Introduction
Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare, immune-mediated disorder in which an aberrant immune response causes demyelination and axonal damage of the peripheral nerves [
1,
2]. The exact aetiology of CIDP remains unknown [
2,
3]. Patients experience progressive weakness, impaired sensory function in the legs and arms, loss of deep tendon reflexes (areflexia), and fatigue [
1,
4,
5].
CIDP is a long-term condition with a variable course that can be relapsing–remitting, stepwise progressive, or gradually progressive [
2,
3]. Axonal damage occurs with further disease progression, resulting in worsening symptoms [
6]. Patient symptom burden can be assessed using a range of functional outcomes that predominantly focus on physical burden, functional impairment, disability, and an impaired ability to perform activities of daily living [
7‐
9]. Impairment assessment tools include the Inflammatory Neuropathy Cause and Treatment (INCAT) scale and the inflammatory Rasch-Built Overall Disability Scale (I-RODS). INCAT assesses physical function from 0 (no functional impairment) to 10 (unable to purposefully move the limbs) [
8‐
10]. I-RODS is a 24-item scale; each item represents a daily activity (e.g., reading a newspaper and running), scored from 0 (impossible to perform) to 2 (easy to perform) [
10]. Despite the existence of such tools, to date, the disease burden and patient impact of CIDP has not been well defined.
European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) guidelines provide recommendations on CIDP treatments, with the goal of reducing symptoms and, if possible, maintaining long-term remission [
11,
12]. Treatment with intravenous immunoglobulin (IVIG) or corticosteroids is recommended in patients with moderate to severe disability. If IVIG and corticosteroids are ineffective, plasma exchange should be considered. If the response is inadequate or the required drug maintenance dose is high, combination treatments of either immunosuppressants or immunomodulators should be considered. No recommendations are provided on long-term management, due to lack of evidence [
11]. Moreover, treatments may be associated with adverse events (AEs) or reduced patient independence [
3,
13]. For example, corticosteroids are associated with long-term tolerability challenges, while IVIG needs to be regularly administered in a clinical setting or at home under nurse supervision [
13‐
16].
Treatment of CIDP is complicated by challenges in diagnosis [
17]. The disease can present with differing symptoms, and there are at least 15 sets of diagnostic criteria that describe CIDP and its variant forms [
1,
6]. Varying presentation of CIDP and misinterpretation of nerve conduction studies result in a high rate of misdiagnosis [
6,
18]. This can result in inappropriate treatment, as patients with CIDP may be misdiagnosed with other polyneuropathies, such as anti-myelin associated glycoprotein (MAG) neuropathy or polyneuropathy of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes), which require different treatments than CIDP [
17].
There are significant challenges in characterising the burden of illness for rare diseases such as CIDP, and evidence can be limited [
19]. Identifying and subsequently recruiting patients to studies are challenging; low sample sizes may impair generalisability and statistical powering [
19]. To date, no publication has comprehensively reviewed the burden of illness of CIDP with respect to epidemiology, humanistic burden, current treatments, and economic burden. The current study provides a systematic review of the literature to characterise the burden of the disease and identify key areas for future research.
Discussion
The current review provides the first systematic assessment of the burden of illness of CIDP. The findings establish that CIDP is a rare disease, associated with impaired HRQoL, particularly relating to physical well-being, and an economic burden. Patients with CIDP may also experience burden due to treatment. Long-term steroid use is associated with a high risk of AEs, and parenteral therapies, such as IVIG, SGIG and plasma exchange, are associated with burden of administration and potential impact on patient independence [
12,
16].
