Evidence of persistent improvements with long‐term subcutaneous immunoglobulin in chronic inflammatory demyelinating polyneuropathy

Intravenous immunoglobulin (IVIg) is among the first-line treatments for chronic inflammatory demyelinating polyneuropathy (CIDP). Recently, subcutaneous administration (SCIg) has been shown to be effective in preserving function in patients who respond to IVIg, with the added benefits of reduced systemic adverse events and more independence for some patients. Despite the widespread use of immunoglobulins for CIDP, there are several gaps in our knowledge that affect everyday clinical decision making. There is no consensus on long-term treatment for patients with CIDP. For example, researchers in the ICE (Immune Globulin Intravenous CIDP Efficacy) study for IVIg used a loading dose of 2 g/kg, followed by 1 g/kg every 3 weeks. However, in another randomized study in which methotrexate was used as an add-on therapy for CIDP, 44% of patients in the placebo arm were able to safely reduce their IVIg dose—from the standard 1 g/kg maintenance regime—by 20% or more. The latter finding provides evidence that some patients receive higher IVIg doses than they actually require. Furthermore, in the PATH (Polyneuropathy and Treatment with Hizentra) study for SCIg, patients responded to a variety of doses ranging from 0.2 to 0.4 g/kg per week, providing evidence not only that some patients require lower doses but that some patients may actually require higher doses. Another area of uncertainty is the length of immunoglobulin treatment, and there is no consensus regarding when to stop therapy; unjustified prolonged treatments can expose patients to harm with no additional benefits, with high costs for the health care system. However, premature termination of therapy can lead to worsening symptoms and increased disability, which is not always easy to control after restarting therapy. For example, in the PATH study, patients who were receiving chronic IVIg had a dependency test whereby they were withdrawn from treatment and followed for 12 weeks; at the end of the 12-week period, only 11% of patients were considered independent. Among the dependent patients, 11% did not reach their previous baseline after 13 weeks of rescue IVIg therapy. Furthermore, of patients who relapsed while receiving SCIg in the randomized phase, 30% did not return to baseline after rescue treatment. In the ICE trial, 56% of patients who responded to IVIg and were rerandomized to placebo did not relapse. Therefore, there seems to be marked heterogeneity in terms of requirement for long-term immunoglobulin treatment for CIDP. While the focus of long-term treatment for CIDP has been on preventing relapse, it is also of interest to understand what happens to those patients who do not relapse and are thus considered stable during long-term treatment. In this issue of Muscle & Nerve, Cirillo et al present long-term data for 14 patients with CIDP who were treated with SCIg for 48 months. All patients showed improvement in clinical and electrophysiological measures after 24 months of therapy, which is in line with results in previous studies. However, patients continued to show further improvement in most measures when reassessed at 48 months. This included the Inflammatory Neuropathy Cause And Treatment sensory sum score, Rasch Overall Disability Scale (R-ODS), and EQ-5D-VAS score as well as electrophysiological measures such as distal motor latencies, compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes, and conduction velocities. These findings are of significant practical importance because they show continuous improvement in clinical and electrophysiological results up to 4 years after initiation of SCIg therapy. The Medical Research Council (MRC) sum score in their cohort did not change between 24 and 48 months, which could have been due to faster improvements in strength compared to sensation. Another plausible explanation could be a ceiling effect of MRC sum score used because the authors included only shoulder abductors, elbow flexors, wrist extensors, knee extensors, and ankle dorsiflexors. The PATH study included, in addition to the above, index finger abduction and great toe extension, and it is possible that these distal muscles could have shown delayed improvements in strength that were not captured by the more concise MRC sum score used in the Cirillo et al study. In the PATH extension study, patients who did not experience a relapse had mean change-scores close to 0 in all measures, indicating stability as a group. However, the range of change was wide, and some patients improved by 28 centile points in the R-ODS, by 19 points in the MRC sum score, and by 29 kPa in grip strength. Findings in the study by Cirillo et al are in keeping with the PATH extension study, providing evidence of a subpopulation of CIDP patients with continuous improvement. Nerve conduction data from the PATH study have not yet been published to further corroborate the findings of this small cohort. However, the role of nerve conduction studies to follow patients with CIDP is unclear because results of some studies have provided evidence of low correlations with clinical measures. Cirillo et al found very high correlations between the electrophysiological parameters and clinical outcomes. In their study, the distal upper limb CMAP had a correlation coefficient of 0.81 with the MRC sum score and of 0.72 with the Received: 24 September 2019 Revised: 30 September 2019 Accepted: 2 October 2019