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Abstract
Chronic inflammatory demyelinating polyneuropathy is a disabling but treatable disorder. However, misdiagnosis is common, and it can be difficult to optimise its treatment. Various agents are used both for first and second line. First-line options are intravenous immunoglobulin, corticosteroids and plasma exchange. Second-line therapies may be introduced as steroid-sparing agents or as more potent escalation therapy. It is also important to consider symptomatic treatment of neuropathic pain and non-pharmacological interventions. We discuss the evidence for the various treatments and explain the practicalities of the different approaches. We also outline strategies for monitoring response and assessing the ongoing need for therapy.
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Data availability statement
All data relevant to the study are included in the article.
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Introduction
Prompt identification of patients with chronic inflammatory demyelinating polyneuropathy (CIDP) is important, as it is a potentially disabling yet eminently treatable disorder. However, misdiagnosis is frequent and, even when the diagnosis is correctly established, patients are commonly overtreated, exposing them to unnecessary adverse effects, or undertreated, risking inadequate neurological recovery. Their management is further complicated the many therapeutic options, each with multiple possible dosing regimens. The evidence supporting some treatment options is patchy at best. Only a proportion of patients will respond, and there is a lack of sensitive biomarkers to monitor disease activity and response to treatment. This article provides guidance on managing CIDP for the practising neurologist.
Diagnostic considerations
CIDP can be divided into ‘typical CIDP’ and ‘CIDP variants’. Typical CIDP manifests as a progressive or relapsing, symmetrical, proximal and distal muscle weakness of upper and lower limbs, with sensory involvement of two or more limbs, developing over at least 8 weeks. Tendon reflexes are absent or reduced in all limbs. CIDP variants include the distal, multifocal, focal, pure motor or sensory forms. The diagnosis of variants can be particularly challenging; the diagnosis is more frequently incorrect, and requires consideration of a distinct set of differentials.
Typical CIDP may present acutely (‘A-CIDP’) with rapid symptom progression within 4 weeks; such patients may initially be diagnosed with Guillain-Barré syndrome (GBS). However, in A-CIDP, the deterioration continues for more than 8 weeks after symptom onset or there are at least three relapses after initial improvement. In CIDP, cranial nerves are rarely affected, and respiratory or autonomic involvement is exceptional. Unfortunately, there are no specific clinical or laboratory elements that can distinguish GBS from A-CIDP in the acute phase.
CIDP mimics include haematological malignancies, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes), myelopathy, amyloid and hereditary neuropathies.1 In distal presentations, the differential includes multiple other causes of a length-dependent neuropathy. Focal or multifocal presentations may instead be due to entrapment, hereditary neuropathy with liability to pressure palsies, peripheral nerve tumours or vasculitis. Pure motor presentations could represent motor neuron disease, myopathy or neuromuscular junction disorders, whereas in pure sensory presentations, sensory neuronopathy is a consideration. Also diabetic neuropathy should be always be considered, as it can cause slowing of conduction, elevated cerebrospinal fluid (CSF) protein and sometimes proximal weakness. Conversely, CIDP remains rare in diabetes, whereas up to 20% of CIDP patients have diabetes.2
It is also important to distinguish CIDP from other immune-mediated neuropathies such as multifocal motor neuropathy, anti-MAG (myelin associated glycoprotein) neuropathy and nodal/paranodal antibody-associated neuropathies (now termed ‘autoimmune nodopathies’,3 as they have different and distinct underlying pathological mechanisms. Crucially, they also respond differently to treatment. Although the presence of a paraprotein does not necessarily exclude CIDP, an IgM paraprotein is a red flag for a non-CIDP diagnosis, and anti-MAG IgM antibodies should be tested for in such cases. IgG and IgA paraproteins likewise raise the possibility of amyloid, POEMS syndrome (especially with a lambda restricted clonal expansion)4 and haematological malignancy. However, the presence of a paraprotein does not exlude CIDP and may simply reflect a monoclonal gammopathy of uncertain significance with a neuropathy that otherwise resembles CIDP in its presentation, presumed mechanism and treatment response.
