Immunoglobulin, steroids and plasma exchange (PLEX) are proven effective therapies in provoking and sustaining remission in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).1–3 Of the three, steroids are most likely to induce prolonged remission, compared with immunoglobulin and PLEX which achieve disease stability more rapidly.4–7 These treatments are often time-consuming requiring intermittent long-term dosing, which is inconvenient and costly. The risks of long-term steroids are considerable and relatively frequent.6 Immunoglobulin therapies are costly and associated with venous and arterial thromboembolism and infusion-related complications.8 The requirement for central venous access for most PLEX relegates this therapy to a third-line and less preferred option. Although CIDP remission is achievable, patient and clinician therapeutic satisfaction is less than ideal and requires improvement. Among the 70% of treatment responders, the response is often incomplete. 30% of patients remain refractory to immunoglobulins, steroids or PLEX.1–3 6 Crucially, present therapies may not entirely arrest disease progression and axonal degeneration, resulting in cumulative disability and impairment despite what may be considered an acceptable treatment response.

Our understanding of CIDP pathogenesis, although far from complete, has expanded considerably in recent years. The discovery of several key disease mechanisms has led researchers to develop novel therapeutics to potentially revolutionise the way we treat CIDP. Although not exhaustive, this narrative review aims to provide an update on progress from the most relevant ongoing clinical trials.

The definition of CIDP is an amalgam of the clinical features, electrodiagnostic investigations and laboratory markers.9 10 ‘Typical CIDP’ is characterised as a progressive or relapsing muscle weakness of the upper and lower limbs, with sensory disturbance in at least two limbs with areflexia or hyporeflexia, and a duration of at least 8 weeks. Variants of CIDP include distal, focal, multifocal, motor and sensory CIDP.11 Neurophysiological criteria exist but are not specific and would be non-diagnostic in isolation.10 Serum immunological testing of monoclonal proteins is advised, such as paraproteins and anti-MAG, particularly in distal CIDP. The autoimmune nodopathies are considered a separate disease, and nodal and paranodal antibodies (anti-NF155, anti-CNTN1, anti-Caspr1) should be considered particularly in acute onset CIDP and those with relevant clinical features, such as very high cerbrospinal fluid (CSF) protein or nephrotic syndrome.

CIDP is an immune-mediated radiculoneuropathy, but there is no single pathognomonic marker; synergistic targeting of peripheral nerve myelin by cell-mediated, humoral and cytokine-driven immune responses occurs.

A T cell-mediated pathology has some support in CIDP. Nerve histopathology has confirmed CD4+, CD8+ and macrophage infiltrates in the endoneurium.12 T cells increase neurovascular permeability, activate matrix metalloproteinases and facilitate the entry of proinflammatory cytokine and chemokine molecules.13 Identifiable damage to the blood–nerve barrier is more associated with ‘typical CIDP’ than multifocal or distal variants.14 Macrophages, both resident and infiltrating are the largest population of proinflammatory cells and disrupt the integrity of the BNB, which promotes inflammation through CD4+-activated cellular release of cytokines and chemokines that cultivate further macrophage activation.15 16 Endoneurial macrophages form inflammatory clusters, present antigen and release proinflammatory cytokines.17 The instigating entity of this immunological pathway is unknown.

CD8+cytotoxic T cells have been shown to be clonally expanded in nerve biopsies.15 IVIG treatment in inflammatory neuropathies is associated with greater suppression of CD8+rather than CD4+ activity, suggesting a greater role of CD8+cells in pathogenesis.18 Such findings have not been replicated in other studies.

Peripheral nerve antigen-specific antibodies are likely to assist in targeting macrophage-delivered destruction of myelin.13 No definitive antibody target has been identified in typical CIDP.10 However, antibodies to the node of Ranvier and paranodal regions including those against contactin-1 (CNTN1), contactin-associated protein 1 (CASPR1), neurofascin-155 (NF155), neurofascin-140 (NF140), neurofascin-186 (NF186) and pan-neurofascin exist for paranodopathies.19 20 The existence of autoimmune nodopathies could suggest that more of the ‘seronegative’ CIDP might have humoral mediation, although any more putative humoral targets remain unidentified.

Nodal and paranodal antibodies characterise a chronic inflammatory polyradiculoneuropathy that has resulted in a restructuring of the conceptual axonal or demyelinating dichotomy in inflammatory nerve disease. Antibodies targeting nodal and paranodal structures can cause conduction slowing without classical demyelination and generate a continuum of pathological changes resulting in conduction slowing, to block, to axotomy.21

Antibody subclasses seem to be an important determinant of disease features and response to treatment. IgG1 antibodies are monospecific with a divalent structure. IgG1 disease exemplifies complement-mediated and intracellular destruction of myelin and Schwann cells, often responsive to IVIg therapy.22 IgG4 is monovalent and bispecific by Fab exchange with other IgG4, does not fix complement and does not result in antigen internalisation.23 IgG4-positive CIDP tends to be severe with a weaker response to IVIG. IgG4 fails to bind C1q, as well as preferentially binding Fc receptor I (FcγRI) over the inhibitory FcγRIIb, which promotes Schwann cells phagocytosis.23 24 As a result, IgG4-positive CIDP is often resistant to IVIG and anti-CD20 drugs have been proven more effective.

Finally, complement pathways play a key role in typical CIDP pathogenesis. Complement acts to a degree both in innate immune processes and in regulating humoral and cytotoxic responses above by activating some or all of the cascade. C3a, C3b and C5a and the membrane attack complex (MAC, C5b-9) are responsible for direct cell lysis, directing pathological antibodies and macrophage-associated Schwann Cell phagocytosis, opsonising macrophages and a propagation cycle of more complement and proinflammatory anaphylatoxins.19 23–26 The downregulation of complement components by successful IVIG treatment lends weak support to the pathogenic effects of complement.22 27 See figure 1 illustrating the pathogenic mechanisms involved in CIDP and the role of novel therapies.

Pathophysiological mechanisms of CIDP and potential therapeutic candidates. (1A) CD4+ T cells cause cytokine release (IL-17, IL-2, IFNɣ) and macrophage activation. Macrophages disrupt the integrity of the blood–nerve barrier. (1B) CD8+ T cells are inferred to cause cytotoxic destruction of myelin. (2B) B cells lose expression of CD20 at the stage of antibody production and gain CD38. Activated antibody-producing cells heavily rely on the proteasome to maintain homeostatic functions. Pathogenic IgG1 and 4 antibodies bind to peripheral nerve structures including the node and paranode leading to conduction block, fixation of complement and demyelination. (2B) Antibodies are recirculated through FcRns within the endothelium, extending IgG half-life within the circulation. (3A) The classical complement pathway is activated when C1q binds to the Fc region of complement-fixing antibodies, leading to generation of C3a and C3b through C3 convertase. This activity underpins the entire complement system leading to anaphylatoxin production and assembly of the MAC. (3B) Activated C5 through C5 convertase is involved in terminal cell lysis mediated by the formating of MAC. CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; MAC, membrane attack complex.