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A 48-year-old woman who had been receiving long-term interferon-β for 8 years for multiple sclerosis developed drug-induced World Health Organization group I pulmonary arterial hypertension. Triple therapy for pulmonary arterial hypertension and suspension of interferon-β led to improvement from a high-risk to low-risk state and improvement in exercise hemodynamics, including vascular distensibility, and right ventricle–pulmonary artery coupling. (Level of Difficulty: Advanced.), Central Illustration

Several predictors of non-response to interferon-β (IFN-β) treatment have been proposed. The aim of the study was to identify metabolite changes in the normal-appearing cortex of the posterior cingulate gyrus (PCG) using MRS (magnetic resonance spectroscopy) and to investigate their usefulness in prognosis of NEDA (no evidence of disease activity) in the 3-year follow-up and in monitoring treatment effects during IFN-β therapy in the parallel period of time in multiple sclerosis (MS) patients. Forty-one relapsing-remitting MS patients and 41 sex- and age-matched healthy subjects underwent routine MRI protocol with MRS sequence with the use of a 1.5 T magnet. A single voxel size of 2x2x2cm was inserted in the cortex of PCG region. Associations between baseline metabolic ratios, conventional MRI findings, demographic and clinical factors, and NEDA status were evaluated using logistic, Cox, and multinomial logistic regression models. MS patients in the initial scan showed a statistically significant decline in NAA/Cr ratio (p 0.0001) and an increase in Cho/Cr ratio (p = 0.016) compared to the control group. None of the MRS parameters predicted NEDA maintenance or the time to loss of NEDA. In treatment monitoring only an improvement in the combination of NAA/Cr + Cho/Cr ratio between the 1st and 2nd year of treatment was connected with a 6.27-fold chance (p = 0.025) of having simultaneous NEDA maintenance. To conclude, metabolite alterations in the PCG region did not predict NEDA maintenance, but they seem to be useful in treatment monitoring.

Predictors of multiple sclerosis (MS) activity during disease-modifying treatment are being extensively investigated. The aim of this study was to assess the prognosis of NEDA (no evidence of disease activity) status during IFN-β (interferon-β) treatment, using apparent diffusion coefficient (ADC) measurements obtained at initial MRI (magnetic resonance imaging). In 87 MS patients treated with IFN-β, ADC values were calculated for 13 regions of normal-appearing white and grey matter (NAWM, NAGM) based on MRI performed with a 1.5 T magnet before (MS0, n = 45) or after one year of therapy (MS1, n = 42). Associations were evaluated between ADC, conventional MRI findings, demographic and clinical factors and NEDA status within the following 3 years using logistic, Cox and multinomial logistic regression models. NEDA rates in the MS0 group were 64.4%, 46.5% and 33.3% after the 1st, 2nd and 3rd year of treatment, respectively and in MS1 patients 71.4% and 48.7% for the periods 1st–2nd and 1st–3rd years of treatment, respectively. ADC values in the NAWM regions contributed to loss of NEDA and its clinical and radiological components, with a 1–3% increase in the risk of NEDA loss (p = 0.0001–0.0489) in both groups. ADC measurements may have an additional prognostic value with regard to NEDA status.

Interferon (IFN)-β has been classified as a drug that is possibly associated with development of pulmonary arterial hypertension (PAH), a devastating disease that can lead to right heart failure and premature death [1]., The possible causal relationship between interferon-β exposure and pulmonary arterial hypertension development requires close follow-up of patients on treatment with interferon-β http://bit.ly/2OPGSVP

Background In systemic lupus erythematosus (SLE), detection of interferon-β (IFNβ) in B cells was found to be most prominent in patients with high anti-Smith (Sm) and renal disease, but a mechanistic connection was not clear. The objective of the present study is to determine the association of IFNβ in peripheral blood naïve B cells with the histopathological features of lupus nephritis (LN). Methods The percentage of IFNβ+ cells in IgD+CD27− naïve CD19+ B cells (B cell IFNβ) among peripheral blood mononuclear cells (PBMCs) from 80 SLE patients were analyzed using flow cytometry. Serological and clinical data were collected. The correlations of B cell IFNβ with LN classification and with histopathological findings (light, electron, and immunofluorescence [IF] microscopic analyses for deposition of IgM, IgG, IgA, C1q, and C3) were determined in 23 available biopsy specimens. Results B cell IFNβ is positively associated with anti-Sm (p = 0.001), anti-DNA (p = 0.013), and LN (p < 0.001) but was negatively associated with oral/nasal ulcer (p = 0.003) and photosensitivity (p = 0.045). B cell IFNβ positively correlated with immune complex (IC) deposit in the glomerular basement membrane (GBM) (p = 0.002) but not in the mesangial (p = 0.107) or tubular region (p = 0.313). Patients with high B cell IFNβ had statistically increased development of the proliferative LN (Classes III, IV and/or V), compared to patients with low B cell IFNβ (p p = 0.023), chronic glomerular lesions indicated by segmental sclerosis (p = 0.033), and a membranous pattern of renal damage indicated by spike/holes (p = 0.015). Conclusion B cell IFNβ correlates with history of severe LN, glomerular basement membrane (GBM) IC deposition, and anatomical features of both active and chronic glomerular lesions.