A small proportion of patients otherwise fulfilling diagnostic criteria for CIDP have antibodies targeting nodal or paranodal molecules (contactin-1—CNTN1, neurofascin-155—NF155, contactin-associated protein 1—Caspr1, and neurofascin isoforms—NF140/186). They often have a more aggressive acute or subacute-onset neuropathy, and additional symptoms, including tremor, ataxia, respiratory failure and/or cranial nerve involvement, features that are less common in CIDP. They tend to have significantly elevated CSF protein levels and resistance to standard treatment with intravenous immunoglobulin, corticosteroids and plasma exchange. Patients with such clinical features should be tested for nodal and paranodal antibodies; if positive, their diagnosis is autoimmune nodopathy. These are no longer regarded as CIDP variants, and emerging evidence supports the use of more targeted treatment, such as the B cell depleting monoclonal antibody rituximab, which can significantly improve functional outcomes in this subset of patients.5
To diagnose typical CIDP and CIDP variants, the 2021 European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) guidelines3 strongly recommend nerve conduction studies (both motor and sensory) to support the clinical findings. If neurophysiology strongly supports demyelination the diagnosis is ‘CIDP’, whereas if neurophysiology only weakly supports demyelination the diagnosis is ‘possible CIDP’. Imaging, CSF testing or nerve biopsy may support the diagnosis of CIDP in patients who fulfil clinical criteria but whose neurophysiology suggests only possible CIDP. However, repeating the neurophysiology and sampling more motor nerves may allow a diagnosis of CIDP to be made without these supportive tests; this may be preferable to more invasive investigations. Conversely, patients with other conditions that mimic CIDP may also meet electrophysiological criteria for demyelination, and sometimes also have similar CSF and imaging findings. Response to treatment with immunomodulatory agents (intravenous immunoglobulin, corticosteroids, plasma exchange) also supports clinical diagnosis; however, a lack of improvement following treatment does not exclude CIDP and a positive response is not specific for CIDP.
Overall, most patients with CIDP respond to first-line treatment with intravenous immunoglobulin, corticosteroids or plasma exchange. The vast majority of those who do not will respond to an alternative first-line treatment. Conversely, placebo responses are common.6
Continued deterioration after initial treatment/s should prompt re-evaluation of the diagnosis. However, some investigations may be more difficult to interpret at this stage. Intravenous immunoglobulin can confound antibody and paraprotein tests, and elevate CSF white cell counts, probably for several weeks. Corticosteroids may mask lymphoma. If an alternative diagnosis cannot be established by other means, the threshold for nerve biopsy falls, particularly so with failure to respond to two first-line therapies. If CIDP remains the most likely diagnosis following investigation for alternative diseases, clinicians can consider alternative immunosuppressive treatment.
When and who to treat
Current treatments aim to suppress the underlying immunopathology. This prevents further nerve injury and hopefully facilitates functional recovery. Patients who are clinically stable or already improving are therefore unlikely to benefit from therapy. The likely limited benefit in those who are mildly functionally affected needs to be weighed against the risk of adverse effects, and the theoretical concern that irreversible deficits will accumulate over time. We tend to favour a watch-and-wait approach in this setting, but would ultimately make the decision in collaboration with the patient, taking account of their opinions and attitudes to risk.
A response to treatment usually means neurological improvement. However, clinical stabilisation after a period of more rapid decline may equally indicate an immunological response, coupled with a reduced capacity for peripheral nerve recovery. Patients who are stable over weeks to months, but have not fully normalised, are therefore unlikely to be undertreated, and may not require continued therapy to remain stable.
How to treat
Choice of first-line therapy
Intravenous immunoglobulin or corticosteroids are the most commonly used first-line therapies in CIDP (table 1). Intravenous immunoglobulin is supported by the highest level of evidence.7 However, NHS England (NHSE) commissioning criteria encourage early use of corticosteroids unless these are contraindicated (eg, if the presentation is pure motor) or there is rapid deterioration and/or severe disability, which requires a more rapid response.8 Furthermore, intravenous immunoglobulin is only commissioned for CIDP if there is ‘significant functional impairment inhibiting normal daily activities’. Plasma exchange is another option, but, due to the impracticalities of its use, is often reserved for patients who have not responded to corticosteroids and/or intravenous immunoglobulin. In practice, patient-specific and pragmatic considerations usually determine the first-line treatment choice. Thus, comorbidities, speed of progression, disease severity and convenience are important factors to consider, alongside the strength of evidence.
