Summary

• The session aimed to talk about the Wallerian degeneration pathway and the molecular mechanisms identified over the past 20–30 years and how this is relevant to the low value regeneration seen in most peripheral neuropathy patients.
• NMNAT2 basically has an inhibitory hold on SARM1 activation, so if NMNAT2 levels are high in axons, SARM1 doesn’t get activated and there is no axonal degeneration.
• It is this close relationship between NMNAT2 and SARM1 activation that allows broad thinking about inhibiting SARM1 as a common final pathway in many different, predominantly axonal neuropathies.

Types of axon degeneration:¹

• Developmental axon pruning: Terminal pruning and large-scale pruning
• Wallerian degeneration: Traumatic or ischemic injury
• Dying back distal axonal degeneration: Metabolic, toxic, genetic injury

Wld^s and Wallerian Degeneration²

• Wld^S mutation spontaneously arose.
• Transected axons survive for long periods of time
• Wld^S partially protects axons against “dying back” Wallerian-like degeneration
• Wld^S is a fusion protein of Nmnat1 and a 70-aa fragment of Ube4b

Wallerian degeneration vs distal axon degeneration: Role of NMNAT^3,4

• Data from WLD^S suggest that axonal NMNAT plays a role in some but not all distal axonal PNs

Loss of NMNAT2 induces Wallerian degeneration

• RNAi of NMNAT2 but not NMNAT1 or NMNAT3 induces axon degeneration in SGC neurons³
• Axon degeneration induced by NMNAT2 RNAi is delayed by WLD^S5
• NMNAT2 is the most labile isoform but overexpression of NMNAT2 delays axon degeneration⁴

Mutations in dSarm block Wallerian degeneration⁵

• Forward genetics in drosophila identified dSarm as a key regulator of axonal degeneration
• Deletion of mouse homologue, SARM1, delays axon degeneration after sciatic nerve transection

Aberrant activation of programmed axon death causes disease⁶

• Loss of NMNAT2 causes developmental failure of axon growth
• This is rescued by Wld^S

Aging and axonal NMNAT2⁷

• Brain NMNAT2 expression level correlates with cognitive function in AD autopsies
• NMNAT2 transport decreased with aging

NMNAT2 mutations in human disease⁸

• Compound heterozygous NMNAT2 variants in 2 brothers with relapsing-remitting neuropathy
• Nmnat2^V98M/R232Q mice have behavioral and electrophysiologic features consistent with a motor neuropathy

Neuronal SARM1 is required for Nmnat2^V98M/R232Qneuropathy⁹

• Both Sarm1 KO and dnSarm1 are protective

GoF mutation of Sarm1 in human disease¹⁰

• Constitutively active SARM1 variants found in ALS patients induce axon degeneration
• Mice injected intrathecally with a SARM1V184G AAV construct develop motor axon degeneration

Does Sarm1 deletion protect against distal axon degeneration as seen in axonal PN?¹¹

• Protects against vincristine neuropathy
  • Outcome measures (IENFD, tail SNAP amplitude and axon degeneration in sural nerve)

Sarm1 KO protects against HFD induced PN¹²

• HFD model of metabolic neuropathy
  • Sarm1 KO mice on HFD do not develop peripheral neuropathy

Sarm1 KO protects against bortezomib induced PN¹³

• BTZ and VCR activate different pathways that converge on Sarm1

Sarm1 KO protects against STZ induced PN¹⁴

• Protects against STZ model of Type 1 diabetes induced neuropathy

Implications:

• The discovery of the NMNAT2–SARM1 axis has fundamentally changed the understanding of axon degeneration, revealing it as a druggable process. This offers a transformative opportunity for developing targeted, mechanism-based therapies for peripheral neuropathies and potentially broader neurodegenerative disorders

Abbreviations

AAV: adeno associated virus, AD: Alzheimer’s disease, ALS: amyotrophic lateral sclerosis, AxPN: axonal peripheral neuropathy, BTZ: bortezomib, CMT1A/1B/2D: Charcot–Marie–Tooth disease type 1A/1B/2D, dnSarm1: dominant negative SARM1, DNA: desoxyribonucleinacid, dSarm: Drosophila sterile alpha and TIR motif–containing protein, EAE: experimental autoimmune encephalomyelitis, HFD: high fat diet, HSP: hereditary spastic paraplegia, IENFD: intraepidermal nerve fiber density, KO: knockout, Nmnat: nicotinamide mononucleotide adenylyltransferase, NMNAT1/2/3: nicotinamide mononucleotide adenylyltransferase isoform 1/2/3, PN: peripheral neuropathy, RNAi: ribonucleic acid interference, Sarm1: sterile alpha and TIR motif–containing protein 1, SCG: superior cervical ganglion, SMA: spinal muscular atrophy, SNAP: sensory nerve action potential, STZ: streptozotocin, Tau: microtubule associated protein tau, Ube4b: ubiquitination factor E4B, VCR: vincristine, WldS: Wallerian degeneration slow protein

References

1. Ropper AH, Samuels MA, Klein JP. Adams and Victor’s Principles of Neurology, 10th ed. McGraw Hill Medical; www.AccessMedicine.com.
2. Coleman MP, et al. Annu Rev Neurosci. 2010;33:245–267.
3. Coleman MP, et al. Nat Rev Neurosci. 2020;21:183–196.
4. Conforti L, et al. Nat Rev Neurosci. 2014;15:394–409.
5. Hill CS, et al. Neural Regen Res. 2020;15:604–605.
6. Gilley J, et al. J Neurosci. 2013;33:9902–9915.
7. Milde S, et al. Neurobiol Aging. 2014;35:279–285.
8. Dingwall CB, et al. J Clin Invest. 2022;132:e154922.
9. Osterloh JM, et al. Science. 2012;337:481–484.
10. Gilley J, et al. Elife. 2021;10:e70964.
11. Geisler S, et al. Brain. 2016;139:936–952.
12. Turkiew E, et al. J Peripher Nerv Syst. 2017;22:90–99.
13. Geisler S, et al. JCI Insight. 2019;4:e129920.
14. Cheng Y, et al. Diabetes. 2019;68:131–142.

Introduction

• Nerve biopsies have a long tradition beginning at the start of the last century, with procedures performed since the middle of the last century. Although light microscopy may seem outdated, there are still new techniques, and nerve biopsies still play an important role in research. There are possibilities to investigate the fibers by new techniques that may hopefully lead to better understanding.
• Diagnostic approaches to peripheral neuropathy include clinical evaluation, neurophysiology, blood markers, imaging (ultrasound, MRI), and nerve biopsy.

Debate on the need of nerve biopsies: Do we still need nerve biopsies?

• Increasing role of serum markers: Autoantibodies, markers of axonal/myelin damage
• Diagnosis of most autoimmune neuropathies is based on clinical and electrophysiological findings
• Mostly sensory nerves used for biopsies ≥ limited value in motor neuropathies
• Invasive, time-consuming

Nerve biopsies in unclear cases

• In unclear cases, nerve biopsy can help—studies show about 27.8% of patients without any working diagnosis benefited, and in another study 14% saw a diagnostic change^1,2.
• Pain is reported post-biopsy, although frequency varies between studies. Nerve biopsy can detect vasculitis, sometimes found unexpectedly in cases not previously suspected².

Case Study

• A 54-year-old female patient presented with distal symmetric, sensory motor, slowly progressive neuropathy for 8 months. She had similar symptoms before.
• Examination showed absent reflexes, mild toe extensor weakness, symmetric hypesthesia of feet and lower legs.
• CSF was normal; nerve conduction studies showed neuropathy. Nerve biopsy showed signs of loss and degeneration, with inflammatory infiltrates.
• Immunohistochemistry confirmed inflammation. Diagnosis: Vasculitis. She was treated accordingly.

When to perform nerve biopsies

• No fixed rules exist on when to perform nerve biopsy; decisions are individual. One flowchart suggested biopsy when disease is severe, progressive, and asymmetric.³
• Muscle biopsy can be done to increase sensitivity. Ultrasound can guide selection of biopsy site⁴.
• CSF and nerve MRI can also help differentiate vasculitis from mimics⁵.
• Findings are not always specific but can help differentiate chronic versus acute pathology⁶.

Nerve biopsy in the EAN/PNS guidelines of CIDP⁷

• Suspected CIDP but not confirmed with clinical, laboratory, imaging and electrodiagnostic studies
• Suspected CIDP but no response to treatment (alternative diagnosis?)
• But only when: experienced facilities (surgeons, laboratory, examiners) are available + symptoms severe enough to justify side effects of a biopsy
• Patients need to be informed about the low accuracy of nerve biopsy.

