Introduction

Idiopathic inflammatory myopathies (IIM) are a group of heterogeneous diseases [1] including dermatomyositis (DM), immune-mediated necrotizing myopathy (IMNM), inclusion body myositis (IBM), anti-synthetase syndrome (ASyS) [2, 3]. IIM may be spontaneous or sometimes associated with cancer (“cancer-associated myositis”) or triggered by drugs (such as statins) [4,5,6]. The common feature is muscle inflammation that may induce severe muscle weakness and/or swallowing troubles [7]. Extra-muscular manifestations include the skin, the lungs, the joints and/or the heart [2]. IIM are chronic and disabling diseases that may present with life-threatening complications [8]. IIM often require prolonged treatment duration, and it is not uncommon that patients present refractory and/or relapsing disease course [9]. Current therapeutic approach includes the combination of corticosteroids (CS) with immunosuppressants (IS) [10]. CS and IS therapy exposes patients to significant, sometimes severe, adverse events [9]. Indeed, CS, IS, and biologic disease-modifying anti-rheumatic drugs are associated with an increased risk of severe infections [11, 12]. In addition, CS are associated with many other side effects including hypertension, diabetes, weight gain, osteoporosis, and muscle weakness (CS-induced myopathy) [13,14,15].

Intravenous immunoglobulins (IVIG) are an alternative with a better safety profile [16]. IVIG have demonstrated their efficacy in many autoimmune diseases [17•]. Data reporting the efficacy and safety of IVIG in IIM are scarce. Furthermore, IVIG availability is limited, and IVIG is an expensive treatment option. In this review, we will review current evidence on the use of IVIG in IIM and provides guidance for their use in clinical practice.

Myositis is a Heterogeneous Group of Diseases Associated with Distinct Clinical Features, Pathophysiology, Prognosis, and Therapeutic Response

IIM Subgroup Characteristics and IIM Subgroup Prognosis

Only 20% of IIM patients achieved a major improvement [9]. IBM and IMNM are diseases that cause significant functional disability with swallowing disorders [18, 19]. In ASyS and DM anti-MDA5, the prognosis is related to ILD [20, 21]. DM are often affected by refractory cutaneous forms, which are responsible for significant psycho-social impact [22, 23]. The one-year mortality rate of IIM is 9 times higher than in the general population [8]. The main causes of death are malignancies and diseases of the circulatory and respiratory system, including ILD (sometimes rapidly progressive) [8, 24,25,26,27,28,29,30]. The elevated relative risk for death from infections was also increased but only between 1 and 5 years after diagnosis [8]. Infections are an important cause of mortality in other systemic diseases, such as lupus, where they are responsible for at least a third of the death [31]. Along that line, in inflammatory bowel diseases, prolonged exposure to synthetic disease-modifying anti-rheumatic drugs such as thiopurines is also associated with an increase in the risk of malignancy [32]. All together, these data point the importance of adverse events in IIM.

Rationale for Using IVIG in IIM and its Subsets

IVIG mechanism of action is broad and not yet fully understood. Mechanisms of action may in fact differ from one disease to another [33•, 34], but most of them remain speculative.

It was previously demonstrated that IVIG inhibits membrane attack complex of the complement (C5b-9) [34]. This mechanism may be of particular importance in DM since the pathophysiology of the disease is characterized by C5b-9 deposition on muscle capillaries [35, 36]. Of note, complement cascade inhibition may also be interesting in IMNM in which growing evidence suggests a pathogenic role of IMNM-specific autoantibodies and the complement pathway [19, 37]; though, complement component 5 inhibitor, in IMNM did not appear to be an effective treatment [38]. IVIG contain anti-idiotype antibodies that may neutralize circulating autoantibodies [34, 39]. This property may be of interest for autoantibody-mediated diseases such as it is suspected for IMNM [19]. IVIG also block the production of type I and type II interferon in lupus [40]. These findings could thus be relevant in acquired interferonopathies such as DM [41, 42].

IVIG Preparation, Safety, and Consumption

IVIG Manufacturing Process and Consumption

IVIG are obtained by pooling polyclonal serum immunoglobulin G from at least 1000 healthy donors according to World Health Organization’s recommendation [43•]. IVIG should contain as little IgA as possible to reduce anaphylaxis risk [44]. Plasma from 10,000 to 60,000 healthy donors depending upon the manufacturer are collected to obtain a large fraction of different antibodies. Immunoglobulin G content varies from 90 to 98% in commercial IVIG preparations. Immunoglobulin A, Immunoglobulin M and other serum immunoglobulins are also present in trace amounts [43•, 45,46,47]. The world collection of plasma in 2022 was estimated at 62 ML, two-thirds being collected in the USA [48]. Half of the plasma collection is used for IVIG production.

