Expert Review of Neurotherapeutics ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/iern20 Outcome measures and biomarkers in chronic inflammatory demyelinating polyradiculoneuropathy: from research to clinical practice Jeffrey A. Allen, Filip Eftimov & Luis Querol To cite this article: Jeffrey A. Allen, Filip Eftimov & Luis Querol (2021) Outcome measures and biomarkers in chronic inflammatory demyelinating polyradiculoneuropathy: from research to clinical practice, Expert Review of Neurotherapeutics, 21:7, 805-816, DOI: 10.1080/14737175.2021.1944104 To link to this article: https://doi.org/10.1080/14737175.2021.1944104 © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. Published online: 02 Jul 2021. Submit your article to this journal Article views: 1913 View related articles View Crossmark data Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=iern20 EXPERT REVIEW OF NEUROTHERAPEUTICS 2021, VOL. 21, NO. 7, 805–816 https://doi.org/10.1080/14737175.2021.1944104 REVIEW Outcome measures and biomarkers in chronic inflammatory demyelinating polyradiculoneuropathy: from research to clinical practice Jeffrey A. Allena,*, Filip Eftimovb,* and Luis Querolc,* a Department of Neurology, University of Minnesota, Minneapolis, MN, USA; bDepartment of Neurology, Amsterdam Neuroscience, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands; cNeuromuscular Diseases Unit, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain ABSTRACT ARTICLE HISTORY Introduction: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an immune- Received 13 April 2021 mediated syndrome characterized clinically by weakness and/or numbness that evolves over 2 months Accepted 14 June 2021 or more. The heterogeneity of clinical features necessitates an individualized approach to disease KEYWORDS monitoring that takes lessons learned from clinical trials and applies them to clinical practice. Chronic inflammatory Areas covered: This review discusses the importance of clinimetrics and biomarkers in CIDP diagnosis demyelinating and disease monitoring. Highlighted are the challenges of defining responses to immunotherapy, the polyradiculoneuropathy; usefulness, and limitations of utilizing evidence-based clinical outcome measures during routine clinical clinical outcome measures; care, and the evolving understanding of how diagnostic and disease activity biomarkers may reshape biomarkers; diagnosis; our treatment and disease monitoring paradigms. disease activity; disability; Expert opinion: Although disability and impairment outcome measures are commonly used in CIDP to impairment; minimal clinically important indicate disease status, the nonspecific nature of these metrics limits the ability to attribute a change in difference any given metric to a change in CIDP. This interpretive challenge may be magnified by inconsistencies in the direction of change as well as a strong placebo effect. There is a need to improve our under­ standing of minimally important changes in existing outcome measures as a means to personalize treatment and to better assess disease activity status with biomarker discovery. 1. Introduction The pathophysiology of CIDP is not fully understood but likely involves diverse mechanisms between patients or per­ Chronic inflammatory demyelinating polyradiculoneuropathy haps even within individual patients at different stages of the (CIDP) is an immune-mediated peripheral nerve syndrome that disease [7,8]. Autoantibodies have traditionally been consid­ affects 1.0 to 8.9 persons per 100,000 and has an incidence of ered central in CIDP pathophysiology given that patients fre­ up to 1.6 per 100,000 per year [1,2]. Although CIDP is clinically quently respond to plasma exchange and intravenous heterogeneous, the core clinical characteristic features include immunoglobulins. The recent description of autoimmune motor and/or sensory dysfunction that evolves over 8 weeks nodopathies, a subset of neuropathies fulfilling CIDP diagnos­ or more in a progressive or relapsing pattern [3–5]. While tic criteria but with specific associated autoantibodies (anti- between 60% and 80% of patients develop relatively sym­ contactin-1 (CNTN1), anti-neurofascin-155 (NF155), anti- metric proximal and distal numbness and weakness, pheno­ contactin-associated protein 1 (CASPR1) and anti-nodal neu­ types with variable degrees of regional (proximal, distal, or rofascin 140/186 (NF140/186)), supports this view [9,10]. asymmetric) or modality (motor or sensory) involvement are However, immune effector mechanisms that play a role in also recognized under the CIDP umbrella [6]. Named variants CIDP also include macrophage-mediated demyelination, auto­ include multifocal CIDP (Lewis–Sumner syndrome, multifocal antibody-dependent damage (both complement-dependent acquired demyelinating sensory and motor [MADSAM] neuro­ and complement-independent) [11–14] and cytotoxic T-cell pathy), distal CIDP (distal acquired demyelinating symmetric damage [15]. Although specific mechanisms may predominate [DADS] neuropathy), sensory CIDP, and motor CIDP [4,5]. At in some disease variants, pathophysiological overlap is pre­ disease onset, motor CIDP and sensory CIDP variants are sumed considering that most patients respond to either intra­ estimated to each make up about 10% of all CIDP, while distal venous immunoglobulins (IVIg) or corticosteroids. CIDP may be slightly more than 10% and asymmetric CIDP The importance of early CIDP diagnosis and treatment slightly less than 10% [6]. Over time, about half of all patients before irreversible nerve injuries have occurred is indisputable. presenting initially with restricted phenotypes develop motor Equally indisputable is the fact that CIDP is misdiagnosed and and sensory symptoms and signs that are proximal, distal, and overtreated [16]. This situation underscores the importance of symmetric [6]. using sound clinimetric markers of treatment response when CONTACT Jeffrey A. Allen jaallen@umn.edu Department of Neurology, University of Minnesota, 516 Delaware