Outcome measures and biomarkers in chronic inflammatory demyelinating polyradiculoneuropathy: from research to clinical practice

Figures & data

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 2 gm/kg followed by 1 gm/kg q 3 weeks	47	48	48
Grip strength, right (kg)	19	12		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 (1000 mg × 2)	Rituximab (1000 mg × 1)		43	IVIg (1 g/kg q3w)	35	IVIg (1 g/kg q2w)		41
Grip strength, right (kg)	23				22		24			25
Grip strength, left (kg)	23				24		14			23

I-RODS, Inflammatory Rasch-built Overall Disability Scale.

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.

Table 4. Clinical outcome measures in clinical trials of CIDP [37–40]

Disability	Impairment	Symptoms	Quality of life
INCAT ONLS Modified Rankin Scale I-RODS*	Grip strength ISS 6-min walk test TUG	mFSS (fatigue)* NRS (pain)*	SF-36* EQ-5D (EuroQol)* CAP-PRI

*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 centile score or 4 points on the centile score	Calculation of MCID using individual standard errors (MCID ≥ ± 1.96 SE) requires an automated tool for calculation 4 points on raw score requires additional research to assess relevance 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 vigorimeter	8 kPa 14 kPa	Repeated measurements are needed for consistency Not practical for patients with very weak grip
Grip strength, Jamar dynamometer	10% change (kg or lb)	Requires values averaged over at least 3 consecutive days 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.

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.

Hughes RA, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet Neurol. 2008;7:136–144.

 PubMed Web of Science ®Google Scholar

RMC Trial Group. Randomised controlled trial of methotrexate for chronic inflammatory demyelinating polyradiculoneuropathy (RMC trial): a pilot, multicentre study. Lancet Neurol. 2009;8(2):158–164.

 PubMed Web of Science ®Google Scholar

van Schaik IN, Eftimov F, Van Doorn PA, et al. Pulsed high-dose dexamethasone versus standard prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT study): a double-blind, randomised, controlled trial. Lancet Neurol. 2010;9(3):245–253.

 PubMed Web of Science ®Google Scholar

Nobile-Orazio E, Cocito D, Jann S, et al. Intravenous immunoglobulin versus intravenous methylprednisolone for chronic inflammatory demyelinating polyradiculoneuropathy: a randomised controlled trial. Lancet Neurol. 2012;11(6):493–502.

 PubMed Web of Science ®Google Scholar

Hughes R, Dalakas MC, Merkies I, et al. Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial): a double-blind, multicentre, randomised controlled trial. Lancet Neurol. 2018;17(8):689–698.

 PubMed Web of Science ®Google Scholar

van Schaik IN, Bril V, van Geloven N, et al. Subcutaneous immunoglobulin for maintenance treatment in chronic inflammatory demyelinating polyneuropathy (PATH): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Neurol. 2018;17(1):35–46.

 PubMed Web of Science ®Google Scholar

Kuitwaard K, Brusse E, Jacobs BC, et al. Randomized trial of intravenous immunoglobulin maintenance treatment regimens in chronic inflammatory demyelinating polyradiculoneuropathy. Eur J Neurol. 2021;28(1):286–296.

 PubMed Web of Science ®Google Scholar

Cornblath DR, Hartung HP, Katzberg HD, et al. A randomised, multi-centre phase III study of 3 different doses of intravenous immunoglobulin 10% in patients with chronic inflammatory demyelinating polyradiculoneuropathy (ProCID trial): study design and protocol. J Peripher Nerv Syst. 2018;23(2):108–114.

 PubMed Web of Science ®Google Scholar

ISRCTN Registry. Intravenous immunoglobulin overtreatment in chronic inflammatory demyelinating polyneuropathy. 2020. [cited 2021 Jun 23]. Available from: http://www.isrctn.com/ISRCTN13637698

 Google Scholar

Mathey EK, Park SB, Hughes RA, et al. Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype. J Neurol Neurosurg Psychiatry. 2015;86(9):973–985.

 PubMed Web of Science ®Google Scholar