The Proven Success of Immune Globulin Therapy to Treat Chronic Inflammatory Demyelinating Polyneuropathy

Certain debilitating conditions can leave doctors and patients frustrated as they grasp for understanding and answers. Chronic inflammatory demyelinating polyneuropathy (CIDP) is certainly one of those conditions. It affects relatively few people and hides behind symptoms that masquerade as any number of neurological ailments. But once a diagnosis has been made, patients are finding hope with clinical breakthroughs and successful treatment study results. The path to managing CIDP isn’t an easy one, but in many cases, patients are seeing their quality of life increase.

What Is CIDP?

CIDP, a rare autoimmune disorder, is reported in one to two new cases per year per 100,000 people.1 Symptoms of CIDP generally develop over eight weeks and include tingling or loss of all feeling in fingers and toes, weakness in arms and legs, loss of tendon reflexes, fatigue and unusual feelings in the body.² The disease can be present for years prior to a diagnosis, so the prevalence reflecting the accumulation of cases over time may be as high as nine per 100,000.¹

Given its rarity, the disease is difficult to diagnose because the symptoms are similar to Guillain-Barré syndrome (GBS), which has been referred to as CIDP’s cousin. Distinctions include the following: GBS is considered acute and begins with an infection, while CIDP is chronic with no infection present. Making CIDP even more difficult to diagnose is the fact that more than 15 sets of diagnostic criteria have been used over the last 50 years.³

CIDP is not genetic, and its cause is unknown. The disease can be traced to inflammation of nerves and nerve roots. As swelling occurs, it can destroy the protective covering around nerves, known as myelin, which can hurt nerve fibers and slow the nerves’ ability to send signals. This is the cause of patients’ numbness, weakness, pain and fatigue.⁴

In general, CIDP affects more men than women and is more common in those over 50 years of age.⁵ Ten percent of the cases are in children, rarely occurring in children under the age of 1 year.⁶

History and Diagnosis

Hermann Eichhorst, MD, a German neurologist, first described patients with CIDP in 1890.⁶ In the 1950s, inflammatory polyneuropathies responded to treatment with corticosteroids. By the 1970s, chronic recurrent inflammatory polyneuropathy was described as a separate disease. Finally, in the 1980s, Peter J. Dyck, MD, and colleagues introduced the English name of CIDP.7 Since then, many varieties and diagnostic criteria have appeared.

In addition to GBS, CIDP can be misdiagnosed as other diseases that impact the nervous system, including multiple sclerosis and amyotrophic lateral sclerosis, making the diagnosis of CIDP a process of elimination. It can include a physical exam to evaluate symptoms, which also may include blood sample collection, a neurologic evaluation, an electromyography test, a lumbar puncture or spinal tap, an MRI or a nerve biopsy.

Treatment Options

Several treatment options are available including:

• Plasma exchange. This process removes proteins from a patient’s blood, including proteins that may cause the disease, and then returns his or her white and red blood cells, as well as platelets, back into the patient’s circulation.
• Corticosteroids. These drugs imitate the effects of hormones produced by the body to suppress the immune system and reduce inflammation.
• Physical therapy. This helps recondition a patient’s muscle strength, function and mobility.
• Immune globulin (IG) therapy. While many patients respond to plasma exchange, corticosteroids and/or physical therapy, others become resistant to them or develop side effects that cause them to discontinue treatment. This issue led to studies to find a safer and more effective method of treatment, namely intravenous immune globulin (IVIG) therapy, followed by subcutaneous immune globulin (SCIG) therapy.

Features of SCIG versus IVIG in CIDP Treatment¹⁹

IVIG Success

IVIG provides antibodies to block the immune and inflammatory processes that attack and destroy myelin. IVIG therapy was established based on five randomized, placebo-controlled trials between 1993 and 2008⁸ in which the percentage of patients with improved disability at 24 weeks was much greater (54 percent) when compared with a placebo (21 percent). IVIG responders also achieved maximal response by week six. In addition, Medical Research Council muscle and grip strength saw significant improvement. In the extension phase of these studies, 87 percent of IVIG-treated patients remained relapse-free over an additional 24 weeks compared to 55 percent of placebo-treated patients.

One systematic review⁹ of randomized controlled trials conducted between January 1985 and May 2008 analyzed 332 participants, with five of the studies (235 participants) comparing IVIG against a placebo. In these studies, a significantly higher proportion of participants improved in disability within one month after IVIG treatment compared with a placebo (risk ratio [RR] 2.40, 95% confidence interval [CI] 1.72 to 3.36; number needed to treat for an additional beneficial outcome 3.03 [95% CI 2.33 to 4.55], high-quality evidence). However, the review noted that the improvements may not be equally clinically relevant since each trial used different disability scales and definitions of significant improvement.

A study¹⁰ of 30 CIDP patients (16 men, 14 women) who received IVIG treatment were compared with 23 people (12 women, 11 men) who were given a placebo; there were two dropouts in the placebo group and one in the IVIG group. The mean average muscle score improved at day 42 when comparing IVIG with placebo (0.63 versus −0.1, p = 0.006), and improved strength was seen by day 10. The placebo group lost strength over this same interval. In the IVIG group, 11 subjects improved by the functional disability scale and none worsened. This differed (p = 0.019) from those in the placebo-treated group (two improved, two got worse and the rest remained unchanged).

In another study¹¹ of 119 CIDP patients who received treatment three times a week for up to 24 weeks (59 received IVIG-chromatography [IVIG-C] purified treatment, and 58 received a placebo), the IVIG therapy was more successful. Fifty-four percent of patients on IVIG-C (10% caprylate/chromatography purified) treatments showed improved functional disability at 24 weeks in comparison to 21 percent of those who received the placebo; 60 percent of patients showed a maximal IVIG response by six weeks.