What did we learn from nerve biopsies in the past?^8-9

Historically, nerve biopsies provided key knowledge in CIDP and autoimmune neuropathies in the 1980s and 1990s. Biopsy materials helped identify antibodies against paranodal proteins, including contactin-1.⁸

• Contactin-1 antibody patients showed preserved myelin on MRI but abnormal nodes due to direct attack on motor terminals. Lucky to have biopsy tissue from patients which showed nodal damage in high-resolution microscopy.⁸
• Other studies from Japan also showed nodal destruction. Research from preserved biopsy tissues provided insights into pathophysiology not visible through routine techniques⁹.

Future perspectives of peripheral neuropathology¹⁰

• Decreasing number of nerve biopsies
• Good storage of biopsy material (biobanking)
• Broad consent for use in research
• Alternative tissue: skin biopsies?
• New techniques: Spatial transcriptomics → tissue needed, Artificial intelligence for analysis and interpretation of tissue sections in the clinical context, Super-resolution microscopy → investigate nerve biopsies on a molecular level

Ultrastructural anatomy of the nodes of Ranvier by STED microscopy¹¹

• Analysis or 12 nodal/paranodal glial and axonal proteins in mouse teased fibers
• Information on the ultrastructure of nodes of Ranvier, organization and periodicity of proteins

dSTORM imaging of nodes of Ranvier of patients with neuropathies¹²

• 190 nm periodic arrangement of cytoskeletal and axoglial adhesion molecules in human nerves
• Increase of periodicity in patients with peripheral neuropathies (axonal & demyelinating)
• Loss of proteins of the axoglial complex & detachment of the axoglial complex from spectrin-2

dSTORM imaging of nodes of Ranvier of a patient with anti-pan-neurofascin autoantibodies¹³

• 14% of the nodes severely damaged (conventional fluorescence microscopy)
• Decreased density of NF155, NF186 and Caspr1 even in normal-looking nodes
• Preserved colocalization, normal density of Nav
• Beta-IV-spectrin only altered in severely damaged nodes

Summary: How can nerve/skin biopsies play a role in the future?

• Skin biopsies used for longitudinal assessment but limited in evaluating myelinated fibers. Detection of nodal structures is hard due to few fibers. Requires multiple sections to get enough data. New techniques like spatial transcriptomics, proteomics, super-resolution microscopy are now used in research.
• Skin biopsies may be a future alternative due to ability to repeat and easier access. Essential to store nerve biopsy tissue safely with patient consent in biobanks for future use.

Abbreviations

AINCAT: Adjusted Inflammatory Neuropathy Cause and Treatment score, Caspr1: Contactin-associated protein 1, CIDP: Chronic Inflammatory Demyelinating Polyneuropathy, CSF: Cerebrospinal Fluid, dSTORM: Direct Stochastic Optical Reconstruction Microscopy, EAN: European Academy of Neurology, INC: Inflammatory Neuropathy Consortium, INCAT: Inflammatory Neuropathy Cause and Treatment score, MRI: Magnetic Resonance Imaging, Nav: Voltage-gated Sodium Channel (Nav family), NF155: Neurofascin155, NF186: Neurofascin186, PNS: Peripheral Nervous System, STED: Stimulated Emission Depletion (superresolution microscopy)

References

1. Lee H, et al. J Clin Neurosci. 2023;109:1–7.
2. Gabriel CM, et al. J Neurol Neurosurg Psychiatry. 2000;69:442–446.
3. Nathani N, et al. Muscle Nerve. 2021;64:22–30.
4. Costa AF, et al. Ann Rheum Dis. 2024;83:155–163.
5. Padilha IG, et al. Neuroimaging Clin N Am. 2024;34:45–60.
6. Therapath Neuropathology. Nerve pathology overview. https://therapath.com/nerve-pathology-overview/. Accessed February 2026.
7. Van den Bergh PYK, et al. J Peripher Nerv Syst. 2021;26:242–268. / Eur J Neurol. 2021;28:3556–3583.
8. Doppler K, et al. Brain. 2016;139:282–295.
9. Koike H, et al. J Neurol Neurosurg Psychiatry. 2017;88:1074–1084.
10. Ono K, et al. Neuropathol Appl Neurobiol. 2024;50:e12967.
11. D’Este E, et al. Proc Natl Acad Sci U S A. 2016;113:132–137.
12. Appeltshauser L, et al. Neurobiol Dis. 2023;185:105599.
13. Da Cruz Neris R, et al. Front Immunol. 2025;16:152345.

Objective

To explore molecular mechanisms underlying peripheral nerve repair, particularly focusing on:

• Schwann cell responses to nerve injury
• The role of Neuregulin-1 (Nrg1) signaling
• Mitochondrial metabolic adaptations
• Leptin receptor signaling in regeneration
• Translational implications for hereditary and acquired neuropathies (e.g., CMT1A, CMT1B, obesity-related neuropathy)

Schwann Cell Repair Program in Acute Injury^1-2

After acute nerve injury, Schwann cells undergo adaptive reprogramming into a "repair Schwann cell" state, enabling nerve regeneration.¹

• These repair Schwann cells break down myelin breakdown (via autophagy) and facilitate axonal regrowth via bands of Büngner.¹
• Unlike development, where axons drive Schwann cell maturation, injury triggers glial-derived neuregulin-1 (NRG1) signaling, essential for repair. ²

Dysregulated Repair in Neuropathies^3-4

In CMT1A (demyelinating neuropathy), Schwann cells exhibit a chronic, maladaptive repair response, leading to onion bulb formations (pathological hallmark).³

• NRG1 signaling, beneficial in acute injury, becomes pathogenic in CMT1A, driving supernumerary Schwann cell survival and concentric remodeling.³
• CMT1B (late-onset demyelination) shows delayed repair activation; NRG1 loss worsens pathology, suggesting context-dependent roles.⁴
• Nrg1 signaling correlates with disease progression in CMT1A and CMT1B mouse models and is elevated in human biopsies.⁴

Metabolic Demands of Repair^3-4

• Schwann cells increase mitochondrial activity and oxidative phosphorylation during repair, fueled by fatty acids from myelin breakdown.³
• Leptin receptor signaling (induced post-injury) regulates mitochondrial expansion and energy metabolism.⁴
• Leptin receptor knockout impairs axon regeneration and remyelination after injury.⁴

Therapeutic Implications³

• Leptin treatment post-injury improved electrophysiological and histological outcomes in mice.
• In obesity-related neuropathy, hyperleptinemia exacerbates pathology; leptin receptor ablation in Schwann cells reduced neuropathic symptoms.

Conclusion

• The Schwann cell repair program is optimized for transient injury but becomes harmful when chronically activated (e.g., in CMT).
• Dual role—promotes regeneration in injury but drives pathology in demyelinating neuropathies.
• Targeting intrinsic (Nrg1) and extrinsic (leptin receptor) pathways offers therapeutic potential, but strategies must differentiate between acute injury and chronic disease states.
• Leptin links adipose tissue to Schwann cell metabolism, offering a therapeutic target for neuropathies (e.g., obesity-related or inherited).
• Interventions must balance repair activation (to aid remyelination) versus suppression (to prevent chronic damage).

Abbreviations

CMT: Charcot Marie Tooth disease, CMT1A: Charcot Marie Tooth disease type 1A, CMT1B: Charcot Marie Tooth disease type 1B, Nrg1 / NRG1: Neuregulin 1

References

1. Stassart RM, et al. Glia. 2018;66:151–167.
2. Stassart RM, Fledrich R, et al. Nat Neurosci. 2013;16:889–897.
3. Fledrich R, Stassart RM, et al. Nat Med. 2014;20:1055–1061.
4. Fledrich R, Akkermann D, et al. Nat Commun. 2019;10:1–15.

Objective

• To highlight the need for continued progress in CIDP management, emphasizing that despite over 25 years of recognition, not much has been done and more needs to be done, with a clear distinction between the goals of induction treatment and remission maintenance.

