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Novel immunotherapeutic strategies in chronic inflammatory demyelinating polyneuropathy

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic immune-mediated neuropathy: it is clinically heterogeneous (relapsing-remitting form, chronic progressive form, monophasic form or CIDP having a Guillain–Barré syndrome-like onset), but potentially treatable. Although its pathophysiology remains largely unknown, CIDP is considered an immune-mediated neuropathy. Therefore, many immunotherapies have been proposed in this peripheral nervous system disorder, the most known efficient treatments being intravenous immunoglobulin, corticosteroids and plasma exchange. However, these therapies remain unsatisfactory for many patients, so numerous other immunotherapeutic strategies have been evaluated, based on their immunosuppressant or immunomodulatory potency. We have performed a large review of the literature about treatment in CIDP, with a special emphasis on novel and alternative immunotherapeutic strategies.

Stéphane Mathis1, JeanMichel Vallat2 & Laurent Magy*,2 1 Department of Neurology, University Hospital of Poitiers, 2 Rue de la Milétrie, 86021 Poitiers, France 2 Department of Neurology, Centre de Référence “Neuropathies Périphériques Rares”, University Hospital of Limoges, 2 Avenue Martin Luther King, 87042 Limoges, France *Author for correspondence: Tel.: +33 555 056 561 Fax: +33 555 056 567 laurent.magy@ unilim.fr

First draft submitted: 7 September 2015; Accepted for publication: 16 November 2015; Published online: 25 January 2016 Keywords: chronic inflammatory demyelinating polyneuropathy • CIDP • corticosteroids • immunomodulation • immunosuppressant • intravenous immunoglobulin • IVIg • plasma exchange

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory disorder of the peripheral nervous system. It is a potentially disabling condition, but approximately 80% of patients respond to various immunotherapeutic drugs [1] . However, although some patients will reach remission after a while, many of them will remain dependent on treatment [2] . Moreover, the patients with an absent or poor response to treatment will sometimes reach a high level of disability. Therefore, there is a need to improve the management of patients with CIDP, especially those who remain ­treatment-­dependent or ­t reatment-resistant. In this review, we describe the evidencebased treatment options for patients with CIDP, and we focus on novel or alternative immunotherapeutic strategies.

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What is chronic inflammatory demyelinating polyradiculoneuropathy? CIDP is a chronic acquired disorder, which usually presents as a progressive or relapsing sensory and motor, proximal and distal neuropathy with generalized areflexia, developing over at least 8 weeks [3] . CIDP is a rare disorder that can occur at any age, with a global prevalence of ∼1–10 per 100,000 [4,5] . Its diagnosis is mostly based on clinical presentation and nerve conduction studies, usually displaying a diffuse and multifocal pattern of abnormalities consistent with a demyelinating process with various degrees of secondary axonal loss [6] . An isolated raised protein content in cerebrospinal fluid (cyto-albuminic dissociation), although inconstant, is supportive, and nerve biopsy findings of s­egmental demyelination associ-

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part of

ISSN 1750-743X

Review  Mathis, Vallat & Magy ated with macrophage-associated myelin damage are sometimes useful to confirm the diagnosis, especially when other laboratory findings are not conclusive [7,8] . Over the years, numerous sets of diagnostic criteria have been proposed in order to improve the diagnosis of CIDP, most of them being based on nerve conduction studies [9] . The currently most widely accepted criteria have been proposed after a large international consensus and take into account clinical and laboratory studies [7] . Despite all these criteria, CIDP misdiagnosis is common; in a recent study, the main diagnosis errors were over-reliance on subjective patient-reported perception of treatment benefit, liberal electrophysiologic interpretation of demyelination and placing an overstated importance on mild or moderate cytoalbuminologic dissociation [10] . Over the years, reports have demonstrated that the clinical spectrum of CIDP is rather heterogeneous, and numerous variants have been described [1] . This may suggest that CIDP is not a single entity, and that different pathogenic m ­ echanisms may account for this clinical variability. Pathophysiological considerations The current view on the pathogenesis of CIDP as an entity is that it is an autoimmune disorder, with cellular and/or humoral mechanisms that are directed toward components of the peripheral nerves to cause cellular damages to the myelin sheath, Schwann cells and ultimately axons [11] . Moreover, the concept of CIDP as an autoimmune disorder is supported by the efficacy of various immunotherapeutic agents like intravenous immunoglobulin (IVIg), corticosteroids and plasma exchange (PLEX), and by the presence of an i­nflammatory response in the peripheral nerves [11] . Inflammatory-driven demyelination, the hallmark of CIDP, predominantly takes place in nerve roots and plexuses, but nerve lesions often disseminate throughout the peripheral nervous system, as demonstrated by pathological changes in nerve biopsies that are taken from distal limb segments [3] . In the peripheral nerves of patients with CIDP is found a mixture of CD4 + T cells, CD8 + T cells and macrophages [11] . This implies a crucial step in the pathogenesis of this disorder, which is the disruption of the blood–nerve barrier, an event that also permits the penetration in the nerve compartment of various molecules such as chemokines and proinflammatory cytokines. Although the respective roles of the different inflammatory cells in the pathogenesis of CIDP remain incompletely understood, similar clonal expansion of CD8 + T cells in the peripheral blood compartment and in the peripheral nerve suggests that these cells play a key role in the pathogenesis of the disorder [12] . The role of circulating regulatory CD4 + T cells (Tregs) is probably important as well in

