Journal of Neurology (2021) 268:3706–3716 https://doi.org/10.1007/s00415-020-09998-8 REVIEW Systematic literature review of burden of illness in chronic inflammatory demyelinating polyneuropathy (CIDP) Luis Querol1 · M. Crabtree2 · M. Herepath3 · E. Priedane2 · I. Viejo Viejo4 · S. Agush2 · P. Sommerer4 Received: 19 March 2020 / Revised: 10 June 2020 / Accepted: 12 June 2020 / Published online: 24 June 2020 © The Author(s) 2020 Abstract Background Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare neurological disorder characterised by muscle weakness and impaired sensory function. The present study provides a comprehensive literature review of the burden of illness of CIDP. Methods Systematic literature search of PubMed, Embase, and key conferences in May 2019. Search terms identified studies on the epidemiology, humanistic burden, current treatment, and economic burden of CIDP published since 2009 in English. Results Forty-five full texts and nineteen conference proceedings were identified on the epidemiology (n = 9), humanistic burden (n = 7), current treatment (n = 40), and economic burden (n = 8) of CIDP. Epidemiological studies showed incidence and prevalence of 0.2–1.6 and 0.8–8.9 per 100,000, respectively, depending on geography and diagnostic criteria. Humanistic burden studies revealed that patients experienced physical and psychosocial burden, including impaired physical function, pain and depression. Publications on current treatments reported on six main types of therapy: intravenous immunoglobulins, subcutaneous immunoglobulins, corticosteroids, plasma exchange, immunosuppressants, and immunomodulators. Treat- ments may be burdensome, due to adverse events and reduced independence caused by treatment administration setting. In Germany, UK, France, and the US, CIDP economic burden was driven by direct costs of treatment and hospitalisation. CIDP was associated with indirect costs driven by impaired productivity. Conclusions This first systematic review of CIDP burden of illness demonstrates the high physical and psychosocial burden of this rare disease. Future research is required to fully characterise the burden of CIDP, and to understand how appropriate treatment can mitigate burden for patients and healthcare systems. Keywords CIDP · Burden · QoL · Epidemiology · Treatment · Cost Introduction damage of the peripheral nerves [1, 2]. The exact aetiology of CIDP remains unknown [2, 3]. Patients experience pro- Chronic inflammatory demyelinating polyneuropathy gressive weakness, impaired sensory function in the legs and (CIDP) is a rare, immune-mediated disorder in which an arms, loss of deep tendon reflexes (areflexia), and fatigue aberrant immune response causes demyelination and axonal [1, 4, 5]. CIDP is a long-term condition with a variable course that can be relapsing–remitting, stepwise progressive, or Electronic supplementary material The online version of this article (https​://doi.org/10.1007/s0041​5-020-09998​-8) contains gradually progressive [2, 3]. Axonal damage occurs with supplementary material, which is available to authorized users. further disease progression, resulting in worsening symp- toms [6]. Patient symptom burden can be assessed using * Luis Querol a range of functional outcomes that predominantly focus LQuerol@santpau.cat on physical burden, functional impairment, disability, and 1 Institut de Recerca Biomèdica Sant Pau, Barcelona, Spain an impaired ability to perform activities of daily living 2 Huron Consulting Group, London, UK [7–9]. Impairment assessment tools include the Inflam- 3 matory Neuropathy Cause and Treatment (INCAT) scale Optimal Access Life Science Consulting Limited, Swansea, UK and the inflammatory Rasch-Built Overall Disability Scale 4 (I-RODS). INCAT assesses physical function from 0 (no CSL Behring, Hattersheim, Germany 13 Vol:.(1234567890) Journal of Neurology (2021) 268:3706–3716 3707 functional impairment) to 10 (unable to purposefully move Methods the limbs) [8–10]. I-RODS is a 24-item scale; each item represents a daily activity (e.g., reading a newspaper and Search strategy running), scored from 0 (impossible to perform) to 2 (easy to perform) [10]. Despite the existence of such tools, to date, Keywords related to the study topics were used to search rel- the disease burden and patient impact of CIDP has not been evant research articles in the MEDLINE (including In-process) well defined. and Embase databases. Only articles including human data European Federation of Neurological Societies/Peripheral and published in English from May, 2009 to May, 2019 were Nerve Society (EFNS/PNS) guidelines provide recommen- included. Separate search terms were used for each review dations on CIDP treatments, with the goal of reducing symp- category. The search algorithms, limits, and number of hits toms and, if possible, maintaining long-term remission [11, obtained are summarised in Online Resource 1. 12]. Treatment with intravenous immunoglobulin (IVIG) or To ensure inclusion of more recent studies that had not corticosteroids is recommended in patients with moderate yet been published in peer-reviewed journals, we reviewed to severe disability. If IVIG and corticosteroids are ineffec- non-peer-reviewed articles from the following neuromuscu- tive, plasma exchange should be considered. If the response lar conferences and conferences relevant to health economic is inadequate or the required drug maintenance dose is high, and outcomes research, published between 2017 and 2019: combination treatments of either immunosuppressants or International Society for Pharmacoeconomics and Outcomes immunomodulators should be considered. No recommen- Research (ISPOR) conference, International Congress on dations are provided on long-term management, due to lack Neuromuscular Diseases (ICNMD), and Annual Meetings of of evidence [11]. Moreover, treatments may be associated the Peripheral Nerve Society (PNS). It was assumed that any with adverse events (AEs) or reduced patient independence conference outputs prior to these dates would have been pub- [3, 13]. For example, corticosteroids are associated with lished in a peer-reviewed journal at the time that the searches long-term tolerability challenges, while IVIG needs to be were conducted. regularly administered in a clinical setting or at home under nurse supervision [13–16]. Study selection Treatment of CIDP is complicated by challenges in diag- nosis [17]. The disease can present with differing symp- Study selection was completed through two levels of study toms, and there are at least 15 sets of diagnostic criteria that screening: abstract screening and full-text screening. Abstract describe CIDP and its variant forms [1, 6]. Varying presen- screening was performed in the web-based software platform, tation of CIDP and misinterpretation of nerve conduction ­abstrackrBeta. Eligible studies were identified by one reviewer studies result in a high rate of misdiagnosis [6, 18]. This can for inclusion in the study according to the predefined inclusion result in inappropriate treatment, as patients with CIDP may and exclusion criteria (Table 1). Studies had to fulfil all inclu- be misdiagnosed with other polyneuropathies, such as anti- sion criteria and none of the exclusion criteria at each level myelin associated glycoprotein (MAG) neuropathy or poly- of screening to be included in the data extraction stage. Full neuropathy of POEMS syndrome (polyneuropathy, orga- articles were retrieved for abstracts deemed relevant, and a full nomegaly, endocrinopathy, M protein, and skin changes), article review determined the final inclusion or exclusion of which require different treatments than CIDP [17]. a study, based on the predetermined criteria. Rejected studies There are significant challenges in characterising the bur- at the abstract and full-text levels were reviewed by a second den of illness for rare diseases such as CIDP, and evidence reviewer and any discrepancies, in terms of rejection decision can be limited [19]. Identifying and subsequently recruiting or reason, were resolved by consensus between the two review- patients to studies are challenging; low sample sizes may ers. Information from the included full texts was extracted into impair generalisability and statistical powering [19]. To date, a data extraction MS Excel table. Data relevant to the inclusion no publication has comprehensively reviewed the burden of criteria were extracted by one reviewer and quality checked by illness of CIDP with respect to epidemiology, humanistic a second reviewer. All included publications were assessed to burden, current treatments, and economic burden. The cur- ensure that there was no duplicate reporting of data. rent study provides a systematic review of the literature to characterise the burden of the disease and identify key areas for future research. Results A total of 2343 studies were identified from the MEDLINE and Embase databases. After abstract screening, 130 full texts were assessed, of which 45 articles met the inclusion 13 3708 Journal of Neurology (2021) 268:3706–3716 Table 1  Study inclusion and exclusion criteria CIDP chronic inflammatory demyelinating polyneuropathy, HRQoL health-related quality of life, INCAT​ inflammatory neuropathy cause and treatment, QoL quality of life criteria and were taken forward to data extraction. After prevalence was higher in males than females and increased inclusion of 21 abstracts identified from the ICNMD, PNS, with age [1, 4, 5], with one study reporting a mean patient and ISPOR conferences, 66 articles were deemed to have age of 57 years [5]. Mahdi-Rogers et al. 2014 reported met the inclusion criteria and were included in the analy- that the mean age of onset of CIDP ranged from 48 to sis. Included articles were categorised by topic: epidemiol- 59.6 years [20]. Pooled crude prevalence data from stud- ogy (n = 9), humanistic burden (n = 7), current treatments ies using the American Academy of Neurology (AAN) (n = 42), and economic burden (n = 8). Figure 1 illustrates diagnostic criteria were lower than those studies using the the study selection process. EFNS 2006 criteria (1.59 and 3.67 per 100,000, respec- tively) [1]. Epidemiology Both studies investigating patient survival reported sim- ilar mortality to the general population [5, 6]. Ryan et al. Epidemiology publications were either based on real-world 2018 reported on one of the first cohorts of patient with studies (n = 6, 67%)—typically derived from patient clini- CIDP from the USA (study conducted in 1975, n = 53), cal databases—or based on literature reviews (n = 3, 33%) with a mortality of 10% over 7.5 years [6]. A more recent [1, 4–7, 20–23]. Real-world studies reported epidemiology study by Hafsteindottir et al. 2016 reported a standardised from Italy (n = 2), England (n = 1), Iceland (n = 1), and The mortality ratio of 0.9 for Iceland (determined using life Netherlands (n = 1) [7, 20–23]; the geography of one study tables), which does not vary from mortality rate of the was not reported [5]. Literature reviews reported on multi- general population [5]. national epidemiology data, including countries within the No clear risk factors for a diagnosis of CIDP were Middle East, Western and Eastern Africa, Europe, North reported, although data highlighted potential associations and South America, and East Asia [1, 4, 6]. with autoimmune disease, diabetes, hypertension, and ante- Incidence and prevalence data identified in the system- cedent infection [6, 7, 20, 21]. Kuitwaard et al. 2009 showed atic review are presented in a graphical summary in the that 5% of the study CIDP cohort (n = 76) were diagnosed Online Resource 2. CIDP incidence ranged from 0.2 to with a common autoimmune disease (e.g., thyroid disorder 1.6 per 100,000 persons per year [1, 4–6], while preva- and rheumatic disorders), which was higher than the fre- lence was in the range of 0.8–10.3 per 100,000 persons quency in the general population [7]. Between 9.9 and 12.6% [1, 4, 6, 20]. Incidence and prevalence rates varied with of patients with CIDP had diabetes and there was a nine- age, gender, and diagnostic criteria [1, 4–7, 20–23]. CIDP fold higher prevalence of CIDP in patients with diabetes, 13 Journal of Neurology (2021) 268:3706–3716 3709 Peer-reviewed publications Search (n=2,343) Full-text articles excluded, with reasons (n=2,213) Records screened Screening EXC1 = 2,072 EXC4 = 1 EXC7 = 0 (n=2,343) EXC2 = 57 EXC5 = 22 EXC8 = 0 EXC3 = 28 EXC6 = 0 EXC9 = 33 Full-text articles excluded, with reasons Full-text articles & conference (n=85) Eligibility abstracts assessed for eligibility EXC1 = 10 EXC4 = 0 EXC7 = 0 (n=130) EXC2 = 17 EXC5 = 22 EXC8 = 0 EXC3 = 4 EXC6 = 0 EXC9 = 32 Non-peer-reviewed publications Studies included in qualitative synthesis (i.e. conference proceedings) Included (n=64) (n=19) Fig. 1  PRISMA diagram. EXC1: not in CIDP OR: CIDP data only systematic reviews, clinical trial—phase III, clinical trial—phase provided pooled with other diseases; EXC2: not relevant for the IV, pragmatic clinical trial, randomised-controlled trial OR: case issues under inquiry, e.g., when the abstract shows no apparent con- reports, conference proceedings, letters, commentaries or editorials; tents of interest; EXC3: does not focus on topics outlined in the EXC6: not in English; EXC7: papers not published between 2009 and inclusion criteria (see Table 1.) EXC4: not in adults (≥ 18); EXC5: 2019; EXC8: only covers animal or in vitro studies; EXC9: replica/no not of the following study types: dataset, guideline, meta-analysis, abstract/no full text multi-centre study, observational study, practice guideline, review, compared with the general population [6, 20]. Despite this, severe fatigue, respectively [7]. A German study (n = 108) studies could not determine whether diabetes was a risk fac- reported a mean INCAT total score of 3.3 [9]; patients with tor for CIDP or if diabetes was more common in patients a score of 3.3 may experience impairments in completing with CIDP [6, 20]. Hypertension was reported in 17% of daily activities (e.g., unzipping, using a knife and fork) or Italian patients in a study by Doneddu et al. 2017 [21]. An require some support to walk outdoors [10]. antecedent