What is refractory CIDP?

In this journal, Kiers et al review treatment options for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) beyond the established first-line therapies of corticosteroids, immunoglobulin and plasma exchange. Their review, framed by the 2021 European association of neurology/ Peripheral nerve society (EAN/PNS) CIDP guidelines, addresses diagnostic challenges in variant presentations and the need to consider alternative diagnoses when first-line treatment response is suboptimal. They discuss current evidence for T-cell and B-cell-directed therapies, including autologous stem cell transplantation, CAR-T cell therapy and proteasome inhibition, as well as novel molecular targets such as FcRN and C1s (complement) inhibitors. Given recent therapeutic developments, limited high-quality evidence for alternatives and associated risks, the review underscores the need to better define ‘refractory CIDP’.

The concept of ‘refractory CIDP’ is imprecise, reflecting diagnostic uncertainty. Expecting a single immunopathology for a clinical phenotype is unlikely. Even phenotypically, ‘refractory CIDP’ may include partial responders, those without sustained response, incomplete responders with fixed disability from axonal loss and truly refractory disease. Kiers and Cruse stress close monitoring using disease-specific outcome measures like INCAT and MRC scores. However, these tools have limitations: INCAT lacks sensitivity to meaningful change and captures little patient experience,¹ while MRC scoring is non-linear, subjective and prone to variability.² Minimum clinically important difference (MCID) must account for measurement noise, reducing precision. Using at least three validated outcome measures, with contiguous sub-MCID changes in two or more, may better indicate disease trajectory.³,⁵ An international CIDP Task Force proposes a multimodal approach to defining disease states—relapsed, stable and refractory—combining patient global impression, disability and impairment measures to enable consensus categorisation (In Press).

A major reason for non-response may be misdiagnosis. The authors advocate careful consideration of CIDP mimics. The 2021 EAN/PNS guidelines prioritise excluding mimics after phenotype identification, though older criteria were less explicit. Historical cohorts and trials of ‘refractory CIDP’ likely included misdiagnosed cases. Mimics with conduction slowing meeting CIDP criteria include POEMS, vasculitis, amyloid, certain CMT variants (eg, PIGG neuropathy) and lymphoma-associated neuropathies. Some, like POEMS, are easier to diagnose with biomarkers such as immunofixation and VEGF, while amyloid and vasculitis still require nerve biopsy; PIGG neuropathy was only recently discovered. Does ‘refractory CIDP’ truly exist or does deeper diagnostic scrutiny often reveal a mimic? Allen et al found misdiagnosis common, explaining apparent treatment resistance.⁶

Kiers et al are keen on diagnostic biomarkers to aid identification of the notorious CIDP variants with an optimistic wish for reliable, bedside indicators of immunopathogenesis in the individual to guide treatment selection. We suggest highly sensitive fluid biomarkers linked to cellular pathology and responsive to disease activity will improve diagnosis and therapy decisions in a more meaningful way. Promising candidates include single molecule array (Simoa)-based immunoassays measuring axonal damage (peripherin) and Schwann cell injury (periaxin).^{7 8} Combining these with neurofilament light chain and clinical scales could enhance decision-making, target therapy more precisely and reduce non-response rates.

Reported rates of ‘refractory CIDP’ in historical studies are likely overestimates. Before adopting alternative therapies—whether in trials or practice—we should prioritise re-evaluating diagnosis and using responsive biomarkers to ensure correct treatment. Applying CIDP guidelines alongside consensus disease activity definitions will improve patient expectations, therapeutic choices and research sophistication in this evolving field.