Interferons (IFNs) are cytokines secreted by infected cells that can interfere with viral replication. Besides activating antiviral defenses, type I IFNs also exhibit diverse biological functions. IFN-β has been shown to have a protective effect against neurotoxic and inflammatory insults on neurons. Therefore, we aimed to investigate the possible role of IFN-β in reducing mechanical allodynia caused by Complete Freund’s Adjuvant (CFA) injection in rats. We assessed the antinociceptive effect of intrathecal IFN-β in naïve rats and the rats with CFA–induced inflammatory pain. After the behavioral test, the spinal cords of the rats were harvested for western blot and immunohistochemical double staining. We found that intrathecal administration of IFN-β in naïve rats can significantly increase the paw withdrawal threshold and paw withdrawal latency. Further, the intrathecal injection of a neutralizing IFN-β antibody can reduce the paw withdrawal threshold and paw withdrawal latency, suggesting that IFN-β is produced in the spinal cord in normal conditions and serves as a tonic inhibitor of pain. In addition, intrathecal injection of IFN-β at dosages from 1000 U to 10000 U demonstrates a significant transient dose-dependent inhibition of CFA-induced inflammatory pain. This analgesic effect is reversed by intrathecal naloxone, suggesting that IFN-β produces an analgesic effect through central opioid receptor-mediated signaling. Increased expression of phospho-µ-opioid receptors after IFN-β injection was observed on western blot, and immunohistochemical staining showed that µ-opioids co-localized with IFN-α/βR in the dorsal horn of the spinal cord. The findings of this study demonstrate that the analgesic effect of IFN-β is through µ-opioid receptors activation in spial cord.

Background The spectrum of interferon-β (IFN-β)-associated nephropathy remains poorly described and the potential features of this uncommon association remain to be determined. Methods In this study we retrospectively analysed the clinical, laboratory, histological and therapeutic data of patients with biopsy-proven renal disease in a context of IFN-β treatment administered for at least 6 months. Results Eighteen patients (13 women, median age 48 years) with biopsy-proven renal disease occurring during IFN-β therapy were included. The median exposure to IFN-β (14 patients were treated with IFN-β1a and 4 patients with IFN-β1b) was 67 months (range 23–165 months). The clinical presentation consists in hypertension (HT; 83%), malignant HT (44%), proteinuria (protU) >1 g/g (94%), reduced renal function (78%), biological hallmark suggesting thrombotic microangiopathy (TMA; 61%), oedematous syndrome (17%) or nephritic syndrome (11%). The pathological findings included typical features of isolated TMAs in 11 cases, isolated focal segmental glomerulosclerosis (FSGS) lesions in 2 cases and 5 cases with concomitant TMA and FSGS lesions. An exploration of the alternative complement pathway performed in 10 cases (63%) did not identify mutations in genes that regulate the complement system. The statistical analysis highlighted that the occurrence of IFN-β-associated TMA was significantly associated with Rebif, with a weekly dose >50 µg and with multiple weekly injections. In all cases, IFN-β therapy was discontinued. Patients with TMA lesions received other therapies, including corticosteroids (44%), eculizumab (13%) and plasma exchanges (25%). At the end of a 36-month median follow-up, persistent HT and persistent protU were observed in 61% and 22% of patients, respectively. Estimated glomerular filtration rate, Graphical Abstract Graphical Abstract