infection, or vaccination, preceded a diagnosis of The impact of CIDP may also extend beyond the physical CIDP in 27% of patients [21]. burden of the disease to depression [7, 9, 28]. Two publica- tions reported that 9 and 12.1% of patients had depression, Humanistic burden based on hospital anxiety and depression scale (HADS) and the Beck Depression Inventory version II (BDI-II) scores in All humanistic burden studies were real-world studies, and The Netherlands and Germany, respectively [7, 9]. Cognitive included data derived from analyses of trial patient cohorts, function is, however, unaffected; a German study (n = 107) clinical patient examinations, or surveys of patient member reported Mini-Mental State Examination (MMSE) scores organisations [7–9, 24–27]. The studies included populations of 28.8 for patients with CIDP [9], where MMSE scores from the UK (n = 2), Netherlands (n = 1), Germany (n = 1), 0–17 and 24–30 reflect severe and no cognitive impairment, and multinational (n = 1) studies, while the geographies of respectively [28]. two studies were not reported [7–9, 24–27]. Humanistic The physical and mental manifestations of CIDP impair burden studies reported on the patient impact of CIDP on patient well-being and quality of life [7–9, 25]. EuroQol- health-related quality of life (HRQoL), functioning, psycho- 5D (EQ-5D) scores among patients with CIDP were 0.62 social welfare, productivity, pain, and fatigue [7–9, 24, 25]. and 0.68 for the UK and Germany, respectively (Fig. 2) CIDP has a substantial physical impact, with patients [9, 25]. Draak et al. 2014 demonstrated that lower EQ-5D reporting pain, fatigue, and impaired physical function- for patients with CIDP was significantly associated with ing [7–9, 24–27]. Kuitwaard et al. 2009 assessed pain and impaired patient physical function [8]. The R2, or frac- fatigue, using the Numeric Pain Rating Scale (NPRS) and tion of variance explained by independent variables from a Fatigue Severity Scale (FSS) scores (n = 76), reporting that regression model, for the relationship between the EQ-5D 17 and 74% of patients with CIDP reported severe pain and and the INCAT Overall Neuropathy Limitations Scale 13 3710 Journal of Neurology (2021) 268:3706–3716 (INCAT-ONLS; R2 = 0.30–0.32) and I-RODS (R2: 0.42) 1 were significant (p < 0.0001) [8]. A study of Dutch patients 0.9 with CIDP (n = 76) also identified that patients scored below normative 36-Item Short Form Survey Instrument (SF-36) 0.8 scores (50) for all the domains of the physical component 0.68 EQ-5D mean index scores and two of the domains of the mental component (vitality 0.7 0.62 and social functioning) (Fig. 3) [7]. The role emotional and 0.6 mental health domains were, however, similar to norma- tive scores [7]. The following World Health Organization 0.5 Quality of Life Brief Version (WHO-QoL BREF) question- 0.4 naire data were also reported on a scale from 0 to 100 in a German population: global (47.2), physical health (55.4), 0.3 psychological health (56.1), social relationships (66.2), and environmental (73.2); no comparison to normal population 0.2 scores was provided [9]. 0.1 Two studies reported that premature retirement due to CIDP occurred among 14–28% of patients [9, 26]. Bjelica 0 et al. 2018 reported that the odds of depression, based on Germany UK BDI-II, and fatigue, based on FSS, were, respectively, 12.2 Mengel et al. 2018 Mahdi-Rogers et al. 2014 n=107 n=43 and 8.2 times greater in retired patients with CIDP, com- pared with non-retired CIDP patients [26]. Fig. 2  EQ-5D mean index scores of patients with CIDP [9, 25]. CIDP chronic inflammatory demyelinating polyneuropathy, EQ-5D Euro- Guidelines and current treatment QoL-5D Publications on current treatments included clinical trials (n = 23, 60%), real-world studies (n = 13, 31%), literature many patients in high-income countries receive IVIG, which reviews (n = 3, 7%) and a combined real-world and clinical has similar efficacy and is associated with fewer AEs [16]. trial (n = 1, 2%). The majority of clinical trials (including IVIG generally achieved high rates of response to treat- the combined real-world and clinical trial) were comparative ment (44–91% response rate, across 11 studies), relative to studies, with either a placebo arm (n = 10, 38%) or an active placebo [12, 30–32, 35–43]. Where comparative data were comparator (n = 9, 35%). A minority of real-world studies reported, IVIG increased the proportion of patients with focused on a single treatment (n = 4, 31%); the remaining CIDP who responded to treatment, relative to comparators, reported on multiple treatments (n = 9, 69%). Sample sizes including corticosteroids and plasma exchange [12, 29, 31]. for the real-world studies, which included analyses of data- Markvardsen et al. 2013 reported that during long-term bases and patient examinations, ranged from 13 to 432, IVIG therapy, intravenous access can become difficult due while the clinical trial sample sizes ranged from 27 to 265. to obliteration of the veins and may necessitate catheterisa- No treatment guidelines were identified. tion of the external jugular vein in some patients [14]. Studies were highly heterogeneous regarding interven- Subcutaneous immunoglobulins (SCIG) provide an alter- tion, comparator, time point, and methodology. Definition native route of administration that may ameliorate some of of “treatment response” varied across studies, and included the challenges associated with intravenous administration predefined score increases in functional outcome scales (e.g., of immunoglobulins [14, 44–48]. Three studies reported on Rankin scale), treating physician assessment, and measure- the clinical stability of patients with CIDP after commencing ment of strength (e.g. grip strength) [15, 29, 30]. Review SCIG, with all studies finding that the majority of patients findings are summarised below for treatment response rate, were clinically stable or improved (83–100%; n = 13–245) patient preference, and treatment tolerability. Further data [39, 47, 48]. The largest trial on SCIG treatment (PATH, are provided in Online Resource 3. n = 172, placebo-controlled) found the proportion of patients Although many patients responded to corticosteroid with a CIDP relapse or who were withdrawn from the trial therapy (48–83% response rate, across nine studies), safety for any other reason which was 63% for patients in the pla- concerns were associated with their long-term use [12, 15, cebo group, 39% for patients in the low-dose SCIG group, 16, 31–35]. Common AEs included hypertension, diabetes and 33% for patients receiving high-dose SCIG [46]. mellitus de novo, glaucoma, depression, cushingoid appear- Studies on SCIG patient-reported outcomes (PRO) data ance, and gastrointestinal complaints [15, 16]. Consequently, predominantly reported on ease of use or patient preference [14, 44, 46, 49]. In Van Schaik et al. 2017, 88% (n = 172) 13 Journal of Neurology (2021) 268:3706–3716 3711 Fig. 3  SF-36 scores in a Dutch 60 cohort of patients with CIDP Adapted from Kuitwaard et al. 50 50 50.1 2009 [7]. The dashed line 45.3 46.2 reflects the