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IntroductionInterferon (IFN)-β is known as an environmental trigger for the occurrence of autoimmune thyroid disease (AITD). However, the association of another type-1 IFN, IFN-β, with AITD is unknown.Material and methodsIn the study, we explored the association of serum IFN-β levels with AITD in an ethnic Chinese (i.e., Taiwanese) population. We enrolled 160 patients with Graves’ disease (GD), 47 patients with Hashimoto’s thyroiditis (HT), and 119 healthy controls. Serum IFN-β and B-cell activating factor (BAFF) levels were quantified in healthy controls at the baseline and in patients with AITD either prior to receiving medication or while under medication. Thyroid function and thyroid-stimulating hormone receptor antibody (TSHRAb) levels were measured at the time of serum collection.ResultsSerum IFN-β levels were lower in the HT group than in the control group (p = 0.031). A significant inverse correlation was observed between IFN-β and TSHRAb levels in men with GD (r = –0.433, p = 0.044). Serum IFN-β levels were also negatively associated with BAFF levels in men with GD, HT, and AITD (r = –0.320, p = 0.032; r = –0.817, p = 0.047; and r = –0.354, p = 0.011, respectively), but not in women with GD, HT, or AITD.ConclusionsSerum IFN-β levels were lower in HT patients. Correlations of serum IFN-β with TSHRAb and BAFF levels were found to be gender-specific. Further well-designed studies with larger sample sizes are required to confirm our findings.

Drug-Induced Pulmonary Arterial Hypertension (PAH) represents a well-known entity, predominantly related to anorexigens. Interferon-β (IFN) is considered to be a drug with a possible risk of inducing PAH. We report a patient with Multiple Sclerosis treated with IFN-β who diagnosed with PAH and her course of disease under specific PAH drug therapy. A review of the literature in IFN-β-induced PAH is provided.

Increased expression of cytosolic DNA sensors, a category of pattern recognition receptor, after control plasmid DNA electrotransfer was observed in our previous studies on B16.F10 murine melanoma cells. This expression was correlated with the upregulation of proinflammatory cytokines and chemokines and was associated with cell death. Here, we expanded our research to include the influence of features of cells in a 3-dimensional environment, which better represents the tumors' organization in vivo. Our results show that lower number of cells were transfected in spheroids compared to 2-dimensional cultures, that growth was delayed after electroporation alone or after electrotransfer of plasmid DNA, and that DNA sensors DDX60, DAI/ZBP1, and p204 were upregulated 4 hours and 24 hours after electrotransfer of plasmid DNA. Moreover, the cytokines interferon β and tumor necrosis factor α were also upregulated but only 4 hours after electrotransfer of plasmid DNA. Thus, our results confirm the results obtained in 2-dimensional cell cultures demonstrating that electrotransfer of plasmid DNA to tumor cells in spheroids also upregulated cytosolic DNA sensors and cytokines.

Therapies - In Press.Proof corrected by the author Available online since lundi 21 janvier 2019

A series of controlled clinical trials have shown that exogenous interferon-beta (IFN-β) benefits patients with relapsing–remitting multiple sclerosis (RRMS) by reducing relapse rate, disability progression, and the formation of new brain and spinal cord lesions on magnetic resonance imaging (MRI) scans. Unfortunately, however, the effectiveness of IFN-β is limited in this setting by the occurrence of treatment non-responsiveness in nearly 25% of patients. Furthermore, clinicians who care for RRMS patients remain unable to accurately identify IFN-β non-responders prior to the initiation of therapy, causing delays in the use of alternative treatments and sometimes requiring that patients turn to medications with more significant side effects to control their disease. Progress has been made toward understanding how both endogenous and exogenous IFN-β act to slow RRMS as well as the related mouse model, experimental autoimmune encephalomyelitis (EAE). Most studies point to its inhibitory actions on circulating immune cells as being important for suppressing both disorders, but multiple potential target cells and inflammatory pathways have been implicated and those essential to confer its benefits remain undefined. This review focuses on the role of both endogenous and exogenous IFN-β in RRMS, paying particular attention to the issue of why certain individuals appear refractory to its disease-modifying effects. A continued goal in this field remains the identification of a convenient biomarker that accurately predicts IFN-β treatment non-responsiveness in individual RRMS patients. Development of such an assay will allow clinicians to customize therapy for patients with this complex disorder.

Key Clinical Message Sarcoidosis is a diagnosis that should be considered in patients receiving interferon therapy, who present with anemia and multiorgan dysfunction regardless of the duration of their treatment. When sarcoidosis is suspected, bone marrow biopsy should be considered especially for cases predominant by extrapulmonary features.

Jokubaitis, Vilija G./0000-0002-3942-4340; Lugaresi, Alessandra/0000-0003-2902-5589; McCombe, Pamela/0000-0003-2704-8517; Kermode, Allan/0000-0002-4476-4016; Slee, Mark/0000-0003-4323-2453; Kalincik, Tomas/0000-0003-3778-1376; Pedrini, Marzena/0000-0002-2614-8607; Butzkueven, Helmut/0000-0003-3940-8727; Trojano, Maria/0000-0002-6329-8946 WOS: 000447789100014 PubMed: 28857680 Objective: This propensity score-matched analysis from MSBase compared the effectiveness of cladribine with interferon , fingolimod or natalizumab. Methods: We identified all patients with relapse-onset multiple sclerosis, exposure to the study therapies and 1-year on-treatment follow-up from MSBase. Three pairwise propensity score-matched analyses compared treatment outcomes over 1year. The outcomes were hazards of first relapse, disability accumulation and disability improvement events. Sensitivity analyses were completed. Results: The cohorts consisted of 37 (cladribine), 1940 (interferon), 1892 (fingolimod) and 1410 patients (natalizumab). The probability of experiencing a relapse on cladribine was lower than on interferon (p=0.05), similar to fingolimod (p=0.31) and higher than on natalizumab (p=0.042). The probability of disability accumulation on cladribine was similar to interferon (p=0.37) and fingolimod (p=0.089) but greater than natalizumab (p=0.021). The probability of disability improvement was higher on cladribine than interferon (p=0.00017), fingolimod (p=0.0025) or natalizumab (p=0.00099). Sensitivity analyses largely confirmed the above results. Conclusion: Cladribine is an effective therapy for relapse-onset multiple sclerosis. Its effect on relapses is comparable to fingolimod and its effect on disability accrual is comparable to interferon and fingolimod. Cladribine may potentially associate with superior recovery from disability relative to interferon, fingolimod and natalizumab. National Health and Medical Research Council of AustraliaNational Health and Medical Research Council of Australia [1129189, 1083539, 1080518]; MerckMerck & Company; BiogenBiogen; NovartisNovartis; RocheRoche Holding; Bayer ScheringBayer AG; Sanofi Genzyme; Teva The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study was financially supported by National Health and Medical Research Council of Australia (project grants 1129189 and 1083539 and practitioner fellowship 1080518). The MSBase Foundation is a not-for-profit organisation that receives support from Merck, Biogen, Novartis, Roche, Bayer Schering, Sanofi Genzyme and Teva.

