ARTICLE OPEN ACCESS

Clinical and Laboratory Features in Anti-NF155Autoimmune NodopathyLorenaMartın-Aguilar MD PhD Cinta Lleixa MSc Elba Pascual-Gontildei MD PhD Marta Caballero-Avila MD

Laura Martınez-Martınez MD PhD Jordi Dıaz-Manera MD PhD Ricard Rojas-Garcıa MD PhD

Elena Cortes-Vicente MD PhD Janina Turon-Sans MD Noemi de Luna PhD Xavier Suarez-Calvet PhD

Eduard Gallardo PhD Yusuf Rajabally MD Sangeeta Scotton MD Bart C Jacobs MD PhD Adaja Baars MD

Andrea Cortese MD PhD Elisa Vegezzi MD Romana Hoftberger MD Fritz Zimprich MD

Cornelia Roesler MD Eduardo Nobile-Orazio MD PhD Giuseppe Liberatore MD Fu Liong Hiew MD

Alicia Martınez-Pintildeeiro MD Alejandra Carvajal MD Raquel Pintildear-Morales MD Mercedes Uson-Martın MD

Olalla Albertı MD Maria Angeles Lopez-Perez MD Fabian Marquez MD Julio Pardo-Fernandez MD PhD

Laura Muntildeoz-Delgado MD Macarena Cabrera-Serrano MD PhD Nicolau Ortiz MD PhD

Manuel BartolomeMD Ozgur DumanMD Vera Bril MDDarwin Segura-ChavezMD Kalliopi Pitarokoili MD

Claudia Steen MD Isabel Illa MD PhD and Luis Querol MD PhD

Neurol Neuroimmunol Neuroinflamm 20229e1098 doi101212NXI0000000000001098

Correspondence

Dr Querol

lquerolsantpaucat

AbstractBackground and ObjectivesTo study the clinical and laboratory features of antineurofascin-155 (NF155)ndashpositive auto-immune nodopathy (AN)

MethodsPatients with anti-NF155 antibodies detected on routine immunologic testing were includedClinical characteristics treatment response and functional scales (modified Rankin Scale[mRS] and Inflammatory Rasch-built Overall Disability Scale [I-RODS]) were retrospectivelycollected at baseline and at the follow-up Autoantibody and neurofilament light (NfL) chainlevels were analyzed at baseline and at the follow-up

ResultsForty NF155+ patients with AN were included Mean age at onset was 424 years Patientspresented with a progressive (75) sensory motor (875) and symmetric distal-predominant weakness in upper (972) and lower extremities (945) with tremor andataxia (75) Patients received a median of 3 (2ndash4) different treatments in 46 months ofmedian follow-up Response to IV immunoglobulin (868) or steroids (722) was poorin most patients whereas 773 responded to rituximab HLA-DRB115 was detected in913 of patients IgG4 anti-NF155 antibodies were predominant in all patients anti-NF155 titers correlated with mRS within the same patient (r = 041 p = 0004) Serum NfL(sNfL) levels were higher in anti-NF155+ AN than in healthy controls (3647 vs 756 pgmL p lt 0001) and correlated with anti-NF155 titers (r = 043 p = 0001) with I-RODS atbaseline (r = minus088 p lt 0001) and with maximum I-RODS achieved (r = minus058 p = 001)Anti-NF155 titers and sNfL levels decreased in all rituximab-treated patients

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Class of EvidenceCriteria for ratingtherapeutic and diagnosticstudies

NPuborgcoe

These authors contributed equally to this work as co-first authors

From the Neuromuscular Diseases Unit (LM-A CL EP-G MC-A RR-G EC-V JT-S EN-O II LQ)DepartmentofNeurologyHospitaldeLaSantaCreu I SantPauUniversitatAutonomadeBarcelona Biomedical Research Institute Sant Pau (IIB Sant Pau) (LM-A CL EP-G MC-A JD-M EC-V XS-C EG) Immunology Department (LM-M) Hospital de La Santa Creu I Sant PauUniversitat Autonoma de Barcelona Spain Centro para La Investigacion Biomedica en Red en Enfermedades Raras (CIBERER) (JD-M RR-G EC-V NL XS-C EG II LQ) University HospitalBirmingham (YR SS) UK ErasmusMedical Center (BCJ AB) Rotterdam the Netherlands IRCCSMondino Foundation (Andrea Cortese EV) Pavia Italy Department of Neurology (RH FZ)Medical University of Vienna Paracelsus Medical University (CR) Salzburg Austria IRCCS Humanitas Research Hospital (GL) Milan University Rozzano Italy Kuala Lumpur General Hospital(FLH) Jalan Pahang Kuala Lumpur Malaysia Hospital Universitari Germans Trias I Pujol (AM-P) Badalona Hospital Universitario Virgen de Las Nieves (Alejandra Carvajal) Granada SpainHospital Universitario Clınico San Cecilio (RP-M) Granada Hospital Son Llatzer (MU-M) Palma de Mallorca Hospital San Jorge (OA) Huesca Espantildea Hospital San Pedro (MAL-P) LogrontildeoHospital Universitari Josep Trueta (FM) Girona Hospital ClınicoUniversitario de Santiago (JP-F) Santiago deCompostela Hospital Universitario VirgenDel Rocıo (LM-DMC-S) Sevilla HospitalUniversitari Sant Joan (NO) Reus ComplejoAsistencial de Avila (MB) Avila Spain AkdenizUniversity (OD) Antalya Turkey TorontoGeneral Hospital (VB) UniversityHealthNetwork Universityof Toronto Canada Instituto Nacional de Ciencias Neurologicas Lima (DS-C) Peru St Josef-Hospital (KP) Ruhr-University Bochum and Sant Joseph Hospital (CS) Berlin Germany

Go to NeurologyorgNN for full disclosures Funding information is provided at the end of the article

The Article Processing Charge was funded by authors

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

DiscussionAnti-NF155 AN presents a distinct clinical profile and good response to rituximab Autoantibody titers and sNfL are useful tomonitor disease status in these patients The use of untagged-NF155 plasmids minimizes the detection of false anti-NF155+ cases

Classification of EvidenceThis study provides Class IV evidence that anti-NF155 antibodies associate with a specific phenotype and response to rituximab

Chronic inflammatory demyelinating polyradiculoneuropathy(CIDP) is a clinically and pathologically diverse autoimmunesyndrome of the peripheral nervous system causing significantdisability12 Disease-specific antibodies targeting proteins at thenode and paranode of Ranvier such as neurofascin 155(NF155)3 nodal neurofascins (NF186 and NF140)4 contactin-1 (CNTN1)5 or CNTN-1caspr-167 have been described insmall subsets of patients with CIDP sharing immunopathologicmechanisms clinical features and treatment response and dif-fering from those of typical CIDP89 This has led to the ap-pearance of the autoimmune nodopathy (AN) diagnostic categoryin the recent update of the European Academy of NeurologyPeripheral Nerve Society CIDP diagnostic guidelines10

Previous case series describe the association of anti-NF155 an-tibodies with predominantly distal motor involvement ataxiaand low-frequency tremor with cerebellar features311 markednerve conduction abnormalities12 and DRB115 human leu-kocyte antigen (HLA)Class II alleles13Moreover these patientsrespond poorly to IV immunoglobulin (IVIg) and usually well torituximab14 Anti-NF155 antibodies almost always of the IgG4isotype15 are pathogenic according to passive transfer experi-ments in animal models16 and pathologic studies detecting IgG4deposition and axoglial junction dissection at the paranode (inthe absence of classical macrophage-mediated demyelination)17

Recently high serum neurofilament light chain (sNfL) levelswere described in a subset of patients with anti-NF155+ AN18

Our work describes the clinical immunologic biomarkertreatment response and prognostic features of the largest anti-NF155+ AN cohort so far