St SE, Minneapolis, MN 55455, USA * These authors contributed equally to this work. © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way. 806 J. A. ALLEN ET AL. be a treatment responder. While benefit may be easy to Article highlights document in some patients, often it is not. ● Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) A ‘test of treatment’ is a strategy frequently employed is a rare and heterogeneous immune-mediated peripheral nerve during the diagnostic process for conditions that lack diag­ syndrome with several clinical variants. nostic biomarkers [25]. Within CIDP diagnostic guidelines, ● Since CIDP misdiagnosis and overtreatment is common, diagnostic and disease activity biomarkers are needed to improve diagnostic ‘objective improvement following immunomodulatory treat­ accuracy and guide treatment decisions. ment’ is considered supportive of a CIDP diagnosis [4]. While ● In clinical trials, CIDP outcome measures commonly used include a ‘test of treatment’ can be diagnostically useful when the metrics for disability, impairment, and quality of life. ● In clinical practice, the collection of structured outcome measures to differential diagnosis is narrow, the pretest probability is high, support a diagnosis and treatment response is highly variable and and there is a measurable objective outcome, problems occur frequently inadequate. when ‘benefit’ is loosely defined. It has been shown that 85% ● There is an evolving understanding of the minimum clinically impor­ tant difference (MCID) for outcome measures typically followed in of patients who were misdiagnosed and treated as CIDP felt patients with CIDP. The rigidity of MCID interpretation in clinical trials better with immunotherapy when benefit was broadly and may not always be needed in clinical practice when outcomes of subjectively defined [26]. Only rarely was there objective evi­ different domains are in agreement. Interpreting MCID becomes challenging when multiple metrics point in different directions. dence of improvement in misdiagnosed patients and, in most ● Although the quest for biomarkers that reflect the underlying patho­ cases, those patients were found to have immune-mediated biology and outcomes of CIDP has been underway for more than disorders that were mismanaged as CIDP. Evidence from ran­ a decade, robust biomarkers for diagnosis and disease monitoring are still lacking. domized controlled trials (RCTs) of CIDP indicates that ● Some areas of biomarker research include tissue status, effector between 30% and 40% of patients randomized to placebo mechanisms, nerve function, and drug effect. are able to reduce or stop other immunotherapies while main­ ● Ideally, a panel of CIDP biomarkers will emerge that can be utilized selectively to capture the full spectrum of CIDP diagnostic hetero­ taining or improving disability [27–34]. These observations geneity and facilitate disease monitoring across a wide range of may reflect the normal fluctuation that occurs in CIDP as clinical scenarios. well as measurement variability with the available clinimetric ● The international registry Inflammatory Neuropathy Consortium Base (INCbase) aims to collect a standard set of clinical outcomes and scales, but also highlight the role that placebo can have on biomaterials from patients across the CIDP spectrum. The study treatment response. In no study is the impact of placebo on expects to uncover enlightening clinical and biological data to better CIDP treatment more striking than in the PATH study of sub­ define the boundaries and immunologic underpinnings of CIDP. cutaneous immunoglobulin (SCIg) [34]. In this RCT, partici­ pants were required to demonstrate immunoglobulin dependency by documenting clinical deterioration after open- label IVIg withdrawal, followed by clinical improvement after treatment response is used as a diagnostic test for CIDP, and open-label IVIg restabilization. Only subjects with decline and highlights the need to develop diagnostic and disease activity then improvement on open-label IVIg were randomized to biomarkers. Monitoring disease activity with a diverse suite of blinded SCIg or placebo. Despite this requirement, 37% (19/ biomarkers (electrophysiology, imaging, soluble axon damage 51) of patients randomized to blinded placebo did not relapse. biomarkers, etc.) that reflect the diverse immunobiological The term ‘placebo effect’ has been used to describe the underpinnings of CIDP may facilitate more targeted use of non-deterioration of patients receiving placebo [35]. Among immunotherapies to maximize therapeutic benefit and avoid factors likely to influence the placebo effect are ‘subject overtreatment. This review examines currently available expectation’ in which a response to treatment is elicited metrics for CIDP disease monitoring in clinical practice and based on what the subject expects to happen; and ‘condition­ explores the state of the art of CIDP biomarker development. ing’ in which there is a learned response to treatment after prolonged use of a medication. These factors almost certainly impact clinical practice similarly to clinical trials, and reinforce the importance of using objective outcomes if a ‘test of treat­ 2. Defining the treatment response: challenges and ment’ strategy is to be employed during routine clinical care. limitations Even then, however, treatment expectations and conditioning IVIg, corticosteroids, and plasma exchange are first-line treat­ may impact on outcome measures in unpredictable ways. It ment options for CIDP[17–20]. Between 80% and 90% of can be difficult to ascertain whether improvement (or dete­ patients respond to one or more of these therapies [21–24]. rioration) is based on a change in disease pathobiology or Although no consensus exists on which first-line intervention whether the metric is instead capturing a placebo phenom­ is best, several factors restrict the use of plasma exchange to enon similar to that observed in the PATH trial. It is within this patients who are severely