Withdrawal of intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy

Authors: Adrichem, ME; Lucke, IM; Vrancken, Alexander F J E; Goedee, HS; Wieske, L; Dijkgraaf, MG; Voermans, NC; Notermans, NC; Faber, CG; Visser, LH; Kuitwaard, K; van Doorn, PA; Merkies, IS; Haan, RJ de; van Schaik, IN; Eftimov, F

Affiliations: Department of Neurology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9 1105 AZ Amsterdam, The Netherlands ; Department of Neurology, University Medical Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands ; Department of Clinical Epidemiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9 1105 AZ Amsterdam, The Netherlands. Department of Neurology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands ; Department of Neurology, Maastricht Academic Medical Center, P. Debyelaan 25, 6229 HX Maastricht, The Netherlands ; Department of Neurology, Elisabeth-Tweesteden Hospital, Hilvarenbeekse weg 60, 5022 GC Tilburg, The Netherlands ; Department of Neurology, Albert Schweitzer Hospital, Albert Schweitzerplaats 25 3318 AT Dordrecht, The Netherlands ; Department of Neurology, Erasmus Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, The Netherlands ; Department of Neurology, Curaçao Medical Center, 193 JHJ. Hamelbergweg, Willemstad, Curacao, The Netherlands; Board of directors, Spaarne Gasthuis, Boerhaavelaan 22, 2035 RC Haarlem, The Netherlands.

Publication: Brain: a journal of neurology; 2022 February

Abstract: Intravenous immunoglobulins (IVIg) are an efficacious treatment for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Biomarkers for disease activity are lacking, making the need for ongoing treatment difficult to assess, leading to potential overtreatment, and high health care costs. Our objective was to determine whether IVIg withdrawal is non-inferior to continuing IVIg treatment and to determine how often patients are overtreated. We performed a randomized, double-blind, IVIg-controlled non-inferiority trial in seven centers in the Netherlands. Adults with clinically stable CIDP using IVIg maintenance treatment for at least 6 months were included. Patients received either IVIg withdrawal (placebo) as investigational treatment or continuation of IVIg treatment (control). The primary outcome was the mean change in logit scores from baseline to 24-weeks follow-up on the patient-reported Inflammatory Rasch-Overall Disability Scale (iRODS). The non-inferiority margin was predefined as between-group difference in mean change scores of -0.65. Patients who deteriorated could reach a relapse endpoint according to predefined criteria. Patients with a relapse endpoint after IVIg withdrawal entered a restabilization phase. All patients from the withdrawal group who remained stable, were included in an open-label extension phase of 52 weeks. We included 60 patients of whom 29 were randomized to IVIg withdrawal and 31 to continuation of treatment. The mean age was 58 years (SD 14.7) and 67% was male. The between-group difference in mean change iRODS scores was -0.47 (95%CI -1.24 to 0.31), indicating that non-inferiority of IVIg withdrawal could not be established. In the IVIg withdrawal group, 41% remained stable for 24 weeks, compared to 58% in the IVIg continuation group (-17%; 95%CI -39 to 8). Of the IVIg withdrawal group, 28% remained stable at end of the extension phase. Of the patients in the restabilization phase, 94% restabilized within 12 weeks. In conclusion, it remains inconclusive whether IVIg withdrawal is non-inferior compared to continuing treatment, partly due to larger than expected confidence intervals leading to an underpowered study. Despite these limitations, a considerable proportion of patients could stop treatment and almost all patients who relapsed were restabilized quickly. Unexpectedly, a high proportion of IVIg treated patients experienced a relapse endpoint, emphasizing the need for more objective measures for disease activity in future trials, as the patient reported outcome measures might not have been able to identify true relapses reliably. Overall, this study suggests that withdrawal attempts are safe and should be performed regularly in clinically stable patients.