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CIDP, and variations in their number and function have been suggested by recent studies [13] . Although many uncertainties remain about the triggering factors of T-cell activation in CIDP, studies have suggested that Fas-mediated T-cell apoptosis impairment might be a key factor in the process of ongoing inflammation and eventually nerve damage in CIDP [14] . Moreover, a defective Fas-mediated T-cell apoptosis in acute inflammatory demyelinating polyneuropathy seems to predict the conversion to CIDP [15] . Finally, macrophages are generally considered the key final effectors in the pathogenesis of CIDP, as they can be seen forming small clusters around endoneurial blood v­ essels [16] , disrupting the myelin sheaths and absorbing myelin debris [17] . To date, no peripheral nerve antigen has been conclusively found as a universal target for T cells in CIDP, although many myelin proteins or glycolipids have been regarded as good candidates. Similarly, no convincing evidence has been provided about an autoantibody response in CIDP until recently, although a good response to PLEX in at least a subset of CIDP patients has been demonstrated long ago. However, recent studies have caught attention on the nodal, paranodal and juxtaparanodal regions of axons. Indeed, neurofascin 155, and the axonal contactin-1/Caspr complex that are located in the paranodal regions of axons and are important in the axoglial maintenance, have been recently shown to be the targets of an autoantibody response in a subset of patients with CIDP [18] . Although the pathological role of these autoantibodies still remains to be thoroughly investigated, this raises the question about an important participation of humoral immunity in CIDP. Current treatment options for chronic inflammatory demyelinating polyradiculoneuropathy The problems of clinical evaluation, studies’ end points & immunotherapy in chronic inflammatory demyelinating polyradiculoneuropathy

Since more than 30 years, various therapeutic regimens have been proposed in CIDP. Some robust data have been obtained with first-line therapies like steroids, IVIg and PLEX although the populations were not identical in different studies. Indeed, some studies included any patient with CIDP, whereas others included only previously untreated patients [19] . Moreover, end points were highly variable between studies because there was no consensus among investigators about which scale to use in order to measure improvement in CIDP and more generally in i­mmune-mediated neuropathies [20,21] . We and others recently reviewed extensively end points

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Novel immunotherapeutic strategies in chronic inflammatory demyelinating polyneuropathy 

and clinical efficacy of first-line treatments of CIDP with a particular emphasis on controlled studies [22,23] . However, recent progress has been made in the field of assessment of impairment and disability in peripheral neuropathies, in order to build a ‘common language’ that could be used to measure the effect of different treatments in routine practice and clinical studies [24,25] . Despite these drawbacks, we recently proposed a general strategy to start and maintain treatment in CIDP according to the initial clinical response [1] . The choice of treatment for patients with CIDP will usually rely on general knowledge of the pathophysiology of the disorder, evidence-based efficacy, potential side-effects and possible contraindications in individual patients. Most of available therapies will target autoimmunity, as CIDP is considered an autoimmune entity based on numerous observations. Although incompletely understood and beyond the scope of this paper, the molecular mechanisms of action of the different drugs that are used in CIDP have been ­extensively reviewed recently [26] . Corticosteroids

Although the efficacy of steroids had been anecdotally reported previously, an unblinded randomized controlled trial demonstrated the efficacy of prednisone in a majority of patients with CIDP [27] . Since then, prednisone has been widely used as first-line treatment in patients with CIDP although evidence was considered weak that steroid treatment reduces disability in this disorder [28] . Moreover, a 6 weeks course of oral prednisolone (starting at 60 mg daily for 2 weeks, with tapering to 10 mg daily) demonstrated the same efficacy as a single course of IVIg at 2.0 g/kg in patients with CIDP [29] . Altogether, oral prednisone or prednisolone has been considered a reasonable first-line option in CIDP and a trial of steroids should be considered in all patients with CIDP and significant disability [30] . Although oral prednisone has been the gold standard steroid treatment for years, alternative regimens have been recently proposed. Pulsed highdose dexamethasone proved as effective as prednisolone in one randomized controlled trial, with a similar amount of side-effects but less sleeplessness and moon facies [31] ; cure or long-term remission can be achieved in about a quarter of patients with CIDP after one or two courses of pulsed dexamethasone or a 8 months daily prednisolone  [32] . More recently, a randomized controlled trial compared a monthly dose of 2 g intravenous (iv.) methylprednisolone with a classical regimen of 2 g/kg/month of IVIg [33] . This work did not demonstrate any clearcut difference between the two drugs, but median time to relapse after discontinuing therapy was significantly longer after iv. methylprednisolone than IVIg [34] .

