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Ther Adv Neurol Disord. 2016 July; 9(4): 336–343.
Published online 2016 April 6. doi:  10.1177/1756285616641583
PMCID: PMC4916522

Subcutaneous immunoglobulins in the treatment of chronic immune-mediated neuropathies

Abstract

Intravenous immunoglobulins represent an established therapy for the treatment of chronic immune-mediated neuropathies, specifically chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs) as well as multifocal motor neuropathies (MMNs). For the treatment of antibody deficiency syndromes, subcutaneous immunoglobulins (SCIgs) have represented a mainstay for decades. An emerging body of evidence suggests that SCIg might also exhibit clinical efficacy in CIDP and MMN. This article reviews the current evidence for clinical effectiveness, as well as safety of SCIg for the treatment of immune-mediated neuropathies, and addresses remaining open questions in this context.

We conclude that despite the need for controlled long-term studies to demonstrate long-term efficacy of SCIg in immune-mediated neuropathies, SCIg may already represent a potential therapeutic alternative for selected patients.

Keywords: CIDP, inflammatory neuropathies, IVIg, MMN, pump-system, SCIg, GBS

Introduction

Immunoglobulins have been used for decades in the treatment of antibody deficiency syndromes and autoimmune diseases. The first immunoglobulin-replacement therapy described by Bruton in 1952 was carried out subcutaneously [Bruton, 1952]. Nonetheless, the intravenous route has established itself in the following years, mainly due to the option of faster application. However, the advent of improved pump technology in the 1980s, enabling application rates of up to 20 ml/h, sparked new interest in subcutaneous administration [Gardulf, 2007].

Pharmacokinetics

The half-life of immunoglobulins does not seem to be affected by the route of administration [Gustafson et al. 2008; Wasserman et al. 2009]. On the other hand, intravenous and subcutaneous administration forms reveal pharmacokinetic differences: the intravenous administration of immunoglobulins leads to an immediate increase in immunoglobulin G (IgG) plasma concentration, followed by a sharp drop in the subsequent 2–8 days and a further gradual decrease in the following weeks [Rajabally, 2014]. The initial sharp drop in the plasma concentration is apparently the result of a shift from the vascular into extracellular compartment, while the subsequent gradual decrease corresponds to the catabolism during the slow passage of immunoglobulins back into the vascular compartment. By contrast, subcutaneously administered immunoglobulins are absorbed into the subcutaneous tissue and gradually released without causing significant peaks in the plasma concentration.

It may well be that a certain plasma concentration must be reached for immunoglobulins to exert their clinical efficacy [van Doorn et al. 2011; Vlam et al. 2014]. In Guillain-Barré syndrome (GBS), a study with 174 patients revealed that the increase in serum IgG (delta IgG) 2 weeks after intravenous immunoglobulin (IVIg) treatment varied considerably between patients (mean 7.8 g/l; standard deviation 5.6 g/l). Low delta IgG levels 2 weeks after the IVIg treatment were an indicator for slow recovery, and fewer patients with low delta IgG reached the ability to walk unaided at 6 months. The authors suggest that patients with a small increase in serum IgG levels may benefit from a higher dosage or a second course of IVIg [Kuitwaard et al. 2009], and that a fast increase is needed to achieve therapeutic effects. A study that followed confirmed the findings in multifocal motor neuropathy (MMN). The study included 23 patients with MMN, receiving their first IVIg treatment at a cumulative dose of 2.0 g/kg in 5 days. Mean delta IgG was higher in IVIg responders than in nonresponders, but the study lacked power to show statistically significant differences. Also, in this study, total IgG and delta IgG levels varied greatly among patients [Vlam et al. 2014].

Other authors argue that continuous plasma levels are necessary to achieve therapeutic effects. A study in 25 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients with active but stable disease revealed that clinically stable CIDP patients showed a steady-state in serum IgG after serial IVIg infusions. The authors suggest that low intra- and inter-patient variability in IgG may indicate that constant levels are required to reach this stability [Kuitwaard et al. 2013].

Berger and Allen hypothesize that the therapeutically known end-of-dose effect is rooted in the fact that therapeutic IgG competes with pathologic autoantibodies, and that different patients may require different IgG levels for optimal therapeutic effects. They suggest subcutaneous IgG as a tool for continuously maintaining high serum IgG levels, resulting in clinical stabilization [Berger and Allen, 2015].

To what extent these pharmacokinetic differences contribute to variations in clinical efficacy remains elusive at the present time.

Immune-mediated neuropathies

In the past decades, it has become clear that the clinical presentations and paraclinical characteristics of chronic immune-mediated neuropathies are diverse, resulting in various subtypes, particularly those of CIDP.