normative value 41.2 38.6 39.1 of SF-36 by healthy patients: 40 50 points. Sample size; n = 76. SF-36 score 32.6 CIDP chronic inflammatory 30 demyelinating polyneuropathy, SF-36 Short Form-36 20 10 0 Physical Role Bodily General Vitality Social Role Mental functioning physical pain health functioning emotional health of patients reported that learning the SCIG administration indicated no improvement in efficacy compared with pla- technique was easy [46]. Three studies reported on patient cebo [52–54]. preference, demonstrating that 53–88% of patients preferred Limited data were available on ability to predict treatment SCIG to IVIG [14, 44, 46]. Reasons for preferring SCIG response; only one study explored the ability to predict treat- included gaining independence, ease of use, increased flex- ment response between diagnostic criteria (EFNS, AAN, ibility during daily life, more stable muscle performance, INCAT, and Saperstein criteria) [35]. Patients responded to and milder side effects, and that the treatment was time sav- IVIG treatment to a similar extent (66–91%, n = 9–22) irre- ing compared with IVIG [44, 46]. Van Schaik et al. 2017 spective of the diagnostic criteria used, although the EFNS reported that an open-label prospective study showed a 2010 criteria were the most diagnostically sensitive [35]. significant reduction in the severity and frequency of head- aches and nausea after SCIG infusions compared with IVIG Economic burden infusions [46]. Cocito et al. 2018 reported that SCIG use was associated with improved QoL and fewer systemic AEs Eight publications reported on the economic burden of CIDP compared to IVIG in observational studies [44]. [9, 24, 25, 55–59]. The majority of studies reported data from Supplementing IVIG with a concomitant immunosup- European countries (n = 5, 62.5%), including the UK (n = 2), pressant may be an effective strategy for improving response France (n = 2), and Germany (n = 1) [9, 24, 25, 55, 56, 58]. rates or reducing IVIG dosages [50, 51]. Querol et al. 2013 Three studies reported data from the USA [56, 57, 59]. Most reported that the percentage of therapy responders was studies had a sample size of less than 150 patients (range higher among patients who received concomitant immuno- 15–1580) [9, 24, 25, 55–59]. A full summary of cost data suppressant treatment than those who received IVIG only identified in the review is provided in Online Resource 4. (71.4 versus 44.0%; OR 3.18) [42]. Mahdi-Rogers et al. CIDP cost of illness varied across geographies, from 2009 showed that methotrexate reduced mean weekly dose £22,086 (2007 costs) annually per patient in the UK, through of IVIG or SCIG in 52% (n = 27) of patients compared with €47,823 (2017 costs) and €45,000 (2013 costs) annually per a 44% (n = 32) reduction in the placebo group [50]. patient in France and Germany, respectively, to $116,330 Plasma exchange may provide an alternative therapy for (costs converted to USD 2016 values) over 2 years in the patients who do not respond to IVIG and corticosteroids USA (Online Resource 4) [9, 25, 55, 56]. [12, 31–34]. Although 48–81% of patients across studies Drug-related costs were the main drivers of direct CIDP responded to plasma exchange [12, 31–34], comparative data expenditure, followed by costs associated with hospital ser- suggest that fewer patients achieve a response for plasma vices (Fig. 4) [25, 57]. In the UK, IVIG and other treatments exchange compared with IVIG [12, 31–34]. In a study of 16 represented the largest proportion of total costs (64.4%), fol- patients with CIDP, plasma exchange was associated with lowed by hospital services (17.8%) [25]. Similarly, in the US, difficulty in accessing veins and deficit of blood coagula- drug-related costs represented 57% of total costs, followed by tion factors [31]. In the same study, a higher proportion of inpatient and outpatient hospital services (35%) [57]. patients experienced AEs with plasma exchange (25%) than CIDP was also associated with indirect costs, driven pre- with corticosteroids (13%) or IVIG (4%) [31]. dominantly by impaired productivity [9, 25]. In Germany, Publications on the use of immunomodulators (oral mean indirect 3-month costs were €1910 per patient, com- fingolimod and intramuscular interferon ß-1a) for CIDP prising 17% of total CIDP costs [9]. Indirect costs included 13 3712 Journal of Neurology (2021) 268:3706–3716 premature retirement (€945), disability (€276), unemploy- Other 100 2.0% ment (€189), sick leave (€283), and reduction of labour time 0.6% Home/social 3.0% (€217) [9]. In the UK, loss of productivity was estimated to 15.9% services 3.0% 90 Primary care cost £5815 per patient per year, and projected to cost the UK 1.1% economy a total of £9.7 M per year, accounting for 26% of 80 Hospital 35.0% the total cost of illness (Online Resource 4) [25]. 17.8% services 70 Total costs and resource use varied depending on the setting of IVIG administration and other factors, such as 60 Percentage patient well-being and physical functioning [9, 55]. Le Mas- son et al. 2018 demonstrated a difference between home and 50 in-hospital therapy (€62,592 versus €106,867 total year cost, 40 respectively, p < 0.0001) associated with hospital admission Drug-related 30 64.4% costs 57.0% and patient care costs [55]. In the US, the majority of IVIG infusions occurred at home (72%), followed by physician 20 offices (16%) and outpatient hospitals (11%) [57]. In France, however, 43%, 49%, and 8% of IVIG infusions require full 10 hospitalisation, day care, and home care, respectively [58]. 0 In Germany, increased direct and medication costs were UK USA significantly associated with functional disability (meas- Mahdi-Rogers et al. 2014 Guptill et al. 2014 ured by INCAT) and clinically relevant depressive symp- n=43 n=73 toms (measured by BDI-II), p < 0.005 for both [9]. The presence of the depressive symptoms was also associated Fig. 4  Distribution of CIDP direct costs by cost components in the with increases in medication costs [9]. Improved WHO-QoL UK and USA [25, 57]. USA costs were calculated on a 2-year basis [57], whereas UK costs are based on an annual estimate [25] BREF and functional disability scores were associated with reduced indirect (p < 0.011) but not direct costs [9]. have a prevalence rate of 200–600/100,000 [4]. Moreover, diagnostic errors, such as over-reliance on subjective patient- Discussion reported outcomes and diverse electrophysiologic interpreta- tions of demyelination, contribute to diagnostic uncertainty The current review provides the first systematic assessment and may impact epidemiology findings [18]. Misdiagnosis of the burden of illness of CIDP. The findings establish that can occur and patients may be treated inappropriately as CIDP is a rare disease, associated with impaired HRQoL, a result [17, 18, 37]. Clinicians may use supportive meas- particularly relating to physical well-being, and an economic ures, such as patient treatment response to confirm a CIDP burden. Patients with CIDP may also experience burden due diagnosis, to improve diagnostic accuracy [3, 11, 12, 37]. to