Intravenous Immunoglobulin Treatment in Rheumatic Diseases

Chapter 61

Intravenous Immunoglobulin Treatment in Rheumatic Diseases Antonella Fioravanti1, Sara Tenti2 1Rheumatology

Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy; 2Department of Medicine, Surgery and Neuroscience, Rheumatology Unit, University of Siena, Policlinico Le Scotte, Siena, Italy

INTRODUCTION Intravenous immunoglobulin (IVIG) is a therapeutic preparation of human polyspecific IgG, derived from the plasma of healthy donors [1]. IVIG was initially administered, in the early 1980s, as a replacement therapy in patients with primary or secondary immunodeficiencies. Since then, IVIG was used in a larger spectrum of autoimmune and systemic inflammatory disorders, thanks to its properties to modulate different pathways of the immune system [2,3]. There are actually several commercially available IVIG preparations that vary in composition and preparations methods with consecutive different efficacy and safety profile [4]. Firstly, in accordance with the World Health Organization (WHO) recommendations, the IVIG manufacturing process includes the purification of pooled donor plasma through fractioning and chromatography to obtain viral inactivation and removal. As a consequence of multiple methods, IVIG differs in the quantity of IgG, IgM, and IgA component, distribution of IgG subclasses, structure and function of Fc portion of IgG, and presence of aggregates. The optimal IVIG formulation should contain at least 80% of intact IgG with a normal IgG subclasses distribution, as little IgA as possible, and no fragments or aggregates [5,6]. Furthermore, IVIG products differ for concentration with higher concentrated formulation requiring smaller infusion volume loads and for the type of stabilizer, as glycine, l-proline, l-isoleucine or glucose, maltose, sucrose, or sorbitol. The use of IVIG preparation containing sucrose could arise some concerns in diabetic patients and is more likely associated to some adverse events, such as acute renal failure. In addition, the sodium content, the osmolarity, and the osmolality vary from an IVIG formulation to another with a greater incidence of adverse effects as renal complications or thromboembolic events associated to hyperosmolar ­solutions [7]. Finally, other differences in the IVIG group lie in the levels of IgA and in the pH with pH close to neutral able to reduce the risk of injection site reaction [8].

MECHANISMS OF ACTION The exact mechanism in which IVIG exerts its immunomodulatory and antiinflammatory effects remains not fully understood, but different pathways targeting the innate and adaptive immune systems are involved [9]. The action of high-dose IVIG administration was modulated either by the F(ab′)2 or the Fc segment. The saturation of the Fc receptors on phagocytic and vascular endothelial cells accelerates the degradation of circulating pathogenic autoantibodies and decreases phagocytosis and the release of inflammatory mediators. In addition, genetic and functional variations in Fc receptors as well as the differential IgG-Fc glycosylation patterns could play a role in modulating an inflammatory response [9]. The supraphysiologic doses of IgG induce the inhibition of the differentiation of the dendritic cells from monocytes with a consequent decrease of the cytokines and chemokines production. Other mechanisms involve the downregulation of B cells receptors and decrease of B cell proliferation and differentiation leading to a consequent reduction of their antibody production and the increase of the number and function of regulatory T cells. Additional IVIG effects include the modulation of pro/antiinflammatory cytokines and of metalloproteinases [9,10]. Furthermore, it was showed that sialic acid–enriched IVIG preparations have a greater antiinflammatory activity [11]. Mosaic of Autoimmunity. https://doi.org/10.1016/B978-0-12-814307-0.00061-X Copyright © 2019 Elsevier Inc. All rights reserved.

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INTRAVENOUS IMMUNOGLOBULIN THERAPY AND RHEUMATOLOGICAL CONDITIONS The Food and Drug Administration–approved indications for IVIG therapy are, actually, limited (Table 61.1) and restricted in the rheumatologic field to the Kawasaki disease (KD); however, several reports demonstrated the beneficial effect of IVIG in a wide variety of other rheumatologic diseases, such as idiopathic inflammatory myopathies (IIM), systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), antineutrophil cytoplasm antibody (ANCA) vasculitis, and systemic sclerosis (SSc) [12,13] (Table 61.2).

TABLE 61.1  The Food and Drug Administration–Approved Indications for Intravenous Immunoglobulin Therapy (https://www.fda.go) Allogenic bone marrow transplantation Chronic lymphocytic leukemia l Common variable immunodeficiency l Chronic inflammatory demyelinating polyneuropathy l Kidney transplantation with a high antibody recipient or with an “ABO” incompatible donor l Primary immunodeficiency disorders associated with defects in humoral immunity l Immune-mediated thrombocytopenia l Kawasaki disease l Hematopoietic stem cell transplantation in patients older than 20 years l Chronic B cell lymphocytic leukemia l Pediatric HIV type 1 infection l l

TABLE 61.2  Summary of the Scientific Evidence on Intravenous Immunoglobulin (IVIG) Therapy in Rheumatic Diseases Indications

Literature Data

DM/PM

IVIG therapy is usually recommended in idiopathic inflammatory myopathies, especially in cases of steroid resistance and aggressive forms.

IBM

Controversial data. There is not sufficient evidence to support or refute the use of IVIG in IBM.

Lupus nephritis

IVIG resulted as effective as CYC in maintaining remission, after an induction therapy.

Refractory SLE

IVIG resulted effective in improving the disease activity scores and some clinical manifestations, when other treatments have failed.

SLE-associated autoimmune hemolytic anemia

The use of IVIG is only reserved to severe life-threatening conditions.

