IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS

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1 IV immunoglobulins as add-on treatment to methylprednisolone for acute relapses in MS P. Soelberg Sorensen, MD, DMSc; J. Haas, MD; F. Sellebjerg, MD, DMSc; T. Olsson, MD; M. Ravnborg, MD, DMSc; and the TARIMS Study Group* Abstract Objective: To investigate if IV immunoglobulins (IVIg) in combination with methylprednisolone make recovery from a relapse faster and more complete than methylprednisolone alone. Design/Methods: The authors studied 76 patients with multiple sclerosis (MS) who had an acute relapse with involvement of visual function, upper limb motor function, or gait, and with onset of symptoms between 24 hours and 14 days before. Patients were treated with either IVIg 1 g/kg or placebo (0.1% human albumin), given 24 hours before treatment with IV methylprednisolone 1 g on 3 consecutive days. Results: Both groups improved, but the authors observed no significant difference between IVIg and placebo patients regarding the primary endpoint, the mean change in the Z-score of the individually chosen targeted neurologic deficit (the most affected system) from baseline to 12 weeks (p 0.89). A slightly better, but not significant remission was seen in the IVIg group in global scores, i.e., Expanded Disability Status Scale (p 0.23) and Multiple Sclerosis Impairment Scale (p 0.24), and in time to next relapse (p 0.22). Conclusions: The results do not justify routine application of IV immunoglobulins as add-on therapy to IV methylprednisolone in the treatment of acute multiple sclerosis attacks. NEUROLOGY 2004;63: Additional material related to this article can be found on the Neurology Web site. Go to and scroll down the Table of Contents for the December 14 issue to find the title link for this article. In the early phase of multiple sclerosis (MS), repeated exacerbations are the main factor determining neurologic disability and quality of life, because with increasing number of relapses the probability of complete clinical remission decreases. 1-3 Resolution of an acute exacerbation can be hastened by treatment with glucocorticoids, but an improvement of the overall degree of recovery or an effect on the long-term course has not been demonstrated. The currently accepted treatment schedule is IV administration of 500 to 1,000 mg of methylprednisolone daily for 3 to 5 days. However, some patients do not respond to high doses of methylprednisolone, and in a substantial number of patients, recovery from the attack is only partial Four double-blind, placebo-controlled trials have provided evidence that repeated IV immunoglobulin (IVIg) administration reduces relapse rate and MRI activity These studies indicate that IVIg has antiinflammatory properties in relapsing-remitting MS. A single study of IVIg therapy of acute exacerbations in MS showed that 68% of patients treated with IVIg during a relapse improved within 24 hours. 16 Taking into account the clinical evidence of an anti-inflammatory and possible remyelinating effect of Ig, we performed a double-blind, randomized study to investigate whether IVIg in combination with methylprednisolone could make recovery from a relapse faster and more complete than methylprednisolone treatment alone. Patients and methods. Patient population. The inclusion criteria were as follows: 1) clinically or laboratory supported definite MS 17 and MRI changes consistent with the diagnosis of MS 18 ;2) relapsing-remitting or relapsing-progressive (secondary progressive with relapses) course of MS; 3) age between 18 and 55 years; 4) Expanded Disability Status Scale (EDSS) 6.0 prior to relapse, and EDSS 2.0 at the time of inclusion 19 ; 5) no planned change of any immunomodulatory therapy (IFN or glatiramer acetate) within the next 3 months; 6) acute relapse with onset of symptoms between 24 hours and 14 days before inclusion; 7) relapse involvement of visual acuity, upper limb motor function, or gait with deterioration of at least one step in the relevant functional system scale (FSS) (vision, pyramidal, or cerebellar) or an increase in EDSS of 1 point or more 19 ; 8) ability to perform valid tests for timed walking, 9-hole peg test (9-HPT), 20 and vision; and 9) documented informed consent. The exclusion criteria were as follows: 1) history of cardiac or renal disease, thromboembolic disease, or parenterally transmitted hepatitis or other parenterally transmitted infections, severe *Members of the TARIMS Study Group are listed in the Appendix on page From the MS Research Unit (Drs. Sorensen and Ravnborg), Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Denmark; Department of Neurology (Dr. Haas), Judisches Krankenhaus, Berlin, Germany; Department of Neurology (Dr. Sellebjerg), Glostrup University Hospital, Denmark; and Neuroimmunology Unit (Dr. Olsson), Centre for Molecular Medicine, Karolinska Hospital, Stockholm, Sweden. P.S.S. has received grant support and speaker s honoraria from Bayer. F.S. has received grant support from Bayer. M.R. has received speaker s honoraria from Bayer. Received April 7, Accepted in final form July 26, Address correspondence and reprint requests to Prof. Per Soelberg Sorensen, MS Research Unit, Department of Neurology 2082, Copenhagen University Hospital, Rigshospitalet, DK-2100 Copenhagen, Denmark; [email protected] 2028 Copyright 2004 by AAN Enterprises, Inc.

