Mechanisms of Action of Intravenous Immunoglobulin in Inflammatory Muscle Disease

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1 DOI /s Mechanisms of Action of Intravenous Immunoglobulin in Inflammatory Muscle Disease Adam Quick & Rup Tandan # Springer Science+Business Media, LLC 2011 Abstract Intravenous immunoglobulin (IVIG) is a unique immune-modulating therapy that has a wide range of effects on the immune system at multiple levels. This allows it to be used successfully in a variety of immune-mediated, systemic, and neurological disorders, including the inflammatory myopathies. It is likely that the specific action of IVIG varies depending on the underlying pathogenesis of a given disease. In dermatomyositis (DM), IVIG has been shown to diminish the activity of complement and deposition of membrane attack complex on capillaries and muscle fibers, the expression of adhesion molecules, and cytokine production. IVIG also appears to modify gene expression in the muscle of DM patients. The mechanism by which IVIG affects muscle in polymyositis and inclusion body myositis has not been wellstudied. However, it may work via suppression of T-cell activation (including cytotoxic T cells) and migration into muscle tissue and alterations in cytokine production. IVIG generally yields the greatest therapeutic benefit in DM and is often of marginal utility in inclusion body myositis. It is generally considered as second-line or adjunctive therapy in the inflammatory myopathies. Keywords Dermatomyositis. IVIG. Intravenous immunoglobulin. Inflammatory myopathy. IBM. Inclusion body myositis. Polymyositis. Mechanism of action A. Quick Ohio State University School of Medicine, Columbus, OH, USA adam.quick@osumc.edu R. Tandan (*) University of Vermont College of Medicine, 89 Beaumont Avenue, Given C225 A, Burlington, VT 05405, USA rup.tandan@uvm.edu Introduction Intravenous immunoglobulin (IVIG) has been used for many years as treatment for an ever-increasing number of diseases that have a known or suspected autoimmune pathogenesis. The immunomodulatory effects of IVIG were first proposed following the successful treatment of patients with idiopathic thrombocytopenic purpura [1, 2]. Since these initial reports, IVIG has been studied in other immune-mediated diseases, beginning initially with multiple sclerosis and myasthenia gravis [3, 4]. In neuromuscular disease, there is class I evidence from controlled clinical trials to support the use of IVIG in Guillain-Barré syndrome, chronic inflammatory polyneuropathy, multifocal motor neuropathy, refractory exacerbations of myasthenia gravis, Lambert-Eaton syndrome, dermatomyositis (DM), and stiff person syndrome [5 ]. Although the exact mechanism of action is unknown, there is clear evidence that IVIG exerts diverse effects on the immune system. Thus, IVIG treatment is often attempted in other putative autoimmune disorders due to its relatively benign side effect profile and the frequent lack of other definitive treatment options. The focus of this review is on the use of IVIG in inflammatory muscle diseases with regard to proposed mechanisms of action and effects demonstrated in clinical studies. Composition of Intravenous Immunoglobulin and General Mechanisms of Action IVIG is produced from pooled plasma of thousands of individual blood donors. The primary component is the IgG molecule, which consists of two heavy chains and two light chains. Each chain contains a variable domain and one or

2 more constant domains. The entire IgG molecule can be divided into two important subunits: the antigen-binding fragment and the constant fragment. The antigen-binding region (Fab) is highly dependent on the variable domains. The portion of the molecule that confers its unique character related to this antigen-binding specificity is referred to as the idiotype. The constant fragment (Fc) defines the isotype and subclass of the immunoglobulin. The Fc region has important functions in mediating the activity of IgG and other immunoglobulins by binding to the Fc receptor (FcR) on immune cell membranes. It is also important in several other functions, such as complement activation [6]. In addition to IgG, most IVIG preparations contain small amounts of IgA, IgM, soluble CD4, CD8, and HLA molecules, along with cytokines [7]. Normal human serum contains many natural autoantibodies generated independently of exposure to foreign antigen and reactive with normal human proteins. Unlike the antibodies produced against foreign antigens, natural autoantibodies are more polyreactive and can bind to multiple different antigens. They may also recognize and bind to other autoantibodies. Thus, IVIG contains large amounts of immune globulin capable of interacting with foreign antigens, self-antigens (natural autoantibodies), and with idiotypes of other antibodies in the preparation [7]. Consequently, a