Intravenous Immunoglobulins Treatment for Autoimmune Diseases: History
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Contributor:
Tsvetelina Velikova
,
Metodija Sekulovski
,
Simona Bogdanova
,
Georgi Vasilev
,
Monika Peshevska-Sekulovska
,
Dimitrina Miteva
,
Tsvetoslav Georgiev

Intravenous administration of immunoglobulins has been routinely used for many years in clinical practice, developed initially as replacement therapy in immunodeficiency disorders. The use of intravenous immunoglobulins (IVIGs) is embedded in the modern algorithms for the management of a few diseases, while in most cases, their application is off-label and thus different from their registered therapeutic indications according to the summary of product characteristics. 

  • intravenous immunoglobulins (IVIGs)
  • autoimmune diseases
  • reproductive failure
  • immunomodulation

1. Introduction

IVIG treatment was introduced for immunodeficient patients for replacement therapy with a dosage regimen of 0.2–0.4 g/kg body weight. The treating doses for patients with immune-mediated diseases are usually higher—1–2 g/kg body weight. After replacement therapy, the expected blood levels of IgG vary between 12–14 mg/mL, whereas after high-dose treatment, the anticipated blood levels of IgG are 25–35 mg/mL [1].
Prior to IVIG administration, serum immunoglobulin levels must be measured. This is recommended because patients with selective IgA deficiency may develop an anaphylactic reaction upon receiving IVIGs due to existing anti-IgA antibodies in their serum. Additionally, a pre-existing hyperglobulinaemia may aggravate, leading to a hyperviscosity state [2].
Among the FDA-approved indications are primary immunodeficiencies, chronic lymphocytic leukemia, pediatric HIV infection, Kawasaki’s disease, allogeneic bone marrow transplantation, chronic inflammatory demyelinating polyneuropathy, kidney transplantation involving a recipient with a high antibody titer or an ABO-incompatible donor and multifocal motor neuropathy [3].
Additional approved conditions, if the needed criteria are met, are neuromuscular disorders (i.e., Guillain–Barré syndrome, relapsing–remitting multiple sclerosis, myasthenia gravis, refractory polymyositis, polyradiculoneuropathy, Lambert–Eaton myasthenic syndrome, opsoclonus–myoclonus, Birdshot retinopathy and refractory dermatomyositis), rheumatic diseases (i.e., ANCA-positive systemic vasculitis, polymyositis, dermatomyositis, anti-phospholipid syndrome, rheumatoid arthritis (RA) and Felty’s syndrome, systemic lupus erythematosus (SLE), juvenile idiopathic arthritis (JIA)), hematologic disorders (i.e., autoimmune hemolytic anemia, severe anemia associated with parvovirus B19, autoimmune neutropenia, neonatal alloimmune thrombocytopenia, HIV-associated thrombocytopenia, graft-versus-host disease, CMV infection or interstitial pneumonia after bone marrow transplantation), dermatologic disorders (i.e., pemphigus vulgaris, pemphigus foliaceous, bullous pemphigoid, mucous–membrane (cicatricial) pemphigoid, epidermolysis bullosa acquisita, toxic epidermal necrolysis or Stevens–Johnson syndrome, necrotizing fasciitis), recurrent spontaneous abortions and sepsis. [3][4].
For some disorders, such as RA, IVIGs may be useful in subsets of RA patients where anti-cytokine blockers or rituximab are contraindicated. Patients with RA and concomitant vasculitis, overlap “rhupus” syndrome, severe active infections and pregnancy are examples of such subgroups of patients. IVIGs may also be used to treat juvenile chronic arthritis (JCA), and adult Still’s disease [5]. However, other sources do not support the use of IVIGs for RA [6].

2. Idiopathic Autoimmune Inflammatory Myositis

Idiopathic inflammatory myopathies (IIM) are diseases that involve the skeletal muscles but can also affect other internal organs such as the gastrointestinal tract, cardiovascular system, lungs and skin [7]. The diseases included in this group are polymyositis, dermatomyositis, inclusion body myositis (IBM), overlap-myositis, immune-mediated necrotizing myositis and antisynthetase syndrome, according to the current classification [8]. Although their clinical presentation is similar, there are differences in the pathogenesis of different types of IIM. For example, in polymyositis and IBM, sensitized CD8+ cytotoxic T cells [9] recognize previously unidentified muscle antigens, leading to phagocytosis and the necrosis of fibers [10]. In dermatomyositis, where a characteristic skin rash is observed, intramuscular microangiopathy occurs, mediated by the attacking complement membranolytic complex C5b-9 [11]. This results in capillary loss, muscle ischemia, muscle fiber necrosis and perifascicular atrophy.
The “conventional” therapy for IIM includes high doses of GCs and immunosuppressive drugs such as cyclophosphamide, cyclosporine A, methotrexate, mycophenolate mofetil, and azathioprine. In refractory cases, IVIGs are also used in treating inflammatory myositis, both polymyositis and dermatomyositis [12]. The effect of IVIG administration is immunomodulatory rather than immunosuppressive [13]. However, the exact mechanisms of action are not fully understood. As a result, their intravenous use leads to a decrease in the migration of inflammatory cells in the muscle fibers, a reduction in the expression of TGFβ in the muscles, inhibition of the maturation of dendritic cells and B-cell proliferation, activation of regulatory T cells (Treg cells) and modulation of proinflammatory cytokines [14].
The recommended dosage of IVIGs for IIM is 2 g/kg, usually divided into two to five separate daily doses with a therapeutic course of 3 to 6 months. IVIG therapy is not usually used as first-line therapy in IIM. Instead, it is often used in refractory, exacerbating, rapidly progressive, or severe polymyositis/dermatomyositis or in patients with contraindications to high-dose GCs. At this stage, no precise guidelines/recommendations have been adopted for IVIG infusions and added to the standard immunosuppressive therapy. However, there is evidence that in patients with dermatomyositis that is refractory to standard treatment, IVIGs in combination with corticosteroids significantly improve muscle strength and motor function and reduce serum creatine phosphokinase (CPK) compared to a placebo [15]. The effect is most pronounced in patients with esophageal involvement [16] or pulmonary involvement [17], as well as in elderly patients [18]. A similar effect was observed in patients with IBM, lasting 2 to 4 months after the administration of IVIGs [19].
Sufficient evidence demonstrated that the administration of immunoglobulins (intravenous or subcutaneous) prolongs life in patients with inflammatory myopathies [20]. Regarding side effects, the medication is relatively well tolerated in patients with IIM. The most common adverse drug reactions observed are headache, fever and nausea [21]. Particular attention is paid to the possibility of thromboembolic incidents.
The ProDERM trial was the first to evaluate the long-term effectiveness and safety of IVIGs (Octagam 10%) in dermatomyositis in a placebo-controlled, blinded, randomized trial. Patients in this trial were given high-dose IVIGs (2.0 g/kg) for up to 40 weeks. However, following an FDA suggestion, the investigators could reduce the dosage to 1.0 g/kg starting at week 28 if the patients’ condition permitted. Because this trial used long-term IVIG medication at a potentially high dosage and because patients with dermatomyositis are at a greater risk of thromboembolic events and hemolytic transfusion responses, special attention was paid to monitoring these complications [22].

3. Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease with a heterogeneous clinical manifestation involving symptoms and syndromes from many organs and systems. It was not until the late 1980s that IVIGs were used to treat SLE [23]. The use of IVIGs in patients with SLE has several indications (i.e., pancytopenia, central nervous system (CNS) involvement, refractory thrombocytopenia, secondary anti-phospholipid syndrome and lupus nephritis).
It has been suggested that patients with SLE have a dysregulation of the FcγR system, where the balance between activating and inhibitory FcγR signaling is disturbed. Although the exact mode of action of IVIGs is not fully understood, it is suggested that the IgG Fc segments of IVIGs bind to macrophage Fc receptors, which in turn inhibit autoantibody binding to these receptors. Furthermore, IVIGs exert their therapeutic properties by inhibiting membrane attack complex formation by restraining the Fc segment from complement components C3b and C4b [24].
IVIG therapy leads to the suppression of T cells [25]. Furthermore, IVIGs decrease the Th1/Th2 ratio, which leads to a change in the peripheral Th1/Th2 balance in favor of the Th2 subpopulation [26]. In addition, IVIGs decrease the activation of FcRIIA and FcRIIC and/or increase the inhibitory FcRIIB. Ultimately, the therapy leads to the inhibition of complement-mediated injury, modulation of cytokines and cytokine antagonists production, T- and B-cells’ function, induction of apoptosis in lymphocytes and monocytes and reduction in the production and neutralization of pathological autoantibodies [27].
The use of IVIGs for treating SLE does not yet have official approval from the Food and Drug Administration (FDA); however, the drug is used off-label in cases where patients are refractory to standard therapy and/or have contraindications. The therapeutic dose of IVIGs in SLE is 2 g/kg divided into five daily doses of 400 mg/kg each to prevent the risk of adverse reactions [28]. Diseases such as severe congestive heart failure, renal failure or evidence of hypercoagulation are a contraindication for the therapy. Depending on the patient’s response and the objective signs of the disease, long-term therapy is carried out for a period of 6–12 months, and treatment courses are repeated every 4–6 weeks. For now, there is evidence that the administration of IVIGs can have a GCs-sparing effect, both on the maintenance dose and the cumulative GCs dose in patients with SLE.
However, data regarding their effect on complement fractions and the reduction of lupus-specific antibody levels are conflicting. IVIGs are known to accelerate autoantibody catabolism by binding to a specific Fc receptor found on endothelial cells called FcRn [28]. FcRn is a transport receptor that binds intracellular IgG and protects it from catabolism and lysosomal degradation. Saturation of FcRn receptors by IVIG treatment prevents the binding of endogenous IgG autoantibodies, which accelerates their degradation and reduces levels of pathogenic autoantibodies.
On the other hand, a proven effect was observed on the reduction of proteinuria induced by lupus nephritis [29]. The Fc receptors suggested to contribute to the deposition of IgG in the kidney in SLE are FcγRI (activating receptor for monomeric Ig), FcγRII (inhibitory immune complex receptor) and FcγRIV (activating immune complex receptors). IVIGs can beneficially affect the balance between activating and inhibitory Fc receptors in the kidney, resulting in more significant degradation and urinary excretion of autoantibodies to minimize renal parenchymal damage [30]. IVIG therapy is indicated in patients with lupus nephritis who have contraindications for conducting conventional immunosuppressive treatment, do not respond to standard therapy, have a concomitant superimposed infection or during pregnancy [31].
IVIGs have also been shown to inhibit the expression of human leukocyte antigen and CD80/86 on dendritic cells leading to a reduction in the differentiation of dendritic cells from blood monocytes, which has an immunomodulatory effect [32]. In addition, clinical studies indicate that IVIG therapy reduces disease activity indices [33]. IVIGs also reduce proinflammatory cytokines such as TNF-α and IL-6 [34].
One of the most significant advantages of IVIG therapy is that, unlike conventional immunosuppressants, which predispose to systemic infections, IVIGs actually prevent infections and provide passive immunity [35]. In addition, the side effects of immunosuppressants, such as neocarcinogenesis, gonadotoxicity, hemorrhagic cystitis and cytopenias, are also avoided.