Treatment approaches

• CIDP treatment has evolved from steroid-responsive therapy in 1958 to IVIG and plasma exchange in the 1980s, SCIG in 2018, and is now progressing toward targeted inhibitors of FcRn, complement, and BTK by 2024.¹
• Distinguished between induction treatment (aimed at achieving initial improvement) and maintenance treatment (focused on sustaining remission).²

Clinical Trial Insights

• Analysis of IVIg vs placebo showed 55% improvement with IVIG vs 23% with placebo. Risk Ratio: 2.40 (CI: 1.72–3.35). Comparison of IVIG vs prednisolone showed no significant difference (Risk Ratio: 0.91)³.
• In the ICE trial (INCAT-DS), 30 IVIG responders were identified, with most showing improvement within 6 weeks^4,5.
• Time to Remission (Dexamethasone vs Prednisolone): Dexamethasone: Median 20 weeks to remission. Prednisolone: Median 39 weeks. Improvement with steroids is slower compared to IVIG in the ICE trial⁶.
• Steroid Remission Outcomes (PREDICT Study): trial with 40 patients comparing dexamethasone and prednisolone. Remission at 1 year: ~40%. Remission at 4.5 years: 26%^6,7.
• The OPTIC trial evaluated IVIG plus intravenous methylprednisolone (IVMP) vs. IVIG alone in untreated CIDP patients, finding no significant difference in 1-year remission rates but showing greater short-term functional improvements with combination therapy; however, safety concerns (thrombotic events) led to early termination⁸.
• Trial focused on induction treatment strategies in CIDP: Combination of IVIG and steroids may offer faster improvement (IVIG) and potentially longer remissions (steroids) but poses safety concerns like thrombosis; the ICE 2008 trial showed IVIG reduces relapse by 40%, yet 50% of placebo patients remained relapse-free for 6 months, raising questions on treatment duration and patient selection⁴.
• In CIDP maintenance, uncertainties persist around overtreatment (seen in 20–40% of cases), optimal timing to taper or stop treatment, and how reliably and rapidly patients can restabilize—though most restabilize fully and quickly. In the IVIG withdrawal, 60 stable patients were randomized; placebo led to 60% relapse versus 40% in the IVIG group, with only 28% in remission after one year, highlighting the challenge of discontinuing therapy and the need for biomarkers to guide maintenance⁹.

Abbreviations

BTK: Bruton's Tyrosine Kinase, CI: Confidence Interval, CIDP: Chronic Inflammatory Demyelinating Polyneuropathy, FcRn: Neonatal Fc Receptor, ICE: Intravenous Immune Globulin for the Treatment of CIDP Efficacy Trial, INCATDS: Inflammatory Neuropathy Cause and Treatment – Disability Score, IV: Intravenous, IVIG: Intravenous Immunoglobulin, IVMP: Intravenous Methylprednisolone, SCIG: Subcutaneous Immunoglobulin

References

1. Mair MJ, et al. J Neurol Neurosurg Psychiatry. 2025;96.
2. Van den Bergh PYK, et al. J Peripher Nerv Syst. 2021;26:242–268 / Eur J Neurol. 2021;28:3556–3583.
3. Eftimov F, et al. Cochrane Database Syst Rev. 2013;2013:CD006459.
4. Hughes RAC, et al. Lancet Neurol. 2008;7:136–144.
5. Latov N, et al. Arch Neurol. 2010;67:1036–1041.
6. van Schaik IN, et al. Lancet Neurol. 2012;11:493–502.
7. Eftimov F, et al. Neurology. 2012;79:188–193.
8. Nobile-Orazio E, et al. Lancet Neurol. 2012;11:493–502.
9. Adrichem ME, et al. Brain. 2022;145:2345–2356.

Agenda

• To summarize recently completed and ongoing trials in CIDP
• To recognize challenges in CIDP trial design
• To recognize challenges for future CIDP trial logistics

The pre-ICE¹ age: Lessons learned

• Randomized placebo-controlled trials are needed
• To perform an adequately power prospective RCT, multicenter multinational collaboration is needed
• With recognition of CIDP as a syndrome, a thoughtful approach to inclusion criteria is needed

The post-ICE¹age

Placebo response rates⁹: Measuring improvement vs relapse.

Two clinical trial scenarios:

• First: Off treatment randomized to study drug or placebo measuring improvement
• Second: On treatment randomized to study drug or placebo measuring relapse

Clinical trials that measure improvement seem less prone to placebo effect than those that measure relapse or worsening.

Summary of post-ICE age trials^2-7

Dependency phase and Adjudication panel

Three studies with trial data show improvements in patients, though some improvements are small and not widely included.

• The question is where the adjudication panel fits within the dependency phase. Looking at placebo effects in various trials, around 37 to 46% of patients in randomized trials did not get worse, even with the dependency phase attempting to sort out patients.⁴
• In comparison, trials without adjudication panels had even higher percentages of patients not worsening, between 60 and 70%.⁴
• The dependency phase with adjudication panels removed only about 11% of patients during withdrawal because they did not get worse.⁴
• In one study, only 2% failed the dependency phase and relapsed. This raises questions about the value of the dependency phase, considering the effort, cost, and anxiety it causes clinicians and patients.⁷
• Despite these challenges, some trials that included advanced adjudication were successful.⁷

Lessons learned so far

• Not very good at assessing disease activity⁴
• Although dependency phases and adjudication panels are not perfect, recent trials without dependency confirmation have had very high placebo response results^2,4
• With a parallel group withdrawal design, the margin to detect benefit is narrow⁷

Trial designs of the following trials were presented:

INVGOR Study – Open label, sequential dose cohort¹⁰

• Drug: NVG-2099, a recombinant Fc fragment immunomodulator
• Cohorts: Three cohorts with different dosing and patient experience levels
• Duration: Screening (6 weeks), Treatment (14 weeks), Follow-up (6 weeks)

CASCA Study – Open label, single group assignment¹¹

• Drug: TAK-411, Hypersialylated Immunoglobulin G
• Dosing: TAK-411 400 mg/kg IV, with potential repeat after 3 weeks
• Outcome: Stability in INCAT at week 24

TAK-881 Study – Open label¹²

• Drug: TAK-881, next-generation IgG + hyaluronidase
• Dosing and Phases: Includes ramp-up and treatment epochs with fSCIG and TAK-881
• Outcome: Primary focus on total IgG levels; secondary on relapse rate and grip strength

IMVT-1401-2401 Trial – Multistage, double-blinded, placebo-controlled withdrawal¹³

• Drug: Batoclimab, an FcRn antagonist
• Outcome: Relapse rate in Period 2

CAPTIVATE Trial – Randomized withdrawal, double-blind, placebo-controlled¹⁴

• Drug: DNTH-103, an aC1s inhibitor
• Outcome: Response improvement in Part A, efficacy (time to relapse) in Part B

ARISE Trial – Withdrawal¹⁵

• Drug: Nipocalimab, an FcRn antagonist
• Phases: Includes stages A and B with open-label and randomized components
• Outcome: Percent responders and time to relapse

VITALIZE Study – Randomized, double-blinded, controlled^{16, 17}

• Drug: Riliprubart, a C1s inhibitorRiliprubart, a C1s inhibitor
• Outcome: Percent of patients improving (aINCAT) at week 24

EMVIGORATE Study – Randomized, double-blinded, controlled¹⁸

• Drug: Empasiprubart, a C2 inhibitor
• Outcome: Percent of patients improving (aINCAT) at week 24

Final thoughts & Summary

• Accurate diagnosis and measuring treatment affect are ongoing challenges for clinical trials
• Optimization of adjudication panels and dependency analysis may help
• Designs that shift toward measuring response rather than relapse may help
• Biomarkers or clinical tools to more reliably detect disease activity (or no evidence of disease activity) are needed
• Finding patients and investigators to sustain trial growth will be a challenge over upcoming years

Abbreviations

aINCAT: Adjusted Inflammatory Neuropathy Cause and Treatment score, CIDP: Chronic Inflammatory Demyelinating Polyneuropathy, C1s: Complement component 1s, C2: Complement component 2, Fc: Fragment crystallizable region, FcRn: Neonatal Fc receptor, fSCIG: Facilitated Subcutaneous Immunoglobulin, GBS: Guillain-Barré Syndrome, ICE: Intravenous Immune Globulin in CIDP Efficacy trial, IG: Immunoglobulin, INCAT: Inflammatory Neuropathy Cause and Treatment score, IV: Intravenous, IVIG: Intravenous Immunoglobulin, RCT: Randomized Controlled Trial, SCIG: Subcutaneous Immunoglobulin

References

1. Hughes RAC, et al. Lancet Neurol. 2008;7:136–144.
2. Van Schaik IN, et al. Lancet Neurol. 2018;17:405–415.
3. Hughes RAC, et al. Lancet Neurol. 2018;17:374–383.
4. Cornblath DR, et al. Brain. 2022;145:2169–2180.
5. Bril V, et al. J Peripher Nerv Syst. 2023;28:123–134.
6. Querol L, et al. J Neurol Neurosurg Psychiatry. 2024;95:450–458.
7. Allen JA, et al. Lancet Neurol. 2024;23:512–523.
8. Nobile-Orazio E. Brain. 2024;147:284–296.
9. Lewis RA, et al. J Peripher Nerv Syst. 2020;25:63–72.
10. ClinicalTrials.gov. NCT07027111. https://clinicaltrials.gov/NCT07027111 (accessed May 2025).
11. ClinicalTrials.gov. NCT06798012. https://clinicaltrials.gov/NCT06798012 (accessed May 2025).
12. ClinicalTrials.gov. NCT06747351. https://clinicaltrials.gov/NCT06747351 (accessed May 2025).
13. ClinicalTrials.gov. NCT05581199. https://clinicaltrials.gov/NCT05581199 (accessed May 2025).
14. ClinicalTrials.gov. NCT06858579. https://clinicaltrials.gov/NCT06858579 (accessed May 2025).
15. ClinicalTrials.gov. NCT05327114. https://clinicaltrials.gov/NCT05327114 (accessed May 2025).
16. ClinicalTrials.gov. NCT06290141. https://clinicaltrials.gov/NCT06290141 (accessed May 2025).
17. ClinicalTrials.gov. NCT06290128. https://clinicaltrials.gov/NCT06290128 (accessed May 2025).
18. ClinicalTrials.gov. NCT06920004. https://clinicaltrials.gov/NCT06920004 (accessed May 2025).