MethodsProtocol Approvals Registrations andPatient ConsentsIn this multicenter retrospective observational study we in-cluded all sera reacting against NF155 transfected cells and

identified during routine testing for nodalparanodal anti-bodies The samples were obtained between May 2010 andDecember 2020 These patients were selected for furthercharacterization between May 2020 and December 2020 De-mographic and clinical data at onset and during follow-up werecollected in a coded database This study was conductedaccording to a protocol approved by the Ethics Committee ofthe Hospital de la Santa Creu i Sant Pau All patients gavewritten informed consent to participate in the study

Data and Sample CollectionData were collected retrospectively by patientsrsquo neurologistsin 24 different centers by chart review European Academy ofNeurologyPeripheral Nerve Society diagnostic criteria forCIDP19 were assessed and patients were classified as havingdefinite probable or possible CIDP Demographic data (ageand gender) and clinical features (initial diagnosis time tonadir the presence of weakness or sensory deficits presenceof ataxia and tremor) were collected Clinical presentationwas defined as sensorimotor pure motor or pure sensoryataxic The results of routine nerve conduction studies(NCS) CSF examination and treatments were also col-lected As an electrophysiologic marker of axonal damagewe used the lowest (left or right) median nerve compoundmuscle action potential (CMAP) negative peak amplitudeand when available the presence of spontaneous activity inthe electromyography (EMG) at the tibialis anterior muscleCSF protein levels higher than 045 gL were consideredrelevant20 Disability scores were collected at nadir and at thefollow-up including the modified Rankin Scale (mRS)21 andthe Inflammatory Rasch-built Overall Disability Scale (I-RODS) scores22 (from 0 to 100 100 indicating no disabil-ity) when available Response to therapy was defined as agood response partial response or no response as classifiedby their primary neurologists after chart review of the neu-rologic examination For rituximab-treated patients mRSwas prospectively collected pretreatment and at least onceposttreatment infusion protocol and adverse events (in-fusion reactions and infections) were also collected Serum

GlossaryCBA = cell-based assay CIDP = chronic inflammatory demyelinating polyradiculoneuropathy CMAP = compound muscle actionpotential CNTN1 = contactin-1 EMG = electromyography GBS = Guillain-Barre syndrome HC = Healthy control HLA =human leukocyte antigen ICC = immunocytochemistry I-RODS = Inflammatory Rasch-built Overall Disability Scale IVIg = IVimmunoglobulinmRS = modified Rankin ScaleNCS = nerve conduction studyNF140 = neurofascin-140NF155 = neurofascin-155 NF186 = neurofascin-186 OD = optical density PLEX = plasma exchange sNfL = serum neurofilament light chain

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samples were obtained at diverse time points during routineautoantibody testing and stored at minus80degC until needed

Anti-NF155 Antibody Detection and TitrationSerum antibodies against NF155 were analyzed in the samelaboratory using a cell-based assay (CBA) with humanrecombinant NF155-transfected HEK293 cells as pre-viously described323 The DDK-myc-tagged RC228652NF155 plasmid (OriGene Rockville MD) was used forinitial anti-NF155 detection and the untagged EX-Z7183-M02 NF155 plasmid (GeneCopoeia Rockville MD) wasused for false positive detection in those patients withdiscrepant results in the CBA and the ELISA ELISA wasused as a confirmatory test and for isotype identificationand titration as previously described3 Optical density(OD) was measured at 450 nm with a Multiskan ELISAreader Blank OD was subtracted to NF155 OD to controlfor unspecific background signal The samples were con-sidered positive by ELISA when they had a DOD higherthan average healthy control (HC) DOD plus 2 SD Titervariation within the same patient was expressed as thepercentage of titer change compared with pretreatmentlevels All samples were tested under the same conditions

Serum NfL MeasurementssNfL levels were measured in all available anti-NF155 ANpatient samples and compared with 78 HCs using the SimoaNF-light kit in the SR-X Immunoassay Simoa analyzer(Quanterix Corp Boston MA) as previously described24

The samples were analyzed in duplicates following the man-ufacturerrsquos instructions and standard procedures All NfLvalues were within the linear ranges of the assay The intra-assay and interassay coefficients of variation at intermediatelevel (1525 pgmL) were 39 and 95 respectively

HLA GenotypingGenomic DNA from the peripheral blood from patients withanti-NF155+ with AN was extracted following standard pro-tocols HLA-DRB1 andHLA-DQB1 genotypes were analyzedas previously described13

Statistical AnalysisA descriptive data analysis was performed Descriptivestatistics are shown as mean (plusmnSD) or median (inter-quartile range) in continuous variables and as frequencies(percentages) in categorical variables Comparisons be-tween patients with anti-NF155+ AN and HC were per-formed by the Wilcoxon rank-sum test The Kruskal-Wallistest was used to compare groups Wilcoxon-Matched PairsSigned Rank test was used to compare baseline anti-NF155titters and sNfL levels at different time points We usedthe Spearman coefficient to assess correlation betweenvariables

Statistical significance for all analyses was set at 005 (2-sided)All statistical analyses were performed with GraphPad Prismv8 and SPSS Statistics version 23 (IBM Corp)

Data AvailabilityAnonymized data not published within this article will bemade available by request from any qualified investigator

ResultsAnti-NF155 Autoantibody ScreeningWe detected 44 sera with a positive staining in the screeningNF155 CBA and negative staining in the NF140NF186CBA After performing a confirmatory study with anti-NF155ELISA 40 patients were confirmed true positives with ELISAand were selected for further characterization The other 4patients were classified as false positives in the CBA (91)We used an untagged neurofascin-155 plasmid and confirmedthat those 4 patients were negative when the myc-DDK tagwas removed (eFigure 1 linkslwwcomNXIA641)

Clinical Features of Anti-NF155 PatientsWith ANThirty-nine patients with anti-NF155+ fulfilled the CIDP di-agnostic criteria in 1 patient antibodies were detected post-mortem (supplementary results linkslwwcomNXIA641)Nine patients were previously reported in other series314152526

The initial diagnosis was CIDP for most patients (80) but 5patients were initially diagnosed with Guillain-Barre syndrome(GBS) Patients with anti-NF155+ AN had a median age atonset of 424 years and were predominantly men (725) Themost frequent clinical presentation was sensory motor (875)and most patients had a progressive (75) and chronic (675)clinical course Most patients had a symmetric weakness withdistal predominance in upper (972) and lower extremities(945) The sensory deficit was symmetric and more frequentin lower (975) than in upper extremities (675) Seventy-fivepercent of patients had tremor and ataxia (of which 5 had onlyataxia 5 tremor and 25 a combination of both) Tremor wasclassified as intention tremor or action tremor in 18 patients(60) Thirty percent of patients had cranial nerve involvementbilateral facial palsy was the most frequent (70) and 2 patientshad bilateral optic neuritis confirmed by evoked potentials27 withnormal brain and spine MRI and negative MOG andantiaquaporin-4 antibodies Further information about diseasecharacteristics is detailed in Table 1

Regarding nerve conduction studies 38 patients fulfilleddefinite electrodiagnostic European Academy of NeurologyPeripheral Nerve Society criteria for CIDP19 1 patient wasdefined as possible CIDP and 1 patient did not have nerveconduction studies performed because diagnosis was con-firmed postmortem We collected 33 (825) NCS in whichonly 26 (65) had needle EMG available Median amplitudeof distal CMAPs of different nerves are shown in eTable 1(linkslwwcomNXIA641) Seventeen of 26 patients(654) had spontaneous activity on EMG CSF was exam-ined in 37 (925) patients most patients had less than 5 cellsin CSF (722) and all patients had high CSF protein levelswith a median of 2 gL (095ndash367)