IVIG consumption has had a steady increase from 8.7% per year since 2000. Europe IVIG needs represent about 25% of worldwide supply but contribute to collection of only 15% of the plasma for fractionation. In contrast, North America uses close to 50% of all IVIG sold worldwide but contributes to the collection of 63% of the plasma for fractionation. Thus, USA supplies the rest of the world. In Europe, the majority of plasma collection is based on free donation of whole blood while in the USA, the majority of plasma is collected from plasmapheresis with financial compensation [49•]. The estimated price of IVIG ranges from 33 euro/g in Asia to 79 euro/g in US (50 euro/g in Europe) [50].

IVIG Safety

IVIG have a good safety profile. Indeed, IVIG have an immunomodulatory effect that does not increase the risk of infection, and its limited overall toxicity makes IVIG an attractive option compared to other immunosuppressive drugs [51]. Nevertheless, IVIG has some side effects including immune- or hyperviscosity-related adverse events. Among immune reactions, the most rare and severe is the anaphylactic shock [52]. Due to isoagglutinin (anti-A and/or anti-B) infused with IVIG in non-O blood group patients, hemolysis may be observed but is most commonly mild [53]. The most frequent side effects are minor and include headaches, fever, nausea, urticaria, or myalgias [54]. Headaches may be due to aseptic meningitis [55]. It is possible that aseptic meningitis could be related to the serum viscosity.

It was also suggested that serum viscosity plays a role in the occurrence of thrombotic events [56]. The rate of thromboembolic events was estimated at 3 to 11.2% of IVIG users [57•, 58, 59, 60••]. IVIG dose of greater than 35 g/day was associated with an increased risk of thrombotic events [57•, 58]. Thrombosis can be either arterial or venous. Arterial events appear to be more frequent, compared with venous events [57•]. A majority of these patients had pre-existing risk factors for thrombotic events such as: higher age, cardiovascular disease, hypertension, diabetes, chronic kidney disease, higher IVIG dose (> 35 g/l) or high infusion rate, immobilization, and previous history of thrombosis [58, 59, 60••]. Most of the above-mentioned adverse effects are related to IVIG infusion rate and can thus be prevented by reducing it [51, 56, 59].

Transfusion-related acute lung injury or transfusion-associated circulatory overload, especially in the presence of heart failure, has also been reported [61]. In the context of renal insufficiency, IVIG can be responsible for a decrease in renal function [62].

For some patients with long-term IVIG treatment, peripheral intravenous access may become difficult and the insertion of an implantable venous access device necessary [63]. Nonetheless, implanted port is not free from complications, infection being the most important [64].

IVIG Dosing and Administration

The recommended IVIG dose for immunomodulatory and anti-inflammatory effect is 2 g/kg to be administered over 2 days with a maximum daily dose of 80 g [65••]. In the presence of additional risk factors for adverse effects (older subjects, chronic kidney disease, and risk factors for thrombosis), IVIG can be administered over 5 days to reduce the infusion rate [51]. Monthly infusion are usually repeated after 1 month because the elimination half-life of IVIG is about 3 weeks [65••, 66].

IVIG Efficacy in IIM

Converging data strongly suggest the efficacy of IVIG in IIM. Most IIM patients included in IVIG studies are classified based on the 1975 Bohan and Peter classification, whereas classification and the nosological framework have evolved. Due to the low level of evidence, recommendations are mainly based on expert opinions and government agencies.

In the USA, IVIG are authorized by the Food and Drug Administration since 2021, following the Aggarwal et al.’s study in DM. In Europe, the European Medicines Agency does not mention yet IIM in its recommendations on the use of IVIG, but European organizations such as the European Federation of Neurological Societies recommend the use of IVIG to treat IIM patients [17•]. Similarly, for example, the French Agency for the Safety of Medicines and Health Products in France and National Health Service in England recommend the use of IVIG in IIM but only in specific situations such as refractory DM or PM.

All RCT and prospective observational studies evaluating IVIG efficacy in IIM are listed in Table 1 and 2.

Table 1 Randomized controlled trials and prospective observational studies evaluating IVIG as first line therapy in myositis
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Table 2 Randomized controlled trials and prospective observational studies evaluating IVIG in refractory myositis
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IVIG in DM

The most robust scientific evidence for the efficacy of IVIG is reported in DM. This subgroup has long been well characterized due to its specific cutaneous phenotype.

