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ARTICLES: G. Birnbaum, B. Cree, I. Altafullah, M. Zinser, and A. T. Reder Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis Neurology 2008; 71: 1390-1395 [Abstract] [Full text] [PDF]

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Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis

Elena Salvatore, Vincenzo Brescia Morra, Giuseppe Orefice   (14 December 2008)

Reply from the author

Gary Birnbaum, Bruce Cree, MD, Irfan Altafullah, MD, Anthony Reder, MD   (14 December 2008)

Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis

Silva Markovic-Plese, Valerie Jewells, and Danielle Speer   (30 September 2008)

Reply from the authors

Gary Birnbaum, MD, Bruce Cree, MD, Irfan Altafullah, MD, Anthony Reder, MD   (30 September 2008)

Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis 14 December 2008
Elena Salvatore, Department of Neurological Sciences, University of Naples Federico II Via Pansini, 5 80131 Napoli, Italy, Vincenzo Brescia Morra, Giuseppe Orefice Send Correspondence to journal: Re: Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis elena.salvatore{at}unina.it Elena Salvatore, et al.	Birnbaum et al. caution against combining IFN beta-1a and atorvatstatin because of increased disease activity in a small cohort of patients with stable relapsing–remitting multiple sclerosis (RRMS). [1] We are investigating the addition of a lower dose of atorvastatin (20 mg daily) to IFN beta-1a (44 mcg subcutaneously three times weekly), in 49 patients with active RRMS over a two-year period. Following the presentation of Birmbaum et al.’s data, we performed an interim analysis of our data. Over 12 months, new gadolinium-enhancing lesions and/or clinical relapses were present in 47% (9/19) of combination therapy patients and 52% (12/23) of patients receiving IFN beta-1a alone. Although the complete data on relapses in the second year are not yet available, currently 2/12 patients in the combination therapy group have experienced a relapse and/or new gadolinium-enhancing lesions during the second year versus 9/18 patients treated with IFN beta-1a alone. This suggests that, over longer time periods, patients in the combination therapy group may have a lower rate of disease activity than those treated solely with IFN beta-1a. We defined disease activity as at least one relapse or gadolinium-enhancing lesion. Possible explanations for the differences between our interim results and those reported by Birnbaum et al. may include different atorvastatin doses (20 vs. 40-80 mg daily), different criteria for patient enrollment (stable vs. active RRMS) used in these two studies, or a combination of both. Next year, the study results concerning the lower dose of atorvastatin (20 mg daily) should be available. Reference 1. Birnbaum G, Cree B, Altafullah I, Zinser M, Reder AT. Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. Neurology. 2008 Jun 4. [Epub ahead of print, doi:10.1212/01.wnl.0000319698.40024.1c], Disclosure: The authors report no disclosures.
Reply from the author 14 December 2008
Gary Birnbaum, MS Treatment and Research Center; Minneapolis Clinic of Neurology 4225 Golden Valley Road, Golden Valley, MN 55422, Bruce Cree, MD, Irfan Altafullah, MD, Anthony Reder, MD Send Correspondence to journal: Re: Reply from the author birnb001{at}tc.umn.edu Gary Birnbaum, et al.	Dr. Salvatore et al. present preliminary data on a trial combining interferon beta with atorvastatin in persons starting on treatment for RRMS. Their data appear to be different than ours because they did not observe an adverse effect on disease course in patients treated with the combination of interferon beta and atorvastatin. They correctly note that there are differences between our two trials. Dr. Salvatore’s protocol uses a lower dosage of statin and their patient populations are different. It is unclear whether their study was randomized and blinded. They present two-year relapse data for only 12 out of 19 (63%) of the initial combination therapy patients but for 19 out of 23 (83%) of the initial monotherapy patients. Was the dropout rate higher in the combination treatment group? If so, will the final data utilize an intention to treat analysis? Finally, the nature of the relapses in the two groups is not mentioned yet this is clinically important. We look forward to the final