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Review
Subcutaneous immunoglobulin therapy for inflammatory neuropathy: current evidence base and future prospects
  1. Yusuf A Rajabally
  1. Correspondence to Dr Yusuf A Rajabally, Regional Neuromuscular Clinic Queen Elizabeth Neuroscience Centre University Hospitals of Birmingham, Birmingham, UK B15 2TH; Yusuf.Rajabally{at}uhb.nhs.uk

Abstract

Intravenous immunoglobulin therapy is of proven effect in chronic inflammatory neuropathies, including chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN). In more recent years, there have been a number of anecdotal case reports and small series, followed by a few trials of variable design, of subcutaneous immunoglobulin therapy in these neuropathies. To date, limited evidence suggests that the subcutaneous route may be a more clinically effective, better-tolerated, at least cost-equivalent and a more patient-friendly option than the still more used intravenous alternative. Long-term efficacy is not as yet established in neuropathic indications by randomised controlled clinical trial evidence, and it is likely that the subcutaneous route may not be suitable in all cases with some hints to this effect appearing from the limited data available to date. Further studies are ongoing, including those of dose comparison, and more are likely to be planned in future. The literature on the use of subcutaneous immunoglobulin therapy in chronic inflammatory neuropathy is reviewed here. The current use in clinical practice, day-to-day benefits, including quality of life measures and health economics as published thus far, are evaluated. The limitations of this form of treatment in CIDP and MMN are also analysed in the light of current literature and taking into account the remaining unknowns. Future prospects and research with this mode of immunoglobulin therapy administration are discussed.

  • NEUROIMMUNOLOGY
  • NEUROPATHY
  • NEUROMUSCULAR
  • PHARMACOLOGY

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Introduction

Immunoglobulin therapy administered through the intravenous route has been used for antibody deficiencies and autoimmune disorders for decades. Interestingly, immunoglobulin replacement treatment was initially introduced in the early 1950s and used subcutaneously with good effect.1 Intravenous infusion then became the preferred method of administration in immunological indications, partly as a result of its speed of delivery. Rapid subcutaneous immunoglobulin (SCIg) therapy was later developed as from the 1980s, with subsequently pump infusion rates of up to 20 mL/h becoming available, gradually increasing even further over the years.2 ,3

There is no established difference in the half-life of immunoglobulins delivered intravenously compared with subcutaneously.4 ,5 SCIg has been used in immunological practice over the past two decades, administered at lower dosages and more frequent intervals than intravenous immunoglobulins (IVIg). This has been shown to result in higher and more stable immunoglobulin G (IgG) serum levels,6 which may prevent end-of-dose reduction in efficacy and perhaps also reduce adverse effects caused by sudden IgG serum elevations.7 Besides these theoretical pharmacokinetic advantages, SCIg offers practical advantages over IVIg in patients requiring immunoglobulins in the long term. The difficulties of venous access and its potential complications represent a well-known issue to patients and treating physicians. Pump-delivered SCIg is easy to use and patient-friendly, and independent home administration after a short period of training is standard practice in immunology.

Use of SCIg in inflammatory neuropathies has been the object of increasing interest in the recent years. This has resulted from the need for long-term administration of immunoglobulin therapy in a substantial proportion of patients with chronic inflammatory neuropathy. This review relates to the English language literature from a Medline search up to September 2013 on subcutaneous immunoglobulin therapy for inflammatory neuropathy, with more recent selected abstracts also discussed.

Clinical evidence base for SCIg in chronic inflammatory neuropathies

The summary of the published literature detailed below is shown in table 1.

Table 1

Published literature on the clinical effectiveness of subcutaneous immunoglobulin therapy in chronic inflammatory neuropathies

Chronic inflammatory demyelinating polyneuropathy

In chronic inflammatory demyelinating polyneuropathy (CIDP), the efficacy of IVIg has been demonstrated in several placebo-controlled trials, as well as in comparative studies versus plasma exchanges and corticosteroids.8 One double-blind, placebo-controlled, response-conditional crossover trial demonstrated prolonged amelioration over 48 weeks.9 In addition, a recently published study showed that IVIg was more efficacious and better tolerated than steroids, although interestingly the use of IVIg was associated with a higher rate of deterioration after the 6-month study period, possibly suggesting that IVIg may induce more dependency on long-term therapy than steroids.10 This could be of relevance to the subsequent need for long-term treatment and eventual consideration of switching to SCIg. The dose and frequency of IVIg treatment vary widely from one individual to another, and treatment is generally tailored to each patient's needs to prevent functional decline in between courses.11