affected or have treatment- ambiguous interpretive space that the need for biological refractory disease. Regardless of which therapy is chosen, if markers of disease activity becomes so important. a benefit is forthcoming, it should be appreciated within 3 months in most instances and probably within 6 months in 2.1. Illustrative case 1: treatment of a naïve patient all patients. Since the definition of ‘benefit’ strongly influences treatment duration, as well as the very diagnosis being trea­ A 41-year-old man presented with 3 years of slowly worsening ted, it is critically important that ‘benefit’ is defined as clearly paresthesia and weakness in his hands and feet as well as and objectively as possible. This task, however, is not without a mild hand tremor. On examination, deep tendon reflexes challenges. There is no universal definition of what it means to were diffusely hypoactive. Nerve conduction studies (NCS) EXPERT REVIEW OF NEUROTHERAPEUTICS 807 showed unequivocal slowing of motor nerve conduction velo­ 3 weeks. In 2015 and 2016, the dose and frequency of IVIg city (CV) with median and ulnar CV in the low 30s m/sec and were optimized such that the patient was stable between peroneal and tibial nerves motor CV in the upper 20s m/sec. infusions, eventually settling at a 1.2 g/kg dose every A 30–50% conduction block was appreciated in the ulnar 2 weeks. Intravenous rituximab (1000 mg × 2) was adminis­ nerve forearm segment. Sensory response amplitudes were tered in October 2019 followed by a single 1000 mg dose in attenuated in the upper limbs and absent in the lower limbs. January 2020. Cerebrospinal fluid (CSF) protein concentration was normal There are no known CIDP biomarkers of disease activity. In (49 mg/dL). this patient receiving high-dose IVIg: 1) what evidence has The patient fulfills the diagnostic criteria for CIDP, although been gathered to justify aggressive immunoglobulin treat­ he would be classified as having the ‘distal CIDP’ variant. ment? 2) is there adequate evidence that the benefits of Considering the many CIDP diagnostic mimics of the distal rituximab therapy outweigh the risks? CIDP variant, genetic testing may be reasonable to pursue in Periodic collection of disability outcomes (e.g. I-RODS) or this patient. If genetic testing is unavailable or inconclusive impairment (e.g. grip strength) can inform evidence-based then a ‘test of treatment’ might be entertained. If immu­ decision-making in CIDP. In this case, I-RODS and grip strength notherapy is initiated, the main clinical questions are as fol­ measurements were well documented prior to initiation of lows: 1) how does treatment response inform conclusions rituximab (Table 2(a,b)). Decreasing the dose and frequency about the diagnosis? 2) how does treatment response inform of IVIg from 1.2 g/kg every 2 weeks to 1 g/kg every 3 weeks justification for long-term therapy? led to a reduction in I-RODS raw scores (from 43 to 33), and Several outcome measures are available to objectify the reduced left-sided grip strength (from 27 to 16 kg). These treatment response in clinical practice. In this patient, grip metrics improved once IVIg dosing was restored to 1 g/kg strength and the Inflammatory Rasch-built Overall Disability every 2 weeks. A similar reduction in IVIg dose was attempted Scale (I-RODS) questionnaire were chosen to monitor disease. after rituximab administration but with the same result; spe­ IVIg therapy led to normalization of I-RODS scores and dou­ cifically, an unequivocal deterioration of grip strength and bling of grip strength (Table 1). The results were diagnostically increase in disability. In the absence of a biomarker that supportive of CIDP and provided justification for continued informs more precisely about disease activity, collecting IVIg treatment. these outcomes during routine clinical care can provide infor­ mation to guide treatment decisions. In this case, the data indicated that rituximab was not beneficial and that high-dose 2.2. Illustrative case 2: treatment optimization IVIg was justified. In 2013, a 78-year-old man developed symmetric proximal and distal numbness and weakness. NCS showed an unequivocal 2.3. Illustrative case 3: treatment withdrawal demyelinating polyneuropathy with multiple conduction blocks. Symptoms progressed over about 6 months and, in A 29-year-old man with acute onset CIDP developed proximal March 2014, he began treatment with high-dose prednisone. and distal motor and sensory deficits and areflexia over Corticosteroids were unhelpful and, in September 2014, the a 4-week period in November and December 2015. NCS patient was switched to IVIg. Treatment began with a 2 g/kg showed unequivocal slowing of CV. CSF protein concentration loading dose, followed by 1 g/kg maintenance therapy every was elevated (111 mg/dL). In December 2015, IVIg treatment Table 1. Case 1: outcomes pre- and post-treatment with intravenous immunoglobulin (IVIg). May 2019 July 2019 August 2019 November 2019 March 2020 July 2020 I-RODS (raw) 43 41 IVIg started 47 48 48 Grip strength, right (kg) 19 12 2 gm/kg followed by 1 gm/kg q 3 weeks 44 Virtual 43 Grip strength, left (kg) 18 10 42 Virtual 40 I-RODS, Inflammatory Rasch-built Overall Disability Scale. Table 2. Case 2: outcomes following treatment with intravenous immunoglobulin (IVIg) or rituximab. October 2018 February 2019 February 2019 April 2019 April 2019 June 2019 I-RODS (raw) IVIg (1.2 g/kg q2w) 45 43 IVIg (1 g/kg q3w) 33 IVIg (1 g/kg q2w) 42 Grip strength, right (kg) 24 23 22 24 Grip strength, left (kg) 23 27 16 22 October 2019 October 2019 January 2020 January 2020 March 2020 May 2020 May 2020 June 2020 I-RODS (raw) 42 Rituximab Rituximab 43 IVIg (1 g/kg q3w) 35 IVIg (1 g/kg 41 Grip strength, right (kg) 23 (1000 mg × 2) (1000 mg × 1) 22 24 q2w) 25 Grip strength, left (kg) 23 24 14 23 I-RODS, Inflammatory Rasch-built Overall Disability Scale. 