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ARTICLES: F. Fazekas, F. D. Lublin, D. Li, M. S. Freedman, H. P. Hartung, P. Rieckmann, P. Soelberg Sørensen, M. Maas-Enriquez, B. Sommerauer, K. Hanna, For the PRIVIG Study Group, and the UBC MS/MRI Research Group Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: A dose-finding trial Neurology 2008; 71: 265-271 [Abstract] [Full text] [PDF]

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Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: A dose-finding trial

W.King Engel   (5 December 2008)

Reply from the authors

Franz Fazekas, F. D. Lublin, D. Li, M. S. Freedman, H. P. Hartung, P. Rieckmann, P. Soelberg Sørensen, M. Maas-Enriquez, B. Sommerauer, K. Hanna   (5 December 2008)

Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: A dose-finding trial

Omar A. Khan, Alexandros Tselis, Aaron Boster   (2 October 2008)

Reply to Khan et al.

Franz Fazekas, Fred D. Lublin, David Li, Mark S. Freedmann, Hans-Peter Hartung, Peter Rieckmann, Per Soelberg Sorensen, Monika Maas-Enriquez and Kim Hanna for the PRIVIG Study Group   (2 October 2008)

Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: A dose-finding trial 5 December 2008
W.King Engel, University of Southern California Keck School of Medicine USC Neuromuscular Ctr, Good Samaritan Hospital, 3rd Flr., 637 S.Lucas Ave, Los Angeles, CA 90017 Send Correspondence to journal: Re: Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: A dose-finding trial askanas{at}usc.edu W.King Engel	Fazekas et al. concluded that IV immunoglobulin (IVIG) did not demonstrate any beneficial signs in relapsing-remitting multiple sclerosis (RRMS). [1] The authors cite other reports in which IVIG benefit in RRMS was "insufficient to recommend it as first-line treatment." [1] I suggest that the answer is flowing in the vein. In the study by Fazekas et al. and in other MS trials [2-4], IVIG was tested in dosing schedules that are, in my experience with CIDP, typically sub-efficacious. Too infrequent dosing, even 0.4 gms/kg once every 2 weeks [4], may underlie its reported ineffectiveness. Gaps too wide may erase the possibility of summating -- or even maintaining -- improvements, making those MS dosings Sisyphean efforts. According to others, and my own results in treating over 200 patients, CIDP improvements from IVIG are often good to excellent. However, not well-known is the limited duration of IVIG efficacy. Reports collected from my repeatedly-treated observant patients with erstwhile chronic-progressive CIDP demarcate cyclic onset and offset of their important benefits. In responsive patients, benefit typically begins within 1-2 days after each IVIG infusion. Optimal improvement usually lasts not more than 1-2 weeks after dosing, at which time patients can re-experience symptoms, e.g. emergence of their IVIG-mitigated pain, which requires resumption of pain medicines; tingling; numbness; gait imbalance; weakness of proximal and distal muscle functions; and neuromuscular fatigue. A gap of 3 weeks can produce more severe symptoms that are not reversible until IVIG has been resumed for 1-2 weeks. Clinical responses are more logical than biological half-lives for planning IVIG dosings. The orthodox schedule is 5 consecutive days IVIG 0.4 gms/kg/day, skip 2 weeks and repeat, repeatedly. Some patients need one “booster dose” on Tuesday of the second skipped week. [5] My own alternative IVIG schedule, used since 1994 especially for CIDP patients with coexisting headaches, hypertension, advanced age, or other conditions of concern, is 0.4 gm/kg/d on two non-consecutive days every week.[5] Only after substantial benefit is achieved with either schedule can the IVIG infusions be gradually spaced as infrequently as each patient's disease permits, in deference to patient’s veins, time, and costs. I limit infusion rates to ≤ 100ml/hr, and use continuing aspirin or another anticoagulant in all IVIG patients. (In one SPMS 10% IVIG trial, in which the authors used very high doses with rapid 3-4 hour infusions of 1 gm/kg/ once monthly, six patients developed significant thrombotic/embolic events. [2]) Subsequent studies utilizing more frequent dosage and cautious infusions of IVIG in MS patients are needed to assess benefit. Especially in progressive forms, it will be important to identify those who have better responses. References 1. Fazekas F, Lublin FD, Li D et al. Intravenous immunoglobulin in relapsing-remitting multiple sclerosis. A dose-finding trial. Neurology 2008;71:265-271. 2. Hommes O, Soerensen P, Fazekas F, et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomized placebo-controlled trial. Lancet 2004;364:1149-1156. 3. Soelberg Sorensen P. Intravenous polyclonal human immunoglobulins in multiple sclerosis. Neurodegner Dis. 2008;5:8-15. 4. Noseworthy JH, O¡¯Brien PC, Weinshenker, et al. IV immunoglobulin does not reverse established weakness in MS. Neurology 2000;55:1135-1143. 5. Engel WK. Intravenous immunoglobulin G is remarkably beneficial in chronic immune dysschwannian/dysneuronal polyneuropathy, diabetes-2 neuropathy, and potentially in severe acute respiratory syndrome. Acta Myologica 2003;22: 97-103. Disclosure: The author reports no disclosures.