Background

• The terms Response, Refractory, Relapse, and Remission are utilized differently by different stakeholders in CIDP—patients, clinicians, payers, and regulators—leading to confusion, miscommunication, and potential barriers to treatment access and evaluation of therapies.
• Over the past year, a leadership collaborative supported by the GBS/CIDP Foundation International has been working to build a common definition related to CIDP and conducting workshops¹. 
  • Key takeaways from patients’ workshops (n=16)
    • General feedback: Workshop participants were skeptical about the key clinical terms presented. Definitions should be reworked to better reflect patients' lived experiences.
    • Definition feedback
      • Response: Patients emphasized that clinicians need to be more attuned to both positive and negative changes they experience. They expressed frustration at having to convince their doctor that a change has occurred. Participants identified successful treatment as the ability to live independently.
      • Refractory: Patients don't want the word "refractory" to provide an excuse to give up.
      • Remission: The remission definition was problematic for CIDP participants. Some felt it meant a lack of flares or presence of disease while continuing treatment, while others described it as occurring after treatment was discontinued. Participants also noted that some people will have residuals for the rest of their lives.
      • Relapse: Distinguish relapse from flare. Clarify time or severity components.
• The goal was to standardize definition to improve communication and care.

Consensus workshop objectives and process overview¹

• The project team, representing the leadership collaborative, met in April to review all feedback from patient workshop.

• Objective

  • Reach consensus on how to employ definitions across patient care and clinical research

  

  • Develop a strategy for broad acceptance of these definitions across all key stakeholders
• Process overview
  • Used a modified approach to reach consensus. The steering committee reviewed relevant literature, drafted a definition, and revised it after discussion.
  • The larger group then reviewed and voted on the definition. Since consensus wasn’t reached initially, panel members discussed key points, followed by group discussions and repeated voting until consensus was achieved.

Consensus definitions & considerations

• Participants voted on a 1–9 scale: 1–3 meant strong disagreement, 4–6 meant partial agreement, and 7–9 meant agreement with most of the definition. A score of 7 or higher was required for agreement, and consensus needed 80% of voting members to score 7 or above.

Consensus level of agreements

• Immune Neuropathy - No Evidence of Disease Activity (IN-NEDA): Consensus (7 or above): 95% agreement (n=20); Revisions: 1

  • Definition components: 1) Patient Global Impression of Change (PGIC); 2): Disability metric defined as a I-RODS² 4-point (centile) change or INCAT³ 1-point change; 3) Impairment metric: Defined as a change in grip strength (8 kPa or 10% averaged change) and MRC 60 sum score (2 points).
  • Proposed IN-NEDA classifications:
    • IN-EDA: Patient perception of change AND a change in disability, impairment, or both. There must be no other condition that better explains change in disability and impairment.
    • IN-NEDA 1: No patient perception of change AND either no decline in Disability OR no decline in Impairment for a duration of 6 months or more.
    • IN-NEDA 2: No patient perception of change AND no decline in Disability AND no decline in Impairment components for a duration of 6 months or more.
  • Recommendation for clinical trials: target NEDA-2 status

   

• Relapse: Consensus: 100% agreement (n=20); Revisions: 1

  • Relapse: Patient perception of change AND decline in disability AND impairment fulfilling IN-EDA definition following a period of stability or improvement, in the absence of a condition that better explains change in function and impairment, over a period of 12 weeks or less.
  • Possible Relapse: Patient perception of change AND decline in disability OR impairment fulfilling IN-NEDA1 definition following a period of stability or improvement, in the absence of a condition that better explains change in function and impairment, over a period of 12 weeks or less.

   

• Response: Minimal / Partial / Optimal

  • Minimal response: Patient perception of improvement AND a minimum change on at least one outcome measure suggesting at least early partial response to a specific treatment, assessed within 12 weeks.
    • Improvement = CIDP Guideline recommendations, minimum range
    • INCAT 1, I-RODS centile 4, MRC 2, GS 8 kPa
    • Consensus: 90% agreement (n=20); Revisions: 1
  • Partial response: Patient perception of improvement AND a change on at least one outcome measure within 24 weeks.
    • Improvement = CIDP Guideline recommendations, maximum range
    • INCAT 1, I-RODS centile 8 (or reaching maximum), MRC 4, GS 14 kP
    • Consensus: 100% agreement (n=19); Revisions: 1
  • Optimal response: Recovery as close as possible to the pre-CIDP functional status excluding potential residuals and fulfilling IN-NEDA 2 criteria sustained for at least 6 months.
    • Consensus: 100% agreement (n=19); Revisions: 2

   

• Refractory: Consensus: 90% agreement (n=20); Revisions: 1

  • Absence of minimal response OR relapse leading to/requiring treatment discontinuation after adequate dosing and duration of the administered therapy.

   

• Remission: Consensus: 100% agreement (n=19); Revisions: 1

  • No signs of disease activity (IN-NEDA 2) with or without residuals without immunosuppressive/immunomodulatory therapy for at least 12 months.

   

• Residuals: Consensus: 95% agreement (n=19); Revisions: 1
  • Signs, symptoms, or impairments related to CIDP that persist despite adequate immunosuppressive/immunomodulatory therapies and are present in a patient who otherwise has no evidence of disease activity (IN-NEDA).

Conclusion

• Patients, clinicians, researchers, regulatory agencies, industry, and payers need standardized key terms for use in clinical practice and clinical trials.
• The consensus-driven definitional blueprint aims to improve management of CIDP, quality of clinical trials, and patient experience.
• The results, along with additional details on the group's deliberations, will be addressed in a forthcoming paper.
  • More work is needed to guide adoption of these consensus-derived terms in practice & research
  • These terms will also be incorporated into a visual patient journey map with lay language to improve comprehension and awareness of the definitions
• Unmet needs
  • The lack of biomarkers is a critical gap in defining key clinical terms in CIDP
  • The definitions will continue to evolve as new biomarkers and treatments become available

Abbreviations

CIDP: Chronic Inflammatory Demyelinating Polyneuropathy, GBS: Guillain-Barré Syndrome, GS: Grip Strength, IRODS: Inflammatory Rasch-Built Overall Disability Scale, INCAT: Inflammatory Neuropathy Cause and Treatment Disability Score, INEDA: Immune Neuropathy – Evidence of Disease Activity, INNEDA 1/2: Immune Neuropathy – No Evidence of Disease Activity Category ½, kPa: Kilopascal, MRC: Medical Research Council Sum Score, PGIC: Patient Global Impression of Change

References

1. GBS|CIDP Foundation International. Leadership Collaborative. https://www.gbs-cidp.org/gbscidp-leadership-collaborative/ (accessed Sept 2025).
2. van Nes SI, et al. Neurology. 2011;76:337–345.
3. Breiner A, et al. Muscle Nerve. 2014;49:246–252.

Agenda & Objectives

• Reflect on the day-to-day challenges patients face, and the unmet needs with current standard treatment approaches
• Explore emerging innovative and targeted treatment approaches with potential to improve patient outcomes 

1) Exploring disease burden and unmet treatment needs in CIDP

• Patients with CIDP face significant burden: impaired quality of life (~60% issues with activity^1,2, 27% anxiety/depression²), disability (~10% wheelchair³, ~60% mobility problems^1,2), neuropathic pain (20%), residual pain (52%), and fatigue (77%) post-treatment^4,5.
• Diagnosis delays median 9 months, with ~20% underdiagnosis6, inconsistent diagnostic criteria use7, neurophysiology misinterpretation⁶, and 32–47% overdiagnosis^6,8.
• Unmet needs include treatment inconvenience^9,10, side effects^10-12, limited response (~30% complete response)¹³, residual disability¹⁴, persistent symptoms¹⁰, and absenteeism¹⁵.
• Monitoring challenges involve assessing disease activity¹⁶, treatment decisions¹⁶, and relapse prediction^16,17.