presentation of Dr. Salvatore’s data yet we still feel that caution should be used in treating relapsing remitting MS patients with a combination of high dose interferon beta and high dose atorvastatin. Disclosures: Dr. Birnbaum has received honoraria and research support from EMD Serono, Pfizer, TEVA Neuroscience, and Berlex. Research grants from Pfizer have exceeded $10,000. Dr. Altafullah received personal compensation from Boehringer Ingelheim, Genenteck, Pfizer, Coaxia, AGA Medical, and Atritech, received a research grant for more than $10,000 from Pfizer, and owns shares in Pfizer worth about $40,000. Dr. Reder received compensation, research support, or honoraria from the following companies: Abbott Laboratories, Immunoscience, Parsippany, NJ; American Medical Association, Chicago, IL; Astra Merck, Wayne, PA; Athena Neurosciences, South San Francisco, CA; Aventis Pharma, Bridgewater, NJ; Berlex Laboratories, Richmond, CA; Biogen and Biogen/Idec, Cambridge, MA; BioMS Medical Corp., Edmonton, Alberta, Canada; Blue Cross, Blue Shield, Chicago, IL; Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT; Caremark Rx, Northbrook, IL; Centocor, Inc., Malvern, PA; Cephalon, Inc., Delaware, MD; Connectics/Connective Therapeutics, Palo Alto, CA; CroMedica Global Inc. Victoria, BC; Elan Pharmaceuticals, Inc., San Diego, CA; Genentech, South San Francisco, CA; Genzyme Corporation, San Antonio, TX; GlaxoSmithKline, Research Triangle Park, NC; Hoechst Marion Roussel Canada Research, Inc., Leval, Quebec; Hoffman-LaRoche, Nutley, NJ; Idec, San Diego, CA; Immunex, Seattle, WA; Institute for Health Care Quality, Minneapolis, MN; Johnson & Johnson, Pharmaceutical Research & Development, LLC, Raritan, NJ; NARCOMS, Yale University, New Haven, CT, & Barrow Neurological Institute, Phoenix, AZ; National Multiple Sclerosis Society & Paralyzed Veterans of America, Pain Panel, New York, NY; Neurocrine Biosciences, San Diego, CA; Novartis Corporation, New York, NY; Parke-Davis, Morris Plains, NJ; Pfizer Inc, New York, NY; Pharmacia & Upjohn, Kalamazoo, MI; Protein Design Labs, Inc, Delaware; Quantum Biotechnologies, Inc., Leval, Quebec; Quintiles, Inc, San Diego, CA; RENEW study (post-marketing study of Novantrone in MS); Serono; Sandoz (now Novartis) & Novartis, East Hanover, NJ; Sention, Inc, Providence, RI; Serono, Norwell, MA; Smith Kline-Beecham, Philadelphia, PA; Specialized Therapeutics, a division of Berlipharm, Inc, Montville, NJ; Takeda Pharmaceuticals, Lincolnshire, IL; Teva-Marion. Dr. Cree has received personal compensation for speaking for Biogen Idec, EMD Serono and Teva Neurosciences and receives grant support from Genentech, Inc. and BioMS.
Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis 30 September 2008
Silva Markovic-Plese, University of North Carolina at Chapel Hill, Department of Neurology, Microbiology and Immunology 6109 Neuroscience Research Building, Univ. of N. Carolina at Chapel Hill, Chapel Hill, NC 27599, Valerie Jewells, and Danielle Speer Send Correspondence to journal: Re: Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis markovics{at}neurology.unc.edu Silva Markovic-Plese, et al.	We read the report by Birnbaum et al.[1] with interest. They report results that differ from multiple studies testing interferon beta (IFNÂ) and statin combination therapy in patients with multiple sclerosis (MS). We completed a 12-month study on 10 patients with clinically isolated syndrome (CIS) suggestive of MS in which simvastatin was added in high dose (80 mg) to an IFNÂ-1a weekly intramuscular therapy in a placebo-controlled approach. We reported that combination therapy was safe and well tolerated in this pilot study. All patients remained clinically stable. [2] Our second ongoing placebo-controlled clinical trial in patients with CIS testing high dose IFNÂ-1a and high dose atorvastatin (80 mg) combination therapy has enrolled 30 patients, 14 of whom completed a 12-month treatment. The treatment was well tolerated, and only three patients whose assignment is still blinded had clinical relapse.[3] Our in vitro Affymetrix gene expression study on peripheral blood mononuclear cells derived from 15 patients with CIS before treatment onset and 7 matched healthy controls did not show inhibition of IFNÂ-induced genes in cultures co-treated with simvastatin. [2] Similarly, interim analysis of a SIMCOMBIN study that has reported data on 47 patients randomized to IFNÂ-1a alone or to a combination of IFNÂ-1a with simvastatin (80 mg daily) reported a comparable annualized relapse rate and the expression of IFNÂ biomarkers in both treatment groups.