808 J. A. ALLEN ET AL. led to near-complete symptom resolution. Relapses in statistical analysis. For example, Inflammatory Neuropathy February 2016 and July 2016 prompted initiation of IVIg main­ Cause and Treatment (INCAT) is an ordinal scale for arm and tenance therapy (July 2016), with dose escalation to 1 g/kg leg disability that is scored from 0 (no disability) to 10 (max­ every 2 weeks in 2017. In 2018 and through 2019, neurologic imum disability) [29]. Because INCAT is an ordinal scale, examination including strength and sensation was normal changes at different positions of the scale (for example, apart from reduced lower limb reflexes. a change from 1 to 2 vs. a change from 7 to 8) do not mean Approximately 30% of patients with CIDP are able to the same thing although, in practice, they are often falsely achieve drug-free remission status at some point during their interpreted as equivalent. Conversely, I-RODS is a 24-item disease [36]. In part because of this, it is standard of care to questionnaire that tabulates a raw I-RODS (ordinal) score of 0 periodically reduce or stop treatment in patients on chronic (maximum disability) to 48 (no disability), which can then be immunoglobulin therapy to understand treatment depen­ translated easily to a centile scale or in logits that can be used dency [4]. With these considerations in mind: 1) what is the in a linear fashion [41]. justification for high-dose IVIg in this patient? 2) are there Most RCTs of CIDP conducted over the last 12 years have objective data that support active immunotherapy- used disability as the primary outcome measure (Table 5) dependent disease? [29,30,33,34,42–46], commonly INCAT which is the preferred The assumption made when treating CIDP is that changes outcome measure of the United States Food & Drug in metrics (e.g. disability, grip strength) indirectly reflect Administration. Although the same outcome measures used change(s) in biological activity targeting peripheral nerves in clinical trials are generally applied in routine clinical prac­ but those which cannot be measured directly. When multiple tice, the objectives, interpretation, and definitions of response measures of different domains change in the same direction, differ by setting. In clinical trials, the objective is to define confidence grows in the assumption that outcomes reflect clinically meaningful differences between treatment groups improvement in neuropathy. However, changes in metrics that are indicative of the efficacy of a certain intervention. are sometimes inconsistent or contradict the patient’s subjec­ Clinical trials typically employ a rigidly defined primary out­ tive experience. When this occurs, it is difficult to know which come measure and multiple supportive secondary measures metric to rely on or if any metric can be used to support the (usually impairment). In clinical practice, the goal of collecting original assumption. data is to support treatment response in individual patients In Case 3, measurements for grip strength, MRC sum score, rather than groups. The practicalities of how that is achieved and sensory examination were stable during IVIg treatment, are much different compared with clinical trials and, too often, whereas the I-RODS disability score deteriorated and the no formal outcomes are collected. In other instances, only patient’s subjective experience slightly worsened (Table 3). loosely defined subjective measures are obtained. While the While strength and sensory scores provide strong evidence same rigidity necessary for clinical trials is not always needed that the neuropathy is stable and that high-dose IVIg is not (or feasible) in clinical practice, the lessons learned from clin­ needed, the importance of a change in disability or subjective ical trials should not be lost completely. In clinical practice, patient experience as a reflection of CIDP disease activity is smaller but consistent changes in outcomes across different less clear. I-RODS scores, and even impairment outcome mea­ scales may be regarded as clinically relevant. Clinical practice sures, are not specific to neuropathy and may be influenced is also not bound to a single predefined measure. Clinicians by a multitude of other factors. Improvement in some metrics may choose among several outcomes that best capture in this patient may have been due to immunotherapy, change in a given patient. While the time and cost considera­ a placebo effect (expectations of ongoing benefit or condi­ tions of outcomes collection in daily practice are real, they tioning), or a nonspecific benefit of IVIg therapy (i.e. IVIg need not be disqualifying if the physician focuses on out­ having a positive biological effect on a non-CIDP disease). comes most relevant to a particular patient. The features of this case emphasize the need for robust bio­ Minimal clinically important difference (MCID) is the smal­ markers to gain a better understanding of these complex lest change in health status that an individual patient would issues. identify as important. Although the concept was developed more than 30 years ago [47], the best method to define MCID remains under discussion. MCID may be derived by using an 3. CIDP outcome measures: from clinical trials to anchor-based or distribution-based approach. In the anchor- clinical practice based method, an external criterion, often Patients’ Global Clinical outcome measures employed in CIDP clinical trials Impression of Change (PGIC), is the gold standard by which include metrics for disability, impairment, symptoms, and to determine clinical importance. Critics of the anchor-based quality of life (QoL) [37–40] (Table 4). Disability is generally approach argue: why not simply use PGIC? The distribution- used as a primary outcome measure, whereas impairment based approach is based on the statistical properties of the measures are often secondary outcomes. In the last few test [48]. Critics of the distribution-based approach argue that years, measures for symptoms (e.g. fatigue and pain) and statistical significance is per definition not the same as clinical QoL have increasingly been incorporated into study