Cutaneous lupus erythematosus

Encouraging, but not sufficient evidence.

Obstetric APS

IVIG therapy should be reserved to patients not responsive to the conventional treatment or in case of association of other autoimmune manifestations such as thrombocytopenia or when concomitant infections exist or in patients in whom anticoagulation is contraindicated.

Nonobstetric APS

Additional therapy with IVIG could be useful to prevent recurrent thrombosis in patients refractory to conventional anticoagulant treatment.

CAPS

The international consensus guidelines recommend a combination therapy with anticoagulants plus corticosteroids, plasma exchange, and/or IVIG.

ANCA vasculitis

IVIG is considered an alternative therapy in particular conditions, as in immunocompromised patients with remittent infections, those with frequent relapses, or with refractory disease.

Systemic sclerosis

IVIG resulted effective in improving muscle and joint involvement, gastrointestinal symptoms, and skin fibrosis.

ANCA, antineutrophil cytoplasm antibody; APS, antiphospholipid syndrome; CAPS, catastrophic APS; CYC, cyclophosphamide; DM, dermatomyositis; IBM, inclusion body myositis; PM, polymyositis; s, systemic lupus erythematosus.

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Kawasaki Disease KD is the most common systemic vasculitis in children that leads to coronary artery aneurysms in a quarter of untreated cases. The efficacy of IVIG therapy in this disease was firstly described in 1984 by Furusho et al. [14] who observed a reduction of coronary abnormalities in KD patients treated with high-dose IVIG (400 mg/kg/die for four consecutive days). Consecutive randomized controlled trials (RCTs) confirmed the efficacy of IVIG in preventing the coronary aneurysms and a Cochrane review on 59 trials concluded that KD patients should be treated with a single high dose of IVIG (2 g/kg) and aspirin within 10 days of onset [15]. Previous metanalyses clearly stated that the efficacy of IVIG in preventing the coronary aneurysms is dose-dependent, so it is recommended to repeat the IVIG infusion 36 h after the first administration in patients with recurrent or persistent fever [16,17]. Different factors were found to affect the response to IVIG therapy in KD, such as high neutrophil count, high C-reactive protein and erythrocyte sedimentation rate, low hemoglobin and albumin levels, high aspartate and alanine aminotransferase levels, low sodium levels, and high total bilirubin and gamma-glutamyltransferase levels [13]. The RCTs to assess immunoglobulin plus steroid efficacy for KD (RAISE study) showed that the combination therapy of IVIG and prednisolone could be a very useful tool to overcome the IVIG resistance [18].

Idiopathic Inflammatory Myopathies The term IIM refers to a heterogeneous group of acquired muscle disorders characterized by muscular weakness and signs of inflammation on muscle biopsy, such as dermatomyositis (DM), polymyositis (PM), and inclusion body myositis (IBM). Despite the scientific evidence on this topic is limited by the rarity of the disease and by the heterogeneity of the published studies, experts usually recommend IVIG in IIM, especially in cases of steroid resistance and aggressive disorder [13,19]. The IVIG therapy is supported by two RCTs and some uncontrolled trials. The first study was published in 1993 by Dalakas et al. [20] and reported a significant improvement in muscle strength and cutaneous rash in patients treated with IVIG at the dosage of 2 g/kg (divided over 2 days) monthly for 3 months, in comparison with placebo. The more recent RCT compared a single course of IVIG (2 g/kg divided over 5 days) with placebo in DM/PM patients refractory to high-dose corticosteroids, reporting no significant difference between the two groups in the primary outcomes, although IVIG resulted significantly superior to the placebo concerning the time to normalization of serum creatine kinase (CK) level and score of swallowing action [21]. The role of IVIG therapy as first-line therapy has been less investigated and only a RCT was published. This study described 60 DM patients who were randomized to receive IVIG (at the dosage of 400 mg/kg per day for 3 days, monthly for 3 times) in association to corticosteroids or steroids alone, reporting a major efficacy of IVIG concerning both clinical and biochemical outcomes at the end of month 3 [22]. However, the real efficacy of IVIG in the short term as firstline therapy in DM/PM population remains not clear because the other open-label studies rarely showed clinical effectiveness of IVIG [23,24]. On the contrary, there is more evidence of a relevant benefit on survival of IVIG in the long term, as demonstrated by studies reporting the maintenance of disease remission at different follow-up times (4–6 months in one study, 4 years in another one, and yet up 28 years in another study, respectively) [25–27]. The role of IVIG in IBM is still controversial and based on few trials showing only modest improvements and not significant differences with placebo [28–30]. In 2011, the American Academy of Neurology clearly stated that there is not sufficient evidence to support or refute the use of IVIG in IBM [31]. Finally, there are some reports showing encouraging results about the use of IVIG in certain subset of IIM, such as juvenile DM, anti-HMGCR antibody-associated autoimmune myopathies or for specific manifestations, such as rash and dysphagia [19].

Systemic Lupus Erythematosus Although the increasing use of IVIG therapy in several different manifestations of SLE, the evidence supporting its efficacy mainly derived from small clinical trials, case series, and case reports. Only one small RCT was published to compare the utility of IVIG with cyclophosphamide (CYC) in 14 patients affected by lupus nephritis [32]. In this study, all patients were initially treated with intravenous (i.v.) CYC to induce the disease remission and then randomized to IVIG therapy (400 mg/kg monthly) or i.v. CYC (1 g/m2 every 2 months for 6 months). At the end of the 18 months follow-up, a significant improvement of renal function was observed in both groups and IVIG resulted as effective as CYC in maintaining remission. Other encouraging results derived from not controlled open trials, as that one of Francioni et al. [33] who evaluated the IVIG treatment (400 mg/kg for 5 days, monthly, for 6–24 months) in patients with chronically active lupus, observing a clinical and serological improvement in 11 of 12 studied subjects.