4. Anti-Phospholipid Syndrome

Anti-phospholipid syndrome (APS) is characterized by the presence of anti-phospholipid antibodies (aPL) (i.e., lupus anticoagulant (LA), anticardiolipin (aCL), anti-2 glycoprotein-I (2GPI) antibodies, anti-annexin antibodies), venous and arterial thromboses and recurrent fetal losses. The current concept for treating thrombotic APS is heparin administration, followed by long-term anticoagulation. In contrast, for obstetric APS, the therapy is low-dose aspirin (LDA) plus preventive unfractionated or low-molecular-weight heparin (LMWH) [36].
Tenti et al. focused on the 35 articles, 14 case reports, 9 case series and 12 clinical trials (9 open-label, 3 randomized controlled) published on IVIGs for APS, with a total of 802 patients, 99% of them being women [36]. However, the evidence for IVIG therapy in nonpregnant APS patients is scarce.
In a study, the patients with high-risk aPL profiles were administered at a dose of 0.4 g/kg/daily IVIG infusions, in addition to conventional therapy (anticoagulants or antiplatelets) for 3 months to obtain primary or secondary thromboprophylaxis. Then, the patients were administered a monthly infusion of 0.4 g/kg/day for 9 months. A 5-year follow-up demonstrated no thrombosis that was clinically or instrumentally proven [37].
However, no significant differences were observed in aPL levels before and after IVIG treatment at 6, 12 and 24 months [31]. Therefore, primary or secondary thrombosis prophylaxis is still controversial, and there is no adequate therapy. Nevertheless, adding IVIGs to conventional treatment as an immunomodulator is promising and encouraging [38]. Furthermore, IVIG administration could be beneficial in preventing recurrent thrombosis in APS patients who are refractory to conventional anticoagulant therapy [36].
Regarding catastrophic APS, some studies employed IVIGs, demonstrating the beneficial effects of immunoglobulins when combined with the standard therapy or biologics (i.e., rituximab) [39], especially when the patients are refractory to conventional anticoagulant therapy [36]. In rare cases, catastrophic APS may be refractory to high-dose IVIGs, then plasma exchange could be performed [40].

5. Systemic Sclerosis

Progressive systemic sclerosis (SSc) is a chronic autoimmune disease characterized by progressive skin fibrosis, obliteration of microvasculature and excessive extracellular matrix deposition. In addition, it leads to multisystem dysfunction [41]. The etiology and pathogenesis of this disease are still not fully understood.
Given the heterogeneous clinical manifestation involving symptoms and syndromes from many organs and systems, the therapeutic challenges to treating this disease are still the subject of extensive research [42]. In addition, the condition is relatively rare, with a variable course and possible severe complications. Several immunomodulatory agents are also used in the therapeutic arsenal of SSc. At this stage, no drug has been proven effective in the long-term control of the disease; thus, treatment has mainly remained symptomatic in recent years [43][44]. New therapies are currently being tested and may potentially alter the disease process and overall clinical outcome [45]. IVIG therapy in patients with SSc has been used since 2000 in various therapeutic doses and regimens [41][42][43][44][45][46].
At this stage, there is a lack of definitive guidelines on when and how to administer IVIG treatment. The usual dose is 1–2 g/kg body weight distributed over 2–5 consecutive days, with the recommendation of 3–4 courses per year. According to the literature data, single cases have been described in which therapy has benefited skin involvement, musculoskeletal symptoms [44] and symptoms of interstitial lung disease. In addition, cases of IVIG-treated SSc patients with active diffuse cutaneous scleroderma (dcSSc) refractory to standard immunosuppressive therapy have been described, with improvement in the modified Rodnan skin score (mRSS) [45]. The same authors also describe the preservation of lung function without deterioration of forced vital capacity (FVC) at follow-up and the improvement in joint function. Still, definitive evidence of delay and/or improvement of interstitial lung disease at this stage is lacking. A similar effect on skin symptoms was also observed in patients with rapidly progressive skin involvement, with no effect on the immunological activity of the disease, i.e., on the antibody titer [44]. In addition, IVIGs reduce systemic inflammation and acute phase indicators [47] and help reduce the daily dose of corticosteroids at the end of treatment.
In patients with musculoskeletal involvement, they lead to a reduction in muscle weakness and pain, a reduction in joint pain and a reduction in serum creatine phosphokinase (CPK) levels [48]. Benefits on gastrointestinal symptoms following courses of IVIGs have been described, resulting in a reduction in the frequency and severity of symptoms of gastro-oesophageal reflux disease. Improvement of motility disorders of the gastrointestinal tract, both in the neuropathic and myopathic stages, is carried out by influencing antibodies against muscarinic-3 receptors (M3-R) [49]. There is no evidence of the influence of IVIG therapy on the manifestations of peripheral vasospasm (Raynaud’s syndrome).
IVIG therapy’s most common side effects are flu-like symptoms [50], headache, facial flushing, malaise, chills, fever, vomiting, diarrhea, nausea, myalgia, back pain, fatigue, dyspnea and changes in blood pressure [51]. These manifestations are reversible with prior application of analgesics, non-steroidal anti-inflammatory drugs, antihistamines or intravenous GCs. Nevertheless, late adverse reactions can be severe and include acute renal failure, thromboembolic vascular events (myocardial infarctions, cerebrovascular events, deep vein thrombosis and pulmonary embolism), aseptic meningitis, neutropenia, autoimmune hemolytic anemia, skin reactions, arthritis and pseudo hyponatremia [52].

6. Kawasaki Disease

Kawasaki disease is a self-limited acute vasculitis that affects small and medium-sized vessels [53]. It is among the leading causes of pediatric-acquired heart disease in developed countries and the second most common type of childhood vasculitis after Henoch–Schönlein purpura [54]. Although the inflammatory process resolves spontaneously in most patients, up to 25% of untreated patients present coronary artery involvement [55], which is reduced to less than 5% in children treated with high-dose intravenous immunoglobulin [56] by a still unknown mechanism [57].
The dosage and time of administration in the disease course remain debatable. However, a recent meta-analysis has shown that IVIGs in the early stage of disease onset might be associated with an increased risk of treatment unresponsiveness. On another note, a timely and adequate IVIG dosage could be a protective factor against the development of coronary artery lesions [56]. The most often prescribed IVIG therapy is at 2 g/kg. Nevertheless, older adolescents with more significant body weights sometimes require higher IVIG dosages, which leads to additional challenges and costs. It is unclear if a 2 g/kg dose of IVIGs is necessary for older children with Kawasaki disease. A study found no significant difference in hospitalization length, but the medical expenses were considerably greater. The number of IVIG side effects was too minor to compare. Based on the fact that IVIGs are a costly medicine, the dosage must be carefully examined [58].

