Accepted Article “Chronic Inflammatory Demyelinating Polyradiculoneuropathy: Clinical aspects and new animal models of auto-immunity to nodal components” Prof. Isabel ILLA ARTHUR ASBURY LECTURE Unitat Neuromuscular Servei Neurología. Hospital Santa Creu i Sant Pau. Universitat Autònoma Barcelona. CIBERER Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic and treatable disorder of the peripheral nerves with clinical and immunological heterogeneity. It is considered to be an autoimmune disorder resulting from synergistic interactions of cell-mediated and humoral immune responses against peripheral nerve antigens although it was only until recently that humoral immune responses have been identified (Mathey, et al., 2015). Currently, the diagnosis of CIDP is based on clinical, laboratory and electrophysiological criteria without attention to immunological findings (Van den Bergh, et al., 2010). Myelinated nerve fibers consist of four domains: the node, paranode, juxtaparanode and internode. Each of these domains expresses a large number of site specific molecules with different functions. Nodes of Ranvier are short gaps in the myelin sheath where an efficient and rapid propagation of the action potentials occur (FIG. 1). The paranodal regions sit at the margin of the nodes of Ranvier. This region is the site where myelin sheath borders (paranodal loops) closely contact the axon and act as shelters, enabling a high density of Na+ channels at the nodes of Ranvier and of K+ channels at the juxtaparanodes. Three cell adhesion molecules, contactin-1 (CNTN1) and contactin-associated protein-1 (CASPR1) in the axons, and neurofascin155 (NF155) in the myelin are responsible for the adhesion and the formation of septate-like junctions (also known as transverse bands) (FIG. 1). Over the past 5 years, several autoantibodies against proteins of the paranodes (CNTN1, CASPR1 and NF155) and nodes of Ranvier (NF186/140) have been described in patients with CIDP. Interestingly, some of these antibodies define specific CIDP subtypes sometimes referred to as nodopathies and can have diagnostic and prognostic implications (Querol, et al., 2017). The clinical characteristics associated This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/jns.12237 This article is protected by copyright. All rights reserved. with the presence of these antibodies and data supporting the immunopathogenic role of the antibodies with implications for treatment will be described below. Accepted Article ANTIBODIES TO PARANODAL GLYCOPROTEINS Anti-CNTN1 antibodies. In 2013 Querol and colleagues described the presence of antibodies to CNTN1 in four patients with CIDP (Querol, et al., 2013). The importance of the finding came from the fact that these patients shared a phenotype that consisted of a predominantly motor neuropathy and an aggressive disease course, sometimes misdiagnosed as Guillain-Barré syndrome (GBS), with demyelinating features and early axonal damage. Additionally they shared two unusual features, a poor response to intravenous immunoglobulins (IVIg) and the finding that the autoantibodies were predominantly of the IgG4 isotype (Table 1). A study by Miura and colleagues (Miura, et al., 2015) confirmed, in a series of 533 patients, that 2.4% of their CIDP cases (n=13) had IgG4 antibodies to CNTN1, 23% of these patients had a subacute onset, and approximately 60% were minimally response to IVIg. Different from our initial series, these patients presented with sensory ataxia and 73% had good response to corticosteroids. The pathology of this subtype of CIDP has subsequently been described by different authors. Doppler and coworkers (Doppler, et al., 2015) performed an immunohistochemical study on dermal myelinated fibers of 4 patients with CNTN1 antibodies and found disruption of the paranodal architecture. Using light and electron microscopy, Koike and colleagues (Koike, et al., 2017) demonstrated detachment of terminal myelin loops from the axolemma without classical macrophage-mediated demyelination antibodies in 1 patient with CNTN1 antibodies. Both studies pointed to specific pathology at the paranodes, where the antigen is located suggesting its involvement in the pathogenesis of the neuropathy. Experimental data further supports the immunopathogenicity of anti-CNTN1 IgG4 antibodies. Using an in vitro model Labasque and coworkers (Labasque, et al., 2014) demonstrated that patient IgG4 anti-CNTN1 antibodies disrupt the binding of the CNTN1-CASPR1 complex to NF155. Using cell aggregation assays they showed that the binding activity of the NF155–CNTN1–CASPR1 complex was functionally blocked and that the CNTN1 antibodies induced alteration of paranodal junctions in This article is protected by copyright. All rights reserved. myelinated neuronal cultures. An animal model recently published by Manso and coworkers (Manso, et al., 2016) revealed that intraneural injections of the antibodies into preparations of sciatic nerve progressively and specifically disrupted the Accepted Article paranodal