treatment. Long-term steroid use is associated with a high This may, however, contribute to misdiagnosis when treat- risk of AEs, and parenteral therapies, such as IVIG, SGIG ment response is not evaluated appropriately [18]. Further and plasma exchange, are associated with burden of adminis- research is needed to fully characterise the impact of false- tration and potential impact on patient independence [12, 16]. positive and false-negative diagnoses. Epidemiology studies confirmed that CIDP is a rare dis- CIDP was associated with impaired patient well-being, ease (incidence: 0.2–1.6/100,000 persons per year; preva- due to the physical impact of CIDP and, in some cases, the lence: 0.8–10.3 per 100,000 persons) [1, 4, 6, 20]. The presence of mental health conditions. Patients with CIDP incidence and prevalence data varied, likely arising from had EQ-5D index scores of 0.68 in Germany and 0.62 in the variations in study sample size (n = 19–360) and diagnostic UK, substantially below normative values for these coun- criteria. Low sample sizes are common when identifying tries (Germany: 0.90; UK: 0.86) [9, 25, 61]. For comparison, and recruiting patients with rare diseases [19]. Through EQ-5D mean scores of 0.77 and 0.57 have been reported for combining datasets, meta-analyses can mitigate some of patients with multiple sclerosis in Germany and the UK, the challenges posed by low sample size and diagnostic respectively [62, 63]. EQ-5D scores were also significantly variation [60]. The study by Broers et al. 2019 used this associated with physical function scores (INCAT-ONLS and approach, reporting incidence and prevalence for CIDP of I-RODS), demonstrating the importance of physical func- 0.33 per 100,000 person-years and 2.81 per 100,000 persons, tion in the well-being of patients with CIDP [8]. The physi- respectively, which places CIDP among the rarest neuropa- cal impact of CIDP can prevent patients from completing thies [1, 4]. In contrast, one of the most common chronic daily activities and walking outdoors without support [9]. polyneuropathies, diabetic polyneuropathy, is estimated to However, physical functioning was implicated in 30–42% of 13 Journal of Neurology (2021) 268:3706–3716 3713 the observed changes in HRQoL in patients with CIDP [8], with CIDP, such as hypertension, Cushingoid appearance, showing that, while physical disability is linked to impaired and gastrointestinal complaints [3, 15, 16]. Long-term use of QoL, there are additional contributing factors. Patients with corticosteroids is typically avoided where possible in other CIDP also reported higher rates of depression in The Neth- diseases; for example, corticosteroid-sparing approaches erlands and Germany, compared with the general population (prescribing alternative treatment strategies to reduce cor- averages reported by the European Brain Council and the ticosteroid dose) are considered important in other autoim- European College of Neuropsychopharmacology (9–12.1 mune diseases, such as Crohn’s disease and uveitis [66, 67]. versus 5.9%) [7, 9, 64]. This may reflect the impact that Although the majority of studies reporting comparative data chronic disabling conditions have on mental health [65]. for IVIG reported a greater response rate relative to other Treatment setting, mental health, and physical function- therapies [12, 15, 16, 31–35], IVIG may be burdensome for ing were associated with an increased economic burden patients [13, 14]. IVIG requires venous access, patient moni- in CIDP; however, only eight studies on economic burden toring, and administration in a clinical setting or through were identified and results need to be interpreted with cau- home nursing services, which may contribute to increases tion. While treatment costs were the primary cost drivers, in healthcare costs and reductions in patient independence research in USA and France indicates that the cost of treat- [13, 14]. ment of CIDP reduces if patients can receive IVIG treatment SCIG has been developed as an alternative to IVIG, pro- at home rather than in a hospital setting [55]. Depression viding flexible self-administration at home [13]. While IVIG and functional disability were also identified as important administration requires a nurse to supervise infusions, SCIG predictors of direct costs [9]. Improving depression and can be administered by the patient or a caregiver without the functional disability may reduce costs in CIDP, although need for other medical support staff, which may decrease further research is required to establish the nature of this healthcare resource use [13]. Patients managed with SCIG relationship. These findings cannot be generalised beyond are not dependent on home nursing visits or maintaining the individual country settings, however, as healthcare sys- proximity to an infusion centre so can travel more freely tems vary extensively across geographies. Publications were [13]. Studies suggest that SCIG has similar efficacy to IVIG, limited to English language studies, impairing identification and confirm that patients prefer SCIG due to reductions in of multinational studies, and economic data from only four AEs and improved independence relative to IVIG [14, 44, countries were represented in the review. 46, 49]. A previous meta-analysis of efficacy and safety The physical and psychological impact of CIDP is impli- of SCIG versus IVIG consolidates these findings, reveal- cated in productivity losses and indirect costs. Early retire- ing that the relative risk of systemic AEs (e.g., headache ment was reported among patients with CIDP [9, 26]. The and fever) was reduced by 28% with SCIG versus IVIG odds of fatigue and depression were higher in retired patients (95% CI 0.11–0.76), while effectiveness was similar between with CIDP, versus non-retired CIDP patients (8.2 and 12.2, the two groups [6]. As CIDP is a chronic disease that is not respectively) [26], and the majority of patients with CIDP associated with increased mortality [5, 6], patients require experience severe fatigue and depression rates that are treatments that are appropriate for long-term use. SCIG may greater than for the general population [7, 9, 64]. Functional benefit patients’ long-term disease management, through disability (measured by INCAT) and impaired HRQoL were decreasing systemic AEs and improving patient independ- also predictors of higher indirect costs in Germany, due to ence compared with alterative treatment options. premature retirement, disability, unemployment, sick leave, EFNS/PNS guidelines (2010) do not provide guidance on and reduced labour time [9]. This impact on productivity long-term management of CIDP, nor on SCIG, as evidence can result in substantial economic costs; for example, pro- on these topics was insufficient at the time of guideline ductivity losses due to CIDP may result in 9.7 M annual development [11]. Treatment selection needs to consider a economic cost for the UK (estimated through value of lost range of variables, such as severity, health status, tolerabil- wages) [25]. Similarly, in Germany premature retirement ity, and contraindications, which