key: cord-0827820-oaqohpj9 authors: Goyal, Namita A.; Karam, Chafic; Sheikh, Kazim A.; Dimachkie, Mazen M. title: Subcutaneous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy date: 2021-07-14 journal: Muscle Nerve DOI: 10.1002/mus.27356 sha: b3a1f6330dfc80f4380bc96f9656796373891226 doc_id: 827820 cord_uid: oaqohpj9 Immunoglobulin G (IgG) therapy is an established long‐term treatment in chronic inflammatory demyelinating polyneuropathy (CIDP) that is commonly administered intravenously (IVIg). The subcutaneous immunoglobulin (SCIg) administration route is a safe and effective alternative option, approved by the United States Food and Drug Administration (FDA) in 2018, for maintenance treatment of adults with CIDP. Physicians and patients alike need to be aware of all their treatment options in order to make informed decisions and plan long‐term treatment strategies. In this review, we collate the evidence for SCIg in CIDP from all published studies and discuss their implications and translation to clinical practice. We also provide guidance on the practicalities of how and when to transition patients from IVIg to SCIg and ongoing patient support. Evidence suggests that IVIg and SCIg have comparable long‐term efficacy in CIDP. However, SCIg can provide additional benefits for some patients, including no requirement for venous access or premedication, and reduced frequency of systemic adverse events. Local‐site reactions are more common with SCIg than IVIg, but these are mostly well‐tolerated and abate with subsequent infusions. Data suggest that many patients prefer SCIg following transition from IVIg. SCIg preference may be a result of the independence and flexibility associated with self‐infusion, whereas IVIg preference may be a result of familiarity and reliance on a healthcare professional for infusions. In practice, individualizing maintenance dosing based on disease behavior and determining the minimally effective IgG dose for individuals are key considerations irrespective of the administration route chosen. Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated neurological disorder causing demyelination of the peripheral nerves. 1 There are several variants and disease courses (progressive, relapsing-remitting or monophasic), but typically CIDP is characterized by symmetrical muscle weakness and impaired sensory function in distal and proximal limbs. 1, 2 Unlike most other neuropathies, CIDP is treatable and reversible. 3 The aim of treatment is to reduce symptoms and improve muscle and sensory function. 4 Approximately 30% of CIDP patients can be cured (stable and off treatment for 5 or more years) or enter remission (stable and off any treatment for less than 5 y). 5 It remains a challenge to balance maintaining longterm remission without overtreating the patient, versus the risk of relapse if treatment is stopped or reduced prematurely. 4, 6 Established first-line induction therapy options include intravenous immunoglobulin (IVIg), corticosteroids, and plasma exchange. 7 Studies have shown that corticosteroids and plasma exchange can effectively treat CIDP on a short-term basis. 7 Short-term corticosteroid use has in some cases led to periods of drug-free remission (up to 12 mo). 8 Evidence suggests corticosteroids may be effective longer term, 8, 9 however, intolerance and side effects often prevent their long-term use. 7 IVIg has demonstrated long-term efficacy in CIDP maintenance therapy, but IV administration can pose challenges for some patients. 10 Subcutaneous immunoglobulin (SCIg) has been used for decades in other areas, but it is a relatively recent mode of immu- Therefore, it is crucial to outline all the treatment options as early as possible to allow informed decisions. In this review, we consolidate the findings of SCIg studies in CIDP with a focus on the practical application of the data. We aim to provide an overview for clinicians including when to consider SCIg, initiating the transition from IVIg to SCIg, dose adjustments, and long-term patient support and retention. IVIg has been approved for CIDP treatment in the United States (US) since 2008 following the randomized, double-blind, placebocontrolled Immunoglobulin Intravenous CIDP Efficacy (ICE) study. 11, 12 Results showed a clinically meaningful improvement in disability (assessed by the Inflammatory Neuropathy Cause and Treatment [INCAT] ) at 24 wk in 54% of patients who received IVIg versus 21% of patients who received placebo. 11 Efficacy of IVIg for up to 52 wk was also seen in a single-arm, open trial, although a higher frequency of adverse events (AEs; 94%) was observed in this trial compared with the 75% seen in the ICE study (75%). 11, 13 In a recent online survey of 100 US community neurologists, nearly half reported using IVIg alone as their first treatment of choice for CIDP. 4 The 2010 European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/ PNS) guidelines recommend that IVIg should be individualized to achieve the lowest effective maintenance dose and periodically reduce the dose, or stop IVIg, to determine the need for ongoing therapy. 14 Guidelines from the EFNS/PNS, currently under development, should provide more clarity on clinical definitions, electrophysiologic criteria, implications of nodal and paranodal antibodies, individualizing treatment, and inclusion of SCIg as an alternative option to maintain patients and optimize treatment. 