axo-glial junction. The effects were extremely specific for anti-CNTN1 IgG4 as none of the controls including IgG1 or IgG4 immunoglobulins against other antigens (e.g., CASPR2) were able to penetrate the paranodes or produce paranodal disruption. Furthermore, the chronic infusion of antibodies induced progressive clinical deterioration combined with gait ataxia and electrophysiological worsening in animals with experimental autoimmune neuritis (EAN). The pathological analysis of the nerves did not show demyelination, axonal degeneration, or immune infiltration. Instead, the animals showed a selective loss of the paranodal specialization in motor neurons characterized by the disappearance of the CNTN1/contactin-1/NF155 complex. These studies clearly indicate that IgG4 anti‑CNTN1 antibodies play a pathogenic role in CNTN1 antibody positive CIDP (CNTN1+CIDP). Anti-NF155 antibodies. Antibodies to different isoforms of neurofascin were first reported in patients with GBS and CIDP (Devaux, et al., 2012; Pruss, et al., 2011; Yan, et al., 2010). Subsequently, antibodies specific to the NF155 isoform were found in a small group (<3%) of patients with CIDP (Ng, et al., 2012) but the phenotype(s) associated with anti-NF antibodies was not defined. Studies by Querol and colleagues (Querol, et al., 2014) and confirmed by others (Devaux, et al., 2016; Ogata, et al., 2015) have demonstrated that patients with CIDP and anti-NF155 antibodies have a distinct phenotype. Our study (Querol, et al., 2014) indicated that patients are young, have predominantly distal weakness, ataxia, often a very disabling low-frequency tremor (3-5 Hz) and demyelinating features on neurophysiological studies (Figure 1). Interestingly, and similar to CNTN1+CIDP patients, patients with NF155 antibodies have a poor response to IVIg and the autoantibodies are predominantly of the IgG4 subtype. Ogata and colleagues (Ogata, et al., 2015) indicated that up to 18% (9/50) of their patients with CIDP had antibodies to NF155 but not to NF186 and confirmed the phenotype, the poor response to IVIg, and the IgG4 subclass of the autoantibodies. They also reported the MRI findings of 7 patients; all had marked symmetric hypertrophy of the cervical and lumbosacral This article is protected by copyright. All rights reserved. roots/plexuses that was greater than seen in anti-NF155 antibody-negative CIDP control patients. The sural nerve biopsy of two patients showed occasional paranodal demyelination, but no inflammatory cell infiltrates or onion bulbs. Devaux and Accepted Article colleagues (Devaux, et al., 2016) screened a large cohort of patients and confirmed the phenotype in 7% (38/533) of CIDP patients. They also described that 8% of their NF155 antibody positive patients had demyelinating lesions in the CNS. A pathogenic role of anti-NF155 antibodies is supported by the morphological study recently performed by Koike and coworkers (Koike, et al., 2017) in 9 sural nerve biopsy specimens from CIDP patients with these antibodies. Using electron microscopy they observed detachment of terminal myelin loops from the axolemma at the paranodes in the NF155 antibody positive patents that was not seen in antibody negative CIDP patients. They also found a positive correlation between the frequencies of axo–glial detachment at the paranode and axonal degeneration. In a study of two patients with anti-NF155 antibodies, Vallat and coworkers (Vallat, et al., 2017), found selective loss of septate-like junctions at all paranodes examined and the interposition of cellular processes between the paranodal loops and the axolemma. These alterations suggest that anti-NF155 antibodies specifically disrupt the NF155–CNTN1–CASPR1 complex at the paranodes. Devaux and coworkers (Manso, et al., 2017) recently presented the preliminary results of the chronic intrathecal exposure of Lewis rats to anti-NF155 IgG4 from CIDP patients’ plasma. The study showed that anti-NF155 IgG4, but not control IgG4, induced progressive clinical deterioration, decreased CAPs amplitude and produced a selective loss of the CASPR1/contactin-1/NF155 complex at paranodes, further supporting a pathogenic role of anti-NF155 IgG4 in this subtype of CIDP. In a collaborative study we found that anti-NF155+ CIDP patients associates with HLADRB15 20 times more frequently than in seronegative CIDP(Martinez-Martinez and coworkers , unpublished observation) (Martinez-Martinez, et al., 2017) further supporting the idea that patients with these antibodies constitute a distinct subset of CIDP. Anti-CASPR-1 antibodies. The presence of anti-CASPR1 antibodies has been reported by Doppler and colleagues (Doppler, et al., 2016) in two patients with inflammatory neuropathies, one classified as CIDP, the other as GBS. Both patients were negative for This article is protected by copyright. All rights reserved. antibodies to the other two components of the paranodal complex (Contactin-1 and NF155). One common feature of these patients was the presence of intense neuropathic pain. The skin biopsy from