Background: Multiple Sclerosis (MS) is one of the most common causes of neurological disability in young and middle-aged adults. Patients with MS face many challenges, both physical and emotional, and see an overall reduction in their autonomy. There is no definitive treatment for MS, though Disease Modifying Drugs (DMDs) have proved effective in reducing the frequency and severity of relapses. Unfortunately, long-term adherence to these therapies is a significant challenge due to practical difficulties as well as a general distrust towards the drugs . Objective: This study follows an original research carried out in 2008. In the first study, patients answered questions on their clinical history and expressed their judgment on the pharmacological treatment, their perceived effectiveness and factors that may undermine compliance. They have been recalled after two years to verify if the reported symptoms have changed and to assess how their knowledge of the disease and “acceptance” of the treatment have been modified. Methods: In spite of the relatively high number of patients participating in the first study (141 patients followed at a single neurological centre), only 16 patients have completed the questionnaire for the long-term survey. A detailed descriptive analysis has been carried out, as well as a pairwise correlation analysis. Results and Conclusions: The interviews carried out gave an insight into how patients’ behavior may have changed over time. Compliance rate is different in newly-diagnosed patients and long-term patients; the latter are more likely to be compliant, given their personal experience with the disease. Communications with neurologists and health personnel should aim at forming therapeutic alliances with patients and detecting their preferences for a qualitatively adequate assistance throughout their illness.

Objective: To evaluate the value of combined interferon β (IFN-β) and platelet (PLT) detection for Kawasaki disease (KD) identification.Methods: Forty-four children who were newly diagnosed with KD were selected as the KD group. They were divided into acute phase of KD and subacute phase of KD. They were also separated into groups with and without coronary artery disease (CAD) (CAD+ and CAD–, respectively). Meanwhile, 44 children hospitalized with febrile disease and 44 healthy children were selected as a febrile control group and normal control group, whom were attended to at Children's Hospital of Soochow University at the same time. We detected the concentration of IFN-β and PLT of peripheral blood serum for all three groups and analyzed the difference.Results: At acute and subacute phases of KD, both IFN-β and PLT are higher than both the febrile control group and healthy control group, especially at subacute phase; the difference between groups was statistically significant, P < 0.05. Receiver operating characteristic (ROC) curve showed that the areas under the ROC curve (AUCs) of IFN-β and PLT at acute phase of KD were 0.81 and 0.72, respectively; the sensitivity and specificity were 97.22 and 63.64%, and 57.89 and 73.86%, respectively. The AUCs of combined IFN-β and PLT were 0.81 at acute phase and 0.96 at subacute phase of KD, with sensitivity and specificity of 97.22 and 55.26%, and 86.36 and 100%, respectively. The cutoff value of combined IFN-β and PLT detection was IFN-β = 3.51 pg/ml and PLT = 303 × 109/L at acute phase of KD, IFN-β = 4.21 pg/ml and PLT = 368 × 109/L at subacute phase from plot vs. criterion values. However, there are no significant differences between the CAD– group and the CAD+ group for combined IFN-β and PLT, both P > 0.5, neither at acute nor at subacute phase of KD.Conclusion: Combined IFN-β and PLT detection is an efficient biomarker for KD identification. The cutoff values are IFN-β = 3.51 pg/ml and PLT = 303 × 109/L at acute phase of KD and IFN-β = 4.21 pg/ml and PLT = 368 × 109/L at subacute phase.

COVID-19 exhibits a global health threat among the elderly and the population with underlying health conditions. During infection, the host's innate immune response acts as a frontline of defense by releasing cytokines such as type I interferon (IFN α and β) thereby initiating antiviral activity. However, this particular interferon response is interrupted by factors such as SARS-CoV-2 non-structural proteins, aging, diabetes, and germ-line errors eventually making the host more susceptible to illness. Therefore, enhancing the host's innate immune response by administering type I IFN could be an effective treatment against COVID-19. Here, we highlight the importance of innate immune response and the role of IFN β monotherapy against COVID-19.

[Background] Multiple sclerosis (MS) is a disease in which biomarker identification is fundamental to predict response to treatments and to deliver the optimal drug to patients. We previously found an association between rs7298096, a polymorphism upstream to the NINJ2 gene, and the 4-year response to interferon-β (IFNβ) treatment in MS patients., [Objectives] To analyse the association between rs7298096 and time to first relapse (TTFR) during IFNβ therapy in MS patients and to better investigate its functional role. [Methods] Survival analysis was applied in three MS cohorts from different countries (n = 1004). We also studied the role of the polymorphism on gene expression using GTEx portal and a luciferase assay. We interrogated GEO datasets to explore the relationship between NINJ2 expression, IFNβ and TTFR. [Results] Rs7298096AA patients show a shorter TTFR than rs7298096G-carriers (Pmeta-analysis = 3 × 10−4, hazard ratio = 1.41). Moreover, rs7298096AA is associated with a higher NINJ2 expression in blood (p = 7.0 × 10−6), which was confirmed in vitro (p = 0.009). Finally, NINJ2 expression is downregulated by IFNβ treatment and related to TTFR. [Conclusions] Rs7298096 could influence MS disease activity during IFNβ treatment by modulating NINJ2 expression in blood. The gene encodes for an adhesion molecule involved in inflammation and endothelial cells activation, supporting its role in MS.