Comparison of first-line treatments for CIDP
Immunoglobulin
The highest certainty evidence in CIDP is for the use of intravenous immunoglobulin. Data from five randomised trials (total 235 patients) show that intravenous immunoglobulin is significantly more likely than placebo to improve disability at 1 month.7 Overall, about 80% of patients with CIDP respond to intravenous immunoglobulin.9 In England, neurologists can start short-term induction regimens (a maximum of 4 g/kg, divided into at least two courses of 1–2 g/kg each, given over a period of 4–8 weeks) to assess response without prospective intravenous immunoglobulin panel authorisation. Long-term treatment requires approval by the panel.
Preassessment
Intravenous immunoglobulin is a blood product and written informed consent is recommended before use. Any required serological tests should ideally be performed before giving intravenous immunoglobulin, as exogenous immunoglobulins can produce false positive results. In theory, any serological test that relies on detecting IgG can be affected. There is evidence that at least some intravenous immunoglobulin preparations contain IgG that can result in false-positive hepatitis, syphilis and Lyme serology, as well as antinuclear antibodies, antineutrophil cytoplasmic antibodies (ANCA), anti-cardiolipin and double stranded DNA antibodies.10 11 Immunoglobulin may also elevate the erythrocyte sedimentation rate and CSF white cell count. Some centres routinely perform a range of serological tests before starting intravenous immunoglobulin, while others do so only if they are clinically indicated, or may be indicated in the future. The risk of thrombotic complications should also be assessed, both at induction and for maintenance therapy, as this influences the maximum recommended daily intravenous immunoglobulin doses and infusion rates (figure 1).
Preassessment and monitoring of intravenous immunoglobulin (IVIg). DVT/PE, deep vein thrombosis/pulmonary embolism; HTN, hypertension; MI, myocardial infarction; PV, plasma viscosity; SPE, serum protein electrophoresis.
Although in randomised trials thromboembolism was not significantly more common with intravenous immunoglobulin than with placebo,12 these primarily involved younger patients with few comorbidities. In clinical practice, rates appear much higher, and recent data suggest that those with cardiovascular risk factors are particularly susceptible.13 There is a notable association of intravenous immunoglobulin exposure with thromboembolism in patients with a previous thrombotic event (number needed to harm of 5.8).14 Administration of daily doses ≥35 g of intravenous immunoglobulin may carry a greater risk of early thromboembolic complications, possibly due to sudden rise in viscosity, although there is no demonstrated convincing association.15 There is less evidence that higher infusion rates themselves elevate risk. The measures outlined in figure 1 are designed to reduce the risk in susceptible individuals, while allowing those with minimal risk to receive their infusions in a timely and efficient manner. IgA deficiency is no longer considered a contraindication to immunoglobulin therapy and urgent treatment should not be withheld because of theoretical concerns of adverse reactions.16
The dose of intravenous immunoglobulin is based on body weight. However, for patients with body mass index of ≥30 kg/m2 or whose actual weight is >20% more than their ideal body weight, NHSE guidelines recommend that prescribers should consider using adjusted-body-weight dosing for immunoglobulin8 (see calculator at https://ivig.transfusionontario.org/dose/). Doses are usually rounded (down) to the nearest whole vial, as long as this is within 10% of the calculated dose.