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Plasma exchange

Two randomized trials showed the short-term efficacy of PLEX in CIDP [35,36] . Although these results were judged consistent, PLEX has remained a second-line treatment in most centers due to the feasibility of the procedure compared with steroids or IVIg. Moreover, most of the responders to PLEX usually relapse shortly (7 to 14 days) after completing the treatment [36] and serious adverse effects are not uncommon especially in middle or old age patients, making the routine use of PLEX problematic in a chronic disease like CIDP [37] . Further work is needed in patients with the newly discovered autoantibodies against neurofascin 155 (see above) to check if a specific response to PLEX is ­consistent or only anecdotal [18] . iv. immunoglobulin

Four randomized controlled trials showed that highdose (2 g/kg) IVIg reduces impairment and disability in the short term in patients with CIDP [19,38–40] . Further studies showed that the efficacy of IVIg is equivalent to PLEX [41] and steroids in patients with CIDP [29] . IVIg has since been considered a reasonable treatment option in CIDP [42] . Nevertheless, patients with CIDP usually have a short-term benefit with IVIg treatment and maintenance therapy with periodic infusions has to be used in most of the patients. Openlabel and randomized controlled studies have shown the long-term efficacy and general safety of IVIg in patients with CIDP, so that this treatment is widely used as first-line therapeutic option in developed countries  [2,43] . Treatment dependence is a serious problem in CIDP: 40% of these patients remain treatment dependent in the long term, with a risk of relapse when they interrupt the treatment [44] . Treatment-dependent patients (compared with treatment withdrawal patients) are more frequently responsive to IVIg and resistant to corticosteroid as first-line treatment, have a longer delay to effective treatment and are more likely to present a multifocal deficit [45] . Subcutaneous immunoglobulin (sc.Ig) replacement is a commonly offered alternative to IVIg for patients with primary or secondary immunodeficiency syndromes. A few single case reports, small series or trials of variable design have been reported in cases of CIDP, and they all suggest at least short-term equivalence of sc.Ig and IVIg in treating this disease. Long-term efficacy of sc.Ig is not yet established in immune-mediated neuropathies [46] , but the noninferiority of sc.Ig over IVIg has been confirmed [47,48] . In a recent nonrandomized partially prospective study on eight CIDP patients, no marked change has been observed in weakness or disability (similar efficacy and better ­tolerability) after the switch from IVIg to sc.Ig [49] . sc.Ig at a concentration

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Review  Mathis, Vallat & Magy of 20% seems to give more improvement in patients’ quality of life in CIDP than sc.Ig at a concentration of 16% [50] . Overall, this immunotherapeutic strategy seems promising, particularly in active patients and in those with poor venous access. Alternative immunotherapeutic strategies for chronic inflammatory demyelinating polyradiculoneuropathy If most patients with CIDP respond to classical therapeutic agents (IVIg, corticosteroids and PLEX), more than half of CIDP patients will relapse, and some of them will develop a recurrent or worsening clinical course (resulting in severe disability and even rarely death)  [51] . Moreover, some patients (up to 21%) present refractoriness to the classical treatments [2,44] . One explanation may be that CIDP is a heterogeneous disorder. Indeed, apart from the classical form of CIDP, other clinical phenotypes have been identified, such as multifocal acquired demyelinating sensory and motor or distal acquired demyelinating symmetric neuropathy: the pathophysiology of these different subtypes of CIDP appears to be distinct, so the variable response to immune treatment may depend on different pathogenic processes [52] . Indeed, a recent study has suggested that CIDP patients with anti-contactin 1 a­ ntibodies have a poor response to IVIg [53] . Since the identification of CIDP as a particular clinical entity, many immunosuppressive or immunomodulatory therapeutics have been tried (Table 1), with various success. Most of the available data result from single cases or small series of cases [54] : only four randomized control trials have been performed, one for azathioprine (27 patients) [55] , two for IFN-β-1a (one with ten patients and another with 67 patients) [56,57] and one with methotrexate (60 patients) [58] . These different trials have failed to show the efficacy of these treatments [59] . However, in an Italian multicenter retrospective study (110 subjects in ten centers), the proportion of patients with CIDP (not adequately responsive to IVIg, corticosteroids or PLEX) who responded to various immunosuppressive drugs (azathioprine, rituximab, cyclophosphamide, mycophenolate mofetil, methotrexate, IFN-α, IFN-β-1a) ranged between 20 and 30% [60] . Immunosuppressive drugs