designs. relevance. Frequently used definitions of MCID in CIDP are The last decade has seen a shift toward the use of linear summarized in Table 6. rather than ordinal scales in CIDP, as differences in ordinal- When assessing MCID in clinical practice, it is important scale data cannot be quantified. The development of linear that outcome measures are performed properly so that results scales enables collection of data more amenable to robust are reproducible. Even then scenarios may arise in which Table 3. Case 3: outcomes following treatment with intravenous immunoglobulin (IVIg). July 2019 August 2019 October 2019 November 2019 January 2020 February 2020 April 2020 May 2020 July 2020 Condition I-RODS (raw) IVIg (1 g/kg q2w) 35 IVIg (1 g/kg q3w) 36 IVIg (1 g/kg q4w) 34 IVIg (0.7 g/kg q4w) 30 IVIg (0.4 g/kg q4w) 28 Worsening Grip strength, right (kg) 57 52 59 Video 56 Stable Grip strength, left (kg) 44 48 50 Video 49 Stable MRC (0–60) sum score 60 60 60 Video 60 Stable Sensory exam Stable Stable Stable Video Stable Stable Subjective experience Stable Stable Stable Patient unsure Possible decline Worsening? I-RODS, Inflammatory Rasch-Built Overall Disability Scale; MRC, Medical Research Council. EXPERT REVIEW OF NEUROTHERAPEUTICS 809 810 J. A. ALLEN ET AL. Table 4. Clinical outcome measures in clinical trials of CIDP [37–40]. Disability Impairment Symptoms Quality of life INCAT Grip strength mFSS (fatigue)* SF-36* ONLS ISS NRS (pain)* EQ-5D (EuroQol)* Modified Rankin Scale 6-min walk test CAP-PRI I-RODS* TUG *Patient reported outcome measure (PROM). CAP-PRI, Chronic Acquired Polyneuropathy Patient-Reported Index; CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; EQ-5D, EuroQol- 5 Dimension; INCAT, Inflammatory Neuropathy Cause and Treatment; ONLS, Overall Neuropathy Limitation Scale; I-RODS, Inflammatory Rasch-Built Overall Disability Scale; ISS, INCAT sensory sum score; mFSS, modified Fatigue Severity Scale; NRS, Numeric Rating Scale; SF-36, 36-Item Short Form Survey; TUG, Timed ‘up and go.’ Table 5. Primary outcome measures in randomized controlled trials for CIDP. Trials Reference Primary outcome measure ICE (IVIg vs placebo) Hughes et al. 2008 [29] INCAT RMC (methotrexate vs placebo) RMC Trial Group 2009 [30] INCAT PREDICT (dexamethasone vs prednisolone) van Schaik et al. 2010 [42] INCAT and Rivermead Mobility Index IMC (IVIg vs prednisolone) Nobile-Orazio et al. 2012 [43] ONLS or modified Rankin score FORCIDP (fingolimod vs placebo) Hughes et al. 2018 [33] INCAT PATH (SCIg vs placebo) van Schaik et al. 2018 [34] INCAT DRIP (different IVIg intervals) Kuitwaard et al. 2020 [44] Grip strength ProCID (different IVIg intervals) Cornblath et al. 2018 [45] INCAT IOC (IVIg continuation vs placebo) ISRCTN Registry [46] I-RODS INCAT, Inflammatory Neuropathy Cause and Treatment; I-RODS, Inflammatory Rasch-Built Overall Disability Scale; IVIg, intravenous immunoglobulin; ONLS, Overall Neuropathy Limitation Scale; SCIg, subcutaneous immunoglobulin. Table 6. Frequently used definitions of minimal clinically important difference (MCID) in CIDP. Scale MCID Remarks (adjusted) INCAT 1 point Not a linear scale Less responsive in some patients May not capture all activities important to all patients I-RODS Individual SE (differs on the scale) on Calculation of MCID using individual standard errors (MCID ≥ ± 1.96 SE) requires an centile score automated tool for calculation or 4 points on raw score requires additional research to assess relevance 4 points on the centile score Raw score (0–48) is easy to collect but less is known about the MCID May not capture all activities important to all patients Grip strength, Martin 8 kPa Repeated measurements are needed for consistency vigorimeter 14 kPa Not practical for patients with very weak grip Grip strength, Jamar 10% change (kg or lb) Requires values averaged over at least 3 consecutive days dynamometer Not practical for patients with very weak grip MRC sum score 2–4 points Usually a total score of 60 points (6 paired muscle groups) Poor interrater reliability Relatively unresponsive, especially to capture deterioration CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; INCAT, Inflammatory Neuropathy Cause and Treatment; I-RODS, Inflammatory Rasch-Built Overall Disability Scale; MRC, Medical Research Council; SE, standard error. directional changes in the measures of different domains are without a true change will not reach the MCID). Taking grip not in agreement. MCID may also vary from patient to patient strength as an example, a change exceeding a MCID of 8 kPa depending on individual treatment goals [48], and MCID may be interpreted as meaningful if the value is consistent thresholds for improvement and deterioration of health status and reproducible. Selecting a cutoff value lower than 8 kPa as are not necessarily identical. These challenges, while not insig­ a sign of change would likely increase sensitivity but worsen nificant, should not discourage application of objective mea­ specificity. Changes less than the MCID may still be important, sures or utilization of MCID during routine clinical care. The especially if they are reflective of other domains. It is none­ reference MCID employed in clinical trials provides a context theless important to exercise caution not to overinterpret for interpreting the magnitude of change. results less than the MCID especially if other metrics are not In order to incorporate MCID into clinical practice during pointing in the same direction. Interpretation of outcomes a ‘test of treatment,’ it is essential that the MCID has a high with disparate directional changes requires a critical assess­ sensitivity (captures change in patients with a real change in ment of the patient’s unique clinical characteristics and other disease activity) and a high specificity (ensures that patients intervening circumstances to understand which, if any, EXPERT REVIEW OF NEUROTHERAPEUTICS 811 outcome is meaningful. Conversely, large changes in an out­ [49,50]. The quest for biomarkers