2 diabetes, any contraindication for methylprednisolone treatment, or other significant medical or psychiatric disorder; 2) known selective IgA deficiency or known IgA antibodies; 3) history of anaphylaxis or severe systemic response to Ig or albumin; 4) treatment with corticosteroids within the last month preceding enrollment; 5) treatment with azathioprine, methotrexate, mitoxantrone, cyclophosphamide, cyclosporine, or IVIg within 6 months prior to enrollment; 5) previous treatment with plasmapheresis, total lymph node irradiation, or any other immunomodulatory or immunosuppressive drug; 6) and pregnancy or breastfeeding. Treatment and follow-up evaluation. Patients were randomized to receive either IVIg (10% IVIG-C, Bayer) IV at a dose of 1 g/kg body weight (maximum 80 g) or placebo (0.1% human albumin in 10% maltose). A one to one central randomization was performed with a block size of 4. Patients received one infusion of study drug 24 hours before the steroid treatment (1,000 mg methylprednisolone IV for 3 days) was started. In order to ensure the integrity of blindness of patients and personnel, human albumin was chosen as placebo, all study drug containers and infusion tubes were covered with plastic wrapper, and administration of IVIg or placebo was performed by a person (physician or study nurse) not involved in the evaluation of the patient. Another blinded physician was responsible for evaluation of all outcome measures. Patients underwent the following tests and procedures prior to treatment. The evaluating physician defined the functional system most affected by the exacerbation (visual function, upper extremities, lower extremities), designated the targeted neurologic deficit. The visual function was assessed by a test of visual acuity (logmar), the function of the upper extremities was assessed by the 9-HPT, and the function of the lower extremities measured as 8 m timed walking. 20 Visual acuity was measured as the number of letters read correctly on a chart. 21,22 If 20 or more letters were read correctly at 4 meters distance the visual acuity score was calculated as the number of letters read plus 30. If fewer than 20 letters were read correctly, the patient was tested on a chart at 1 meter (Pat. No ). The visual acuity score was then just the number of letters read correctly. If no letters were read at 1 meter, the visual acuity score was 0. The visual acuity score was used to calculate logmar values as described in the Ischemic Optic Neuropathy Decompression Trial (IONDT). 21 Each letter on the chart has a logmar of The following formula was used: logmar (1.70 to 0.02 N), where N is the total number of letters read correctly. For patients unable to read any letters even at 1 meter, the logmar was defined as follows: finger count: logmar 2.00; hand motion: logmar 2.30; light perception: logmar 2.60; no light perception: logmar Upper extremity deficits were measured by the 9-HPT according to the published norms. 23,24 Two tests were performed with each arm and the average time (seconds) was used. If one value was missing for one arm by chance, the value for the other arm was used as average. In the case that one arm became so disabled during the trial that the patient was not able to perform the 9-HPT, the value 777 seconds was used as time for this arm. Lower extremity deficits were measured by 8 m timed walking. Two tests were performed and the average time (seconds) was used. If one value was missing by chance, the single value for the test was used as average. In the case that the patient became so disabled during the trial that he or she was not able to walk 8 m, the slowest time of all finalized measurements was used. Global scores of the neurologic examinations were obtained by means of FSS, EDSS, 19 and the Multiple Sclerosis Impairment Scale (MSIS). 25 Laboratory tests as safety measure included hemoglobin, hematocrit, platelets, leukocytes, alanine-amino-transaminase, alkaline phosphatase, lactate dehydrogenase, plasma electrolytes, plasma-creatinine, blood glucose, and pregnancy test (if indicated). At 4 days, 3, 12, and 26 weeks after infusion of study medication, all patients underwent neurologic examination including FSS, EDSS, and MSIS, examination of visual acuity, 9-HPT, and 8 m timed walking. Patients were questioned about adverse events and concomitant medication. At the 26-week visit, patients, study nurse, and evaluating physician were asked to complete a questionnaire to determine the maintenance of blinding. In case of an acute relapse during the study period, the patient had to attend the study center for evaluation. The definition for a relapse was the following: development of new or worsening of existing neurologic symptoms or signs, in the absence of fever, persisting for more than 24 hours and with a previous period for more than 30 days with a stable or improving condition. The exacerbation had to be equivalent to an increase of at least one