Azathioprine, a purine analog causing inhibition of proliferating B and T lymphocytes, is used as an immunosuppressant drug since the 1960s. This treatment is cheap, but it has potentially serious side-effects like gastrointestinal disorders (nausea, vomiting and diarrhea), allergic reactions, hepatotoxicity and bone ­ marrow ­suppression (with an increase risk of infection and a

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late risk of neoplasm) [54] . Azathioprine has been tried in CIDP as soon as 1970 [61,62] . In the only controlled trial  [55] , azathioprine was associated with prednisone: no significant effect was observed; however, in this study, the patients’ number was small (16 patients), the dose was low (2 mg/kg) and the length of the survey was short (9 months). In a more recent Italian retrospective study, azathioprine was the most frequently used immunosuppressant: 21 of 77 CIDP patients improved with this drug [60] . Whereas anecdotal success can be obtained with this treatment, it is usually used as a steroid-sparing agent (2–3 mg/kg/day) [55] . Mycophenolate mofetil (initially developed as a replacement of azathioprine) acts by inhibiting inosine monophosphate dehydrogenase, thereby limiting the proliferation of B and T lymphocytes. Its main adverse effects are diarrhea, leukopenia and an increased risk of cytomegalovirus infection. As azathioprine, mycophenolate mofetil may be used as a steroid-sparing agent in CIDP [63] . Cyclophosphamide is an alkylating agent (depleting both B and T cells) widely used in the treatment of neoplastic and autoimmune diseases [64] . An observation has reported a remission for more than 3 years after treatment with highdose cyclophosphamide and autologous blood stem cell transplantation in a patient with resistant CIDP [65] . Highdose cyclophosphamide has also showed improvement (on clinical follow-up and quality of life) in four of five patients with severe refractory CIDP [66] . Its effectiveness in CIDP may result from naive T-cell destruction [67] . However, one in a series of ten CIDP patients treated with cyclophosphamide died from cytomegalovirus pneumonia [67] ; because of its toxicity to all human cells (to differing degrees), it should be restricted to selected patients who have not responded to other less toxic alternatives [64] . Cyclosporine A and tacrolimus are both calcineurin inhibitors [68] . Cyclosporine A is a cyclic 11 amino-acid peptide that (through calcineurin inhibition) suppresses the transcription of proinflammatory cytokine (IL-2 and IFN-γ) genes. Its most important side-effect is nephrotoxicity, and this treatment is contraindicated in patients with systemic infection, history of previous hypersensitivity reaction, uncontrolled hypertension and malignancy [69] . Improvement with cyclosporine A has been observed in some cases of refractory CIDP patients within 2 to 3 months of treatment initiation  [70,71] . Tacrolimus is a macrolide lactone (fungal product from Streptomyces tsukubaensis) with a similar mechanism of action and side-effects as cyclosporine A. Strength improvement has been reported in one case of CIDP treated with prednisolone, PLEX, then tacrolimus  [72] , and in another case treated by ­tacrolimus after liver transplantation [73] .

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11

6

5

2

4

4

8

9

1

8

13

2

1986

1994

1997

1998

1998

2000

2001

2002

2003

2003

2004

2006

Alemtuzumab

Rituximab

sc.Ig

Etanercept

Hematopoietic stem cell transplantation

Mycophenolate mofetil

Methotrexate

Selective immunoadsorption

Tacrolimus

IFN-α

IFN-β

Cyclosporin A

IVIg

Lymphoid irradiation

Fresh -frozen plasma

PLEX

Polyinosinic-polycytidylic acid

Cyclophosphamide

Depletion of T and B cells

Inhibition of proliferating lymphocytes

Immunosuppression and regulation of inflammation

Mechanism of action

HMA directed against CD52

CMA directed against CD20

Pooled preparation of purified human subcutaneous IgG

TNF-α antagonist

–

Antimetabolite

Antimetabolite

–

Calcineurin inhibitor

Type I interferon (from leukocytes)

Type I interferon (from fibroblasts)

Antimetabolite

Pooled preparation of purified human iv. IgG

–

–

–

Depletion of CD4 + and CD8 + T cells

B-cell depletion

Immunomodulation

Depletion of T cells, B cells and macrophages

Immune system resetting

Inhibition of the proliferation of T and B cells

Inhibition of DNA synthesis in proliferating cells

Selective apheresis

Inhibition of T cells activation and proliferation

Immunomodulation

Immunomodulation

Inhibition of the proliferation of T cells

Immunomodulation

–

–

Apheresis

Synthetic analog of double stranded Interferon induction and RNA immunomodulation

Alkylating agent

Antimetabolite

Prednisone and prednisolone

Description

† Validated treatments of chronic inflammatory demyelinating polyneuropathy. CMA: Chimeric (human/murine) monoclonal antibody; HMA: Humanized monoclonal antibody; IgG: Immunoglobulin G; iv.: intravenous; IVIg: intravenous immunoglobulin; PLEX: Plasma exchange; SC: Systemic circulation; sc.Ig: Subcutaneous immunoglobulin; SLO: Secondary lymphoid organs.