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Furthermore, IVIG seems to significantly improve the disease activity scores, as demonstrated by Schroeder et al. [34] in 12 patients treated with two courses of high-dose IVIG and by Levy et al. [35] in 17 of 20 individuals treated monthly with IVIG (400 mg/kg per day for 5 consecutive days). In the first study the improvement was observed within 6 weeks from the treatment and lasted 5–12 months; in the second study, 80% of patients presented improvements of disease activity score, hypocomplementemia, and autoantibody titer after one to eight IVIG courses. IVIG may also have a steroid-sparing effect, as showed by Zandman-Goddard et al. [36] who observed that 9 of 11 SLE patients treated with IVIG (400 mg/kg/die for 5 days) monthly for 6 months presented a full or partial remission, measured by SLEDAI score and a reduction of steroids consumption. Finally, promising results derived from a large retrospective study [37] in which 62 SLE patients received low-dose IVIG (500 mg/kg in a single administration every 5 ± 2 weeks). Good responses for many clinical manifestations were observed, as well as consistent reduction of SLEDAI score. However, some manifestations, such as thrombocytopenia, alopecia, vasculitis, and proteinuria, failed to respond to IVIG, pointing out the importance of the appropriate IVIG dosage. Actually, IVIG in SLE is indicated in refractory disease where other therapies have failed, in acute severe flares, and in lupus nephritis as maintenance therapy or when SLE can be controlled only with high-dose steroids [36,38].

Particular Clinical Manifestations Associated to Systemic Lupus Erythematosus Autoimmune hemolytic anemia is frequently associated with SLE and is in first line managed with corticosteroids; the use of IVIG is reserved to severe life-threatening conditions. On this respect, the available data are in fact controversial, mainly because the evidence is limited to small case series and the only retrospective study on 73 patients reported a significative response of hemoglobin levels in 40% of cases [39]. Some encouraging, but still limited, data on the use of IVIG were published in SLE patients with skin lesions. A prospective study was conducted to investigate the efficacy of IVIG, administered for the first two times at the dosage of 1 g/kg over 2 days and followed by 400 mg/kg monthly for no more than 6 months in 12 patients with cutaneous lupus erythematosus (LE). The authors observed a full remission in 40% patients, a partial remission in 20%, and no or limited response in 40% [40]. Good results with IVIG therapy were also obtained in case series of patients with chronic discoid LE and in lupus panniculitis resistant to other treatments [41,42]. However, contrasting results were described by De Pita et al. [43] who reported SLE and cutaneous LE patients with no improvement or even with exacerbation after IVIG and by Wollina et al. [44] who observed no response in patients with SLE.

Antiphospholipid Syndrome APS is recognized as the most common cause of acquired thrombophilia in the general population, presenting as early pregnancy loss or arteriovenous thrombosis. Obstetric APS should be treated by a multidisciplinary team of specialists with experience in this field. In this contest, secondary thromboprophylaxis with low-dose aspirin (LDA) and heparin is the mainstay of treatment, and hydroxychloroquine is usually added for patients suffering from SLE [45]. Although an optimal therapeutic target was not often reached, several new emerging therapies have been implemented in the last years. Among these IVIG showed a beneficial effect in some case reports/series and observational or randomized trials [46]. The literature data seem controversial; indeed, while some studies demonstrated a decrease of pregnancy complications or of the abortion rate, other trials concluded that no benefits derived from the use of IVIG in association with LDA and low molecular weight heparin (LMWH) compared with LDA and LMWH alone [47–50]. At the moment, IVIG therapy in obstetric APS seems to be reserved to selected situations, such as patients not responsive to the conventional treatment or in case of association of other autoimmune manifestations such as thrombocytopenia or when concomitant infections exist or in patients in whom anticoagulation is contraindicated. It’s noteworthy to underline that the IVIG dosage and the schedule of the treatment were different in each study varying from 200 mg/kg per day until 32 week of gestation to 1 g/kg per day for 2 consecutive days each month until week 36. The evidence about the efficacy and safety of IVIG therapy in not-pregnant APS patients is scarce; in particular the use of IVIG in the primary or secondary thromboprophylaxis was described only in two prospective open studies and in few case reports. According to these data, it seems that an additional therapy with IVIG could be useful to prevent recurrent thrombosis in APS patients refractory to conventional anticoagulant treatment [51,52]. Catastrophic APS (CAPS) is a severe subset of APS characterized by multiorgan failure originated by widespread thrombotic disease, which usually affects small vessels over a short period and is associated with high mortality rates [53]. Combination therapy with anticoagulants plus corticosteroids, plasma exchange (PE), and/or IVIG (“triple therapy”) was

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the most commonly used treatment for CAPS, in agreement with the international consensus guidelines [54]. IVIG is used in a dose of 0.4 g/d/kg for 5 days and should be administered after the last day of PE, when planned, to prevent their removal. IVIG is well tolerated, but they should be used with caution in case of thrombosis, particularly in those patients whose anticoagulation was discontinued because of bleeding. Avoiding products with high osmolality, reducing the rate of IVIG infusion, hydration, and using nonsucrose IVIG products (especially in patients with renal failure) are strategies that can reduce thrombosis risk [55]. Elderly patients with diabetes, hypertension, or hypercholesterolemia should also be infused with care, with a reduced rate of IVIG infusion. IVIG is strongly recommended in CAPS patients with severe thrombocytopenia refractory to high-dose steroid therapy or when a concomitant infection exists [56]. As there were no metanalyses or RCTs, most of the scientific evidence derives from the online available “CAPS Registry” that includes the description of 342 cases of CAPS and their treatments. The analysis of this registry confirms that the “triple therapy” strategy improves the survival rate (around 70%) [56,57].