Reply from the authors 5 December 2008
Franz Fazekas, Medical University Graz Auenbruggerplatz 22, A-8036 Graz, Austria, F. D. Lublin, D. Li, M. S. Freedman, H. P. Hartung, P. Rieckmann, P. Soelberg Sørensen, M. Maas-Enriquez, B. Sommerauer, K. Hanna Send Correspondence to journal: Re: Reply from the authors franz.fazekas{at}meduni-graz.at Franz Fazekas, et al.	Dr. Engel reports his experience with IVIG treatment of CIDP using more frequent dosing and suggests a similar approach in MS. This question was not specifically addressed by the PRIVIG trial but a substantial contribution to efficacy by proposed measures appears unlikely given that the biological half-life of most IgG subclasses is approximately 15-30 days. [6] References 6. Sekul EA, Cupler Ej, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med 1994;121:259-262. factors. Ann Intern Med 1994;121:259-262. Disclosures: F. Fazekas received consulting fees or honoraria from Bayer Vital, Baxter, Biogen Idec, Merck Serono, Schering, and Teva / Sanofi-Aventis. F. Lublin received consulting fees and honoraria from Biogen Idec, Bayer, EMD Serono, Pfizer, Teva Neuroscience, Novartis,Genentech, Medicinova, Eisai, Genmab, BioMS and Cognition Therapeutics. D. Li is the Director of the UBC MS/MRI Research Group, which has been contracted to perform central analysis of MRI scans for therapeutic trials with Angiotech, Bayer, Berlex-Schering, Bio-MS, Centocor, Hoffmann-LaRoche, Schering-Plough, Teva Neurosciences, Sanofi-Aventis, Serono, Transition Therapeutics. M.S. Freedman received consulting fees or honoraria from Bayer, EMD Serono, Teva, Novartis, BioMS, and Sanofi-Aventis. H.-P. Hartung received honoraria for consulting and/or speaking at scientific symposia from Bayer Vital, Biogen Idec, GSK, Merck Serono, Schering, Teva. P. Rieckmann received consulting fees and honoraria from the study sponsor and Biogen Idec, Merck Serono, Bayer Schering, Teva and Sanofi-Aventis. P. Soelberg Sørensen received consulting fees, honoraria for lectures at symposia and grant support from Bayer Vital, Biogen Idec, Merck Serono, Bayer Schering, Teva, Genmab, and Sanofi-Aventis. M. Maas-Enriquez is an employee of the sponsor. B. Sommerauer is an employee of the sponsor. K. Hanna is an employee of the sponsor.
Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: A dose-finding trial 2 October 2008
Omar A. Khan, Wayne State University School of Medicine 4201 St Antoine, 8D-UHC, Detroit, MI 48323, Alexandros Tselis, Aaron Boster Send Correspondence to journal: Re: Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: A dose-finding trial okhan{at}med.wayne.edu Omar A. Khan, et al.	We read with interest the Prevention of Relapse with Intravenous Immunoglobulin (PRIVIG) dose finding trial in relapsing-remitting multiple sclerosis (RRMS) by Fazekas et al. [1] The authors concluded that the trial “seriously questions the utility of IVIG for the treatment of relapsing- remitting MS” and that the “negative results of the PRIVIG trial therefore can not be attributed to a problem of data quality.” However, we feel that the results of the PRIVIG trial should be carefully interpreted because of several methodologic limitations. The rationale for choosing the two doses of IVIG at 0.2 and 0.4 gm/kg is unclear considering that higher doses of IVIG (2.0 gm/kg) have been used in previous studies. The authors did not present any immunologic rationale for choosing the two doses. It may have been interesting to examine higher doses including the possibility of a third arm at doses > 1.0 gm/kg. It is also unclear why the primary endpoint of “proportion of relapse-free patients after only 48 weeks” was chosen. This endpoint has never been used as a primary outcome in any of the pivotal trials. Furthermore, the expectation of demonstrating an increase of 50% relapse-free patients in the active arm compared to placebo arm that was expected to have 50% relapse-free patients is also overly optimistic. This magnitude of effect in the proportion of relapse-free patients has not been demonstrated in several pivotal phase trials with interferon-beta, glatiramer acetate, or natalizumab. [2-4] Several of the pivotal trials did not even report the proportion of relapse free patients after one year. Although the authors refer to the results of the Austrian IVIG study (a two-year study) as the basis for their sample size calculation, expecting a 50% difference in the proportion of relapse-free patients in less than one year (48 weeks) is a serious limitation of this trial. [5] It would be helpful to know if the self-reported relapses (17%) were equally distributed across the three treatment arms. It would be important to know how the self-reported relapses were recorded. We agree with the authors that the behavior of the placebo group in the PRIVIG trial was unusual. An adequately powered trial conducted for two years using a more traditional primary endpoint may have provided more valuable information regarding the utility of IVIG in RRMS. The results of the PRIVIG trial should be interpreted with caution. References 1. Fazekas F, Lublin FD, Li D, et al. Intravenous immunolglobulin in relapsing- remitting multiple sclerosis. A dose finding trial. Neurology 2008;71:265-271. 