both showed paranodal disruption on Accepted Article myelinated fibers. The isotype of the anti-CASPR1 antibodies in the CIDP patient was IgG4 and complement activation was absent. In the GBS patient the isotype of the CASPR1 antibodies was IgG3. The CASPR1+ CIDP patient received rituximab and achieved clinical stability and disappearance of the autoantibodies. This specific phenotype and the relationship to pain have not yet been confirmed in other series. ANTIBODIES TO NODAL GLYCOPROTEINS. Anti-NF186/140 antibodies. Recently nodal neurofascins were reported by Delmont and coworkers (Delmont, et al., 2017) as the main targets of autoantibodies in five patients with IgG reactivity against the nodes of Ranvier; the antibodies were predominantly IgG4. The serum of the patients showed strong IgG reactivity toward the nodes of Ranvier on teased nerve fibers without paranodal reactivity. The neurofascins located at the nodes of Ranvier are NF186 and NF140 while NF155 as noted above is located at the paranodes. These patients presented with clinical features distinct from those of patients with anti-NF155 IgG4 antibodies. Four of these patients had subacute onset of sensory ataxia and interestingly, in comparison with patients with anti-NF155 antibodies, none had tremor. Concomitant diseases were present in three of the patients, two with nephrotic syndrome and one with IgG4 related retroperitoneal fibrosis. The predominant neurophysiological features were conduction blocks and decreased distal motor amplitude. Intravenous immunoglobulin and corticosteroids were effective in three patients, and one patient remitted following rituximab treatment. Of interest, in two patients, the autoantibodies depleted and the neurophysiological data recovered after treatment. This recent description further indicates that CIDP is a heterogeneous autoimmune disorder with multiple immune targets. Other nodal antigens Different studies (Querol, et al., 2017) indicate that sera from some patients with CIDP show reactivity to components of the compact myelin, nodes or paranodes but the specific antigen target(s) has not been identified. This article is protected by copyright. All rights reserved. Treatment of nodopathies. The primary goal of therapy in patients with immune-mediated neuropathies is to Accepted Article improve strength and functional ability. Additional goals include improvement in pain, sensory loss, gait, and autonomic instability. The EFNS/PNS guidelines (Van den Bergh, et al., 2010) include as first line treatment plasmapheresis (Plex), corticosteroids, and IVIg. Plasmapheresis. Most patients with CIDP show an excellent response to Plex (Eftimov, et al., 2013). A similar good response to Plex has been reported in patients with nodal and paranodal antibody+ CIDP with the exception of one patient with anti-NF186/140 antibodies. Good response to Plex is further support for a pathogenic role of the autoantibodies. However, for maintenance treatment, Plex may be less tolerated than IVIg or corticosteroids or has more side-effects. Corticosteroids are considered a first line treatment in patients with CIDP (Van den Bergh, et al., 2010) as they have been reported to be superior to no treatment in an unblended randomized control trial and in many observational studies. The EFNS/PNS task force (Van den Bergh, et al., 2010) recommended a trial of corticosteroids in patients with significant disability (level C recommendation). In patients with nodal and paranodal antibodies, corticosteroids are reported effective in approximately 40-60% of cases (Table 2) IVIg. The most widely used treatment for CIDP is IVIg (Mehndiratta, et al., 2015) due to its proven efficacy in approximately 80% of patients. Also, crossover trials have shown no significant short-term difference between IVIg and Plex or prednisolone. Contrary to the expected good response, the percentage of patients with nodal and paranodal antibodies responsive to IVIg is much lower as only around 40% of these patients respond. An exception are patients with anti-NF186/140+ CIDP for whom a response of 80% is similar to regular CIDP. Nodal and paranodal autoantibodies are almost all of the IgG4 isotype and a similar lack of response to IVIg therapy has been described for other IgG4 mediated diseases. Antibodies of the IgG4 isotype do not activate complement or bind to Ig Fc domain receptors, elements that are involved in IVIg action mechanisms (Lunemann, et al., 2015) . This could account for the lack of response to IVIg of these patients. This article is protected by copyright. All rights reserved. Rituximab. A very good response to rituximab, a B‑cell-depleting therapy, has been reported repeatedly in small series and case reports (Delmont, et al., 2017; Doppler, et al., 2016; Querol, et al., 2015) in patients with CIDP and IgG4-antibodies who do not Accepted Article respond to conventional first line treatments. Importantly, the response is long-lasting and in those patients in whom the antibodies have been screened a decline of