Antineutrophil Cytoplasm Antibody–Associated Vasculitis ANCA vasculitis is a group of systemic small vessel vasculitis associated with circulating ANCA that includes granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis. The therapeutic strategy usually comprises high-dose corticosteroids often associated to immunosuppressive agents, such as CYC, rituximab, azathioprine (AZT), methotrexate, or leflunomide. Considering the possible toxicity of these treatments, IVIG was studied as adjuvant or alternative therapy. Also the British Society for Rheumatology, in 2007, regarding ANCA vasculitis described IVIG as “an alternative therapy in patients with refractory disease or in patients for whom conventional therapy is contra-indicated, for example, in the presence of infection, in the severely ill patient or in pregnancy” [58]. A 2009 Cochrane review (recently updated) [59] identified only a RCT with 34 participants who were equally and randomly assigned to receive IVIG (a single course of 400 mg/kg daily for 5 days) or placebo in addition to AZT and corticosteroids for remission maintenance. There were no significant differences between adjuvant IVIG and adjuvant placebo in mortality, serious adverse events, time to relapse, and infection rates. The authors demonstrated that a single course of high-dose IVIG reduces disease activity in ANCA vasculitis where active disease persists, but the benefit of IVIG was not maintained beyond 3 months [60]. A recent French multicentre retrospective study was published on 92 ANCA vasculitis patients and it showed that 83% of individuals treated with IVIG for relapsing disease for a median of 6 months were more likely to go into remission and required less corticosteroid [61]. Other studies demonstrated the usefulness of IVIG therapy during the acute flares of vasculitis in patients with concomitant infection and at high risks for immunosuppressive treatment [62,63]. Based on this evidence, we can consider IVIG not a first-line therapy in clinical practice but a good option in particular conditions, as in immunocompromised patients with remittent infections, those with frequent relapses, or with refractory disease.

Systemic Sclerosis Considering both immunomodulatory and antifibrotic properties of IVIG, it was studied as a potential promising therapy in SSc. IVIG resulted effective in improving muscle involvement in SSc, as demonstrated by a reduction of muscle pain, Medical Research Council test, and CK serum levels [64], confirming the good results of IVIG in IIM. A significant decrease of tender and swollen counts with recovery of joint function was also observed in an open-label trial of seven SSc patients [65]. Promising data derive from IVIG therapy for gastrointestinal involvement in SSc, as reported by a not controlled study [64] and a case series [66]. In both papers, the authors described a reduction of frequency and severity of Gastroesophageal reflux disease (GERD) and gastrointestinal symptoms. Regarding skin involvement several studies reported a benefit of IVIG therapy in reducing skin score and fibrosis. In 2015, Poelman et al. [67] presented their experience with 30 patients with severe, refractory, active diffuse cutaneous scleroderma treated with adjunctive IVIG (2 g/kg per month for 6 months). The authors observed a significant reduction of skin thickening, and the improvement of modified Rodnan skin score (mRSS) was greater in IVIG-treated patients at 12 months follow-up compared with data from historical controls from negative trials. Furthermore, the only RCT study conducted on IVIG therapy in SSc patients reported no significant difference in the mRSS score between the group of participants treated with IVIG (400 mg/kg per day for 5 consecutive days in a single course) compared with patients who had received placebo, but when a second cycle of IVIG was administered skin sclerosis significantly ameliorated in the IVIG group [68]. More recently, a French nationwide cohort study analyzed the data of 46 SSc patients treated with at least an infusion of IVIG (at a dosage >1 g/kg/cycle) reporting a significant improvement of musculoskeletal and gastrointestinal involvement, systemic inflammation, and a reduction of steroid consumption, but it failed to demonstrate a benefit in skin and lung fibrosis [69].

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Other Rheumatic Diseases Many other rheumatological conditions were successfully treated with IVIG, such as peripheral neuropathy associated to Sjogren syndrome (SS). Over the years, 10 case reports showed the benefit of IVIG therapy in SS patients with peripheral nervous system involvement. At this regard, the largest study dated back to 2011, when Rist et al. [70] retrospectively evaluated the efficacy and tolerability of at least an infusion of IVIG in 19 patients with SS complicated with peripheral neuropathy. The authors observed an improvement or at least a stabilization of the clinical symptoms, measured by the disability Modified Rankin Scale and the global evaluation of the physician, in most cases. Particularly, IVIG resulted more useful in patients with sensorimotor or nonataxic sensory neuropathy without necrotizing vasculitis. Furthermore, considering the ability of IVIG to counteract the placental transport of autoantibodies and to exert an antiidiotype regulation, this therapy was employed in the treatment of fetal congenital heart block (CHB), a severe complication in pregnant women anti-Ro or anti-La positive. The use of IVIG alone or in association to steroids failed to prevent CHB occurrence at the dosages used (usually one single IVIG course during pregnancy) [71–74]. More recently, IVIG was administered in association to weekly sessions of plasmapheresis and betamethasone (4 mg/day) in 12 pregnant women positive to anti-SSA/Ro and/or anti-SSB/La in whom CHB was diagnosed. Of six fetuses who presented atrioventricular block of second type, two returned to a first-type block and one to a normal conduction, whereas the six fetuses with block of third type remained stable during the pregnancy and no fetal complications or neonatal deaths were reported. On these basis, a combination therapy including IVIG seems effective in the management of the second-type CHB [75]. The beneficial effect of IVIG therapy was also described in case series or reports on patients affected by Behcet’s disease.