2. Johnson KP, Brooks BR, Cohen JA, et al. Copolymer-1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: Results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology 1995;45:1268-1276. 3. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann Neurol 196;39:285-294. 4. Polman CH, O’Connor P, Havrdova E, et al. A randomized trial of natalizumab for relapsing multiple sclerosis. N Eng J Med 2006;354:899-910. 5. Fazekas F, Deisenhammer F, Strasser-Fuchs, Nahler G, Mamoli B; for the Austrian Immunoglobulin in Multiple Sclerosis Study Group. Randomized placebo-controlled trial of monthly intravenous immunoglobulin therapy in relapsing-remitting multiple sclerosis. Lancet 1997;349:589-593. Disclosure: The authors report no disclosures.
Reply to Khan et al. 2 October 2008
Franz Fazekas, Department of Neurology, Medical University Graz Auenbruggerplatz 22, A-8036 Graz, Austria, Fred D. Lublin, David Li, Mark S. Freedmann, Hans-Peter Hartung, Peter Rieckmann, Per Soelberg Sorensen, Monika Maas-Enriquez and Kim Hanna for the PRIVIG Study Group Send Correspondence to journal: Re: Reply to Khan et al. franz.fazekas{at}meduni-graz.at Franz Fazekas, et al.	We thank Dr. Khan et al. for their comments regarding the interpretation of the PRIVIG dose-finding trial in RRMS. [1] The design and outcome of the PPRIVIG trial should be viewed within the context of earlier research on the efficacy of intravenous immunoglobulin (IVIG) in MS. These studies suggested benefit in RRMS but had several limitations. [6] Our goals were to provide supportive data for a suppression of disease activity by IVIG including frequent MRI and to clarify the most adequate dose. We chose to test IVIG monthly at 0.2g/kg and 0.4g/kg bodyweight because similar doses had been successfully used in previous trials of RRMS including the Austrian Immunoglobulin in MS study which had the largest number of RRMS patients. [5] Alternatively, no signals of efficacy were observed in the European Study on Intravenous Immunoglobulin in Multiple Sclerosis (ESIMS), the largest trial of IVIG in MS, including MRI endpoints. [7,8] The reported reduction of relapse rate and the proportion of relapse-free patients in the AIMS study were also the basis for sample size calculations for PRIVIG. Although these estimates were optimistic, we felt that a study which included frequent MRI should indicate trends in the right direction and the results would not have become positive even with much larger sample sizes. The negative clinical outcome cannot be explained by a skewed distribution of self-reported relapses (17%) across treatment arms. In the absence of earlier trials with IVIG, we may have opted for a more “conventional” study design. We also recognize the limitations imposed by the one-year duration yet this provided the advantage of being able to perform a comparison against placebo. We believe that the negative results of PRIVIG are indicative of an absence of benefit. Frequent MRI should have indicated at least a beneficial trend for IVIG, unless MRI activity is irrelevant for treatment effects with this substance, which appears unlikely. These results provide no rationale for conducting a longer trial. References 6. Sørensen P, Fazekas F, Lee M. Intravenous immunoglobulin G for the treatment of relapsing-remitting multiple sclerosis: a meta-analysis. Eur J Neurol 2002;2002:557-563. 7. Hommes O, Soerensen P, Fazekas F, et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised, placebo-controlled trial. Lancet 2004;364:1149-1156. 8. Fazekas F, Sorensen P, Filippi M, et al. MRI results from the European Study on Intravenous Immunoglobulin in Secondary Progressive Multiple Sclerosis (ESIMS). Mult Scler 2005;11:433-440. Disclosures: F.F. received consulting fees or honoraria from Bayer Vital, Baxter, Biogen Idec, Merck Serono, Schering, and Teva/Sanofi-Aventis. F.D.L. received consulting fees and honoraria from Biogen Idec, Bayer, EMD Serono, Pfizer, Teva Neuroscience, Novartis, Genentech, Medicinova, Eisai, Genmab, Bio-MS, and Cognition Therapeutics. D.L. is the Director of the UBC MS/MRI Research Group, which has been contracted to perform central analysis of MRI scans for therapeutic trials with Angiotech, Bayer, Berlex-Schering, Bio-MS, Centocor, Hoffmann-LaRoche, Schering-Plough, Teva Neurosciences, Sanofi-Aventis, Serono, and Transition Therapeutics. M.S.F. received consulting fees or honoraria from Bayer, EMD Serono, Teva, Novartis, Bio-MS, and Sanofi-Aventis. H.P.H. received honoraria for consulting and/or speaking at scientific symposia from Bayer Vital, Biogen Idec, GSK, Merck Serono, Schering, and Teva. P.R. received consulting fees and honoraria from the study sponsor and Biogen Idec, Merck Serono, Bayer Schering, Teva, and Sanofi-Aventis. P.S.S. received consulting fees, honoraria for lectures at symposia, and grant support from Bayer Vital, Biogen Idec, Merck Serono, Bayer Schering, Teva, Genmab, and Sanofi-Aventis. M.M.-E., B.S., and K.H. are employees of the sponsor.