the low plasma VWF levels are from its accelerated removal from plasma by five different mechanisms, including autoantibodies. Because of the reduced half-life of endogenous-exogenous plasma VWF, bleeding of AVWS cannot be managed with desmopressin or factor VIII/VWF concentrates. Clinical use of intravenous immunoglobulin (IVIg) in AVWS has been reported since 1988. IVIg is most effective in AVWS with type immunoglobulin (Ig) G monoclonal gammopathies of undetermined significance and in other cases with IgG autoantibodies. IVIg can correct factor VIII and von Willebrand factor complex activities for about 15–20 days, and repeated injections induce remission of AVWS in these patients. Prospective studies are required to evaluate the efficacy and safety of IVIg in AVWS.

Intravenous Immunoglobulin Therapy in Vasculitis: Speculation or Evidence?

Initially, intravenous immunoglobulins (IVIgs) were used as replacement therapy in primary and secondary antibody-deficiency syndromes. The clinical use of IVIg has been extended during the past decade to a wide variety of clinical conditions, such as infectious processes, neuroimmunological diseases, and different systemic autoimmune diseases. The mode of action of IVIg is complex, involving modulation of the Fc receptors, interference with the complement and cytokine network, and effects on the activation and differentiation of T and B-cells. Kawasaki disease (KD) was one of the first diseases within the group of primary vasculitides in which IVIg were used. Today, there is a clear evidence of benefit for IVIg in the treatment of coronary artery abnormalities related to KD. Subsequently, various reports have suggested a beneficial effect in other vasculitides; however, there are few data from controlled studies. For antineutrophil cytoplasmic antibody-associated vasculitis (AAV) one placebo-controlled and several open-label studies have shown a beneficial effect on the disease activity in patients with Wegener's granulomatosis or microscopic polyangiitis refractory to standard therapy with prednisone and cyclophosphamide. For other vasculitides, such as polyarteritis nodosa or Henoch-Schonlein purpura, only case reports have described an inhibition of a disease progression by IVIg so far. However, the effect was partly only temporary. In conclusion, KD and AAV are the only vasculitides with a definite beneficial use of IVIg. For other vasculitides, the efficacy of IVIg has not been proven properly but may be useful in single cases.

Therapeutic intravenous immunoglobulins

Intravenous immunoglobulins (IVIg) are concentrated formulations of human IgG prepared by industrial fractionation of large pools of individual plasma donations. IVIg were developed 20 years ago for the prophylaxis support of immunodeficient patients. However, IVIg have been increasingly used since 10 years, in the treatment of many autoimmune and inflammatory diseases raising the possibility of product shortages and ever increasing costs in the near future. Surprisingly, the immunomodulatory mechanisms of action of IVIg are unclear because of the diversity and often contradictory Fc, F(ab′) 2, and non-IgG-related mechanisms that have been proposed from clinical observations and from results obtained in various in vitro and in vivo experimental models. These concepts are reviewed here and we discuss in more details three areas of active research, namely the mechanisms of IVIg action in Idiopathic Thrombocytopenic Purpura (ITP), the effects of IVIg on activated B lymphocytes and the possible involvement of autoantibodies of IgG isotype (auto-IgG) in the immunomodulatory effects of IVIg. The elucidation of the mechanisms of action of IVIg is crucial for a more rationalized clinical use of IVIg and for developing substitutes for some of the immunomodulatory indications in order to ensure long-term availability of plasma-derived IVIg for immunodeficient patients.

Intravenous immunoglobulin therapy of antiphospholipid syndrome.

To review the role of intravenous immunoglobulin (IVIg) in antiphospholipid syndrome (APS). A literature search was carried out for the immunopathogenesis of APS, laboratory evidence for the beneficial effect of IVIg in APS, and the clinical use of IVIg in APS. There is both laboratory and clinical evidence for the beneficial role of IVIg in APS. IVIg succeeded in in vitro inhibition of anticardiolipin antibodies and lupus anticoagulant, and in the amelioration of experimental APS. Although there are few case reports about IVIg therapy in the haematological manifestations of APS, most of the reports focus on the use of IVIg in the obstetric complications of APS. Hence, in several patient series the use of IVIg either solely or in combination with aspirin/heparin resulted in successful pregnancy outcome in the vast majority of APS patients with recurrent abortions. In addition, IVIg was also beneficial in antiphospholipid antibody-positive patients undergoing in vitro fertilization. APS, an autoimmune disease whose main features are vascular thrombosis and pregnancy morbidity, is a good candidate for immunotherapy with IVIg that contains anti-idiotypes directed towards patients' pathogenic antiphospholipid antibodies. Future research should determine when to use anticoagulation, IVIg or both in the treatment of APS.

Intravenous immunoglobulin therapy of autoimmune and systemic inflammatory diseases.

The proven beneficial effect of intravenous immunoglobulins (IVIg) in certain autoimmune disorders has led to the development of clinical trials in other autoimmune and systemic inflammatory diseases. In parallel, experimental studies are being carried out to better understand the mechanisms of action of IVIg. In this review, we discuss the clinical use of IVIg in autoimmune disorder and the possible mechanisms by which IVIg may be effective in the various diseases. A better understanding of the mechanisms of action of IVIg in autoimmune disease will allow optimization of their use as a therapeutic alternative to conventional immunosuppression.