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Abstract: Malignant atrophic papulosis/Köhlmeier-Degos disease was first described in 1941 by Köhlmeier in an anecdotal case report that described a young man who presented with extensive multiple intestinal perforations and a papular skin rash. Köhlmeier-Degos disease represents a unique vasculopathy targeting both the microvasculature and the arterial system. One of its most characteristic features is reflected by the discrete multifocal depressed porcelain lesions involving the skin and gastrointestinal tract. The pathological findings are striking and can be broadly categorized into those that are vascular in nature versus extravascular matrix production in the context of extensive extravascular hyaluronic acid and collagen deposition. A dynamic evolutionary morphology is observed not only clinically but also histologically. The microvascular alterations are particularly evident in the skin and are characterized by endothelial cell necrosis with subsequent endothelial cell detachment accompanied by intraluminal fibrin deposition, defining a thrombogenic microangiopathy that in later stage lesions is typically pauci-inflammatory. The arterial lesions are very distinctive and include significant neointimal proliferation with vascular luminal occlusion by amorphous plugs of collagen intimately admixed with platelets. Pathogenetically enhanced type I interferon signaling and endothelial cell injury mediated by the membranolytic attack complex (ie, C5b-9) are key in the evolution of the thrombotic microvascular and obliterative fibrosing arteriopathic changes. We describe a case of Köhlmeier-Degos disease that developed in the setting of tumor necrosis factor (TNF)-alpha inhibitor therapy with the drug golimumab. The clinical features, light microscopic findings, and a pathophysiologic paradigm based on the critical role of TNF-alpha in controlling the type I interferon response are discussed., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic (DA) neurons in the substantia nigra (SN). Microglia-mediated neuroinflammation has been largely considered one of main factors to the PD pathology. MicroRNA-218-5p (miR-218-5p) is a microRNA that plays a role in neurodevelopment and function, while its potential function in PD and neuroinflammation remains unclear., Methods: We explore the involvement of miR-218-5p in the PD in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model. The miR-218-5p agomir used for overexpression was delivered into the substantia nigra (SN) by bilateral stereotaxic infusions. The loss of dopaminergic (DA) neurons and microglial inflammation in the SN was determined using Western blotting and immunofluorescence. Motor function was assessed using the rotarod test. RNA sequencing (RNA-seq) was performed to explore the pathways regulated by miR-218-5p. The target genes of miR-218-5p were predicted using TargetScan and confirmed using dual luciferase reporter assays. The effects of miR-218-5p on microglial inflammation and related pathways were verified in murine microglia-like BV2 cells. To stimulate BV2 cells, SH-SY5Y cells were treated with 1-methyl-4-phenylpyridinium (MPP + ) and the conditioned media (CM) were collected., Results: MiR-218-5p expression was reduced in both the SN of MPTP-induced mice and MPP + -treated BV2 cells. MiR-218-5p overexpression significantly alleviated MPTP-induced microglial inflammation, loss of DA neurons, and motor dysfunction. RNA sequence and gene set enrichment analysis showed that type I interferon (IFN-I) pathways were upregulated in MPTP-induced mice, while this upregulation was reversed by miR-218-5p overexpression. A luciferase reporter assay verified that Ddx41 was a target gene of miR-218-5p. In vitro, miR-218-5p overexpression or Ddx41 knockdown inhibited the IFN-I response and expression of inflammatory cytokines in BV2 cells stimulated with MPP + -CM., Conclusions: MiR-218-5p suppresses microglia-mediated neuroinflammation and preserves DA neurons via Ddx41/IFN-I. Hence, miR-218-5p-Ddx41 is a promising therapeutic target for PD., (© 2024. The Author(s).)