1

1

1982

29

37

1979†

1985†

1

1978

1985

13

1976

Azathioprine

Corticosteroids

27

10

Therapy

Publications (n)

1970

1958

†

First publication (year) 

Table 1. Chronology and characteristics of the main immunotherapies tried in chronic inflammatory demyelinating polyneuropathy.

Novel immunotherapeutic strategies in chronic inflammatory demyelinating polyneuropathy 

Review

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1 2014

Validated treatments of chronic inflammatory demyelinating polyneuropathy. CMA: Chimeric (human/murine) monoclonal antibody; HMA: Humanized monoclonal antibody; IgG: Immunoglobulin G; iv.: intravenous; IVIg: intravenous immunoglobulin; PLEX: Plasma exchange; SC: Systemic circulation; sc.Ig: Subcutaneous immunoglobulin; SLO: Secondary lymphoid organs.

Quinolin-3-carboxamide Laquininmod

1 2013

Reducing leukocyte migration

Antimetabolite Fludarabine

3 2013

Immunotherapy (Epub ahead of print)

†

Sphingosine-1-phosphate receptor modulator Fingolimod

1 2013

Depletion of B cells

HMA directed against complement protein C5 Eculizumab

Regulation of lymphocytes trafficking from SLO into the SC

Prevention of adhesion and transmigration of both T and B cells HMA directed against α4-integrin Natalizumab 2 2010

Complement blockade

Mechanism of action Description Therapy Publications (n) First publication (year) 

Table 1. Chronology and characteristics of the main immunotherapies tried in chronic inflammatory demyelinating polyneuropathy (cont.).

Review  Mathis, Vallat & Magy Methothrexate, a structural analog of folic acid (exerting an antiproliferative effect by metabolic interference with DNA), is used as a cost-effective immunosuppressant in autoimmune diseases such as rheumatoid arthritis. Some of the most frequent adverse effects are nausea, dyspepsia, mild alopecia, increase of liver enzymes, peritoneal abscess, hypoalbuminemia, severe rash and atypical pneumonia. In 2009, the RMC trial group had published a pilot multicenter randomized double-blind controlled study on 59 CIDP patients treated with methotrexate (7.5 mg weekly for 4 weeks, then 10 mg weekly for 4 weeks, and 15 mg weekly for 32 weeks): no clear benefit was observed, but with some limitations in the trial design mostly due to a larger than expected placebo effect [58] . Etanercept is a recombinant human TNF receptor p75Fc fusion protein (TNF-α antagonist), used for many years in autoimmune rheumatic disorders [74] . Whereas a higher risk of infection, its long-term tolerability seems to be acceptable. Ten patients with refractory CIDP (or intolerant to standard therapies) have been treated with etarnecept (25 mg twice per week, subcutaneously): the authors described a significant improvement (4–6 months after the beginning of the treatment) in three patients, a possible improvement in three patients and no improvement for the others [75] . Fludarabine, an antimetabolite inhibiting ribonucleotide reductase, DNA polymerase, DNA primase and ligase (it may inhibit apoptosis), is a strong immunosuppressive nucleoside tried in IgM paraproteinaemic neuropathy  [76] . An improvement in refractory CIDP (distal acquired demyelinating symmetric form) has been reported in one patient, but after a combination of cyclophosphamide and fludarabine (42 mg iv.) [77] . Myelosuppression is the most frequent adverse effect of this treatment. Monoclonal antibodies

For many years, monoclonal antibodies have been used in various immune disorders [78] . Rituximab, a chimeric (human/murine) monoclonal antibody directed against CD20 antigen, was the first to be approved for use in oncology and in the treatment of B-cell malignancies [78] ; infusion reactions (within 24 h after the first infusion) and infections are the most frequent adverse effects. Logically rituximab was the first monoclonal antibody to be tried in immune-mediated neuropathies. Initially used in polyneuropathy associated with IgM monoclonal gammopathy and autoreactivity to the myelin-associated glycoprotein MAG [79,80] , it has then been first tried in CIDP in 2004 [81] , with good response in some cases reports. In 2011, in a ­ retrospective o­bservational (multicenter) study

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Novel immunotherapeutic strategies in chronic inflammatory demyelinating polyneuropathy 