TOLERABILITY IVIG is usually well tolerated with mild and transient side effects. The majority of the adverse reactions are related to the infusion rate and include headache, nausea, malaise, myalgia, arthralgia, and fewer. Other side effects depend on the use of different formulations in certain at risk patients. For example, patients at risk of renal failure should avoid IVIG stabilized with sucrose, which is shown to cause osmotic nephrosis. In these patients, also formulations with high content of sodium or with high osmolality/osmolarity should be avoided and reduced and fractionated doses should be preferred. In patients with cardiovascular disease or at risk of thromboembolic events, the appropriate IVIG preparation should have low osmolarity with a concentration of 5%–10% and should be administered in more days’ course and at slow rate infusion. Furthermore, high-dose treatment was demonstrated to be related to the onset of hemolysis or to aseptic meningitis, particularly in case of rapid infusion. Finally, the content of IgA is another property to be considered because of the described severe anaphylactic or anaphylactoid reactions in patients with IgA deficiency. To minimize the risk of side effects, the prescription of IVIG therapy and the choice of the product should be individualized according to the medical history and the patient’s comorbidities, such as diabetes, obesity, hypercholesterolemia, cardiovascular and renal diseases, and thrombotic events. Before the infusion, the patients need a proper hydration. The rate of the infusion depends on the different IVIG formulation, and during the first administration, a low rate of infusion with gradual increases is recommended; in case of adverse events, the rate of infusion has to be decreased [6,7].

SUBCUTANEOUS IMMUNOGLOBULIN THERAPY Although the subcutaneous (SC) route of administration of immunoglobulin (IG) was employed from the 1940s in primary immunodeficiencies, there has recently been an increased interest in this kind of IG. Several studies demonstrated that there is no difference between SCIG and IVIG in terms of efficacy and that SC formulation resulted to be well tolerated. Indeed, the fractionating of the dosage into smaller but more frequent portions prevents the systemic adverse events described with IVIG, and the adverse reactions usually described with SCIG are mild, mostly consisting in localized injection site reactions. SCIG presents the undoubted advantage to permit a better quality of life to the patients, assuring them to preserve their independence and to save missed working days. Furthermore, the therapy with SCIG is associated to reduced costs in comparison with IVIG and there are no reports of renal failure with this formulation of IG. On the other side, SCIG treatment requires an appropriate education and training of the patients, a more frequent administration and some patients continue to prefer IVIG to SCIG [76]. The scientific evidence on SCIG derives mainly from studies on primary and secondary immunodeficiency diseases. In 2011, Danieli et al. [77] firstly reported the efficacy and tolerability of SCIG in PM and DM patients and then some data were collected also in IBM. The above-mentioned trials confirmed the equivalence in efficacy between SCIG and IVIG but pointed out the problem to administer a large amount of IgG, as requested in autoimmune disorders. Recently, the

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feasibility of SCIG in IIM was demonstrated by Cherin et al. [78] who described 19 patients with long-standing PM, DM, and IBM treated with SCIG (at the median dosage of 1.9 g/kg per month, with a frequency of two infusions per week). The authors observed significant improvement in muscle strength and disability in the majority of the patients and a good tolerability of this therapy in the long term.