Induction regimens
The recommended initial cycle is 2 g/kg divided over 2–5 days (figure 2), with the response usually best assessed after 3 weeks. Except in patients who have fully normalised, we favour giving a further 2 g/kg at 6 weeks. Almost all patients responsive to intravenous immunoglobulin will improve after these two treatment cycles. Other induction regimens follow the initial 2 g/kg with 1 g/kg at three and 6 weeks. However, some patients require more than 1 g/kg/cycle to respond, and the full benefit of the first cycle may not be apparent by 3 weeks. The PRIMA (efficacy and safety of Privigen in patients with chronic inflammatory demyelinating polyneuropathy) and PRISM (an international multicentre efficacy and safety study of IqYmune in initial and maintenance treatment of patients with chronic inflammatory demyelinating polyradiculoneuropathy) studies showed that intravenous immunoglobulin given as a 2 g/kg induction dose gave a response rate of 60.7% whereas given as a 1 g/kg maintenance dose every 3 weeks gave a response rate of 76.2%. Both studies showed that patients not responding after 6 weeks treatment may still respond at a later time point.17 18 The PRISM study suggested that CIDP patients should be maintained on intravenous immunoglobulin for 6 months to assess sufficiently for clinical response before switching to alternative therapy if required. The median time to response was 15 weeks and 29% of the patients responded after 6 weeks.18
Treatment algorithm to optimise dosing of intravenous immunoglobulin.19
Suspending further treatment after the week six cycle allows assessment of ongoing disease activity (indicated by redeterioration following a period of improvement and/or stability), and individual optimisation of the subsequent dosing interval. Some patients may achieve sustained remission after the induction regimen alone, without requiring further therapy. Others may begin to deteriorate as early as week 2 or as late as week 10. Longer lasting responses are uncommon in the presence of persistently immunologically active disease.19
Maintenance
Standardised doses (eg, 1 g/kg every 3 weeks) are sometimes used. However, patients’ dose requirements are not uniform. For this reason, we favour individually optimising both the dose per cycle and treatment interval. To do this, we give two further full dose (2 g/kg) cycles, separated by an interval just shorter than the empirically determined time to relapse after the second cycle. Thereafter, we progressively reduce the dose per cycle by 20% each time, to establish the minimum dose required for response (figure 2).19 Clinicians should then consider shortening the interval between infusions if there is an ongoing response with deterioration before the next scheduled dose.
Subcutaneous immunoglobulin
Patients generally prefer subcutaneous immunoglobulin as it is more convenient and has fewer associated infusion-related adverse effects. Infusions can be given at home and lead to more stable immunoglobulin concentrations as well as less clinical fluctuation. Subcutaneous immunoglobulin with hyaluronidase (HyQvia) may be more suitable for patients using relatively higher doses. Placebo controlled studies show that subcutaneous immunoglobulin is effective at preventing relapse following a switch from intravenous immunoglobulin.20–22 However, it is still uncertain whether it is effective as an induction therapy, and the response to dose changes may take longer to manifest clinically than with intravenous immunoglobulin. Home administration also requires training and logistical support. This may usefully be provided by immunology departments, which often have longstanding experience with subcutaneous immunoglobulin. Given these issues, and that a proportion of patients do not need long-term therapy, we prefer to assess response and optimise dosing using intravenous therapy. Patients can then be offered the option to switch to subcutaneous administration if needed, typically at the same average monthly dose. Only a small proportion (<10%) subsequently need or choose to revert to the intravenous route.
Corticosteroids
Despite little evidence from randomised controlled trials to support the use of prednisolone compared with no treatment,23 anecdotal evidence from clinical practice and observational studies strongly suggests that corticosteroids are effective in CIDP, and current NHSE guidelines strongly suggests considering their use first line in CIDP unless there is a specific reason not to.8 Two studies have directly compared corticosteroids with intravenous immunoglobulin. Broadly, they found little difference in overall disability outcomes, though intravenous immunoglobulin may work more quickly. High-dose intravenous methylprednisolone, 2 g over 4 days every 4 weeks for 6 months, was more often stopped due to perceived lack of efficacy or intolerance.24 However, it was more likely to induce short-term remission. Response rates are difficult to disentangle from stopping for reasons other than no benefit, but are probably 50%–70% for corticosteroids and 70%–80% for intravenous immunoglobulin. Those that improved with intravenous methylprednisolone did not relapse within 6 months of stopping treatment, whereas 38% of those treated with intravenous immunoglobulin did.25 A comparative study of daily prednisolone versus pulsed monthly dexamethasone found that these approaches were broadly similar, though steroid-induced adverse events, namely weight gain, hypertension and diabetes mellitus, were more severe in the patients receiving prednisolone.26
In addition to the usual concerns with corticosteroid use, clinicians should be cautious regarding purely motor presentations in particular, where ‘paradoxical’ worsening can be seen following corticosteroids.27
Many different corticosteroid regimens have been proposed for CIDP and should be individualised to the patient. Table 2 provides a comparison between four of these over a 6-month course, based on study protocols and our own recommendations. The very high doses given over short periods in pulsed regimens may produce additional, more rapid, non-genomic effects,28 29 disproportionate to those expected from simply calculating the average daily dose for the duration of the cycle. It remains to be seen whether this translates into improved efficacy in suppressing disease activity and inducing long-term remission. Pulsed regimens are also easier to stop quickly. Trial evidence suggests that pulsed corticosteroid regimes give fewer longer-term adverse effects than daily prednisolone, but more advere effects in the short term26; nevertheless, many patients find pulsed corticosteroid regimes difficult to tolerate.