may present challenges to was the second highest cost element of all cost categories healthcare professionals [68]. Treatments further need to be when assessing the costs associated with CIDP, following reviewed on an ongoing basis to ensure that treatments are cost of medication [9]. appropriate and avoid unnecessary burden. For example, it Current therapies can improve patient well-being, but is recommended that IVIG is periodically reduced or with- are also associated with tolerability issues and challenges drawn to avoid excessive costs, while corticosteroids should around route of administration [13]. IVIG and corticoster- be reviewed or withdrawn to avoid AEs [15, 39]. CIDP sub- oids are both effective in achieving a treatment response, type and varied diagnostic criteria may also be important reflecting EFNS/PNS recommendations to use as the first- in treatment decisions; however, the evidence is unclear. line therapies [11]. However, long-term use of corticoster- Patient populations varied extensively between the publica- oids has been associated with serious side effects in patients tions captured in the current review and the heterogeneity 13 3714 Journal of Neurology (2021) 268:3706–3716 presents challenges to drawing robust conclusions [35]. The appropriate treatment can support mitigating disease burden limited evidence available suggests that treatment outcomes for patients and healthcare systems. do not vary based on diagnostic criteria used to determine the presence of CIDP; however, further research is required Acknowledgements Funding for the study was provided by CSL Behring GmbH. The authors would like to thank Dr Nick Leach for to establish this and the role of subpopulations in determin- providing medical writing and editorial support, which was funded by ing response to treatment. Further research incorporating CSL Behring GmbH in accordance with Good Publication Practice SCIG as a long-term treatment option for CIDP may also (GPP3) guidelines. inform future disease management strategies. Compliance with ethical standards Limitations Ethics statement No primary research was performed as part of this study. There may be additional publications not identified in this review that are important for characterising the burden of Conflicts of interest LQ has provided expert testimony for Grifols, disease in CIDP. For example, relevant data may have been Sanofi-Genzyme, Novartis, UCB, Roche, and CSL Behring, and re- published that were excluded as a result of the limits to the ceived research funds from Novartis Spain, Sanofi-Genzyme, and Gri- study type and publication dates. Searches were restricted fols. MC, EP, and SA are, or were, employees of Huron Consulting to English language publications, which may have excluded Group. Huron Consulting Group received funding from CSL Behring GmbH to perform the study. IV and PS are, or were, employees of CSL relevant studies published in other languages. Behring GmbH. MH is an employee of Optimal Access Life Science No studies were identified related to treatment guidelines Consulting Limited and received funding from CSL Behring. in the current review; however, the EFNS/PNS guidelines on management of chronic inflammatory demyelinating Open Access This article is licensed under a Creative Commons Attri- polyradiculoneuropathy” were published within the dates in bution 4.0 International License, which permits use, sharing, adapta- tion, distribution and reproduction in any medium or format, as long scope [11]. This publication was not captured in this review, as you give appropriate credit to the original author(s) and the source, as the search algorithm was limited to “adults” and these provide a link to the Creative Commons licence, and indicate if changes guidelines included paediatric considerations and so were were made. The images or other third party material in this article are not indexed to “adults” within the searched databases. included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in Limitations characteristic of CIDP were identified, such the article’s Creative Commons licence and your intended use is not as low number of relevant publications and low sample permitted by statutory regulation or exceeds the permitted use, you will sizes in studies. The limited number of publications avail- need to obtain permission directly from the copyright holder. To view a able on epidemiology, humanistic burden, and economic copy of this licence, visit http://creat​iveco​mmons​.org/licen​ses/by/4.0/. 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 References face greater challenges in recruiting patients and obtaining 1. Broers M, Bunschoten C, Nieboer D et al (2019) Incidence and funding, because more common diseases have a greater eco- prevalence of CIDP: a systematic review and meta-analysis. Neu- nomic impact [19]. The majority of studies across categories roepidemiology 52(3–4):161–172. https​://doi.org/10.1159/00049​ included fewer than 150 patients, reflecting the challenges 4291 in patient identification and recruitment in rare diseases 2. Mathey EK, Park SB, Hughes RAC et al (2015) Chronic inflam- matory demyelinating polyradiculoneuropathy: from pathology to [19]. Low sample sizes introduce challenges for deriving phenotype. J Neurol Neurosurg Psychiatry 86(9):973. https​://doi. insights from the data, such as poor generalisability and lack org/10.1136/jnnp-2014-30969​7 of ­statistical powering [19]. 3. Oaklander AL, Lunn MP, Hughes RA et al (2017) Treatments for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP): an overview of systematic reviews. Cochrane Database System Rev 1(1):Cd010369. https​://doi.org/10.1002/14651​858. cd010​369.pub2 Conclusion 4. Hanewinckel R, Ikram MA, Van Doorn PA (2016) Peripheral neuropathies. Handb Clin Neurol 138:263–282. https​: //doi. This review provides the first systematic assessment of the org/10.1016/b978-0-12-80297​3-2.00015​-x burden of illness across all aspects of CIDP. The findings 5. Hafsteinsdottir B, Olafsson E (2016) Incidence and natural history of idiopathic chronic inflammatory demyelinating polyneuropa- establish that CIDP is among the rarest neuropathies and is thy: a population-based study in Iceland. Eur Neurol 75(5–6):263– associated with substantial patient burden. Further research 268. https​://doi.org/10.1159/00044​5884 is required to fully characterise the burden of CIDP, particu- 6. Ryan M, Ryan SJ (2018) Chronic inflammatory demyelinating larly the physical impact on patients, and to understand how polyneuropathy: considerations for diagnosis, management, and population health. Am J Managed Care 24(17):S371–S379 13 Journal of Neurology (2021) 268:3706–3716 3715 7. Kuitwaard K, Bos-Eyssen ME, Blomkwist-Markens PH et al 22. Ikeda S, Nishi R, Kawagashira Y et al (2017) Clinicopathological (2009) Recurrences, vaccinations and long-term symptoms in features among CIDP subtypes. In: PNS 2017 annual meeting, GBS and CIDP. J Periph Nerv Syst 14(4):310–315. https​://doi. Sitges, Barcelona July 8–12 org/10.1111/j.1529-8027.2009.00243​.x 23. Doneddu PE, Cocito D, Santoro L et al (2017) Lifestyle