REFERENCES [1] Kivity S, Katz U, Daniel N, Nussinovitch U, Papageorgiou N, Shoenfeld Y. Evidence for the use of intravenous immunoglobulins–a review of the literature. Clin Rev Allergy Immunol 2010;38:201–69. [2] Katz U, Shoenfeld Y, Zandman-Goddard G. Update on intravenous immunoglobulins (IVIg) mechanisms of action and off- label use in autoimmune diseases. Curr Pharm Des 2011;17:3166–75. [3] Zandman-Goddard G, Krauthammer A, Levy Y, Langevitz P, Shoenfeld Y. Long-term therapy with intravenous immunoglobulin is beneficial in patients with autoimmune diseases. Clin Rev Allergy Immunol 2012;42:247–55. [4] Hooper JA. Intravenous immunoglobulins: evolution of commercial IVIG preparations. Immunol Allergy Clin North Am 2008;28:765–78. [5] Martin TD. IGIV: contents, properties, and methods of industrial production–evolving closer to a more physiologic product. Int Immunopharmacol 2006;6:517–22. [6] Cherin P, Marie I, Michallet M, Pelus E, Dantal J, Crave JC, et al. Management of adverse events in the treatment of patients with immunoglobulin therapy: a review of evidence. Autoimmun Rev 2016;15:71–81. [7] Chérin P, Cabane J. Relevant criteria for selecting an intravenous immunoglobulin preparation for clinical use. BioDrugs 2010;24:211–23. [8] Lemm G. Composition and properties of IVIg preparations that affect tolerability and therapeutic efficacy. Neurology 2002;59:S28–32. [9] Gelfand EW. Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med 2012;367:2015–25. [10] Basyreva LY, Brodsky IB, Gusev AA, Zhapparova ON, Mikhalchik EV, Gusev SA, et al. The effect of Intravenous Immunoglobulin (IVIG) on \ textit{ex vivo} activation of human leukocytes. Hum Antibodies 2016;24:39–44. [11] von Gunten S, Shoenfeld Y, Blank M, Branch DR, Vassilev T, Käsermann F, et al. IVIG pluripotency and the concept of Fc-sialylation: challenges to the scientist. Nat Rev Immunol 2014;14:349. [12] Mulhearn B, Bruce IN. Indications for IVIG in rheumatic diseases. Rheumatology (Oxf) 2015;54:383–91. [13] Bayry J, Negi VS, Kaveri SV. Intravenous immunoglobulin therapy in rheumatic diseases. Nat Rev Rheumatol 2011;7:349–59. [14] Furusho K, Kamiya T, Nakano H, Kiyosawa N, Shinomiya K, Hayashidera T, et al. High-dose intravenous gammaglobulin for Kawasaki disease. Lancet 1984;2:1055–8. [15] Oates-Whitehead RM, Baumer JH, Haines L, Love S, Maconochie IK, Gupta A, et al. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev 2003;4:CD004000. [16] Terai M, Shulman ST. Prevalence of coronary artery abnormalities in Kawasaki disease is highly dependent on gamma globulin dose but independent of salicylate dose. J Pediatr 1997;131:888–93. [17] Shulman ST. Intravenous immunoglobulin for the treatment of Kawasaki disease. Pediatr Ann 2017;46:e25–8. [18] Kobayashi T, Saji T, Otani T, Takeuchi K, Nakamura T, Arakawa H, et al. Efficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial. Lancet 2012;379:1613–20. [19] Anh-Tu Hoa S, Hudson M. Critical review of the role of intravenous immunoglobulins in idiopathic inflammatory myopathies. Semin Arthritis Rheum 2017;46:488–508. [20] Dalakas MC, Illa I, Dambrosia JM, Soueidan SA, Stein DP, Otero C, Dinsmore ST, McCrosky S. A controlled trial of high-dose intravenous immune globulin infusions as treatment for dermatomyositis. N Engl J Med 1993;329:1993–2000. [21] Miyasaka N, Hara M, Koike T, Saito E, Yamada M, Tanaka Y. GB-0998 Study Group. Effects of intravenous immunoglobulin therapy in Japanese patients with polymyositis and dermatomyositis resistant to corticosteroids: a randomized double-blind placebo-controlled trial. Mod Rheumatol 2012;22:382–93. [22] Tian J, Gao JS, Chen JW, Li F, Xie X, Du JF. Efficacy and safety of the combined treatment with intravenous immunoglobulin and oral glucocorticoid in the elderly with dermatomyositis. Chin J Geriatr 2008;27:588–90. [23] Cherin P, Piette JC, Wechsler B, Bletry O, Ziza JM, Laraki R, et al. Intravenous gamma globulin as first line therapy in polymyositis and dermatomyositis: an open study in 11 adult patients. J Rheumatol 1994;21:1092–7. [24] Göttfried I, Seeber A, Anegg B, Rieger A, Stingl G, Volc-Platzer B. High dose intravenous immunoglobulin (IVIG) in dermatomyositis: clinical responses and effect on sIL-2R levels. Eur J Dermatol 2000;10:29–35. [25] Cherin P, Pelletier S, Teixeira A, Laforet P, Genereau T, Simon A, et al. Results and long-term followup of intravenous immunoglobulin infusions in chronic, refractory polymyositis: an open study with thirty-five adult patients. Arthritis Rheum 2002;46:467–74. [26] Danieli MG, Malcangi G, Palmieri C, Logullo F, Salvi A, Piani M, et al. Cyclosporin A and intravenous immunoglobulin treatment in polymyositis/ dermatomyositis. Ann Rheum Dis 2002;61:37–41. [27] Danieli MG, Gambini S, Pettinari L, Logullo F, Veronesi G, Gabrielli A. Impact of treatment on survival in polymyositis and dermatomyositis. A single-centre long-term follow-up study. Autoimmun Rev 2014;13:1048–54. [28] Dalakas MC, Sonies B, Dambrosia J, Sekul E, Cupler E, Sivakumar K. Treatment of inclusion-body myositis with IVIg: a double-blind, placebocontrolled study. Neurology 1997;48:712–6. [29] Walter MC, Lochmüller H, Toepfer M, Schlotter B, Reilich P, Schröder M, et al. High-dose immunoglobulin therapy in sporadic inclusion body myositis: a double-blind, placebo-controlled study. J Neurol 2000;247:22–8.