Objective: Multiple sclerosis (MS) is one of the leading neurodegenerative causes of physical disability world-wide. Genetic aberrations of autoimmunity pathway components have been demonstrated to significantly influence MS development. Cluster of Differentiation 58 (CD58) is pertained to a group of genes which had been assayed in several recent association studies. Given the significance of CD58 in modulation of T regulatory cells that control autoimmune responses, the present study was conducted to investigate the frequency of rs12044852 polymorphism and its effect on the outcome of interferon beta (IFN-β) therapy in a subset of Iranian MS patients. Materials and Methods: Two hundred MS patients and equal number of healthy controls were recruited to be genotyped in an experimental case-control based study through polymerase chain reaction using specific sequence primers (PCR-SSP). Relapsing remitting multiple sclerosis (RRMS) patients administered IFN-β therapy were followed up with clinical visits every three months up to two years. The mean of multiple sclerosis severity score (MSSS) and expanded disability status scale (EDSS) were measured to monitor the change in severity of MS in response to IFN-β therapy. Pearson’s Chi-square and analysis of variance (ANOVA) tests were the main statistical methods used in this study. Results: Strong association was found between the CC genotype and onset of MS (p=0.001, OR=2.22). However, there was no association between rs12044852 and various classifications and severity of MS. Pharmacogenetics-based analysis indicated that carriers of CC genotype had the highest MSSS score compared to others, implying a negative impact of rs12044852 on response to IFN-β t herapy. Conclusion: Taken together, our findings revealed the critical effect of rs12044852 polymorphism of CD58 on the progression of MS disease. This indicates that genotyping of MS patients may expedite achieving personalized medical management of MS patients.

We originated and characterized melanoma cell lines derived from tumors of two feline and two canine veterinary patients. These lines reestablished the morphology, physiology and cell heterogeneity of their respective parental tumors. We evaluated the cytotoxicity of bleomycin (BLM) alone, or combined with interferon-β (IFN-β) or HSVtk/GCV suicide gene (SG) lipofection on these cells. Although the four animals presented stage III disease (WHO system), SG treated feline tumors displayed stable disease in vivo, while the canine ones exhibited partial response. Their derived cell lines reflected this behavior. Feline were significantly more sensitive than canine cells to IFN-β gene transfer. BLM improved the antitumor effects of both genes. The higher levels of reactive oxygen species (ROS) significantly correlated with membrane and DNA damages, emphasizing ROS intervention in apoptotic and necrotic cell death. After 3 days of BLM alone or combined with gene treatments, the colony forming capacity of two canine and one feline treatments survivor cells almost disappeared. Taken together, these results suggest that the treatments eradicated tumor initiating cells and support the clinical potential of the tested combinations. Fil: Agnetti, Lucrecia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología ; Argentina Fil: Fondello, Chiara. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología ; Argentina Fil: Villaverde, Marcela Solange. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología ; Argentina Fil: Glikin, Gerardo Claudio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología ; Argentina Fil: Finocchiaro, Liliana Maria Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Oncología ; Argentina

Human type I interferons are a family of pleiotropic cytokines with antiviral, anti-proliferative and immunomodulatory activities. They signal through the same cell surface receptors IFNAR1 and IFNAR2 yet evoking markedly different physiological effects. One differentiating factor of interferon-beta (IFN-β) from other type I interferons is the presence of theAsn-Gly-Arg (NGR) sequence motif, which, upon deamidation, converts to Asp-Gly-Arg (DGR) and iso-Asp-Gly-Arg (iso-DGR) motifs. In other proteins, the NGR and iso-DGR motifs are reported as CD13- and αvβ3, αvβ5, αvβ6, αvβ8 and α5β1 integrin-binding motifs, respectively. The scope of this study was to perform exploratory surface plasmon resonance (SPR) experiments to assess the binding properties of a deamidated IFN-β variant to integrins. For this purpose, integrin αvβ3 was selected as a reference model within the iso-DGR- integrin binding members. The obtained results show that deamidated IFN-β binds integrin αvβ3 with nanomolar affinity and that the response was dependent on the deamidation extent. Based on these results, it can be expected that deamidated IFN-β also binds to other integrin family members that are able to bind to the iso-DGR binding motif. The novel binding properties could help elucidate specific IFN-β attributes that under physiological conditions may be modulated by the deamidation.