Three initial case reports were reported by two groups of CIDP patients for whom SCIg showed good efficacy on strength and function without inducing major side effects.12 ,13 Köller et al's12 biopsy-proven single CIDP patient had previously been on IVIg with the effects not described by the authors. He was on oral steroids when SCIg was commenced. Inflammatory Neuropathy Cause and Treatment group (INCAT) score improved by two points 6 months after treatment initiation. Medical Research Council (MRC) sum score also improved. In the report by Lee et al,13 the first CIDP patient had multiple previous therapies but was on monthly IVIg, which led to transient improvement, however, with persistent underlying disease progression. He had also been put on Mycophenolate mofetil. Overall disability sum score (ODSS) improved by two points on SCIg, and there was also amelioration of MRC sum score. The second patient, initially IVg-responsive, had subsequently received immunosuppressants for disease progression. In view of worsening on Mycophenolate mofetil, SCIg was added. ODSS improved by one point after about 2 months, and MRC sum score improved marginally by one point. Subsequently, five Italian CIDP patients diagnosed according to the original version of the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) criteria,14 previously treated with IVIg for 12 months or more, and stable for at least 3 months, were prospectively studied during a switch to SCIg at equivalent monthly dose and started 7–15 days after the last intravenous course.15 Assessments used as primary outcome measures included MRC sum scores, overall neuropathy limitation scale (ONLS), grip dynamometry and sensory sum score. Secondary outcomes were evaluated by the SF-36 quality of life questionnaire, patient satisfaction scale using the Modified Life Quality Index (LQI) and simple questioning of the patients regarding their preferred administration method and where they were treated. The results showed no significant differences with SCIg in comparison with IVIg, neither in the objective strength and functional assessments nor in the secondary, patient-oriented outcomes. No side effects were observed, including in the patients who had previously had headaches or hypertension with IVIg. More recently, the effectiveness of SCIg in two patients with the Lewis–Sumner syndrome variant of CIDP was also described.16 Both had been on long-term IVIg with short-lasting benefit following each course, and in one, occurrence of ischaemic cerebrovascular and spinal events with intravenous therapy. In both patients, equivalent doses of SCIg produced similar beneficial effects on neurological function as determined by ODSS and stable MRC sum scores, with clinical stabilisation for 3 and nearly 4 years, respectively. There were no significant adverse events. These are to date the longest reported cases of maintained effectiveness of SCIg in inflammatory neuropathy.

An open-label study of 16 patients with CIDP switched from IVIg to SCIg was communicated in abstract form only in 2009.17 A weekly dose of 0.1 g/kg was administered during 12 weeks, then 0.1 g/kg every 14 days during 24 weeks. The primary endpoint was absence of relapse during treatment. Follow-up consisted of clinical evaluation (sum MRC, INCAT sensory sum score, ONLS and ataxia score) and nerve conduction studies before treatment and at 12 and 36 weeks. Treatment was discontinued in patients clinically stable after 36 weeks. Two patients relapsed shortly after initiation of treatment, and the other 14 completed the study. Thirteen patients were stable, and one had a slight deterioration of the sensory score. One patient opted to go back to IVIg. Twelve weeks after discontinuation, seven patients were still stable and considered in remission. Six had relapsed. The authors concluded that a subset of patients with CIDP may benefit from very low doses of SCIg administered at short intervals. They acknowledged some of their patients may have been treated during spontaneous remission of their disease, but considered that almost 50% had a truly active disease as shown by their early relapse after discontinuation of therapy. They concluded that low-dose SCIg may be a reasonable option for long-term treatment in CIDP.