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[30] Dalakas MC, Koffman B, Fujii M, Spector S, Sivakumar K, Cupler E. A controlled study of intravenous immunoglobulin combined with prednisone in the treatment of IBM. Neurology 2001;56:323–7. [31] Patwa HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2012;78:1009–15. [32] Boletis JN, Ioannidis JP, Boki KA, Moutsopoulos HM. Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis. Lancet 1999;354:569–70. [33] Francioni C, Galeazzi M, Fioravanti A, Gelli R, Megale F, Marcolongo R. Long-term i.v. Ig treatment in systemic lupus erythematosus. Clin Exp Rheumatol 1994;12:163–8. [34] Schroeder JO, Zeuner RA, Euler HH, Löffler H. High dose intravenous immunoglobulins in systemic lupus erythematosus: clinical and serological results of a pilot study. J Rheumatol 1996;23:71–5. [35] Levy Y, Sherer Y, Ahmed A, Langevitz P, George J, Fabbrizzi F, et al. A study of 20 SLE patients with intravenous immunoglobulin–clinical and serologic response. Lupus 1999;8:705–12. [36] Zandman-Goddard G, Blank M, Shoenfeld Y. Intravenous immunoglobulins in systemic lupus erythematosus: from the bench to the bedside. Lupus 2009;18:884–8. [37] Sherer Y, Kuechler S, Jose Scali J, Rovensky J, Levy Y, Zandman-Goddard G, et al. Low dose intravenous immunoglobulin in systemic lupus erythematosus: analysis of 62 cases. Isr Med Assoc J 2008;10:55–7. [38] Watad A, Amital H, Shoenfeld Y. Intravenous immunoglobulin: a biological corticosteroid-sparing agent in some autoimmune conditions. Lupus 2017;26:1015–22. [39] Flores G, Cunningham-Rundles C, Newland AC, Bussel JB. Efficacy of intravenous immunoglobulin in the treatment of autoimmune hemolytic anemia: results in 73 patients. Am J Hematol 1993;44:237–42. [40] Goodfield M, Davison K, Bowden K. Intravenous immunoglobulin (IVIg) for therapy-resistant cutaneous lupus erythematosus (LE). J Dermatol Treat 2004;15:46–50. [41] Piette JC, Frances C, Roy S, et al. High-dose immunoglobulins in the treatment of refractory kg/day for five consecutive days each month for a 12-cutaneous lupus erythematosus: open trial in 5 patients. Arthritis Rheum 1995;38(Suppl. 9):304. [42] Espírito Santo J, Gomes MF, Gomes MJ, Peixoto L, Pereira SC, Acabado A, et al. Intravenous immunoglobulin in lupus panniculitis. Clin Rev Allergy Immunol 2010;38:307–18. [43] De Pità O, Bellucci AM, Ruffelli M, Girardelli CR, Puddu P. Intravenous immunoglobulin therapy is not able to efficiently control cutaneous manifestations in patients with lupus erythematosus. Lupus 1997;6:415–7. [44] Wollina U, Looks A, Kammler H-J. Intravenous immunoglobulin therapy in dermatology: overview and center experience. An Bras Dermatol 1998;73:255–9. [45] Alijotas-Reig J. Treatment of refractory obstetric antiphospholipid syndrome: the state of the art and new trends in the therapeutic management. Lupus 2013;22:6–17. [46] Tenti S, Cheleschi S, Guidelli GM, Galeazzi M, Fioravanti A. Intravenous immunoglobulins and antiphospholipid syndrome: how, when and why? A review of the literature. Autoimmun Rev 2016;15:226–35. [47] Branch DW, Peaceman AM, Druzin M, Silver RK, El-Sayed Y, Silver RM, et al. A multicenter, placebo-controlled pilot study of intravenous immune globulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol 2000;182:122–7. [48] Triolo G, Ferrante A, Ciccia F, Accardo-Palumbo A, Perino A, Castelli A, et al. Randomized study of subcutaneous low molecular weight heparin plus aspirin versus intravenous immunoglobulin in the treatment of recurrent fetal loss associated with antiphospholipid antibodies. Arthritis Rheum 2003;48:728–31. [49] Jeremić K, Pervulov M, Gojnić M, Dukanac J, Ljubić A, Stojnić J. Comparison of two therapeutic protocols in patients with antiphospholipid antibodies and recurrent miscarriages. Vojnosanit Pregl 2005;62:435–9. [50] Dendrinos S, Sakkas E, Makrakis E. Low-molecular-weight heparin versus intravenous immunoglobulin for recurrent abortion associated with antiphospholipid antibody syndrome. Int J Gynaecol Obstet 2009;104:223–5. [51] Sciascia S, Giachino O, Roccatello D. Prevention of thrombosis relapse in antiphospholipid syndrome patients refractory to conventional therapy using intravenous immunoglobulin. Clin Exp Rheumatol 2012;30:409–13. [52] Tenti S, Guidelli GM, Bellisai F, Galeazzi M, Fioravanti A. Long-term treatment of antiphospholipid syndrome with intravenous immunoglobulin in addition to conventional therapy. Clin Exp Rheumatol 2013;31:877–82. [53] Cervera R, Bucciarelli S, Plasín MA, Gómez-Puerta JA, Plaza J, Pons-Estel G, et al. Catastrophic antiphospholipid syndrome (CAPS) registry project group (European forum on antiphospholipid antibodies). Catastrophic antiphospholipid syndrome (CAPS): descriptive analysis of a series of 280 patients from the “CAPS Registry”. J Autoimmun 2009;32:240–5. [54] Asherson RA, Cervera R, de Groot PG, Erkan D, Boffa MC, Piette JC, et al. Catastrophic Antiphospholipid Syndrome Registry Project Group. Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus 2003;12:530–4. [55] Cervera R. Update on the diagnosis, treatment, and prognosis of the catastrophic antiphospholipid syndrome. Curr Rheumatol Rep 2010;12:70–6. [56] Cervera R, Rodríguez-Pintó I, Colafrancesco S, Conti F, Valesini G, Rosário C, et al. 14th international congress on antiphospholipid antibodies task force report on catastrophic antiphospholipid syndrome. Autoimmun Rev 2014;13:699–707. [57] Bucciarelli S, Cervera R, Espinosa G, Gómez-Puerta JA, Ramos-Casals M, Font J. Mortalityn in the catastrophic antiphospholipid syndrome: causes of death and prognostic factors. Autoimmun Rev 2006;6:72–5.

