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Inflammation & Allergy - Drug Targets, 2012, 11, 375-381 375

Intravenous Immunoglobulin as a Potential Therapy for Refractory Urticaria - A Review


Casey Watkins1, Emma Peiris1, Hana Saleh1 and Guha Krishnaswamy*,2,3
Department of Medicine and the 2Division of Allergy, Asthma and Clinical Immunology, Quillen College of Medicine and the 3James. H. Quillen VA Medical Center, Johnson City, Tennessee, USA
Abstract: Urticaria can be a chronic and debilitating affliction and is a relatively common disorder affecting between 1020% of the population. Common causes include reactions to medication, food allergen, physical stimuli and venoms. Urticaria can be acute or chronic. Chronic urticaria lasts for more than 6 weeks and is commonly difficult to treat. The use of immunosuppressive agents for this disorder when antihistamines fail can result in significant morbidity. Recent advances in the pathogenesis, etiology, diagnosis and management of chronic urticaria have led to new paradigms in treatment of this disorder. Cyclosporine is often the most effective but has some unique adverse effects that may prevent it from being used in some patients. The use of intravenous immunoglobulin (IVIG) has proven effective in a variety of reports and we will review the mechanisms likely involved in the successful control of urticarial symptoms by immunomodulating therapy using IVIG. In this review, we will discuss mechanisms and pathogenesis of urticaria and the specific role of intravenous immunoglobulin (IVIG) in this disorder, especially in refractory or steroid-dependent cases.
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Keywords: Antibody, autoimmune, chronic urticaria, immunoglobulin, intravenous, urticarial, vasculitis. INTRODUCTION Urticaria, also referred to as hives, are pruritic, edematous lesions involving the skin (Fig. 1) [1, 2]. In many cases, urticaria may be accompanied by other manifestations, including angioedema and dermatographism. A physical component may also be present such as delayed pressure urticaria or angioedema. Urticaria with or without angioedema is fairly common, and may occur in an estimated 10-20% of the population. When accompanied by fever, elevated sedimentation rate, arthralgias and multisystem involvement, urticarial vasculitis should also be suspected [1, 3]. In some cases, urticaria may be a manifestation of systemic anaphylaxis, which can be fatal [4, 5]. In such situations, common causes include reactions to medication, food allergen, injected venoms or hormones (such as progesterone). In general, urticaria can be divided into several subgroups: (1) acute urticaria, (2) chronic urticaria, (3) physical urticaria, (4) urticarial vasculitis and (5) the urticarial syndromes [1, 2, 6, 7]. Acute urticaria, which lasts less than 6 weeks, is usually due to a recognizable etiology, such as a food, medication, venom injection or an infection. The acute urticarias are usually easier to manage with antihistamines, oral steroids and removal of the inciting trigger. Chronic urticaria lasts for more than 6 weeks and is usually more difficult to treat. Antihistamines are typically considered first-line therapy, in addition to removal of any known inciting agents. Chronic urticaria has been shown to
*Address correspondence to this author at the Asthma and Clinical Immunology, Quillen College of Medicine, P.O. Box 70622, Department of Medicine, East Tennessee State University, Johnson City, TN 37614-0622, USA; Tel: (423) 439-6368; Fax: (423) 439-6387; E-mail: krishnas@etsu.edu 2212-4055/12 $58.00+.00

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Fig. (1). Examples of autoimmune urticaria and angioedema, of varying severity. A-Severe autoimmune urticaria in an elderly patient who tested strongly positive for autoantibody directed against Fc R1. B-Autoimmune urticarial eruption in a young child. C-Angioedema in a patient with autoimmune urticaria associated with hypogammaglobulinemia.

have a significant impact on several quality-of-life measures, including sleep, emotion and activities of daily living [8].
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Moreover, the use of immunosuppressive agents for this disorder when antihistamines fail can result in significant morbidity. Recent advances in the pathogenesis, etiology, diagnosis and management of chronic urticaria have led to new paradigms in treatment of this disorder [6, 8-11]. Second line agents for the treatment of difficult-to-manage or refractory chronic urticaria include antihistamines, leukotriene antagonists, omalizumab, immunomodulatory drugs such as colchicine and hydroxychloroquine and immunosuppressive medications such as azathioprine, mycophenolate and cyclosporine [8-11]. Of these medications, cyclosporine is often the most effective but has some unique adverse effects, such as nephropathy and hypertension, in addition to immunosuppression [9]. In this review, we will discuss mechanisms of urticaria and the specific role of intravenous immunoglobulin (IVIG) in this disorder, especially in refractory or steroid-dependent cases. The presumed mechanisms of IVIG and reported efficacy of this medication in some forms of chronic urticaria will be discussed. DISCUSSION Urticaria is a relatively common chronic disease with several known trigger mechanisms (Fig. 2). Allergens and additives are commonly identified triggers. Infectious triggers such as pyogenic bacterial infections and helicobacter pylori have also been described [12, 13]. Additionally, physical triggers including pressure, heat, cold, exercise are well established causes of urticaria [14-16]. Hormones [17] and medications such as salicyclates have been indicated as well as autoimmunity [18-21].

