Ubat intravenous immunoglobulin (IVIg) untuk 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.

Keywords: autoimmunity, immunoglobulin, vasculitis, sepsis, transplantation

Introduction

Intravenous immunoglobulins (IVIgs) are therapeutic preparations of pooled polyspecific IgG obtained from the plasma of a large number of healthy individuals. These preparations were commercialized in the early 1980s to replace intramuscular preparations of polyspecific IgG, which were the only available substitutive therapy at that time for patients with primary or secondary immunodeficiencies. For patients with primary immunodeficiencies, IVIg (or subcutaneous immunoglobulin – SCIg) remains the treatment option of choice.

In 1981, Imbach and colleagues reported that, in patients with Wiskott–Aldrich syndrome who presented with thrombocytopenia and hypogammaglobulinaemia, high-dose IVIg infusion was followed by an increase in the platelet count [

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Since then, IVIg has been demonstrated to be effective in idiopathic thrombocytopenic purpura (ITP) and a large number of autoimmune and/or systemic inflammatory diseases, notably Kawasaki disease, and in immune-mediated neurological disorders such as Guillain–Barré syndrome (GBS), chronic idiopathic demyelinating polyneuropathy (CIDP), multi-focal neuropathy with conduction block (MNCB) and acute myasthenia gravis [

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For other diseases, IVIg is not always used as a first-line therapy. It may be administered as a steroid-sparing agent and in certain conditions may represent an alternative to other available therapeutic approaches, such as immunosuppressants, plasma exchange or monoclonal antibodies. IVIg is also often employed to treat diseases that are refractory to other treatments or where conventional therapies result in unacceptable side effects. Combination therapy of IVIg with immunosuppressants has been applied successfully in several conditions, including autoimmune vasculitis, dermato- and polymyositis, transplantation and sepsis [

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When considering the emerging uses of IVIg, it is important to consider the evidence base. In some patient populations the therapeutic value of IVIg has been proven in large controlled trials, while in other patient populations only small, uncontrolled studies or case reports are available, often due to the small numbers of patients with these rare diseases.

IVIg for the treatment of autoimmune and inflammatory disorders

Despite the large number of autoimmune diseases being treated with IVIg, guidance on the clinical usage is limited to only three conditions: ITP, GBS and Kawasaki disease. Because of the costs, finite supply and time for the patient receiving IVIg therapy, there is a need to rationalize and prioritize the disorders for which, based on currently available evidence, IVIg is adopted. In France, the Comité d'Evaluation et de Diffusion des Innovations Technologiques (CEDIT) IVIg expert group, chaired by Professor Loïc Guillevin, aims to identify scientifically validated uses and issue recommendations regarding the usage of IVIg [

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 Guidelines for the use of immunoglobulin have also been developed in the United Kingdom [

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 Canada [

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Australia [

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and elsewhere.

Indications have been divided into those patients for whom the benefit of IVIg treatment is recognized, those under evaluation and those where benefit is not documented. Recognized indications include ITP, Kawasaki disease, myasthenia gravis, dermatomyositis (DM), as well as autoimmune neuropathies such as GBS, chronic inflammatory demyelinating polyradiculoneuropathy, multi-focal motor neuropathy (MMN) and stiff person syndrome. IVIg efficacy is also recognized in rare diseases, such as parvovirus B19 infection, autoimmune erythroblastopenia and neutropenia, acquired hypocoagulability and birdshot retinochoroidopathy; however, no prospective randomized studies in these indications exist, due mainly to the rarity of these conditions.

Indications that are currently under evaluation by CEDIT include inclusion body myositis (IBM), demyelinating central nervous system diseases (but not multiple sclerosis or Devic syndrome), corticoresistant polymyositis, autoimmune encephalitis and refractory epilepsy. The efficacy of IVIg in the treatment of select populations of transplant patients, haemolytic anaemia, adult-onset Still's disease, anti-phospholipid syndrome, anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitides and pemphigus vulgaris is also under evaluation.

IVIg for the treatment of autoimmune vasculitides

Systemic vasculitides are classified based on the diameter of the vessels involved. Large vessel involvement is found in giant cell arteritis and Takayasu's arteritis, while medium vessels are affected in diseases such as polyarteritis nodosa and Kawasaki disease. Small vessels are involved in necrotizing glomerulonephritis and ANCA-associated systemic vasculitides.