substantial amount of IVIG is composed of IgG dimers due to idiotype anti-idiotype complex formation between IgG molecules from different individuals. This differs from normal human serum, in which IgG molecules exist predominantly as monomers [8]. The presence of these IgG dimers and multimers in IVIG has important consequences, one of which is reduction of T-cell priming by dendritic cells. It has been demonstrated that dendritic cells treated with IVIG have IgG bound to their surface. These cells are then recognized by natural killer cells, which destroy them via antibody-dependent cellular cytotoxicity, a process that only occurs in the setting of IgG multimers and dimers. This reduces the pool of immunogenic antigen-presenting cells moving from inflamed tissues into lymph nodes. In addition to reduced T-cell priming by dendritic cell destruction, IVIG also inhibits the maturation of dendritic cells. It suppresses upregulation of co-stimulatory molecules and reduces the capacity of dendritic cells to secrete interleukin-12, which is important in activation and proliferation of T cells, including cytotoxic T cells [9, 10]. The presence of anti-idiotype antibodies in IVIG also likely accounts for some of its beneficial effects in antibody-mediated autoimmune disease. In fact, Fab fragments in IVIG have been shown to directly bind with and inhibit pathogenic autoantibodies [11]. Anti-idiotype antibodies also inhibit growth of autoreactive B-cell clones, help maintain self-tolerance, inhibit differentiation of B cells, and downregulate autoantibody production [7, 12, 13]. In addition, the presence of anti-fas molecules in IVIG preparations induces apoptotic cell death of human T- and B-lymphocyte and monocyte lines [14]. In addition to its potent effects on autoantibodies and T- cell priming, IVIG has significant anti-inflammatory activity. One of the most important aspects of this is preventing the generation of the membrane attack complex (MAC) and the subsequent complement-mediated tissue damage. IVIG has been shown to bind activated components of the complement cascade and to limit MAC deposition [15]. It prevents tissue damage mediated by immune complexes containing C3b by accelerating its decay into inactive form [7]. Furthermore, IVIG decreases inflammation by reducing proinflammatory cytokine production and increasing levels of inflammatory cytokine antagonists [16]. IVIG also helps restore balance between T-helper type 1 and T-helper type 2 cells [7]. IVIG has significant action in reducing migration of inflammatory cells into tissue by decreasing expression of adhesion molecules such as intercellular adhesion molecule 1 (ICAM-1) on vascular endothelial and immune cells. It promotes tissue repair by modulating levels of matrix metalloproteinases (MMPs) proteolytic enzymes that are involved in degrading and remodeling the extracellular matrix and their tissue inhibitors. This has significant effects in limiting the invasion of inflammatory cells into tissue and may help limit T-cell mediated cytotoxicity [17 19]. IVIG yields several significant effects via the Fc portion of the molecule. One of these effects, noted previously, is the antibody-dependent cellular cytotoxicity of dendritic cells by natural killer cells. Beyond this, IVIG appears to upregulate expression of a specific class of inhibitory FcR (FcγRIIB), which reduces phagocytosis by macrophages and leads to inhibition of antigen-induced blastogenesis and proliferation of B cells exposed to antigen complexed with IgG [20, 21]. In addition to working via the upregulation of FcγRIIB, there is evidence that monomeric IgG in IVIG preparations can block the interaction of immune complexes with activating FcRs, thereby inhibiting endocytosis and phagocytosis by dendritic cells and macrophages [22 ]. Mechanisms of Action of Intravenous Immunoglobulin in Specific Muscle Diseases It is evident that IVIG has broad and diverse activity on both the adaptive and innate immune system. However, despite the progress that has been made in understanding the effects of IVIG on specific components of the immune system, it remains unclear how or if these multiple effects work in concert with one another. It is also likely that