A single, double-blind parallel group placebo-controlled randomised controlled trial (RCT) of SCIg has to date been conducted in five centres in Denmark from 2010–2011 in 30 patients with CIDP fulfilling EFNS/PNS criteria who had shown previous response to IVIg.18 In this study, patients were randomised to SCIg at a dose equivalent to their previous IVIg dose, or subcutaneous saline, administered twice or three times weekly, for 12 weeks. Patients were evaluated 2 weeks before the study, on the day of starting the trial and after 10 and 12 weeks. The primary outcome measure was the change in muscle strength evaluated by isokinetic dynamometry. Secondary outcomes were a modified MRC sum score, including nine muscles groups bilaterally and Jamar hand grip dynamometry. Other measures were the ODSS, nine-hole peg test and 40 m walking test. Side effects and patient preference, as well as the blinded patients’ assumptions about which of SCIg or placebo they thought themselves to have received, were recorded. Due to one withdrawal, 14 patients received SCIg and 15 received placebo. The two groups were at baseline comparable in terms of gender, age, height, weight, disease duration, previous IVIg requirements, MRC scores, ODSS, nine hole-peg test and 40 m walk and electrophysiology. The primary outcome measure, the average change in isokinetic muscle strength, improved in the SCIg group (5.5±9.5%; p=0.049) but deteriorated in the placebo group (−14.4±20.3%; p=0.02). A significant difference in isokinetic strength change was found between the two groups in favour of the SCIg-treated subjects (p=0.004). Similarly, in terms of secondary outcome measures, MRC sum scores, grip dynamometry and 40 m walk improved significantly in the SCIg group in comparison with the placebo group (p=0.04,  0.01 and  0.04, respectively). Although the improvement of the nine hole-peg test was also greater in the SCIg group, this did not reach significance. In total, 6 of 14 patients in the SCIg group (42.8%) versus 2 of 15 patients in the placebo group (13.3%) reported side effects. These were mild and localised to the injection sites without generalised symptoms, and included redness, rash and itching. In total, 9 of 16 respondents were able to correctly identify in which group they had been, and 20 out of the 29 participants, that is, including 6 of 15 placebo-treated patients, said they preferred subcutaneous infusion to the intravenous route. Of note, explanations given mainly related to increased flexibility or time saving (18 respondents), with less emphasis on more stable neurological function (5 respondents) or fewer side effects (3 respondents). Finally, comparing previous IVIg response to that with SCIg, there were importantly no significant differences in MRC sum score or grip dynamometry. However, some degree of isokinetic muscle strength improvement (p=0.049) was noted in SCIg-treated patients compared with baseline with the previously administered IVIg therapy. The authors hypothesised that frequent subcutaneous infusions with low doses of immunoglobulins may allow maintaining strength at a more stable level than with intermittent intravenous administration. However, they could not find any correlations between change in isokinetic muscle strength and plasma IgG levels in the SCIg or the placebo group. Seventy percentage of investigated subjects preferred subcutaneous therapy, but a non-negligible 30% stated they would opt for intravenous treatment.

A commercial trial of SCIg is currently recruiting patients with ‘definite or probable’ CIDP as per latest EFNS/PNS diagnostic criteria19 (ClinicalTrials.gov NCT01545076).20 This is a prospective international multicentre RCT versus placebo consisting of a parallel-group, three-arm design investigating two different doses of SCIg versus placebo for maintenance of patients with CIDP, officially designated as the ‘Randomized, Multicenter, Double-blind, Placebo-controlled, Parallel-group Phase III Study to Investigate the Efficacy, Safety, and Tolerability of 2 Different Doses of IgPro20 (Subcutaneous Immunoglobulin) for the Treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)—the PATH Study’. The overall study duration is set at 52 weeks, and the primary outcome measure defined as the percentage of patients relapsing during the SCIg treatment period. Secondary outcome measures include change in mean INCAT score, mean maximum grip strength and MRC sum scores, time to relapse and rate of adverse events. This trial is planned to be completed at the end of 2014. It appears likely that other similar commercial trials of SCIg may be considered in CIDP in the future.

Multifocal motor neuropathy

The benefit of IVIg was initially described in the early 1990s in multifocal motor neuropathy (MMN).21–24 Four RCTs with crossover design but relatively small numbers of patients and different methodologies have been conducted and published to date.25–28 Another more recent study has been completed, but the results are not yet published.29 A Cochrane review demonstrated MRC-measured muscle strength improvement in 78% of IVIg-treated subjects versus 4% of those having received placebo (pooled relative risk of 11.00 (95% CI 2.86 to 42.5)).30 Importantly, however, functional benefit has not been shown. More recently, a large Dutch cohort study reported MRC score improvement in 94% of a total of 84 IVIg-treated patients in a national cross-sectional descriptive analysis.31 The evidence for IVIg relates to short-term benefit, with little current data on long-term effects.