Conclusion: here is a need to improve diagnosis, treatment, and monitoring due to misdiagnosis, morbidity, disability, pain, fatigue, and variable responses.

Rationale of existing immunotherapies:

• IVIG has a 70% response rate with side effects like headache, fever, hypertension, and rare thromboembolism; SCIG increases patient autonomy¹⁸.
  • Corticosteroids are effective but take longer to improve and relapse, with more side effects than IVIG¹⁸.
  • PLEX offers short-term improvement but risks rapid deterioration, requires central access, hospital stays, and carries risk of fatal adverse events¹⁸.
  • Existing immunotherapies lack strong efficacy evidence due to significant trial design limitations¹⁸.

2) Evaluating emerging targeted therapies for CIDP

• The EAN/PNS guidelines provide a structured approach to CIDP treatment, starting with IVIG and corticosteroids, and considering diagnosis reassessment before escalating to off-label immunotherapies¹⁹.
• B-cell depleting therapy with rituximab showed ~60% benefit in case series²⁰, but clinical trials (Japanese²¹ and Italian²²) failed to meet primary endpoints. Complement inhibitors are under investigation: CAPTIVATE trial (C1s), an ongoing C2 inhibitor trial, and a Phase 2 open-label study showing high stability/improvement rates across standard, refractory, and naive cohorts²³. Phase 3 trials (MOBILIZE²⁴/VITALIZE²⁵) are testing similar endpoints.
• FcRn antagonists (Efgartigimod²⁶, Nipocalimab²⁸, Rozanolixizumab²⁷) block IgG recycling; ADHERE showed 66-70% response and a 61% relapse risk reduction²⁶, while the Rozanolixizumab trial was negative²⁷. Key issues remain in patient selection and transition strategies^26,28. 

Patient profile: Difficult to treat

• A 76-year-old man with rapid proximal and distal weakness, absent leg reflexes, normal sensory function, elevated CSF protein, and abnormal motor studies was diagnosed with CIDP.
• Initial IVIG treatment improved strength temporarily, but deterioration followed.
• Repeat neurophysiology confirmed typical CIDP features. Plasma exchange and steroids led to significant improvement and near-normal function.
• The case highlights diagnostic challenges, treatment adjustments, limited biomarkers, and the use of patient outcomes and objective measures to guide therapy.

Summary

• CIDP patients face significant disease burden and disability, with delays and inaccuracies in diagnosis impacting care. Current immunotherapies have limitations including side effects and incomplete efficacy.
• There is an unmet need for more effective, targeted, and safer treatments. Improved monitoring tools and standardized diagnostic criteria are essential to optimize treatment and manage progression.
• Emerging targeted therapies and patient-centric clinical trials offer promise. Diagnosis is challenging without definitive biomarkers, requiring individualized treatment and clinical judgment to avoid over- or under-treatment.

Abbreviations 

CIDP: Chronic Inflammatory Demyelinating Polyneuropathy, CSF: Cerebrospinal Fluid, EAN: European Academy of Neurology, FcRn: Neonatal Fc Receptor, IgG: Immunoglobulin G, IVIG: Intravenous Immunoglobulin, PNS: Peripheral Nerve Society, PLEX: Plasma Exchange, SCIG: Subcutaneous Immunoglobulin 

References 

1. Mahdi-Rogers M, et al. Eur J Neurol. 2014;21:34–39
2. Bus SRM, et al. J Neurol. 2022;269:945–955
3. Hafsteinsdottir B Olafsson E. Eur J Neurol. 2016;75:263–268
4. Bjelika B, et al. J Peripher Nerv Syst. 2019;24:180–186
5. Busnotchen C, et al. J Peripher Nerv Syst. 2019;24:253–259
6. Broers M, et al. Eur J Neurol. 2021;28:2065–2072
7. Gelinas D, et al. J Neurol Sci. 2019;397:84–91
8. Allen JA, Neurol Ther. 2020;9:43–54
9. Watkin JM, et al. J Neurosci Nurs. 2019;51(4):198-203
10. Querol L, et al. J Neurol. 2020;267:3706–3716
11. Dalakas M. Pharmacol Ther. 2004;102:177–193
12. Choi K, et al. Front Neurol. 2024;15:1456835
13. Rajabally YA, et al. Eur J Neurol. 2024;31:e16399
14. Allen JA, et al. Lancet Neurol. 2024;23:1013–1024
15. Allen JA, et al. Adv Ther. 2021;38:316–328
16. Fisse AL, et al. Neurol Res Pract. 2020;2:42
17. Bus SRM, et al. J Neurol. 2022;269:945–955
18. Mair D, et al. J Neurol Neurosurg Psychiatry. 2025;96:38-46
19. Van den Bergh PYK, et al. J Peripher Nerv Syst. 2021;26:242–268
20. Chaganti S, et al. Neuromuscul Disord. 2022;32:621–7
21. Shimizu S, et al. JMIR Res Protoc. 2020;9(4):e17117
22. Nobile-Orazio E, et al. Brain. 2025;148:11 12–21
23. Dianthus Therapeutics. Corporate presentation. March 2025
24. https://clinicaltrials.gov/study/NCT06290128 (accessed May 2025)
25. https://clinicaltrials.gov/study/NCT06290141 (accessed May 2025)
26. Allen JA, et al. Lancet Neurol. 2024;23:1013–24
27. Querol L, et al. J Neurol Neurosurg Psychiatry. 2024;95:845–54
28. Levine T, Muley S. J Neurol Sci 2024 468(10):123313 

Agenda & Objectives

• To understand the evidence supporting CIDP management to enhance clinical knowledge and practice
• To explore strategies for integrating evidence-based practices into clinical decision-making to help improve patient outcomes
• To learn from case studies and expert insights to navigate common challenges in CIDP management, with the goal of delivering improved patient care and achieving better clinical outcomes 

Integrating evidence and experience into CIDP care

Case study 1: A 56-year-old from a remote area in British Columbia experiences progressive motor and sensory symptoms.

• Diagnostic tests showed demyelination and conduction block, indicating typical CIDP.
• A survey was conducted and most of the audience selects IVIG as the initial treatment, but the patient was treated with dexamethasone due to geographic and logistic constraints.
• He showed significant improvement and returns to work

Therapies recommended by the EAN/PNS 2021 guidelines for the treatment of CIDP:Three first-line CIDP treatments: plasma exchange, corticosteroids, and IVIG were discussed

• Plasma Exchange¹: Effective but less commonly used due to access and side effects.
• Five exchanges over 2 weeks; Central line often required for induction therapy; Maintenance therapy tailored to patient, peripheral lines if possible
• Corticosteroids¹: Several regimens exist. Real-world evidence shows efficacy, particularly with pulse regimes, though not recommended for motor-predominant CIDP.
• Daily prednisone or prednisolone 1-1.5 mg/kg, at least 6 weeks, then slow taper over ≥8 months
• Monthly oral pulsed dexamethasone 40 mg daily, 4 days per month for 6 months
• Monthly IV pulsed methylprednisolone 500 mg daily, 4 days, then 1-2g/month thereafter for 6 months
• IVIG²: Strong evidence from randomized trials, with rare serious side effects.
• Panelists from the survey weigh factors such as cost, logistics, remission potential, and patient preferences when choosing a treatment.
• Clinicians stress individualized decisions based on efficacy, access, patient preference, and side effect profiles.

Case study 2: A 60-year-old healthcare worker with mild to moderate CIDP and a history of osteopenia prefers avoiding corticosteroids. She was started on IVIG, improved significantly by 4 months, and returned to work. 

• Ongoing Treatment Discussion: A range of treatment continuation strategies were debated
• Options include stopping IVIG, tapering, continuing for a fixed duration (e.g., one year), or ongoing treatment to prevent relapse.
• Audience responses from the survey were mixed, reflecting diverse clinical practices. 

IVIG for longer-term treatment of CIDP:

ICE Study 2008, maintained response to IVIG over 6 and 12 months³

When to stop first-line treatment: 80% response rate to IVIG at 18 weeks (based on knowledge and clinical experience of speaker). Good practice point: if the first-line treatment is effective, continuation should be considered until the maximum benefit has been achieved1.

Poll panel preferences: One panelist prefers immediate cessation of IVIG with the option to restart quickly if needed. Others favor a fast taper or interval extension to reduce relapse anxiety. Emphasis is placed on managing patient expectations early, clarifying that CIDP treatment is not necessarily indefinite.

