Chronic inflammatory demyelinating polyneuropathy (CIDP) is a progressive immune-mediated disorder of the peripheral nerves attributed to demyelination and impairment of signal conduction in motor and/or sensory nerves.1,2 Symptoms include loss of strength and sensation typically causing symmetrical, proximal, and distal weakness.1 Disease progression is variable, with many patients experiencing chronic patterns of relapse and remission.2 Prevalence in the United States has been reported between 1.9 and 8.9 per 100 000 depending on the patient population.1,3 Typically, CIDP arises between 40 and 60 years old with common initial symptoms of weakness and numbness in extremities.4
Widely used guidelines from the European Federation of Neurological Societies and Peripheral Nerve Society outline a combination of clinical, electrodiagnostic, and supportive criteria to diagnose CIDP accurately.5 However, diagnosis can be challenging due to disease variability and other neurological conditions that can mimic CIDP. An overreliance on subjective patient-reported measures may also contribute to misdiagnosis.6–8 If left untreated, progressive axonal damage can occur. Therefore, early assessment from a neuromuscular specialist is important to minimize delays between symptom appearance and treatment initiation. CIDP treatments aim to improve functional ability and maintain long-term remission.4 Most patients will require long-term treatment. Choice of treatment depends on various factors including CIDP variant, severity, age, general health, and comorbidities.9 Intravenous immunoglobulin (IVIG) is often used for long-term treatment, but other first-line treatment options include corticosteroids or plasma exchange. Immunosuppressants can also be prescribed, often as “add-on” therapies.5 A 2017 nationwide United States survey of 475 patients with CIDP conducted by the GBS/CIDP Foundation International reported the 2 most common treatments as IVIG (63% currently using; 93% have ever used) and corticosteroids (19% currently using; 59% have ever used).10
This article highlights current unmet needs with IVIG therapy and raises awareness of subcutaneous immunoglobulin (SCIG), a 20% solution stabilized with L-proline, as an option for maintenance therapy in CIDP. We also provide practical information on initiating and monitoring SCIG.
Unmet Needs in CIDP: Challenges With IVIG
Challenges with IVIG treatment include systemic adverse events (AEs), some of which can be serious. Within 3 retrospective cohort studies of inflammatory neuropathy patients, including CIDP, treated with IVIG, incidence of thromboembolic events (TEs) was reported to range from 10.2% to 11.3%.11–13 A retrospective analysis, by Rajabally and Kearney,11 highlighted further risk factors for TEs in patients with CIDP, multifocal motor neuropathy, or Guillain-Barré syndrome. These included being male; being older than 60 years; a diagnosis of diabetes, dyslipidemia, hypertension, or coronary disease; being unable to walk unaided during IVIG treatment; or a family history of TE disease or atrial fibrillation. Many patients with CIDP have one or more of these risk factors, especially as CIDP is more common in adult men with most diagnosed patients aged between 50 and 70 years. In addition, patients are more prone to be sedentary because of lower limb weakness. Patients at risk of TEs should be hydrated and monitored closely during infusions at the minimally effective dose and rate.14 Thromboembolic events can also occur in the absence of known risk factors.15 Rarer AEs can include hemolysis, aseptic meningitis, and renal dysfunction. A retrospective review has provided evidence that a significant number of patients during long-term IVIG therapy had a decline in hematocrit and/or glomerular filtration rates.16 Systemic AEs, such as headache, nausea, and flu-like symptoms, may occur frequently because of the rate of infusion and the requirement for high infusion volumes.17 Chronic inflammatory demyelinating polyneuropathy is treated with IVIG at doses of 1 to 2 g/kg per month with infusions requiring monitoring by a clinician and lasting 4 or more hours over several days. Regular peripheral venous access can be difficult to maintain for chronic IV treatments. In addition, treatments can be difficult to schedule if patients work or travel.