Intravenous Immunoglobulin Treatment in Rheumatic Diseases Chapter | 61  651

[58] Lapraik C, Watts R, Bacon P, Carruthers D, Chakravarty K, D’Cruz D, et al. BSR and BHPR guidelines for the management of adults with ANCA associated vasculitis. Rheumatology (Oxf) 2007;46:1615–6. [59] Fortin PM, Tejani AM, Bassett K, Musini VM. Intravenous immunoglobulin as adjuvant therapy for Wegener’s granulomatosis. Cochrane Database Syst Rev 2013;1:CD007057. [60] Jayne DR, Chapel H, Adu D, Misbah S, O’Donoghue D, Scott D, et al. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. Q J Med 2000;93:433–9. [61] Crickx E, Machelart I, Lazaro E, Kahn JE, Cohen-Aubart F, Martin T, et al. Intravenous immunoglobulin as an immunomodulating agent in antineutrophil cytoplasmic antibody-associated vasculitides: a French nationwide study of ninety-two patients. French Vasculitis Study Group. Arthritis Rheumatol 2016;68:702–12. [62] Simoes J, Sciascia S, Camara I, Baldovino S, Karim Y, Roccatello D, et al. Use of intravenous immunoglobulin in patients with active vasculitis associated with concomitant infection. J Clin Rheumatol 2015;21:35–7. [63] Guidelli GM, Tenti S, Pascarelli NA, Galeazzi M, Fioravanti A. Granulomatosis with polyangiitis and intravenous immunoglobulins: a case series and review of the literature. Autoimmun Rev 2015;14:659–64. [64] Raja J, Nihtyanova SI, Murray CD, Denton CP, Ong VH. Sustained benefit from intravenous immunoglobulin therapy for gastrointestinal involvement in systemic sclerosis. Rheumatology (Oxf) 2016;55:115–9. [65] Nacci F, Righi A, Conforti ML, Miniati I, Fiori G, Martinovic D, et al. Intravenous immunoglobulins improve the function and ameliorate joint involvement in systemic sclerosis: a pilot study. Ann Rheum Dis 2007;66:977–9. [66] Clark KE, Etomi O, Denton CP, Ong VH, Murray CD. Intravenous immunoglobulin therapy for severe gastrointestinal involvement in systemic sclerosis. Clin Exp Rheumatol 2015;33(4 Suppl. 91):S168–70. [67] Poelman CL, Hummers LK, Wigley FM, Anderson C, Boin F, Shah AA. Intravenous immunoglobulin may be an effective therapy for refractory, active diffuse cutaneous systemic sclerosis. J Rheumatol 2015;42:236–42. [68] Takehara K, Ihn H, Sato S. A randomized, double-blind, placebo-controlled trial: intravenous immunoglobulin treatment in patients with diffuse cutaneous systemic sclerosis. Clin Exp Rheumatol 2013;31:151–6. [69] Sanges S, Rivière S, Mekinian A, Martin T, Le Quellec A, Chatelus E, et al. Intravenous immunoglobulins in systemic sclerosis: data from a French nationwide cohort of 46 patients and review of the literature. Autoimmun Rev 2017;16:377–84. [70] Rist S, Sellam J, Hachulla E, Sordet C, Puéchal X, Hatron PY, et al. Experience of intravenous immunoglobulin therapy in neuropathy associated with primary Sjögren’s syndrome: a national multicentric retrospective study. Arthritis Care Res (Hoboken) 2011;63:1339–44. [71] Friedman DM, Llanos C, Izmirly PM, Brock B, Byron J, Copel J, et al. Evaluation of fetuses in a study of intravenous immunoglobulin as preventive therapy for congenital heart block: results of a multicenter, prospective, open-label clinical trial. Arthritis Rheum 2010;62:1138–46. [72] Pisoni CN, Brucato A, Ruffatti A, Espinosa G, Cervera R, Belmonte-Serrano M, et al. Failure of intravenous immunoglobulin to prevent congenital heart block: findings of a multicenter, prospective, observational study. Arthritis Rheum 2010;62:1147–52. [73] Brucato A, Cimaz R, Caporali R, Ramoni V, Buyon J. Pregnancy outcomes in patients with autoimmune diseases and anti-Ro/SSA antibodies. Clin Rev Allergy Immunol 2011;40:27–41. [74] Brucato A, Ramoni V, Gerosa M, Pisoni MP. Congenital fetal heart block: a potential therapeutic role for intravenous immunoglobulin. Obstet Gynecol 2011;117:177. [75] Ruffatti A, Cerutti A, Favaro M, Del Ross T, Calligaro A, Hoxha A, Marson P, Leoni L, Milanesi O. Plasmapheresis, intravenous immunoglobulins and bethametasone - a combined protocol to treat autoimmune congenital heart block: a prospective cohort study. Clin Exp Rheumatol 2016;344:706–13. [76] Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, et al. Update on the use of immunoglobulin in human disease: a review of evidence. J Allergy Clin Immunol 2017;139:S1–46. [77] Danieli MG, Pettinari L, Moretti R, Logullo F, Gabrielli A. Subcutaneous immunoglobulin in polymyositis and dermatomyositis: a novel application. Autoimmun Rev 2011;10:144–9. [78] Cherin P, Belizna C, Cartry O, Lascu-Dubos G, de Jaeger C, Delain JC, Crave JC, Hachulla E. Long-term subcutaneous immunoglobulin use in inflammatory myopathies: a retrospective review of 19 cases. Autoimmun Rev 2016;15:281–6.