BACKGROUND We present a case of acute rhabdomyolysis in the setting of interferon-β treatment and concomitant pomelo juice ingestion, with concern of possible pharmacological interaction, which has not yet been described in the literature. CASE PRESENTATION A young Caucasian female with multiple sclerosis on chronic therapy with interferon-β presented with acute rhabdomyolysis after mild exercise and concomitant ingestion of pomelo extract. After stopping the suspected drugs, the signs of rhabdomyolysis diminished, the subsequent course was favorable. CONCLUSIONS The most probable cause of rhabdomyolysis in our patient could have been the combination of interferon effect, which down-regulates P450 expression, with inhibition of the P450 activity by furanocoumarin derivatives from pomelo juice. Therefore, patients treated with drugs that have a possible interaction with inhibitors of cytochrome P450 should be warned against pomelo ingestion. .

Background Peritendinous adhesion is the most common complication after tendon surgery, particularly in zone II of the hand. Prevention of inflammation around the tendon, which develops after trauma and surgery, can decrease the tendon adhesion formation. This study compares the effect of some anti-inflammatory cytokines with 5-fluorouracil (5-FU) on the tensile strength and in prevention of peritendinous adhesion formation. Methods Sixteen rabbits were allocated equally into 4 groups. Tendons of the index and ring fingers in zone II of the right hind paw were cut in all animals and then repaired. Interferon (IFN)-α in group 1, 5-FU in group 2, normal saline in group 3, and IFN-β in group 4 were locally applied to the repaired sites. Three weeks later, tensometric and histopathologic evaluations were performed. Results The force required for removing the tendon from the sheath was not different between the groups (P = 0.130), but the time required for removal was significantly shorter in 5-FU group (P = 0.049). The strength of repair was not different between the groups in terms of force and time needed for rupture (P = 0.11 and 0.67, respectively). In histopathologic examination, normal architecture of the tendon and peritendon environment was less disturbed in the IFN groups, especially in IFN-β specimens. Conclusions Local application of 5-FU significantly reduced peritendinous adhesion. Local IFN-α and IFN-β had no significant effect on the prevention of peritendinous adhesion formation. The strength of the repair was not affected by these cytokines and 5-FU.

Methylprednisolone (MP) has been recommended as a standard drug in MS therapies. We previously demonstrated that IFNβ-secreting human bone marrow-derived mesenchymal stem cells (MSCs-IFNβ) exert immunomodulatory effects in experimental autoimmune encephalomyelitic (EAE) mice. In this study, we evaluated whether a combined treatment of MP and MSCs-IFNβ had enhanced therapeutic effects on EAE mice. The combination treatment resulted in enhanced immunomodulatory effects, including reduced production of pro-inflammatory cytokines and increased production of anti-inflammatory cytokines. Thus, our results provide a framework for designing novel experimental protocols to enhance the therapeutic effects of existing MS treatments.

Background TRIF is a key protein in antiviral innate immunity, operating downstream of TLRs. TRIF activation leads to the production of interferon-β and pro-inflammatory cytokines. There is evidence from experiments to suggest that the N-terminal domain of TRIF binds to its TIR domain to avoid constitutive activation. However, no structure of a complex between the N-terminal domain and the TIR domain exists till date. The disordered nature of the region connecting the N-terminal domain and the TIR domain compounds the issue of elucidating the mechanism of autoinhibition of TRIF. In this study, we have employed an integrative approach consisting of mutual information analysis, docking, molecular dynamics simulations and residue network analysis, in combination with existing experimental data to provide a glimpse of TRIF in its autoinhibited state. Results Our extensive docking approach reveals that the N-terminal domain binds to the BB loop-B helix region of the TIR domain, consistent with experimental observations. Long length molecular dynamics simulations of 1 microsecond performed on the docked model highlights residues participating in hydrogen bonding and hydrophobic interactions at the interface. A pair of residues present in the vicinity of the interface is also predicted by mutual information analysis, to co-evolve. Residues mediating long-range interactions within the TIR domain of TRIF were identified using residue network analysis. Conclusions Based on the results of the modelling and residue network analysis, we propose that the N-terminal domain binds to the BB loop region of the TIR domain, thereby preventing its homodimersation. The binding of TRIF to TLR3 or TRAM could induce a slight conformational change, causing the interactions between the N-terminal domain and TIR domain to disrupt, thereby exposing the BB loop and rendering it amenable for higher-order oligomerisation. Reviewers This article was reviewed by Michael Gromiha, Srikrishna Subramaniam and Peter Bond (nominated by Chandra Verma). Electronic supplementary material The online version of this article (doi:10.1186/s13062-017-0179-0) contains supplementary material, which is available to authorized users.

Background: Whereas cellular immune function depends on energy supply and mitochondrial function, little is known on the impact of immunotherapies on cellular energy metabolism. Objective: The objective of this paper is to assess the effects of interferon-beta (IFN-β) on mitochondrial function of CD4+ T cells. Methods: Intracellular adenosine triphosphate (iATP) in phytohemagglutinin (PHA)-stimulated CD4+ cells of multiple sclerosis (MS) patients treated with IFN-β and controls were analyzed in a luciferase-based assay. Mitochondrial-transmembrane potential (ΔΨm) in IFN-β-treated peripheral blood mononuclear cells (PBMCs) was investigated by flow cytometry. Expression of genes involved in mitochondrial oxidative phosphorylation (OXPHOS) in CD4+ cells of IFN-β-treated individuals and correlations between genetic variants in the key metabolism regulator PGC-1α and IFN-β response in MS were analyzed. Results: IFN-β-treated MS patients exhibited a dose-dependent reduction of iATP levels in CD4+ T cells compared to controls ( p < 0.001). Mitochondrial effects were reflected by depolarization of ΔΨm. Expression data revealed changes in the transcription of OXPHOS-genes. iATP levels in IFN-β-responders were reduced compared to non-responders ( p < 0.05), and the major T allele of the SNP rs7665116 of PGC-1α correlated with iATP-levels. Conclusion: Reduced iATP-synthesis ex vivo and differential expression of OXPHOS-genes in CD4+ T cells point to unknown IFN-β effects on mitochondrial energy metabolism, adding to potential pleiotropic mechanisms of action.