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Treatment Response and Clinical Follow-upThe median number of treatments received was 3 (2ndash4)Most patients were treated with IVIg (95) andor cortico-steroids (90) and approximately half of patients (462)were treated with plasma exchange (PLEX) with a mediannumber of sessions of 6 (5ndash9) Twenty-three patients(575) were treated with rituximab and 1 patient was in-cluded in a blinded clinical trial of rituximab vs placebo Ofthose patients treated with rituximab (n = 23) 13 were alsotreated with plasma exchange before starting rituximab and10 patients were treated with rituximab alone Nine patientswere treated with azathioprine and 8 patients received other

Table 1 Demographic and Clinical Characteristics ofPatients With NF155+ AN

Baseline characteristics

Age at onset (mean plusmn SD) 4240 plusmn 1948

Age at diagnosis (mean plusmn SD) 4325 plusmn 1930

Sex (male n ) 29 (725)

Initial diagnosis (n )

CIDP 32 (80)

GBS 5 (125)

Sensory neuropathy 1 (25)

Demyelinating neuropathy 1 (25)

Cervical myelopathy 1 (25)

CIDP clinical course (n )

Progressive 30 (75)

Relapsing-remitting 10 (25)

Time to nadir (n )

Acute (lt1 mo) 2 (5)

Subacute (1ndash2 mo) 11 (275)

Chronic (gt2 mo) 27 (675)

Clinical presentation (n )

Sensory motor 35 (875)

Pure sensoryataxic 4 (10)

Pure motor 1 (25)

Weakness (n )

Upper extremity weakness 35 (875)

Symmetric 33 (943)

Proximal and distal 15 (429)

Distal 19 (543)

Proximal 1 (29)

Lower extremity weakness 37 (925)

Symmetric 34 (919)

Proximal and distal 17 (459)

Distal 18 (486)

Proximal 2 (54)

Sensory deficit (n )

Arm sensory deficit 27 (675)

Symmetric 26 (963)

Modality

Vibration 16 (593)

Pinprick 16 (593)

Table 1 Demographic and Clinical Characteristics ofPatients With NF155+ AN (continued)

Baseline characteristics

Superficial sensation 22 (815)

Leg sensory deficit 39 (975)

Symmetric 38 (95)

Modality

Vibration 37 (925)

Pinprick 32 (80)

Superficial sensation 31 (775)

Reflexes (n )

Absent 30 (75)

Decreased 10 (25)

Ataxia (n ) 30 (75)

Tremor (n ) 30 (75)

Cranial nerve involvement (n ) 12 (30)

Bilateral facial palsy 7

Ophthalmoparesis 3

Optic nerve 2

Clinical scales

mRS (median IQR)

Sampling (n = 27) 3 (2ndash4)

Maximum (n = 37) 4 (2ndash4)

Final (n = 37) 2 (1ndash3)

I-RODS (median IQR)

Sampling (n = 14) 49 (38ndash68)

Maximum (n = 17) 40 (29ndash57)

Final (n = 22) 59 (54ndash88)

Abbreviations AN = autoimmune nodopathy CIDP = chronic inflammatorydemyelinating polyradiculoneuropathy GBS = Guillain-Barre syndrome I-RODS = Inflammatory Rasch-built Overall Disability Scale IQR = interquartilerange mRS = modified Rankin Scale

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treatments (mycophenolate methotrexate cyclosporine orinterferon beta1a)

Only 5 of 38 (131) patients had a good response to IVIg 10of 36 (278) patients had a good response to steroids and 7 of18 (389) had a good response to PLEX On the contrary 17of 23 (773) patients had a good response to rituximab and 13of 23 (565) patients have an improvement of ge2 points inmRS after rituximab treatment Rituximab-treated patients inwhich mRS remained stable had lower median follow-up timealthough differences were not statistically significant (eTable 2linkslwwcomNXIA641) Of the 4 rituximab-treated patientswithout detectable improvement in the mRS score 2 patientswere classified as nonresponders by their primary physicians(median follow-up time of 37 months) and 2 patients wereclassified as partial responders (median follow-up time of 6months) Most frequent infusion protocol (364) was 4

weekly + 2 monthly 375 mgm2 doses followed by 1 + 1(separated 2 weeks) 1000 mg doses (273) and 4 weekly 375mgm2 doses (273) Five (217) patients had a relapse amedian of 21 (45ndash595) months after induction with ritux-imab 11 (478) patients received rituximab reinfusions Four(17) patients had adverse effects related to rituximab 2 mildinfusion reactions 1 pneumonia and 1 disseminated varicellainfection Treatment frequencies doses and responses totreatment are further detailed in Table 2

The clinical scales at baseline at nadir and after treatment aredescribed in Table 1 The median follow-up time was 46(20ndash81) months Patients with facial diplegia had lowermaximum and final I-RODS than patients who did not havefacial involvement (median maximum I-RODS 22 vs 47 p =0003 and median final I-RODS 43 vs 61 p = 0035 (eTable 3linkslwwcomNXIA641) Three patients died duringfollow-up 1 because of CIDP disease course 1 because ofaspiration pneumonia and 1 because of a disseminated vari-cella infection Patients who received rituximab had highermedian mRS and lower I-RODS at nadir although differenceswere not statistically significant (4 [3ndash4] vs 3 [2ndash4] p = 0540 [29ndash49] vs 47 [9ndash77] p = 078 Table 3) They received ahigher number of previous treatments than those patientswho did not received rituximab (4 [3ndash5] vs 2 [2ndash3] p = 003)including PLEX but they did not differ at the final mRS orI-RODS from those patients not treated with rituximab de-spite being more drug resistant (Table 3) There were nodifferences between patients treated with PLEX and rituximab(n = 13) or with rituximab alone (n = 10) regarding responsetreatment relapses or reinfusions needed

Baseline Immunologic CharacteristicsAll sera with an anti-NF155+ CBA were also positive byELISA anti-NF155 titers ranged from 1300 to 172300Autoantibodies were predominantly of the IgG4 subclass in allpatients In addition we evaluated NF155 positivity in 4 CSFfrom patients with anti-NF155+ AN and 3 of them testedpositive for NF155 antibodies We were able to performsubclass analysis and titration in 2 CSF samples both wereIgG4 and their titers significantly lower than in sera (1160 inboth CSF samples and 124300 and 172300 in sera)

Regarding the HLA genotyping DRB115 alleles (DRB11501 or DRB11502) were present in 21 of 23 patients with anti-NF155+ AN (913) Most frequent allele was DRB11501(n = 13 722) No clinical differences were observed betweenpatients with DRB11501 and DRB11502 except for a trendto younger age in patients with DRB11502 (452 plusmn 205 vs306 plusmn 146 p = 014) In contrast HLA-DRB115 is found in17 of Spanish population 12 of North Italy population25 of Southern France population and 20 of Englishpopulation28

Baseline Serum NfL LevelsSerum NfL levels were determined in all samples available(3640) at baseline Anti-NF155 + AN patients had

Table 2 Treatment and Clinical Response

Treatment

No ofpatients(n )

Response(n ) DoseProtocol

IVIg 38 (95) Yes 5 (131)Partial 9(237)No 24 (632)

2gkg per course

Steroids 36 (90) Yes 10 (278)Partial 16(444)No 10 (278)

1 mgkgd 23 (639)MP iv pulse 4 (111)MP iv pulse + mgkgd 5(139)Others 4 (111)

PLEX 18 (462) Yes 7 (389)Partial 6(333)No 5 (278)

No of sessions (medianIQR) 6 (5ndash9)

Rituximabab 23 (575) Yes 17 (773)Partial 3(136)No 2 (91)

4 + 2 8 (364)4 6 (273)1 + 1 6 (273)Others 2 (91)