3 certain mechanisms of action have yet to be elucidated. Lack of complete knowledge in the pathogenesis of many muscle diseases also inhibits understanding with regard to how IVIG works in these disorders. Nevertheless, some mechanisms have been reasonably well-studied in vivo or in vitro. Others remain primarily speculative and hypothetical. It is probable that a predominant mechanism exists for each disorder, and other effects of IVIG support this primary action. Dermatomyositis The best studied of the inflammatory myopathies with regard to the specific effects of IVIG is DM. This disease has historically been viewed as an endomysial microangiopathy mediated by complement and deposition of MAC on intramuscular capillaries. This was thought to produce the characteristic loss of capillaries and subsequent muscle fiber necrosis and perifascicular atrophy seen histologically via an array of immunologic mechanisms. In addition, cytokines and chemokines related to the activation of complement lead to upregulation of adhesion molecules such as ICAM-1 and vascular cell adhesion molecule 1, facilitating the entry of inflammatory cells into the perimysial and endomysial spaces [23]. In a doubleblind, placebo-controlled trial of IVIG in this disease [17], five individuals who had demonstrated significant improvement underwent repeat muscle biopsies following treatment. These patients demonstrated marked improvement in histologic muscle findings, including increased mean muscle fiber diameter, reduced endomysial inflammatory infiltrates, and increased number of capillaries per muscle fiber. Immunopathological staining has demonstrated reduction of ICAM-1 expression on endothelial cells of capillaries and on lymphocytes in the inflammatory infiltrates. Deposition of MAC, which was prominent on capillaries and several muscle fibers, became undetectable. The expression of major histocompatibility complex I antigen on muscle fibers was also significantly reduced. Subsequent studies using a C3 uptake assay clearly demonstrated reduced C3 uptake from patient serum samples following treatment with IVIG as compared with pretreatment levels [15]. IVIG was shown to abrogate the deposition of C3b in immune complexes necessary for subsequent formation of MAC. The mechanism was believed to be the formation of complexes between acceptor sites within the IgG molecules and C3b [15]. In addition to these effects, IVIG has been shown to suppress the upregulated expression of the cytokine transforming growth factor-β1 in the muscles of DM patients. This cytokine has multiple functions, including an important role in reorganization of the extracellular matrix. It may have proinflammatory activity when expressed in excess and is associated with endomysial fibrosis. Thus, it is has been speculated to play a role in promoting the chronicity of the inflammatory response in DM [24]. IVIG also demonstrates significant effects on gene expression in DM [25]. There is altered regulation of multiple cytokine and chemokine genes. In particular, suppression of the CCL18 gene, which regulates one of the most abundant chemokines produced by immature dendritic cells, supports a role for these cells in the pathogenesis of the disease. This is important in light of the capacity of IVIG to induce antibody-dependent cellular cytotoxicity of dendritic cells, as previously noted. Several genes associated with cell adhesion, including KAL-1 and ICAM-I, are also downregulated, as is the complementrelated gene C1q; these observations are consistent with the known effects of IVIG on muscle histology following treatment. There is also downregulation of multiple genes involved in muscle architecture and stabilization of the muscle membrane [25]. More recently, the theorized pathogenesis of DM as a primary complement-mediated microangiopathy has been questioned. Gene microarray studies of muscle tissue have demonstrated a high proportion of differentially expressed gene transcripts inducedbytype1interferons. Plasmacytoid dendritic cells, which have a high capacity for interferon production, have been found abundantly in the muscle tissue of patients with DM. It has been suggested that endothelial and myofiber injury in DM may be caused by chronic intracellular overproduction of these interferon-inducible proteins [26]. The relevance of these newly proposed pathophysiologic mechanisms to the therapeutic benefit of IVIG in DM has not yet been studied. However, the significant effects IVIG has on dendritic cell maturation and function may well play a significant role. Inclusion Body Myositis and Polymyositis Similar to DM, the pathogenesis of inclusion body myositis (IBM) and polymyositis (PM) is not fully understood. Immunopathologically, the muscle tissue in these two disorders is characterized by infiltration of T cells, which may be clonally restricted, suggesting that an antigenmediated response is possible. CD8 + cytotoxic T cells and macrophages are found invading non-necrotic muscle fibers, which have ubiquitously expressed major histocompatibility complex I antigen, leading to muscle fiber destruction. Overexpression of MMP-2 and MMP-9 has been demonstrated on non-necrotic muscle fibers, and it has been shown that MMP-9 is produced by cytotoxic T cells. These findings implicate MMP in the facilitation of lymphocyte migration and T-cell mediated cytotoxicity. In addition, muscle in IBM and PM contains infiltrates of B

