Kamm CP, El-Koussy M, Humpert S, Findling O, Burren Y, Schwegler G, Donati F, Müller M, Müller F, Slotboom J, Kappos L, Naegelin Y, Mattle HP; SWABIMS Study Group.Atorvastatin Added to Interferon Beta for Relapsing Multiple Sclerosis: 12-Month Treatment Extension of the Randomized Multicenter SWABIMS Trial.PLoS One. 2014; 9(1):e86663
BACKGROUND: Statins have anti-inflammatory and immunomodulatory properties in addition to lipid-lowering effects.
OBJECTIVES:To report the 12-month extension of a phase II trial evaluating the efficacy, safety and tolerability of atorvastatin 40 mg/d added to interferon beta-1b (IFNB-1b) in relapsing-remitting multiple sclerosis (RRMS).
METHODS:In the randomized, multicenter, parallel-group, rater-blinded core study, 77 RRMS patients started IFNB-1b. At month three they were randomized 1∶1 to receive atorvastatin 40 mg/d or not in addition to IFNB-1b until month 15. In the subsequent extension study, patients continued with unchanged medication for another 12 months. Data at study end were compared to data at month three of the core study.
RESULTS:27 of 72 patients that finished the core study entered the extension study. 45 patients were lost mainly due to a safety analysis during the core study including a recruitment stop for the extension study. The primary end point, the proportion of patients with new lesions on T2-weighted images was equal in both groups (odds ratio 1.926; 95% CI 0.265-14.0007; p = 0.51). All secondary endpoints including number of new lesions and total lesion volume on T2-weighted images, total number of Gd-enhancing lesions on T1-weighted images, volume of grey and white matter, EDSS, MSFC, relapse rate, number of relapse-free patients and neutralizing antibodies did not show significant differences either. The combination therapy was well tolerated.
CONCLUSIONS:Atorvastatin 40 mg/day in addition to IFNB-1b did not have any beneficial effects on RRMS compared to IFNB-1b monotherapy over a period of 24 months.
So there is no added value of the statin above anything offers by beta interferon but I wonder what the chances of showing anything positive with a group size of about thirty people is. The chances are slim. Does this means it is the end for statins as you see below there is an endless set of small trials. Some of them suggesting it makes things worse.
Lanzillo R, et al: Atorvastatin combined to interferon to verify the efficacy (ACTIVE) in relapsing-remitting active multiple sclerosis patients: a longitudinal controlled trial of combination therapy. Mult Scler 2010, 16:450–454.
Togha M, et al: Simvastatin treatment in patients with relapsing-remitting multiple sclerosis receiving interferon beta 1a: a double-blind randomized controlled trial. Mult Scler 2010, 16:848–854.
Sorensen PS, et al: Simvastatin as add-on therapy to interferon beta-1a for relapsing remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol 2011, 10:691–701.
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(18):1390–1395.
Vollmer T, et al: Oral simvastatin treatment in relapsing–remitting multiple sclerosis. Lancet 2004, 363:1607–1608.
Waubant E, et al: Randomized controlled trial of atorvastatin in clinically isolatedsyndrome: the STAyCIS study. Neurology 2012, 78:1171–1178.
However the idea was sold on statins working on Th2, which was not particularly consistent with our data, and I guess the originators of the idea have begun to wobble and now think it blocks the proliferation on the T cells but given the effects in humans one wonders
Weber MS, Prod Homme T, Youssef S, Dunn SE, Steinman L, Zamvil SS. Neither T-helper type 2 nor Foxp3+ regulatory T cells are necessary for therapeutic benefit of atorvastatin in treatment of central nervous system autoimmunity. J Neuroinflammation. 2014 Feb;11(1):29. [Epub ahead of print]
Oral atorvastatin has prevented or reversed (check this meaning out here) paralysis in the multiple sclerosis (MS) model experimental autoimmune encephalomyelitis (EAE), and reduced development of new MS lesions in clinical trials. Besides inhibiting development of encephalitogenic T cells, atorvastatin treatment of EAE has been associated with an induction of anti-inflammatory myelin-reactive T-helper type (Th)-2 cells. To investigate the clinical significance of atorvastatin-mediated Th2 differentiation, we first evaluated atorvastatin treatment in interleukin (IL)-4 green fluorescent protein-enhanced transcript (4-GET) reporter mice. Atorvastatin treatment failed to induce IL-4-producing Th2 cells in vivo; however, when T cells from atorvastatin-treated 4-GET mice were reactivated in vitro, T cells preferentially differentiated into Th2 cells, while antigen-specific T-cell proliferation and secretion of proinflammatory cytokines (interferon gamma, IL-17, tumor necrosis factor and IL-12) were reduced. Oral atorvastatin also prevented or reversed EAE in signal transducer and activator of transcription 6-deficient (STAT6-/-) mice, which cannot generate IL-4-producing Th2 cells. Further, atorvastatin treatment did not induce or expand Foxp3+ regulatory T cells in either wild-type or STAT6-/- mice. In vivo proliferation of T cells, as measured by incorporation of bromodeoxyuridine, was inhibited in atorvastatin-treated wild-type and STAT6-/- mice. These data imply that atorvastatin ameliorates central nervous system autoimmune disease by inhibiting the proliferation of encephalitogenic T cells, as opposed to induction of Th2 cells. This cytostatic effect may be a relevant mechanism of action when considering use of statins in MS and other inflammatory conditions.
So another Nature paper bites the dust, there are other ideas about what statins do and this is not related to T cell proliferation.