Azathioprine 9 (225) Yes 1 (111)Partial 4(444)No 4 (444)

mdash

Mycophenolate 3 (75) Partial 1(333)No 2 (667)

mdash

Methotrexate 3 (75) Partial 1(333)No 2 (667)

mdash

Cyclosporine 1 (25) No 1 (100) mdash

Interferon beta1a

1 (25) No 1 (100) mdash

Abbreviations IVIg = IV immunoglobulin MP = methylprednisolone PLEX =plasma exchange4 + 2 375 mgm2 every week for 4 consecutive weeks and then monthly forthe next 2 months 1 + 1 2 1 g doses separated by 2 weeks 4 375 mgm2

every week for 4 consecutive weeksa One patient included in a blinded clinical trial of rituximab vs placebob Improvement in mRS after rituximab treatment is detailed in eTable 1(linkslwwcomNXIA641)

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significantly higher sNfL levels than HC (3647 pgmLvs 756 pgmL p lt 0001 Figure 1 and Table 4) at baselinesNfL levels correlated with age in HC (r = 073 p lt 0001)but not in patients with anti-NF155 + AN (r = 026p = 012) The samples collected pretreatment (n = 12)have higher sNfL levels than those collected after treat-ment had been started (n = 24) (6584 vs 1841 pgmLp = 0002)

Relationship Between NF155 Titers sNfLLevels and Clinical StatusAbsolute anti-NF155 titers did not correlate with clinicalstatus across patients but they did when we evaluatedfollow-up NF155 titers using baseline titers as the reference(r = 041 p = 0004 eFigures 2 and 3 linkslwwcomNXIA641) Baseline sNfL levels negatively correlated withI-RODS at blood sampling (r = minus088 p lt 0001) and withmaximum I-RODS achieved (r = minus058 p = 001) (eFigure 4linkslwwcomNXIA641) However correlation between thesNfL levels and the final I-RODS (r = minus036 p = 01) didnot reach statistical significance sNfL levels correlated withNF155 titers at baseline (n = 36 r = 043 p = 0001) andat every time point available (n = 105 r = 034 p lt 0001)

Baseline sNfL levels did not correlate with lowest CMAP innerve conduction studies in any of the nerves tested Althoughpatients showing spontaneous activity in the needle EMG ofthe tibialis anterior showed higher sNfL levels than patients

without spontaneous activity (6733 vs 2512 pgmL p = 01)the differences were not statistically significant

Relationship Between NF155 Titers sNfLLevels and Treatment Response to RituximabKineticsIn rituximab-treated patients with anti-NF155+ AN in whichfollow-up samples at regular time points were available (n =7) antibody titers decreased during follow-up This declinewas significant as early as 3 months after administration ofrituximab (mean decrease of 667 Figure 2) At 1 year amean titer reduction of 986 in rituximab-treated patientswas achieved In patients not treated with rituximab in whichfollow-up sample at 1 year (n = 6) was available no signif-icant decrease of antibodies was observed (2 patients had amedian decrease of 94 2 patients remained stable and 2patients increased their NF155 titers) (Figure 3) sNfL levelswere higher in rituximab-treated patients compared withthose not treated with rituximab (4769 vs 1443 pgmL p =008 Table 3) but differences were not statistically signifi-cant sNfL levels decreased at 1 year in rituximab-treatedpatients (median of 3798 pgmL at baseline vs 1172 pgmLat 1 year p = 004) In patients not treated with rituximabmedian baseline sNfL levels were normal and no changeswere observed at 1 year (762 vs 695 pgmL p = 016)Clinical status improved at 1 year in both groups but onlythe rituximab-treated group improved significantly (medianof mRS 4 [3ndash4] at baseline vs 2 [1ndash2] at the 1-year follow-up

Table 3 Rituximab Treatmenta

Patients treated with rituximab (n = 23) Patients not treated with rituximab (n = 16) p Value

Age at onset (mean plusmn SD) 441 plusmn 207 3925 plusmn 186 051

Age at diagnosis (mean plusmn SD) 452 plusmn 207 398 plusmn 1812 044

Sex (male n ) 17 (773) 11 (688) 041

Baseline NfL levels (median IQR) (n = 36) 4769 (1887ndash15429) 1443 (758ndash6468) 008

NF155 titers (median IQR) 124300 (18100ndash124300) 18100 (12700ndash124300) 019

No of previous treatments (median IQR) 4 (3ndash5) 2 (2ndash3) 003

PLEX (n ) 14 (636) 4 (25) 002

mRS (median IQR)

Baseline (n = 27) 3 (2ndash4) 3 (1ndash4) 094

Maximum (n = 37) 4 (3ndash4) 3 (2ndash4) 053

Final (n = 37) 2 (1ndash2) 2 (1ndash3) 062

R-ODS (median IQR)

Baseline (n = 13) 45 (40ndash60) 61 (18ndash86) 083

Maximum (n = 16) 40 (29ndash49) 47 (9ndash77) 078

Final (n = 21) 58 (51ndash88) 60 (55ndash88) 069

Abbreviations IQR = interquartile range I-RODS = Inflammatory Rasch-built Overall Disability Scale MP =methylprednisolone mRS =modified Rankin ScaleNF155 = neurofascin-155 PLEX = plasma exchangea We exclude 1 patient included in a blinded clinical trial of rituximab vs placebo

6 Neurology Neuroimmunology amp Neuroinflammation | Volume 9 Number 1 | January 2022 NeurologyorgNN

p = 0004 in rituximab-treated AN patients and 3 [2ndash4] atbaseline vs 2 [1ndash4] at 1 year p = 025 in patients not treatedwith rituximab)

DiscussionOur study describes the clinical laboratory treatment re-sponse and prognostic features of the largest anti-NF155+AN cohort published so far341529-31 It confirms that pa-tients with AN with autoantibodies against NF155 presentat a younger age (including a significant proportion ofpatients below 30 years)5 with a specific clinical phenotypewith distal weakness tremor and ataxia The presence ofthese features in a patient fulfilling the CIDP criteria shouldimmediately prompt anti-NF155 antibody testing as rec-ommended in the recently published revision of the EANPNS CIDP diagnostic guidelines10 Other associated fea-tures which may suggest the presence of anti-NF155 ANand prompt antinodalparanodal autoantibody testing arethe presence of cranial nerve palsies particularly facialpalsy high CSF protein content and poor response to IVIgAn important implication of our study for the testing rec-ommendations in diagnostic guidelines is that almost 10of the patients testing positive for anti-NF155 in CBAperformed with the myc-DDK tagged NF155 plasmid arefalse positives This agrees with our previous observationthat demonstrated that a positive test in the NF155 CBAcould be due to antibodies targeting the myc-DDK tag andnot NF155 itself32 This implies that untagged-NF155

plasmids should be preferentially used and that a secondtest (ELISA or teased-nerve immunohistochemistry) isalways recommended

Previous case series and systematic reviews suggested that pa-tients with anti-NF155+ AN respond poorly to IVIg or that IVIgresponse is less frequent than in seronegative CIDP3303133 Thishas been described in other IgG4-mediated diseases such as anti-muscle-specific tyrosine kinase-positive myasthenia gravis34

There are different hypotheses on why this happens in IgG4-mediated diseases although none has been validated On the onehand complement and cell-mediated cytotoxicity do not happenin IgG4 diseases and thus any effect that IVIg may have overcomplement effector mechanisms or cytotoxic cells may be lostOn the other hand IgG4 is secreted exclusively by IL10+ reg-ulatory B-cells and these cells interestingly have significantlylower expression of the inhibitory immunoglobulin receptorFCGRIIb on their surface (and this could decrease the ability ofIgG4-producing cells to be inhibited by IgG)35 Our study hasalso found that most patients with anti-NF155+ AN do notrespond appropriately to IVIg (or to a lower extent cortico-steroids) according to their physicians On the contrary mostpatients respond to rituximab even when they are refractory toIVIg and corticosteroid therapy (this also happens in other IgG4-mediated diseases3637) More than 50 of patients in our cohortwere treated with rituximab after a poor response to othertherapies and more than 75 had a good response This im-provement agrees with prospectively collected follow-up mRSscores that show that most patients improved at least 1 point

Figure 1 Baseline Serum NfL in Anti-NF155 + Patients With AN and Healthy Controls