and die- 8. Draak TH, Vanhoutte EK, van Nes SI et al (2014) Changing out- tary habits as predisposing factors for the onset and progression come in inflammatory neuropathies: Rasch-comparative respon- of CIDP: a case-control study from the Italian CIDP database. In: siveness. Neurology 83(23):2124–2132. https​://doi.org/10.1212/ PNS 2017 Annual Meeting, Sitges, Barcelona July 8–12 wnl.00000​00000​00104​4 24. Alexandrescu R, Siegert RJ, Turner-Stokes L (2014) Functional 9. Mengel D, Fraune L, Sommer N et al (2018) Costs of illness in outcomes and efficiency of rehabilitation in a national cohort chronic inflammatory demyelinating polyneuropathy in Germany. of patients with Guillain–Barre syndrome and other inflamma- Muscle Nerve 58(5):681–687. https:​ //doi.org/10.1002/mus.26315​ tory polyneuropathies. PLoS One 9(11):e110532. https​://doi. 10. PolyNeuroexchange (2020) Chronic Inflammatory Demyelinat- org/10.1371/journ​al.pone.01105​32 ing Polyneuropathy (CIDP) Assessment Tools. https​://www. 25. Mahdi-Rogers M, McCrone P, Hughes RA (2014) Economic costs polyn​euroe​xchan​ge.com/cidp/asses​sment​-tools​#incat​-conta​iner. and quality of life in chronic inflammatory neuropathies in South- Accessed 15 Jan 2020 east England. Eur J Neurol 21(1):34–39. https​://doi.org/10.1111/ 11. Van den Bergh PY, Hadden RD, Bouche P et al (2010) European ene.12245​ Federation of Neurological Societies/Peripheral Nerve Society 26. Bjelica B, Bozovic I, Basta I et al (2018) Predictors of early Guideline on Management of Chronic Inflammatory Demyelinat- retirement in patients with chronic inflammatory demyelinating ing Polyradiculoneuropathy: report of a Joint Task Force of the polyradiculoneuropathy. In: 15th international congress on neu- European Federation of Neurological Societies and the Peripheral romuscular diseases, Vienna, Austria, July 6–10 Nerve Society—first revision. Eur J Neurol 17(3):356–363. https​ 27. Spina E, Topa A, Iodice R et al (2017) Predictive factors of long- ://doi.org/10.1111/j.1468-1331.2009.02930​.x term disability in CIDP. In: PNS 2017 annual meeting, Sitges, 12. Gorson KC, Katz J (2013) Chronic inflammatory demyelinat- Barcelona July 8–12 ing polyneuropathy. Neurol Clin 31(2):511–532. https​://doi. 28. Journal of the American College of Cardiology (2019) Mini-Men- org/10.1016/j.ncl.2013.01.006 tal State Examination (MMSE). http://www.onlin​ejacc​.org/conte​ 13. Allen JA, Gelinas DF, Freimer M et al (2020) Immunoglobulin nt/accj/69/12/1609/DC1/embed​/media​-1.pdf?downl​oad=true. administration for the treatment of CIDP: IVIG or SCIG? J Neurol Accessed Aug 2019 Sci 408:116497. https​://doi.org/10.1016/j.jns.2019.11649​7 29. Kuitwaard K, Van Den Berg LH, Vermeulen M et al (2010) Ran- 14. Markvardsen LH, Debost JC, Harbo T et al (2013) Subcutane- domised controlled trial comparing two different intravenous ous immunoglobulin in responders to intravenous therapy with immunoglobulins in chronic inflammatory demyelinating poly- chronic inflammatory demyelinating polyradiculoneuropathy. Eur radiculoneuropathy. J Neurol Neurosurg Psychiatry 81(12):1374– J Neurol 20(5):836–842. https​://doi.org/10.1111/ene.12080​ 1379. https​://doi.org/10.1136/jnnp.2010.20659​9 15. van Lieverloo GGA, Peric S, Doneddu PE et al (2018) Corticos- 30. Kuwabara S, Mori M, Misawa S et al (2017) Intravenous immu- teroids in chronic inflammatory demyelinating polyneuropathy: noglobulin for maintenance treatment of chronic inflammatory a retrospective, multicentre study, comparing efficacy and safety demyelinating polyneuropathy: a multicentre, open-label, 52-week of daily prednisolone, pulsed dexamethasone, and pulsed intrave- phase III trial. J Neurol Neurosurg Psychiatry 88(10):832–838. nous methylprednisolone. J Neurol 265(9):2052–2059. https:​ //doi. https​://doi.org/10.1136/jnnp-2017-31642​7 org/10.1007/s0041​5-018-8948-y 31. Cocito D, Paolasso I, Antonini G et al (2010) A nationwide ret- 16. van Schaik IN, Eftimov F, van Doorn PA et al (2010) Pulsed rospective analysis on the effect of immune therapies in patients high-dose dexamethasone versus standard prednisolone treatment with chronic inflammatory demyelinating polyradiculoneu- for chronic inflammatory demyelinating polyradiculoneuropa- ropathy. Eur J Neurol 17(2):289–294. https​://doi.org/10.111 thy (PREDICT Study): a double-blind, randomised, Controlled 1/j.1468-1331.2009.02802​.x Trial. Lancet Neurol 9(3):245–253. https:​ //doi.org/10.1016/s1474​ 32. Kuitwaard K, Hahn AF, Vermeulen M et al (2015) Intravenous -4422(10)70021​-1 immunoglobulin response in treatment-naive chronic inflamma- 17. Vallat JM, Sommer C, Magy L (2010) Chronic inflammatory tory demyelinating polyradiculoneuropathy. J Neurol Neurosurg demyelinating polyradiculoneuropathy: diagnostic and therapeutic Psychiatry 86(12):1331–1336. https:​ //doi.org/10.1136/jnnp-2014- challenges for a treatable condition. Lancet Neurol 9(4):402–412. 30904​2 https​://doi.org/10.1016/s1474​-4422(10)70041​-7 33. Kuwabara S, Isose S, Mori M et al (2015) Different electrophysi- 18. Allen JA, Lewis RA (2015) CIDP diagnostic pitfalls and percep- ological profiles and treatment response in ‘typical’ and ‘atypi- tion of treatment benefit. Neurology 85(6):498–504. https​://doi. cal’ chronic inflammatory demyelinating polyneuropathy. J Neurol org/10.1212/wnl.00000​00000​00183​3 Neurosurg Psychiatry 86(10):1054–1059. https:​ //doi.org/10.1136/ 19. Griggs RC, Batshaw M, Dunkle M et al (2009) Clinical research jnnp-2014-30845​2 for rare disease: opportunities, challenges, and solutions. Mol 34. Nobile-Orazio E, Liberatore G, Doneddu PE (2018) Diagnosis and Genet Metab 96(1):20–26. https​: //doi.org/10.1016/j.ymgme​ treatment of CIDP: lesson from the databases. In: 15th interna- .2008.10.003 tional congress on neuromuscular diseases, Vienna, Austria, July 20. Mahdi-Rogers M, Hughes RA (2014) Epidemiology of chronic 6-10 inflammatory neuropathies in Southeast England. Eur J Neurol 35. Pasnoor M, Roach C, Barohn RJ et al (2017) CIDP diagnostic 21(1):28–33. https​://doi.org/10.1111/ene.12190​ criteria and treatment response. In: PNS 2017 annual meeting, 21. Doneddu PECD, Santoro L, Fazio R, Filosto M, Mazzeo A, Jann Sitges, Barcelona July 8–12 S, Cortese A, Beghi E, Carpo M, Clerici M, Luigetti M, Lauria G, 36. Merkies IS, Bril V, Dalakas MC et al (2009) Health-related Fierro B, Antonini G, Briani C, Cavaletti G, Rosso T, Benedetti L, quality-of-life improvements in CIDP with immune globulin IV Marfia G, Liberatore G, Peci E, Manganelli F, Velardo D, Tode- 10%: the ICE study. Neurology 72(15):1337–1344. https​://doi. schini A, Toscano A, Verrengia EP, Piccolo L (2017) Frequency, org/10.1212/WNL.0b013​e3181​a0fd8​0 progression and therapy of atypical CIDP: data from the Italian 37. Kaplan A, Brannagan TH 3rd (2017) Evaluation of patients with database on CIDP. In: PNS 2017 annual meeting, Sitges, Barce- refractory chronic inflammatory demyelinating polyneuropathy. lona July 8–12 Muscle Nerve 55(4):476–482. https:​ //doi.org/10.1002/mus.25271​ 13 3716 Journal of Neurology (2021) 268:3706–3716 38. Latov N, Deng C, Dalakas MC et al (2010) Timing and course