Epidemiology studies confirmed that CIDP is a rare disease (incidence: 0.2–1.6/100,000 persons per year; prevalence: 0.8–10.3 per 100,000 persons) [
1,
4,
6,
20]. The incidence and prevalence data varied, likely arising from variations in study sample size (
n = 19–360) and diagnostic criteria. Low sample sizes are common when identifying and recruiting patients with rare diseases [
19]. Through combining datasets, meta-analyses can mitigate some of the challenges posed by low sample size and diagnostic variation [
60]. The study by Broers et al. 2019 used this approach, reporting incidence and prevalence for CIDP of 0.33 per 100,000 person-years and 2.81 per 100,000 persons, respectively, which places CIDP among the rarest neuropathies [
1,
4]. In contrast, one of the most common chronic polyneuropathies, diabetic polyneuropathy, is estimated to have a prevalence rate of 200–600/100,000 [
4]. Moreover, diagnostic errors, such as over-reliance on subjective patient-reported outcomes and diverse electrophysiologic interpretations of demyelination, contribute to diagnostic uncertainty and may impact epidemiology findings [
18]. Misdiagnosis can occur and patients may be treated inappropriately as a result [
17,
18,
37]. Clinicians may use supportive measures, such as patient treatment response to confirm a CIDP diagnosis, to improve diagnostic accuracy [
3,
11,
12,
37]. This may, however, contribute to misdiagnosis when treatment response is not evaluated appropriately [
18]. Further research is needed to fully characterise the impact of false-positive and false-negative diagnoses.
CIDP was associated with impaired patient well-being, due to the physical impact of CIDP and, in some cases, the presence of mental health conditions. Patients with CIDP had EQ-5D index scores of 0.68 in Germany and 0.62 in the UK, substantially below normative values for these countries (Germany: 0.90; UK: 0.86) [
9,
25,
61]. For comparison, EQ-5D mean scores of 0.77 and 0.57 have been reported for patients with multiple sclerosis in Germany and the UK, respectively [
62,
63]. EQ-5D scores were also significantly associated with physical function scores (INCAT-ONLS and I-RODS), demonstrating the importance of physical function in the well-being of patients with CIDP [
8]. The physical impact of CIDP can prevent patients from completing daily activities and walking outdoors without support [
9]. However, physical functioning was implicated in 30–42% of the observed changes in HRQoL in patients with CIDP [
8], showing that, while physical disability is linked to impaired QoL, there are additional contributing factors. Patients with CIDP also reported higher rates of depression in The Netherlands and Germany, compared with the general population averages reported by the European Brain Council and the European College of Neuropsychopharmacology (9–12.1 versus 5.9%) [
7,
9,
64]. This may reflect the impact that chronic disabling conditions have on mental health [
65].
Treatment setting, mental health, and physical functioning were associated with an increased economic burden in CIDP; however, only eight studies on economic burden were identified and results need to be interpreted with caution. While treatment costs were the primary cost drivers, research in USA and France indicates that the cost of treatment of CIDP reduces if patients can receive IVIG treatment at home rather than in a hospital setting [
55]. Depression and functional disability were also identified as important predictors of direct costs [
9]. Improving depression and functional disability may reduce costs in CIDP, although further research is required to establish the nature of this relationship. These findings cannot be generalised beyond the individual country settings, however, as healthcare systems vary extensively across geographies. Publications were limited to English language studies, impairing identification of multinational studies, and economic data from only four countries were represented in the review.
The physical and psychological impact of CIDP is implicated in productivity losses and indirect costs. Early retirement was reported among patients with CIDP [
9,
26]. The odds of fatigue and depression were higher in retired patients with CIDP, versus non-retired CIDP patients (8.2 and 12.2, respectively) [
26], and the majority of patients with CIDP experience severe fatigue and depression rates that are greater than for the general population [
7,
9,
64]. Functional disability (measured by INCAT) and impaired HRQoL were also predictors of higher indirect costs in Germany, due to premature retirement, disability, unemployment, sick leave, and reduced labour time [
9]. This impact on productivity can result in substantial economic costs; for example, productivity losses due to CIDP may result in 9.7 M annual economic cost for the UK (estimated through value of lost wages) [
25]. Similarly, in Germany premature retirement was the second highest cost element of all cost categories when assessing the costs associated with CIDP, following cost of medication [
9].