(13 Italian patients), an improvement (starting for a median period of 2 months after the beginning of rituximab, and lasting for a median period of 1 year) has been also observed in nine patients with refractory CIDP [82] . More recently, the efficacy of rituximab has been suggested in treatment-resistant CIDP with antibodies against paranodal proteins, further confirming the potential interest of these recently identified ­biomarkers to predict the response to treatment [83] . Alemtuzumab (Campath-1H), another form of monoclonal antibody, is a humanized monoclonal IgG1k directed against the CD52 glycoprotein inducing a profound depletion of circulatory lymphocytes  [68] . Infusion reactions and infections are the most frequent adverse effects. Some improvement has been observed in patients with refractory CIDP, in a multicenter study (seven patients) where two patients had prolonged remission and two patients had a ­partial response (no clear benefit was observed in the ­remaining three patients) [84] . Natalizumab is a monoclonal antibody against α4 integrin (present on the surface of lymphocytes): it inhibits the binding of lymphocytes to VCAM-1 of endothelial cells and blocks the penetration of encephalitogenic T cells into the CNS. Hypersensitivity reactions and elevations of liver enzymes are the most frequent adverse effects; it has been approved for multiple sclerosis, and has been tried in refractory CIDP. In 2010, no improvement has been reported in a single observation with a single course of this treatment  [85] . However, recently, we have observed a significant improvement in two of three patients (refractory CIDP) treated with natalizumab (the third patient, who did not respond, having the same electrophysiological and clinical phenotype than the patients of Wolf et al., hypertrophy of nerve roots and a severe ­secondary axonal loss) [86] . Finally, eculizumab is a humanized monoclonal antibody targeting human complement C5; it has been approved by the US FDA for the treatment of two diseases resulting in intravascular complementmediated hemolysis: paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. The first results of a clinical trial about the use of eculizumab in children with CD59 deficiency and CIDP (NCT01579838  [87]) tend to show a stabilization of hemolysis and a cessation of CIDP relapses [88] . Immunomodulatory drugs

Interferons represent a family of helical cytokines interfering with viral replication (with also antiproliferative and immunomodulatory effects); IFN-α and IFN-β are type I interferons [89] . Interferon-β (1a and

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1b) is a safe and effective treatment used in multiple sclerosis for more than 20 years. In CIDP, the efficacy of IFN-β has been suggested in some studies [90] , but in a more recent study (double-blind randomized trial), this treatment did not provide significant benefit over IVIg therapy alone for 67 patients with CIDP [57] . IFN-α, used for its properties of inducing an ‘antiviral’ state in cells, has been approved by the FDA for the treatment of viral infections like hepatitis C and some hematologic and nonhematologic malignancies  [89] . Only anecdotal observations have mentioned the use of this category of interferon in CIDP, with no clear efficacy; moreover, the use of type I IFN in CIDP (particularly IFN-α) is debated because of their potential neurotoxicity (IFN-α may cause optic neuropathy, but also ­demyelinating ­neuropathies such as CIDP) [91] . Fingolimod is a sphingosine-1 phosphate receptor modulator approved for the treatment of relapsing forms of multiple sclerosis. The main adverse effects are infections, headache, gastrointestinal disturbances, bradycardia and elevation of liver enzymes. Some studies in animal have showed that it also promotes the generation of a regeneration-associated Schwann cell phenotype [92] ; moreover, sphingosine-1 phosphate receptor modulators may play a therapeutic role in autoimmune neuropathies [93] . These findings suggest that fingolimod could be used as treatment for peripheral nerve injuries and diseases [94] : clinical and electrophysiological improvement was observed in one patient presenting a peripheral demyelinating polyneuropathy in a context of CNS inflammatory disease [95] . The first results of a trial in CIDP patients (FORCIDP trial) have confirmed that fingolimod may delay ­d isability progression in patients with CIDP [96] . Polyosinic-polycytidilic acid is a synthetic analog of double-stranded RNA and an agonist of TLR3 and retinoic acid inducible gene I-like receptors, used in oncology as a vaccine adjuvant to enhance innate and adaptative immune responses, to alter a tumor microenvironment, and to directly trigger apoptosis in cancer cells [97] . This chemotherapy (100 μg/kg by iv. infusion over 30 min, once weekly for 7 weeks) has been tried in only one observation of refractory CIDP (prednisone and azathioprine), with a motor ­improvement  [98] . Laquinimod (chinoline derivative), an oral immunomodulatory drug that induces anti-inflammatory effects by modulating immune cells (resulting in reduced synthesis of several cytokines), is used in Crohn’s disease, lupus nephritis and multiple sclerosis, and is under evaluation in Huntington’s ­disease. Its main adverse effect is elevated liver enzymes