15 SCIg was first approved by the FDA in 2018 for maintenance therapy in adult patients with CIDP based on the Polyneuropathy and Treatment with Hizentra (PATH) study findings, 16 but has been used successfully in other conditions such as primary immunodeficiency (PID) for over two decades. 17 Collective experience with over 300 patients with CIDP, treated with various SCIg products over the past 15 y, supports the use of SCIg as a maintenance therapy for CIDP (Table 1) . Additionally, long-term SCIg data are now available supporting continued stabilization and, in some cases, improvements in function and quality of life (QoL), for up to 7 y post initiation of SCIg therapy (N = 17, SCIg mean duration was 4.8 y [2-7 y] and an average dose of 18.5 g/wk). 18 Currently, there are no data available from head-to-head trials comparing relapse rates in maintenance therapy with IVIg and SCIg. 19 Findings from the studies outlined in Table 1 suggest similar efficacy. A 2017 meta-analysis of eight studies concluded that the efficacy (measured by muscle strength) of SCIg is comparable with IVIg in the treatment of CIDP (n = 88) and multifocal motor neuropathy (MMN) (n = 50). 20 IVIg and SCIg therapy have distinguishing attributes that will appeal to patients differently depending on their circumstances and lifestyle (Table 2) . SCIg can offer important safety and QoL advantages compared with IVIg, such as avoidance of regular venous access and reduced systemic AEs. However, disadvantages of SCIg for some patients can be the need for weekly infusions and the potential for local-site reaction. The study demonstrated that SCIg was efficacious and well tolerated in patients with CIDP previously stabilized on IVIg and treated for 24 wk. 16 Patients were randomized to receive 24 wk of weekly SCIg doses at 0.2 g/kg (n = 57), 0.4 g/kg (n = 58), or placebo (n = 57). 16 Fewer patients treated with SCIg relapsed compared with placebo. patients could be maintained on 0.2 g/kg without relapse ( Figure SS1 ). 41 This disparity portrays the inter-patient heterogeneity in terms of IgG threshold and the importance of determining the minimum effective dose on a case-by-case basis. SCIg is currently not approved for induction therapy in CIDP, where typically a higher dose is used to stabilize patients starting IgG therapy. 35 IVIg is delivered directly into the bloodstream resulting in a rapid rise in IgG levels which has been shown to lead to a faster onset of action, quicker improvements in disability, and (in many patients) "an energy boost". 42 In comparison, SCIg had a slower onset of action due to slower absorption into the bloodstream. SCIg has previously been investigated as a first-line treatment option in patients with CIDP. 31 Differences in symptom control and systemic side effects may be attributed to differences in pharmacokinetics between IVIg and SCIg. 33, 42 IVIg is administered as a large intermittent bolus, typically every 3-4 wk, whereas SCIg is administered in more frequent (typically weekly) smaller doses. 37 Low IgG trough levels toward the end of IVIg dosing intervals may lead to cyclic fluctuations in disability and a return of symptoms in some patients referred to as "wear-off" effects 37 (Figure 1 ). Weekly SCIg dosing results in a steadier IgG concentration that is consistent between infusions, but with a peak serum IgG concentration that is lower than that achieved with IVIg. 19 To self-administer SCIg, patients should be adequately trained and monitored by a healthcare professional (HCP). Patients often report that learning self-administration is easy. 16 SCIg may be a preferred route of IgG administration for many patients with CIDP due to its ease of use, safety profile, and patient independence. 61 Often, newly diagnosed patients with CIDP and those experiencing issues with their current treatment may be more receptive to SCIg, but all patients, whether new or established, should be made aware of their options with IgG therapy and the potential pros and cons associated with both IVIg and SCIg use. Table 3 provides examples of potential candidates who may prefer to remain on IVIg, and Some patients may be unwilling, or lack the skills, necessary to take on an element of their own disease management. Setting appropriate patient expectations when discussing SCIg is important to outline the responsibilities of self-administration and to help assess whether the patient would derive more benefit from an HCP-assisted mode of administration Patient unable to self-administer due to poor dexterity, fear of needles or no reliable support network Patients with poor manual dexterity or fear of needles may struggle with aspects of the self-administration technique (drawing solution from vial into syringe, etc.). A reliable caregiver (eg, spouse, family member, or friend) nearby to provide support or assist with the infusion can be considered if available. The use of a SCIg pre-filled syringe to simplify the process can also be an option. In the absence of the above options, remaining on IVIg may be a more appropriate plan Patient preferring treatment in a clinic setting or administered by an HCP Some patients may prefer