The initial description of SCIg therapy in MMN was published in relation to two patients in 2006.12 In one, the effects on strength and function were better or comparable to those of IVIg, whereas the other subject failed to tolerate SCIg, which was accompanied by generalised exanthema that led to interruption of subcutaneous treatment after 8 weeks. Of concern, that particular patient, although not having similar dermatological problems after IVIg was resumed, however, failed to reimprove neurologically back to her previous baseline. A further single case of MMN was reported as stabilised on SCIg for over 6 months after an initial IVIg response.32 This patient was also part of a larger subsequently reported case series and later detailed in this review.

A first trial comparing SCIg with IVIg in patients with MMN in a randomised single-blinded crossover design was performed in three centres in Denmark between 2005 and 2008 and published in May 2009.33 Nine IVIg responders were allocated to receive either SCIg or IVIg for a period equivalent to three IVIg intervals and then crossed over to the alternative treatment. The two interventional periods were separated by two doses of IVIg at regular intervals as ‘wash-out’ treatment. Immunoglobulin dependency had been, importantly, ascertained prior to the study by a prolonged treatment-free interval. SCIg was administered 2–3 times weekly in abdominal wall tissues at the rate of 20 mL/h/pump with a maximal volume of 20 mL per site. This was done using a small portable pump connected to a 20 mL syringe and butterfly needle. The patients received 80–155 mL at 4–8 injection sites each week at an infusion time of 2–4 h using two pumps simultaneously. The primary outcome measure was the combined dynamometric strength score expressed relative to normal strength in 5–6 affected muscle groups at three joints and at hand grip. Secondary outcome measures included MRC sum score, nine-hole peg test, 10 m walk, anti-GM1 antibody level, electrophysiology and quality of life scores (validated Danish version of the SF-36 questionnaire). The results demonstrated treatment equivalence for the primary outcome (change of 3.6% with SCIg vs 4.5% with IVIg; p=0.86). Interestingly, there was significant strength improvement during the SCIg study period (p=0.02), with a trend for improvement during the IVIg study period (p=0.11). There were no significant differences in secondary clinical outcomes, anti-GM1 titres, quality of life parameters or electrophysiology. Six of nine SCIg-treated patients experienced mild and transient local side effects, whereas three had adverse reactions with IVIg, including one with a Port A Cath infection. Five of the nine study patients opted for continuing with SCIg in replacement of IVIg. The authors concluded that SCIg was as effective as IVIg in the short-term treatment of MMN. The absence of significant differences in quality of life and adverse reaction rates (in favour of SCIg) was hypothesised by the authors to potentially relate to previous habituation to hospital treatment in this patient population and the higher incidence of side effects with SCIg on initiation of this therapy compared with subsequent continuation of the treatment.