point in the pyramidal, cerebellar, brainstem, sensory, or visual functional systems or an increase of at least half a point on the EDSS. Outcome measures and statistical methods. The primary outcome measure was the mean change in the Z-score of the targeted deficit from baseline to 12 weeks after inclusion. Secondary efficacy measures included 1) the mean change in the Z-score of the targeted deficit from baseline to 4 days, 3, and 26 weeks after inclusion; 2) the mean changes in a combined Z-score of visual acuity, 9-HPT, and 8 m timed walking from baseline to 4 days, 3, 12, and 26 weeks after inclusion; 3) the mean differences in scores of the MSIS, FSS, and EDSS between baseline and 3, 12, and 26 weeks after inclusion. Tertiary efficacy endpoints were the time to the next relapse and the proportion of relapse-free patients during the 26 weeks following inclusion. Safety measures consisted of adverse events and laboratory tests. All statistical tests were two-sided and performed at the 0.05 level. Intention-to-treat (ITT) analyses were used as primary efficacy analyses. The primary efficacy criterion was the mean change in the Z-score of the targeted deficit; for each patient the Z-score of the individually most affected system (visual acuity, 9-HPT, or 8 m timed walking) was calculated. The Z-scores were constructed as follows: for the visual acuity the value of the most affected eye was used to create the Z-score out of the logmar scale. For the 9-HPT the score was obtained in the following way: first, the measures of each hand were averaged. Thereafter the values were converted to the reciprocals and the reciprocals were averaged. For the 8 m timed walking the two values were averaged and converted to the reciprocal. For each of the three components, the test result of the baseline measurements of all patients in the trial was used for creating Z-scores. This was created in the following way for each component: Z-score (individual value baseline mean)/baseline SD. The combination of the Z-scores was done in the following way: combined Z-score (Z-score of 9-HPT Z-score of 8 m timed walking Z-score of visual acuity)/3. We used two-way analysis of covariance with baseline as covariate, treatment and most affected system as factors (main effect model) Analyses of secondary efficacy measures were performed analogously to the primary efficacy criterion. Changes in MSIS and EDSS were assessed by analyses of covariance with baseline as covariate, treatment and most affected system as fixed factors for all time points compared to baseline (main effect model). Kaplan Meier statistics and log-rank test, adjusted for most affected system, were used to assess the time to next relapse and the Cochran-Mantel-Haenszel test, adjusted for most affected system, to compare the proportions of relapse-free patients. For the blinding check, contingency tables were generated. A prediction of the mean and SD of remission in the two groups was not possible. Therefore, the sample size was calculated from a proposed treatment effect, D (m1 m2)/, of 0.5 indicating that a difference in the mean remission between the two groups above /2 was regarded as clinically relevant. The alpha level was set to 0.05, two-sided testing, and the power was set to 80%. Based on these premises, the minimum sample size would have been 126 patients assuming normality. After adjustment by 15% for multicenter effect and 10% for dropouts, a sample size estimation using a program (n-query) for non-normal distribution (Wilcoxon test) resulted in a total sample size of 172 patients. Results. The study was discontinued after inclusion of 76 patients because of shortage of test drugs. Due to slow recruitment, the allotted study medication expired, and it was not possible to get additional supply from the sponsor. The premature discontinuation of the study reduced the statistical power. Using the same assumptions as described in the sample size calculations, the reduction of the sample size to 76 patients decreased the power to 44%. Of the 76 enrolled patients, 36 were allocated to treat- December (1 of 2) 2004 NEUROLOGY

3 Table 1 Demographics and baseline characteristics of patients IVIg, n 36 Placebo, n 40 p Value* Age, y, mean SD * Female, % Age at onset of MS, y, mean SD * Time since first symptoms, y, mean SD * EDSS score prior to relapse, mean SD * Interval between last EDSS score and relapse, d, mean SD * Duration of relapse at enrollment, d, mean SD * MSIS score at enrollment, mean SD * EDSS score at enrollment, mean SD * * Analysis of variance (main effect model: treatment and center as fixed factors). Cochran-Mantel-Haenszel test adjusted for centers. MS multiple sclerosis; EDSS Expanded Disability Status Scale; MSIS Multiple Sclerosis Impairment Scale. ment with IVIg and 40 were allocated to placebo treatment. All patients allocated to IVIg therapy received an IVIg infusion of 400 to 800 ml according to the dose calculation. All enrolled