In the past, CIDP used to be clinically defined by the subacute onset of symmetric proximal and distal weakness; meanwhile, however, further subtypes have been defined, which are characterized by either only distal symmetric paresis or sensory affection, or by asymmetric paresis with or without sensory affection [Köller et al. 2005a]. A specific subgroup of CIDP is multifocal motor neuropathy (MMN), clinically characterized by asymmetric paresis that usually begins distally in the arms and tends to be within the myotome of an individual peripheral nerve. Classically, this condition presents with multiple conduction blocks in nerve conduction studies. MMN is associated with the presence of immunoglobulin M (IgM) antibodies against ganglioside GM1 and responds to immunomodulatory treatments [Feldman et al. 1991; Pestronk et al. 1988], since patients with evidence of conduction blocks or anti-GM1 antibodies do not differ from other MMN patients in terms of the prognosis and therapeutic response.

Autoantibodies also play a role in CIDP [Devaux, 2012; Peltier and Donofrio, 2012] and acute motor axonal neuropathy (AMAN) [Plomp and Willison, 2009; Yuki, 2012].

The heterogeneous antibody profiles in the different inflammatory conditions target different functional components of peripheral nerves such as Schwann cells, myelin, nodes of Ranvier and axons, which lead to alterations of nodal structure and alterations in the distribution of ion channels, and culminates in impaired conduction or disturbed axonal function [Berger et al. 2013; Boerio et al. 2010; Dyck et al. 2015; Franssen and Straver, 2013; Kiernan et al. 2000; Lin et al. 2011; Pollard and Armati, 2011; Yuki and Hartung, 2012]. In this context, well known pathologic changes such as demyelination or destruction of axons, as well as autoantibody-induced alterations of nodal, paranodal and juxtaparanodal regions lead to a functional impairment [Dalakas, 2015; Peltier and Donofrio, 2012].

Further clinical studies investigating clinical subgroups are needed to study these main differences in the pathophysiology of peripheral nerve inflammatory conditions and to devise specific treatment protocols. Until then, the clinical and immunopathogenetic heterogeneity of immune-mediated neuropathies will remain a therapeutic challenge.

Immunoglobulins in chronic immune-mediated neuropathies

With the currently established therapeutic strategies, corticosteroids, plasma separation and IVIg, therapeutic response is achieved in up to 80% of patients [Köller et al. 2005b].

In randomized, controlled trials, IVIg treatment resulted in a significant clinical improvement compared with placebo [Gold and Kieseier, 2006]. However, the limitation of the early studies was a short observation period. The ICE study [Hughes et al. 2008], a randomized, double-blind, placebo-controlled study of 24 weeks, followed by re-randomization and an extension period for an additional 24 weeks, was the first study reporting significant clinical improvement resulting from IVIg therapy compared with placebo over long-term exposure.

Likewise, the efficacy of immunoglobulins in the treatment of MMN was demonstrated in some randomized, double-blind, placebo-controlled studies and a few case reports [Kieseier et al. 2002; Nobile-Orazio et al. 2005], such as Federico and colleagues showing that IVIg improved functional self-assessment, the standardized neurological examination, as well as the formal strength testing and nerve-conduction studies compared with placebo [Federico et al. 2000].

Usually, the therapeutically administered dose in immune-mediated neuropathies, including MMN, is 0.4 g/kg body weight per day for 5 days, while any maintenance dose depends on the individual clinical course. If necessary, dose and possibly frequency of administration are increased in order to achieve long-term therapeutic success [Koski, 2005; Umapathi et al. 2002]. In contrast to CIDP cases, corticosteroids and plasma separation are ineffective in MMN [Lehmann et al. 2008], rendering immunoglobulins the first-line therapeutic option in this neuropathy.

Subcutaneous immunoglobulins in immune-mediated neuropathies

The increasing use of immunoglobulins to treat chronic immune-mediated neuropathies, particularly in patients with long-term need for this therapy, has sparked new interest in its subcutaneous administration. The administration via a pump system offers patients greater independence because it can be performed at home. But there are also theoretical pharmacokinetic advantages: continuous subcutaneous administration of immunoglobulins attains higher and more stable serum levels [Waniewski et al. 1994], leading to a reduced end-of-dose phenomena, (i.e. clinical worsening at the end of the intravenous treatment interval).