Case study 3: A 40-year-old male started with pulse methylprednisolone but switched to IVIG due to psychological side effects and lack of improvement. Responded well to IVIG (100g every 5 weeks) but disliked the impact on work and migraines. Switched to facilitated SCIG (fSCIG), self-administered every 4 weeks (80g/840ml), which he preferred. Patient reported greater flexibility with fSCIG and fewer peak-related side effects, though it caused abdominal swelling and mild skin reactions.

fSCIG vs conventional SCIG:

• Conventional SCIG: Lower bioavailability (~2/3 absorption), weekly smaller doses⁴.
• fSCIG: Uses hyaluronidase for faster, larger volume infusions, higher bioavailability⁴.

The ADVANCE-CIDP 1 trial⁵: A Phase 3, double-blind, placebo-controlled trial conducted at 54 sites in 21 countries. The trial evaluated fSCIG efficacy and safety in preventing CIDP relapse.

• fSCIG reduced relapse (9.7% vs. 31.4% placebo); some placebo patients may have been in remission.
• fSCIG was well-tolerated with mild local reactions and fewer headaches than IVIG.
• Most patients preferred fSCIG over IVIG.

The ADVANCE-CIDP 3 trial⁶: An open-label extension (33 months median): fSCIG safe and effective (4.5% annual relapse rate); 91% of eligible patients chose to continue the study.

Summary

• Clinical use of fSCIG: Best suited for high-dose patients wanting more autonomy/lifestyle flexibility. Training like SCIG with 3–4 nurse visits plus ongoing support.
• Switching is patient-specific: Some prefer hospital IVIG, others value independence.
• Monitoring Tools: Patients are followed clinically using PROs (R-ODS, fatigue, QoL, pain scores), objective tools (grip strength, MRC sum score, 10m walk, 9-hole peg test). EMG/NCS is used selectively for relapse assessment, pre-tapering, or diagnosis (not routinely).
• Relapse Management: If relapse occurs after remission, restart previous treatment, possibly without full induction if relapse is mild. CIDP relapses vary where some are progressive, others relapsing-remitting.
• Biomarkers: No reliable biomarkers to predict remission. Higher filament levels may indicate poorer outcomes but not routinely used.
• CIDP Variants & Treatment Decisions: Clinical features and variants influence treatment. For multifocal CIDP, evidence is conflicting. IVIG dependency more common. For pure motor CIDP, IVIG preferred. Steroids often tried first in less disabling multifocal cases.

Abbreviations 

CIDP: Chronic Inflammatory Demyelinating Polyneuropathy, EAN: European Academy of Neurology, EMG: Electromyography, fSCIG: Facilitated Subcutaneous Immunoglobulin, IV: Intravenous, IVIG: Intravenous Immunoglobulin, MRC: Medical Research Council, NCS: Nerve Conduction Study, PNS: Peripheral Nerve Society, PROs: Patient-Reported Outcomes, QoL: Quality of Life, R-ODS: Rasch-built Overall Disability Scale, SCIG: Subcutaneous Immunoglobulin 

References 

1. Van den Bergh PYK, et al., J Peripher Nerv Syst. 2021;26(3):242-268
2. Bus SRM, et al, Cochrane Database Syst Rev, 2024;2(2):CD001797
3. Hughes RAC, et al., Lancet Neurol, 2008;7:136-144
4. Hadden RDM, et al., touchREVIEWS in Neurology. 2025;21(1):63-72
5. Bril V, et al, J Peripher Nerv Syst, 2023;28(3):436-449
6. Hadden RDM, et al, J Peripher Nerv Syst, 2024;29(4):441-452

Agenda & Objectives

• The educational symposium provided a focused review of mechanisms of action of key CIDP therapies, highlighting the disease’s heterogeneity and need for better patient profiling to enable personalized, mechanism-based treatment and move beyond trial-and-error approaches.

1) Mechanisms of action of key therapies for CIDP

• CIDP is a heterogeneous disorder comprising diverse underlying mechanisms (autoantibodies, complement activation, T-cell Infiltration, B-cell, etc.) and clinical variants¹.
• While segmental demyelination is the pathological hallmark of CIDP, diagnosis relies primarily on electrophysiological testing, as biopsies are rarely performed¹.
• Absence of validated biomarkers hampers the ability to align patients with optimal therapies, leading to trial-&-error treatment approaches that may not reflect underlying disease drivers¹.
• Therapeutic landscape summary presented at the meeting:

Summary

• The current trial-and-error approach to treating CIDP underscores a critical need for precision medicine.
• Profiling patients on their predominant pathophysiology can enable more effective, individualized treatment.
• Leveraging emerging therapies and technologies to better phenotype patients (clinically and pathophysiologically) presents an opportunity to shift from one-size-fits-all strategies toward more personalized care.

2) Tailoring CIDP therapies: Optimizing care with patients in mind

Objective

• The symposium provided a practical clinical perspective on how to optimize CIDP treatment by minimizing trial-and-error approaches, individualizing therapy based on patient characteristics, and incorporating simple monitoring tools and emerging biomarkers.

Key highlights

• Getting it right first time:
• Accurate diagnosis is essential. Clinical history and examination remain the foundation of patient assessment. In a retrospective review study, Twenty-seven patients (47%) failed to meet minimal CIDP diagnostic standards¹⁸.
• Misdiagnosis of CIDP often results from misinterpretation of neurophysiology, particularly the use of the term “demyelination” instead of “conduction slowing,” which may also be seen in conditions like diabetes¹⁸.
• The use of red flags, such as TTR mutations or distal phenotypes, can help raise suspicion for alternative diagnosis²⁰.
• Sensory nerve biopsy is suggested in cases when two first-line treatments have failed, when tissue diagnosis is needed to confirm an alternative condition, or when it's unclear whether the patient has anti-MAG neuropathy or CIDP²⁰.
• Treatment strategies
• IVIG (89% respond after 3 doses)²¹, corticosteroids (Long term remission achieved following 1 or 2 courses of pulsed dexamethasone or an 8-month regimen of daily prednisolone²², and plasma exchange (various regimens) remain first-line therapies (personal choice).
• Sudden cessation vs. gradual tapering shows similar outcomes, but sudden cessation identifies non-responders faster (~17 vs. 40 weeks)²³. ~1/4th of patients achieve long-term remission without treatment; avoid indefinite therapy in non-responders²³.
• Early discontinuation in non-responders reduces unnecessary treatment costs (~£113,623 saved per patient)²³.
• Measuring response: Simple monitoring using patient feedback and 1–2 functional measures (e.g., grip strength, RODS score) is often sufficient to assess treatment response²⁴.
• Biomarker data (e.g., neurofilament light chain) is inconsistent²⁴; however, periaxin shows potential in distinguishing active vs. remission states²⁵.
• For refractory patients, alternative options include CD20 depletion^26,27,28,29(e.g., rituximab), mycophenolate, cyclophosphamide²⁰, and emerging immunotherapies such as complement inhibitors³⁰, BTKi³¹, ASCT³², and CAR-T therapy³³.

Summary

• Shift from trial-and-error toward a mechanism-driven approach using early diagnostics and therapy response assessment.
• Pharmacokinetic-guided dosing and structured withdrawal trials can save healthcare costs and reduce patient burden.
• While current practice still depends on empirical decision-making, the future holds promise through biomarker validation and tailored immunotherapies to enable true personalization in CIDP care.

Abbreviations 

ASCT: Autologous Stem Cell Transplantation, BTKi: Bruton's Tyrosine Kinase Inhibitor, CAR-T: Chimeric Antigen Receptor T cell, CIDP: Chronic Inflammatory Demyelinating Polyneuropathy, CD20: Cluster of Differentiation 20, MAG: Myelin-Associated Glycoprotein, FcRn: Neonatal Fc Receptor, IgG: Immunoglobulin G, IgM: Immunoglobulin M, IVIG: Intravenous Immunoglobulin, MRC: Medical Research Council, R-ODS: Rasch-built Overall Disability Scale, TTR: Transthyretin