patients were included in the safety and intention-to-treat analyses. Four patients in the placebo group had major protocol violations and were excluded from the per-protocol analyses (not reported). The baseline characteristics of the patients (table 1) showed no significant differences regarding all disease characteristics. Immunomodulatory drugs, either interferon-beta or glatiramer acetate, were taken by 67% of the patients in the IVIg group and 63% of the patients in the placebo group. Both groups improved regarding the primary outcome measure, the mean change in the Z-score of the targeted deficit (the most affected system) from baseline to 12 weeks, but we observed no significant difference between IVIg and placebo (table 2). Descriptive statistics of Z-scores of the targeted deficits, visual acuity, arm function, or gait, used for calculation of the primary endpoint, can be found in table E-1 on the Neurology Web site at Improvement at 12 weeks appeared to be more pronounced in the IVIg group in visual acuity and arm function, whereas almost no difference was seen regarding gait function. We performed two post hoc subgroup analyses regarding the primary outcome measure and observed insignificant trends toward a better improvement in patients who received treatment within 7 days after onset of symptoms, and in patients who were without immunomodulatory treatment. Secondary endpoints included the mean change in the Z-score of the targeted deficit, from baseline to 4 days, 3 weeks, and 6 months after inclusion. No significant differences between IVIg and placebo treatment were seen at any time (see table 2). The Z-scores of the individually chosen targeted deficits, visual acuity, arm function, or gait (table E-1), the raw scores and Z-scores of visual acuity, 9-HPT, and 8 m timed walking for all patients (table E-2), and a composite score of visual acuity (logmar), 9-HPT, and timed 8 m walking (table E-3) can be found on the Neurology Web site at Again, although we found a trend toward more improvement in the IVIg group, the differences between the two groups were not significant at any time. The remission in the IVIg group was higher than in the placebo group with regard to the global scores of MSIS and EDSS, but the difference did not reach significance (table 3). At the end of the 6-month follow-up 24 patients (67%) in the IVIg group and 22 patients (55%) in the placebo group were still relapse-free (p 0.30). The time to first relapse is presented as Kaplan-Meier survival plot in the figure. Table 2 Z-scores of the most affected system at baseline and changes from baseline Baseline or change from baseline IVIg 10%, n 36 Placebo, n 40 p Value of ANCOVA* Baseline Day Week Week Month Values are mean SD. * p Value for treatment differences of the main effect model (treatment and most affected system as fixed factors, baseline Z-score as covariate). Primary outcome measure. ANCOVA analysis of covariance NEUROLOGY 63 December (1 of 2) 2004

4 Table 3 MSIS and EDSS scores at baseline and changes from baseline Score Baseline or change from baseline IVIg 10%, n 36 Placebo, n 40 p Value MSIS Baseline Week Week Month EDSS Baseline Day Week Week Month Values are mean SD. MSIS Multiple Sclerosis Impairment Scale; EDSS Expanded Disability Status Scale. Despite the descriptively lower relapse rate in the IVIg group, the difference was not significant (p 0.22, logrank test adjusted for most affected system). Overall, the treatment was well tolerated. Twenty-six (72%) patients of the IVIg group and 30 (75%) patients of the placebo group experienced at least one adverse event during treatment, most frequently adverse events (relapses) associated with MS (table E-4). It should be noticed that all patients were treated with IV methylprednisolone 24 hours after the infusion of study medication, and many adverse events could more likely be ascribed to the high dose glucocorticoid therapy. No patient discontinued the study because of an adverse event. The trial was generally well blinded. At the final 26- week visit, 58% of patients correctly guessed that they had received IVIg, and 43% correctly guessed that they had received placebo. The neurologist correctly identified 42% of the patients who had been treated with IVIg and 55% of the patients who had received placebo. Discussion. The study failed to show any effect of IVIg and methylprednisolone compared to placebo and methylprednisolone treatment. The study was prematurely terminated, when only 76 patients were included. However, the difference between the two Figure. Kaplan-Meier analysis of the time to first relapse and proportion of relapse-free patients in IV immunoglobulin (IVIg) group (solid line) and placebo group (dashed line) (p 0.22 log-rank test adjusted for most affected system). treatment groups was less than 0.1 Z-score points, which was much less than the expected treatment effect of 0.5 Z-score points. Therefore, although the power of