4 cells, myeloid dendritic cells, and plasma cells; much of this inflammatory activity is generated by the production of proinflammatory cytokines and chemokines within the muscle in these disorders [23, 27]. A clearer understanding of the pathogenesis of IBM is further complicated by the fact that abnormal accumulation of amyloid-related molecules occurs within the characteristic rimmed vacuoles of IBM muscle. These include amyloid precursor protein, amyloid β-42, phosphorylated tau, presenilin-1, apolipoprotein E, γ-tubulin, clusterin, α-synuclein, gelsolin, and the nuclear-related proteins TAR DNA-binding protein 43 and valosincontaining protein. It is presently unknown whether these findings represent the effects of chronic inflammation or a primary degenerative myopathy with a secondary inflammatory response [28 ]. Based on the known effects of IVIG on the function of T cells (including cytotoxic T cells), B cells, and dendritic cells, and on cytokine production, Fc receptors, and MMP, there is a good theoretical rationale to consider its potential effect in the treatment of IBM and PM. As discussed in the following section, although controlled trials are lacking in PM, there does appear to be benefit from use of IVIG based on uncontrolled studies and case series [29, 30]. These reports have neither examined muscle biopsy findings pre- and posttreatment with IVIG nor performed immunopathological analysis or gene expression studies in a manner similar to that in DM. Thus, the mechanism of action of IVIG in PM remains speculative. Unfortunately, in IBM, a beneficial effect of IVIG treatment has not been consistently seen in clinical studies, for unclear reasons. Individual patients do occasionally demonstrate significant improvement, which is often restricted to specific muscle groups, particularly the muscles involved in swallowing [31 33]. Studies of the evaluation of muscle histology and the immune-modulating effects of IVIG are more limited in IBM as compared with DM. In one controlled study, the amount of inflammation and amyloid deposition within vacuolated muscle fibers in biopsies from patients who responded objectively to IVIG was not different compared with patients who showed no improvement [31]. In another study comparing the effects of a combination of IVIG and prednisone with that of placebo plus prednisone, muscle biopsies following treatment did show significant reduction in the number of necrotic muscle fibers and foci of endomysial inflammation as compared with pretreatment in the group that received IVIG; however, this did not translate into clinical improvement in strength. Additionally, no changes were observed in muscle cytoarchitecture, and the level of transforming growth factor-β1 was unaffected, which is in contrast to what has been demonstrated in post-treatment biopsies in DM patients [24, 34]. Studies of Intravenous Immunoglobulin Treatment in the Inflammatory Myopathies Dermatomyositis One class I (double-blind, randomized, crossover) trial has been published in which high-dose IVIG was shown to be effective in treating steroid-resistant DM [17]. Several class IV studies have confirmed the effectiveness of IVIG as adjunctive therapy to steroids in treating DM [30, 35 39]. However, the results from at least one study imply that IVIG may not be effective as monotherapy for PM or DM [40]. As dermatomyositis tends to be steroid responsive, IVIG therapy is generally recommended as add-on treatment in refractory cases. Although there are no controlled studies of IVIG treatment in juvenile DM, some case series [41, 42] and a retrospective analysis of experience in a small number of patients with steroid-refractory disease [43] have reported benefit or a steroid-sparing effect of IVIG. Polymyositis No double-blind, controlled studies of IVIG have been reported in PM, perhaps because of the difficulty of acquiring a sufficient number of suitable individuals with biopsy-proven disease. Two uncontrolled studies have yielded conflicting results. In a small study, Cherin et al. [44] treated five PM patients with IVIG, none of whom showed improvement in strength. An open-label study of 35 patients with PM refractory to immunosuppressive medications administered early in disease by the same authors reported benefit in more than 70% of patients [29]. In yet another study published by these researchers, significant improvement was recorded in 10 of 14 patients with PM after IVIG infusions [30]. Among those responding to IVIG, the doses of corticosteroids could be reduced in 9 of 14 patients, and the serum creatine kinase levels dropped in all patients who initially had elevated levels [30]. Thus, IVIG appears to be more effective as an adjuvant treatment than as first-line therapy in PM patients [40]. At present, no definitive guidelines are available regarding initial dose, total days of administration, and timing or dosing of subsequent administration of IVIG for DM or PM. Several studies have administered IVIG at a dose of 2 g/kg body weight over a 5-day period as the initial course, followed by monthly booster doses over 1 to 3 days for a period of 3 to 6 months. Dalakas [45] believes that improvement tends to occur by the end of the first or second IVIG course, and if no improvement is seen by the end of the second infusion, additional IVIG is unlikely to be effective. In some patients, sustained improvement may be achieved using lower maintenance doses [46]; other