polyradiculoneuropathy. Neurology 74(8):651–657. https​://doi. of clinical response to intravenous immunoglobulin in chronic org/10.1212/WNL.0b013​e3181​d1a86​2 inflammatory demyelinating polyradiculoneuropathy. Arch Neurol 53. Hughes R, Dalakas MC, Merkies I et al (2018) Oral fingolimod 67(7):802–807. https​://doi.org/10.1001/archn​eurol​.2010.105 for chronic inflammatory demyelinating polyradiculoneuropa- 39. Mielke O, Bril V, Cornblath DR et al (2019) Restabilization treat- thy (FORCIDP Trial): a double-blind, multicentre. Randomised ment after intravenous immunoglobulin withdrawal in chronic controlled trial. Lancet Neurol 17(8):689–698. https ​ : //doi. inflammatory demyelinating polyneuropathy: results from the org/10.1016/s1474​-4422(18)30202​-3 pre-randomization phase of the polyneuropathy and treatment 54. Hughes R, Cornblath D, Dalakas M et al (2017) Inflammatory with Hizentra study. J Peripheral Nerv Syst 24(1):72–79. https​:// demyelinating polyradiculoneuropathy (FORCIDP Trial): sub- doi.org/10.1111/jns.12303​ group analyses. In: PNS 2017 annual meeting, Sitges, Barcelona 40. Leger JM, De Bleecker JL, Sommer C et al (2013) Efficacy and July 8–12 Safety of Privigen((R)) in patients with chronic inflammatory 55. Le Masson G, Sole G, Desnuelle C et al (2018) Home versus demyelinating polyneuropathy: results of a prospective, single- hospital immunoglobulin treatment for autoimmune neuropathies: arm, open-label phase III study (The PRIMA Study). J Peripheral a cost minimization analysis. Brain Behav 8(2):e00923. https​:// Nerv Syst 18(2):130–140. https​://doi.org/10.1111/jns5.12017​ doi.org/10.1002/brb3.923 41. Merkies ISJ, van Schaik IN, Léger JM et al (2019) Efficacy and 56. Divino V, Mallick R, DeKoven M et al (2018) The economic safety of IVIG in CIDP: combined data of the PRIMA and PATH burden Of CIDP in the United States: a case-control study. PLoS studies. J Periph Nerv Syst 24(1):48–55. https​://doi.org/10.1111/ One 13(10):e0206205. https:​ //doi.org/10.1371/journa​ l.pone.02062​ jns.12302​ 05 42. Querol L, Rojas-Garcia R, Casasnovas C et al (2013) Long-term 57. Guptill JT, Bromberg MB, Zhu L et al (2014) Patient demograph- outcome in chronic inflammatory demyelinating polyneuropathy ics and health plan paid costs in chronic inflammatory demyeli- patients treated with intravenous immunoglobulin: a retrospec- nating polyneuropathy. Muscle Nerve 50(1):47–51. https​://doi. tive study. Muscle Nerve 48(6):870–876. https​://doi.org/10.1002/ org/10.1002/mus.24109​ mus.23843​ 58. Rosier C, Graveline N, Lacour A et al (2019) Intravenous immu- 43. Wietek S (2018) For chronic inflammatory demyelinating poly- noglobulin for treatment of chronic inflammatory demyelinat- neuropathy: results from three observational studies. Neuro- ing polyneuropathy and multifocal motor neuropathy in France: degenerat Dis Manage 8(4):227–231. https​://doi.org/10.2217/ are daily practices in accordance with guidelines? Eur J Neurol nmt-2018-0006 26(4):575–580. https​://doi.org/10.1111/ene.13841​ 44. Cocito D, Peci E, Romagnolo A et al (2018) Feasibility of switch- 59. Krishnarajah S, Divino V, Mallick R et al (2017) The Burden and ing from intravenous to subcutaneous Ig therapy in CIDP: PATH journey of patients with CIDP: a case-control analysis. In: PNS trial results versus clinical experience. In: 15th international con- 2017 annual meeting, Sitges, Barcelona July 8–12 gress on neuromuscular diseases, Vienna, Austria, July 6–10 60. Haidich AB (2010) Meta-analysis in medical research. Hippokra- 45. Markvardsen LH, Sindrup SH, Christiansen I et al (2017) Subcu- tia 14(Suppl 1):29–37 taneous immunoglobulin as first-line therapy in treatment-naive 61. Janssen MF, Szende A, Cabases J et al (2019) Population norms patients with chronic inflammatory demyelinating polyneuropa- for the EQ-5D-3L: a cross-country analysis of population surveys thy: randomized controlled trial study. Eur J Neurol 24(2):412– for 20 countries. Eur J Health Econ 20(2):205–216. https​://doi. 418. https​://doi.org/10.1111/ene.13218​ org/10.1007/s1019​8-018-0955-5 46. van Schaik IN, Bril V, van Geloven N et al (2018) Subcutaneous 62. Jones KH, Ford DV, Jones PA et al (2013) How people with mul- immunoglobulin for maintenance treatment in chronic inflam- tiple sclerosis rate their quality of life: an EQ-5D survey via the matory demyelinating polyneuropathy (PATH): a randomised, UK MS register. PLoS One 8(6):e65640. https​://doi.org/10.1371/ double-blind, placebo-controlled, phase 3 trial. Lancet Neurol journ​al.pone.00656​40 17(1):35–46. https​://doi.org/10.1016/s1474​-4422(17)30378​-2 63. Reese JP, Wienemann G, John A et al (2013) Preference- 47. Shebl A, Durn BL, Bril V et al (2018) Benefit-risk profile of based health status in a german outpatient cohort with mul- intravenous immunoglobulin (IVIG) and subcutaneous immuno- tiple sclerosis. Health Qual Life Outcom 11:162. https​://doi. globulin (SCIG) in CIDP: the PATH study. In: 15th international org/10.1186/1477-7525-11-162 congress on neuromuscular diseases, Vienna, Austria, July 6–10 64. Wittchen HU, Jacobi F, Rehm J et al (2011) The size and burden 48. Topa A, Spina E, Iodice R et al (2017) Subcutaneous immuno- of mental disorders and other disorders of the brain in Europe globulin in CIDP: a two-year experience paper. In: PNS 2017 2010. Eur Neuropsychopharmacol 21(9):655–679. https​://doi. annual meeting, Sitges, Barcelona July 8–12 org/10.1016/j.euron​euro.2011.07.018 49. Hartung HP, Mallick R, Bril V et al (2018) Treatment satisfaction 65. Renoir T, Hasebe K, Gray L (2013) Mind and body: how the and work productivity in a clinical study of IgPro20 maintenance health of the body impacts on neuropsychiatry. Front Pharmacol treatment of CIDP. In: 2018 PNS annual meeting, Baltimore 4:158. https​://doi.org/10.3389/fphar​.2013.00158​ Maryland, July 22–25 66. Plevy SE (2002) Corticosteroid-sparing treatments in patients with 50. Mahdi-Rogers M, Rutterford C, Hughes RAC et al (2009) Ran- Crohn’s Disease. Am J Gastroenterol 97(7):1607–1617. https​:// domised controlled trial of methotrexate for chronic inflamma- doi.org/10.1111/j.1572-0241.2002.05818​.x tory demyelinating polyradiculoneuropathy (RMC trial): a pilot. 67. Esterberg E, Acharya NR (2012) Corticosteroid-sparing therapy: Multicentre study. Lancet Neurol 8(2):158–164. https​://doi. practice patterns among uveitis specialists. J Ophthal Inflam Infect org/10.1016/S1474​-4422(08)70299​-0 2(1):21–28. https​://doi.org/10.1007/s1234​8-011-0047-5 51. Benedetti L, Briani C, Franciotta D et al (2011) Rituximab in 68. Ripellino P, Fleetwood T, Cantello R et al (2014) Treatment patients with chronic inflammatory demyelinating polyradicu- of chronic inflammatory demyelinating polyneuropathy: from loneuropathy: a report of 13 cases and review of the literature. molecular bases to practical considerations. Autoimmune Dis J Neurol Neurosurg Psychiatry 82(3):306–308. https ​ : //doi. 2014:201657. https​://doi.org/10.1155/2014/20165​7 org/10.1136/jnnp.2009.18891​2 52. Hughes RA, Gorson KC, Cros D et al (2010) Intramuscu- lar interferon beta-1a in chronic inflammatory demyelinating 13