Background Multiple sclerosis (MS) as a chronic autoimmune demyelinating disorder of the central nervous system has been associated with numerous genetic and environmental factors among them are functional variants within the angiotensin I converting enzyme (ACE) gene. Methods In the present study, we genotyped the rs4359 (C/T) and rs1799752 (Insertion (I)/Deletion (D)) of this gene in 391 MS patients and 380 age- and sex-matched controls. Results We found significant overrepresentation of the I allele of the rs1799752 in MS patients compared with healthy subjects (Adjusted P value = 0.03, OR (95% CI) = 1.28 (1.05–1.57). The same allele was associated with MS risk in co-dominant and dominant models (Adjusted P values of 0.007 and 0.002 respectively). The allele and genotype frequencies of the rs4359 were not significantly different between cases and controls. Moreover, the I allele of the rs1799752 was significantly overrepresented in MS patients who were irresponsive to IFN-β compared with healthy subjects (Adjusted P value = 0.04, OR (95% CI) = 1.57 (1.08–2.29)). The same allele was associated with irresponsiveness to IFN-β in dominant model (Adjusted P value = 0.02, OR (95% CI) = 2.32 (1.22–4.42)). Conclusion The present study provides further evidences for the role of ACE in MS risk or response of patients to IFN-β treatment.

Ischemic stroke is devastating and a major cause of morbidity and mortality worldwide. To date, only clot retrieval devices and/or intravenous tissue plasminogen activators (tPA) have been approved by the US‐FDA for the treatment of acute ischemic stroke. Therefore, there is an urgent need to develop an effective treatment for stroke that can have limited shortcomings and broad spectrum of applications. Interferon‐beta (IFN‐β), an endogenous cytokine and a key anti‐inflammatory agent, contributes toward obviating deleterious stroke outcomes. Therefore, exploring the role of IFN‐β may be a promising alternative approach for stroke intervention in the future. In the present review, we have discussed about IFN‐β along with its different mechanistic roles in ischemic stroke. Furthermore, therapeutic approaches targeting the inflammatory cascade with IFN‐β therapy that may be helpful in improving stroke outcome are also discussed.

Background Interferon-β has been approved for the treatment of relapsing-remitting (RR) multiple sclerosis (MS), whereas its efficacy in preventing long-term disability and conversion to secondary progressive (SP) MS is still debated. We aim to compare long-term clinical evolution of newly-diagnosed RRMS patients treated with different Interferon-β formulations. Methods 507 patients were included in the analysis and followed-up for 8.5 ± 3.9 years. 37.6% were treated with subcutaneous Interferon-β1a 44mcg, 33.4% with intramuscular Interferon-β1a 30mcg, and 29.0% with subcutaneous Interferon-β1b 250mcg. Relapse occurrence, 1-point EDSS progression, reaching of EDSS 4.0 and conversion to SP were recorded as outcome measures. To reduce the selection bias, we calculated the propensity score of receiving the specific treatment considering age (32.7 ± 8.3 years), gender (female 63.1%), disease duration (2.7 ± 2.8 years), and baseline EDSS (1.5, range 1.0–3.5). Propensity score and covariates (age, gender, disease duration and EDSS) were included in the statistical models. Results At Cox regression models, the reaching of EDSS 4.0 was not-significantly higher for Interferon-β1b 250mcg (HR = 1.207; p=0.063) and for Interferon-β1a 30mcg (HR = 1.363; p=0.095), when compared with Interferon-β1a 44mcg. The rate of SP conversion was higher for Interferon-β1b 250mcg (HR = 2.054; p=0.042), and not-significantly higher for Interferon-β1a 30mcg (HR = 1.884; p=0.081), when compared with Interferon-β1a 44mcg. Conclusions Patients treated with Interferon-β1a 44mcg presented with a marginally reduced risk of disability accrual in the long-term, when compared with Interferon-β1b 250mcg and, at least in part, with Interferon-β1a 30mcg. Formulation, frequency of administration and dose of Interferon-β might affect the long-term clinical evolution of RRMS.