The major advancement in understanding the immunopathogenesis of chronic urticaria occurred approximately two decades ago with the discovery of an autoimmune basis for the disease [22-24]. Hence, some forms of chronic idiopathic urticaria came to be referred to as chronic autoimmune urticaria [15, 18-21]. There has also been an association between certain autoimmune disease and autoimmune urticaria, especially thyroid disease [25, 26]. According to some investigators, thyroid autoimmunity mediated by IgE anti-thyroid peroxidase antibodies may be responsible for mast cell activation, though it is still unclear how an antigenic thyroid peroxidase would activate IgE antibodies on human mast cell or basophil surfaces [25]. Up to 25% of patients with chronic urticaria may have associated thyroid disease [26]. Some small case series and anecdotal reports suggest that treatment with thyroxine even in euthyroid patients may lead to amelioration of urticarial lesions [26]. This finding has not been confirmed in larger, well-designed trials. Nevertheless, the relatively common association of autoimmune thyroid disease with chronic urticaria does suggest a dominant autoimmune mechanism in some of these patients. Recent studies suggest that up to 30-60% of patients with chronic urticaria may demonstrate evidence of autoimmune phenomena or markers [27]. These include anti-IgE and antiFc RI antibodies, the latter being IgG antibodies directed against the high affinity IgE receptor present on mast cells and basophils (Fig. 2) [27]. The presence of these antibodies is demonstrable by either in vivo autologous serum skin test (ASST) or in vitro laboratory measurement of anti-Fc R1 antibody using methods such as basophil histamine release. Rare antibodies may also be directed against the low affinity IgE receptor Fc RII (CD23) on mast cells and basophils. The
Triggers Medication Infection Allergens Cholinergic stimuli (exercise, heat/cold)

1 IgE FcHRII FcHRI 2

Cytokines Complement Antibodies Allergens (Food/Latex)

Mast cell
3 FcHRI IgE

1=Anti-IgE antibody (IgG) 2=Anti-FcHRI antibody (IgG) 3=Anti-FcHRII/CD23 antibody (IgG) 4=Allergen-IgE-FcHRI Allergen

FcHRI 4 Mast Cell Degranulation Histamine Leukotrienes Cytokines TNF- and IL-3 IL-5, IL-8, GM-CSF Endothelial activation Cell adhesion molecule expression Cytokines, chemokines, monokines Recruitment Leukocytes T-cells

Urticaria Angioedema

Fig. (2). Demonstrating various pathways of mast cell activation in urticarial syndromes. 1-3 demonstrates autoantibody-mediated activation, of which type 2 is probably the commonest. 4=activation of mast cells by allergen (food, latex, medication) and allergen-specific IgE.