The aim of this retrospective study was to preliminarily assess whether the EP-score, a summary score derived from multimodal evoked potentials tests, might be used as a measure of treatment efficacy in multiple sclerosis (MS).A sample of 56 relapsing remitting MS (RRMS) patients who at diagnosis started treatment with interferon β (INFβ, n = 19), glatiramer acetate (GA, n = 15) or refused any chronic treatment were assessed at baseline (before treatment) and at a median of 1.7 and 3.6 years thereafter. Outcome variables were Expanded Disability Status Scale (EDSS), EP-Score, visual evoked potentials (VEP) and somatosensory evoked potentials (SEP) scores measured as differences between baseline and follow-ups. Statistical differences between groups and follow-ups were assessed using non-parametric analyses.Treatment effects were not significant for EDSS both at the first and at the second follow-up, while a trend toward significance was observed in the EP-score only in the first follow-up (p = 0.07). Post-hoc analysis showed a greater decrease in median VEP-score for the IFNβ group compared to the GA and DF groups at both the first and second follow-ups.We found no evidence that either INFβ or GA significantly improved disability in RRMS patients. Using the EP-score as an outcome measure, we found that it was improved at both follow-ups in the INFβ group mainly due to a decrease in the VEP-score. This finding supports the proposal to include the EP-score as an additional outcome variable in future studies of treatment efficacy in MS.

Various diseases require the selection of preferable treatment out of available alternatives. Multiple sclerosis (MS), an autoimmune inflammatory/neurodegenerative disease of the CNS, requires long-term medication with either specific disease-modifying therapy (DMT) – IFN-β or glatiramer acetate (GA) – which remain the only first-line DMTs in all countries. A significant share of MS patients are resistant to treatment with one or the other DMT; therefore, the earliest choice of preferable DMT is of particular importance. A number of conventional pharmacogenetic studies performed up to the present day have identified the treatment-sensitive genetic biomarkers that might be specific for the particular drug; however, the suitable biomarkers for selection of one or another first-line DMT are remained to be found. Comparative pharmacogenetic analysis may allow the identification of the discriminative genetic biomarkers, which may be more informative for an a priori DMT choice than those found in conventional pharmacogenetic studies. The search for discriminative markers of preferable first-line DMT, which differ in carriage between IFN-β responders and GA responders as well as between IFN-β nonresponders and GA nonresponders, has been performed in 253 IFN-β-treated MS patients and 285 GA-treated MS patients. A bioinformatics algorithm for identification of composite biomarkers (allelic sets) was applied on a unified set of immune-response genes, which are relevant for IFN-β and/or GA modes of action, and identical clinical criteria of treatment response. We found the range of discriminative markers, which include polymorphic variants of CCR5, IFNAR1, TGFB1, DRB1 or CTLA4 genes, in different combinations. Every allelic set includes the CCR5 genetic variant, which probably suggests its crucial role in the modulation of the DMT response. Special attention should be given to the (CCR5*d+ IFNAR1*G) discriminative combination, which clearly points towards IFN-β treatment choice for carriers of this combination. As a whole the comparative approach provides an option for the identification of prognostic composite biomarkers for a preferable medication among available alternatives.

Schilder disease, also termed diffuse myelinoclastic sclerosis, is characterized by a large demyelinating lesion involving 1 or both sides of the centrum semiovale of the cerebral hemispheres. It often presents with tumorlike features and poses a diagnostic challenge. Schilder disease can be monophasic or relapsing, and disease-modifying therapy for the latter scenario is largely empirical. Here, we report a 14-year-old girl with relapsing Schilder disease within 1 year after disease onset. She has been followed-up for nearly 10 years and remains in sustained remission ever since interferon-β therapy was prescribed after the second attack. In this case study, it is suggested that interferon-β may induce long-term remission in relapsing Schilder disease and is therefore worth considering in this regard.

RIG-I senses viral RNA in the cytosol and initiates host innate immune response by triggering the production of type 1 interferon. A recent RNAi knockdown screen yielded close to hundred host genes whose products affected viral RNA-induced IFN-β production and highlighted the complexity of the antiviral response. The stress granule protein G3BP1, known to arrest mRNA translation, was identified as a regulator of RIG-I-induced IFN-β production. How G3BP1 functions in RIG-I signaling is not known, however. Here, we overexpress G3BP1 with RIG-I in HEK293T cells and found that G3BP1 significantly enhances RIG-I-induced

A 77-year-old man with a history of surgical resection of malignant melanoma involving the fifth toe of his left foot 14 years ago presented at the Kariya Toyota General Hospital with a 3-month history of skin ulcer at the same site and red nodules on the lower left leg. Malignant melanoma was suspected, and the patient was referred to our department. On examination, a skin ulcer measuring 25 × 20 mm was observed at the amputation site on the left foot. In addition, multiple red nodules were observed on the lower left leg. Skin biopsies of the ulcer and nodules revealed recurrent malignant melanoma with in-transit metastasis. Two weeks later, he developed acute myocardial infarction and was hospitalized at the Kariya Toyota General Hospital. One month later, the myocardial infarction ameliorated, and he was transferred to our department. As the myocardial infarction had decreased the patient's tolerance to surgery, interferon-β was administered by intravenous infusion. The skin ulcer and red nodules on the lower left leg disappeared 26 weeks after infusion had been initiated. The patient's progress has been satisfactory, with no evidence of recurrence or metastasis at 1 year and 9 months after the initiation of intravenous infusion.

We present a case report of a 37-year-old woman with multiple sclerosis (MS) who developed nephrotic-range proteinuria secondary to membrano proliferative glomerulonephritis (MPGN)-like disease with mesangial C3 deposition without evidence of immune-complex deposition in the context of long-term interferon-β (IFN-β) therapy. The complete remission of proteinuria following cessation of IFN-β, strongly suggests causality. To our knowledge, this is the second case report of MPGN associated with IFN-β use. This being the case, the negative immune screen, normal inflammatory markers and the absence of immune complex deposits would imply a different pathway to that previously suggested.