References 

1. Caballero Avila M, et, al, Front Immunol 2025;16;1575464;2
2. Hughes RAC, et al, Randomized Controlled Trial Lancet Neurol 2008,7(2):136-144
3. Mendell JR et al, Neurology 2001,56(4):445-449
4. Vermeulen M, et al, J Neurol Neurosurg Psychiatry 1993,56(1):36-39
5. Thompson N, et al, Clinical Trial J Neurol 1996,243(3):280-285
6. Hahn AF, et al, Brain 1996,119(4):1067-1077
7. Hahn AF, et al, Brain 1996,119(4):1055-1066
8. Mehndiratta MM, et al, Cochrane Database Syst Rev, 2015(8)CD003906
9. Lieverloo GGA et al, J Neurol 2018,265(9):2052-2059
10. Allen JA, et al, Lancet Neurol 2024,23(10):1013-1024
11. Querol L, et al, Neurology, 2024,102(7_supplement_1)
12. Fisto AL, et al, Neurol Res Pract, 2020,8:2:42
13. Mahdi-Rogers M & Rajabally YA Biologics,2010,4:45-49
14. Hadden RD, et al, Neurology 1999,53(1):57-61
15. Nobile Orazio E, et al, Brain 2025,148(4):1112-1121
16. Du Y, et al, Ann Clin Transl Neurol 2025,12(1):180-191
17. Zheng Y, et al, J Peripher Nerve Syst 2024,29(3):350-355
18. Allen JA and Lewis RA, Neurology 2015,85(6);498-504
19. Breiner A et al, Muscle Nerve 2019,60(2);180-183
20. Van den Bergh PYK, et, al, Eur J Neurol. 2021,28(11):3556-3583
21. Cornblath, et al, Brain 2022 15;145(3):887–896
22. Eftimov F. et al, Neurology, 2012,78(14):1079-1084
23. Kapoor M. et al, J peripher nerv syst, 2021,26(4):461-468
24. Rayabally YA et al, J Neurol Sci 2025; 744:123654
25. Bellanti R and Lunn M. et al, submitted to Brain
26. Hu J, et al, J Neurol. 2022;269(3):1250-1263
27. Du Y, et al, Ann Clin Transl Neurol.2025;12(1):180-191
28. Doneddu PE, et al, J Neurol Neurosurg Psychiatry,2024;95(9):838-844
29. Nobile-Orazio, et al, Brain 2025;148(4):1112-1121
30. Querol LA, et al, Neurotherapeutics 2022;19(3):864-873
31. Rajabally YA, Immunotargets Ther 2024;13:99
32. Axelson HW, et al, BMJ Case Rep. 2009ber092008.0927
33. Zhang W, et al, hLife 2024;2(8):434-438

Agenda & Objectives

• To highlight disease burden, diagnostic challenges, and pathogenic mechanisms of CIDP, with a focus on:
• Clinical variability and diagnostic pitfalls
• Early axonal damage as a key driver of long-term disability 

1) Disease Burden & Diagnostic Challenges

• CIDP is a chronic, immune-mediated disorder1 causing demyelination, axonal damage, and symptoms like proximal/distal weakness, sensory loss, and hyporeflexia².
• Typical CIDP (proximal + distal weakness) is easiest to diagnose, while atypical variants (motor, sensory, distal, focal) often overlap with other conditions, complicating diagnosis³.
• Acute-onset CIDP-like presentations may indicate autoimmune nodopathies or Guillain-Barré syndrome⁴. Hematologic comorbidities (MGUS) may coexist but require distinct management⁵.
• Patients experience significant burdens like pain, muscle weakness, and frequent misdiagnoses⁶.
• Though CIDP is immune-mediated, early axonal damage is common⁷, predictive of long-term disability⁸, and highlights need for early recognition and prevention.

Summary

• A comprehensive understanding of CIDP’s clinical variability, early axonal involvement, and underlying complement-mediated mechanisms is essential to improving diagnostic precision, patient-centered care, and the development of targeted therapies that can reduce long-term disability.

2) Axonal Integrity and the Role of Complement

Objective

• To explore the physiological and pathological roles of the complement system in maintaining axonal integrity, and its relevance to CIDP and related neuromuscular diseases.

Complement System in CIDP Pathogenesis

• Axonal damage can occur early in CIDP7 and significantly contributes to cumulative disability⁸. Maintaining axonal integrity is a valid therapeutic approach^8,9.
• Communication between neurons and Schwann cells supports nerve repair and function¹⁰. Mitochondrial function and turnover are essential due to high energy demand in neurons¹¹.
• Beyond its cytotoxic or inflammation related functions, complement system helps maintain axonal integrity¹².
• Classical (initiated by antibodies) and lectin (initiated by carbohydrates) pathways converge to activate C3 and C5, driving both protective and inflammatory responses¹³.
• Complement fragments (C3b, C3a, C5a) are involved in immune activation, opsonization, and inflammation¹⁴.
• Tight regulation by inhibitors such as CD59 is critical; dysfunction can lead to excessive tissue damage¹⁵.
• C1q and C3 mediate synaptic pruning during development, with C1q promoting axonal outgrowth, while downstream factors (C3) may inhibit it¹⁶.
• Complement fragments (C3a, C5a) play a role in tissue repair and promote inflammatory response to infection or injury¹⁷. Dysregulated complement activation contributes to neuroinflammation¹³.
• Complement-mediated pathology is implicated in diseases like CIDP, myasthenia gravis, etc¹⁷.

Summary

• The complement system has dual roles: maintaining axonal integrity (physiological) and driving pathology when dysregulated (e.g., in neuroinflammatory diseases).
• Targeting specific complement pathways (e.g., C1q, C3, MAC) offers therapeutic potential for PNS disorders.
• Approved complement inhibitors demonstrate clinical efficacy, reinforcing their relevance in neuromuscular disease treatment.

3) Demyelination and Axonal Damage Interplay in CIDP

Objective

• To examine the mechanisms contributing to demyelination and axonal injury in CIDP, and evaluate the role of complement activation, immune cell infiltration, and biomarkers in disease progression, diagnosis, and treatment monitoring..

CIDP pathophysiology & Complement’s Role in CIDP

• CIDP pathogenesis involves both cellular and humoral immune responses, creating a pro-inflammatory environment that damages both myelin and axons¹⁸.
• Complement activation (e.g., C3b, MAC formation) promotes demyelination and axonal damage¹⁸.
• Macrophages infiltrate nerves, targeting myelin sheaths (nodes of Ranvier, internodes) and small blood vessels¹⁸.

Axonal damage in CIDP

• Occurs early in disease progression (seen in nerve biopsies)¹⁹.
• Two proposed mechanisms (likely act in parallel, rather than exclusively):.
• Primary axonal injury: Antibodies bind paranodal proteins → complement activation → MAC formation → pore-induced axonal damage¹⁹.
• Secondary axonal injury: Demyelination → loss of axonal protection → MAC-mediated damage¹⁹.
• Axonal loss strongly correlates with long-term disability (more than demyelination alone)⁷.

Biomarkers

• Emerging biomarkers in CIDP include:
• Neurofilament light chain (NFL): associated with axonal damage and potential treatment monitoring (for axonal damage)²⁰.
• Sphingomyelin: elevated in active CIDP (for myelin damage)²¹.
• C5a²² and IL-8²³: elevated in CIDP compared to controls; potential diagnostic utility (for inflammation).
• Peripherin: may help differentiate CIDP from other neuropathies like GBS (for axonal damage)²⁰.
• MRI and ultrasound show promise for visualizing nerve enlargement and inflammation, and treatment response²⁴.

Conclusion

• Demyelination and axonal damage in CIDP are interconnected, with complement activation (e.g., via MAC) contributing to injury. Early axonal involvement underscores the importance of timely treatment to prevent long-term disability.
• Although no single biomarker is definitive, a combined approach using fluid, imaging, and electrophysiological tools may improve diagnosis and treatment monitoring as evidence evolves.

4) Opportunities to target the pathobiology of CIDP

Objective

• To evaluate current and emerging treatment strategies for CIDP, focusing on mechanisms of action, therapeutic targets (e.g., complement, B-cells, FcRn), and future directions for personalized management to improve long-term outcomes.

Key highlights

• IVIG², corticosteroids²⁵, plasma exchange²⁶, and FcRn antagonists²⁶ are standard treatments with varied administration routes and onset times.
• Mechanisms range from immunoglobulin modulation and anti-inflammatory effects to antibody removal and immunosuppression^27,28.
• Emerging Targeted Therapies:
• FcRn Antagonists: Reduce IgG levels by 70% by blocking recycling²⁹, promoting lysosomal degradation³⁰.
• B-Cell Depletion: Targets CD20+ B-cells (not plasma cells); limited evidence but used off-label^28,31.
• Complement Inhibition: Upstream (C1q/C2) vs. terminal (MAC) blockade: Upstream inhibition may reduce inflammation and opsonization (vs. MAC-focused therapies like anti-C5). Potential to spare axonal damage if initiated early³².
• Personalized treatment approaches targeting specific immune mechanisms (FcRn, B-cell, complement) are a major area of interest.
• Biomarker development (fluid, imaging, and electrophysiologic) is essential for early diagnosis, treatment selection, and monitoring³³.
• Addressing axonal damage in CIDP may prevent subclinical degeneration, reduce treatment side effects, minimize disability, and lower relapse and wear-off rates in incomplete responders³⁴.

Conclusion

• A personalized, patient-centered approach that leverages biomarkers to guide early, targeted interventions (FcRn blockers, B-cell therapies, or complement inhibitors), offers the potential to improve outcomes, preserve axonal integrity, and reduce the overall treatment burden in CIDP.