A feasibility and safety single-centre, non-controlled study from the Netherlands was published in June 2009 and evaluated in an open-label, pilot, interventional design switch of patients from two Dutch Neuromuscular centres to either SCIg at a dose equivalent to 50% of the previous IVIg maintenance dose or, alternatively, to the full IVIg maintenance dose.34 The rationale behind using lower dosage was based on studies on primary immunodeficiency syndrome in which SCIg led to higher serum IgG levels compared with those achieved with IVIg.3 This half-dose regimen represented the original study protocol, which was however amended with Ethics Committee approval after recruitment of the first five patients, who all deteriorated, except one who withdrew after experiencing side effects to SCIg. The primary outcome was the MRC sum score from 10 muscle groups. Secondary outcome measures included grip and pinch strength, dexterity, disability, quality of life, adverse events and serum immunoglobulin G concentrations. Five patients were included in both groups. SCIg was initiated 1 week after the last course of IVIg and was administered once or twice weekly. Following the switch, patients were followed up for 6 months. Patients who deteriorated on the lower SCIg dose had the dose doubled. If this did not suffice, they were then loaded with IVIg at the dose of 1 g/kg while maintained on SCIg therapy. Results demonstrated comparable demographics and baseline MRC sum scores in both groups. In the lower dose (50% of IVIg maintenance dose) SCIg group, four of five patients deteriorated and one withdrew from the study. Doubling the dose of SCIg only resulted in modest improvement in two patients but failed to produce any benefit in the other two. All required resuming IVIg for sufficient improvement. In the higher SCIg dose group (100% of IVIg maintenance dose), four patients maintained their baseline MRC sum score during the 6-month follow-up period. Of these four patients, three opted to remain on SCIg in the longer term. One patient deteriorated, but as he had a strong preference for SCIg, he was treated with doses reaching 166% of his previous IVIg maintenance dose (0.65 g/kg/month) and stabilised. Interestingly, this patient had a body mass index (BMI) of 39.6 kg/m2, whereas the four responders in this group had a mean BMI of 26.5 kg/m2. In terms of secondary outcome measures, grip and pinch strength, as well as dexterity, worsened from baseline using lower dose SCIg therapy. No significant differences could be ascertained in the higher SCIg dose group comparing baseline and final assessment, including quality of life. However, and of note, dexterity improved in the high-dose SCIg group at final assessment compared with baseline. Also noteworthy was the reported local adverse events with SCIg by all treated subjects throughout the 330 administered courses, with a declining frequency with time. Nine mild systemic side effects were reported by three patients. After the 20 baseline IVIg treatments, 16 systemic adverse events were reported by seven patients. Overall, the severity of adverse events did not however differ between SCIg and IVIg as administered in all previously. The authors concluded that despite their small sample size, SCIg at equivalent dose to the previous IVIg maintenance dose was a feasible and effective alternative to IVIg, producing less systemic adverse events, although common local reactions. Most subcutaneous infusions were administered at the rate of 20 mL/h (3.2 g/h) at one or two injection sites, and the authors felt that their findings suggested that patients requiring high doses of IVIg should probably not be candidates for a switch to SCIg.

The same Danish group that conducted the initial previously mentioned study also published in 2010 the first long-term study of SCIg in MMN.35 This case series consisted of a small group of six IVIg-responsive patients maintained on long-term SCIg at a dose equivalent to their previous IVIg regimen for a period of 2 years. This series consisted of the five described in their first study as having preferred SCIg at study completion,33 to which they added one newly diagnosed case. Patients were assessed prospectively at 3, 6, 9, 18 and 24 months. Evaluation methods included isokinetic dynamometry, neurologic impairment score (NIS) and ODSS. The number of weekly SCIg infusions varied from 4 to 16, with doses of IgG administered ranging from 12.8 to doses as high as 51.2 g weekly. The results showed that isokinetic muscle strength remained stable during SCIg treatment, as did NIS and ODSS. Four patients required a small increase in dose of SCIg therapy to stabilise strength. Mild local side effects at injection sites occurred in all six patients. No systemic effects were reported. The authors concluded that their study demonstrated the efficacy and safety of SCIg for 2 years of treatment in MMN.

Another, again small, but multicentre, analysis was published in 2011.36 This was an open-label and uncontrolled evaluation of eight patients with MMN from three European centres (one already reported32) on stable IVIg doses switched to SCIg at equivalent dosage using what the authors described as a ‘smooth transition protocol’. This protocol consisted in, during the first SCIg infusion (week 1), 25% of the total weekly SCIg dose being administered on the same day as the last IVIg dose, followed by, in week 2, 50% of the total weekly SCIg dose being administered, and then followed by, as from week 3 onwards, 100% of the weekly dose (maintenance dose) being infused every week. The primary outcome measure was the change from baseline to study completion at 24 weeks in muscle strength using the MRC sum score of 40 muscle groups. In addition, a modified Guy's neurological disability scale, as well as a non-validated individualised selected task scale as had previously been used in a study of MMN,28 was also used together with health-related quality of life using a patient perception questionnaire, LQI and global health status. The main results demonstrated that only one patient deteriorated and was considered to be a non-responder to SCIg. There was no overall change in MRC sum scores or modified Guy's disability score. Patients’ satisfaction was unchanged or improved, and LQI was improved in six of eight patients. All seven patients completing the study decided to continue with SCIg rather than reverting back to IVIg. Mean serum IgG levels on SCIg were comparable with mean serum trough IgG levels preceding the last IVIg infusion. Interestingly, in the case of SCIg failure, serum IgG levels remained low despite increasing SCIg dosage, although the patient's levels and clinical state eventually improved when she was reverted back to IVIg. Also of note, this patient had a particularly low BMI of 16.3 kg/m2, which may have contributed to poor absorption of SCIg. Four of eight patients experienced a total of 18 adverse events, most of which were mild except two (influenza and spontaneous hematoma). None led to SCIg discontinuation. The authors concluded that their findings were consistent with those of the Danish and Dutch studies33 ,34 and demonstrated that SCIg can be as effective as IVIg at equivalent dose using their protocol for switching with minimal side effects and likely patient preference.