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role of these antibodies in inducing degranulation of mast cells is shown in Fig. (2) [27]. Mast cell degranulation leads to expression of histamine, leukotrienes, proteases, cytokines, eosinophils, lymphocytes and complement. The release of proteases and inflammatory cytokines results in further cellular recruitment, endothelial activation and cutaneous inflammation. These factors culminate in the changes of urticaria or urticarial vasculitis, depending on the inciting agent and progression of inflammatory paradigms [28-32]. IVIG MECHANISMS OF ACTION IVIG appears to have several effects on immunity and the inflammatory response. Patients with humoral immune deficiency are more predisposed to other autoimmune disorders, including rheumatoid arthritis, lupus-like disease, sprue-like illness, hematological dyscrasias and autoimmune thyroiditis. This suggests that, in some way, immunoglobulins regulate autoreactivity, however, the mechanisms remain unclear [33]. The mode of action of IVIG in autoimmune and inflammatory disease may involve either the Fab or the IgG Fc component interactions with corresponding Fc receptors. The result is modulation of complement, cytokine and cellular networks and pathways [33]. Cellular pathways influenced by IVIG may include T cell differentiation, B cell survival/function and activity of antigen presenting cells (APC) such as dendritic cells [34]. Many theories have been proposed including blockade of Fc receptors on inflammatory cells, neutralization of autoantibody, cytokine regulation and neutralization of activated complement products [34]. Typically indicated for treatment of hypogammaglobulinemia (such as common variable immune deficiency, X-linked agammaglobulinemia or functional antibody defici-ency syndromes), IVIG is beginning to be used more frequently for a variety of autoimmune and severe inflammatory reactions [35]. Since some forms of chronic urticaria are deemed to be autoimmune in etiology, it is likely that IVIG may have similar effects in this disease [9, 37, 38]. Studies over the last several decades have demonstrated a multiplicity of IVIG effects in inflammatory and non-immunodeficiency disease [35]. Replacement doses of IVIG in immunodeficiency diseases are usually between 400-600 mg/Kg every 4 weeks. Doses used in severe autoimmune disease such as immune thrombocytopenia or Kawasaki disease are much higher (1-2 g/Kg given over 5 days, and sometimes repeated) [36-39]. Fever, chills and headache are considered common adverse effects of IVIG, especially with high dose infusion. More serious complications include hypercoagulabilty and thromoboembolic disease, renal failure or transmission of infection. Anaphylaxis is more likely to occur in patients with selective IgA deficiency or severe primary immune deficiency, and probably less likely to occur in the setting of autoimmune disease. Nevertheless, constant vigilance and monitoring for adverse effects is essential. Sometimes pretreatment with antihistamines or glucocorticoids may be necessary. Effects of IVIG on Innate Immunity IVIG infusion seems to be associated with modulation of both innate and adaptive immune systems (Table 1) [37, 40].

IVIG limits complement activation, probably by binding activated complement components and anaphylataxins via the Fc receptor [37]. Inhibition of C3 convertase, C3a, and C3b may occur and results in a significant dampening of complement-mediated vascular and tissue injury. In some forms of immunologically-mediated urticaria and urticarial vasculitis, complement is involved in mediating the inflammatory effects including capillary leakage and cellular infiltration. Thus, the immunomodulatory effects of IVIG may be important in these cases. IVIG also appears to have effects on dendritic cell (DC) maturation and activation/function [37]. This may be mediated via inhibition of expression of CD40, HLA class I/II molecules as well as CD80/86 co-stimulatory molecules. The effects on DC function result in altered T cell activation and hence B lymphocyte synthesis of autoantibody. DC secretion of IL-12 may also be effected by IVIG, resulting in decreased T cell activation and differentiation. Several effects of IVIG have been described on monocyte-macrophage lineage cells. These include inhibition of inflammatory cytokine expression and induction of inhibitory cytokines which then can lead to altered cellular recruitment. It is important to emphasize that IVIG therapy is immunoregulatory rather than immunosuppressive. Several aspects of the immune response may be simultaneously or sequentially modified, with the end result being immunoregulation (Fig. 3). This unique characteristic of IVIG sets it apart from traditional second generation urticarial therapies such as cyclosporine, which act via immunosuppression. Effects of IVIG on Adaptive Immunity Both T lymphocyte and B lymphocyte function could be modified by IVIG infusion. Seite and colleagues demonstrated repression of toll-like receptor 9 responses in B lymphocytes by IVIG [41]. This appears to be mediated by induction of CD22, recruitment if inhibitory SHP-1 (Src homology phosphatase-1) and decreased inflammatory cytokine production [41]. IVIG also induces the inhibitory receptor Fc RIIb on B lymphocytes, which leads to reduced cytokine production and B cell activation. B cell apoptosis can also be induced by IVIG by either a CD22- or an Fc RIIb-mediated mechanism. IVIG may also directlyinhibit B cell growth factors such as BAFF (B cell activating factor) or APRIL (a proliferation-inducing ligand) [37, 41]. These factors may also reduce the ability of B lymphocytes to function as APC. T cell effects of IVIG are important to discuss in the setting of chronic autoimmune urticaria. T cell function may be altered indirectly by modulation of APC function, altered cytokine expression by DC, and induction of T regulatory cell activity. Antigen presentation is affected by decreased expression of costimulatory molecules such as CD40, CD80/86 or HLA molecules. T regulatory cells may be induced by IVIG by upregulation of CD25+/CD4+/FOXP3+ or via complex cytokine pathways [5, 37, 42, 44, 45]. Induction of CD25+/CD4+/FOXP3+ T regulatory cells by IVIG may have further immunoregulatory effects through synthesis of IL-10 or TGF beta. Padet et al. suggest that the T cell effects of IVIG are mediated indirectly by neutralization of lectin by glycans present in the Fab component of the infused IgG molecules [5].

