Impact of the updated chronic inflammatory demyelinating polyneuropathy guideline on everyday clinical practice

Introduction

Chronic inflammatory demyelinating polyneuropathy (CIDP) is an immune-mediated inflammatory neuropathy, leading to proximal and distal arm and leg weakness, sensory ataxia, and diffuse hyporeflexia or areflexia. ¹ The primary pathological process of demyelination causes secondary axonal degeneration, leading to disability. Early diagnosis and treatment can minimize the severity of axonal degeneration. ¹ Therefore, diagnostic criteria for CIDP should be implemented widely to prevent misdiagnosis and delayed treatment.

In 2021, the European Academy of Neurology/Peripheral Nerve Society (EAN/PNS) updated the CIDP guideline using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology with the aim to formulate evidence-based recommendations. Here, we discuss the impact of these updates on the diagnosis of CIDP and its implications on everyday clinical practice. ¹

EAN/PNS guideline updates on diagnosis and treatment of CIDP

The main updates within the 2021 EAN/PNS CIDP guideline include: simplification of the clinical definitions of CIDP and possible CIDP, introduction of the term ‘CIDP variants’ that replaces ‘atypical CIDP’, addition of subcutaneous immunoglobulin (SCIg) as strongly recommended maintenance therapy, reclassification of patients with CIDP and nodal antibodies, and exclusion of chronic immune sensory polyradiculopathy (CISP) as a variant of CIDP. Although the updated guideline simplifies the CIDP classification, it also creates ambiguity in the diagnosis of patients with nodal antibodies and classifies CISP as a new disease entity.^1,2

Clinical definitions of CIDP

The 2010 EFNS/PNS guideline was a good diagnostic tool adopted by neurologists worldwide.^2,3 However, delayed and misdiagnosis continued to be a problem ⁴ and further clarity in clinical definitions of CIDP was needed.

In our opinion, electrodiagnostic and clinical criteria should allow for expeditious and accurate CIDP diagnosis by primarily ensuring that patients have an acquired demyelinating neuropathy; these criteria have now been included in the guideline to facilitate diagnosis. The importance of clear guideline diagnosis criteria is highlighted by recent reports showing that neurologists do not always consider the presence of demyelinating electrophysiological findings as mandatory for CIDP diagnosis. ⁵ In addition, we support the simplification of the electrodiagnostic criteria to either CIDP or possible CIDP, instead of the previous three categories (definite, probable, and possible).^1,2

Diagnostic presentation of CIDP

As CIDP has a heterogeneous clinical presentation, the updated guideline refines the definition of CIDP to ‘typical CIDP’ and replaces the collective term ‘atypical CIDP’ with the term ‘CIDP variants’, which includes distal, multifocal/focal, motor, and sensory CIDP. ¹ Electrodiagnostic findings of acquired demyelination are strongly recommended to support the clinical diagnosis of CIDP and CIDP variants. If electrodiagnostic findings demonstrate weak evidence of demyelination, the updated guideline recommends several supportive criteria to further assist in diagnosis (e.g. treatment trial with objective validated measures of a positive response, imaging studies, cerebrospinal fluid examination, nerve biopsy, presence of monoclonal proteins, and additional immunologic and antibody testing). ¹ Consequently, we believe that the updated guideline will reduce CIDP misdiagnosis.

Autoimmune nodopathies, despite their clinical and electrophysiologic resemblance to typical CIDP, have been excluded from the CIDP cohort given the lack of typical pathological findings such as inflammation, macrophage-mediated demyelination, and robust response to intravenous immunoglobulin (IVIg). ¹ The diagnosis of these nodopathies is largely based on antibody testing (e.g. neurofascin), which the guideline and a recent review acknowledge is not readily available.^1,6 The current CIDP guideline does not advise testing for these antibodies early in the disease course for all patients with CIDP but only recommends them if available. The guideline advises antibody testing in CIDP patients with specific features such as resistance to IVIG; however, late antibody testing may delay diagnosis, optimal treatment, and increase diagnostic confusion among general neurologists. Although we acknowledge the challenges caused by CIDP heterogeneity for the discovery of new drugs and biomarkers, and agree with the use of a more restricted CIDP category when designing new clinical trials and academic research, we recommend regarding nodopathies as variants of CIDP, given their clinical and electrophysiologic resemblance, until such drugs and biomarkers have been discovered and antibody testing becomes easily accessible in the clinics (Table 1). Furthermore, we believe that future guidelines should include more advice on treatment strategies when nodopathies are diagnosed after antibody testing, to avoid a lack of practical guidance for this patient population.

Table 1.

Overview of the suggested edits to the 2021 EAN/PNS CIDP guideline.