Corticosteroid regimens for CIDP
Plasma exchange
Plasma exchange is an effective and relatively safe option for treating CIDP, at least in the short term, though has several logistical drawbacks that limit its use. There have been two double-blind randomised controlled trials assessing its efficacy in CIDP. The first compared plasma versus sham exchange in 29 patients treated twice weekly for 3 weeks.30 The second trial recruited fewer patients, with only 15 completing the trial, receiving 10 plasma or sham exchanges over 4 weeks. Patients were crossed over to alternate treatments after a wash-out period of 5 weeks.31 In both studies, plasma exchange gave clear benefit compared with sham exchange, in both disability scores and nerve conduction studies. Comparative studies between plasma exchange and intravenous immunoglobulin suggest they are equally effective in the short term. There are no data regarding the safety and efficacy of plasma exchange as maintenance therapy. Broadly speaking, there are two different plasma exchange technologies used in the UK. One removes plasma proteins using a membrane filtration system, and the other uses a blood cell separator via a centrifugal system. The advantage of the latter is that continuous low flow (vs intermittent in central venous catheterisation) permits the use of a peripheral cannula, thus avoiding the risks associated with a central venous catheterisation. It also allows a more convenient maintenance regimen of one exchange every 2–3 weeks. In hospitals where centrifugal machines are available, an outpatient-based day-treatment service can potentially be offered. It is typical that 1–1.5 plasma volumes are removed at each procedure and replaced with isotonic 4.5% human albumin solution. A single plasma volume exchange removes about 66% of an intravascular constituent and a double plasma volume exchange approximately 85%. The optimum treatment volume for each procedure is 100%–150% of the patient’s plasma volume where one plasma volume is 0.07 × (1-haematocrit) × weight (kg).
There is no evidence-based established protocol for plasma exchange in CIDP, and typically five initial daily exchanges of one plasma volume each are prescribed, with subsequent therapy being guided by clinical response. Patients are often given plasma exchange at 4–6 weekly intervals, using between three to five exchanges per cycle, having first determined the patient’s individual response characteristics.
Although plasma exchange is generally regarded as well tolerated, there is only sparse evidence for its safety and tolerability, with evidence largely from small case series.32 Plasma exchange with albumin or saline causes a transient fall in blood-clotting factors, and mild prolongation of prothrombin and activated partial thromboplastin times. These generally recover in 4–24 hours. Clinically significant bleeding is rare. More common risks include vasovagal episodes, fluid overload, under-replacement, and hypotension from rapid shifts in fluid between compartments. To minimise this risk, clinicians should consider suspending anti-hypertensives on treatment days. More rarely, allergic or anaphylactic reactions result from the plasma or human albumin solution infusion. If central or large bore access is required, complications related to line insertion and use may occur. These include haematomas at the point of insertion, venous thrombosis, vascular damage secondary to line insertion, and line sepsis.
All patients should have daily full blood count, clotting, fibrinogen, U&E, renal, liver, magnesium and bone profile. For infection control purposes, all patients require pretreatment virology including hepatitis B surface and core antibodies, hepatitis C antibody, HIV and HTLV 1 and 2. It is also useful to check baseline immunoglobulin levels, as these can be rapidly depleted.
Monitoring response and ongoing requirement for therapy
The NHSE specifies that a selection of three outcome measures be used to monitor for clinically meaningful response to immunoglobulin.8 The latest EAN/PNS guidelines recommend that improvement to at least one disability and one impairment scale be used to confirm objective response to treatment.3 Ideally, the chosen measures should be as objective as possible and sensitive to change.