for monitoring disease activ­ come that exceed the MCID may be discounted if they are ity in CIDP has been underway for decades. Although multiple easily explained by unrelated factors. Although no diagnostic disease activity targets have been explored – including auto­ test will ever have 100% sensitivity and specificity, further antibodies, cytokines and complement proteins, Fc receptor study is needed to better understand how MCID can reflect modulators and IgG levels, pathological markers, electrophy­ clinically meaningful changes in different patients more inclu­ siological and imaging measures – at present, robust biomar­ sively, under different clinical scenarios and during different kers for diagnosis and disease monitoring in CIDP are lacking. stages of disease. A full understanding of the ‘sensitivity’ and The complex pathophysiology of CIDP [5] (Figure 1) suggests ‘specificity’ of a MCID is an active area of research, although that multiple biomarkers to assess tissue status, effector limited by the absence of gold standard disease activity mechanisms, functional aspects and drug efficacy may be biomarkers. required to fully capture its pathophysiological diversity. 4. Disease activity biomarkers: current landscape 4.1. Tissue status and future trends Tissue status biomarkers are used to evaluate damage to the Biomarkers are measures that reflect the underlying pathobiol­ targeted tissue and may include imaging, skin or nerve biopsy, ogy and outcomes of a disease but are not clinical markers and serum biomarkers for axonal or myelin damage. Figure 1. Immunopathology of chronic inflammatory demyelinating polyneuropathy Reproduced with permission from [5]. Inset: Effects of autoantibody binding at the node of Ranvier. (A) Interference of saltatory conduction (B) Binding of an autoantibodies followed by complement fixation and deposition of membrane attack complexes (MAC) leading to disruption or destruction of nodal and adjacent neuronal areas. Ag, antigen; APC, antigen presenting cell; C5b-9/MAC, complement terminal C5b-9/membrane attack complex; ICAM, intercellular adhesion molecules; Kv, voltage-gated K+ channels; Nav, voltage-dependent Na+ channels; PNS, peripheral nervous system; VCAM, vascular cell adhesion molecules. 812 J. A. ALLEN ET AL. The convenience of ultrasound makes it an attractive 4.2. Effector mechanisms of CIDP method of exploring tissue status in CIDP. Some authors Effector mechanism biomarkers aim to provide insight into the have shown that nerve morphology on ultrasound correlates pathobiological underpinnings of CIDP. The levels and activ­ with clinical outcomes following CIDP treatment [51] and that ities of serum autoantibodies, as well as serum and CSF com­ median and ulnar nerve size normalizes or decreases in CIDP plement and cytokine profiles, may be particularly patients in remission [52]. However, at present, imaging bio­ relevant [58]. markers are more appropriate for comparing patient cohorts Autoantibodies against proteins including the different than for prospectively following the treatment course of indi­ neurofascin isoforms (NF155 and NF140/186), CNTN1, or vidual patients. Ultrasound-based approaches require further CASPR1 have been described in approximately 10% of CIDP study and should not be used at present to assess CIDP patients. Patients harboring these autoantibodies have diverse disease activity status during routine clinical care. characteristic clinical features depending on the specific auto­ Although more invasive than ultrasound, skin biopsies antibody but which include poor responsiveness to IVIg may provide insight into CIDP tissue status. In a study of [9,59,60]. Although RCT data are lacking, numerous anecdotal 52 patients with demyelinating neuropathies, an increased reports and case series suggest that B cell depletion therapy frequency of elongated nodes of Ranvier and dispersion of with rituximab elicits a robust clinical response that is mirrored contactin-associated protein staining was shown in cuta­ by a decrease in CNTN1 or NF155 autoantibody concentration neous nerves compared with axonal neuropathies [61]. In these CIDP subtypes, disease activity monitoring can (p < 0.05); and broadening of neurofascin staining was potentially be assisted by autoantibody biomarkers provided detectable more frequently in demyelinating neuropathies that the autoantibodies can be accurately and reliably compared with normal controls (p < 0.05) [53]. measured. A subsequent study of four CIDP patients who harbored In the vast majority of patients with CIDP no pathogenic high-titer autoantibodies against CNTN1 by ELISA showed autoantibody is detected. Protein microarray studies have paranodal anti-contactin-1 immunofluorescence labeling of attempted to explore autoantibody repertoires in such dermal myelinated nerve fibers [54]. While these observa­ patients. Although no CIDP specific antibodies have thus far tions are promising, the application of skin biopsy for CIDP been identified using this technique, in one proteomic study diagnosis or as a means to detect disease activity or treat­ of about 16,000 bait proteins autoantibody profiles emerged ment response requires further study and, at present, has that were able to distinguish patients by age, clinical features, no role during routine clinical care. and IVIG responsiveness [62]. Anchoring junction proteins Serum neurofilament light chain (sNfL) has been explored were over-represented in CIDP patients. These findings pro­ as an axonal biomarker for several neurologic disease states, vide insight into antigenic targets that require further investi­ including CIDP. In a study of 29 patients starting IVIg, sNfL gation, and suggest that in some patients antigen repertoires, levels were significantly higher (p = 0.01) than in age-matched rather than individual specific autoantibodies, may be better controls (n = 30), but there were no significant differences suited as a diagnostic or disease activity biomarker. T-cell between controls and