SCIG in CIDP
Evolution of SCIG
Intravenous immunoglobulin therapy, first introduced in the 1980s, has been the standard of care for chronic replacement therapy in patients with primary immunodeficiency disease (PIDD) associated with hypogammaglobulinemia and impaired antibody production or function. Since the first SCIG product was approved in 2006 in the United States, there has been an increasing trend in PIDD toward SCIG administration due to the lower rate of systemic AEs, the lack of need for vascular access, and the feasibility of home self-administration.18 IVIG and SCIG demonstrate comparable efficacy, but SCIG provides improved tolerability compared with IVIG.19 Learnings from introducing SCIG in PIDD indicate that many patients benefit from taking an active role in their disease management.20 In recent years, the focus on patient centricity has amplified. Patients with CIDP who are stable on IVIG may also consider SCIG maintenance therapy. Subcutaneous immunoglobulin offers independence, flexibility and makes self-administration more accessible. Therefore, many patients with PIDD choose SCIG for reasons beyond tolerability.21–23
The last decade has seen many small studies assessing SCIG in CIDP to better address the gap in treatment options. Racosta et al24 analyzed results from 8 of these studies, comprising 88 patients with CIDP, and found that SCIG demonstrated a 28% reduction in AE relative risk, indicating a significantly improved safety profile. In addition, a systematic review of health-related quality of life (HRQL) measures in inflammatory neuropathies concluded that SCIG may be a superior administration route compared with IVIG.25 Improved safety and positive HRQL provided evidence that SCIG improved long-term outcomes for some patients with CIDP, but a larger study was needed to consolidate the evidence from these small trials. Thus, the Polyneuropathy and Treatment with Hizentra (PATH) study, a randomized trial comparing relapse rates in patients treated with SCIG or placebo, was designed assessing efficacy, safety, and tolerability of weekly SCIG.
The PATH Study
The PATH study was a global phase III, double-blind, randomized, placebo-controlled trial evaluating 2 doses of 20% SCIG (IgPro20, Hizentra, CSL Behring) as maintenance treatment in 172 adult patients with CIDP.26 Patients received weekly placebo (2% albumin) or IgPro20 at 0.2- or 0.4-g/kg body weight (bw), equivalent to 1 or 2 mL/kg, respectively, for a 24-week subcutaneous treatment period (placebo, n = 57; 0.2 g/kg, n = 57; 0.4 g/kg, n = 58). CIDP relapse was defined as a deterioration (ie, increase) by 1 point or higher in the total adjusted inflammatory neuropathy cause and treatment score (range, 0 [healthy] to 10 [unable to make any purposeful movements with arms or legs]) compared with baseline.
Of patients on placebo, 63% relapsed or withdrew during the 24 weeks, compared with 39% on 0.2 g/kg and 33% on 0.4 g/kg of IgPro20, equating to reductions in the absolute risk of relapse/withdrawal of 25% for 0.2 g/kg (P = .007) and 30% for 0.4 g/kg (P = .001). Both doses differed significantly from placebo in this efficacy outcome with no statistical difference between the 0.2- and 0.4-g/kg doses. Subcutaneous immunoglobulin was initiated 1 week after the last IVIG dose, administered via infusion pumps during 1 to 2 consecutive days over 1 to 2 sessions weekly. Patients infused a median average of 20 mL/site as tolerated (maximum, 50 mL), with a median infusion rate of 20 mL/h per site as tolerated (maximum, 50 mL/h per site). The infusions were performed at appropriate infusion sites (Fig 1). Irrespective of number of sites, the median infusion time for each session was approximately 1 hour. The maximum total infusion volume per session was 140 mL (Supplemental Digital Content 1, available at http://links.lww.com/JNN/A172). Patients used a median of 4 infusion sites in parallel, with the number of sites dependent on dose and investigator judgment. However, up to 8 sites in parallel were permitted with at least 2 inches required between sites. Subcutaneous immunoglobulin infusions were administered at home after the patient or caregiver demonstrated their ability to self-administer.