7. ANCA-Associated Vasculitides

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs) are granulomatosis with polyangiitis (GPA, Wegener’s granulomatosis), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg–Strauss syndrome). The European League Against Rheumatism (EULAR) revised their recommendations for the treatment of AAV in 2016, including IVIGs [2].
A randomized, placebo-controlled trial investigated the potential of IVIGs for patients with AAV with a single course of a total dose of 2 g/kg in previously-treated AAVs with persistent disease activity. It was shown that IVIGs exerted less toxicity than conventional immunosuppressive agents while reducing disease activity. However, this effect was not maintained after 3 months [59].
Fortin et al. aimed to investigate the IVIGs as adjuvant therapy for WG as a therapeutic advantage over and above treatment with systemic corticosteroids in combination with immunosuppressants. One randomized controlled trial was included in the analysis. The decreased disease activity score was slightly more excellent for the IVIG treatment than the placebo, and the total adverse effects were fewer in the IVIG-treated group. However, the analysis could not confirm the therapeutic advantages of IVIGs above other conventional therapy, and the authors concluded that given the high cost of IVIGs, IVIGs should be limited to WG treatment in the context of well-conducted randomized controlled trials [60].
A study by Muso et al. also demonstrated a high safety profile of IVIGs at 0.4 g/kg/day administered for 5 consecutive days before or with conventional immunosuppressive therapy to 30 myeloperoxidase (MPO) ANCA-positive rapidly progressive glomerulonephritis patients [61].
Based on these studies, EULAR recommends adjunctive therapy with IVIGs for patients who fail to achieve remission and have a persistent low activity to help maintain remission [2]. In addition, ACR recommends the following: for GPA/MPA that is refractory to remission induction therapy, adding IVIGs (2 mg/kg as adjunctive therapy for short-term control, while waiting for remission induction therapy (i.e., cyclophosphamide or rituximab) to become effective. Additionally, according to ACR recommendations, IVIGs should not be used routinely to treat GPA/MPA [62].

8. Gastrointestinal Autoimmune Diseases

An organ manifestation of autoimmune dysautonomia, autoimmune gastrointestinal dysmotility (AGID), is a newly characterized clinical condition that can be either an idiopathic or paraneoplastic phenomenon [63]. Generalized dysautonomia may be accompanied by gastrointestinal hypomotility or hypermotility, or it may be a feature of a multifocal paraneoplastic autoimmune neurological illness. The symptoms may include gastroparesis, colonic inertia or intestinal pseudoobstruction [64]. In a few rare cases, pyloric obstruction or anal spasms have also been reported as well. Early satiety, nausea, vomiting, bloating, diarrhea, constipation and involuntary weight loss are among the symptoms [65].
As far as treatment is concerned, there have been several options, among which is IVIG administration. In their study, Schofield et al., presented approximately 85% clinical improvement in IVIG-treated patients because of autoimmune dysautonomia. They included 38 patients, 8 of whom had GI dysmotility [66]. Kawanishi et al. reported another interesting case report about a 37-year-old woman who had been diagnosed with idiopathic chronic intestinal pseudoobstruction as a clinical presentation of AGID. They treated her with total parenteral nutrition, a gastrointestinal prokinetic agent and opiates as pain relievers. However, breakthrough pain continued; thus, Kawanishi et al. applied IVIGs with slight improvement [67]. AGID could also be a post-viral complication except for paraneoplastic and idiopathic characteristics, for example, the case reported by Montalvo et al. of a patient with AGID resulting from SARS-CoV-2. Despite various medications, her condition has worsened to total parenteral feeding. Hence, the IVIG administration has been initiated. The patient started to improve after the second infusion and tolerated oral nutrition. After four months of IVIG treatment, her symptoms significantly improved, and she tolerated a full oral diet without any symptoms [68].

9. Autoimmune Neurological Disorders

Moralez-Ruiz et al., in their systematic review and meta-analysis, focused on the efficacy of IVIGs in autoimmune neurological diseases, including Guillain–Barré syndrome, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, optic neuritis and multiple sclerosis [69]. The results demonstrated that IVIG administration outweighed the placebo, had similar efficacy as plasmapheresis and did not differ significantly from GCs [69].
Guillain–Barré syndrome (GBS) is an autoimmune-mediated disorder of the peripheral nervous system that is the most common cause of acute-onset flaccid paralysis in the developed world nowadays. It typically presents with weakness and sensory phenomena affecting the distal areas of the lower limbs at first and then ascending proximally, but several variants of the disease exist [70].
As the natural history of the disease usually follows a viral or bacterial infection in the previous few weeks, it is firmly believed that the pathogenesis of GBS includes an antibody response to microbial structures, especially those of Campylobacter jejuni, mimicking neuronal gangliosides and glycolipids [71]. In the most severe forms of the disease, where marked axonal degeneration heralds a grave prognosis, IgG antibodies against GM1, GD1b and/or GD1a gangliosides of peripheral neurons are encountered [72].
The first randomized controlled trial comparing the effectiveness of IVIGs vs. plasma exchange in patients with Guillain–Barré syndrome found that not only treatment with an IVIG dose of 0.4 g/kg body weight per day for 5 days was not only at least as effective as plasma exchange but also led to improved motor functions and hastened recovery in significantly more patients than plasma exchange. In addition, patients treated with IVIGs experienced fewer adverse events [73].
In a double-blind, multi-center trial in France, the optimal duration of IVIGs in Guillain–Barré syndrome was studied. The primary end-point was the time needed to regain the ability to walk with assistance. The study found that a longer course of 5 to 6 days of IVIG treatment (resulting in 2 g and 2.4 g total IVIG doses, respectively) leads to improved recovery, compared to a shorter, 3-day course (1.2 g total dose) [74].
Intravenous immunoglobulins have appeared to be crucial in managing acute exacerbations of neuromuscular disorders, most notably in Myasthenia Gravis and Lambert–Eaton Myasthenic syndrome. Myasthenia Gravis presents with fluctuating muscle weakness and pathological muscle fatiguability affecting the extraocular, bulbar, skeletal and respiratory muscles. The first trial comparing the effectiveness of IVIGs vs. plasma exchange in acute myasthenic crises was undertaken between 1996 and 2002 and found comparable results of both interventions with fewer adverse events and ease of application in the IVIG-treated group. Interestingly, a shorter 3-day course of 1.2 g total dose was superior to longer courses, contrasting with the findings in Guillain–Barré syndrome treatment [75].
IVIGs have also been implemented to manage Lambert–Eaton Myasthenic syndrome exacerbations. It is a disorder caused by autoantibodies directed against calcium voltage-gated membrane channels. In a placebo-controlled trial, a short course of 1 g/kg of IVIGs for 2 days markedly improved muscle strength and reduced serum calcium channel autoantibodies titers [76].