Background: Factors driving disease-modifying therapy (DMT) switch behavior are not well understood. Objective: The objective of this paper is to identify patient characteristics and clinical events predictive of therapy switching in patients with suboptimal response to DMT. Methods: This retrospective study analyzed patients with relapsing–remitting multiple sclerosis (MS) and a suboptimal response to initial therapy with either interferon β or glatiramer acetate. Suboptimal responders were defined as patients with ≥1 MS event (clinical relapse, worsening disability, or MRI worsening) while on DMT. Switchers were defined as those who changed DMT within six to 12 months after the MS event. Results: Of 606 suboptimal responders, 214 (35.3%) switched therapy. Switchers were younger at symptom onset ( p = 0.012), MS diagnosis ( p = 0.004), DMT initiation ( p < 0.001), and first MS event ( p = 0.011) compared with nonswitchers. Compared with one relapse alone, MRI worsening alone most strongly predicted switch behavior (odds ratio 6.3; 95% CI, 3.1–12.9; p < 0.001), followed by ≥2 relapses (2.8; 95% CI, 1.1–7.3; p = 0.040), EDSS plus MRI worsening (2.5; 95% CI, 1.1–5.9; p = 0.031) and EDSS worsening alone (2.2; 95% CI, 1.2–4.1; p = 0.009). Conclusions: Younger patients with disease activity, especially MRI changes, are more likely to have their therapy switched sooner than patients who are older at the time of MS diagnosis and DMT initiation.

The early initiation of appropriate treatment is important for a better prognosis for patients with multiple sclerosis (MS). Although interferon (IFN-β) has been the most prescribed therapy for MS, some patients are poor responders to this therapy. Therefore, finding biomarkers to predict treatment responsiveness is required. Some patients with MS have high serum Sema4A and concurrently have characteristics of Th17-skewing conditions, and do not respond well to IFN-β therapy. In the present review, we discuss Sema4A and responsiveness to IFN-β therapy. In addition, we review biomarkers relevant to IFN-β therapy responsiveness.

Aim : to evaluate the impact of subcutaneous interferon β -1a on matrix metalloproteinases 3, 8, 9 (MMP), cytokines (tumor necrosis factor α — TNF α , and transforming growth factor β 1 — TGF β 1) levels in serum of children with relapsing-remitting multiple sclerosis. Patients and methods : the results of treatment of 32 patients with relapsing-remitting multiple sclerosis aged 12–18 years (22 girls and 10 boys) were analyzed. Treatment efficacy was assessed by the number of relapsing-remitting multiple sclerosis exacerbations during 12 months, MRI data, MMP and cytokines dynamics in serum. Results : statistical evidence acquired for MMPs, their tissue inhibitor and cytokines levels decrease (p < 0,005) in patients receiving therapy with subcutaneous INF β -1a. Conclusions : subcutaneous interferon β -1 а is highly efficient in treatment of relapsing-remitting multiple sclerosis in children and adolescents.

Recombinant DNA-derived biopharmaceuticals are structurally complex proteins derived from genetically modified living cells or organisms that are difficult to characterize. Because of inherent variability in the biological system and the manufacturing process, any biologic will exhibit microheterogeneity—that is, there will be a certain degree of variability even between different batches of the same product. Several biological products have lost patent protection in recent years, particularly in Europe and to a lesser extent (but soon to change) in the United States (US). This, in turn, has created significant clinical and economic opportunities for pharmaceutical companies to develop and seek marketing authorization for a number of biopharmaceuticals [e.g., human growth hormone, erythropoiesis-stimulating agents [ESAs], granulocyte colony-stimulating factors (GCSFs)]—and in the not-so-distant future, insulin, interferon β, recombinant follicle stimulating hormone and various monoclonal antibodies.1-3 Drawing upon our work on the clinical efficacy and safety of biosimilar recombinant human erythropoietin4-8 and filgrastim,9-11 as evidenced in registration trials and post-approval studies, we review here three issues of relevance to the bioengineering field: (1) definition, (2) development and (3) differentiation of biosimilars. For the purpose of this article, we limit the scope to biosimilar ESAs and GCSFs already approved by the European Medicines Agency (EMA) because, to date, the US Food and Drug Administration (FDA) has not approved a biological product as biosimilar or interchangeable. A few product reviews have been accepted under the FDAs conventional Biologics License Application (BLA) pathway, including the GCSF Tbo-filgrastim, which is the same agent as XM02 approved by the EMA. Epoetin theta was approved by the EMA as a stand-alone product. It is technically not considered a biosimilar by some12 but is practically and clinically viewed by others as such.4,13 There are biosimilars produced in less regulated markets; however, they are not considered in this article.

International audience; In this review we discuss the role of mimiviruses as potential human pathogens focusing on clinical and evolutionary evidence. We also propose a novel antiviral immunomodulatory pathway controlled by interferon-beta (IFN-beta) and mediated by immune-responsive gene 1 (IRG1) and itaconic acid, its product. Acanthamoeba polyphaga Mimivirus (APMV) was isolated from amoebae in a hospital while investigating a pneumonia outbreak. Mimivirus ubiquity and role as protist pathogens are well understood, and its putative status as a human pathogen has been gaining strength as more evidence is being found. The study of APMV and human cells interaction revealed that the virus is able to evade the IFN system by inhibiting the regulation of interferon-stimulated genes, suggesting that the virus and humans have had host-pathogen interactions. It also has shown that the virus is capable of growing on IFN-alpha 2, but not on IFN-beta-treated cells, hinting at an exclusive IFN-beta antiviral pathway. Our hypothesis based on preliminary data and published articles is that IFN-beta preferentially upregulates IRG1 in human macrophagic cells, which in turn produces itaconic acid. This metabolite links metabolism to antiviral activity by inactivating the virus, in a novel immunomodulatory pathway relevant for APMV infections and probably to other infectious diseases as well.