Objectives: To characterise the efficacy and safety of anifrolumab in patients with systemic lupus erythematosus (SLE) according to interferon gene signature (IFNGS), demographic and clinical subgroups., Methods: We performed post hoc analyses of pooled data from the 52-week phase III TULIP-1/TULIP-2 placebo-controlled trials of intravenous anifrolumab in moderate-to-severe SLE. Outcomes were assessed in predefined subgroups: IFNGS (high/low), age, sex, body mass index, race, geographic region, age of onset, glucocorticoid use, disease activity and serological markers., Results: In pooled data, patients received anifrolumab 300 mg (360/726) or placebo (366/726); 82.6% were IFNGS-high. IFNGS-high patients had greater baseline disease activity and were more likely to have abnormal serological markers versus IFNGS-low patients. In the total population, a greater proportion of patients treated with anifrolumab versus placebo achieved British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response at week 52 (difference 16.6%; nominal p<0.001). BICLA response treatment differences with anifrolumab versus placebo were comparable to the total population across most predefined subgroups, including subgroups for baseline glucocorticoid dosage (<10/≥10 mg/day prednisone/equivalent) and for clinical disease activity (SLE Disease Activity Index 2000 score <10/≥10). Subgroups with larger treatment differences included IFNGS-high patients (18.2%), patients with abnormal baseline serological markers (23.1%) and Asian patients (29.2%). The safety profile of anifrolumab was similar across subgroups., Conclusions: Overall, this study supports the consistent efficacy and safety of anifrolumab across a range of patients with moderate-to-severe SLE. In a few subgroups, small sample sizes limited conclusions from being drawn regarding the treatment benefit with anifrolumab., Trial Registration Number: NCT02446912, NCT02446899., Competing Interests: Competing interests: EMV has received grant support from AstraZeneca, Roche/Genentech and Sandoz; received consulting fees from AstraZeneca, GlaxoSmithKline, Roche/Genentech, Aurinia and Sandoz; and was a speaker at a speaker bureau for Becton Dickinson and GlaxoSmithKline. JTM has received grant/research support from Bristol Myers Squibb and GlaxoSmithKline, and consultancy fees from AbbVie, Amgen, AstraZeneca, Aurinia, Bristol Myers Squibb, EMD Serono, GlaxoSmithKline, Janssen, Provention, Remegen and UCB. EFM has received grant support from, was a consultant for and was a speaker at a speaker bureau for AstraZeneca; received grant support and consulting fees from AbbVie, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssen, Merck Serono and UCB; received grant support from Bristol Myers Squibb and received consulting fees from Amgen, Biogen, CSL, Neovacs and Wolf Biotherapeutics. RAF has received grant/research support and consulting fees from AstraZeneca. INB is a National Institute for Health Research (NIHR) Senior Investigator Emeritus and is funded by the NIHR Manchester Biomedical Research Centre; has received grant/research support from Genzyme/Sanofi, GlaxoSmithKline, Roche and UCB; received consulting fees from Eli Lilly, GlaxoSmithKline, ILTOO, Merck Serono and UCB and was a speaker for AstraZeneca, GlaxoSmithKline and UCB. YT has received speaking fees and/or honoraria from AbbVie, Amgen, Astellas, AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Chugai, Eisai, Eli Lilly, Gilead, Mitsubishi-Tanabe and YL Biologics, and has received research grants from AbbVie, Asahi-Kasei, Chugai, Boehringer-Ingelheim, Corrona, Daiichi-Sankyo, Eisai, Kowa, Mitsubishi-Tanabe and Takeda. SM has received grant/research support and consulting fees from AstraZeneca. KCK has received consulting fees from AstraZeneca. RNK, KS, GA and RJ are employees of AstraZeneca., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Type I interferon (IFN-I) mediates tissue damage in a wide range of kidney disorders, directly affecting the biology and function of several renal cell types including podocytes, mesangial, endothelial, and parietal epithelial cells. Enhanced IFN-I signaling is observed in the context of viral infections, autoimmunity (e.g., systemic lupus erythematosus), and type 1 interferonopathies, rare monogenic disorders characterized by constitutive activation of the IFN-I pathway. All these IFN-I-related disorders can cause renal dysfunction and share pathogenic and histopathological features. Collapsing glomerulopathy, a histopathological lesion characterized by podocyte loss, collapse of the vascular tuft, and parietal epithelial cell proliferation, is commonly associated with viral infections, has been described in type 1 interferonopathies such as Aicardi-Goutières syndrome and stimulator of IFN genes-associated vasculopathy with onset in infancy, and can also be induced by recombinant IFN therapy. In all these conditions, podocytes and parietal epithelial cells seem to be the primary target of IFN-I-mediated damage. Additionally, immune-mediated glomerular injury is common to viral infections, systemic lupus erythematosus, and type 1 interferonopathies such as coatomer subunit-α syndrome (COPA) and DNASE1L3 deficiency, diseases in which IFN-I apparently promotes immune-mediated kidney injury. Finally, kidney pathology primarily characterized by vascular lesions (e.g., thrombotic microangiopathy and vasculitis) is a hallmark of type 1 interferonopathy adenosine deaminase 2 deficiency as well as of systemic lupus erythematosus, viral infections, and IFN therapy. Defining the nosology, pathogenic mechanisms, and histopathological patterns of IFN-I-related kidney disorders has diagnostic and therapeutic implications, especially considering the likely near-term availability of novel drugs targeting the IFN-I pathway., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

To compare lupus pathogenesis in disparate tissues, we analyzed gene expression profiles of human discoid lupus erythematosus (DLE) and lupus nephritis (LN). We found common increases in myeloid cell-defining gene sets and decreases in genes controlling glucose and lipid metabolism in lupus-affected skin and kidney. Regression models in DLE indicated increased glycolysis was correlated with keratinocyte, endothelial, and inflammatory cell transcripts, and decreased tricarboxylic (TCA) cycle genes were correlated with the keratinocyte signature. In LN, regression models demonstrated decreased glycolysis and TCA cycle genes were correlated with increased endothelial or decreased kidney cell transcripts, respectively. Less severe glomerular LN exhibited similar alterations in metabolism and tissue cell transcripts before monocyte/myeloid cell infiltration in some patients. Additionally, changes to mitochondrial and peroxisomal transcripts were associated with specific cells rather than global signal changes. Examination of murine LN gene expression demonstrated metabolic changes were not driven by acute exposure to type I interferon and could be restored after immunosuppression. Finally, expression of HAVCR1, a tubule damage marker, was negatively correlated with the TCA cycle signature in LN models. These results indicate that altered metabolic dysfunction is a common, reversible change in lupus-affected tissues and appears to reflect damage downstream of immunologic processes., (© 2021. The Author(s).)