10. Other Autoimmune Diseases

However, many other autoimmune and immune-mediated conditions may benefit from IVIG administration. For the selected dermatological autoimmune disease (pemphigus vulgaris, pemphigus foliaceous, bullous pemphigoid, mucous membrane pemphigoid, epidermolysis bullosa acquisita, and cutaneous lupus erythematosus), IVIGs are commonly used, but as a second- or third-line treatment. Serious side effects were rare; the most common adverse effects reported were febrile infusion reactions, nausea, headache and fatigue [77].
A systemic review of Gao et al. on IVIG administration in livedoid vasculopathy (LV) concluded that IVIGs at a 1–2.1 g/kg body weight every 4 weeks is a safe and effective treatment alternative for refractory LV patients [78]. The patients demonstrated a good clinical response (i.e., reduction in pain, skin ulcerations and neurological symptoms) and decreased dependence on GCs and immunosuppressive agents. Moreover, IVIG infusions were well tolerated, and no severe adverse events were observed.

This entry is adapted from the peer-reviewed paper 10.3390/antib12010020

References

  1. Schwab, I.; Nimmerjahn, F. Intravenous immunoglobulin therapy: How does IgG modulate the immune system? Nat. Rev. Immunol. 2013, 13, 176–189.
  2. Yates, M.; A Watts, R.; Bajema, I.M.; Cid, M.C.; Crestani, B.; Hauser, T.; Hellmich, B.; Holle, J.U.; Laudien, M.; A Little, M.; et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann. Rheum. Dis. 2016, 75, 1583–1594, Erratum in: Ann. Rheum Dis. 2017, 76, 1480; Erratum in: Ann. Rheum Dis. 2022, 81, e109.
  3. Gelfand, E.W. Intravenous Immune Globulin in Autoimmune and Inflammatory Diseases. N. Engl. J. Med. 2012, 367, 2015–2025.
  4. Negi, V.-S.; Elluru, S.R.; Siberil, S.; Graff-Dubois, S.; Mouthon, L.; Kazatchkine, M.D.; Lacroix-Desmazes, S.; Bayry, J.; Kaveri, S.V. Intravenous Immunoglobulin: An Update on the Clinical Use and Mechanisms of Action. J. Clin. Immunol. 2007, 27, 233–245.
  5. Katz-Agranov, N.; Khattri, S.; Zandman-Goddard, G. The role of intravenous immunoglobulins in the treatment of rheumatoid arthritis. Autoimmun. Rev. 2015, 14, 651–658.
  6. Mulhearn, B.; Bruce, I.N. Indications for IVIG in rheumatic diseases. Rheumatology 2014, 54, 383–391.
  7. Dalakas, M.C. Inflammatory Myopathies. In Handbook of Clinical Neurology; Rowland, L.P., DiMauro, S., Eds.; Elsevier Science: Amsterdam, The Netherlands, 1992; Volume 18, pp. 369–390.
  8. Dalakas, M.C. Inflammatory myopathies. Curr. Opin. Neurol. Neurosurg 1990, 3, 689–696.
  9. Emslie-Smith, A.M.; Arahata, K.; Engel, A.G. Major histocompatibility complex class I antigen expression, immunolocalization of interferon subtypes, and T cell-mediated cytotoxicity in myopathies. Hum. Pathol. 1989, 20, 224–231.
  10. Engel, A.G.; Arahata, K. Mononuclear cells in myopathies: Quantitation of functionally distinct subsets, recognition of antigen-specific cell-mediated cytotoxicity in some diseases, and implications for the pathogenesis of the different inflammatory myopathies. Hum. Pathol. 1986, 17, 704–721.
  11. Kissel, J.T.; Mendell, J.R.; Rammohan, K.W. Microvascular deposition of complement membrane attack complex in dermatomyositis. N. Engl. J. Med. 1986, 314, 329–334.
  12. Oxford Centre for Evidence-Based Medicine: Levels of Evidence (March 2009). Available online: https://www.cebm.ox.ac.uk/resources/levels-of-evidence/oxford-centre-for-evidence-based-medicine-levels-of-evidence-march-2009 (accessed on 15 February 2023).
  13. Oddis, C.V. Update on the pharmacological treatment of adult myositis. J. Intern. Med. 2016, 280, 63–74.
  14. Dalakas, M.C. Mechanistic Effects of IVIg in Neuroinflammatory Diseases: Conclusions Based on Clinicopathologic Correlations. J. Clin. Immunol. 2014, 34, S120–S126.
  15. Dalakas, M.C.; Illa, I.; Dambrosia, J.M.; Soueidan, S.A.; Stein, D.P.; Otero, C.; Dinsmore, S.T.; McCrosky, S. A Controlled Trial of High-Dose Intravenous Immune Globulin Infusions as Treatment for Dermatomyositis. N. Engl. J. Med. 1993, 329, 1993–2000.
  16. Marie, I.; Menard, J.-F.; Hatron, P.Y.; Hachulla, E.; Mouthon, L.; Tiev, K.; Ducrotte, P.; Cherin, P. Intravenous immunoglobulins for steroid-refractory esophageal involvement related to polymyositis and dermatomyositis: A series of 73 patients. Arthritis Care Res. 2010, 62, 1748–1755.
  17. Suzuki, Y.; Hayakawa, H.; Miwa, S.; Shirai, M.; Fujii, M.; Gemma, H.; Suda, T.; Chida, K. Intravenous Immunoglobulin Therapy for Refractory Interstitial Lung Disease Associated with Polymyositis/Dermatomyositis. Lung 2009, 187, 201–206.