Kawasaki disease is characterized by a systemic inflammation of the blood vessels and affects predominantly children under the age of 5 years [

The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version. It is one of the first vasculitides reported to be treated with IVIg, with or without acetyl salicylic acid (aspirin) [

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 Since then, IVIg in combination with aspirin has become the standard of care for patients with Kawasaki disease [

The following popper user interface control may not be accessible. Tab to the next button to revert the control to an accessible version. A meta-analysis of 16 prospective randomized trials was conducted in 2003, showing that there is a significant decrease in new coronary abnormalities at day 30 in patients treated with IVIg compared with placebo and demonstrated that infusion of a single dose of 2 g/kg body weight induces a significant reduction in coronary aneurysms at day 30

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. The analysis concluded that children fulfilling the diagnostic criteria for Kawasaki disease should be treated with 2 g/kg of IVIg within 10 days of the first symptoms in order to gain the maximum benefit [

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Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg–Strauss syndrome (CSS) are small-sized vessel vasculitides that are associated frequently with anti-neutrophil cytoplasmic autoantibodies [

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ANCA-associated vasculitides are characterized by vascular necrosis either in the glomerular visceral epithelial cells or in other visceral tissues. Renal and lung involvement is often observed. The major target of anti-neutrophil antibodies in WG is proteinase 3, whereas in MPA and CSS the antibodies target myeloperoxidase (MPO). Treatment of ANCA-associated vasculitides is initiated commonly with induction therapy of corticosteroids, cyclophosphamide and sometimes plasma exchanges. Maintenance therapy usually involves azathioprine, methotrexate or mycophenolate mofetil (MMF). Relapses of ANCA-associated vasculitides are often treated with immunosuppressants, such as cyclophosphamide or methotrexate or with biologicals such as IVIg, anti-TNF or anti-CD20 therapy. Plasma exchanges can also be used in this setting.

Several small prospective clinical studies of IVIg treatment of ANCA-associated vasculitides have been conducted The first open prospective study of seven patients with WG, MPA or rheumatoid vasculitis was performed in 1991 and showed promising results, with six patients in complete remission and one with transient response to IVIg therapy (total dose 2 g/kg) [

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This study was followed by an extensive report on 26 patients, showing that 8 weeks after IVIg treatment 13 patients were in full and 13 in partial remission [

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. The clinical benefit was maintained in 18 patients for up to 1 year after IVIg therapy. Conflicting results were obtained in another study of 15 patients with ANCA-associated vasculitis who responded poorly to conventional therapy. These patients were treated with single or multiple courses of IVIg, to a total dose of 30 g/day over 5 days [

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 Six of 15 patients experienced significant clinical benefit; however, no patient experienced complete remission. Another study with patients resistant to conventional treatment similarly showed that IVIg treatment was effective in six of 10 patients [

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Only one randomized, placebo-controlled trial of IVIg in ANCA-associated vasculitis has been conducted to date. The study investigated the efficacy of a single course of IVIg (total dose 2 g/kg) in previously treated patients with persistent disease. At the 3-month time-point (primary end-point), 14 of 17 patients showed improvement in response to IVIg treatment, compared with six of 17 in the placebo group (P = 0·035). However, this was a short trial of only 3 months, so there is still need for additional data in this setting [

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Clinical studies of the use of intravenous immunoglobulin (IVIg) for the treatment of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis.

A recent open, prospective non-randomized study evaluated the efficacy and safety of IVIg administered for 6 months for the treatment of relapses of WG, MPA or CSS that occurred during or within 1 year following the withdrawal of corticosteroids and/or immunosuppressants [

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. The study evaluated 22 patients (21 with ANCA-specific antibodies). Twenty-one patients experienced partial initial responses and, at 9 months, 13 patients experienced complete remission. At 24 months, eight patients were in complete remission in the absence of any other treatment, while another 10 were in remission with the help of treatment modification.

Although studies in a number of ANCA-associated vasculitides have shown some benefit of IVIg treatment, proven efficacy is observed in only a handful of conditions. For example, the benefits of IVIg in the treatment of Kawasaki disease are well documented, and the data suggest that children meeting the diagnostic criteria for this disease must be treated within 10 days of the onset of symptoms. IVIg may also represent an option in patients with relapsing ANCA-associated vasculitides, but additional randomized controlled trials are needed in this field.

Combination therapy with IVIg in autoimmune mucocutaneous blistering diseases

Autoimmune mucocutaneous blistering diseases (AMBDs) are rare but potentially fatal diseases. Since the introduction of corticosteroids, the annual mortality rate due to blistering diseases has fallen; nonetheless patients suffering from these conditions continue to experience high morbidity and mortality.