Patients with anti-NF155 + AN had significantly higher sNfL levels than HC The line in the center represents the median value and the whiskers indicate theinterquartile range AN = autoimmune nodopathy CIDP = chronic inflammatory demyelinating polyradiculoneuropathy HC = healthy control NF155 =neurofascin-155 sNfL = serum neurofilament light chain

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 9 Number 1 | January 2022 7

(826) and a significant proportion (565) improved 2 ormore points despite being resistant to other therapies Indeeddespite rituximab-treated patients had used a higher number ofdifferent drugs and showed higher disability and sNfL levels atbaseline their final prognosis did not differ from patients whoresponded to first-line therapies The great benefit that rituximabprovides to these patients supports that it could be used as anearlier therapeutic option although careful assessment of the risk-benefit balance and vaccination status needs to be performedbefore rituximab treatment as one patient died due to an in-fection aggravated by immune-suppresion Approximately 50ofthe patients in our cohort received PLEX This is the result of 2facts first patients presented with an aggressive neuropathy thatdid not respond to first-line therapies and second because rit-uximab effect is not clearly seen until the third month of diseaseand PLEX is used to eliminate as much autoantibody as possiblebefore the use of rituximab to shorten the recovery period Ourstudy did not find differences in treatment response relapses orreinfusions between the group of rituximab-treated patients withanti-NF155 AN pretreated with PLEX and the group nontreatedwith PLEX but larger dedicated studies are needed to clarify theutility of this therapeutic strategy

Anti-NF155 antibodies are pathogenic according to in vitro andin vivo models16 As such we hypothesized that their titersshould correlate with disease severityWe found that IgG4 anti-NF155 antibody titers correlate with clinical status within thesame patient but not across patients This is something that hasbeen described in other IgG4 autoimmune diseases treatedwith rituximab such as anti-muscle-specific tyrosine kinasemyasthenia gravis3738 and in other polyneuropathies as IgMantimyelin-associated glycoprotein neuropathy3940 Severalfactors may explain why autoantibody titers do not correlatewith clinical activity across patients autoantibody affinity fortheir target antigen and diverse biases arising from the retro-spective nature of the study (diverse time points diversetreatment regimens and diverse baseline severities and ages)among others However our study proves that anti-NF155

antibody titers can be a good biomarker for disease activity andtreatment response when assessed in individual patients andrepresented as changes relative to baseline levels Indeed inthose patients treated with rituximab IgG4 anti-NF155 de-creased more than a 90 relative to baseline titers or evenbecame negative in a few patients This suggests that thereappearance or a significant increase in the pathogenic auto-antibody may precede a relapse and thus could guide treat-ment reinfusions Again this use of the autoantibodies needs tobe validated prospectively but the temporal evolution of theautoantibody titers paralleling the sNfL levels and the clinicalstatus in the few patients in which prospective follow-up wasavailable is promising

We identified IgG4 anti-NF155 antibodies in the CSF of 3 of4 patients in which a CSF sample was available Intrathecalantipan neurofascin has been previously described41 andanti-NF155 antibodies in CSF have been described in 2patients with combined central and peripheral de-myelination42 but not in anti-NF155 AN so far The highprotein content in CSF the absence of oligoclonal bandsand the presence of higher anti-NF155 titers in serum thanin CSF suggests that anti-NF155 antibodies appear in theCSF because of blood-brain barrier disruption and not be-cause of intrathecal synthesis The presence of these auto-antibodies in the CSF could help explaining the cerebellarfeatures in patients with anti-NF155+ AN but larger cohortsincluding patients with and without tremor in which CSF isanalyzed are needed

Our study also showed that sNfL levels were higher in patientswith anti-NF155+ AN than in HC High sNfL levels have alsobeen recently described in CIDP particularly in a small subsetof patients with anti-NF155+ AN who showed higher sNfLlevels than seronegative CIDP18 In our study we found a

Table 4 Baseline SerumNfL in Anti-NF155 + PatientsWithAN and Healthy Controls

NF155 + patientswith AN HC p Value

Age at samplingmean plusmn SD

4787 plusmn 2016 48 plusmn 181 078

Sex n male 28 (718) 31 (397) 0001

sNfL (pgmL) lt0001

n 36 78

Median 3647 756

Max 53664 5682

Min 344 230

Abbreviations AN = autoimmune nodopathy HC = healthy control NF155 =neurofascin-155 sNfL = serum neurofilament light chain

Figure 2 Clinical Status NF155 Titers and sNfL Levels AfterRituximab Treatment Induction Kinetics

Rituximab treated anti-NF-155 patientswith follow-up samples at regular timepoints show improvement in the mRS scale a decrease in NF155 titers and adecrease in sNfL levels starting on the thirdmonth of treatment infusion Theline in the center represents the median value and the whiskers indicate theinterquartile range mRS = modified Rankin Scale NF155 = neurofascin-155NF155 = neurofascin-155 sNfL = serum neurofilament light chain

8 Neurology Neuroimmunology amp Neuroinflammation | Volume 9 Number 1 | January 2022 NeurologyorgNN

strong correlation between baseline sNfL levels and initialI-RODS and maximum I-RODS achieved but not with finalI-RODS suggesting that the final outcomes are not completelydetermined by initial severity because effective therapieschange the course of the disease and most patients improvesignificantly regardless of the treatment used These data differfrom those found in GBS24 a monophasic disorder in whichinitial events determine long-term outcomes but nonethelesssuggest that sNfL may be useful to monitor disease because itseems to happen in other peripheral neuropathies43-45

Our study was not designed to correlate sNfL levels withelectrophysiologic parameters because EMG and sNfL levelswere not performed at the same time points but we exploredpotential correlations between CMAP amplitudes the pres-ence of spontaneous activity at distal most affected musclesand sNfL levels We failed to find strong associations sNfLlevels did not correlate with CMAP amplitudes but they ten-ded to be higher in patients with spontaneous activity Thusour results although preliminary support the ability of sNfL tomonitor axonal damage Altogether the correlation of sNfLwith disability scales and less strongly with the appearance ofresidual disability or spontaneous activity agrees with the rel-atively frequent presence of distal muscle atrophy because ofsecondary axonal damage that some of these patients displayand would support the use of sNfL as an early marker ofpotential axonal damage that could guide treatment selection toprevent the appearance of this permanent damage

sNfL levels and anti-NF155 antibody titers decreased in allpatients in which prospective follow-up was performed onrituximab therapy whereas neither sNfL or anti-N155 levelsshowed comparable changes with other treatments The ob-servation of the rituximab-treated prospectively followedsubset of patients suggests considering the caveats of clinicalevaluation in monitoring disease activity in autoimmuneneuropathies that monitoring sNfL levels that inform about

the tissue status and anti-NF155 titers that inform about theimmunologic effector mechanism at regular intervals aftertreatment could be useful to guide treatment choices anddetect suboptimal therapeutic responses Hypothetically aneventual increase in autoantibody titers or sNfL levels couldherald a subsequent relapse and detecting the biomarker in-crease could help prevent it However the need of retreat-ment should be assessed individually based on patientrsquosclinical status and not only based on the laboratory data

HLA loci are the group of genetic factors that has most fre-quently been associated with autoimmune diseases includingstrong associations with other IgG4-mediated diseases46-48

Previous studies have shown a strong association between aspecific Class II allele HLA-DRB115 (either 1501 or 1502) and patients with anti-NF155+ AN13 Our study shows astronger association than previously reported (913) con-firming that this HLA allele is a constitutive risk factor thatassociated with unknown environmental factors may bedriving the appearance of the anti-NF155 autoantibodies Thestudy of this genetic association in conjunction with geo-graphic distribution of the disorder lifestyle concomitantdisorders microbiome or environmental triggers may yieldinteresting pathophysiologic insights but requires significantlylarger cohorts of patients