Polling Results Highlighted by Speakers:

• Biggest challenge in CIDP: "Suboptimal response to current treatments in patients" and "timely accurate diagnosis" were top concerns.
• Biomarker utility: Majority voted for "treatment monitoring" (NFL favored for axonal damage).
• Future research priority: "Personalized treatment approaches" topped the poll.

Abbreviations 

C1/2/3/5: Complement component 1/2/3/5, CD20/59: Cluster of Differentiation 20/59, CIDP: Chronic Inflammatory Demyelinating Polyneuropathy, FcRn: Neonatal Fc Receptor, GBS: Guillain-Barré Syndrome, IgG: Immunoglobulin G, IL-8: Interleukin 8, IVIG: Intravenous Immunoglobulin, MAC: Membrane Attack Complex, MGUS: Monoclonal Gammopathy of Undetermined Significance, MRI: Magnetic Resonance Imaging, NFL: Neurofilament light chain, PNS: Peripheral Nerve Society  

References 

1. Broers MC, et al. Neuroepidemiology. 2019;52(3-4):161–172
2. Bunschoten C, et al. Lancet Neurol. 2019;18(8):784-794
3. Allen J. Neurol Ther. 2020;9:43-54
4. Lewis RA, et al. J Neurol Sci. 2022;443:120478
5. Mathey EK, et al. J Neurol Neurosurg Psychiatry. 2015;86(9):973-985
6. https://www.gbs-cidp.org/support/connect-with-gbs-cidp-community/patient-stories/
7. Al-Zuhairy A, et al. Clinical Neurophys. 2021;132(4):1000-1007
8. Grüter T, et al. Eur J Neurol. 2022;29(2):583-592
9. Ricciardi D, et al. Brain Sci. 2022;12(11):1510
10. Trends Neurosci. 2012;35(2):123-134 (https://pubmed.ncbi.nlm.nih.gov/22192173/)
11. Chamberlain KA, Sheng ZH. J Neurosci Res. 2019;97(8):897-913
12. Yuan Y, et al. Front Neurol. 2022;13:908148
13. Schartz ND, Tenner AJ. J Neuroinflammation. 2020;17(1):354
14. Liszewski MK, Atkinson JP. Hum Genomics. 2015;10;9(1):7
15. Karbian N, et al. J Neuroinflammation. 2023;20(1):245
16. Warwick CA, et al. J Biol Chem. 2021;297(3):101085
17. Dalakas MC, et al. Nat Rev Neurol. 2020;16(11):601-617
18. Querol LA, et al. Neurotherapeutics. 2022;19(3):864-873
19. Al-Zuhairy A, et al. Muscle Nerve. 2022;66(6):715-722
20. Keddie S, et al. Brain. 2023;146(11):4562-4573
21. Capodivento G, et al. J Neurol Neurosurg Psychiatry. 2021;92(3):303-310
22. Quast I, et al. Ann Clin Transl Neurol. 2016;3(9):730-735
23. Kmezic I, et al. Front Immunol. 2023;14:1241199
24. Härtig F, et al. Neurother. 2018;15(2):439-451
25. Hughes RAC, et al. Cochrane Database Syst Rev. 2017;11(11):CD002062
26. Mina-Osorio P, et al. Transfus Med Rev. 2024;38(1):150767
27. Mair D, et al. J Neurol Neurosurg Psychiatry. 2025;96:38-46
28. Briani C, Visentin A. Neurotherapeutics. 2022;19:874-884
29. Mina-Osorio P, et al. Transfus Med Rev. 2024;38(1):150767
30. Gable KL, Guptill JT. Front Immunol. 2020;10:3052
31. Forsthuber TG, et al. Ther Adv Neurol Disord. 2018;11:1756286418761697
32. Querol L, et al. J Peripher Nerv Syst. 2023; 28(2):276-285
33. Dalakas MC. Nat Rev Neurol. 2011;7(9):507-517
34. Ryan M, et al. AJMC. 2018;24(17):S371–S379

Agenda & Objectives

• To deepen the understanding MMN immunopathogenesis and the critical role of complement activation in its progression
• To raise awareness on the importance of monitoring disease activity in MMN management, focusing on using MMN-RODS as a key tool
• To highlight the needs and expectations of patients with MMN regarding future therapeutic approaches 

Patient’s perspective – Living with MMN

At 44, a male patient began with right shoulder pain, misdiagnosed as a sports injury. Symptoms worsened to muscle atrophy, drop wrist, and severe weakness, impacting daily tasks. After multiple inconclusive tests and a misdiagnosis of ALS, he was finally diagnosed with MMN after seeing seven neurologists and 25 healthcare professionals.

• This case stresses the need for quantitative tools in clinical discussions as current monitoring is mostly qualitative. The median diagnosis time for MMN can be up to five years, and untreated disease severity worsens.

MMN pathogenesis and the role of complement

• MMN is an autoimmune disorder driven by IgM anti-GM1 antibodies, which activate the classical complement pathway¹.
• These antibodies bind particularly at the node of Ranvier—a site uniquely lacking in complement regulatory proteins like CD59—making it especially vulnerable to membrane attack complex (MAC)-mediated damage^2,3.
• Complement activation not only damages membranes but also triggers an inflammatory cascade involving cytokines, chemokines, and antigen presentation^1,4.
• This multi-step process includes antibody leakage, nerve binding, reversible conduction block, and ultimately axonal degeneration and muscle atrophy, explaining the patient’s sudden losses in strength^1,4.
• Therapeutically, complement pathway inhibition offers promise. Depending on the target—such as C1 in the classical pathway or C5 for terminal MAC formation—different parts of the cascade can be modulated, each with different clinical implications^5,6.
• Understanding this immunopathogenesis is essential for both developing therapies and interpreting patient responses^1,7.

Measuring MMN Outcomes: The MMN-RODS

• Historically, a variety of metrics have been applied such as Grip strength¹⁰ (Martin Vigorimeter), MRC scores¹¹, 9-Hole Peg Test¹², GBS Disability Score, EQ-5D, etc. to measure MMN progression and treatment efficacy. However, these vary in responsiveness⁸, reliability⁹, and cross-cultural validity^13,14.
  • The MMN-RODS (Rasch-built Overall Disability Scale) was developed to address these gaps. Initially distilled from 146 daily activities, it now includes 25 items focusing on fine motor skills, capturing daily function with three simple response options.⁸ Though it appears simple, the scale transforms responses into linear measures suitable for statistical analysis and parametric modeling⁸.
  • MMN-RODS has been validated in multiple studies, demonstrating high internal consistency, convergent validity, and promising responsiveness.¹⁵ It is currently being evaluated further in ongoing phase 2 and 3 trials involving over 50 patients across 40 sites in Europe and North America.¹⁶ The goal is to strengthen its utility in both clinical practice and research.¹⁵

Abbreviations 

ALS: Amyotrophic Lateral Sclerosis, CD59: Cluster of Differentiation 59, CIDP: Chronic Inflammatory Demyelinating Polyneuropathy, C1: Complement component 1, C5: Complement component 5, EQ-5D: EuroQol 5 Dimensions, GBS: Guillain-Barré Syndrome, GM1: Ganglioside M1, IgM: Immunoglobulin M, MAC: Membrane Attack Complex, MMN: Multifocal Motor Neuropathy, MMN-RODS: Multifocal Motor Neuropathy Rasch-built Overall Disability Scale, MRC: Medical Research Council 

References 

1. Harschnitz O, et al. J clin Immunol. 2014;34(suppl 1):S112-S119
2. Vlam L, et al. Nat Rev Neurol. 2011;8(48):48-58
3. Karbian N, et al. J Neuroinflamm. 2023;20(1):245
4. McGonigal R, et al. J Clin. Invest. 2022;132(14):e158524
5. Garred P, et al. Pharmacol Rev. 2021;73(2):792–827
6. Ricklin D, et al. Nat Rev Drug Discov. 2019
7. Beadon K, et al. Curr Opin Neurol. 2018;31(5):559-564
8. Vanhoutte EK, et al. J Peripher Nerv Syst. 2015;20(3):296-305
9. Pruppers MHJ, et al. J Peripher Nerv Syst. 2015;20:306-318
10. Neumann S, et al. In Vivo. 2017;31(5):917-924
11. Chia PK, et al. J Clin Neurosci. 2019;69:114–119
12. Moreno-Morente G, et al. Int J Environ Res Public Health. 2022;19(16):10080
13. Van Nes SI, et al. J Peripher Nerv Syst. 2009;14:268–278
14. Sharrack B and Hughes RAC, Multi Scler. 1999;5(4):223-233
15. ArgenX. Data on File. 2025 (Data on File will be made available from ArgenX upon request)
16. https://clinicaltrials.gov/ NCT05225675