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Table 1.

Mechanism of Action of IVIG in Autoimmunity


Effect of IVIG

Immune Component Innate Immunity Phagocyte Complement Cytokines Alters cellular recruitment [37, 43]

Limits complement activation and dampens complement-mediated vascular and tissue injury [37] Inhibits inflammatory cytokines and induces inhibitory cytokines By altering Th1/2 or Th17 maturation as well as modulating glucocorticoid receptors or Fcgamma receptors on T cells and inflammatory cells [34, 42, 44, 45] or by inhibiting T cell activation [5, 37] Decreased adhesion to endothelial cells [43]

Neutrophils Adaptive Immunity T lymphocyte T regulatory cell

Decreased activation [5] due to APC or B cell functional defects Increased regulation by T regulatory cells [5, 34, 37, 41] Induced by upregulation of CD25+/CD4+/FOXP3+ or via complex cytokine pathways [5, 37, 42, 44, 45]

B lymphocyte

Decreases activation by decreasing TLR-9 receptor expression Induces B cell apoptosis via CD22 or Fc RIIb Directly inhibits B cell growth factors (BAFF, APRIL) [37, 41, 46]

Anthony et al. have recently reported that some of the observed anti-inflammatory effects of IVIG are mediated by a minor population of IgG crystallizable fragments that possess glycans and sialic acids that bind to DC-SIGN (dendritic cell specific ICAM-3 grabbing non-integrin) [42]. DC-SIGN is of importance to innate immunity and functions as a pathogen recognition receptor, binding sugars such as mannose on bacterial surfaces. Binding of DC-SIGN by these sialylated IgG fragments led to induction of IL-33 which induced basophil expression of IL-4, in turn culminating in Fc RIIb expression on effector macrophages known to suppress autoimmune inflammatory responses. The same Fc RIIb on B cells can lead to apoptosis and altered APC function, in turn leading to decreased autoantibody synthesis (though IL-4 infusion apparently down-regulated Fc RIIb in this murine model) [42]. How applicable these findings are to the human immune response is unclear, but this model does provide one pathway for better understanding the beneficial effects of IVIG infusion in autoimmune disease, such as autoimmune urticaria. Other effects have also been demonstrated with IVIG, including decreased neutrophil-endothelial adhesion [43], alterations in expression of glucocorticoid receptors [44], inhibition of differentiation and activity of TH17 cells [45], attenuated TLR9 activation in B cells [46] and modulation of programmed cell death pathways [47]. IVIG can thus be regarded as a model immunoregulatory agent with some effects being immune-enhancing or reconstitutive (such as when used in immunodeficiency) and some being immunosuppressive (Fig. 3) [48]. ThisYin-Yang effect of IGIV in autoimmune urticaria- balancing immunoregulation and immune reconstitution with selective immunosuppression (autoantibody expression)- may provide one attractive rationale for use in refractory or difficult-to-control urticariaas opposed to the more potent immunosuppressive and toxic agents such as glucocorticoids, cyclosporine or mycophenolate.

EFFICACY OF IVIG IN URTICARIAL SYNDROMES Given the toxicity of immunosuppressive drugs and the serious adverse effects associated with glucocorticoid therapy, alternative approaches are required in patients with either severe autoimmune urticaria or severe steroiddependent urticaria. In patients who have failed to tolerate cyclosporine or mycophenolate or may not qualify for other experimental therapies such as omalizumab or rituximab, IVIG infusion may provide a safer and less immunosuppressive alternative [35]. IVIG has been given a level 3 (nonanalytical studies, case reports, case series) and grade D (extrapolated from level 3 studies) recommendation for use in chronic urticaria. IVIG has been used in solar urticaria [22, 23, 49-52]. Solar urticaria is characterized by development of urticarial eruption within a few minutes of exposure to ultraviolet radiation. This photodermatosis commonly results in itching and burning, but in some patients systemic manifestations may occur, including wheezing, hypotension and syncope. Adamski et al. reported on a retrospective, multicenter study using a mailed questionnaire [22]. Seven patients (5 women) aged 32-55 years with a diagnosis of solar urticaria were given IVIG. Five of 7 patients achieved complete remission following 1-3 courses of therapy. Hughes and coworkers demonstrated efficacy of IVIG infusion in two patients with solar urticaria who had failed plasma exchange, photopheresis and cyclosporine [49]. IVIG was infused at the dose of 2g/Kg over 5 days and both patients achieved prolonged remission after several courses. One case of severe solar urticaria remitted completely following a single infusion of IVIG administered in the dose of 2g/Kg [50]. Correia et al. and Darras et al. also reported on remission of severe solar urticaria in single patients following high dose IVIG infusion [51, 52]. While the poor response seen in the one report by Llamas-Velasco et al., may have been due to differences in product or dosage protocol, it is also quite possible that solar urticaria is a heterogeneous disease, with