a clinic setting for their infusions due to the confidence and relationships built with staff. IVIg has the advantage of access to laboratory testing at the time of initiating the IV line. There is also potentially less risk of dosing errors in treatment administered by an HCP and the reliance on an HCP to monitor for side effects Patient familiarity and extensive history with IVIg For established patients with CIDP, they may have received IVIg for a long time and feel comfortable with a therapy they know and trust. Patients may not get as much subjective benefit from SCIg compared with IVIg due to the route of administration and slower absorption. Physicians should periodically reassess the patient's perception of SCIg as the attributes which did not initially appeal may be viewed more favorably with changing patient circumstances Patient preferring more infrequent infusions Some patients may find the infrequent infusion schedule (and potentially fewer disease reminders) associated with IVIg every 3 or more weeks fits in better with their lifestyle. As above, periodic discussions on the most suitable mode of administration should take place to reflect changing circumstances Low BMI patients requiring large IgG doses Self-administration of large volumes of SCIg may be unappealing or challenging for low BMI patients who have less available subcutaneous tissue for infusions. Often a SCIg infusion regimen can be designed to accommodate these patients, but this may require a higher number of infusion sites Abbreviation: BMI, body mass index. a (Figure 2 ). Consequently, physicians should thoroughly evaluate and discuss with patients before transitioning them between IgG therapies as some may need additional support with self-administration or have other reasons for preferring to remain on IVIg. 17 Although patients often prefer the convenience of home-based IgG administration, Ness et al. highlights that there is some variation in patient preference with regard to clinic versus home-based therapy. 38 Some patients may feel overwhelmed by the number of injections associated with SCIg, the idea of managing their own treatment or the loss of a regular HCP touchpoint; these patients may prefer treatment to be administered by a HCP. 37 A support program for patients opting to transition to SCIg is important to build confidence with selfadministration for successful long-term adherence. 64 In one study, a nurse-led individualized program that included teaching sessions, writ- States, SCIg carries a US FDA-mandated "black box" class warning for thrombosis. 35, 37 IVIg is associated with rare but potentially serious AEs, such as thromboembolic events (TEEs), aseptic meningitis, hemolysis, and renal dysfunction. 65 Although less common, these serious AEs can also still occur with SCIg. IVIg is also associated with systemic AEs such as headache, nausea, and flu-like symptoms, which may be due to the high infusion volumes required and rapid rise in IgG concentration following infusion. 42 Local-site reactions tend to be the most common AE reported by patients receiving SCIg. 16, 24, 33, 67 Local-site reactions are usually mild to moderate in intensity and have been reported to significantly decrease with subsequent infusions. 16 The decline in local-site reactions is potentially a result of improving patient self-administration technique and habituation to subcutaneous infusions. Local site reactions are rarely reported with IVIg infusions, although bruising can occur at the site of infusion. Another important difference of SCIg is that it does not require venous access. The majority of patients with CIDP are over 60 y of age and may need treatment for many years. 68 The ability to establish peripheral venous access that remains viable throughout the infusion can become progressively more difficult, and a central venous line may need to be inserted, carrying additional risks. 69 SCIg should always be considered before resorting to a port. Eliminating the need for venous access with SCIg therapy may also provide more treatment flexibility as patients are able to self-administer at a variety of locations at their own convenience, which may be even more beneficial in the context of the COVID-19 pandemic. Studies comparing the economic burden of SCIg vs IVIg in CIDP report mixed results and have primarily been conducted in European settings. [70] [71] [72] In general, studies agree that home-based infusions vs hospital-based result in cost reductions irrespective of the route of administration. 19, 71, 72 The primary cost driver is often the product itself and, in turn, the dose requirement. However, comparisons are complicated by the indirect costs associated with site of care, HCP resource, and long-term requirement for hospitalizations due to AEs or other disease-related complications. In reality, it is often unclear which route of administration will prove most cost effective, as the slightly more expensive cost of the SCIg product can eventually be offset indirectly by associated infusion cost savings and reduce productivity loss for patients as a result of hospital/infusion-related absenteeism. 