In the placebo group, 37% of patients experienced an AE (rate per infusion, 0.034), compared with 58% of patients receiving 0.2 g/kg (rate per infusion, 0.079) and 52% of patients receiving 0.4 g/kg (rate per infusion, 0.051). The most frequent AEs were local site reactions, such as erythema and swelling, which were either mild (94.5%) or moderate (5.5%) in intensity. None led to treatment discontinuation (Supplemental Digital Content 2, available at http://links.lww.com/JNN/A173). Of patients receiving SCIG, 77% did not report any local reactions. Furthermore, there was a noticeable reduction in local reactions as patients continued treatment. Similar to other SCIG trials, systemic AE rates per infusion were lower than those reported with IVIG.27,28 Systemic AEs of specific relevance, such as headache and nausea, were on average 3.6 times lower in both SCIG groups (rate per infusion, 0.027) than a preceding IVIG period (rate per infusion, 0.098).14 Patients using higher infusion rates reported similar proportions of AEs as those using lower infusion rates (0.056 for <35 mL/h vs 0.053 for ≥35 mL/h of AEs per infusion). During the subcutaneous treatment period, no serious systemic AEs such as TEs, aseptic meningitis, or hemolysis occurred.
All patients required 4 or less training sessions, and 88% reported that learning self-administration was easy. Of 85 patients who received either 0.2 or 0.4 g/kg and had available data, 53% preferred SCIG over their previous IVIG treatment compared with 18% who preferred IVIG (Fig 2). Greater independence was the primary reason for SCIG preference.
The PATH study demonstrated that SCIG was efficacious in maintaining patients previously stabilized on IVIG. Subcutaneous immunoglobulin was well tolerated at a range of infusion volumes and rates, with an improved safety profile compared with preceding IVIG infusions. On the basis of these results, SCIG was US Food and Drug Administration–approved as a maintenance treatment for CIDP in 2018.
Nursing Considerations for CIDP Management
The nurse is a critical component of care coordination to ensure a smooth transition.29 Successful transition to SCIG therapy depends on assessment of several key factors, including motivation, ability to learn, and compliance. The patient’s manual dexterity, or the presence of other physical limitations, should also be considered. The availability of a caregiver who can assist as needed can mitigate concerns, allowing more patients to transition successfully. Patients should be given information about the administration process including anticipated infusion time, number of sites, volume per site, and local skin reactions. Providing written or web-based materials before SCIG can prepare patients and set appropriate expectations. Nurses can help set patient expectations by discussing common local site reactions and sharing ways these can be alleviated or when to notify the health care professional (Supplemental Digital Content 3, available at http://links.lww.com/JNN/A174). In the trial, the most common skin AEs were mild erythema and localized edema, with itching or burning sensation reported rarely, with most symptoms reported during therapy initiation and resolved within 24 hours. The intensity and frequency of local reactions decreased during subsequent infusions. As per the PATH study, weekly infusion of SCIG may be initiated at either 0.2- or 0.4-g/kg bw (1 or 2 mL/kg of 20% SCIG), beginning 1 week after the last IVIG infusion (Supplemental Digital Content 4, available at http://links.lww.com/JNN/A175). The first dose should be given at a volume of less than or equal to 20 mL/site and a rate of less than or equal to 20 mL/h per site as tolerated. After the initial dose, the volume may be gradually increased to less than or equal to 50 mL/site based on clinical judgment and patient tolerability. The rate may be increased subsequently to less than or equal to 50 mL/h per site as tolerated. Adjusting 1 variable at a time allows optimization of the regimen. Periodic assessment of satisfaction with the infusion regimen is important and allows for patient input to achieve an optimal number of sites or infusion time.