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Review  Mathis, Vallat & Magy (>3 × upper normal limit). The use of this molecule in an animal model of inflammatory neuropathy (experimental autoimmune neuritis) has showed a decrease of demyelination and inflammation in the peripheral nerves, suggesting that laquinimod may represent a therapeutic option in human autoimmune ­neuropathies such as CIDP [99] . Other treatment options

Because of the risks of long-term use of immunosuppressive drug and highdose steroid therapy, alternative treatments have been tried in CIDP. Hematopoietic stem cell transplantation (HSCT) refers to a procedure in which hematopoietic stem cells obtained from the transplant recipient (autologous HSCT) or from a donor (allogeneic HSCT), are infused to restore bone marrow function. The use of allogenic HSCT in immune diseases is limited; only one observation has been reported in refractory CIDP (in a 26-year-old patient): the authors described a full recovery with no relapse during 6.5 years [100] . Autologous HSCT has been more frequently tried in refractory CIDP, in single case report and small series: in a small retrospective series of 11 patients, a benefit was observed with this treatment [101] ; however, in another series of six patients, this benefit was slight (with relapse), with serious adverse events (neutropenic ­septicaemia and pneumonia) [102] . Total lymphoid irradiation was originally developed as a nonmyeloablative treatment for Hodgkin’s disease. Only one paper reported the use of this therapeutic agent in refractory CIDP in four patients (total dose = 2000 rads): three of them had an improvement in distal muscle strength (in association with increased functional capabilities in two patients) and a patchy improvement on nerve conduction studies [103] . Immunoadsorption can be the treatment of choice of immune-mediated neuromuscular disorders when intensive apheretic protocols or long-term treatments must be performed, in patients needing frequent apheresis to keep a stable clinical condition, in case of unresponsiveness to corticosteroids and immunosuppressive treatments, or failure with PLEX or IVIg, and in patients with contraindications to long-term corticosteroids [104] . Various results have been obtained in CIDP with this therapeutic [105,106] , but immunoadsorption is ­unsatisfactory as a first-line treatment in this disease [107] . Vitamine D deficiency has been observed in patients with primary immune-mediated peripheral neuropathies (compared with healthy subjects and patients with motor neuron disease) [108] . The immune-regulatory effect of active vitamin D seems to reside in an increased amount of regulatory T cells, confirmed through recent studies on healthy individuals [109] . No

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trial has been performed for vitamin D in CIDP, but some authors suggest a monitoring of vitamin D ­status in patients with autoimmune neuropathies, since immune cells are responsive to the ameliorative effects of vitamin D [108] . Chronic inflammatory demyelinating polyradiculoneuropathy treatment in children Few systematic epidemiological studies have been performed in CIDP. The prevalence of CIDP in adults has been estimated to be up to 8.9 per 100,000 in Olmsted County (MN, USA) [110] , but was evaluated between 0.8 and 7.7 per 100,000 population in other studies [4] . In children as well as in adults, males are more frequently affected than females: incidence per 100,000 is 0.58 in males and 0.38 in females [111] . However, prevalence of CIDP is lower in patients under 20, estimated to be 0.48 per 100,000 in the region of New South Wales (Australia) [5] . Age-dependent incidence rates were found to be 0.06 in age group 0–15 years, 0.40 in adults (15–55 years) and 0.73 in age group more than 55 years [111] . In the study of McLeod et al. (Australia), an incidence rate at 0.23 was found in the age group of 0–9 years, versus 0.48 per 100,000 in the 10–19-year age group [5] . Most polyneuropathies (68%) in childhood are genetically determined [112] ; if the acquired causes of neuropathies are mostly inflammatory [112] , CIDP may represent only up to 3% of neuropathies of patients under 20 [113] ; most of childhood CIDP occurs before 10 years of age [114] . Pathophysiological mechanisms of CIDP are similar in children and adults [7] ; however, children have a more relapsing or polyphasic course than adults [115] ; 20% of children with CIDP have an initial presentation indistinguishable from Guillain–Barré syndrome [115] , against 16% of adults [116] . Moreover, the outcome seems to be more favorable in children than in adults [115] . As for adults, in children, CIDP is known to respond effectively to the classical treatments (IVIg, corticosteroids and PLEX) [117] . However, it remains unclear which treatment is the best first-line option [118] . Because PLEX poses the greatest array of logistical hurdles, it can be difficult to use in clinical practice, especially in children [118] , even if some patients have good long-term response to PLEX [119] . Most children (80%) show a good response to initial IVIg therapy (at the dose of 1 g/kg during 2 days, before being placed on maintenance therapy of IVIg: 1–2 g/kg every 4 weeks), with usually a good tolerance [115] . A good response has also been observed in children treated with corticosteroids, but this treatment is now usually proposed as a second-line treatment [115] . Among ­a lternative treatments (third-line treatments), azathio-

