damage after an attack. they can also remove other reactive oxygen species it is also known that uric acid levels decrease during the course of the disease bilirubin has been found to have immunomodulatory properties, apart from the already known antioxidant properties and it is a possible future treatment. use of drugs to suppress myelin-reactive effector memory t cells by blocking voltage-gated kv1.3 channels in these cells. hydralazine: due to its ability to damage myelin nerve sheaths, acrolein may be a factor in the development of multiple sclerosis. the antihypertensive drug hydralazine, a known scavenger of acrolein, was found to reduce myelin damage and significantly improve behavioral outcomes in a mouse model of multiple sclerosis (experimental autoimmune encephalomyelitis). helminthic therapy: a study showed a negative association between ms and infection with intestinal parasites, such as hookworm, indicating that parasites may protect against multiple sclerosis. helminth therapy involves ingesting helminth eggs by the names of trichuris suis, which are non parasitic worms. this is done in hopes that the body will redirect the immune response away from attacking the myelin, which produce lesions and target the helminths. the study by dr fleming shows this is affective in reducing the extent of lesions seen through mri's taken before and after the study. bcg vaccine: the common, live, attenuated vaccine against tuberculosis, has substantially reduced recurrence of symptoms in multiple sclerosis patients. the frequency of new enhancing lesions as detected by gd-enhanced mri was reduced by more than half in 12 patients, comparing the six-month run-in phase to the six-month post bcg phase of the experiment. persistence at subsequent mr scan was reduced from 18 to 1 lesion, and evolution to black holes was reduced from 28 to 6 lesions. the conventional explanation of such protection is that parasites (including bacteria) modulate the sensitivity of the immune system. bcg appears safe as a treatment for multiple sclerosis. low dose naltrexone is also known as ldn. naltrexone, a pure opiate antagonist, licensed by the fda for the treatment of alcohol and opioid addictions, is being studied at a lower dosage for ms patients. a small, short-duration clinical trial with ms patients was conducted at the university of california, san francisco. in october 2007 data was presented at the european congress of ms in prague regarding safety findings of a pilot study of low dose naltrexone therapy in multiple sclerosis by neurological researchers in milan, italy. however, no compelling efficacy results for ldn in ms therapy have been published. ldn is available to ms patients in the us by off-label prescription. minocycline: the antibiotic minocycline has shown an effect on clinical and magnetic resonance imaging (mri) outcomes and serum immune molecules in ms patients over 24 months of open-label minocycline treatment. despite a moderately high pretreatment relapse rate in patients in the study prior to treatment, no relapses occurred between months 6 and 24. the only patient with gadolinium-enhancing lesions on mri at 12 and 24 months was on half-dose minocycline. clinical and mri outcomes in this study were supported by systemic immunological changes and call for further investigation of minocycline in ms. pixantrone: pixantrone (bbr2778) is an analogue of mitoxantrone devoid of toxic effects on cardiac tissue. it is as potent as mitoxantrone in animal models of ms; however, results of human trials had not been published in 2007. plasmapheresis. pattern ii ms lesions have been reported to respond to plasmapheresis, which points to something pathogenic into the blood serum, and the percentage reported of pattern ii is very close to the 47% reported in kir4.1 ms cases, turning kir4.1 patients into candidates for plasma exchange. prolactin: in 2007 it was published that the hormone prolactin can ease the effects of demyelination in animal models of ms. this effect of prolactin may be the reason why pregnancy tends to reduce the effects of multiple sclerosis in women. statins: a family of cholesterol-lowering drugs, the statins, have shown anti-inflammatory effects in animal models of ms. however, there is no evidence that statins are beneficial in the treatment of human ms patients, and concerns exist that, if ever shown to be effective, the high doses needed would prevent long-term use due to the potential for liver damage and muscle-wasting disease. one of them, atorvastatin, has been tried in combination with several approved treatments, though with little success. other, simvastatin (zocor) has shown good results in progressive variants testosterone has been studied for its potential benefits in men with multiple sclerosis, but the results are preliminary. vitamin d: a 2004 study found that women who took vitamin d supplements were 40% less likely to develop ms than women who did not take supplements. however, this study does not provide enough data to conclude that vitamin d has a beneficial influence on ongoing ms. furthermore, it could not distinguish between a beneficial effect of vitamin d and that of multivitamin supplements including vitamin e and various b vitamins, which may also exert a protective effect. a new study on this in the same sense was published in 2013 omega-3 fatty acid: one study found that omega-3 fatty acid supplementation decreases matrix metalloproteinase-9 production in relapsing-remitting multiple sclerosis combined therapies several combinations of drugs have been tested. some of them are couples of approved drugs. other tests try one approved drug with one experimental substance. finally, at some point there could appear some trials testing couples of non-approved drugs. as of 2016, there are 10 active principles approved which are: two interferons (interferon beta-1a and interferon beta-1b), glatiramer acetate, mitoxantrone, fingolimod, teriflunomide, dimethyl fumarate and finally three monoclonal antibodies (natalizumab, alemtuzumab and since may 