A specialty pharmacy provider (SPP) nurse will train patients on self-administration in the home setting during 3 to 5 training visits over several weeks to ensure that the patient and/or caregiver understand and can independently perform the procedure. Most SPPs are familiar with SCIG due to experience using it as a treatment for PIDD. The clinic nurse should be familiar with the infusion equipment. The clinic nurse will act as the point for communication with the SPP to individualize and optimize the infusion parameters. Although the recommended doses for CIDP management are higher than those used in PIDD, patient training requirements are similar. The nurse has a critical role in providing education and ongoing support to optimize infusions. After initial training, patients may benefit from frequent clinic follow-ups, by phone or in person, to assess treatment response, identify treatment barriers, and monitor compliance.29 Availability to answer questions and provide additional training sessions if needed develops patient confidence with self-administration. The SPP can also monitor dose, volume, rate, and tolerability more closely during the initial months. Specialty pharmacy provider progress notes on changes in infusion routine, AEs, technical issues, and compliance should be communicated with clinic staff. For example, if a patient complains of local reactions, such as redness or leaking at the infusion site, an additional training visit to assess technique or optimize needle length or site selection may be warranted. Many tools developed for PIDD aimed at improving infusion technique and AE management can be useful in CIDP. For example, a flowchart for managing local site reactions is largely applicable across therapy areas (Supplemental Digital Content 5, available at http://links.lww.com/JNN/A176).21 Several materials exist to help address patient concerns, such as needle blocks to demonstrate the actual size of needles and self-administration training videos to visually show the process. Ultimately, each individual patient’s follow-up requirements will differ with some achieving greater levels of independence than others. The anticipated shift from clinic to home self-infusion highlights the importance of integrated patient management and the need for good communication between SPP and clinic staff.
The PATH study provides evidence to support weekly infusion of SCIG at either 0.2- or 0.4-g/kg bw (1 or 2 mL/kg of 20% SCIG) as an efficacious and well-tolerated alternative option for maintenance treatment in CIDP. Subcutaneous immunoglobulin offers some important safety benefits in reduced systemic serious/nonserious AEs and no requirement for venous access. Beyond tolerability and safety reasons, SCIG may also appeal to patients because of relief of the treatment burden, autonomy, and improved HRQL.
Subcutaneous immunoglobulin may change the care paradigm by developing patient independence. Addressing the impact of this increased shift from clinic to home-based care is important to ensure optimal patient management, training, and AE monitoring. Here, we have outlined nursing considerations, initial infusion parameters for new patients transitioning to SCIG based on the PATH study, and recommendations for optimal maintenance therapy. Experienced SPPs can also provide practical advice on local site reactions, infusion technique, and infusion optimization. Widespread access to educational resources will enhance patient learnings and facilitate support in this therapeutic journey.
We thank Prof Ivo van Schaik for critically reviewing this article on behalf of the PATH steering committee. We also thank Ann Leon for her insights and critical review of this article.
1. Mathey EK, Park SB, Hughes RA, et al. Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype. J Neurol Neurosurg Psychiatry
2. Wakerley BR, Yuki N. Peripheral neuropathies: subcutaneous immunoglobulin—the future of CIDP treatment? Nat Rev Neurol
3. Laughlin RS, Dyck PJ, Melton LJ 3rd, Leibson C, Ransom J, Dyck PJ. Incidence and prevalence of CIDP and the association of diabetes mellitus. Neurology
4. Gorson KC. An update on the management of chronic inflammatory demyelinating polyneuropathy. Ther Adv Neurol Disord
5. Van den Bergh PY, Hadden RD, Bouche P, et al. 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. Eur J Neurol
6. Allen JA, Lewis RA. CIDP diagnostic pitfalls and perception of treatment benefit. Neurology
7. Dimachkie MM, Barohn RJ, Katz J. Multifocal motor neuropathy, multifocal acquired demyelinating sensory and motor neuropathy, and other chronic acquired demyelinating polyneuropathy variants. Neurol Clin
8. Staudt M, Diederich JM, Meisel C, Meisel A, Klehmet J. Differences in peripheral myelin antigen-specific T cell responses and T memory subsets in atypical versus typical CIDP. BMC Neurol
9. Ripellino P, Fleetwood T, Cantello R, Comi C. Treatment of chronic inflammatory demyelinating polyneuropathy: from molecular bases to practical considerations. Autoimmune Dis
. 2014;2014: 201657.