There are currently two approaches to the pharmacological management of AMBDs. One approach targets the production of the autoantibody in the bone marrow, spleen and lymph nodes, and involves the use of immunosuppressive drugs such as azathioprine, MMF, cyclophosphamide and methotrexate. The other approach targets the sites at which the autoantibodies exert their effects, namely in the skin or mucosal surfaces. This approach uses anti-inflammatory drugs, such as prednisone and dapsone, to ameliorate the effects of the autoantibodies [

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].

Conventional immunosuppressive therapy for the treatment of AMBDs involves high-dose corticosteroids (80–240 mg/day) for prolonged periods of time. However, this therapy is not always effective and usually results in a poor quality of life. Conventional immunosuppression has a variety of reversible and non-reversible side effects, including prolonged vulnerability to infection and increased risk of cancer. Indeed, the side effects of such therapies are often the ultimate cause of death in these patients.

IVIg is usually employed when conventional therapy fails, causes side effects or is contraindicated. Beneficial clinical effects of IVIg have been demonstrated in the treatment of a number of AMBDs, including pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid and epidermolysis bullosa aquisita (EBA). A ‘Consensus Statement’ on the use of IVIg in these diseases recommends a dose of 2 g/kg/cycle, given monthly until clinical control, with a progressive increase of the intervals between the cycles thereafter to 6, 8, 10, 12 and 14 weeks [

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. The last cycle is given after a 16-week interval, and is considered as the end of therapy.

In a recent study, 156 patients with AMBD treated with IVIg using this protocol demonstrated successful clinical outcomes [

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. In these patients IVIg could be used as monotherapy, once concomitant prednisone and immunosuppressive agents were gradually discontinued. These included 42 patients with pemphigus vulgaris, 26 with pemphigus foliaceus, 32 with bullous pemphigoid, 68 with mucous membrane (cicatricial) pemphigoid and nine with epidermolysis bullosa acquisita. IVIg produced long-term, sustained remission for at least 2 years of follow-up, after discontinuing IVIg therapy. The patients were in serological remission and enjoyed a high quality of life. It could be speculated that, compared to previous therapies, IVIg changed the clinical course of these diseases [

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As a therapeutic option, the costs associated with IVIg use are often perceived to be high. However, when the true costs of conventional therapy are calculated, including the costs of the treatment of side effects and hospitalizations, they are approximately two- to threefold higher than the costs of IVIg therapy. According to one US analysis, the true cost of conventional therapy for pemphigus vulgaris was $US 123 133 per patient per year, while the mean annual cost of IVIg was $US 76 249 [

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A large study analysed 275 patients who had been treated according to the Consensus Statement protocol and who remained in clinical remission for a minimum of 2 years after discontinuing IVIg (unpublished data). About 70% of the patients responded to IVIg monotherapy and were considered high responders. The remaining 30% were partial responders or non-responders. Partial responders, in whom the dose of prednisone and immunosuppressive agent was reduced by 50% or less, were subclassified as mild (clinical response of 50% or less) or moderate (clinical response between 50% and 100%) responders. Moderate responders were treated subsequently with 50–150 mg dapsone daily. Clinical improvement was achieved in less than 4 months (mean 3·8, range 2·1–7·5). Mild responders were treated with oral methotrexate (5–20 mg/weekly) and dapsone (50–150 mg daily). These patients responded to therapy within 6 months (mean 5·7, range 4–8·6). Thereafter, the clinical response of each group of patients was the same as that observed in the high responder group. Non-responders were patients whose disease, in spite of adjunctive therapy, flared if the interval between cycles was increased by more than 4 weeks, or who continued to have active disease after 1 year of IVIg therapy. These patients were treated with rituximab and IVIg, and all showed clinical improvement.

It has been demonstrated previously that the combination of IVIg and rituximab is effective in patients with refractory pemphigus vulgaris who had inadequate responses to conventional therapy and IVIg. Patients were treated with two cycles of rituximab (375 mg/m² of body-surface area) once weekly for 3 weeks and IVIg (2 g/kg) in the fourth week, followed by a monthly infusion of rituximab and IVIg for 4 months [

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In this study, nine of 11 patients showed rapid resolution of lesions and a clinical remission lasting 22–37 months (mean 31·1 months). All immunosuppressive therapy, including prednisone, could be discontinued. Two patients were treated with rituximab only during recurrences and had sustained remission. None of the patients in this study had serious side effects, although the long-term consequences of rituximab and IVIg combination therapy in such patients with autoimmune diseases are unknown and need to be investigated.