Kawasaki disease (KD) is an acute systemic vasculitis presenting as an infantile febrile disease. In Japan, the widespread cedar plantation commenced in 1945 has been correlated with the increased incidences of both KD and allergic rhinitis (pollinosis) since the early 1960s. We previously showed that KD was a pollen-induced, delayed-type hypersensitivity that displays biphasic peaks in both summer and winter. KD incidences decrease suddenly around February, particularly after influenza epidemics. Here we investigated the reason for a drastic decrease in KD onsets directly before spring pollen release following rapid increase after autumn pollen release leading to the biphasic pattern. We separately analyzed weekly incidences of KD and influenza in Tokyo (1987-2010) and Kanagawa (1991-2002). Repeated measures for the analysis of variance followed by Bonferroni's multiple comparison tests were performed to compare KD incidence over 3 consecutive weeks, including the weeks when the mean KD prevalence showed the steepest decrease. Next, the week with peak influenza incidence was reset for each year. KD incidence over 3 consecutive weeks, including the new origin week (adjusted week 0), was similarly analyzed. In Tokyo and Kanagawa, KD incidence significantly decreased only after resetting the influenza peak time. These findings suggested that influenza epidemics suppressed KD onset.

Background: The objective of this study was to evaluate monthly intramuscular adrenocorticotropic hormone (ACTH) gel versus intravenous methylprednisolone (IVMP) add-on therapy to interferon β for breakthrough disease in patients with relapsing forms of multiple sclerosis. Methods: This was a prospective, open-label, examiner-blinded, 15-month pilot study evaluating patients with Expanded Disability Status Scale (EDSS) score 3.0–6.5 and at least one clinical relapse or new T2 or gadolinium-enhanced lesion in the previous year. Twenty-three patients were randomized to ACTH ( n = 12) or IVMP ( n = 11) and completed the study. The primary outcome measure was the cumulative number of relapses. Secondary outcomes included EDSS, Mental Health Inventory (MHI), plasma cytokines, MS Functional Composite (MSFC), Quality-of-Life (MS-QOL) score, bone mineral density (BMD), and new or worsened psychiatric symptoms per month. Brain magnetic resonance imaging was analyzed post hoc. This was a preliminary and small-scale study. Results: Relapse rates differed significantly [ACTH 0.08, 95% confidence interval (CI) 0.01–0.54 versus IVMP 0.80, 95% CI 0.36–1.75; rate ratio, IVMP versus ACTH: 9.56, 95% CI 1.23–74.6; p = 0.03]. ACTH improved ( p = 0.03) MHI (slope 0.95 ± 0.38 points/month; p = 0.02 versus slope −0.38 ± 0.43 points/month; p = 0.39). On-study decreases (all p < 0.05) in eight cytokine levels occurred only in the ACTH group. However, on-study EDSS, MSFC, MS-QOL, BMD, and MRI lesion changes were not significant between groups. Psychiatric symptoms per patient were greater with IVMP than ACTH (0.55, 95% CI 0.12–2.6 versus 0; p < 0.0001). Other common adverse events were insomnia and urinary tract infections (IVMP, seven events each) and fatigue or flu symptoms (ACTH, five events each). Conclusions: This study provided class II evidence that ACTH produced better examiner-assessed cumulative rates of relapses per patient than IVMP in the adjunctive treatment of breakthrough disease in multiple sclerosis.

Fingolimod is an oral sphingosine-1-phosphate receptor modulator approved for the treatment of active relapsing-remitting multiple sclerosis (RRMS). Recent reports have highlighted the possible risk of rebound disease activity after withdrawal of fingolimod. We describe a case of a patient who developed severe tumefactive lesions on discontinuing fingolimod treatment. A 32-year-old woman with RRMS escalated treatment from interferon β to fingolimod due to ongoing relapses. She developed side effects on fingolimod including persistent lymphopenia (

Stressful events can induce immunological alterations and could possibly impact the course of multiple sclerosis (MS)1 ,2 Thus stress management may be important to prevent relapse and reduce brain lesions in MS.3 ,4 Although major natural disasters cause severe physical and psychological stresses, few studies have analysed the influence of such natural disasters on MS and neuromyelitis optica spectrum disorders (NMOSD). The Great East Japan Earthquake that measured magnitude 9.0 and triggered tsunami on 11 March 2011, devastated the Pacific coastal regions of Eastern Japan, especially the Iwate, Miyagi and Fukushima prefectures. Numerous aftershocks followed. Meltdown at the Fukushima No.1 nuclear power plant also resulted from the disaster. A total of 18 000 people died or are still unaccounted for, and half of them were Miyagi residents. About 320 000 people had to be evacuated at least temporarily in Miyagi prefecture alone. We studied the impact of the disaster in people with MS and NMOSD in Sendai City, the Miyagi prefecture's capital with a population of one million. Two hundred and three patients (140 with MS fulfilling the 2010 McDonald Criteria and 63 with aquaporin 4-IgG-positive NMOSD fulfilling the 2015 International Consensus Diagnostic Criteria) seen at Tohoku University Hospital and three other major hospitals in Sendai, Japan, enrolled in the study (age: 42.8±11.9 in MS, 54.0±13.4 in NMOSD, disease duration: 12.7±9.9 in MS, 13.0±10.7 in NMOSD, annualised relapse rate: 0.68±0.57 in MS, 0.62±0.58 in NMOSD in the previous year of the disaster). They accounted for 62% of the patients registered in Miyagi prefecture for the national registry of MS and NMOSD. We surveyed the survival, living conditions including refuge, continuation of therapy (interferon β for MS and oral corticosteroid and/or immunosuppressants for NMOSD), available healthcare services by a self-developed questionnaire and stress by the Visual Analogue Scale (VAS), …