IVIG as First Line Therapy in DM

The use of IVIG as first line therapy has been tested in a randomized, double-blind, placebo-controlled trial in 2008 [67]. Sixty adults DM were randomized to receive corticosteroid alone or corticosteroid with monthly infusions of IVIG at a dose of 2 g/kg/month. At 14 weeks, a significant increase in muscle strength and decrease in creatine kinase (CK) level was demonstrated in the IVIG group. Another prospective study by Gottfried et al. [68] including 6 subjects using IVIG on first-line therapy (with CS alone, n = 1 and CS and IS, n = 5) showed that 50% of subjects improved skin and muscle strength [68].

IVIG as First-Line Therapy in PM/DM

A prospective study by Cherin et al. [69] found that first-line IVIG alone was not very effective with only 3 of the 11 patients responding significantly. More recently, another prospective study by Lim et al. [70] reported 20 IIM patients (DM n = 9, IMNM n = 6, overlap myositis n = 4, and ASyS n = 1) treated with IVIG monotherapy. At week 9, they reported a moderate response in 42% of patients. Of note, 3 patients with cancer-associated DM showed clear improvement [70].

IVIG in Refractory DM

In most studies discussed below, refractory disease was defined as an insufficient improvement (muscle and/or skin domains) after treatment with high-dose CS and IS, or relapses upon CS therapy tapering. Two RCTs have evaluated the efficacy of IVIG in refractory DM. The first study was performed by Dalakas et al. [71•] in 1993 and randomized 15 patients to receive monthly infusions of IVIG at a dose of 2 g/kg or placebo for 3 months, followed by crossover. In this study, a significant improvement of muscle strength was reported at 12 weeks [71•]. Recently, a large study by Aggarwal et al. [60••] evaluated the efficacy of IVIG in refractory DM (n = 95). Subjects were randomized to receive double-blind, placebo-controlled, monthly IVIG 2 g/kg infusions. Eighty-eight percent of patients were treated with stable CS dose, and 68% of patients had an IS for at least 3 months prior to enrollment. The primary endpoint was a total improvement score ≥ 20 at week 16. This endpoint was achieved in 79% of patients in the IVIG group and 44% in the placebo group (p < 0.001). The secondary endpoint showed a total improvement score of ≥ 40 (moderate) and ≥ 60 (major) in 68% and 32% of patients, respectively, in the IVIG group. The time to at least moderate improvement was 85 days in the IVIG group and 197 days in the placebo group. The study transitioned into open-label extension at week 16 and all patients, except those who demonstrated no respond while receiving IVIG, were allowed to continue the study. IVIG efficacy improved with longer follow-up with a total improvement score of ≥ 40 reported in 60% of patients at week 40 [60••].

IVIG in Refractory DM/PM

In 2012, Miyasaka et al. [72] performed a randomized, double-blind, placebo-controlled, crossover trial including 10 refractory DM and 16 refractory PM. Subjects were randomized to receive 1 infusion of IVIG at a dose of 0.4 g daily for 5 consecutive days combined with a stable-dose of CS, IS versus CS, IS, placebo with crossover at week 8. No significant improvement in muscle strength was demonstrated after only 1 infusion of IVIG [72]. Another prospective open-label and other retrospective trials assessing IVIG efficacy in refractory DM/PM subjects have been reported [73,74,75,76,77,78,79,80,81,82]. Most studies have reported at least partial clinical response with muscle improvement of 70–100% of patient in refractory DM/PM [73,74,75,76,77,78,79,80,81,82].

IVIG for Cutaneous Disease in DM

In the RCT by Dalakas and al. [71•] mentioned above, clearance of active violaceous rash was reported in 53% of patients with IVIG [71•]. Aggarwal et al. [60••] reported a different mean improvement of 8 points on the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI, scores range from 0 to 100) in patients treated with IVIG compared with placebo [60••]. In another prospective study [68], 19 DM patients were treated with IVIG for 6 to 12 months and mean cutaneous score (local score, sores range from 0 to 2) decrease from 1.24 (+ / − 0.9) to 0.5 (+ / − 0.7) [68]. Two other retrospective studies evaluated the clinical response of IVIG in refractory cutaneous DM in patients with DM and amyopathic DM. In a study by Bounfour et al. [83], 27 refractory DM with isolated skin disease activity were treated with IVIG and 19 had major clinical response after several infusions [83]. In another study by Femia et al. [84], all 13 patients (9 amyopathic DM, 4 DM) improved with IVIG, and complete clinical response was achieved in 8 of 13 patients [84]. Overall, an efficacy has been reported with IVIG in refractory cutaneous disease in DM.

IVIG in Other IIM Subgroups

Historically, the PM subgroup most often included IMMN, ASyS, and sometimes even IBM. Today, new studies are specific to IIM clusters.