10. Allen JA, Butler L, Levine TD, Bullinger AL, Koski CL. CIDP Disease Burden—Results of a US Nationwide Patient Survey. Poster presented at Peripheral Nerve Society (PNS) Annual Meeting; July 22–25, 2018. Baltimore, MD; 2018.
11. Rajabally YA, Kearney DA. Thromboembolic complications of intravenous immunoglobulin therapy in patients with neuropathy: a two-year study. J Neurol Sci
12. Ramírez E, Romero-Garrido JA, López-Granados E, et al. Symptomatic thromboembolic events in patients treated with intravenous-immunoglobulins: results from a retrospective cohort study. Thromb Res
13. Spillane J, Englezou C, Sarri-Gonzales S, et al. Thromboembolic events in inflammatory neuropathy patients on IVIG. Paper presented at: Peripheral Nerve Society; 2017; Barcelona, Spain.
14. Hizentra, Immune Globulin Subcutaneous (Human), 20% Liquid Prescribing Information. CSL Behring LLC; 2018.
15. Bonilla FA. Adverse effects of immunoglobulin G therapy: thromboembolism and haemolysis. Clin Exp Immunol
. 2014;178(suppl 1):72–74.
16. Levine AA, Levine TD, Clarke K, Saperstein D. Renal and hematologic side effects of long-term intravenous immunoglobulin therapy in patients with neurologic disorders. Muscle Nerve
17. Oaklander AL, Lunn MP, Hughes RA, van Schaik IN, Frost C, Chalk CH. Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews. Cochrane Database Syst Rev
18. Gardulf A, Hammarström L, Smith CI. Home treatment of hypogammaglobulinaemia with subcutaneous gammaglobulin by rapid infusion. Lancet
19. Chapel HM, Spickett GP, Ericson D, Engl W, Eibl MM, Bjorkander J. The comparison of the efficacy and safety of intravenous versus subcutaneous immunoglobulin replacement therapy. J Clin Immunol
20. Jiang F, Torgerson TR, Ayars AG. Health-related quality of life in patients with primary immunodeficiency disease. Allergy Asthma Clin Immunol
. 2015;11: 27.
21. Younger ME, Blouin W, Duff C, Epland KB, Murphy E, Sedlak D. Subcutaneous immunoglobulin replacement therapy: ensuring success. J Infus Nurs
22. Garnero M, Fabbri S, Gemelli C, et al. Subcutaneous immunoglobulins are a valuable treatment option in myasthenia gravis. J Clin Neurol
23. Jones C, Rojavin M, Baggish J. Patients with primary immunodeficiency receiving subcutaneous immune globulin Hizentra maintain health-related quality of life and treatment satisfaction in a multicentre extension study of efficacy, tolerability and safety. J Pharm Health Serv Res
24. Racosta JM, Sposato LA, Kimpinski K. Subcutaneous versus intravenous immunoglobulin for chronic autoimmune neuropathies: a meta-analysis. Muscle Nerve
25. Rajabally YA, Cavanna AE. Health-related quality of life in chronic inflammatory neuropathies: a systematic review. J Neurol Sci
26. van Schaik IN, Bril V, van Geloven N, et al. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol
27. Markvardsen LH, Christiansen I, Andersen H, Jakobsen J. Headache and nausea after treatment with high-dose subcutaneous versus intravenous immunoglobulin. Basic Clin Pharmacol Toxicol
28. Lunemann JD, Quast I, Dalakas MC. Efficacy of intravenous immunoglobulin in neurological diseases. Neurotherapeutics
29. Suleman A, Theoret L, Bourque P, Pringle E, Cameron DW, Cowan J. Evaluation of a personalized subcutaneous immunoglobulin treatment program for neurological patients. Can J Neurol Sci