Two useful outcome measures that assess disability are the inflammatory neuropathy Rasch-built Overall Disability Score (increase of ≥4 points)21 33 34 and the Inflammatory Neuropathy Cause and Treatment disability scale (decrease of ≥1 point).35 36 Further outcome measures are selected based on the individual patients’ disability or impairment, for example, the MRC sum score (increase of ≥2 points) could be used if limb weakness predominates, or a 10 m timed-walk test used if gait disturbance predominates. Grip strength is another well validated measure of impairment,37 and quality of life assessments can also be valuable.
By 6–12 months, a significant proportion of patients can stop treatment without relapsing,38 in which case we favour suspending treatment with careful monitoring for objective worsening. Slow tapers (either increasing the dose interval or reducing the dose) seem prone to heightening anxiety while also frequently being less informative regarding underlying disease activity, but may be unavoidable in the setting of long-term daily corticosteroids. The ongoing requirement for immunoglobulin should be assessed at least annually for the first 3 years, and probably less often thereafter, when long-term dependence is much more likely. In those who relapse on treatment withdrawal, restabilisation on the previously effective maintenance therapy can be rapidly achieved,39 though may require another initial induction dose (2 g/kg), and should be accompanied by considering second-line agents.
Second line and escalation therapies
Corticosteroid (or intravenous immunoglobulin)-sparing agents
When first-line therapies have proved effective, but long-term treatment is required to maintain clinical stability, various immunosuppressive agents can help to reduce corticosteroid or intravenous immunoglobulin requirements. These include azathioprine, methotrexate, mycophenolate mofetil and ciclosporin. Evidence supporting the use of azathioprine comes from one, low-quality trial of relatively short duration.40 A single methotrexate study showed no evidence of benefit. Though this trial was compromised by a large proportion of patients in the placebo group being able to reduce or even stop their existing therapy, and methotrexate has been widely used in clinical practice, the latest iteration of the CIDP guidelines advise against its use.6 There is also no evidence to determine whether these agents reduce the chance of future relapse in patients who achieve remission or have a relapsing-remitting disease course. The use of any of these agents in CIDP, therefore, requires careful consideration and open discussion with the patients regarding the uncertainty of the potential benefits and the potential for adverse events. Such use should be evaluated against the option of simply remaining solely on an apparently effective first-line therapy. If second-line therapies are deemed appropriate, immunosuppression checklists can help to evaluate and manage the associated risks.41 Monitoring requirements once on therapy will usually need to be carefully coordinated with primary care, and explicit shared care arrangements can be helpful in this regard.
More potent immunosuppression
More potent forms of immunosuppression are usually considered in the context of markedly inadequate responses to first-line therapies. As before, the first step must be to reconsider the possibility of a non-CIDP diagnosis. However, although there have been no controlled trials, observational studies suggest >30% of patients refractory to first-line therapies can respond to escalation therapies (notably rituximab or cyclophosphamide).42 A positive response to rituximab may be even more likely in the context of a paraprotein or nodal/paranodal antibody.5 43 44
Haematopoietic stem cell transplantation
In the largest case series reported to date, 66 CIDP patients who were dependent on or failed to respond to intravenous immunoglobulin or plasma exchange underwent haematopoietic stem cell transplantation, in a prospective open-label study, and were assessed up to 5 years after treatment.45 Almost all patients requiring assistance to walk became and remained independently mobile, and 83% of patients were immune therapy free at 5 years. Despite these promising results, the evidence for the use of haematopoietic stem cell transplantation in refractory or treatment-dependent severely affected patients remains insufficient, and its morbidities and mortality risk are significant, mainly related to infections and long-lasting immunodeficiency. Therefore, haematopoietic stem cell transplantation should only be considered as a last resort treatment in specialised CIDP centres.
