CIDP trials pursue treatment biomarkers, but clinical expertise in diagnosis, treatment remains shaky

Will Pass

Chronic inflammatory demyelinating polyneuropathy (CIDP) can be a difficult condition for neurologists to navigate, and yet most clinicians may be failing to follow current standards for diagnosis and treatment, based on a nationwide survey.

The survey, recently published in Journal of Neurological Sciences, involved 100 community neurologists from across the United States. Of the respondents, only 13% reported using the 2010 EFNS/PNS (European Federation of Neurological Societies/Peripheral Nerve Society) guideline, revealing a concerning practice gap, according to coauthor John D. England, MD, chair of the department of neurology at Louisiana State University Health Sciences Center in New Orleans, and colleagues.

John D. England, MD

The investigators pointed out that the EFNS/PNS guideline is widely accepted as the preferred CIDP decision-making tool for both research and clinical use because of its balance between specificity (61%-97%) and sensitivity (81%-99%). In lieu of the EFNS/PNS guideline, 21% of neurologists reported using the 1991 American Academy of Neurology guideline, which was originally designed for research purposes. As such, the AAN guideline has very high specificity (100%), but also has very low sensitivity, as low as 3.6%.

Although slightly more neurologists with multiple board certifications reported using a guideline of some kind for diagnosing CIDP than did those with a single board certification (74% vs. 55%), adoption of the EFNS/PNS guideline remained low even among those with multiple board certifications, at 12%. Most community neurologists reported using four or five clinical features to diagnose CIDP, most often absence of deep tendon reflexes (84%), progression of symptoms over 8 weeks (86%), and weakness (87%).

“Unexpectedly,” the investigators wrote, “many of the respondents cited features that are not typically associated with CIDP,” including cranial nerve involvement (18%), pain (29%), and autonomic involvement (31%). And about half of the neurologists described reliance upon extraneous electrophysiologic features unnecessary to diagnosis of CIDP, such as jitter on single-fiber EMG or absent distal latency motor unit number estimate.

While most neurologists appeared familiar with a typical presentation of CIDP, almost half answered at least one question about atypical forms incorrectly, and about one-third cited pain and fatigue as reasons to administer treatment, even though, according to the investigators, pain and fatigue are “less reliable prognostic indicators and are generally not used to guide dosing decisions.”

Concerning specific treatments, most respondents correctly identified intravenous immunoglobulin (IVIg) as the preferred first-line treatment, with steroids coming next, but many also reported giving doses of IVIg that were too low, or continuing treatment for unnecessarily long periods without efforts to taper off.

“There is … a need for more education about CIDP diagnosis and treatment, especially on atypical CIDP phenotypes,” the investigators concluded. “It may be impactful to pursue proactive changes (e.g., more IT innovations that support clinical decisions, enhanced training for medical students, residents, fellows, and practicing physicians on guideline usage, patient education through [the GBS/CIDP Foundation], and greater access to recognized experts) to support guideline adoption and adherence.”

In addition to more training, the investigators suggested that a new guideline may be needed to improve adherence.

“[The survey] findings led us to believe there remains a need for a guideline on CIDP diagnosis and treatment that is brief, clear, and actionable, in particular stressing the need for objective outcomes when determining response to therapy,” the investigators wrote.

“[The survey] findings led us to believe there remains a need for a guideline on CIDP diagnosis and treatment that is brief, clear, and actionable, in particular stressing the need for objective outcomes when determining response to therapy,” the investigators wrote.

In an interview, Dr. England said that there is “not currently” a plan or effort in place to create such a guideline. In the meantime, he suggested that some clinicians should consider stepping aside if unprepared.

“[CIDP] is frequently misdiagnosed and treated inappropriately,” Dr. England said. “If physicians are not familiar with the disease, they should refer patients to neurologists with expertise in the disease.”

For those who would like to bring themselves up to date, Dr. England recommended referring to the EFNS/PNS guideline and he offered some insight into emerging topics in CIDP treatment.

“[CIDP] is frequently misdiagnosed and treated inappropriately,” Dr. England said. “If physicians are not familiar with the disease, they should refer patients to neurologists with expertise in the disease.”

Leading clinical trials

According to ClinicalTrials.gov, there are at least 20 trials planned or active to investigate the diagnosis or treatment of CIDP. The majority of therapeutic studies are focused on various regimens of immunoglobulin, either intravenous or subcutaneous, while two trials are evaluating hematopoietic stem cell transplantation (HSCT) and one is comparing rituximab between CIDP subtypes.