More recently, more data on efficacy and quality of life have been reported in abstract form in SCIg-treated MMN patients.37 These are in keeping with previous studies showing no differences with preceding IVIg therapy. Further open-label studies of safety and efficacy of SCIg are also ongoing.38

SCIg versus IVIg: adverse effects, health economics and quality of life

From the point of view of side effect profile, besides the favourable findings of the limited neurological literature reviewed here, there is substantial evidence from the immunological literature of less adverse events with SCIg compared with IVIg. A recent systematic review and meta-analysis of nearly 1500 patients with primary antibody deficiencies from 47 publications appeared to demonstrate this unequivocally (OR favouring SCIg vs IVIg 0.09; range 0.07–0.11; p<0.001).39 The risk of serious adverse effects such as thromboembolism or anaphylactic shock is documented with IVIg in inflammatory neuropathy.40 This risk has been generally considered lower with SCIg. More recently, however, a worldwide study of four IVIg products and two SCIg products demonstrated a thromboembolic reporting rate with subcutaneous therapy, which was equal for the two brands studied and, importantly, higher than that with three of four IVIg products considered.41 These latest data cast some doubt about definite relative safety of SCIg versus IVIg in relation to thromboembolic risk. This study also importantly indicated that it may be possible to evaluate the thrombogenicity of immunoglobulin batches and therefore minimise the risk of treatment-related events by using clotting tests prior to batch release. This may represent the way forward for prevention irrespective of immunoglobulin administration route.

The economic issue is of paramount importance in the treatment of immune-mediated neuropathies. Previous Swedish and German studies have, among others, shown the economic sense underlying SCIg preference in immunology patients.42 ,43 The former study calculated a saving of over US$ 10 000 per patient per year. This, however, was to a large extent related to lower SCIg versus IVIg costs. Such differences are neither present in all countries nor are they always in favour of the subcutaneous form. More recent health economic studies from France44 ,45 and Canada46 have been performed. With different methods, and mostly assuming equivalent basic drug costs for subcutaneous and intravenous forms, these studies found impressive reductions in non-drug costs of up to 85%. To date, a single economic analysis has been performed specifically in inflammatory neuropathies in a cohort of five CIDP and five MMN patients from Italy.47 Using a simulation for a 70 kg patient treated for 12 months with a dose of 1 g/kg, the authors found a marginal global saving of 1.6% of treatment cost with SCIg, corresponding to €685/year. Interestingly, the difference in basic drug cost was minimal (€49.20/g for SCIg vs €48/g for IVIg) and in keeping with current price differences in the UK for instance. This suggests that these results may be applicable to other countries. In summary, from a health-economics perspective, the immunological experience and data, as well as the recent neurological literature, show SCIg as at least cost-equivalent to IVIg.

Besides, the above-mentioned Italian economic study reported significant improvement for LQI parameters, that is, treatment interference, therapy-related problems and therapy setting.47 The role-physical, role-emotional and social functioning components of the SF-36 questionnaire were significantly better on SCIg compared with IVIg, with all other components being non-inferior. In their series, side effects were otherwise absent with SCIg but had occurred in 6 of 10 patients with IVIg. Similarly, a cross-sectional study from the UK demonstrated improved LQI and total SF36-v2 health-related quality of life score for seven SCIg-treated MMN patients versus nine patients treated with IVIg, although not reaching significance, except for the vitality domain.48 Treatment satisfaction, as evaluated by the Treatment Satisfaction for Medication Questionnaire, was significantly greater with SCIg. In the Danish33 and Dutch34 MMN studies, no significant differences in quality of life parameters between SCIg and IVIg were found, and the small multicentre analysis reported for its part improved LQI in six of eight patients without further details.36 The available data globally point towards, at the very least, non-inferiority of SCIg in comparison with IVIg on quality of life parameters.