  18. Cherin, P.; Pelletier, S.; Teixeira, A.; Laforet, P.; Genereau, T.; Simon, A.; Maisonobe, T.; Eymard, B.; Herson, S. Results and long-term follow-up of intravenous immunoglobulin infusions in chronic, refractory polymyositis: An open study with thirty-five adult patients. Arthritis Rheum. 2002, 46, 467–474.
  19. Soueidan, S.A.; Dalakas, M.C. Treatment of inclusion-body myositis with high-dose intravenous immunoglobulin. Neurology 1993, 43, 876.
  20. Danieli, M.G.; 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, 1048–1054.
  21. Aggarwal, R.; Charles-Schoeman, C.; Schessl, J.; Bata-Csorgo, Z.; Dimachkie, M.; Zoltan, G.; Sergey, M.; Chester, O.; Elena, S.; Jiri, V.; et al. The ProDERM study: Safety and Tolerability Results from randomized, double-blind, placebo-controlled Phase-III-Trial in Patients with Dermatomyositis (P3-1.004). Neurology 2022, 98 (Suppl. S18), 2564.
  22. Aggarwal, R.; Charles-Schoeman, C.; Schessl, J.; Dimachkie, M.M.; Beckmann, I.; Levine, T. Prospective, double-blind, randomized, placebo-controlled phase III study evaluating efficacy and safety of octagam 10% in patients with dermatomyositis (“ProDERM Study”). Medicine 2021, 100, e23677.
  23. Corvetta, A.; Della Bitta, R.; Gabrielli, A.; Spaeth, P.J.; Danieli, G. Use of high-dose intravenous immunoglobulin in systemic lupus erythematosus: Report of three cases. Ann. Rheum. Dis. 1989, 7, 295–299.
  24. Basta, M. Modulation of complement-mediated immune damage by intravenous immune globulin. Clin. Exp. Immunol. 1996, 104, 21–25.
  25. Ballow, M. Mechanisms of action of intravenous immunoglobulin therapy and potential use in autoimmune connective tissue diseases. Cancer 1991, 68 (Suppl. S6), 1430–1436.
  26. HYamada; Morikawa, M.; Furuta, I.; Kato, E.; Shimada, S.; Iwabuchi, K.; Minakami, H. Intravenous immunoglobulin treatment in women with recurrent abortions: Increased cytokine levels and reduced Th1/Th2 lymphocyte ratio in peripheral blood. Am. J. Reprod. Immunol. 2003, 49, 84.
  27. Toubi, E.; Kessel, A.; Shoenfeld, Y. High-Dose Intravenous Immunoglobulins: An Option in the Treatment of Systemic Lupus Erythematosus. Hum. Immunol. 2005, 66, 395–402.
  28. Akilesh, S.; Petkova, S.; Sproule, T.; Shaffer, D.; Christianson, G.; Roopenian, D. The MHC class I-like Fc receptor promotes humorally mediated autoimmune disease. J. Clin. Investig. 2004, 113, 1328.
  29. Boletis, J.N.; Ioannidis, J.P.; A Boki, K.; Moutsopoulos, H.M. Intravenous immunoglobulin compared with cyclophosphamide for proliferative lupus nephritis. Lancet 1999, 354, 569–570.
  30. Wenderfer, S.E.; Thacker, T. Intravenous Immunoglobulin in the Management of Lupus Nephritis. Autoimmune Dis. 2012, 2012, 589359.
  31. Ruiz-Irastorza, G.; Espinosa, G.; Frutos, M.; Jiménez-Alonso, J.; Praga, M.; Pallarés, L.; Riverag, F.; Marhuendah, Á.R.; Segarrai, A.; Queredaj, C. Diagnosis and treatment of lupus nephritis: Consensus document from the systemic autoimmune disease group (GEAS) of the Spanish Society of Internal Medicine (SEMI) and the Spanish Society of Nephrology (S.E.N.). Nefrologia 2012, 32 (Suppl. S1), 1–45.
  32. Bayry, S.; Lacroix-Desmazes, S.; Deligant, L.; Mouthon, B.; Weill, M.D. Kazatchkine IVIG abrogates dendritic cell differentiation induced by interferon-α present in serum from patients with SLE. Arthritis Rheum. 2003, 48, 3497.
  33. Schroeder, J.; A Zeuner, R.; Euler, H.H.; Löffler, H. High dose intravenous immunoglobulins in systemic lupus erythematosus: Clinical and serological results of a pilot study. J. Rheumatol. 1996, 23, 71–75.
  34. Karin, N. Induction of protective therapy for autoimmune diseases by targeted DNA vaccines encoding proinflammatory cytokines and chemokine. Curr. Opin. Mol. Ther. 2004, 6, 27.
  35. Molica, S.; Musto, P.; Chiurazzi, F.; Specchia, G.; Brugiatelli, M.; Cicoira, L.; Levato, D.; Nobile, F.; Carotenuto, M.; Liso, V.; et al. Prophylaxis against infections with low-dose intravenous immunoglobulins (IVIG) in chronic lymphocytic leukemia. Results of a crossover study. Haematologica 1996, 81, 121–126.
  36. Tenti, S.; Cheleschi, S.; Guidelli, G.M.; Galeazzi, M.; Fioravanti, A. Intravenous immunoglobulins and antiphospholipid syndrome: How, when and why? A review of the literature. Autoimmun. Rev. 2016, 15, 226–235.
  37. Sciascia, S.; Giachino, O.; Roccatello, D. Prevention of thrombosis relapse in anti-phospholipid syndrome patients refractory to conventional therapy using intravenous immunoglobulin. Clin. Exp. Rheumatol. 2012, 30, 409–413.