Dr. England identified the phase II rituximab study, RECIPE, as a leading trial that could alter clinical practice. The trial is evaluating treatment responses to rituximab in relation to immunoglobulin G4 (IgG4) autoantibody status. An estimated 25 patients with CIDP will be enrolled and treated with rituximab (375 mg/m2 IV infusion once weekly for four doses) or placebo, with patients grouped by IgG4 positivity or negativity. The primary outcome will be the rate of patients who show improvements in adjusted Inflammatory Neuropathy Cause and Treatment disability scale with up to a year of follow-up. Over the same time frame, 19 secondary outcomes will be measured, including physical changes ranging from grip strength to Rasch-built Overall Disability Scale score, various motor nerve measures, rituximab pharmacokinetics, serum antibody titers of IgG4, and serum neurofilament. The RECIPE trial commenced in March 2019 and is being led by investigators from Nagoya (Japan) University.

The other study Dr. England highlighted as a possible practice-changer is BIOMARK. Like RECIPE, BIOMARK is concerned with identifying predictive biomarkers that may guide treatment decisions, but instead of IgG4 status, patient transcriptomes will be analyzed. An estimated 25 patients with treatment-naive CIDP will be given standard treatment with IVIg. Over the course of a year, CIDP patients will be followed with clinical assessments and grouped into responders and nonresponders. Concurrently, serial blood samples will be drawn to evaluate transcriptomes across all participants, comparing changes between CIDP responders, nonresponders, and a group of 20 age- and sex-matched healthy controls healthy controls. The BIOMARK trial began in April 2014 and is being led by investigators from the Adolphe de Rothschild Foundation in Paris.

Future directions

Looking to the future, Dr. England predicted that CIDP may one day be treated with complement inhibitors such as eculizumab (Soliris).

According to Christian W. Keller, MD, PhD, of the Institute of Experimental Immunology at the University of Zürich and colleagues, complement inhibition stands out as a potential therapeutic strategy for CIDP since affected patients exhibit deposition of complement component C3d on Schwann cells and compact myelin, and have elevated levels of terminal complement activation products in serum and cerebrospinal fluid.

A clear relationship between complement products and CIDP, however, remains unclear. Dr. Keller and his colleagues recently conducted a study that involved measurement of complement levels in 39 patients who participated in ICE, the largest CIDP trial to date. The study, published recently in the Journal of Neuroimmunology, showed that serum complement levels were unaffected by standard treatment with IVIg regardless of whether patients responded to therapy, maintained steady disease, or progressed.

“These results suggest that the therapeutic efficacy of IVIg in CIDP is based on immunomodulatory mechanisms different from complement inhibition,” the investigators wrote. “Terminal complement activation merits further investigation as a surrogate marker for disease progression and therapeutic target in patients with CIDP.”

According to ClinicalTrials.gov, no trials are currently planned or underway to test complement inhibition in patients with CIDP; however, two phase II trials have been conducted for the acute counterpart of CIDP, Guillain-Barré syndrome (GBS). Both studies tested the safety and efficacy of IVIg in combination with eculizumab.

The first trial, ICA-GBS, was conducted in Great Britain and ran into an “unexpectedly large number of exclusions of potentially eligible subjects at prescreening,” according to the investigators, leaving just two patients in the placebo group and five in the eculizumab group. Results, which were published in the Journal of the Peripheral Nervous System in 2016, showed that combination therapy with IVIg and eculizumab appeared safe and well tolerated, but the small sample size precluded “statistically meaningful analysis.”

The second trial, JET-GBS, was conducted in Japan and involved a larger patient population, all of whom were unable to walk independently at enrollment. Out of 34 patients, 11 received IVIg plus placebo while 23 received IVIg plus eculizumab. After 24 weeks, 61% of patients in the eculizumab group were able to walk independently, compared with 45% of patients in the placebo group; however, sample sizes were again too small for statistical comparison. Concerning safety, two patients in the eculizumab group had serious adverse events: One experienced anaphylaxis and the other developed intracranial hemorrhage and abscess. In their 2018 Lancet Neurology article, the investigators noted that a relationship between these adverse events and eculizumab “could not be excluded.”

“The efficacy and safety of eculizumab deserve further investigation in larger, multinational, randomized controlled trials,” they concluded.

The CIDP practice survey was funded by Grifols, a manufacturer of IVIg. Dr. England and coinvestigators disclosed additional relationships with Baxalta, GBS/CIDP Foundation International, and others. Dr. Keller and colleagues reported study funding from the University of Zürich, the Austrian Academy of Sciences, the Swiss National Foundation, and others, with no conflicts of interest. The ICA-GBS trial was funded by Alexion Pharmaceuticals, with no conflicts of interest reported. The JET-GBS trial was funded by the Ministry of Health, Labor and Welfare research grants and the Japan Agency for Medical Research and Development; eculizumab was provided free of charge by Alexion Pharmaceuticals. The JET-GBS investigators reported additional relationships with Novartis, Takeda, Otsuka, Sanofi, and others.