Tolerability is a relevant issue in intravenous administration. Systemic adverse reactions to IVIg include fever, fatigue, joint swelling, ‘flu-like’ symptoms, anaphylactoid symptoms, flushing, headache, dizziness, aseptic meningitis, shortness of breath, arterial hypotension or hypertension, chest pain, nausea, vomiting, cramping, urticaria and pruritus. The symptoms vary in severity, but are generally mild. At some point during the course of therapy, 20% or more of patients experience such reactions. Severe reactions occur in less than 1% of patients [Bonilla, 2008].

A prospective audit of adverse reactions in primary antibody-deficient patients receiving IVIg failed to show any severe reactions, with an overall low reaction rate of 0.8%, which could have been even lower if predisposing factors responsible for some reactions had been considered before infusion [Brennan et al. 2003].

Bonilla suggests that when mild reactions occur, discontinuing the infusion of IVIg is rarely required. In such cases, it is most often enough to slow the infusion rate or halt the infusion until symptoms have subsided. However, this might inconvenience the patient, since subsequent infusions may have to be administered more slowly, or smaller doses administered more frequently [Bonilla, 2008]. This suggests that slow administration reduces the rate of mild infusion reaction, making subcutaneous immunoglobulin (SCIg) more tolerable.

In rare cases, anaphylactic IVIg reactions were reported in patients with IgG anti-IgA antibodies, mainly in patients with common variable immunodeficiency (CVID) having undetectable IgA. It is notable that the patients with anti-IgA antibodies who had experienced anaphylaxis with IVIg, actually tolerated SCIg [Horn et al. 2007].

In a recent study, in which 27 CIDP and MMN patients were treated with SCIg, less severe headache, nausea and reduced fluctuation of side effects in relation to the injections were reported [Markvardsen et al. 2015]. Hence, the potential benefit of SCIg therapy for the treatment of CIDP and MMN has recently been studied in case series and some clinical studies that are listed in Tables 1 and and22.

Table 1.
Reports of subcutaneous immunoglobulins in patients with chronic inflammatory demyelinating polyneuropathies.
Table 2.
Reports of subcutaneous immunoglobulins in patients with multifocal motor neuropathies.

Subcutaneous immunoglobulins in CIDP

Only one placebo-controlled, double-blind clinical trial on the efficacy and tolerability of SCIgs in patients with CIDP has been reported so far [Markvardsen et al. 2013]. This study included 30 patients with a conclusive diagnosis of CIDP (defined according to the EFNS/PNS criteria) (PNS, 2010a, 2010b] who had responded well to IVIg before. Following a 1:1 randomization, half of the patients received placebo, and the other half were administered SCIg corresponding to their IVIg pretreatment dose, 2–3 times a week over a period of 12 weeks; the switch of therapies was initiated for scientific reasons. This study unequivocally demonstrated that SCIg was clinically superior to placebo. The open-label follow-up study included 17 CIDP patients who formerly responded to IVIg and had participated in the previous study. They continued on SCIg treatment at weekly equal dosage and were evaluated after 3, 6 and 12 months. The study showed that SCIg preserves muscle strength and functional ability [Markvardsen et al. 2014].

In an Italian prospective observational study, 66 CIDP patients were switched from IVIg to SCIg and clinically monitored for 4 months. Within this short observation period, an equivalent efficacy of SCIg was demonstrated in these patients [Cocito et al. 2014]. Apart from these two studies there are case series and case reports of classes III and IV evidence [Bayas et al. 2013; Cocito et al. 2013; Köller et al. 2006; Lee et al. 2008; Markvardsen et al. 2015], which also provide data that corroborate the utility of SCIg in patients with CIDP; one, even as a long-term clinical follow up [Yoon et al. 2015]. The switch was due to various reasons such as stabilization by IVIg only, with short treatment intervals, side effects associated with IVIg therapy (e.g. recurrent transient ischemic attacks (TIAs) following IVIgs, related increase in blood viscosity, headache and skin eruptions), and to improve the patient’s quality of life.

Subcutaneous immunoglobulins in MMN

A single-blind cross-over study in MMN patients revealed therapeutic equivalence of SCIg and IVIg [Harbo et al. 2009]. Notably, however, the design did not allow robust conclusions due to the small sample size of only nine patients enrolled. A further 24-month observation of the clinical course in five of the nine patients, as well as in one additional patient, confirmed sustained efficacy and tolerability of SCIg. Again, the small sample size represents a limiting factor affecting the validity of this observation [Harbo et al. 2010]. The previously mentioned Italian observational study in CIDP patients included 21 patients with MMN. Equivalent clinical efficacy of SCIg after switching from IVIg was demonstrated in these patients as well, based on data gathered in the short 16-week observational period [Cocito et al. 2014]. Additional smaller case series or case reports emphasize the potential efficacy of SCIg in patients with MMN [Dacci et al. 2010; Eftimov et al. 2009; Hadden and Marreno, 2015; Köller et al. 2006; Markvardsen et al. 2015; Misbah et al. 2011; Yoon et al. 2015]. The switches from IVIg to SCIg were performed for the same reasons as mentioned in the reports in CIDP.

