Untangling CIDP

The Challenge of Variants

After their 2015 paper on diagnostic pitfalls, Dr. Lewis and Dr. Allen, along with colleagues in the United States and Europe, started looking deeper into outcome measures and how to better follow and track patients with CIDP. In 2021 they helped create the first comprehensive clinical guidelines for CIDP in over a decade.

Much of their effort focused on atypical presentations, or what are now called variants, of CIDP — people with predominantly distal disease, asymmetrical symptomology, focal symptoms, or exclusively motor or sensory symptoms. With classical CIDP, “we don’t really have a problem with misdiagnosis,” Dr. Lewis said. With variants, however, misdiagnoses are extremely common. The 2021 guidelines try to address this, proposing differential diagnoses for each of the variants and ways to investigate them.

The guidelines also removed a subgroup of patients previously included as having CIDP. These patients, who comprise about 10% of cases, have antibodies to components of the Node of Ranvier, part of the axonal membrane, and the paranodal myelin. The autoimmune nodopathies do not respond to treatment with immunoglobulins or steroids in the way classical CIDP and its variants do. However, many patients have seen success with the immunotherapy rituximab.

“CIDP is a syndrome, not one disease,” Dr. Lewis said. “So it has been difficult to get guidelines or criteria that are sensitive to all the different forms of the disease, and yet specific for the disease and not overlapping. The nodopathies were pulled out because they don’t respond to usual treatments for CIDP. Hopefully over the years we’ll have even more specific diagnoses and can split out more patients.”
 

A Need for Better Biomarkers

With the neuromuscular autoimmune disease myasthenia gravis, 85% of patients have antibodies against the muscle acetylcholine receptor (AChR). Another 6% will have antibodies against muscle-specific kinase (MuSK).

Antibody profiles have long guided treatment decisions in myasthenia gravis, with AChR-positive patients responding to corticosteroids, IVIg, complement inhibitors, and other agents. MuSK-positive myasthenia gravis patients, similar to people with autoimmune nodopathies, respond poorly to IVIg but can have dramatic responses when treated with B cell–depleting therapies like rituximab.

Antibodies to nodal proteins neurofascin-155 and contactin-1 have been shown to be involved with the nodopathies. Assays for these are now commercially available, and Dr. Allen recommended that clinicians seek them for patients with a more rapid course, with tremor and ataxia, or who do not respond to standard CIDP treatments.

Still, no dominant autoantibody has been identified for the majority of presentations, including classical presentations. “I suspect it’s a heterogeneous group of multiple antibodies causing the disease,” Dr. Silvestri said. “That may explain to an extent the different manifestations and the different responses to treatment.”

Dr. Lewis said he thinks that, while more antibodies are likely to be discovered in the coming years, “we’re still identifying fewer than 20% of CIDP patients by specific antibodies, so we have a long way to go.”
 

Promising Trial Landscape

“CIDP is a challenging disease to study because of the diagnostic issues,” Dr. Allen said. “We know that a [nontrivial] percentage of patients ... can go into a drug-free remission. They actually don’t need treatment during that time. We don’t have any way to measure that. And if you put them in a clinical trial, it’s difficult to measure changes in the trial if they didn’t need the drug in the first place.”

In the global ADHERE trail, which looked at efgartigimod alfa and hyaluronidase-qvfc in CIDP patients, the investigators, led by Dr. Allen and Dr. Lewis, challenged patients to be off therapy for 12 weeks and allowed only those with active disease to enroll. They also used an adjudication panel of CIDP experts to review the records of each patient to assure patients had CIDP.

If two experts on the panel independently agreed that it was CIDP, Dr. Lewis said, then patients were eligible for enrollment. “If they both said they weren’t CIDP, they were not eligible. And if there was an argument between the two of them, then a third adjudicator would come in.”

About half of patients screened (n = 221) ended up included, and adjudication panels are now used in most CIDP trials.

The trial saw a positive outcome for efgartigimod alfa and hyaluronidase-qvfc, an antibody fragment that targets neonatal Fc receptor (FcRn), as a way to reduce to levels of pathogenic IgG autoantibodies. (The treatment was previously approved for myasthenia gravis.) The fact that two thirds of participants in the trial responded pointed to the likelihood that most CIDP patients have an IgG-related disease, Dr. Lewis said.

Different types of therapies are now being investigated in CIDP, among them other FcRn-inhibiting drugs and drugs inhibiting complement. Results from these trials may shed more light on the pathophysiology of the disease, which Dr. Silvestri said would be welcome.

“If I can test for antibodies, I can make a more timely diagnosis,” he said. “I’m assuming that some people with CIDP have non–antibody-driven disease. And in those cases, I want to avoid using drugs like Vyvgart, which are targeting antibodies. I want to give them a different therapy.”