patients receiving IVIg maintenance repertoires have also been explored in CIDP. CD4+ and CD8+ treatment (n = 24) or those in long-term remission without T cells in peripheral blood of CIDP patients receiving (n = 11) treatment (n = 27). The results suggest that sNfL may be useful or not receiving (n = 14) IVIg revealed reduced oligoclonal as a biomarker of disease activity in a subset of CIDP patients expansions of both cell populations in the treatment group. who have increased sNfL before the start of treatment [55]. The results suggested that highly activated T cells may con­ Before sNFL can be widely adopted as a tissue status biomar­ tribute to the therapeutic effects of IVIg [63]. The results need ker, prospective studies that assess axonal damage longitud­ to be confirmed in larger studies before T cell status can be inally and relative to baseline levels in the same patient are used as a CIDP treatment biomarker during routine clinical needed. care. There is no known biomarker that reliably reflects myelin damage. Plasma levels of the Schwann cell-specific transmem­ brane protease serine 5 protein (TMPRSS5) were shown to be 4.3. Nerve function significantly elevated in Charcot-Marie-Tooth disease [56]; however, its role as a biomarker in acquired demyelinating Electrophysiology provides the best surrogate biomarker of neuropathies is unknown. There is some evidence that CSF nerve function in CIDP. A post hoc analysis of clinical trial sphingomyelin, a myelin-enriched lipid, may be a useful diag­ electrophysiological data demonstrated improvement in elec­ nostic and disease activity biomarker. Diagnostically, sensitiv­ trophysiologic parameters after initiation of immunotherapy ity (80.8%) and specificity (98.8%) in patients with acute and [64]. Other investigators have shown that patients with wor­ chronic demyelinating polyradiculoneuropathies is favorable. sening demyelinating abnormalities during treatment are CSF sphingomyelin also has been shown to be higher in more likely to relapse following therapy discontinuation than patients with active CIDP compared to those with stable dis­ patients with stable or improved NCS [65]. While these find­ ease and compared to axonal controls, suggesting its potential ings suggest that serial electrophysiologic assessments may be role as a disease activity biomarker [57]. Further study of CSF useful to determine treatment response, correlation between sphingomyelin in large cohorts of patients at various stages of electrophysiologic parameters and treatment outcome has not disease is needed before it can be adopted into routine clinical been appreciated in other groups of patients receiving chronic care. IVIg therapy [66,67]. An alternative functional biomarker is the EXPERT REVIEW OF NEUROTHERAPEUTICS 813 motor unit number index (MUNIX) sum score which estimates will be needed to comprehensively monitor the disease. While axonal loss and number of functional motor units within some biomarkers may play a larger diagnostic role to identify a nerve [68]. The MUNIX sum score was significantly lower in disease subtypes (autoantibodies, electrophysiology or ima­ CIDP patients than in healthy controls (p < 0.001) and corre­ ging), others may be more useful to detect subclinical disease lated with motor and sensory function as well as patient activity over time (sNfL) or to identify treatment failure disability [69]. Although electrophysiological studies play an (CD19 + B cell counts). Validation of a ‘set’ of biomarkers, important role in CIDP diagnosis, their role in monitoring with definitions specifying situations in which they may be disease status is less clear. Similar to imaging biomarkers, useful, would facilitate the application of biomarker panels electrophysiology biomarkers are more appropriate for com­ capable of addressing specific questions in unique patients paring patient cohorts than for following the treatment course at different disease stages. As an example, detection of anti- of individual patients. NF155 antibodies in a treatment-naïve patient helps to classify disease subtype. While the anti-NF155 antibody begins as an effector mechanism diagnostic biomarker, it also informs on 4.4. Drug effect the likelihood of a response to specific immunotherapies and Biomarkers for drug effect assess the mechanism of action and therein guides treatment decisions. If B cell depletion therapy degree of response following treatment. Several candidates is administered, the antibody level along with B cell counts have been explored, including cytokine profiles, B cell signa­ may be used as drug effect biomarkers and, hence, inform if tures, and immunoglobulin levels. However, their value as true and when re-treatment is needed. Collection of sNfL before disease biomarkers or as biomarkers of the drug effect on the and during treatment adds information about ongoing axonal disease (and not just of the pharmacokinetics of the drug) is degeneration as a tissue status biomarker. This set of biomar­ frequently unknown. kers collectively objectifies diagnosis with effector mechan­ B cell signatures measured by flow cytometry have demon­ isms (autoantibodies), directs treatment (autoantibody, B cell strated reduced peripheral total B cells but markedly increased counts), and informs on tissue status (sNfL) in a manner that is mature plasma cells in patients with CIDP (n = 8) and multi­ not possible with clinical outcomes alone. focal motor neuropathy (n = 22). Following IVIg treatment, plasma cell numbers fell rapidly, whereas B cell numbers were 5. Conclusion unchanged. The results suggested the involvement of plasma cells in the immunopathogenesis of chronic immune neuro­ Despite good clinimetric tools for CIDP, disease diversity pre­ pathies including CIDP and their use as a potential biomarker cludes using a single metric for all patients managed in clinical for IVIg treatment response [70]. Similarly, the effect of ritux­ practice. Outcome measures should be customized to indivi­ imab is monitored in