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Cytokines as Biomarkers of Treatment Response to IFN ? in Relapsing-Remitting Multiple Sclerosis.

ABSTRACT: Background. MS patients show a remarkable heterogeneity in their response to disease modifying treatments. Given the need for early treatment initiation and the diversity of available options, a predictive marker that indicates good or poor response to treatment is highly desirable. Objective. To find a biomarker for treatment response to IFN? among pro- and anti-inflammatory cytokines. Materials and Methods. IFN-?, TNF-?, IL-2, IL-4, IL-6, IL-10, IL-17A, and TGF-?1 levels were measured in serum and CSF of 43 patients with RR-MS who were followed up for a mean period of 5.3 years. Thirty-five patients received IFN? treatment and were divided into good responders (GR, n = 19) and poor responders (PR, n = 16). The remaining 8 patients showed a very favorable outcome and remained untreated (noRx). Results. GR had significantly higher serum baseline levels of IL-17A than PR and significantly higher serum levels of IL-17A, IFN-?, TNF-?, and IL-2 than noRx. PR had significantly higher IFN-? serum levels than noRx. No significant differences were observed in serum levels of IL-6, IL-4, IL-10, and TGF-?1 or the levels of all cytokines measured in CSF between the 3 groups of patients. Conclusions. Baseline serum levels of IL-17A can be used as a biomarker of IFN? treatment response.

SUBMITTER: Dimisianos N

PROVIDER: S-EPMC4134814 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Cytokines as Biomarkers of Treatment Response to IFN β in Relapsing-Remitting Multiple Sclerosis.

Dimisianos Nikolaos N Rodi Maria M Kalavrizioti Dimitra D Georgiou Vasileios V Papathanasopoulos Panagiotis P Mouzaki Athanasia A

Multiple sclerosis international 20140722

Background. MS patients show a remarkable heterogeneity in their response to disease modifying treatments. Given the need for early treatment initiation and the diversity of available options, a predictive marker that indicates good or poor response to treatment is highly desirable. Objective. To find a biomarker for treatment response to IFNβ among pro- and anti-inflammatory cytokines. Materials and Methods. IFN-γ, TNF-α, IL-2, IL-4, IL-6, IL-10, IL-17A, and TGF-β1 levels were measured in serum ...[more]

PMID: 25152817

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Project description:BACKGROUND: Numerous cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS), but studies are often limited to whole blood (WB) or peripheral blood mononuclear cells (PBMCs), thereby omitting important information about the cellular origin of the cytokines. Knowledge about the relation between blood and cerebrospinal fluid (CSF) cell expression of cytokines and the cellular source of CSF cytokines is even more scarce. METHODS: We studied gene expression of a broad panel of cytokines in WB from relapsing-remitting multiple sclerosis (RRMS) patients in remission and healthy controls (HCs). Subsequently we determined the gene expression of the dysregulated cytokines in isolated PBMC subsets (CD4+, CD8+T-cells, NK-cells, B-cells, monocytes and dendritic cells) from RRMS patients and HCs and in CSF-cells from RRMS patients in clinical relapse and non-inflammatory neurological controls (NIND). RESULTS: RRMS patients had increased expression of IFN-gamma (IFNG), interleukin (IL) 1-beta (IL1B), IL7, IL10, IL12A, IL15, IL23, IL27, lymphotoxin-alpha (LTA) and lymphotoxin-beta (LTB) in WB. In PBMC subsets the main sources of pro-inflammatory cytokines were T- and B-cells, whereas monocytes were the most prominent source of immunoregulatory cytokines. In CSF-cells, RRMS patients had increased expression of IFNG and CD19 and decreased expression of IL10 and CD14 compared to NINDs. CD19 expression correlated with expression of IFNG, IL7, IL12A, IL15 and LTA whereas CD14 expression correlated with IL10 expression. CONCLUSIONS: Using a systematic approach, we show that expression of pro-inflammatory cytokines in peripheral blood primarily originates from T- and B-cells, with an important exception of IFNG which is most strongly expressed by NK-cells. In CSF-cell studies, B-cells appear to be enriched in RRMS and associated with expression of pro-inflammatory cytokines; contrarily, monocytes are relatively scarce in CSF from RRMS patients and are associated with IL10 expression. Thus, our findings suggest a pathogenetic role of B-cells and an immunoregulatory role of monocytes in RRMS.