IVIG in IMNM

IVIG as First-Line Therapy in IMNM

Recently, a retrospective study evaluated IVIG efficacy in anti-HMGCR IMNM as first-line therapy [85]. Eleven patients were treated with high-dose (1 mg/kg/day), methotrexate, and IVIG 0.4 g/kg daily for 5 days and then monthly, for at least 3 months or until remission was achieved. Two other patients were treated with high-dose CS and monthly IVIG without methotrexate. With these 2 approaches, all patients achieved remission defined as the absence of muscle symptoms, recovered muscle strength, and normalization of CK. Only 3 patients relapsed during progressive tapering of CS or discontinuation of IS and/or IVIG [85]. In the absence of a control group without IVIG, it remains difficult to measure the effect of IVIG as first-line therapy.

IVIG in Refractory IMNM

IMNM is a disease associated with severe muscular damage and a high relapse rate, resulting in significant functional impairment [19]. In one study [86], only 50% of IMNM patients recovered normal muscle strength after 4 years of treatments [86, 87]. On magnetic resonance imaging, IMNM is characterized by a higher proportion of thigh muscle damage including muscle atrophy and fat replacement compared to patients with DM, PM, or IBM patients [88, 89]. In one retrospective studies [90], 3 anti-HMGCR IMNM patients with a contraindication to CS were treated with IVIG monotherapy. After two to three monthly infusions of IVIG, mean CK level decreased and muscle strength increase. It should be noted that despite the significant decline in CK level, it did not completely normalize [91]. Recently, another retrospective study [92] evaluated 20 IMNM patients treated by IVIG; in addition, CS and IS during 6 months and 96% of patients displayed a decrease in CK level accompanied by an increase in muscle strength in only 29% of patients [92]. In other retrospective studies [93], 7 of 20 IMNM patients were treated with IVIG (anti-HMGCR n = 2 and anti-SRP n = 2). Three of 7 patients achieved complete recovery of muscle strength, but all required long-term IS treatment [93]. In retrospective studies [94], 9 anti-SRP IMNM patients treated with combination of CS, IS, and IVIG presented muscle strength and CK level improvement, but a high relapse rate upon IVIG discontinuation (67%) [94].

IVIG in ASyS

In ASyS, damage burden is often less severe compared to IMNM with only 30% of patients presenting severe muscle damage [95]. In a retrospective study [96], 39 of 86 anti-Jo-1 ASyS were treated with IVIG which led to clinical muscle improvement in 69% of cases [96].

IVIG in IIM-Associated ILD

ASyS patient prognosis is highly dependent on the severity of ILD [96]. ILD is often treated with CS and IS [97]. Therefore, IVIG has been tested in the situation of ILD; Suzuki et al. [98] retrospectively evaluated 57 ASyS patients with ILD in their cohort. Only 5 patients were treated with IVIG for acute ILD. All patients received concomitantly high dose CS and IS. Only two patients survived [98]. In a more recent study [99], Huapaya et al. reported treatment profile of 17 ASyS patients with ILD (anti-Jo1 n = 10, anti-PL12 n = 3, anti-PL7 n = 3, anti-EJ n = 1). Seventeen patients were treated with IVIG and CS, sixteen had concomitant immunosuppressive treatment and 3 of them were introduced during IVIG. This study demonstrated that 41% patients (7/17) with ILD-ASyS responded and had a > 10% increase in percentage of forced vital capacity [99]. In a cohort of 12 anti-Jo1 [100], 3 refractory patients received IVIG in combination with CS and IS. All 3 patients presented an improvement in muscle strength, but ILD only improved in 2 patients on chest CT scan [100].

Anti-MDA5 is sometimes associated with more severe pulmonary involvement including rapidly progressive ILD with bad prognosis [101, 102]. A retrospective study by Wang et al. [103] included 48 patients with rapidly progressive ILD and found a lower mortality rate in patients treated with IVIG compared to patients treated without IVIG (22.6% vs 52.9%%, p = 0.033). Patients in the IVIG group had a higher remission rate at 3 months (71.0% vs 41.2%; p = 0.044). Overall, the study by Wang et al. [103] seems to suggest a beneficial effect of IVIG in ILD, but difference in initial immunosuppressive regimen influenced the outcome between the IVIG and non-IVIG groups.

IVIG Efficacy in Dysphagia

Cherin et al. [78] performed an open-label prospective study including 35 PM patients, 11 of them presenting with dysphagia. All subjects received IVIG 2 g/kg monthly during 6 months in association with a combination of CS and IS drugs. Swallowing difficulties disappeared in 72% patients [78]. In other retrospective studies, the use of IVIG allowed for a resolution of dysphagia in 82.2–100% of cases [104, 105].