Guidelines statements	Suggested modifications	References, supporting documentation
Autoimmune nodopathies, defined by the detection of antibodies against nodal-paranodal cell adhesion molecules, should no longer be regarded as CIDP variants Testing for nodal and paranodal antibodies should be considered in all patients with clinical suspicion of CIDP when these tests are available and meet quality standards	As long as antibody testing is not readily available to confirm the diagnosis, nodopathies should be considered as a CIDP variant to avoid confusion, diagnostic, and treatment delays Future guidelines should include advice on treatment strategies when nodopathies diagnoses are made after antibody testing, to avoid a lack of practical guidance for this patient population	Lewis et al.6: review confirming the lack of availability of good quality antibody testing
There is not enough evidence to determine if CISP is demyelinating or related to sensory CIDP, and CISP has therefore not been included in the CIDP variant classification	Given the clinical resemblance to sensory CIDP, responsiveness to IVIg, and similar cerebrospinal fluid findings, classifying CISP as a separate entity might further delay diagnosis and treatment. Therefore, CISP should be classified as a CIDP variant	Rajabally et al.7: editorial discussing the inclusion of chronic immune polyradiculopathies in the CIDP classification

CIDP, Chronic inflammatory demyelinating polyneuropathy; CISP, chronic immune sensory polyradiculopathy; EAN/PNS, European Academy of Neurology/Peripheral Nerve Society; IVIg, intravenous immunoglobulin.

CISP has also been classified as a separate disease rather than a variant of CIDP. ¹ As discussed in a recent editorial, ⁷ we also believe that, given the clinical resemblance to sensory CIDP, responsiveness to IVIg, and similar cerebrospinal fluid findings, classifying CISP as a separate entity might further complicate diagnosis (Table 1). Furthermore, payers are less likely to approve IVIg treatment for patients not classified as having CIDP.

Treatment decisions

The updated guideline strongly recommends the use of corticosteroids, IVIg, or plasma exchange as first-line treatment for CIDP. ¹ We consider several factors in choosing the first-line treatment, such as comorbidities, availability, and disease characteristics. Although steroids were historically the first efficient CIDP treatment, ⁸ IVIg tends to be the first-line treatment for most patients, because of faster onset of action and better tolerability compared with corticosteroids. ⁹ The updated guideline discusses comparable efficacy of oral and pulsed corticosteroids, and the lack of evidence for superiority of pulsed treatment. ¹ In our practice, we use daily oral over pulsed steroids for easier implementation and practicality. We rarely use plasma exchange, given the lack of long-term data and for logistical challenges, except in patients refractory to IVIg and steroids.

If objective response to a first-line therapy is inadequate or results in significant adverse effects, the updated guideline recommends an alternative first-line treatment before considering combination first-line or second-line therapies. ¹ Based on our clinical experience, we would recommend early testing for nodal antibodies if there is suboptimal response to first-line treatments, which could prevent delay in implementing more effective B-cell depleting therapies for those patients. Long-term immunosuppressants can be useful when used as steroid- or IVIG-sparing agents, or in patients with suboptimal response to first-line treatment. Rituximab data in CIDP are inadequate but if all other available treatments fail, its use can be considered; particularly in patients with nodopathies associated with IgG4 antibodies who may have a more robust response to B cell depleting therapies than to IVIg, which target memory B cells and IgG4-producing CD20-positive short-lived plasma cells. ¹⁰

The updated guideline strongly recommends SCIg as a maintenance treatment of CIDP after patients have improved with IVIg. The use of SCIg might be particularly helpful in centers where home-based IVIG infusions are not available. In our clinical experience, SCIg can be useful as long-term maintenance treatment because of its flexibility, autonomy, and both lack of systemic adverse effects and need for intravenous access; and its use should always take the patients’ preference into account. ¹¹ The weekly regimen of SCIg rather than less frequent IV infusions can be limiting for some patients, and patient’s preference in this regard should be assessed. In patients with inadequate response to lower doses of SCIg (0.2 g/kg/week), infusion optimization and dose adjustment (e.g. up-titrate to 0.4 g/kg/week) should be considered before exploring other treatments.

Conclusion

The 2021 EAN/PNS consensus guideline provides updated clinical definitions, presentations, and treatment regimens for CIDP. In addition, it supports the use of electrodiagnostic and clinical criteria for the diagnosis and treatment of CIDP. To avoid misdiagnosis and therefore delayed treatment, it remains critical that this guideline be widely understood and followed. We highlight the key updates with the hope that the guideline will be consistently used in everyday clinical practice worldwide; and discuss where some of the changes, such as the exclusion of autoimmune nodopathies and CISP, may have complicated the diagnostic algorithm. We hope that some of these issues can be further discussed and addressed in the next update.