  38. Erkan, D.; Aguiar, C.L.; Andrade, D.; Cohen, H.; Cuadrado, M.J.; Danowski, A.; Levy, R.A.; Ortel, T.L.; Rahman, A.; Salmon, J.E.; et al. 14th International Congress on Anti-phospholipid Antibodies: Task force report on anti-phospholipid syndrome treatment trends. Autoimmun. Rev. 2014, 13, 685–696.
  39. Rymarz, A.; Niemczyk, S. The complex treatment including rituximab in the Management of Catastrophic Antiphospholid Syndrome with renal involvement. BMC Nephrol. 2018, 19, 132.
  40. James, T.E.; Martin, L.J.; Warkentin, T.E.; Crowther, M.A. Catastrophic antiphospholipid syndrome refractory to high-dose intravenous immunoglobulin responsive to therapeutic plasma exchange. Platelets 2020, 32, 828–831.
  41. Gomes, J.P.F.; Santos, L.; Shoenfeld, Y. Intravenous immunoglobulin (IVIG) in the vanguard therapy of Systemic Sclerosis. Clin. Immunol. 2018, 199, 25–28.
  42. Cantarini, L.; Rigante, D.; Vitale, A.; Napodano, S.; Sakkas, L.I.; Bogdanos, D.P.; Shoenfeld, Y. Intravenous immunoglobulins (IVIG) in systemic sclerosis: A challenging yet promising future. Immunol. Res. 2014, 61, 326–337.
  43. Levy, Y.; Sherer, Y.; Langevitz, P.; Lorber, M.; Rotman, P.; Fabrizzi, F.; Shoenfeld, Y. Skin score decrease in systemic sclerosis patients treated with intravenous immunoglobulin—A preliminary report. Clin. Rheumatol. 2000, 19, 207–211.
  44. Nacci, F.; Righi, A.; Conforti, M.L.; Miniati, I.; Fiori, G.; Martinovic, D.; Melchiorre, D.; Sapir, T.; Blank, M.; Shoenfeld, Y.; et al. Intravenous immunoglobulins improve the function and ameliorate joint involvement in systemic sclerosis: A pilot study. Ann. Rheum. Dis. 2007, 66, 977–979.
  45. Poelman, C.L.; Hummers, L.K.; Wigley, F.M.; Anderson, C.; Boin, F.; Shah, A.A. Intravenous Immunoglobulin May Be an Effective Therapy for Refractory, Active Diffuse Cutaneous Systemic Sclerosis. J. Rheumatol. 2014, 42, 236–242.
  46. Takehara, K.; Ihn, H.; Sato, S. A randomized, double-blind, placebo-controlled trial: Intravenous immunoglobulin treatment in patients with diffuse cutaneous systemic sclerosis. Ann. Rheum. Dis. 2013, 31 (Suppl. S76), 151–156.
  47. Blank, M.; Levy, Y.; Amital, H.; Shoenfeld, Y.; Pines, M.; Genina, O. The role of intravenous immunoglobulin therapy in mediating skin fibrosis in high skin mice. Arthritis Rheum. 2002, 46, 1689–1690.
  48. Sanges, S.; Rivière, S.; Mekinian, A.; Martin, T.; Le Quellec, A.; Chatelus, E.; Lescoat, A.; Jego, P.; Cazalets, C.; Quéméneur, T.; et al. Launay Intravenous immunoglobulins in systemic sclerosis: Data from a French nationwide cohort of 46 patients and review of the literature. Autoimmun. Rev. 2017, 16, 377–384.
  49. Kumar, S.; Singh, J.; Kedika, R.; Mendoza, F.; Jimenez, S.; Blomain, E.S.; Dimarino, A.J.; Cohen, S.; Rattan, S. Role of muscarinic-3 receptor antibody in systemic sclerosis: Correlation with disease duration and effects of IVIG. Am. J. Physiol. Liver Physiol. 2016, 310, G1052–G1060.
  50. Sherer, Y.; Levy, Y.; Langevitz, P.; Rauova, L.; Fabrizzi, F.; Shoenfeld, Y. Adverse effects of intravenous immunoglobulin therapy in 56 patients with autoimmune diseases. Pharmacology 2001, 62, 133–137.
  51. Orbach, H.; Katz, U.; Sherer, Y.; Shoenfeld, Y. Intravenous immunoglobulin: Adverse effects and safe administration. Clin. Rev. Allergy Immunol. 2005, 29, 173–184.
  52. Katz, U.; Achiron, A.; Sherer, Y.; Shoenfeld, Y. Safety of intravenous immunoglobulin (IVIG) therapy. Autoimmun. Rev. 2007, 6, 257–259.
  53. Sharma, D.; Singh, S. Kawasaki disease—A common childhood vasculitis. Indian J. Rheumatol. 2015, 10, S78–S83.
  54. Taubert, K.A.; Rowley, A.H.; Shulman, S.T. Nationwide survey of Kawasaki disease and acute rheumatic fever. J. Pediatr. 1991, 119, 279–282.
  55. Newburger, J.W.; Takahashi, M.; Gerber, M.A.; Gewitz, M.H.; Tani, Y.; Burns, J.C.; Shulman, S.T.; Bolger, F.; Ferrieri, P.; Baltimore, R.S.; et al. Diagnosis, treatment, and long-term management of Kawasaki disease: A statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics 2004, 114, 1708–1733.
  56. Yan, F.; Zhang, H.; Xiong, R.; Cheng, X.; Chen, Y.; Zhang, F. Effect of Early Intravenous Immunoglobulin Therapy in Kawasaki Disease: A Systematic Review and Meta-Analysis. Front. Pediatr. 2020, 8, 593435.
  57. McCrindle, B.W.; Rowley, A.H.; Newburger, J.W.; Burns, J.C.; Bolger, A.F.; Gewitz, M.; Baker, A.L.; Jackson, M.A.; Takahashi, M.; Shah, P.B.; et al. Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease: A Scientific Statement for Health Professionals from the American Heart Association. Circulation 2017, 135, e927–e999.