Themain limitations of our study arise from the small numberof patients and its retrospective nature including the retro-spective analysis of treatment efficacy using chart reviewFurthermore considering that patients were identifiedthrough routine diagnostic testing it is likely that our cohort isenriched in patients with tremor or a lack of response to IVIgbecause of selection bias However since anti-NF155+ ANaccount for approximately 5 of all patients with CIDP with40 patients our cohort provides the largest cohort in which acomprehensive clinical serologic and treatment responseanalysis has been performed

Figure 3 Rituximab Treatment Response Clinical Status NF155 Titers and sNfL Levels

Clinical improvement is present in patients treated with first-line therapies or rituximab but only the rituximab-treated group improved significantly Anti-NF155 titers and sNfL levels decreased only in rituximab-treated group The line in the center represents the median value and the whiskers indicate theinterquartile range IVIg = IV immunoglobulin mRS= modified Rankin Scale NF155= neurofascin-155 sNfL= serum neurofilament light chain

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 9 Number 1 | January 2022 9

In conclusion our study confirms that anti-NF155+ ANconstitutes a defined subset of patients with characteristicclinical epidemiologic and immunologic features thatresponse to IVIg and steroids is often poor whereas rit-uximab is an effective therapy for most patients and thatanti-NF155 antibody titers and sNfL levels could be used incombination to monitor clinical activity ongoing axonaldamage and treatment response

AcknowledgmentThe authors would like to acknowledge the Department ofMedicine at the Universitat Autonoma de Barcelona Severalauthors of this publication are members of the EuropeanReference Network for rare neuromuscular diseases (EURO-NMD)

Study FundingThis work is supported by Fondo de Investigaciones San-itarias (FIS) Instituto de Salud Carlos III Spain andFEDER under grant FIS190140 and personal grantINT2000080 personal grant GBS-CIDP Foundation toCL personal grant Rio Hortega CM1900042 to LMA andthe ER20P3AC7624 project of the ACCI call of theCIBERER network Madrid Spain XSC was supported bya ldquoSara Borrellrdquo postdoctoral fellowship project ldquoCD1800195rdquo funded by Instituto de Salud Carlos III and co-funded by European Union (ERDFESF ldquoA way to makeEuroperdquoldquoInvesting in your futurerdquo) AC thanks theMedical Research Council (MRT0017121) the Fonda-zione CARIPLO (2019-1836) the Italian Ministry ofHealth-Ricerca Corrente the Inherited Neuropathy Con-sortium (INC) and Fondazione Regionale per la RicercaBiomedica for grant suport

DisclosureL Querol has provided expert testimony for Grifols Sanofi-Genzyme Novartis UCB Roche and CSL Behring and re-ceived research funds from Novartis Spain Sanofi-Genzymeand Grifols L Martın-Aguilar has received speaking hono-raria from Roche E Pascual-Gontildei has received speakinghonoraria from Roche and Biogen J Dıaz-Manera hasprovided expert testimony for PTC and Sanofi-Genzymehas been external advisor for Sanofi Sarepta and Audentesand received research funds from Sanofi-Genzyme andBoehringer G Liberatore reported travel grants to attendscientific meetings from CSL Behring and Kedrion MCabrera-Serrano has received honoraria from Biogen forscientific translation works K Pitarokoili received travelgrants and speakersrsquo honoraria from Novartis Biogen idecTeva Bayer Celgene CSL Behring and Grifols all not re-lated to the manuscript The other authors report no dis-closures Go to NeurologyorgNN for full disclosures

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationMarch 2 2021 Accepted in final form September 27 2021

Appendix Authors

Name Location Contribution

LorenaMartın-Aguilar MDPhD

Hospital de la Santa Creu iSant Pau IIB-Sant PauBarcelona Spain

Acquisition of dataperformed the experimentsanalyzed the data draftedthe manuscript forintellectual content

Cinta LleixaMSc

Hospital de la Santa Creu iSant Pau IIB-Sant PauBarcelona Spain

Acquisition of dataperformed the experimentsdrafted and revised themanuscript for intellectualcontent

Elba Pascual-Gontildei MDPhD

Hospital de la Santa Creu iSant Pau IIB-Sant PauBarcelona Spain

Acquisition of data revisedthe manuscript forintellectual content

MartaCaballeroMD

Hospital de la Santa Creu iSant Pau Barcelona Spain

Acquisition of data revisedthe manuscript forintellectual content

LauraMartınez-MartınezMD PhD

Hospital de la Santa Creu iSant Pau Barcelona Spain

Performed HLAexperiments and analyzedthe data revised themanuscript for intellectualcontent

Jordi Diaz-Manera MDPhD

Hospital de la Santa Creu iSant Pau Barcelona Spain

Acquisition of samples anddata Revised themanuscript for intellectualcontent

Ricard Rojas-Garcıa MDPhD

Hospital de la Santa Creu iSant Pau Barcelona Spain

Acquisition of samples anddata revised themanuscript for intellectualcontent

Elena Cortes-Vicente MDPhD

Hospital de la Santa Creu iSant Pau IIB-Sant PauBarcelona Spain

Acquisition of samples anddata revised themanuscript for intellectualcontent

Janina Turon-Sans MD

Hospital de la Santa Creu iSant Pau Barcelona Spain

Acquisition of samples anddata revised themanuscript for intellectualcontent

Noemı deLuna PhD

IIB-Sant Pau BarcelonaSpain

Revised the manuscript forintellectual content

XavierSuarez-Calvet PhD

IIB-Sant Pau BarcelonaSpain

Revised the manuscript forintellectual content

EduardGallardo PhD

IIB-Sant Pau BarcelonaSpain

Revised the manuscript forintellectual content

YusufRajabally MD

University HospitalBirmingham BirminghamUK

Acquisition of samples anddata revised themanuscript for intellectualcontent

SangeetaScotton MD

University HospitalBirmingham BirminghamUK

Acquisition of samples anddata revised themanuscript for intellectualcontent

Bart CJacobs MDPhD

Erasmus Medical CenterRotterdam TheNetherlands

Acquisition of samples anddata revised themanuscript for intellectualcontent

Adaja BaarsMD

Erasmus Medical CenterRotterdam TheNetherlands

Acquisition of samples anddata revised themanuscript for intellectualcontent

10 Neurology Neuroimmunology amp Neuroinflammation | Volume 9 Number 1 | January 2022 NeurologyorgNN

References1 Lehmann HC Burke D Kuwabara S Chronic inflammatory demyelinating poly-

neuropathy update on diagnosis immunopathogenesis and treatment J NeurolNeurosurg Psychiatry 201990(9)981-987

2 Mathey EK Park SB Hughes RA et al Chronic inflammatory demyelinating poly-radiculoneuropathy from pathology to phenotype J Neurol Neurosurg Psychiatry201586(9)973-985

3 Querol L Nogales-Gadea G Rojas-Garcia R et al Neurofascin IgG4 antibodies inCIDP associate with disabling tremor and poor response to IVIg Neurology 201482(10)879-886

4 Delmont EMansoC Querol L et al Autoantibodies to nodal isoforms of neurofascin inchronic inflammatory demyelinating polyneuropathy Brain 2017140(7)1851-1858

Appendix (continued)