Project description:Several treatments are currently available for relapsing-remitting multiple sclerosis. Among them, interferon (IFN) beta remains a valid treatment approach because of its good benefit/risk profile. Due to the need for frequent administration (weekly, at a minimum), the use of IFN beta is limited by uncomfortable side effects that could reduce adherence to and persistence with the treatment. The use of subcutaneous polyethylene glycol (PEG)ylated interferon beta-1a (PEG-IFN) has been proposed to offer a better combination of pharmacokinetic and pharmacodynamic profiles and therapy-related side effects. A 125 μg dose of PEG-IFN given every 2 or 4 weeks was tested in two Phase I studies and shown to be as safe and efficient as IFN beta-1a but with a longer half-life. A Phase III trial (ADVANCE) comparing 125 μg of PEG-IFN given every 2 or 4 weeks with placebo in 1,512 patients with relapsing-remitting multiple sclerosis showed significant reductions in both the annualized relapse rate (ARR) and the occurrence of new or newly enlarged T2 brain lesions in both experimental groups versus placebo after the first year. Moreover, 38% fewer patients showed progression of disability (P=0.04) in the PEG-IFN groups. During the second year, the ARR was further reduced in the PEG-IFN 2-week treatment group (0.230 at 1 year versus 0.178 at 2 years) and was maintained in the 4-week treatment group. Patients who received immediate PEG-IFN treatment showed improved clinical efficacy (ARR, risk of relapse, 12-week disability progression) and magnetic resonance imaging parameters (new T2 and newly enlarging lesions, gadolinium-positive lesions) compared with those with delayed treatment. The effects were more evident with the 2-week dose for all endpoints considered. Furthermore, PEG-IFN was well tolerated, and no new safety concerns arose. In conclusion, PEG-IFN has good efficacy and a good safety profile. The available data support the use of PEG-IFN as a suitable therapeutic option in patients with relapsing-remitting multiple sclerosis.

Project description:Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system and mainly affects young adults. Its natural history has changed in recent years with the advent of disease-modifying drugs, which have been available since the early 1990s. The increasing number of first-line and second-line treatment options, together with the variable course of the disease and patient lifestyles and expectations, makes the therapeutic decision a real challenge. The aim of this review is to give a comprehensive overview of the main present and some future drugs for relapsing-remitting MS, including risk-benefit considerations, to enable readers to draw their own conclusions regarding the risk-benefit assessment of personalized treatment strategies, taking into account not only treatment-related but also disease-related risks. We performed a Medline literature search to identify studies on the treatment of MS with risk stratification and risk-benefit considerations. We focused our attention on studies of disease-modifying, immunomodulating, and immunosuppressive drugs, including monoclonal antibodies. Here we offer personal considerations, stemming from long-term experience in the treatment of MS and thorough discussions with other neurologists closely involved in the care of patients with the disease. MS specialists need to know not only the specific risks and benefits of single drugs, but also about drug interactions, either in simultaneous or serial combination therapy, and patient comorbidities, preferences, and fears. This has to be put into perspective, considering also the risks of untreated disease in patients with different clinical and radiological characteristics. There is no single best treatment strategy, but therapy has to be tailored to the patient. This is a time-consuming task, rich in complexity, and influenced by the attitude towards risk on the parts of both the patient and the clinical team. The broader the MS drug market becomes, the harder it will be for the clinician to help the patient decide which therapeutic strategy to opt for.

Project description:BACKGROUND:Recent data from animal models of multiple sclerosis (MS) and from a pilot study indicated a possible beneficial impact of statins on MS. METHODOLOGY/PRINCIPAL FINDINGS:Safety, tolerability and effects on disease activity of atorvastatin given alone or in combination with interferon-beta (IFN-beta) were assessed in a phase II open-label baseline-to-treatment trial in relapsing-remitting MS (RRMS). Patients with at least one gadolinium-enhancing lesion (CEL) at screening by magnetic resonance imaging (MRI) were eligible for the study. After a baseline period of 3 monthly MRI scans (months -2 to 0), patients followed a 9-month treatment period on 80 mg atorvastatin daily. The number of CEL in treatment months 6 to 9 compared to baseline served as the primary endpoint. Other MRI-based parameters as well as changes in clinical scores and immune responses served as secondary endpoints. Of 80 RRMS patients screened, 41 were included, among them 16 with IFN-beta comedication. The high dose of 80 mg atorvastatin was well tolerated in the majority of patients, regardless of IFN-beta comedication. Atorvastatin treatment led to a substantial reduction in the number and volume of CEL in two-sided multivariate analysis (p = 0.003 and p = 0.008). A trend towards a significant decrease in number and volume of CEL was also detected in patients with IFN-beta comedication (p = 0.060 and p = 0.062), in contrast to patients without IFN-beta comedication (p = 0.170 and p = 0.140). Immunological investigations showed no suppression in T cell response but a significant increase in IL-10 production. CONCLUSIONS/SIGNIFICANCE:Our data suggest that high-dose atorvastatin treatment in RRMS is safe and well tolerated. Moreover, MRI analysis indicates a possible beneficial effect of atorvastatin, alone or in combination with IFN-beta, on the development of new CEL. Thus, our findings provide a rationale for phase II/III trials, including combination of atorvastatin with already approved immunomodulatory therapy regimens. TRIAL REGISTRATION:ClinicalTrials.gov NCT00616187.

Dataset Information

Cytokines as Biomarkers of Treatment Response to IFN ? in Relapsing-Remitting Multiple Sclerosis.

Publications

Cytokines as Biomarkers of Treatment Response to IFN β in Relapsing-Remitting Multiple Sclerosis.

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