Discussion

The current clinical evidence base for use of SCIg in inflammatory neuropathies, although still limited, has convincingly built up in the last few years. There is a need for more adapted, less costly and more patient-suited immunoglobulin administration in individuals with CIDP and MMN requiring long-term therapy. Improved adverse effect profile is also desirable. IVIg, although of known proven benefit, remains impractical for patients due to repeated hospital admissions, transport inconvenience and costs and absence from work, as well as difficulties relating to venous access and side effects. Home administration of IVIg has become routine practice in some countries and may be a good option for some patients, even offering the advantage over SCIg of less frequent infusion requirements. However, home IVIg does not fully resolve the many other issues surrounding long-term immunoglobulin treatment.49 SCIg consequently appears as a very interesting alternative. Another Italian analysis recently found improved LQI measures with equivalent clinical efficacy following a switch from 16% SCIg to 20% SCIg, which allowed reduced frequency and time of infusions.50 This study provides insight into the potential benefit of higher concentration SCIg products in future.

The only double-blind RCT of SCIg versus placebo has to date been in CIDP.18 The results clearly demonstrate the efficacy of SCIg versus placebo, both in strength and also in functional measures. In MMN, only one single-blinded crossover study provided demonstration of equivalence of SCIg to IVIg,33 although the suboptimal study design and low numbers clearly do not allow definitive conclusions. Long-term data are scarce,16 ,35 and more larger studies are needed to evaluate SCIg efficacy over prolonged periods. CIDP and MMN may fluctuate and remit, thereby requiring regular neurological functional monitoring. Substantial numbers of CIDP patients may be overtreated, and the possibility that this may be made worse by inadequately monitored home SCIg should not be discounted. Given probable lower remission rates in MMN than in CIDP without treatment31 ,51 ,52 and possible benefits from long-term high-dose therapy to avoid axonal loss and progression,53 MMN patients may represent the ideal candidates for SCIg therapy. As regards choice of adequate patients, the currently limited literature may suggest that caution may be advisable with patients with very low BMIs36 as those with confirmed very high-dose requirements.34 The latter remains controversial, and an attempt of SCIg may still remain advisable to assess tolerability of the larger infusion volumes required, particularly in view of published although limited data on high-dose SCIg usage.35 In those with high BMIs, on the other hand, it may be useful to consider gradual increase in SCIg doses above the IVIg dose previously administered if not effective.34

Interestingly, both RCTs performed suggested a possible better effect of SCIg than the previously administered IVIg on isokinetic strength.18 ,33 This may relate to more stable serum IgG levels as a result of frequent infusions rather than use of the subcutaneous route itself. However, how important maintaining steady serum IgG levels or reaching a high peak level may be, with immunoglobulin therapy to achieve optimal response, and how this may be linked to dose and frequency requirements remain uncertain. Recent studies have provided, using different methodologies, partly diverging conclusions in this regard in CIDP.54 ,55 Data on MMN have also appeared, even more recently, and suggested a role of IgG-level rise on therapeutic response.56 Further pharmacokinetic studies will be required in future in an attempt to shed light on this important but still poorly understood area. This may aid the decision of optimal therapy, including choice of the most suited administration method.

In conclusion, emerging, although still limited, clinical evidence, adverse effect data and health economics analyses, as well as quality of life measures, all currently suggest at least short-term equivalence of SCIg and IVIg in treating chronic inflammatory neuropathies. Ongoing and future SCIg trials, including of dose comparison and long-term outcomes together with pharmacokinetic studies, may bring additional support for the optimal use of this promising therapy in these new indications. The obvious benefits and current data, however, appear to already provide justification for extended consideration of SCIg in routine clinical practice, with the appropriate surveillance and functional monitoring.

References

Footnotes

  • Competing interests YAR has received speaker/consultancy honoraria from LfB France, Griffols and BPL. YAR has received educational sponsorships from LfB France, CSL Behring and Baxter.

  • Provenance and peer review Commissioned and externally peer reviewed.