Immunoadsorption
A less commonly offered treatment option in the UK, available only in selected centres, is immunoadsorption. This involves passing the separated plasma through an absorption column to selectively remove IgG. Other circulating factors largely remain in the fluid exiting the column, which is then returned back to the patient. Low-quality evidence from case reports and small case series suggest that some patients with CIDP can respond to this treatment modality.46–48 Two, small, randomised studies, one with a high risk of bias, did not find a significant difference in these response rates when compared with intravenous immunoglobulin or plasma exchange.49 50 The theoretical advantage of immunoadsorption over plasma exchange is that it can be given more intensively, without disturbing clotting and without the need for replacement fluid. However, the extent to which the removal of additional circulating factors by plasma exchange is therapeutically important remains unclear. Overall, it is unlikely that IgG is the sole pathological agent in CIDP, though it may have more primary importance in some subtypes. Further evidence is needed before immunoadsorption can be widely recommended for CIDP.
Symptomatic and non-pharmacological treatments
The aim of immunotherapy in CIDP is to improve functional status by reversing or stabilising peripheral nerve injury, and in turn preventing motor and sensory deficit. It is important not to overlook the treatment of other disabling symptoms, such as pain or fatigue, as well as non-pharmacological management, as these complement drug treatment in optimising clinical outcome, and can in themselves improve patient quality of life.
Physiotherapy and occupational therapy support physical recovery and can help to maintain independence. Orthotics can help mitigate the impact of foot drop.
Neuropathic pain is common in CIDP,51 although information regarding the association of pain during the disease course and response to different treatments is limited and only comes from small case series. Some data suggest immunotherapy for CIDP may be sufficient to treat neuropathic pain, though specific treatments for neuropathic pain are also often used.51
Fatigue correlates poorly with specific markers of peripheral dysfunction in immune-mediated neuropathies such as CIDP.52 Conversely, fatigue is significantly associated with the use of sedatives, older age, poor sleep and depression.53 Thus, where possible, these factors should be addressed, and ideally optimised. There are no clearly beneficial pharmacological or other treatments for fatigue specifically in peripheral nerve disorders.54
Future directions
Trials of the neonatal Fc receptor (FcRn) blocking agents as alternatives to intravenous immunoglobulin are currently in progress,55 and an evaluation of complement inhibition is planned.56 An increasing number of targeted biological immunotherapies have now been developed for other indications. Anti-CD20 agents such as rituximab and ocrelizumab target B cells, and CTLA-4 fusion proteins (abatacept) block T cell activation. Proteasome inhibitors (bortezomib, carfilzomib) and Bruton’s tyrosine kinase inhibitors (ibrutinib, zanubrutinib) target long-lived plasma cells. The hope for the future is to be able to identify the key underlying mechanisms in individual patients, and then specifically and directly target treatments to these.
Further reading
Neligan A, Reilly MM, Lunn MP. CIDP: mimics and chameleons. Pract Neurol 2014;14:399–408
Van den Bergh PYK et al. European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision. J Peripher Nerv Syst. 2021;26:242–68.
Allen JA, Ney J, Lewis RA. Electrodiagnostic errors contribute to chronic inflammatory demyelinating polyneuropathy misdiagnosis. Muscle Nerve 2018;57:542–9.
Lunn MP, Ellis L, Hadden RD, et al. A proposed dosing algorithm for the individualized dosing of human immunoglobulin in chronic inflammatory neuropathies. J Peripher Nerv Syst 2016;21:33–7
Key points
Misdiagnosis is common in chronic inflammatory demyelinating polyneuropathy (CIDP)
CIDP is a treatable disorder with a wide range of potential therapies
Most patients with CIDP respond to one or other of the first-line options (intravenous immunoglobulin, corticosteroids or plasma exchange)
Clinicians should measure the response to treatment with validated outcome measures
A substantial proportion of patients do not require continuous, long-term treatment to remain in remission
Second-line and escalation therapies need careful consideration and monitoring
Data availability statement
All data relevant to the study are included in the article.
Ethics statements
Patient consent for publication
Ethics approval
Not applicable.
References
Footnotes
Contributors JF and SR wrote the original draft of the manuscript. RB contributed to subsequent drafts and revisions. AB specifically wrote the section relating to plasma exchange. SAM provided expertise regarding Immunoglobulin and in particular subcutaneous administration. All authors approved the final version.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed by Rob Hadden, London, UK, and Michael Lunn, London, UK.
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