28, 73 Currently, only one 20% SCIg solution is approved for use in adult patients with CIDP, 35 but other 10%-20% SC formulations are in various phases of development. In addition, an ongoing trial is exploring the tolerability and safety of hyaluronidase facilitated SCIg (fSCIg) in CIDP (NCT02955355). This method utilizes 10% SCIg and hyaluronidase in a two-step infusion, which can theoretically deliver volumes greater than 700 mL compared with the recommended maximum of 50 mL per site with conventional SCIg. 35, 74 fSCIg allows infusions at similar rates and volumes to IVIg, but with potential reductions in systemic AEs comparable with SCIg. Data on long-term safety and cost comparisons for fSCIg are lacking and there is limited evidence to suggest any differences in QoL between SCIg and fSCIg in either CIDP or other neuromuscular disorders. [75] [76] [77] To date, the United States has the highest IgG usage per capita, followed by Canada, Australia, and some European countries. 78 Uptake of SCIg stands at 15% of total IgG use in the US market (of which currently 61% is used in PID). 78 The use of IgG in neurological indications is growing and is anticipated to continue with highdose neurological indications, such as CIDP. Given the expanding IgG therapy options in CIDP and the high cost of treatment, exploring opportunities for cost minimization are important. To conclude, there is a role for both IVIg and SCIg in CIDP maintenance therapy. The most appropriate route of administration should be individualized and will be determined by the patient. Ensuring patients are familiar with the benefits of each route is important to aid in treatment optimization and provide a better chance of longterm adherence and success. We thank Prof. van Schaik for providing a critical review of this manuscript. Editorial assistance was provided by Meridian HealthComms Ltd, funded by CSL Behring. All medical writing assistance was guided by the authors, and all authors reviewed and approved each draft. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. All data included in this manuscript is publicly available. The authors will consider requests for additional data from genuine researchers on an individual basis. Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype Immune globulin subcutaneous (human) 20% (Hizentra[ ® ]): a review in chronic inflammatory demyelinating polyneuropathy Chronic inflammatory demyelinating polyneuropathy Current practice patterns in CIDP: a cross-sectional survey of neurologists in the United States Chronic inflammatory demyelinating polyneuropathy disease activity status: recommendations for clinical research standards and use in clinical practice Evidence of persistent improvements with long-term subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews Pulsed high-dose dexamethasone versus standard prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT study): a double-blind, randomised, controlled trial Intravenous immunoglobulin versus intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy: a randomised controlled trial Efficacy and tolerability of intravenous immunoglobulin and subcutaneous immunoglobulin in neurologic diseases Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial Immunosuppressive and immunomodulatory therapies for neuromuscular diseases. Part I: Traditional agents Intravenous immunoglobulin for maintenance treatment of chronic inflammatory demyelinating polyneuropathy: a multicentre, open-label, 52-week phase III trial European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society -first revision Diagnostic Snares in Chronic Inflammatory Demyelinating Polyneuropathy -Medscape Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebocontrolled, phase 3 trial Immunosuppressive and immunomodulatory therapies for neuromuscular diseases. Part II: new and novel agents Longterm treatment with subcutaneous immunoglobulin in patients with chronic inflammatory demyelinating polyradiculoneuropathy: a follow-up period up to 7 years Immunoglobulin administration for the treatment of CIDP: IVIG or SCIG? Subcutaneous versus intravenous immunoglobulin for chronic autoimmune neuropathies: a metaanalysis Subcutaneous self-infusions of immunoglobulins as a potential therapeutic regimen in immune-mediated neuropathies Subcutaneous immunoglobulin infusion: a new therapeutic option in chronic inflammatory demyelinating polyneuropathy The efficacy of subcutaneous immunoglobulin administration in chronic inflammatory demyelinating polyneuropathy responders to intravenous immunoglobulin Subcutaneous immunoglobulin in responders to intravenous therapy with chronic inflammatory demyelinating polyradiculoneuropathy Improvement of quality of life in patients with chronic inflammatory demyelinating polyneuropathy shifting from 16 to 20% subcutaneous immunoglobulins Subcutaneous immunoglobulin preserves muscle strength in chronic inflammatory demyelinating polyneuropathy Subcutaneous immunoglobulin in CIDP and MMN: a short-term nationwide study Switch from intravenous to subcutaneous immunoglobulin in CIDP and MMN: improved tolerability and patient satisfaction Subcutaneous immunoglobulin in treating inflammatory neuromuscular disorders Subcutaneous immunoglobulin in CIDP and MMN: a different long-term clinical response? Subcutaneous immunoglobulin as first-line therapy in treatment-naive patients with chronic inflammatory demyelinating polyneuropathy: randomized controlled trial study Long-term neurophysiological and clinical response in patients with chronic inflammatory demyelinating polyradiculoneuropathy treated with subcutaneous immunoglobulin Long-term safety and efficacy of subcutaneous immunoglobulin IgPro20 in CIDP: PATH extension study Gamunex-C Prescribing Information Hizentra Prescribing Information Privigen Prescribing Information IgPro20, the polyneuropathy and treatment with Hizentra([R]) study (PATH), and the treatment of chronic inflammatory demyelinating polyradiculoneuropathy with subcutaneous IgG Differentiating characteristics and evaluating intravenous and subcutaneous immunoglobulin Efficacy and patient satisfaction in the use of subcutaneous immunoglobulin immunotherapy for the treatment of auto-immune neuromuscular diseases Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (the PATH study): study protocol for a randomized controlled trial Long-term Safety and Efficacy of Subcutaneous Immunoglobulin IgPro20 in CIDP: the PATH Extension Study Bioavailability of IgG administered by the subcutaneous route High-dose subcutaneous immunoglobulin in patients with multifocal motor neuropathy: a nursing perspective A smooth transition protocol for patients with multifocal motor neuropathy going from intravenous to subcutaneous immunoglobulin therapy: an open-label proof-ofconcept study Canada Product Monograph HIzentra subcutaneous immunoglobulin (Human) 20% solution Hizentra Summary of Product Characteristics Pharmacokinetics of subcutaneous immunoglobulin and their use in dosing of replacement therapy in patients with primary immunodeficiencies Improvement of hemoglobin levels after a switch from intravenous to subcutaneous administration of immunoglobulin in chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy A proposed dosing algorithm for the individualized dosing of human immunoglobulin in chronic inflammatory neuropathies Serum IgG levels in IV immunoglobulin treated chronic inflammatory demyelinating polyneuropathy Daily grip strength response to intravenous immunoglobulin in chronic immune neuropathies History, diagnosis, and Management of Chronic Inflammatory Demyelinating Polyradiculoneuropathy Combined intravenous immunoglobulin and methylprednisolone as induction treatment in chronic inflammatory demyelinating polyneuropathy (OPTIC protocol): a prospective pilot study Intravenous immunoglobulin treatment in chronic inflammatory demyelinating polyneuropathy. A double-blind, placebo-controlled, cross-over study Prefilled syringes for immunoglobulin G (IgG) replacement therapy: clinical experience from other disease settings Rapid push vs pump-infused subcutaneous immunoglobulin treatment: a randomized crossover study of quality of life in primary immunodeficiency patients Subcutaneous immunoglobulin: rapid push vs. infusion pump in pediatrics Subcutaneous immunoglobulin therapy given by subcutaneous rapid push vs infusion pump: a retrospective analysis Subcutaneous immunoglobulin (16 or 20%) therapy in obese patients with primary immunodeficiency: a retrospective analysis of administration by infusion pump or subcutaneous rapid push Subcutaneous immunoglobulin therapy for chronic inflammatory demyelinating polyneuropathy: a nursing perspective Practical Application of Subcutaneous Immunoglobulin for Maintenance Treatment in Chronic Inflammatory Demyelinating Polyneuropathy -The PATH Study Health-related quality of life in chronic inflammatory neuropathies: a systematic review Patient-reported outcomes with subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy: the PATH study Evaluation of a personalized subcutaneous immunoglobulin treatment program for neurological patients Adverse effects of immunoglobulin therapy Randomised controlled trial comparing two different intravenous immunoglobulins in chronic inflammatory demyelinating polyradiculoneuropathy Subcutaneous immunoglobulin treatment in CIDP and MMN. Efficacy, treatment satisfaction and costs Incidence and prevalence of CIDP and the association of diabetes mellitus Central line catheters and associated complications: a review Home-based subcutaneous immunoglobulin for chronic inflammatory demyelinating polyneuropathy patients: a Swiss cost-minimization analysis Home versus hospital immunoglobulin treatment for autoimmune neuropathies: a cost minimization analysis Subcutaneous vs intravenous administration of immunoglobulin in chronic inflammatory demyelinating polyneuropathy: an Italian cost-minimization analysis The economic burden and managed care implications of chronic inflammatory demyelinating polyneuropathy Hyaluronidase facilitated subcutaneous immunoglobulin in primary immunodeficiency Rationale and Design of a Phase 3b study of the long-term tolerability and safety of HyQvia in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): ADVANCE-CIDP 3 (4331) Human immune globulin 10% with recombinant human hyaluronidase in multifocal motor neuropathy Randomized trial of facilitated subcutaneous immunoglobulin in multifocal motor neuropathy The growing importance of achieving national self-sufficiency in immunoglobulin in Italy. The emergence of a national imperative Additional supporting information may be found online in the Supporting Information section at the end of this article.