By Norman Latov, MD, PhD
Professor of Neurology and Neuroscience, Weill Cornell Medical College; Director of the Neuropathy Center, Weill Cornell Medicine
SYNOPSIS: In this comparative trial of different doses of intravenous immunoglobulin treatment for chronic inflammatory demyelinating polyneuropathy, higher doses appeared to result in a higher percentage of patients who improved. However, there was no control group and there were many confounding issues that make it difficult to reach a definitive conclusion around optimal dosing.
SOURCE: Cornblath DR, van Doorn PA, Hartung HP, et al. Randomized trial of three IVIg doses for treating chronic inflammatory demyelinating polyneuropathy. Brain 2022;145:887-896.
Patients with chronic inflammatory demyelinating polyneuropathy (CIDP) were randomized 1:2:1 to receive a standard intravenous immunoglobulin (IVIg) dose of 2 g/kg followed by maintenance doses of either 0.5 g/kg, 1 g/kg, or 2 g/kg every three weeks, and the results were compared to historical responses. The primary end point was the rate of response in the 1 g/kg group at week 6 that is maintained at week 24, as determined by an improvement of ≥ 1 point in the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score, which is considered to be a minimal clinically meaningful improvement. Of the participants, 87.1% were treated previously with corticosteroids, with 36% continued on prednisolone ≤ 20 mg/day. The response rates in the 0.5 g/kg, 1 g/kg, and 2 g/kg groups were 65%, 80%, and 92%, respectively. The difference was statistically significant between the 0.5 g/kg and 2 g/kg doses, but not between the other groups. Seven of 14 patients (54%) who failed to respond to 0.5 g/kg or 1 g/kg improved after treatment with 2 g/kg. The authors concluded that a maintenance dose of 1 g/kg every three weeks was efficacious and that further studies of different doses are warranted.
COMMENTARY
The study confirmed that the therapeutic response to IVIg is dose-dependent, based on comparison of the 0.5 g/kg and 2 g/kg groups, and that treatment with 2 g/kg followed by a maintenance dose of 1 g/kg every three weeks was efficacious when compared to historical responses.1 Although the study was not powered to compare the three doses, with half as many subjects included in the 0.5 g/kg and 2 g/kg groups compared to the 1 g/kg group, the authors suggested that “a lower maintenance dose of 0.5 g/kg is sufficient to achieve and maintain a therapeutic response in 65% of patients, but that a higher dose may be beneficial to improve those not responding to low or standard dosing.”
A confounding factor is the lack of an internal placebo control group, with the calculations based on comparison to historical responses from other studies that differed in their patient populations, use of corticosteroids, and treatment responses. The relatively high rate of prior or concomitant use of corticosteroids particularly is problematic. Corticosteroids and IVIg can have additive effects and the effect of corticosteroids can be long-lasting, as evidenced by the slower rate of relapse following their discontinuation, in comparison to IVIg.2,3 In the current study, for example, the response rate in those previously on corticosteroids was 82% compared to 61% for those previously on IVIg. As such, the higher response rates in the current study, compared to historical responses, could have been the result of the additive effect of corticosteroids, which might disproportionally bolster the lower IVIg dose group, bringing into question the study’s conclusions and authors’ suggestions.
In practice, the therapeutic dose of IVIg can vary considerably between patients, likely because of differences in the inflammatory response, the half-life of the IVIg, and other immune or genetic factors.4-6 In one retrospective study, the lowest effective dose and frequency required to maintain improvement varied in range between 18 g and 108 g and two to 17 weeks, respectively.7 In a previous study comparing two doses of subcutaneous immunoglobulin, the relapse rate was significantly higher in those maintained on 0.2 g/kg than 0.4 g/kg per week (equivalent to 0.6 g/kg and 1.2 g/kg every three weeks, respectively), and 51% of patients on the higher dose relapsed after reduction to 0.2 g/kg, with 92% improving after resuming the 0.4 g/kg dose.8
A more fundamental issue to consider is whether the optimal dose of a particular drug, including IVIg, should be based on measures of a minimal therapeutic response, as in the current study, or on the magnitude of the improvement, which was not considered in the current study. Patients exhibiting an initial response to IVIg can continue to improve over time, with the degree of response also likely to be dose-dependent.9,10 Electrodiagnostic studies show that underlying disease activity can continue while under treatment, as evidenced by the occurrence of new demyelinating abnormalities that correlates with IVIg dependence, similar to “silent” magnetic resonance imaging lesions in multiple sclerosis.11 Optimal treatment ideally should be directed at completely suppressing rather than only reducing the inflammation that is responsible for the cumulative axonal and neuronal loss and progression to disability.12,13
REFERENCES
- Cornblath DR, van Doorn PA, Hartung HP, et al. Randomized trial of three IVIg doses for treating chronic inflammatory demyelinating polyneuropathy. Brain 2022;145:887-896.
- Pollard JD, Armati PJ. CIDP – the relevance of recent advances in Schwann cell/axonal neurobiology. J Periph Nerv Syst 2011;16:15-23.
- Nobile-Orazio E, Cocito D, Jann S, et al. Frequency and time to relapse after discontinuing 6-month therapy with IVIg or pulsed methylprednisolone in CIDP. J Neurol Neurosurg Psychiatry 2015;86:729-734.
- Bonilla FA. Pharmacokinetics of immunoglobulin administered via intravenous or subcutaneous routes. Immunol Allergy Clin North Am 2008;28:803-819.
- Tackenberg B, Jelcic I, Baerenwaldt A, et al. Impaired inhibitory Fcgamma receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy. Proc Natl Acad Sci U S A 2009;106:4788-4792.
- Kuitwaard K, van Doorn PA, Bengrine T, et al. Genetic biomarkers for intravenous immunoglobulin response in chronic inflammatory demyelinating polyradiculoneuropathy. Eur J Neurol 2021;28:1677-1683.
- Rajabally YA, Seow H, Wilson P. Dose of intravenous immunoglobulins in chronic inflammatory demyelinating polyneuropathy. J Periph Nerv Syst 2006;11:325-329.
- van Schaik IN, Mielke O, Bril V, et al. Long-term safety and efficacy of subcutaneous immunoglobulin IgPro20 in CIDP: PATH extension study. Neurol Neuroimmunol Neuroinflamm 2019;6:e590.
- Latov N, Deng C, Dalakas MC, et al. Timing and course of clinical response to intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy. Arch Neurol 2010;67:802-807.
- Baumann A, Hess CW, Sturzenegger M. IVIg dose increase in multifocal motor neuropathy: A prospective six month follow-up. J Neurol 2009;256:608-614.
- Chin RL, Deng C, Bril V, et al. Follow-up nerve conduction studies in CIDP after treatment with IVIG-C: Comparison of patients with and without subsequent relapse. Muscle Nerve 2015;52:498-502.
- Harbo T, Andersen H, Jakobsen J. Length-dependent weakness and electrophysiological signs of secondary axonal loss in chronic inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve 2008;38:1036-1045.
- Nagamatsu M, Terao S, Misu K, et al. Axonal and perikaryal involvement in chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry 1999;66:727-733.