Objective: To investigate the association between activity during interferon-beta (IFNβ) therapy and disability outcomes in patients with relapsing–remitting multiple sclerosis (RRMS). Methods: A longitudinal study based on two previously described cohorts of IFNβ-treated RRMS patients was conducted. Patients were classified according to clinical activity after 2 years (clinical cohort) or to clinical and radiological activity after 1 year (magnetic resonance imaging (MRI) cohort). Multivariate Cox models were calculated for early disease activity predicting long-term disability. Results: A total of 516 patients from two different cohorts were included in the analyses. Persistent clinical disease activity during the first 2 years of therapy predicted severe long-term disability (clinical cohort). In the MRI cohort, modified Rio score and no or minimal evidence of disease activity (NEDA/MEDA) did not identify patients with risk of Expanded Disability Status Scale (EDSS) worsening. However, a Rio score ≥ 2 (hazard ratio (HR): 3.3, 95% confidence interval (CI): 1.7–6.4); ≥3 new T2 lesions (HR: 2.9, 95% CI: 1.5–5.6); or ≥2 Gd-enhancing lesions (HR: 2.1, 95% CI: 1.1–4) were able to identify patients with EDSS worsening. Conclusion: Although early activity during IFNβ therapy is associated with poor long-term outcomes, minimal degree of activity does not seem to be predictive of EDSS worsening over 6.7-year mean follow-up.

Background We previously reported that Vδ2+Vγ9+ γδ T cells were significantly decreased in multiple sclerosis (MS) patients without disease-modifying therapies (untreated MS) and were negatively correlated with Expanded Disability Status Scale (EDSS) scores, suggesting protective roles of Vδ2+Vγ9+ γδ T cells. Interferon-β (IFN-β) is one of the first-line disease-modifying drugs for MS. However, no previous studies have reported changes in γδ T cell subsets under IFN-β treatment. Therefore, we aimed to clarify the effects of the long-term usage of IFN-β on γδ T cell subsets in MS patients. Methods Comprehensive flow cytometric immunophenotyping was performed in 35 untreated MS and 21 MS patients on IFN-β for more than 2 years (IFN-β-treated MS) including eight super-responders fulfilling no evidence of disease activity criteria, and 44 healthy controls (HCs). Results The percentages of Vδ2+Vγ9+ cells in γδ T cells were significantly lower in untreated and IFN-β-treated MS patients than in HCs. By contrast, the percentages of Vδ1−Vδ2−Vγ9− cells in γδ T cells were markedly higher in IFN-β-treated MS patients than in HCs and untreated MS patients (both p < 0.001). A significant negative correlation between the percentages of Vδ2+Vγ9+ cells in γδ T cells and EDSS scores was confirmed in untreated MS but not evident in IFN-β-treated MS. Moreover, class-switched memory B cells were decreased in IFN-β-treated MS compared with HCs (p < 0.001) and untreated MS patients (p = 0.006). Interestingly, the percentages of Vδ1−Vδ2−Vγ9− cells in γδ T cells were negatively correlated with class-switched memory B cell percentages in all MS patients (r = − 0.369, p = 0.005), and the percentages of Vδ1−Vδ2−Vγ9− cells in Vδ1−Vδ2− γδ T cells were negatively correlated with EDSS scores only in IFN-β super-responders (r = − 0.976, p < 0.001). Conclusions The present study suggests that long-term usage of IFN-β increases Vδ1−Vδ2−Vγ9− γδ T cells, which are associated with a better outcome, especially in IFN-β super-responders. Thus, increased Vδ1−Vδ2−Vγ9− cells together with decreased class-switched memory B cells may contribute to the suppression of disease activity in MS patients under IFN-β treatment.

Viral infections are associated with increased incidence of severe sepsis. Particularly during the early stages, type I interferons (IFNs) are known mediators of detrimental effects. However, the functional role of early interferon &beta, (IFN&beta, ) and its cellular source during sepsis in the context of preexisting viral infections has not been defined. Using the colon ascendens stent peritonitis (CASP) model, we demonstrate that IFN&beta, &minus, /&minus, and type I IFN receptor (IFNAR1)&minus, mice were less susceptible to sepsis after pre-stimulation with the viral mimetic poly(I:C). Wild type (WT) mice treated with poly(I:C) exhibited altered expression patterns of TNF and IL-12p40 during CASP which were dependent on IFN&beta, or IFNAR1, suggesting a mechanism for the increased sepsis susceptibility of WT mice. Using a double cytokine reporter mouse model, we present novel data on the simultaneous expression of IFN&beta, and IL-12p40 on a single cell level during polymicrobial sepsis in vivo. Conventional dendritic cells (cDCs) were identified as primary source of IFN&beta, and the protective cytokine IL-12p40 after CASP surgery irrespective of poly(I:C) pre-stimulation. These data demonstrated that if polymicrobial sepsis is preceded by a viral infection, IFN&beta, and IL-12p40 are expressed by polyfunctional cDCs suggesting that these cells can play both detrimental and beneficial roles during sepsis development.