the antibody titers is observed in parallel to the clinical and neurophysiological improvement. Of clinical interest, the better responders were patients with short disease duration, probably due to the presence of less permanent axonal damage (Querol, et al., 2015). Although the efficacy of rituximab in patients with IgG4‑related CIDP is supported only by these small series and case reports, the effectiveness of rituximab in other IgG4‑mediated diseases with diverse target organs (Diaz-Manera, et al., 2012; Joly, et al., 2007) strongly supports considering B‑cell-depleting therapies as the treatment of choice in patients with CIDP and anti‑CNTN1, anti‑NF155, anti-CASPR1 or antiNF186/140 antibodies who have not responded to IVIg or corticosteroids. In patients with CIDP the effects of rituximab are not as clear (Velardo, et al., 2017). A trial could demonstrate if rituximab should be used as first line therapy when the presence of antibodies is confirmed. Conclusions. The clinical and immunological heterogeneity of CIDP is being unraveled with the description of specific autoantibodies and their association with disease phenotypes. The percentage of patients with CIDP in whom specific nodal or paranodal autoantibodies can be detected is low and to date only Contactin-1, NF155, CASPR1 and NF186/140 glycoproteins have been identified as targets. However, for Contactin1+ CIDP and NF155+ CIDP, morphological as well as in vivo and in vitro studies have demonstrated a pathogenic role of these antibodies in the immune neuropathies. Therefore, the detection of antibodies has implications for diagnosis, prognosis, follow-up, and importantly for treatment selection. On-going research will likely identify novel antigenic targets revealing that the heterogeneity of CIDP is due in part to a large number of immune responses that represent small groups of patients. Currently, the diagnosis of CIDP is based on clinical and electrophysiological criteria. This article is protected by copyright. All rights reserved. New diagnostic criteria should be developed that incorporate the presence of immune biomarkers. Accepted Article Acknowledgements: The biomarker studies in CIDP have been supported by grants from: Fondo de Investigaciones Sanitarias, Ministerio Economia y Competitividad , Instituto de Salud Carlos III, PI16/01440 to I.I.; The Agence Nationale pour la Recherche and Instituto de Salud Carlos III CIBERER for the ACAMIN project under the E-Rare-2 (ERA-Net for Research on Rare Diseases) framework (grant to J.J.D., O.P. and I.I) and The GBS/ CIDP Foundation to I.I. Special recognition to the investigators Luis Querol and J.J. Devaux. This article is protected by copyright. All rights reserved. Accepted Article Table 1. Characteristics of the CIDP associated to nodal protein antibodies. Summary of published cases. ANTICONTACTIN-1 (21 patients) 2.4- 7.5% ANTINF155 (51 patients) 7 - 18% ANTICASPR1 (2 patients) 3% ANTINF186/140 (5 patients) 2% Onset Aggressive acute/ subacute/ chronic Subacute or chronic Acute or chronic Subacute 4/5 Mean age (range) 60 (33-81) 38 (10-67) 30 (GBS) 69 (CIDP) 61 (2–70) Clinical features Severe motor, sensory ataxia >Distal weakness, ataxia, tremor (35 Hz) Sensory ataxia, no tremor Neurophysiological studies Demyelinating features CSF protein levels (range) Yes Early axonal loss Yes >Distal weakness, distal hyperesthesia, pain Yes Mean 190 mgr/dl (70-693) Mean 250 mgr/dl (40-600) CIDP: 520mgr/dl Nerve biopsy: Paranodal pathology without inflammation Electron microscopy: Detachment of terminal myelin loops from the axolemma Predominant IgG isotype Yes Yes Yes median 179mg/dl, range 80200g/l NR Yes Yes NR NR IgG4 IgG4 IgG4 IgG4 MRI: hypertrophy of cervical/lumbosacral roots/nerves and/or swelling Associated diseases Yes (in 2/2 patients reported) Yes (in 7/7 patients reported) NR NR Demyelinating CNS lesions NR NR Nephrotic syndrome (2 patients); retroperitoneal fibrosis (1) NR % of CIDP patients Nephrotic syndrome (1 patient) NR: Not Reported This article is protected by copyright. All rights reserved. 8% Yes Accepted Article Table 2 Response to Treatment Contactin-1 Plasmapheresis Good NF155 Good Few non responders CASPR1 GBS: ND CIDP: good IVIg <40% <20%-40% Corticosteroids 20%-73% 25%-70% Rituximab long lasting >80% long lasting >80% CIDP; 1 patient, not effective GBS: ND 3/4 CIDP: slight improvement in a few weeks GBS: ND CIDP: long Excellent in lasting 1 patient GBS: ND This article is protected by copyright. All rights reserved. NF186/140 2/5 patients improved; 1/5 worsened 3/4 Accepted Article FIGURE 1.- Schematic representation of the nodal and paranodal components of myelinated fibers to which antibodies have been described. Neurofascin 186 (NF186) is located at the nodes and the glycoprotein complex formed by Contactin-1, CASPR1 and NF155 and is involved in the adhesion between the myelin sheath borders and the axons at the paranodes. This article is protected by copyright. All rights reserved. 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