many diseases treated with B cell deplet­ dual patients during routine clinical care, both in terms of ing therapies by analyzing CD-19+ B cell counts [71]. In this which outcome(s) are selected and what is regarded as the case, the detection of higher-than-expected B cell counts in MCID. In the absence of gold standard biomarkers of diagnosis a patient not responding adequately to rituximab could serve and disease activity, an important message is to diversify out­ as a means of detecting anti-drug neutralizing antibodies. In comes in order to gather complementary information across the same setting, monitoring immunoglobulin levels could different domains. assist in detecting patients at risk of secondary immune defi­ Biomarkers are essential to improve informed decision- ciencies who are candidates for immunoglobulin replacement making. Biomarkers investigated to date are highly heteroge­ therapy [72]. neous and have largely been investigated in small mono­ The role of serum IgG level monitoring during IVIg treat­ centric studies. The development and validation of new ment is unknown. Measuring serum IgG levels in 25 CIDP diagnostic and disease activity biomarkers is a priority in patients treated with individually tailored doses of IVIg CIDP research to generate biomarker sets that, when inte­ showed that clinically stable patients achieved a steady-state grated with clinical outcome measures, have the capacity to in serum IgG levels following serial IVIg infusions [73] transform CIDP clinical trial design and treatment paradigms Although a change in serum IgG levels correlated significantly during routine clinical care. with IVIg dose (p < 0.001) [73], changes in immunoglobulin levels did not correlate with disease activity in a sepa­ 6. Expert opinion rate cohort of 25 CIDP patients receiving chronic IVIg [74] suggesting that disease activity and immunoglobulin doses Our experience is that clinical outcomes collection during depend on individual factors and that longitudinal assessment routine clinical care is feasible and informative when recording of immunoglobulin levels is not useful for disease activity treatment response for patients with CIDP. In addition to monitoring or treatment needs. assessing disability status with I-RODS or INCAT and strength impairment with grip strength, it is useful to focus also on an important task in the patient’s daily life, as specific activities 4.5. Combined biomarkers important to individual patients may not always be repre­ Considering the diversity of CIDP pathophysiological mechan­ sented in disability tools. Formal assessments of gait, fatigue, isms and treatment regimens, it is likely that, instead of single pain, QoL, and a patient’s overall assessment of CIDP disease multivalent parameters, a set of biomarkers that capture nerve activity can add another layer of information, although these integrity, nerve function, drug effect and effector mechanisms measures require cautious interpretation and should not be 814 J. A. ALLEN ET AL. used as the sole basis for making treatment changes. We Funding envision an evolving understanding of the way in which indi­ The manuscript was developed from the proceedings of a Grifols- vidual outcomes inform about a patient’s clinical status during sponsored virtual symposium, held on 28 October 2020 as part of the treatment, specifically with respect to how MCIDs from multi­ 2020 Peripheral Nerve Society Virtual Event. ple measures can be used to better understand treatment response and differentiate true physiological changes from placebo responses. The best approach for addressing the Declaration of interest placebo response in CIDP is one of active discussion. The JA Allen has received consulting fees from Argenx, Alexion, Akcea, CSL impact of the placebo effect on CIDP clinical trials and routine Behring, Grifols, and Takeda, speaker honorarium from Akcea and CSL clinical care is neither trivial nor benign. Behring. F Eftimov has received grants for research in CIDP from ZonMw (a Despite all efforts to objectify treatment response with clin­ Dutch governmental agency) and Prinses Beatrix Spierfonds (Dutch ical outcomes there are scenarios that invariably cannot be Charity Funds). As principal investigator of INCbase, an international reg­ addressed by clinical measures alone. Even outcomes developed istry for CIDP, he has received grants for investigator-initiated studies within INCbase from various pharmaceutical companies. All grants were specifically for CIDP are not truly specific to that condition. paid to his institution. He has received speakers fee from CSL Behring, INCAT and I-RODS disability scores may be influenced by Kedrion Biopharma and Grifols. Also he has received departmental honor­ a multitude of concomitant factors. Even grip strength, arguably aria for serving on scientific advisory boards of CSL Behring, UCB pharma the most straightforward CIDP metric, can be influenced by and Takeda Pharmaceuticals. L Querol has received research grants from technique, pain, or effort, and thus is not entirely reliable or Instituto de Salud Carlos III Ministry of Economy and Innovation Spain, GBS CIDP Foundation International, Grifols, Novartis Pharma Spain, and specific to neuropathy despite our assumptions. Biomarker dis­ Roche; has provided expert testimony to Alexion, Annexon, CSL Behring, covery is poised to transform CIDP diagnostic and treatment Grifols, Merck, Novartis, Roche, Sanofi Genzyme, and UCB; serves on paradigms. Although no disease activity biomarkers are currently Clinical Trial Steering Committees for Sanofi Genzyme and UCB. The ready for widespread use in clinical practice, intriguing candi­ authors have no other relevant affiliations or financial involvement with dates that require further study include sNfL, complement, and any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those cytokine profiles, T and B cell repertoires, and autoantibodies to disclosed. CNTN1 or NF155. 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