Name Location Contribution

AndreaCortese MDPhD

IRCCS Mondino FoundationPavia Italy

Acquisition of samples anddata revised themanuscript for intellectualcontent

Elisa VegezziMD

IRCCS Mondino FoundationPavia Italy

Acquisition of samples anddata revised themanuscript for intellectualcontent

RomanaHoftbergerMD

Medical University ofVienna Vienna Austria

Acquisition of samples anddata revised themanuscript for intellectualcontent

FritzZimprich MD

Medical University ofVienna Vienna Austria

Acquisition of samples anddata revised themanuscript for intellectualcontent

CorneliaRoesler MD

Paracelsus MedicalUniversity Salzburg Austria

Acquisition of samples anddata revised themanuscript for intellectualcontent

EduardoNobile-Orazio MDPhD

Humanitas Clinical andResearch Institute MilanItaly

Acquisition of samples anddata revised themanuscript for intellectualcontent

GiuseppeLiberatoreMD

Humanitas Clinical andResearch Institute MilanItaly

Acquisition of samples anddata revised themanuscript for intellectualcontent

Hiew FuLiong MD

Kuala Lumpur GeneralHospital Jalan PahangKuala Lumpur Malaysia

Acquisition of samples anddata revised themanuscript for intellectualcontent

AliciaMartınez-Pintildeeiro MD

Hospital UniversitariGermans Trias i PujolBadalona Spain

Acquisition of samples anddata revised themanuscript for intellectualcontent

AlejandraCarvajal MD

Hospital Universitario deGranada Granada Spain

Acquisition of samples anddata revised themanuscript for intellectualcontent

Raquel Pintildear-Morales MD

Hospital UniversitarioClınico San Cecilio GranadaSpain

Acquisition of samples anddata revised themanuscript for intellectualcontent

MercedesUson-MartınMD

Hospital Son Llatzer Palmade Mallorca Spain

Acquisition of samples anddata revised themanuscript for intellectualcontent

Olalla AlbertıMD

Hospital San Jorge HuescaSpain

Acquisition of samples anddata revised themanuscript for intellectualcontent

MariaAngelesLopez-PerezMD

Hospital San PedroLogrontildeo Spain

Acquisition of samples anddata revised themanuscript for intellectualcontent

FabianMarquez MD

Hospital Universitari JosepTrueta Girona Spain

Acquisition of samples anddata revised themanuscript for intellectualcontent

Appendix (continued)

Name Location Contribution

Julio Pardo-FernandezMD PhD

Hospital ClınicoUniversitario de SantiagoSantiago de CompostelaSpain

Acquisition of samples anddata revised themanuscript for intellectualcontent

Laura Muntildeoz-Delgado MD

Hospital UniversitarioVirgen del Rocıo SevillaSpain

Acquisition of samples anddata revised themanuscript for intellectualcontent

MacarenaCabrera-Serrano MDPhD

Hospital UniversitarioVirgen del Rocıo SevillaSpain

Acquisition of samples anddata revised themanuscript for intellectualcontent

Nicolau OrtizMD PhD

Hospital Universitari SantJoan de Reus TarragonaBarcelona

Acquisition of samples anddata revised themanuscript for intellectualcontent

ManuelBartolomeMD

Complejo Asistencial deAvila Avila Spain

Acquisition of samples anddata revised themanuscript for intellectualcontent

OzgurDuman MD

Akdeniz University AntalyaTurkey

Acquisition of samples anddata revised themanuscript for intellectualcontent

Vera Bril MD Toronto General HospitalUniversity Health NetworkUniversity of TorontoToronto Canada

Acquisition of samples anddata revised themanuscript for intellectualcontent

DarwinSegura-Chavez MD

Instituto Nacional deCiencias NeurologicasLima Peru

Acquisition of samples anddata revised themanuscript for intellectualcontent

KalliopiPitarokoiliMD

St Josef-Hospital Ruhr-University BochumBochum Germany

Acquisition of samples anddata revised themanuscript for intellectualcontent

ClaudiaSteen MD

Sant Joseph Hospital BerlinGermany

Acquisition of samples anddata revised themanuscript for intellectualcontent

Isabel IllaMD PhD

Hospital de la Santa Creui Sant Pau BarcelonaSpain

Revised the manuscript forintellectual content

Luis QuerolMD PhD

Hospital de la Santa Creu iSant Pau Barcelona Spain

Design and conceptualizedthe study interpreted thedata revised themanuscript for intellectualcontent

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 9 Number 1 | January 2022 11

5 Querol L Nogales-Gadea G Rojas-Garcia R et al Antibodies to contactin-1 inchronic inflammatory demyelinating polyneuropathy Ann Neurol 201373(3)370-380

6 Doppler K Appeltshauser L Villmann C et al Auto-antibodies to contactin-associated protein 1 (Caspr) in two patients with painful inflammatory neuropathyBrain 2016139(pt 10)2617-2630

7 Pascual-Gontildei E Fehmi J Lleixa C et al Antibodies to the Caspr1contactin-1complex in chronic inflammatory demyelinating polyradiculoneuropathy Brain2021144(4)1183-1196

8 Pascual-Gontildei E Martın-Aguilar L Querol L Autoantibodies in chronic inflammatorydemyelinating polyradiculoneuropathy Curr Opin Neurol 201932(5)651-657

9 Querol L Devaux J Rojas-Garcia R Illa I Autoantibodies in chronic inflammatory neu-ropathies diagnostic and therapeutic implications Nat Rev Neurol 201713(9)533-547

10 Van den Bergh PYK Doorn PA Hadden RDM et al European Academy ofNeurologyPeripheral Nerve Society Guideline on diagnosis and treatment of chronicinflammatory demyelinating polyradiculoneuropathy report of a Joint Task ForcemdashSecond Revision J Peripher Nerv Syst 202126(3)242-268

11 Painous C Lopez-Perez MA Illa I Querol L Head and voice tremor improving withimmunotherapy in an anti-NF155 positive CIDP patient Ann Clin Transl Neurol20185(4)499-501

12 Kouton L Boucraut J Devaux J et al Electrophysiological features of chronic in-flammatory demyelinating polyradiculoneuropathy associated with IgG4 antibodiestargeting neurofascin 155 or contactin 1 glycoproteins Clin Neurophysiol 2020131(4)921-927

13 Martinez-Martinez L Lleixa MC Boera-Carnicero G et al Anti-NF155 chronic in-flammatory demyelinating polyradiculoneuropathy strongly associates to HLA-DRB15 J Neuroinflammation 201714(1)1-6

14 Querol L Rojas-Garcıa R Diaz-Manera J et al Rituximab in treatment-resistant CIDPwith antibodies against paranodal proteins Neurol Neuroimmunol Neuroinflamm20152(5)e149

15 Cortese A Lombardi R Briani C et al Antibodies to neurofascin contactin-1 andcontactin-associated protein 1 in CIDP clinical relevance of IgG isotype NeurolNeuroimmunol Neuroinflamm 20207(1)e639

16 Manso C Querol L Lleixa C et al Anti-neurofascin-155 IgG4 antibodies preventparanodal complex formation in vivo J Clin Invest 2019129(6)2222-2236

17 Koike H Kadoya M Kaida KI et al Paranodal dissection in chronic inflammatorydemyelinating polyneuropathy with anti-neurofascin-155 and anti-contactin-1 anti-bodies J Neurol Neurosurg Psychiatry 201788(6)465-473

18 Fukami Y Iijima M Koike H Yamada S Hashizume A Katsuno M Association ofserum neurofilament light chain levels with clinicopathology of chronic inflammatorydemyelinating polyneuropathy including NF155 reactive patients J Neurol 2021268(10)3835-3844

19 Van den Bergh PYK Hadden RDM Bouche P et al European Federation of Neu-rological SocietiesPeripheral Nerve Society Guideline on management of chronicinflammatory demyelinating polyradiculoneuropathy Report of a Joint Task Force ofthe European Federation of Neurological Societies and the Peripher Eur J Neurol201017356-363

20 Breiner A Bourque PR Allen JA Updated cerebrospinal fluid total protein referencevalues improve chronic inflammatory demyelinating polyneuropathy diagnosisMuscle Nerve 201960(9)180-183

21 Quinn TJ Dawson J Walters MR Lees KR Functional outcome measures in con-temporary stroke trials Int J Stroke 20094(9)200-205

22 Van Nes SI Vanhoutte EK Van Doorn PA et al Rasch-built Overall Disability Scale (R-ODS) for immune-mediated peripheral neuropathies Neurology 201176(9)337-345