Background: Interleukin-17 (IL-17), which is secreted by Th17 cells, is a proinflammatory cytokine that is implicated in the pathogenesis of multiple sclerosis (MS) and plays a role in nonresponse of MS patients to interferon-β (IFN-β) therapy. Objectives: The purpose of this study was to establish a correlation between nonresponders (NR) and IL-17A serum titers and binding antibodies (BAbs) to IFN-β, as well as to find a correlation between IL-17A serum levels and other features of MS patients. Methods: Our prospective study included 72 inactive relapsing–remitting multiple sclerosis (RRMS) patients that had been treated for at least 18 months with IFN-β and 15 healthy subjects. We determined the serum levels of IL-17A and of BAbs. IL-17A levels were considered elevated (IL-17A+) if the recorded value was greater than 1.6 pg/ml. Results: Twenty-seven patients (37.5%) were NR and had a significantly higher serum IL-17A level compared to the responders group. Nineteen patients (26.4%) were IL-17A+ and had had a significantly higher number of relapses in the previous year and a higher Expanded Disability Status Score. The majority of IL-17A+ patients were NR and had a shorter MS duration. Conclusions: RRMS patients with high serum IL-17A levels do not respond well to IFN-β therapy and have shorter MS duration compared to patients with low IL-17A levels. This response is not influenced by the presence of BAbs.

Disease-modifying treatments for multiple sclerosis (MS) have now been available for almost 20 years. Interferon β (IFN-β) products and glatiramer acetate (GA) were the first available options and are now considered first-line agents for the treatment of MS. These medications have several years of favorable safety data, but are not effective in completely controlling disease activity in all patients. Alternate medications with increased efficacy have been developed and identified; however, these newer medications have known or potential safety concerns which have prompted clinicians to view them as second-line agents. Highly efficacious and safe medications are continuously being searched for and developed; however, time is needed to establish the long-term safety of any new therapeutic agent. MS practitioners are faced with the clinical dilemma of treating patients with very safe modestly effective medications or using more efficacious and potentially riskier agents. The risk–benefit profile of every medication will have to be weighed carefully and clinicians will need to gage the risk tolerance of each patient in order to tailor treatment. This review will summarize benefits and risks of recently approved therapies in MS and will provide a perspective view on the placement of these medications within the MS treatment algorithm in the near future.

OBJECTIVE: This study investigated use of mesenchymal stem cells (MSCs) genetically engineered to produce interferon-β (IFN-β) as a gene delivery system to treat prostate cancer in an animal model. METHODS: To measure the effects on tumour cell growth in vitro, IFN-β-producing MSCs (IFN-β-MSCs) were co-cultured with the prostate cancer cell line PC-3. The in vivo migration of intravenously injected fluorescently-labelled MSCs to healthy tissues and PC-3 xenograft tumours grown in immunodeficient mice was determined by fluorescence microscopy. The antitumour effects of intravenously injected IFN-β-MSCs on PC-3 xenograft growth and animal survival were also investigated. RESULTS: IFN-β-MSCs inhibited the growth of PC-3 cells in vitro. Fluorescently-labelled MSCs migrated to the margins and centre of tumour masses but not into healthy tissues. Intravenously injected IFN-β-MSCs significantly reduced PC-3 xenograft tumour weight and increased animal survival compared with controls. CONCLUSIONS: Intravenously injected IFN-β-MSCs inhibited PC-3 xenograft growth. This could be an effective gene delivery system for treatment of solid human tumours.

症例は25歳 女性．ダウン症候群と診断され，幼少期に心室中隔欠損症術を受けた際に輸血あり．20歳時にC型肝炎ウイルス（HCV）の感染を指摘された．肝機能異常あり，HCV genotype 2a，ウイルス量3.2 logIU/ml であった．インターフェロン適応ありと判断し，ペグインターフェロンα-2aを投与した．しかし白血球減少症を来し，以後インターフェロンβに切り替え投与した．その後合併症なく治療を完遂し，HCV-RNA陰性化およびトランスアミナーゼ正常化が得られた．ダウン症候群合併C型肝炎では，インターフェロンによるウイルス学的著効が得られる症例は稀とされている．また精神的な副作用を予測し難いため，治療をためらう事例も多い．しかし近年，ダウン症候群の余命は延長し，C型肝炎合併例では肝炎が予後を左右する場合もある．本症例は，ウイルス側および宿主側に著効し易い素因を持ち，かつインターフェロンβによる治療完遂が可能であった．この様な症例では積極的な抗ウイルス療法を考慮する必要がある．

Background: Radiotherapy is an established treatment for malignant localised disease. Pancreatic cancer however seems relatively insensitive to this form of therapy. Methods: Pancreatic cancer cell lines MiaPaca-2 and Panc-1 were pre-treated with 3000 IU/ml IFN alpha or 100 IU/ml IFN beta followed by 0, 2, 4, or 6 Gray (Gy) irradiation. Colony forming assay was used to assess the effects on cellgrowth. To measure the surviving fraction at the clinically relevant dose of 2 Gy (SF2), cells were pre-treated with 1000-10.000 IU/ml IFN alpha or 50-500 IU/ml IFN beta followed by 2 Gy irradiation. Results: The plating efficiency was 49% for MiaPaca-2 and 22% for Panc-1. MiaPaca-2 was more radiosensitive than Panc-1 (surviving fraction of 0.28 versus 0.50 at 4 Gray). The SF2 of MiaPaca-2 was 0.77 while the SF2 of Panc-1 was 0.70. The SF2 significantly decreased after pretreatment with IFN alpha 1000 IU/ml (p < 0.001) and IFN beta 100 IU/ml (p < 0.001) in MiaPaca-2 and with IFN alpha 5000 IU/ml (p < 0.001) and IFN beta 100 IU/ml (p < 0.01) in Panc-1. The sensitising enhancement ratio (SER) for IFN alpha 3000 IU/ml was 2.15 in MiaPaca-2 and 1.90 in Panc-1. For IFN beta 100 IU/ml the SER was 1.72 for in MiaPaca-2 and 1.51 in Panc-1. Conclusions: Type I interferons have radiosensitising effects in pancreatic cancer cell lines. This radiosensitising property might lead to an improved response to treatment in pancreatic cancer. Interferon beta is the most promising drug due to its effect in clinically obtainable doses. (C) 2011 Elsevier Ltd. All rights reserved.