Current therapies can improve patient well-being, but are also associated with tolerability issues and challenges around route of administration [
13]. IVIG and corticosteroids are both effective in achieving a treatment response, reflecting EFNS/PNS recommendations to use as the first-line therapies [
11]. However, long-term use of corticosteroids has been associated with serious side effects in patients with CIDP, such as hypertension, Cushingoid appearance, and gastrointestinal complaints [
3,
15,
16]. Long-term use of corticosteroids is typically avoided where possible in other diseases; for example, corticosteroid-sparing approaches (prescribing alternative treatment strategies to reduce corticosteroid dose) are considered important in other autoimmune diseases, such as Crohn’s disease and uveitis [
66,
67]. Although the majority of studies reporting comparative data for IVIG reported a greater response rate relative to other therapies [
12,
15,
16,
31‐
35], IVIG may be burdensome for patients [
13,
14]. IVIG requires venous access, patient monitoring, and administration in a clinical setting or through home nursing services, which may contribute to increases in healthcare costs and reductions in patient independence [
13,
14].
SCIG has been developed as an alternative to IVIG, providing flexible self-administration at home [
13]. While IVIG administration requires a nurse to supervise infusions, SCIG can be administered by the patient or a caregiver without the need for other medical support staff, which may decrease healthcare resource use [
13]. Patients managed with SCIG are not dependent on home nursing visits or maintaining proximity to an infusion centre so can travel more freely [
13]. Studies suggest that SCIG has similar efficacy to IVIG, and confirm that patients prefer SCIG due to reductions in AEs and improved independence relative to IVIG [
14,
44,
46,
49]. A previous meta-analysis of efficacy and safety of SCIG versus IVIG consolidates these findings, revealing that the relative risk of systemic AEs (e.g., headache and fever) was reduced by 28% with SCIG versus IVIG (95% CI 0.11–0.76), while effectiveness was similar between the two groups [
6]. As CIDP is a chronic disease that is not associated with increased mortality [
5,
6], patients require treatments that are appropriate for long-term use. SCIG may benefit patients’ long-term disease management, through decreasing systemic AEs and improving patient independence compared with alterative treatment options.
EFNS/PNS guidelines (2010) do not provide guidance on long-term management of CIDP, nor on SCIG, as evidence on these topics was insufficient at the time of guideline development [
11]. Treatment selection needs to consider a range of variables, such as severity, health status, tolerability, and contraindications, which may present challenges to healthcare professionals [
68]. Treatments further need to be reviewed on an ongoing basis to ensure that treatments are appropriate and avoid unnecessary burden. For example, it is recommended that IVIG is periodically reduced or withdrawn to avoid excessive costs, while corticosteroids should be reviewed or withdrawn to avoid AEs [
15,
39]. CIDP subtype and varied diagnostic criteria may also be important in treatment decisions; however, the evidence is unclear. Patient populations varied extensively between the publications captured in the current review and the heterogeneity presents challenges to drawing robust conclusions [
35]. The limited evidence available suggests that treatment outcomes do not vary based on diagnostic criteria used to determine the presence of CIDP; however, further research is required to establish this and the role of subpopulations in determining response to treatment. Further research incorporating SCIG as a long-term treatment option for CIDP may also inform future disease management strategies.
Limitations
There may be additional publications not identified in this review that are important for characterising the burden of disease in CIDP. For example, relevant data may have been published that were excluded as a result of the limits to the study type and publication dates. Searches were restricted to English language publications, which may have excluded relevant studies published in other languages.
No studies were identified related to treatment guidelines in the current review; however, the EFNS/PNS guidelines on management of chronic inflammatory demyelinating polyradiculoneuropathy” were published within the dates in scope [
11]. This publication was not captured in this review, as the search algorithm was limited to “adults” and these guidelines included paediatric considerations and so were not indexed to “adults” within the searched databases.
Limitations characteristic of CIDP were identified, such as low number of relevant publications and low sample sizes in studies. The limited number of publications available on epidemiology, humanistic burden, and economic burden impairs the current assessment of the burden of disease. The low number of publications identified reflects the rarity of the disease, as research into rare disease may face greater challenges in recruiting patients and obtaining funding, because more common diseases have a greater economic impact [
19]. The majority of studies across categories included fewer than 150 patients, reflecting the challenges in patient identification and recruitment in rare diseases [
19]. Low sample sizes introduce challenges for deriving insights from the data, such as poor generalisability and lack of statistical powering [
19].