23 Querol L Siles AM Alba-Rovira R et al Antibodies against peripheral nerve antigens inchronic inflammatory demyelinating polyradiculoneuropathy Sci Rep 20177(9)14411

24 Martın-Aguilar L Camps-Renom P Lleixa C et al Serum neurofilament light chainpredicts long-term prognosis in Guillain-Barre syndrome patients J Neurol NeurosurgPsychiatry 20219270-77

25 Athanasopoulos D Motte J Fisse AL et al Longitudinal study on nerve ultrasoundand corneal confocal microscopy in NF155 paranodopathy Ann Clin Transl Neurol20207(6)1061-1068

26 De Simoni D Ricken G Winklehner M et al Antibodies to nodalparanodal proteinsin paediatric immune-mediated neuropathy Neurol Neuroimmunol Neuro-inflammation 20207(4)e763

27 Verghese A Hiew FL Chia YK Querol L Visual pathway demyelination inneurofascin-155 IGG4- positive combined central and peripheral demyelinationJ Neurol Sci 2019405196-197

28 Allele Frequency Net Database Accessed October 29 2021 allelefrequenciesnet29 Ogata H Yamasaki R Hiwatashi A et al Characterization of IgG4 anti-neurofascin

155 antibody-positive polyneuropathy Ann Clin Transl Neurol 20152(10)960-97130 Devaux JJ Miura Y Fukami Y et al Neurofascin-155 IgG4 in chronic inflammatory

demyelinating polyneuropathy Neurology 201686(9)800-80731 Hu W Xin Y He Z Zhao Y Association of neurofascin IgG4 and atypical chronic

inflammatory demyelinating polyneuropathy a systematic review and meta‐analysisBrain Behav 20188(10)e01115

32 Martın-Aguilar L Pascual-Gontildei E Lleixa C et al Antibodies against nodo-paranodalproteins are not present in genetic neuropathies Neurology 202095(4)e427-e433

33 Guo X Tang L Huang Q Tang X A systematic review and meta-analysis of auto-antibodies for diagnosis and prognosis in patients with chronic inflammatory de-myelinating Polyradiculoneuropathy Front Neurosci 202115637336

34 Oh SJ Morgan MB Lu L et al Different characteristic phenotypes according toantibody in myasthenia gravis J Clin Neuromuscul Dis 201214(2)57-65

35 Van De Veen W Stanic B Yaman G et al IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responsesJ Allergy Clin Immunol 2013131(4)1204-1212

36 Joly P Mouquet H Roujeau J-C et al A single cycle of rituximab for the treatment ofsevere pemphigus N Engl J Med 2007357(6)545-552

37 Dıaz-Manera J Martınez-Hernandez E Querol L et al Long-lasting treatment effectof rituximab in MuSK myasthenia Neurology 201278(3)189-193

38 Marino M Basile U Spagni G et al Long-Lasting rituximab-induced reduction ofspecificmdashbut not totalmdashIgG4 in MuSK-positive myasthenia gravis Front Immunol2020111-9

39 Svahn J Petiot P Antoine JC et al Anti-MAG antibodies in 202 patients clinico-pathological and therapeutic features J Neurol Neurosurg Psychiatry 201889(5)499-505

40 Dalakas MC Rakocevic G SalajeghehM et al Placebo-controlled trial of rituximab inIgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy AnnNeurol 200965(3)286-293

41 Stengel H Vural A Brunder AM et al Anti-pan-neurofascin IgG3 as a marker offulminant autoimmune neuropathy Neurol Neuroimmunol Neuroinflamm 20196(5)e603

42 Kawamura N Yamasaki R Yonekawa T et al Anti-neurofascin antibody in patientswith combined central and peripheral demyelinationNeurology 201381(8)714-722

43 Lieverloo GGA Wieske L Verhamme C et al Serum neurofilament light chain inchronic inflammatory demyelinating polyneuropathy J Peripher Nerv Syst 201924(2)187-194

44 Sandelius Aring Zetterberg H Blennow K et al Plasma neurofilament light chain con-centration in the inherited peripheral neuropathies Neurology 201890(6)e518-e524

45 Kapoor M Foiani M Heslegrave A et al Plasma neurofilament light chain concen-tration is increased and correlates with the severity of neuropathy in hereditarytransthyretin amyloidosis J Peripher Nerv Syst 201924(4)314-319

46 Niks EH Kuks JBM Roep BO et al Strong association of MuSK antibody-positivemyasthenia gravis and HLA-DR14-DQ5 Neurology 200666(11)1772-1774

47 Huijbers MG Querol LA Niks EH et al The expanding field of IgG4-mediatedneurological autoimmune disorders Eur J Neurol 201522(8)1151-1161

48 Kim TJ Lee ST Moon J et al Anti-LGI1 encephalitis is associated with unique HLAsubtypes Ann Neurol 201781(2)183-192

12 Neurology Neuroimmunology amp Neuroinflammation | Volume 9 Number 1 | January 2022 NeurologyorgNN

DOI 101212NXI000000000000109820229 Neurol Neuroimmunol Neuroinflamm

Lorena Martiacuten-Aguilar Cinta Lleixagrave Elba Pascual-Gontildei et al Clinical and Laboratory Features in Anti-NF155 Autoimmune Nodopathy

This information is current as of November 2 2021

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

ServicesUpdated Information amp

httpnnneurologyorgcontent91e1098fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent91e1098fullhtmlref-list-1

This article cites 47 articles 7 of which you can access for free at

Citations httpnnneurologyorgcontent91e1098fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpnnneurologyorgcgicollectionclass_ivClass IV

nating_polyneuropathyhttpnnneurologyorgcgicollectionchronic_inflammatory_demyeliChronic inflammatory demyelinating polyneuropathyfollowing collection(s) This article along with others on similar topics appears in the

Errata

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nextAn erratum has been published regarding this article Please see

Permissions amp Licensing

httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

ServicesUpdated Information amp

httpnnneurologyorgcontent91e1098fullhtmlincluding high resolution figures can be found at

References httpnnneurologyorgcontent91e1098fullhtmlref-list-1

This article cites 47 articles 7 of which you can access for free at

Citations httpnnneurologyorgcontent91e1098fullhtmlotherarticles

This article has been cited by 1 HighWire-hosted articles

Subspecialty Collections

httpnnneurologyorgcgicollectionclass_ivClass IV

nating_polyneuropathyhttpnnneurologyorgcgicollectionchronic_inflammatory_demyeliChronic inflammatory demyelinating polyneuropathyfollowing collection(s) This article along with others on similar topics appears in the

Errata

content91e1129fullpdf or page

nextAn erratum has been published regarding this article Please see

Permissions amp Licensing

httpnnneurologyorgmiscaboutxhtmlpermissionsits entirety can be found online atInformation about reproducing this article in parts (figurestables) or in

Reprints

httpnnneurologyorgmiscaddirxhtmlreprintsusInformation about ordering reprints can be found online

Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

CORRECTION

Clinical and Laboratory Features in Anti-NF155 AutoimmuneNodopathyNeurol Neuroimmunol Neuroinflamm 20229e1129 doi101212NXI0000000000001129

In the Article ldquoClinical and Laboratory Features in Anti-NF155 Autoimmune Nodopathyrdquo byMartın-Aguilar et al1 the affiliation for author Eduardo Nobile-Orazio should have been listedas ldquoIRCCS Humanitas Research Hospital Milan University Rozzano Italyrdquo The publisherregrets the error

Reference1 Martın-Aguilar L Lleixa C Pascual-Gontildei E et al Clinical and laboratory features in anti-nf155 autoimmune nodopathy Neurol

Neuroimmunol Neuroinflamm 20229(1)e1098 doi 101212NXI0000000000001098

Copyright copy 2021 American Academy of Neurology 1

Copyright copy 2021 American Academy of Neurology Unauthorized reproduction of this article is prohibited