[4] A gene expression study by Rudick et al.[5] in 40 patients treated with both IFNÂ-1a and 20 mg simvastatin found no evidence that statins antagonize the IFNÂ effects. All the above-mentioned studies have used high dose statins in combination with IFNÂ. The above results are consistent with the open-label baseline-to-treatment study by Friedmann et al. [6] who reported a significant decrease in the number and volume of Gd-enhancing lesions in 41 patients with relapsing-remitting (RR) MS treated with high dose atorvastatin (80 mg daily) or atorvastatin and IFNÂ. An open label study by Orefice et al. [7] on 34 patients with RRMS testing IFNÂ-1a and atorvastatin combination therapy reported good tolerability and no significant difference in the clinical outcome measures between the two groups. Statins are currently being tested as a monotherapy or combination therapy in six clinical trials in patients at various stages of MS, and the results from those studies will provide more definitive data on the therapeutic potential of statins in MS. Disclosure: The study to which the authors refer2 was funded by an unrestricted research grant from Biogen Idec. Biogen Idec played no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.
Reply from the authors 30 September 2008
Gary Birnbaum, MD, Minneapolis Clinic of Neurology Minneapolis, MN, Bruce Cree, MD, Irfan Altafullah, MD, Anthony Reder, MD Send Correspondence to journal: Re: Reply from the authors birnb001{at}tc.umn.edu Gary Birnbaum, MD, et al.	Dr. Markovic-Plese and colleagues cite four clinical trials in their correspondence to refute the data presented in our article. [1] Three of the trials were reported in abstract form and one was published in Future Neurology, which is not indexed by Medline so the full trial data are not accessible. There are multiple differences between the trials cited by Dr. Markovic-Plese et al. and our study, making comparisons difficult. Several of the trials cited, in contrast to our trial, were open label, non-randomized, retrospective, or not placebo controlled. Biases induced by such variables in trial design are well known and make interpretation of the results problematic. [8] Several of the trials used simvastatin rather than atorvastatin. There are significant differences between these two statins in terms of biologic half-life and lipophilicity, raising the possibility that there may be differences in their effects on immune cells and on the genes activated by interferon beta. In addition, the study by Rudick et al. was a retrospective study with data gleaned from the pivotal trials of natalizumab, and exact dosages of drugs in individuals were not presented. [5] Several of the trials utilized treatment with low dose interferon beta-1a, 30 mcg per week. Our study involved patients receiving high dose interferon beta-1a, 44 mcg three times per week. This variable is critical because there are data suggesting that lower doses of interferon beta-1a may not be as effective as higher doses, making detection of decreased responses with statin therapy more difficult. [9] Most importantly, there were major differences in the patient populations studied. Our trial evaluated patients with RRMS, stable on high dose interferon beta-1a for at least 6 months, who were randomized to receive either placebo or two higher doses of atorvastatin. This patient population is very different from the patients with CIS studied in some of the trials or the patients with RRMS who either failed therapy with interferon or were just being started on interferon therapy. Our clinical trial involved a relatively small number of patients. It is possible, though statistically unlikely, that our observations of worsening MS in patients previously stable on thrice weekly interferon beta-1a upon addition of high dose atorvastatin was coincidental. As we noted, there are questions that remain regarding the role of statins in combination with high or low dose interferon betas, and whether there are differences among the statins and their effect on either the course of MS or interactions with interferons. These questions will only be answered with large, well-designed, prospective, randomized, double blind, placebo-controlled trials, using carefully predefined endpoints. References 1. Birnbaum G, Cree B, Altafullah I, Zinser M, Reder AT. Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. Neurology 2008;71:1390-1395. 2. Jewells V, Speer D, Chen Y, et al. Statin and intramuscular interferon beta-1a combination therapy is safe and well tolerated in patients with clinically isolated syndrome suggestive of multiple sclerosis: a pilot study. Mult Scler 2007;13:S270. 3. Markovic-Plese S, Singh AK, Singh I. Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair. Future Neurology 2008;3:153-167. 4. Sorensen PS, Frederiksen JL, Lycke J, et al.: Does simvastatin antagonize the effect of interferon beta? Interim safety analysis of the ongoing SIMCOMBIN study. Multiple Sclerosis 2007; 3: S7-S273. 5. Rudick R, Pace A, Panzara M, et al. Effects of statins on intramuscular interferon beta-1a for relapsing-remitting multiple sclerosis. Multiple Sclerosis 2007; 13: S7-S273. 6. Friedmann P, Aktas O, Waiczies S, et al. High dose atorvastatin alone or in combination with interferon-beta (IFN-beta) in the treatment of relapsing-remitting multiple sclerosis (RR MS) Neurology 2008;70 (suppl 1):02.145. 7. Orefice G, Quarantelli M, Salvatore M, et al. Interferon beta-1a and atorvastatin combination therapy: 12-month results from an open-label, randomized, clinical study. Neurology 2008;70(suppl 1):02.139. 8. Rudick RA, Goodkin DE. Multiple Sclerosis Therapeutics. Philadelphia: Taylor & Francis; 1999. 9. Schwid SR, Panitch HS. Full results of the Evidence of Interferon Dose-Response-European North American Comparative Efficacy (EVIDENCE) study: a multicenter, randomized, assessor-blinded comparison of low-dose weekly versus high-dose, high-frequency interferon beta-1a for relapsing multiple sclerosis. Clin Ther 2007;29:2031–2048. Disclosures: Dr. Birnbaum has received honoraria and research support from EMD Serono, Pfizer, TEVA Neuroscience, and Berlex. Research grants from Pfizer have exceeded $10,000. Dr. Altafullah received personal compensation from Boehringer Ingelheim, Genenteck, Pfizer, Coaxia, AGA Medical, and Atritech, received a research grant for more than $10,000 from Pfizer, and owns shares in Pfizer worth about $40,000. Dr. Reder received compensation, research support, or honoraria from the following companies: Abbott Laboratories, Immunoscience, Parsippany, NJ; American Medical Association, Chicago, IL; Astra Merck, Wayne, PA; Athena Neurosciences, South San Francisco, CA; Aventis Pharma, Bridgewater, NJ; Berlex Laboratories, Richmond, CA; Biogen and Biogen/Idec, Cambridge, MA; BioMS Medical Corp., Edmonton, Alberta, Canada; Blue Cross, Blue Shield, Chicago, IL; Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT; Caremark Rx, Northbrook, IL; Centocor, Inc., Malvern, PA; Cephalon, Inc., Delaware, MD; Connectics/Connective Therapeutics, Palo Alto, CA ; CroMedica Global Inc., Victoria, BC; Elan Pharmaceuticals, Inc., San Diego, CA; Genentech, South San Francisco, CA; Genzyme Corporation, San Antonio, TX; Glaxo- SmithKline, Research Triangle Park, NC; Hoechst Marion Roussel Canada Research, Inc., Leval, Quebec; Hoffman-LaRoche, Nutley, NJ; Idec, San Diego, CA; Immunex, Seattle, WA; Institute for Health Care Quality, Minneapolis, MN; Johnson & Johnson, Pharmaceutical Research & Development, LLC, Raritan, NJ; NARCOMS, Yale University, New Haven, CT, & Barrow Neurological Institute, Phoenix, AZ; National Multiple Sclerosis Society & Paralyzed Veterans of America, Pain Panel, New York, NY; Neurocrine Biosciences, San Diego, CA; Novartis Corporation, New York, NY; Parke-Davis, Morris Plains, NJ; Pfizer Inc., New York, NY; Pharmacia & Upjohn, Kalamazoo, MI; Protein Design Labs, Inc., Delaware; Quantum Biotechnologies, Inc., Leval, Quebec; Quintiles, Inc., San Diego, CA; RENEW study (post-marketing study of Novantrone in MS); Serono; Sandoz (now Novartis) & Novartis, East Hanover, NJ; Sention, Inc., Providence, RI; Serono, Norwell, MA; Smith Kline-Beecham, Philadelphia, PA; Specialized Therapeutics, a division of Berlipharm, Inc., Montville, NJ; Takeda Pharmaceuticals, Lincolnshire, IL; Teva-Marion. Dr. Cree has received personal compensation for speaking from Biogen Idec, EMD Serono, and Teva Neurosciences and receives grant support from Genentech, Inc. and BioMS.