5 patients may require IVIG infusions every 2 to 3 weeks to maintain function. Inclusion Body Myositis Clinical response to any therapeutic modality in IBM is marginal at best. Three randomized, double-blind, controlled studies have been conducted to address the efficacy of IVIG in IBM (class I) [31, 34, 47]. Dalakas et al. [31] performed a placebo-controlled, crossover study in 19 patients and showed mild improvement in swallowing and leg strength in about one third of the cases; nevertheless, no statistically significant improvement was noted in overall muscle strength. Walter et al. [47] undertook a placebocontrolled study in 22 IBM patients. They found variable improvement in muscle strength, with stabilization of the disorder in about 90% of patients and mild improvement in others. Dalakas et al. [34] performed a 3-month study of IVIG combined with prednisone versus prednisone alone in 36 patients. They found no significant clinical improvement in strength in the IVIG and prednisone combined group, although muscle biopsies obtained before and after therapy showed a reduction in endomysial inflammation and in the number of necrotic muscle fibers. Recommendations for Treatment of Inflammatory Myopathies with Intravenous Immunoglobulin Dermatomyositis The European Scientific Task Force has the following recommendations for IVIG use in DM: as second-line treatment in combination with prednisone in patients not showing an adequate response to steroids (level B), and as treatment to lower steroid dose in combination with immunosuppressive medications (level C). Treatment with IVIG is not recommended as monotherapy (good practice point) [48 ]. Polymyositis The European Scientific Task Force recommends that IVIG may be considered among treatment options in PM patients who are unresponsive to first-line immunosuppressive therapies (level C) [48 ]. Inclusion Body Myositis On the basis of the results from the three small randomized trials, the European Scientific Task Force does not recommend IVIG for the treatment of sporadic IBM (level A) [48 ]. However, because some studies suggest a mild to moderate improvement in swallowing and leg strength after IVIG administration, treatment may be advised in patients with rapidly progressive disease for a defined time period, and continued if impressive improvement ensues. Some investigators suggest a 3-month treatment series with high-dose (2 g/kg) monthly IVIG infusions in an attempt to identify responders [49]. Others report improvement from low doses of IVIG infusions (0.3 g/kg per day) given on 2 consecutive days per month [50]. Conclusions IVIG is a unique therapy that has been shown to be effective in a broad spectrum of immune- mediated diseases. It modulates the immune system via multiple putative mechanisms to yield a therapeutic effect; however, the specific effect in particular disease states remains incompletely understood. Several actions of IVIG likely work in concert to provide benefit in individual disorders. In the inflammatory muscle diseases, there is sound theoretical rationale for the use of IVIG treatment. Evidence from the literature of benefit from IVIG treatment is greatest in DM and PM, typically as second-line or addon therapy to other immune-modulating medications, such as steroids. Effects appear to be limited in IBM, in which its use remains controversial. Disclosure Dr. Tandan has served as a consultant for Crescent Healthcare and RxSolutions. Dr. Quick reported no potential conflict of interest relevant to this article. References Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance 1. Imbach P, Barandun S, d Apuzzo V, et al. High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet. 1981;1: Bussel JB, Kimberly RP, Inman RD, et al. Intravenous gammaglobulin treatment of chronic idiopathic thrombocytopenic purpura. Blood. 1983;62: Schuller E, Govaerts A. First results of immunotherapy with immunoglobulin G in multiple sclerosis patients. Eur Neurol. 1983;22: Gajdos P, Outin H, Elkharrat D, et al. High-dose intravenous gammaglobulin for myasthenia gravis. Lancet. 1984;1: Donofrio PD, Berger A, Brannagan 3rd TH, et al. Consensus statement: the use of intravenous immunoglobulin in the treatment of neuromuscular conditions report of the AANEM Ad Hoc

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