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Immune Regulation
Autoimmunity

Immune Suppression

IGIV
Immune Reconstitution

Immunodeficiency

Immune Regulation
Fig. (3). Yin-Yang effects of IVIG in autoimmune urticaria- balancing immunoregulation and immune reconstitution with selective immunosuppression (autoantibody expression)- which may provide one attractive rationale for use in refractory or difficult-to-control urticaria-as opposed to the more potent immunosuppressive and toxic agents such as glucocorticoids, cyclosporine or mycophenolate.

some forms being responsive to IVIG and other forms being resistant [23]. There has been one report of IVIG use in delayed pressure urticaria (DPU), a frustrating and difficult-to-treat disorder [53]. In this study, Dawn and coworkers evaluated the efficacy of IVIG in 8 patients with DPU. IVIG was administered at doses of 2g/Kg over a 2-3 day period. Autologous serum testing was performed on the majority of the patients. Five out of the 8 cases responded favorably to IVIG infusion. IVIG has also been used for chronic idiopathic or autoimmune urticaria, in both children [54] and adults [9, 54-63]. Mitzel-Kaoukhov and others used high dose IVIG (2g/Kg every 4-6 weeks) in 6 patients with chronic spontaneous urticaria resistant to other therapies [56]. Four of 6 patients had complete remission after 2-4 cycles and symptoms such as itching, hives, and edema were greatly reduced soon after the first treatment. Dodig and colleagues reported on 3 children with chronic autoimmune urticaria who required high dose IVIG [54]. In this study, neither age of the patient or severity of the disease correlated with a serum-induced basophil histamine release test, used as a surrogate measure of autoantibody. Pereira C et al. studied a group of 29 patients with chronic autoimmune urticaria [55]. The patients were given low dose IVIG (150 mg/Kg every 4 weeks) for anywhere between 6 and 51 months. Twenty-six out of these 29 patients demonstrated improvement measured by decreased severity of urticarial lesions and decreased medication usage. Nineteen of the 26 patients achieved complete remission of symptoms, which appears quite remarkable given the low dose of IVIG used in this

study. Twenty of 26 patients went into sustained remission up to 12 months after cessation of therapy. Wetter and colleagues reported on the Mayo Clinic experience in the use of IVIG in various dermatological diseases. Of these, one patient with chronic urticaria had complete remission following treatment [64]. The role of high dose IVIG (0.4 mg/Kg given daily over 5 days) in chronic urticaria was evaluated in a group of 10 patients with severe disease unresponsive or poorly responsive to conventional therapies [63]. Urticarial activity was measured using wheal and itch scores and a visual analog score as well as objectively monitored using the autologous serum skin test. Clinical benefit was noted in 9/10 patients with 3 patients in continued prolonged remission. A reduced wheal and flare response to autologous serum was also observed post-treatment. Minimal adverse effects were experienced by the subjects enrolled in this study [63]. In a few instances, IVIG has also been used in some forms of urticarial vasculitis, a complement-mediated inflammatory disorder characterized by leukocytoclasia [65, 66]. CONCLUSION Chronic urticaria is a difficult disorder to treat and investigation into new therapeutic options is essential. When patients with refractory urticaria become dependent on steroids or immunosuppressive agents such as cyclosporine, the adverse effects may dictate a need for discontinuation of the medication. In such cases, a trial of IVIG may be considered. Multiple case reports support the efficacy of IVIG and our review of the mechanisms of urticaria and IVIG support, in theory, the usefulness of this agent in

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autoimmune cases. The Yin-Yang effect of IGIV in autoimmune urticaria- balancing immunoregulation and immune reconstitution with selective immunosuppression (autoantibody expression)- may provide one attractive rationale for use in refractory or difficult-to-control urticariaas opposed to the more potent immunosuppressive and toxic agents such as glucocorticoids, cyclosporine or mycophenolate (Fig. 3). Further controlled studies of larger patient populations are needed to confirm the promising role of IVIG in the treatment of chronic urticaria. CONFLICT OF INTEREST

[16] [17]

[18]

[19]

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript. ACKNOWLEDGEMENTS

[20] [21]

[22]

This work was supported in part by a grant from CSL Behring.


[23]

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Received: February 9, 2012

Revised: May 15, 2012

Accepted: May 17, 2012