Early intervention is the key to minimizing disability for patients with chronic inflammatory demyelinating polyneuropathy (CIDP), and data from several recent studies support the monoclonal anti-CD20 antibody rituximab as a possible treatment when first-line treatments are not effective.
CIDP is a rare disease involving the inflammation of nerve roots and peripheral nerves, with destructions of the myelin sheath covering these nerves. It occurs in approximately 5-7 per 100,000 individuals and may arise in any decade of life, although the average age of onset is 50 years, according to the National Organization for Rare Disorders. Affected individuals may experience weakness, paralysis, impaired motor function, and sensory problems; motor and sensory impairments are usually bilateral.
In the absence of established treatments for refractory CIDP patients who have failed intravenous immunoglobulin (IVIG), glucocorticoids, and plasma exchange, studies of alternatives such as rituximab (Rituxan) are important, Suraj A. Muley, MD, of St. Joseph’s Hospital and Medical Center, Phoenix, said in an interview.
Suraj A. Muley, MD
Dr. Muley’s take-home message to clinicians is to consider rituximab for CIDP patients who are refractory to first-line treatments.
Most recent study of rituximab
In the most recently published study of rituximab for CIDP, published in the journal Muscle & Nerve, Dr. Muley and colleagues reviewed neuromuscular Medical Research Council (MRC) sum scores, Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, and functional status in 11 adults with CIDP before and after treatment with rituximab for an average of 12 months. The average age of these patients was 54 years, and 10 of 11 were quadriparetic at baseline. All patients had been treated with glucocorticoids and IVIG.
Overall, patients began to show improvement (defined as an improvement of at least 1 point on the INCAT score) within 3 months, and the time to maximum improvement ranged from 2 to 18 months. The baseline INCAT scores ranged from 2 to 10, with an average of 6.18. The overall change in INCAT scores averaged 4.54 points; 10 of 11 patients improved by 2 or more points, and 8 of 11 improved by 4 or more points. The average change in MRC score from pre- to post treatment was 23.63, ranging from 0 to 60.
The infusions were well tolerated and no significant adverse effects were reported.
“The degree of improvement correlated with the severity of baseline disability, which suggests that more severely affected patients may experience the greatest improvement,” the researchers wrote.
Dr. Muley said that he was somewhat surprised by the magnitude of response in some patients.
“Rituximab is a B-cell depleting agent and tends to be most effective in antibody-mediated diseases,” he explained. “The precise immune mechanism of CIDP is largely unknown, although some patients have antibodies to nodal proteins such as neurofascin. I was therefore not confident that rituximab [would] work for CIDP patients.”
Dr. Muley’s take-home message to clinicians is to consider rituximab for CIDP patients who are refractory to first-line treatments.
“We are still not clear whether there is a subset of patients with CIDP who respond well to rituximab and what the marker of that subset of patients is,” he noted.
“The obvious question is whether presence of nodal antibodies predict responsiveness to rituximab, although some of our patients were negative for these antibodies. Also, there may be other antibodies or biomarkers at play that are as yet unidentified that may predict responsiveness,” he added. “Future research should be directed to find markers of responsiveness in CIDP.”
Other rituximab studies
The latest study by Dr. Muley and colleagues builds on results from earlier studies. A research report published in the Journal of the Peripheral Nervous System in 2018 was the largest to date. Of 28 CIDP patients, 21 responded to rituximab, which was defined as meeting any of three conditions:
- a 5-point increase in the MRC sum score or a 1-point decrease in the Overall Neuropathy Limitations Scale score, compared with the scores at the first rituximab infusion
- stopping first-line treatments
- if patients could not reduce their first-line treatment without having a relapse, an increase of at least 1 week in the interval between courses of IVIG or plasma exchange, compared with patients’ ability to wean themselves from dependence on first-line treatment for at least 6 months after the onset of the treatment.
The researchers reported an excellent safety profile, noting that none of the seven nonresponders showed any deterioration of disease.
In addition, a series of 13 cases published in 2010 in the Journal of Neurology, Neurosurgery & Psychiatry showed that 9 of 13 patients given rituximab responded with improvement of at least 2 points on the MRC and INCAT scales.
In the ongoing CIDPRIT study conducted by Eduardo Nobile-Orazio, MD, PhD, of Milan and colleagues, CIDP patients on IVIG or subcutaneous immunoglobulin (SCIG) are randomized to 1 g of rituximab or a placebo on day 1, 14, and 180, with a primary endpoint assessing relapse at 12 months, followed by secondary endpoint assessments of relapse at 18 and 24 months; the IVIG or SCIG treatments are discontinued at 6 months after study enrollment.
“The Italian study will provide evidence of efficacy of rituximab in CIDP patients on IVIG or SCIG,” Dr. Muley said. “In other words, it will answer the question as to whether rituximab is an effective immunoglobulin-sparing agent. Currently, steroid- or immunoglobulin-sparing agents used in CIDP include azathioprine and mycophenolate, for which the evidence of efficacy is unproven. If rituximab is effective in this study, it will be the first proven immunoglobulin-sparing agent.”
However, he noted that the Italian study will not prove immunoglobulin dependency because there is no withdrawal from immunoglobulin prior to enrollment. “The results could be erroneous since a subset of patients who do not relapse at 12-24 months may have already been in remission while on immunoglobulin. This will hopefully even out in the placebo and treatment groups, but the distribution of these nonactive patients will not be clear,” he said.
Another clinical trial of rituximab in CIDP patients is underway in Japan. Masahiro Iijima, MD, of Nagoya University and colleagues seek to randomize 25 patients to 375 mg/m2 of rituximab or a placebo infusion once a week for 4 weeks. The primary outcome of patient improvement will be assessed using the adjusted INCAT disability scale.
The Japanese study “will provide evidence whether rituximab is safe and efficacious in the treatment of patients with CIDP with and without IgG4 antibodies to neurofascin and contactin, and may provide evidence of whether the response to treatment is different for patients with antibodies and without these antibodies,” Dr. Muley commented.
The strength of the study is that it will characterize patients with and without nodal antibodies which will allow us to determine if these antibodies dictate responsiveness to rituximab.
“The strength of the study is that it will characterize patients with and without nodal antibodies which will allow us to determine if these antibodies dictate responsiveness to rituximab,” he said. Potential limitations include the 8-week treatment time, which may be inadequate since some patients respond beyond 8 weeks.
“Patients who have been on long-term immunosuppressant for 12 weeks are excluded. It is well known that patient on azathioprine and mycophenolate start responding at 3-6 months, and the response continues for 12-18 months,” he noted.
In addition to rituximab, similar drugs, including rozanolixizumab and ocrelizumab, are being explored for treatment of CIDP. A phase 2 study under development by UCB will randomize CIDP patients to rozanolixizumab or placebo to assess efficacy, safety, and tolerability.
Dr. Muley had no relevant conflicts of interest to disclose.