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Novel immunotherapeutic strategies in chronic inflammatory demyelinating polyneuropathy 

prine is the most commonly used in childhood, with some beneficial effect (combined to steroids) [120] . Conclusion CIDP is a relatively rare immune-mediated neuropathy, with an overall response to conventional treatments of about 70%. Many patients are unresponsive to first line therapy and others remain treatment dependent. Therefore, there is an important need to develop novel immunotherapeutic strategies for patients with CIDP. Development of biomarkers and prognostic factors will certainly help to design new treatment strategies in the near future. The use of available immunomodulatory agents (some of them being already prescribed for other immune-mediated disorders like multiple sclerosis) that have shown some efficacy in individual patients or small series has to be investigated in controlled trials in order to confirm their efficacy. Besides these considerations, an important body of work is underway to develop clinical scales and surrogate markers, that will permit to evaluate more securely and adequately the response to any therapeutic strategy and to allow patients to benefit from the best available care.

Review

Future perspective CIDP is a rare and heterogeneous disorder. Further works will be necessary to better understand its pathophysiology and characterize the immune components that act against the peripheral nervous system in this disorder. From a phenotypic point of view, the development of comprehensive databases is an urgent need in order to share clinical, neurophysiological and biological data in multicenter efforts. Such tools would allow better characterizing CIDP in prospective cohort studies, and selecting homogeneous groups of patients for future trials. To better understand the pathophysiology of CIDP, the development of biomarkers is also an important need. Ideally, these markers would help understanding the different pathogenic mechanisms that probably underlie the different phenotypes of this disorder. Moreover, understanding the changes in biological networks under any single treatment will help anticipating the clinical response to specific therapies and developing a more personalized approach to treatment in CIDP. Finally, the development of clinical outcome measures and surrogate markers should optimize the

Executive summary Chronic inflammatory demyelinating polyradiculoneuropathy as a heterogeneous disorder • Several lines of evidence suggest that chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a heterogeneous disorder. The clinical phenotype of CIDP has expanded over time ranging from multifocal to diffuse, from sensory to motor, from benign to severe and from relapsing to progressive. CIDP has long been viewed as an autoimmune neuropathy but biomarkers are currently lacking. Several recent works have shown that nodal and paranodal structures are crucial in the maintenance of axoglial apparatus and that some molecules that are present in these regions may behave as autoantigens.

First-line treatment of chronic inflammatory demyelinating polyradiculoneuropathy • More than 30 years after their first use in CIDP, steroids, intravenous immunoglobulin and plasma exchange are still the cornerstone of CIDP treatment. Their therapeutic effect is positive in the short and long term and they are widely used, with efficacy in 70 to 80% of patients.

Alternative & complementary treatment for chronic inflammatory demyelinating polyradiculoneuropathy • There is a need to develop alternative treatments in patients with dependent or refractory CIDP. Various immunosuppressants, monoclonal antibodies and immunomodulatory treatments have been proposed. Small case series and anecdotal reports seem to favor the use of some of these treatments but to date, evidence is insufficient to propose clear guidelines as no randomized controlled trial has confirm efficacy of alternative therapies in CIDP.

Toward personalized medicine in chronic inflammatory demyelinating polyradiculoneuropathy • Very recently, the humoral part of the immune system has gained interest in the pathophysiology of CIDP, and subtypes with specific autoantibodies have emerged. These subtypes seem to have rather specific phenotypes and responses to treatment. Expanding the field of biomarkers in CIDP will probably lead to a more personalized way to treat this disorder in individuals.

Future directions • Deciphering the pathophysiology of CIDP is an important challenge. Several biomarkers are already available but they are likely to be involved in a minority of cases. The respective roles of cellular and humoral factors in subpopulations of patients will probably in the near future allow reclassifying CIDP as a spectrum of disorders that are linked by phenotypic characteristics, but are separated by different immunologic features. In a therapeutic perspective, a rigorous scientific approach will be necessary to evaluate each individual drug in randomized controlled trials as in cohort follow-up. This obviously will represent a great amount of work but ongoing studies are already very encouraging for patients with a sometimes very disabling disease as CIDP.

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Review  Mathis, Vallat & Magy conduct and interpretation of clinical trials in such a rare condition as CIDP.

L Magy has received honoraria and consultancies from CSL Behring, LFB and Novartis Pharma. The authors have no other

r­ elevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

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Review

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Review  Mathis, Vallat & Magy and eleven published series. Neuromuscul. Disord. 23(2), 103–111 (2013).

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Childhood chronic inflammatory demyelinating polyradiculoneuropathy: combined analysis of a large cohort

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Immunotherapy (Epub ahead of print)

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An interesting review on CIDP in children.

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