Tumor vasculature plays a central role in tumor progression, making it an attractive therapeutic target. In this study, we explore the antiangiogenic potential of our melanoma gene therapy approach combining interferon β (IFNβ) and p19Arf gene transfer. Since these proteins are modulators of tumor vasculature, we explore the impact of IFNβ and p19Arf gene transfer on murine endothelial cells (tEnd). Adenovirus-mediated gene transfer of p19Arf to tEnd cells inhibited proliferation, tube formation, migration, and led to increased expression of genes related to the p53 cell death pathway, yet IFNβ gene transfer had no significant impact on tEnd viability. Alternatively, tEnd cells were exposed to the factors generated by transduced B16 (mouse melanoma) cells using either coculture or conditioned medium. In either case, transduction of B16 cells with the IFNβ vector, whether alone or in combination with p19Arf, resulted in endothelial cell death. Strikingly, treatment of tEnd cells with recombinant IFNβ did not induce death, demonstrating that additional factors produced by B16 cells contributed to the demise of tEnd cells. In this work, we have shown that our melanoma gene therapy strategy produces desirable negative effects on endothelial cells, possibly correlating with antiangiogenic activity.

The hemolytic uremic syndrome (HUS) is one of the thrombotic microangiopathies and it consists of the triad of nonimmune microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. The atypical form of HUS (aHUS) is related to causative mutations in complement genes. Some conditions act as a trigger for aHUS in individuals that have a genetic background predisposing to complement activation. Interferon β is a recombinant-protein therapy approved to treat multiple sclerosis (MS), and can be a causative agent in the occurrence of HUS through anti-angiogenic activity. In this paper, we briefly review aHUS clinical and genetic characteristics. Furthermore, we present a case of a 48-year-old woman, diagnosed with MS and treated with INFβ-1b from 2008. In December 2015, she presented with asthenia and loss of muscular strength in the legs and she quickly developed aHUS. Our case suggests that INFβ is a possible triggering factor for HUS.

Highlights • As Add-on therapy, IFN β-1b shortened the time to clinical improvement. • IFN β-1b significantly increased the discharge rate at day 14. • IFN β-1b reduced overall 28-day mortality. • IFN β-1b related adverse effects were mild and did not cause treatment interruptions., In this study, efficacy and safety of interferon (IFN) β-1b in the treatment of patients with severe COVID-19 were evaluated. Among an open-label, randomized clinical trial, adult patients (≥18 years old) with severe COVID-19 were randomly assigned (1:1) to the IFN group or the control group. Patients in the IFN group received IFN β-1b (250 mcg subcutaneously every other day for two consecutive weeks) along with the national protocol medications while in the control group, patients received only the national protocol medications (lopinavir/ritonavir or atazanavir/ritonavir plus hydroxychloroquine for 7–10 days). The primary outcome of the study was time to clinical improvement. Secondary outcomes were in-hospital complications and 28-daymortality. Between April 20 and May 20, 2020, 80 patients were enrolled and finally 33 patients in each group completed the study. Time to clinical improvment in the IFN group was significantly shorter than the control group ([9(6–10) vs. 11(9–15) days respectively, p = 0.002, HR = 2.30; 95% CI: 1.33–3.39]). At day 14, the percentage of discharged patients was 78.79% and 54.55% in the IFN and control groups respectively (OR = 3.09; 95% CI: 1.05–9.11, p = 0.03). ICU admission rate in the control group was significantly higher than the IFN group (66.66% vs. 42.42%, p = 0.04). The duration of hospitalization and ICU stay were not significantly different between the groups All-cause 28-day mortality was 6.06% and 18.18% in the IFN and control groups respectively (p = 0.12). IFN β-1b was effective in shortening the time to clinical improvement without serious adverse events in patients with severe COVID-19. Furthermore, admission in ICU and need for invasive mechanical ventilation decreased following administration of IFN β-1b. Although 28-day mortality was lower in the IFN group, further randomized clinical trials with large sample size are needed for exact estimation of survival benefit of IFN β-1b.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.