IVIG in IBM

Three RCTs have examined the role of IVIG in IBM. The first study by Dalakas et al. [106] investigated the efficacy of 19 IBM patients. Subjects were randomized to receive monthly infusions of IVIG or placebo for 3 months and followed by the alternative therapy (crossover) for another 3 months. An improvement in muscle strength was observed in the IVIG-treated group. No significant difference in mean MRC score improvement was observed [106]. A second RCT by Walter et al. [107] included 22 subjects who were randomized to receive monthly infusions of IVIG or placebo for 6 months, followed by crossover. In this study, no significant difference in change of muscle strength was observed between the IVIG and placebo groups [107]. The third RCT by Dalakas et al. was a randomized, double-blind, placebo-controlled, crossover trial including 36 IBM patients. Subjects were randomized to receive monthly IVIG for 3 months combined with CS, compared to placebo with CS. No significant change in muscle strength was observed [108]. Overall, there is no clear evidence of efficacy of IVIG in IBM.

Subcutaneous Immunoglobulin in IIM

Subcutaneous immunoglobulins are already used and presently approved by the FDA in immune deficiencies and some autoimmune diseases such as idiopathic thrombocytopenic purpura and chronic inflammatory demyelinating polyradiculoneuropathy. Subcutaneous immunoglobulin can be used at home without the need for a venous access. Indeed, one limitation of IVIG remains the availability of intravenous access in patients with long-term treatment duration. In a prospective study [109], 27 patients (16 PM and 11 DM) were treated with 20% IgG concentration subcutaneous immunoglobulin at the weekly dose of 0.1–0.2 g/kg as (all patients also received CS and IS). They reported remission of muscle involvement in 24/27 patients and a partial response in 3/27, respectively. For swallowing disorders, significant improvement was found in 11/14 (78.6%), respectively [109]. A recent meta-analysis [110] with 4 prospective and 3 retrospective subcutaneous immunoglobulin studies has been demonstrated that subcutaneous immunoglobulin led to improvement of muscle strength, skin rash, and swallowing difficulties in refractory IIM [110]. These preliminary data are promising and several RCTs are in progress [111, 112].

Application in Clinical Practice

Based on the above-mentioned published evidence, we proposed (Table 3) five questions to ask before using IVIG.

Table 3 Five points to consider before using IVIG
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First, it is important to determine what the domain of disease “activity” is and to distinguish damages from reversible lesions. The benefit of IVIG seems established for the muscle and skin domains but not obvious for other extra-muscular involvement (ILD, joint, etc.). Next, the severity of disease activity may lead to consider IVIG as first line when a rapid remission is required (e.g., bedridden and swallowing disorders). IVIG may also be used as an alternative of high dose of CS and/or IS in specific situation (e.g., pregnancy, severe immunosuppression, and concomitant malignancy). In addition, when a DM or IMNM has failed at least two second-line treatments, IVIG can be used to induce disease remission. For ASyS, the risk of refractory musculoskeletal disease activity is low as well as the risk of musculoskeletal damages. For ILD and IVIG, there are only sparse data and alternative approaches such as Rituximab are better supported by clinical data [113]. IVIG are not usually effective in IBM and are not recommended. IVIG dependence concern mainly refractory IMNM [19, 86, 90] and some DM. In this situation, maintenance treatment with IVIG may be proposed, if there is no alternative.

Conclusion

IVIG have been used for decades to treat IIM patients, despite limitations related to accessibility, high costs, and the limited body of evidence. IVIG remain a key therapy in myositis because of its good safety profile compared to conventional immunosuppressive therapy. Cost-utility analysis suggests that IVIG may remain cost-effective in myositis [114•]. Recently, the efficacy of IVIG in refractory DM was established with a RCT [60••]. IVIG may be effective in other myositis subgroups, but controlled studies are still needed. Improvement in IIM classification and our understanding of pathophysiology in each IIM subgroup should allow the recruitment of more homogeneous subsets of patients in clinical trials.

Improving our understanding of mechanism underlying the efficacy of IVIG in IIM patients could allow for the development of novel innovative approaches. Along that line, blockage of IgG recycling has been demonstrated efficacious in autoantibody dependent diseases such as myasthenia and idiopathic thrombocytopenic purpura [115, 116]. Efgartigimod is an Fc fragment derived from human immunoglobulin G 1 that binds to the FcRn receptor leading to rapid degradation of all IgG, including disease-related autoantibodies. This approach is being currently tested in DM, IMNM, and ASyS [117].