  58. Suzuki, T.; Michihata, N.; Yoshikawa, T.; Hata, T.; Matsui, H.; Fushimi, K.; Yasunaga, H. High-dose versus low-dose intravenous immunoglobulin for treatment of children with Kawasaki disease weighing 25 kg or more. Eur. J. Pediatr. 2020, 179, 1901–1907.
  59. Jayne, D.; Chapel, H.; Adu, D.; Misbah, S.; O’Donoghue, D.; Scott, D.; Lockwood, C. Intravenous immunoglobulin for ANCA-associated systemic vasculitis with persistent disease activity. Qjm: Int. J. Med. 2000, 93, 433–439.
  60. Fortin, P.M.; Tejani, A.M.; Bassett, K.; Musini, V. Intravenous immunoglobulin as adjuvant therapy for Wegener’s granulomatosis. Cochrane Database Syst. Rev. 2013, 31, CD007057.
  61. Muso, E.; Ito-Ihara, T.; Ono, T.; Imai, E.; Yamagata, K.; Akamatsu, A.; Suzuki, K. Intravenous immunoglobulin (IVIg) therapy in MPO-ANCA related polyangiitis with rapidly progressive glomerulonephritis in Japan. Jpn. J. Infect. Dis. 2004, 57, S17–S18.
  62. Chung, S.A.; Langford, C.A.; Maz, M.; Abril, A.; Gorelik, M.; Guyatt, G.; Archer, A.M.; Conn, D.L.; Full, K.A.; Grayson, P.C.; et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis. Arthritis Rheumatol. 2021, 73, 1366–1383.
  63. Pasha, S.F.; Lunsford, T.N.; Lennon, V.A. Autoimmune Gastrointestinal Dysmotility Treated Successfully With Pyridostigmine. Gastroenterology 2006, 131, 1592–1596.
  64. Dhamija, R.; Tan, K.M.; Pittock, S.J.; Foxx–Orenstein, A.; Benarroch, E.; Lennon, V.A. Serologic Profiles Aiding the Diagnosis of Autoimmune Gastrointestinal Dysmotility. Clin. Gastroenterol. Hepatol. 2008, 6, 988–992.
  65. Flanagan, E.P.; Saito, Y.A.; Lennon, V.A.; McKeon, A.; Fealey, R.D.; Szarka, L.A.; Murray, J.A.; Foxx-Orenstein, A.E.; Fox, J.C.; Pittock, S.J. Immunotherapy trial as diagnostic test in evaluating patients with presumed autoimmune gastrointestinal dysmotility. Neurogastroenterol. Motil. 2014, 26, 1285–1297.
  66. Schofield, J.R.; Chemali, K.R. Intravenous Immunoglobulin Therapy in Refractory Autoimmune Dysautonomias: A Retrospective Analysis of 38 Patients. Am. J. Ther. 2019, 26, e570–e582.
  67. Kawanishi, K.; Moribata, K.; Kato, J.; Murata, K.; Fukatsu, K.; Tamaki, H.; Itou, D.; Wada, Y.; Ichinose, M. . Nihon Shokakibyo Gakkai Zasshi 2015, 112, 62–69.
  68. Montalvo, M.; Nallapaneni, P.; Hassan, S.; Nurko, S.; Pittock, S.J.; Khlevner, J. Autoimmune gastrointestinal dysmotility following SARS-CoV-2 infection successfully treated with intravenous immunoglobulin. Neurogastroenterol. Motil. 2022, 34, e14314.
  69. Morales-Ruiz, V.; Juárez-Vaquera, V.H.; Rosetti-Sciutto, M.; Sánchez-Muñoz, F.; Adalid-Peralta, L. Efficacy of intravenous immunoglobulin in autoimmune neurological diseases. Literature systematic review and meta-analysis. Autoimmun. Rev. 2021, 21, 103019.
  70. Leonhard, S.E.; Mandarakas, M.R.; Gondim, F.A.A.; Bateman, K.; Ferreira, M.L.B.; Cornblath, D.R.; Van Doorn, P.A.; Dourado, M.E.; Hughes, R.A.C.; Islam, B.; et al. Diagnosis and management of Guillain–Barré syndrome in ten steps. Nat. Rev. Neurol. 2019, 15, 671–683.
  71. Dalakas, M.C. Intravenous Immunoglobulin in Autoimmune Neuromuscular Diseases. JAMA 2004, 291, 2367–2375.
  72. Hughes, R.A.C.; Hadden, R.D.M.; Gregson, N.A.; Smith, K.J. Pathogenesis of Guillain–Barré syndrome. J. Neuroimmunol. 1999, 100, 74–97.
  73. van der Meché, F.; Schmitz, P. A Randomized Trial Comparing Intravenous Immune Globulin and Plasma Exchange in Guillain–Barré Syndrome. N. Engl. J. Med. 1992, 326, 1123–1129.
  74. Raphael, J.; Chevret, S.; Harboun, M.; M-Ce Jars-Guincestre for the French Guillain-Barré Syndrome Cooperative Group. Intravenous immune globulins in patients with Guillain-Barré syndrome and contraindications to plasma exchange: 3 days versus 6 days. J. Neurol. Neurosurg. Psychiatry 2001, 71, 235–238.
  75. Gajdos, P.; Chevret, S.; Clair, B.; Tranchant, C.; Chastang, C. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Ann. Neurol. 1997, 41, 789–796.
  76. Bain, P.G.; Motomura, M.; Newsom-Davis, J.; Misbah, S.A.; Chapel, H.M.; Lee, M.L.; Vincent, A.; Lang, B. Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology 1996, 47, 678–683.
  77. Hoffmann, J.H.O.; Enk, A.H. High-Dose Intravenous Immunoglobulin in Skin Autoimmune Disease. Front. Immunol. 2019, 10, 1090.
  78. Gao, Y.; Jin, H. Efficacy and safety of intravenous immunoglobulin for treating refractory livedoid vasculopathy: A systematic review. Ther. Adv. Chronic Dis. 2022, 13, 20406223221097331.
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