It should be noted that there are currently no reliable data for the long-term use of SCIg in the treatment of chronic immune-mediated neuropathies. Both CIDP and MMN may fluctuate widely in their clinical course and show partial remission, and thus larger studies are required, testing the efficiency of SCIg.

Aspects for patient-tailored treatment decisions

The decision to switch from IVIg to SCIg treatment has thus far always been a decision made on a case-by-case basis by doctors and patients. This decision is influenced by the patient’s individual medical history and past response to treatment(s), the attitude towards his or her medical condition, the transportation connections to the specialized tertiary-care treatment center as well as compliance with therapy and lifestyle issues.

Generally, IVIg treatment should be preferred in patients with a more complex disease, because in this case the clinical setting guarantees regular clinical evaluation and supervision. Also, for patients in whom the individual dose has not yet been determined, a lack of evaluation with dose and interval adjustment may lead to less-than-optimal treatment outcomes. The aspect of ensuring a higher level of safety by regular doctor-patient contact is important for a certain group of patients; in particular, patients with a history of severe anaphylactic reactions. The small group of patients who continuously require a very high IVIg dose to ensure stable disease is the group for whom subcutaneous administration is an obstacle.

Another important aspect that should be discussed with the patients is that home infusion several times a week is a constant reminder of their disease; further aggravated by the medical equipment kept at home. IVIg treatment may be advantageous for patients who need a regional distance and prefer letting someone else handle the therapeutic procedure to be able to better cope with their medical condition.

The patients’ practical skills and good compliance are prerequisites for carrying out SCIg therapy at home. Patients with well controlled disease, but a high frequency in IVIg treatment with or without a marked end-of-dose effect, may benefit from SCIg treatment. Also, patients with severe but transient side effects after infusions may be candidates for SCIg. Some patients prefer treatment at home because it reduces the time and cost of traveling to a clinical setting; furthermore, the treatment can be performed with a certain flexibility in the privacy of their homes.

Conclusion

The recent results, particularly those from the two randomized, controlled clinical trials, suggest that SCIg could make an interesting alternative to conventional IVIg products with respect to efficacy, tolerability and quality of life. An Italian pharmacoeconomic study suggests that the use of SCIg in CIDP may deliver cost savings [Lazzaro et al. 2014]. Nevertheless, many questions still remain open. First and foremost, there is a need for controlled long-term studies to demonstrate long-term efficacy of SCIg in immune-mediated neuropathies. The optimal dose still needs to be defined. Whether or not continuous IgG serum levels represent a factor in achieving clinical efficacy remains to be elucidated in further studies.

Despite all of the outstanding issues, for selected patients with immune-mediated neuropathies, SCIg may already represent an interesting and practical alternative in individually tailored therapeutic attempts.

Footnotes

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.

Conflict of interest statement: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: V. Leussink: Received speaking honoraria from Biogen, Genzyme, Novartis and support for research from Novartis. H. P. Hartung: Has received honoraria for consulting and speaking at symposia from Bayer, Biogen Idec, Genzyme, Merck Serono, Novartis Pharma, Roche and Teva Sanofi-Aventis, with approval by the Rector. B. C. Kieseier: Received honoraria for lecturing, travel expenses for attending meetings, and financial support for research from Bayer Health Care, Biogen, Genzyme/Sanofi Aventis, Grifols, Merck Serono, Mitsubishi Europe, Novartis, Roche, Talecris, and TEVA. Since summer 2015 he is also employee of Biogen. M. Stettner: Received speaking honoraria or travel expense reimbursement for participation in scientific meetings from Biogen Idec, UCB, Genzyme, Novartis Pharma, and Teva.

Contributor Information

Verena I. Leussink, Department of Neurology, Medical Faculty, Research Group for Clinical and Experimental Neuroimmunology, Heinrich-Heine-University, Düsseldorf, Germany.

Hans-Peter Hartung, Department of Neurology, Medical Faculty, Research Group for Clinical and Experimental Neuroimmunology, Heinrich-Heine-University, Düsseldorf, Germany.

Bernd C. Kieseier, Department of Neurology, Medical Faculty, Research Group for Clinical and Experimental Neuroimmunology, Heinrich-Heine-University, Düsseldorf, Germany.

Mark Stettner, Department of Neurology, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany.

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