Even with such results, reports suggest the effects of IVIG can wear off for some patients between doses, and some patients experience adverse effects to IVIG. This makes them good candidates to transition to IG therapy that is administered via the subcutaneous route (SCIG), which was approved by the U.S. Food and Drug Administration (FDA) in 2018.

SCIG Success

SCIG is a process in which IG infusions are given by slowly injecting purified IG into fatty tissue underneath the skin. This requires patients or caregivers to administer one to three injections per week to multiple injection sites based on personal preference, often in the lower abdomen. SCIG doesn’t require venous access or premedication, and it has a reduced frequency of systemic adverse events than IVIG, making it a good option for some patients, especially given the clinical results of SCIG therapy.

A short-term observational study¹² reported successful results after reviewing four-month follow-up data of 66 CIDP (and 21 multifocal motor neuropathy) patients who transitioned from IVIG to SCIG treatment. The Overall Neuropathy Limitation Scale score improved in the group of 66 CIDP patients (P = 0.018), with one subject reporting a worsening of one point. This study confirmed the short-term clinical equivalence of SCIG versus IVIG and a possible improvement in the patients’ perception of a therapeutic setting with SCIG.

A long-term study¹³ followed 17 CIDP patients (10 men, seven women) over seven years to consider the safety, tolerability and patients’ perception of SCIG treatment. All patients had been treated with IVIG every four to six weeks before being switched to SCIG treatment. Fifteen of the 17 patients exhibited a good SCIG compliance. The other two patients decided to stop treatment after two years and six years, respectively. Another patient returned to IVIG for personal reasons, despite a clear clinical stabilization. And one patient was not satisfied with SCIG, so she continued with steroids and IVIG boluses, still with mild benefit. When submitted to the Life Quality Index questionnaire score, all 17 patients evidenced an improvement. During the follow up, two patients relapsed four and 36 months, respectively, after starting SCIG treatment.

The Polyneuropathy and Treatment with Hizentra (PATH) study¹⁴ published in 2019 showed SCIG was efficacious in CIDP maintenance. One hundred and seventy-two subjects were randomized to placebo (n = 57), 0.2 g/kg IgPro20 (n = 57) and 0.4 g/kg IgPro20 (n = 58). Much higher proportions of IgPro20-treated subjects improved and maintained their health status on the EQ-5D usual activities dimension, as well as in additional dimensions (mobility and pain/discomfort) in sensitivity analyses. TSQM and WPAI-GH scores were more stable with IgPro20 treatment compared with placebo.

Another study¹⁵ included 15 CIDP subjects who transitioned from IVIG to SCIG, with four of the participants meeting one of two endpoints. According to the study, the Short-Form 36-item Health Survey showed a statistically significant improvement for the domain of role limitations-physical after 24 weeks (P = .03), with no significant differences observed in other domains. The Treatment Satisfaction Questionnaire for Medication and Chronic Acquired Polyneuropathy Patient-Reported Index also showed significant differences in favor of SCIG (P = .003 and .02, respectively). No significant differences were observed in efficacy after 24 weeks, except for limb motor strength testing, which favored SCIG (P = .003). Eight of the 12 study completers (67 percent) continued treatment with SCIG.

Most recently, a study¹⁶ was conducted to assess whether facilitated subcutaneous immune globulin (fSCIG) 10% could prevent relapse in patients with definite or probable CIDP who had received stable IVIG for equal to or more than 12 weeks before screening. The Phase III, double-blind, placebo-controlled ADVANCE-CIDP 1 trial conducted at 54 sites in 21 countries found that CIDP relapse was reduced with fSCIG 10% versus placebo. And while adverse events were more frequent with fSCIG 10% than placebo, severe and serious adverse events were less common.

Further Study: FcRN Inhibitors

The use of FcRN inhibitors, or blockers, to treat CIDP is currently under investigation.

One such FcRN inhibitor, efgartigimod (VYVGART), has been approved by FDA to treat myasthenia gravis (MG), another autoimmune neuromuscular disease. One study¹⁷ included treatment with efgartigimod alfa plus hyaluronidase-QVFC and led to a significantly lower risk of relapse. The study evaluated 322 adults with CIDP for up to 12 weeks. Responders from Stage A were randomly assigned efgartigimod alfa plus hyaluronidase-QVFC or a placebo for 48 weeks (Stage B). Patients in Stage A showed that 67 percent (n = 214/322) of patients met the primary endpoint. Among the 221 responders who entered Stage B, treatment with efgartigimod alfa plus hyaluronidase-QVFC reduced the risk for CIDP relapse by 61 percent at week 48 compared with a placebo.

Rozanolixizumab (Rystiggo), another FcRN inhibitor, is also being assessed for CIDP treatment. It is being developed to treat autoimmune diseases and has been approved in the United States for treatment of generalized MG in adults who are anti-acetylcholine receptor or anti-muscle-specific kinase antibody positive. In a study¹⁸ conducted between 2019 and 2021, in which 17 subjects were given a subcutaneous injection once weekly for 12 weeks, five did not complete it due to lack of efficacy; one withdrew. Seventeen subjects were given a placebo; four did not complete it due to lack of efficacy, one relapsed and none withdrew.

It should be noted there are no direct parallels that can yet be drawn between these products and IG treatments.

IG Offers the Greatest Efficacy

Presently, IVIG and SCIG offer patients the most promising treatment. The remarkable clinical results, enhanced muscle and grip strength and a higher rate of relapse-free periods offer a compelling picture of its efficacy. And, while IVIG has been a lifeline for many and may continue to be for some patients, SCIG offers a more convenient, well-tolerated and potentially longer-lasting solution for many patients.