2016, daclizumab) combination of approved drugs mitoxantrone and glatiramer acetate: a study in the united kingdom revealed interesting results, when using a combination of mitoxantrone and glatiramer acetate. in an open-label study of 27 patients with rrms, the results suggested a rapid and sustained suppression of relapses. a three-year controlled study of 60 patients is now being launched at 10 centres across the uk. in another clinical trial, glatiramer acetate (copaxone) has been combined with mitoxantrone in such a way that every course of mitoxantrone is followed by ga treatment. it has yielded promising results twice, in a consistent way. natalizumab and glatiramer acetate: this combination has been found to be safe and well tolerated after six months. mitoxantrone and beta-interferon: this combination has worked in some cases but not in others beta-interferon and glatiramer acetate: in phase iii, with good results published interferon beta 1a and natalizumab: dangerous but effective. linked with pml, but is remarkable that natalizumab alone is also linked with it. natalizumab and fingolimod. no formal research has been done, but some problems have been reported. interferon beta 1a and glatimer acetate: no additional benefits found alemtuzumab and glatiramer acetate: a combination trial of alemtuzumab with glatiramer acetate (copaxone) is being considered, and is expected to work synergistically. laquinimod and fampridine, with good results, subject to patent where applicable mitoxantrone and rituximab: human anti-chimeric antibodies (haca) appear in patients treated with rituximab. mtx reduces them. a safety analysis of ra patients treated with rituximab in combination with mtx in clinical trials showed that 11% of patients developed a positive titer for haca's at least once during treatment with rituximab. laquinimod and dimethyl fumarate: (patented by teva pharmaceutical industries ltd): it has been tested and looks promising. approved and experimental drugs combined glatiramer acetate and minocycline. good results avonex and atorvastatin: avonex (beta-1a) has also been combined with atorvastatin in a clinical trial showing that is safe in its conditions, even though high-dose statins are expected to produce liver problems and muscle-wasting disease over the long-term. other clinical trials have found problems combining ifn beta with atorvastatin interferon beta-1b and atorvastatin: betaseron (beta-1b) has also been combined with atorvastatin with good safety results but poor performance. the combined treatment did not have any beneficial effects on rrms compared to ifnb-1b monotherapy. cyclophosphamide and beta-interferon has been tried on ifnbeta-unresponsive patients with success, but it is still under study. avonex and inosine: avonex (interferon beta-1a) was combined with inosine. available data suggests that this combination is safe and well tolerated, though with no improvements respect interferon beta alone. the lack of additional benefits respect avonex have been confirmed, and it has been reported that 2gr/day should be considered as the maximum safe dosage. avonex and lipoic acid: lipoic acid is another common antioxidant siponimod and laquinimod: patent pending ponesimod and dimethyl fumarate (tecfidera): under study summary table summarizing in a table which combinations have been tried: interferon beta-1a interferon beta-1b (betaseron) glatiramer acetate (copaxone) mitoxantrone natalizumab (tysabri) fingolimod (gilenya) teriflunomide (aubagio) dimethyl fumarate bg12 (tecfidera) alemtuzumab (lemtrada) interferon beta-1a — — — — — — — — — interferon beta-1b (betaseron) no — — — — — — — — glatiramer acetate (copaxone) yes no — — — — — — — mitoxantrone no no yes — — — — — — natalizumab (tysabri) yes (linked to pml) no yes no — — — — — fingolimod (gilenya) no no no no no — — — — teriflunomide (aubagio) no no no no no no — — — dymetyl fumarate bg12 (tecfidera) no no no no no no no — — alemtuzumab (lemtrada) no no no no no no no no — atorvastatin (lipitor) yes yes no no no no no no no cyclophosphamide no yes no no no no no no no inosine yes no no no no no no no no biomarkers for the expected response personalized treatment or theranostics in ms is an active field or research that is trying to predict the response to the different known medications. interferons beta-interferons are contraindicated in cases of anti-aqp4 or anti-mog seropositivity. interferon injections can induce neutralising antibodies against them, turning the medication ineffective. ifn-β 1b is more immunogenic than ifn-β 1a, and the subcutaneous administration has a higher risk than the intramuscular administration both interferons should induce mxa (myxovirus protein a) mrna, being its absence a negative indicator there is heterogeneity in the immunologic pathways even restricted to rrms population, and it correlates with ifn-β response. in a small study patients were clustered into 6 distinct subsets by baseline cytokine profiles. two subsets were associated with patients who responded poorly to therapy. two other subsets showed a significant reduction in relapse rates and no worsening of disability. glatimer acetate for glatimer acetate, the biomarkers for response are interleukins. il-27 is a biomarker for response, and il-18 and il-4 are also possible good biomarkers it also seems that phosphorylated sirt1 expression in mrna is also a biomarker for response. mitoxantrone the best predictive biomarker for mitoxantrone available is the number of relapses in separate areas within the past 24 months before treatment. natalizumab natalizumab can also induce neutralising antibodies 4 to 6 months after treatment initiation. fetuin-a (alpha-2-hs-glycoprotein) and circulating cd49 expression are emerging biomarkers for the therapeutic efficacy of natalizumab. fingolimod lymphocyte subpopulations in peripheral blood is a promising tool to select rrms candidate for fingolimod treatment. rituximab and anti-cd20 gadolinium enhancement before treatment initiation as a predictor of anti-cd20 response in ms.