the study was reduced to 44% due to a smaller sample size than planned, it is unlikely that a significant treatment effect could have been shown for primary efficacy endpoint, even if the planned patient number had been recruited. Despite that remission of relapse-related symptoms was on average slightly more pronounced in the IVIg group, the differences compared to the placebo group were far from significant at any time point. Apart from IV methylprednisolone there are no established treatments for acute relapses in MS patients and no routine therapy for relapses with incomplete or failing remission after treatment with high-dose corticosteroids. A randomized study indicated a beneficial effect of plasma exchange in patients with severe neurologic deficits from attacks of inflammatory demyelinating disease who failed to recover after treatment with IV corticosteroids. 26 In many immune-mediated neurologic disorders, like Guillain-Barré syndrome and myasthenia gravis, IVIg and plasma exchange seem to have comparable efficacy, 27,28 and hence it would appear plausible that IVIg could be of benefit in patients with incomplete recovery from MS attacks. In acute disseminated encephalomyelitis, a number of case reports have described a beneficial effect of IVIg in patients who failed to respond to high-dose IV methylprednisolone Low-dose IVIg (50 mg/kg) for treatment of acute exacerbations in MS gave improvement in 15 (68%) of 22 patients within 24 hours, but the improvement persisted only 2 weeks. 16 Dramatic recovery from a severe brainstem relapse after IVIg was reported in a patient who did not respond to glucocorticoid and corticotropin therapy. 32 The combination of IVIg and prednisone dramatically decreased the enhancement in serial gadolinium-enhanced MRI, whereas IVIg alone did not have any effect on enhancement. This indicates December (1 of 2) 2004 NEUROLOGY

5 that any beneficial influence of IVIg in acute relapses of MS is not mediated by improvement of the blood brain barrier damage. 33 A small, randomized pilot study, in which IVIg 0.4 g/kg or placebo was administered for 5 consecutive days after treatment with 500 mg methylprednisolone IV to 19 patients with an acute relapse, did not show any beneficial effect of IVIg. 34 Studies have indicated that IVIg may promote remyelination in demyelinating disease in humans, which would require that IVIg enters the CNS. 35 A controlled study reported a significant increase in the CSF IgG concentration during IVIg therapy in MS patients and suggested that measurable amounts of IgG enter the CNS during IVIg treatment, or alternatively, that IVIg might induce an alteration of the intrathecal immune response. 12 A preliminary trial of five patients with stable deficits after optic neuritis showed improvement in optic nerve function after IVIg treatment and suggested that IVIg could induce remyelination in the optic nerve. 36 These results could not be reproduced in a subsequent double blind study in 55 patients with persistent loss of visual acuity after optic neuritis. IVIg 0.4 g/kg daily for 5 days followed by 0.4 g/kg every 4 weeks for 3 months was not superior to placebo regarding improvement in visual acuity at 6 months, although a positive trend favoring IVIg was found at 12 months. 37 Neither did IVIg treatment in 67 MS patients with persistent muscle weakness induce better recovery of muscle strength compared to placebo. 38 However, it is a question whether apparently irreversible motor deficits are caused by demyelination, or if such deficits result from irreversible axonal loss. An interesting observation in the present study was that a single IVIg dose increased the proportion of relapse-free patients by 27% compared to placebo and increased the time to the first relapse during the 6-month observation period, although these differences did not reach statistical significance, probably due to the low number of patients. These findings support the results of previous studies showing a beneficial effect of repeated IVIg administration on relapse rate and MRI activity The safety results in this study were in accordance with the known side-effect profile of IVIg 39 indicating that the use of IVIg (10% IVIg-C) is safe for the treatment of relapses in MS. Although it cannot be excluded that IVIg may be of benefit in a selected group of patients with an acute relapse of MS, e.g., patients with no or minimal recovery after IV methylprednisolone, the results of the present study do not justify routine application of IVIg as add-on therapy to IV methylprednisolone in the treatment of acute MS attacks. Acknowledgment IVIg (10% IVIg-C, Bayer) and placebo were provided by Bayer Vital GmbH, Leverkusen, Germany. The authors thank Dr. Monika Maas Enriquez, Bayer Vital, for help during the planning and conduct of the study and Dr. Bernd Sommerauer, Bayer Vital, for help with the statistical computations. 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