Patti F, Nicoletti A, Pappalardo A, Castiglione A, Lo Fermo S, Messina S, D’Amico E, Cimino V, Zappia M. Frequency and severity of headache is worsened by Interferon-β therapy in patients with multiple sclerosis. Acta Neurol Scand: 2012: 125: 91–95. © 2011 John Wiley & Sons A/S. Background – The relationship between multiple sclerosis (MS) and headache (HA) is not well known. It was reported that interferon-beta (IFNβ) could induce or worsen HA. Objective – To evaluate the impact of IFNβ treatment on HA and the relationship between HA and the various commercial preparations of IFNβ in mildly disabled patients with MS. Methods – A specific questionnaire was administered to 357 relapsing-remitting MS patients. Characteristics of HAs were considered, including the temporal relationships with IFNβ administration. Results – One hundred and seventeen patients were treated with weekly intramuscular injections of interferon IFNβ-1a (Avonex®), 84 with subcutaneous injections of IFNβ-1b (Betaferon®) every other day, 48 and 108 with three times weekly subcutaneous injections of IFNβ-1a (Rebif®) 22 mcg or IFNβ-1a (Rebif®) 44 mcg, respectively. Three hundred and fourteen patients were affected by HA, and among them, 219 patients suffered of pre-existing HA. In this latter group, 121 subjects (55%) noted a worsening of their HA after starting IFNβ therapy; this was more frequently reported by patients treated with Avonex® and Rebif® 44. Ninety-five patients experienced new HA. Conclusion – IFNβ treatment could worsen HA in patients with pre-existing HA or cause the appearance of new HA. Among different IFNβ preparations, Rebif® 44 and Avonex® seemed to be more cephalalgic than the other drugs.

Many patients with multiple sclerosis relapse or experience continued disease progression despite disease-modifying therapies, such as interferon β. This Review explores responses to interferon β treatment in patients with multiple sclerosis, discusses early identification of nonresponders, and describes a practical approach for incorporating clinical data, biological markers and MRI measures of disease activity into the management of these patients. Many patients with multiple sclerosis (MS) experience clinical relapses or progression of disability, or exhibit evidence of disease activity on MRI, despite the use of disease-modifying therapy. Although evidence clearly supports the efficacy of interferon β (IFN-β) in treating MS, the factors that determine the response to this drug in individual patients have not been fully elucidated. As more treatment options become available, the early identification of factors that can affect or predict the efficacy of agents in individual patients is important, because such knowledge facilitates early switching of treatment. Despite years of research and numerous reports of promising therapy markers for MS, few markers have emerged as clinically useful. Several studies suggest, however, that development of MRI lesions within 6–24 months after the initiation of IFN-β treatment predicts an unfavorable response. In addition, persistently high titers of neutralizing antibodies diminish or abrogate the therapeutic effects of IFN-β, and help to identify patients who do not respond. This Review highlights advances in research on the response to IFN-β in patients with MS and aims to provide a practical approach for incorporating clinical data, biological markers and MRI measures of disease activity into their therapeutic management.

Background and Aims: Double-filtration plasmapheresis (DFPP) together with interferon (IFN) administration produces a substantial reduction in the viral load during the early stages of treatment. Methods: Based on their responses to previous pegylated IFN and ribavirin (PEG-IFN/RBV) therapy, 20 patients were divided into null virological response (NVR; n = 12) and relapse (n = 8) groups. DFPP was used in combination with IFN-β/RBV with subsequent administration of PEG-IFN-α2a/RBV therapy (DFPP + IFN-β/RBV then PEG-IFN/RBV). Early viral dynamics was assessed, focusing especially on complete early virological response (cEVR) associated with sustained virological response. Additionally, the interleukin 28B gene, the IFN/RBV resistance-determining region, the IFN sensitivity-determining region and the core regions were analyzed. Results: Rapid virological response was achieved in 0% (0/12) of NVR and in 75% (6/8) of relapse patients, with a significant difference between the two groups (p = 0.001). Similarly, cEVR was achieved in 8% (1/12) of NVR and in 88% (7/8) of relapse patients, with a significant difference between the two groups (p = 0.037). By multivariate logistic regression analysis, interleukin-28B major was a significant determiner of cEVR (odds ratio = 24.19, p = 0.037). Conclusion: DFPP + IFN-β/RBV then PEG-IFN/RBV therapy is indicated more for relapse than for NVR patients.

Interferon-β is the first-line treatment to inhibit neuroinflammation of the central nervous system in patients with relapsing–remitting multiple sclerosis. The mechanism of action of interferon-β is complex. The study of Doi et al. in the present issue provides a new mechanism of interferon-β function in multiple sclerosis patients. Recent investigations of Th17 and Th9 cells in multiple sclerosis are summarized.

Background: As new biomarkers are validated and their significance in the natural history of specific diseases is established, these technologies can be rapidly transferred to clinical application. Since it has been shown that a single post-interferon-β (IFNβ) injection measurement of myxovirus-protein-A (MxA) mRNA correlates with IFNβ bioactivity in IFNβ treated patients with multiple sclerosis (MS), we had previously validated an assay for its quantification. Methods: We introduced a real-time PCR relative quantification assay into routine clinical practice and measured MxA mRNA expression in 564 samples from 500 unselected IFNβ treated MS patients over a 4-year period. Results: We confirmed that the assay is reproducible over time, and found that the percentage of patients lacking MxA mRNA induction is comparable to that described in studies performed worldwide after patient selection by pre-screening for the presence of anti-IFNβ antibodies. Conclusions: In view of its simplicity and reproducibility, this MxA assay is an alternative to anti-IFNβ antibody determinations for use in routine clinical practice. Clin Chem Lab Med 2010;48:1235–8.