Background: Ulcerative colitis (UC) is a chronic relapsing inflammatory disease that markedly elevates the risk of colon cancers and results in disability. The disrupted immune homeostasis has been recognized as a predominant player in the pathogenesis of UC. However, the overall remission rate of current therapies based on immunoregulation is still unsatisfactory. Si-Ni-San (SNS) has been found effective in relieving UC through thousands of years of clinical practice, yet the specific mechanisms of the protective effect of SNS were not fully elucidated., Purpose: We aim to investigate the therapeutic effects of SNS against the development of chronic colitis and the underlying mechanisms., Methods: We established a DSS-induced chronic experimental colitis mouse model to evaluate the effect of SNS. RNA-sequencing, bioinformatic analysis, and in vitro studies were performed to investigate the underlying mechanisms., Results: Our data demonstrated that SNS significantly ameliorated chronic experimental colitis via inhibiting the expression of genes associated with inflammatory responses. Interestingly, SNS significantly suppressed DSS-induced type I interferon (IFN) responses instead of directly downregulating the production of pro-inflammatory cytokines, such as Il-6. In vitro study further found that SNS selectively inhibited STING and RIG-I pathway-induced type I IFN responses by modulating TBK1- and IRF3-dependent signaling transduction. SNS also suppressed the expression of IFN-stimulated genes by directly inhibiting STAT1 and STAT2 activation., Conclusion: Our study not only provides novel insights into the pathogenic role of type I IFN responses in colitis but also suggested that SNS or bioactive compounds derived from SNS may serve as novel therapeutic strategies for the treatment of UC via interfering type I IFN-mediated inflammation., (Copyright © 2021. Published by Elsevier GmbH.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), is a recently emerged respiratory coronavirus that has infected >23 million people worldwide with >800,000 deaths. Few COVID-19 therapeutics are available, and the basis for severe infections is poorly understood. Here, we investigated properties of type I (β), II (γ), and III (λ1) interferons (IFNs), potent immune cytokines that are normally produced during infection and that upregulate IFN-stimulated gene (ISG) effectors to limit virus replication. IFNs are already in clinical trials to treat COVID-19. However, recent studies highlight the potential for IFNs to enhance expression of host angiotensin-converting enzyme 2 (ACE2), suggesting that IFN therapy or natural coinfections could exacerbate COVID-19 by upregulating this critical virus entry receptor. Using a cell line model, we found that beta interferon (IFN-β) strongly upregulated expression of canonical antiviral ISGs, as well as ACE2 at the mRNA and cell surface protein levels. Strikingly, IFN-λ1 upregulated antiviral ISGs, but ACE2 mRNA was only marginally elevated and did not lead to detectably increased ACE2 protein at the cell surface. IFN-γ induced the weakest ISG response but clearly enhanced surface expression of ACE2. Importantly, all IFN types inhibited SARS-CoV-2 replication in a dose-dependent manner, and IFN-β and IFN-λ1 exhibited potent antiviral activity in primary human bronchial epithelial cells. Our data imply that type-specific mechanisms or kinetics shape IFN-enhanced ACE2 transcript and cell surface levels but that the antiviral action of IFNs against SARS-CoV-2 counterbalances any proviral effects of ACE2 induction. These insights should aid in evaluating the benefits of specific IFNs, particularly IFN-λ, as repurposed therapeutics. IMPORTANCE Repurposing existing, clinically approved, antiviral drugs as COVID-19 therapeutics is a rapid way to help combat the SARS-CoV-2 pandemic. Interferons (IFNs) usually form part of the body's natural innate immune defenses against viruses, and they have been used with partial success to treat previous new viral threats, such as HIV, hepatitis C virus, and Ebola virus. Nevertheless, IFNs can have undesirable side effects, and recent reports indicate that IFNs upregulate the expression of host ACE2 (a critical entry receptor for SARS-CoV-2), raising the possibility that IFN treatments could exacerbate COVID-19. Here, we studied the antiviral- and ACE2-inducing properties of different IFN types in both a human lung cell line model and primary human bronchial epithelial cells. We observed differences between IFNs with respect to their induction of antiviral genes and abilities to enhance the cell surface expression of ACE2. Nevertheless, all the IFNs limited SARS-CoV-2 replication, suggesting that their antiviral actions can counterbalance increased ACE2., (Copyright © 2020 Busnadiego et al.)

Background: There is no vaccine or specific antiviral treatment for HCoVs infection. The use of type I interferons for coronavirus is still under great debate in clinical practice., Materials and Methods: A literature search of all relevant studies published on PubMed, Cochrane library, Web of Science database, Science Direct, Wanfang Data, and China National Knowledge Infrastructure (CNKI) until February 2020 was performed., Results: Of the 1081 identified articles, only 15 studies were included in the final analysis. Comorbidities and delay in diagnosis were significantly associated with case mortality. Type I interferons seem to improve respiratory distress, relieve lung abnormalities, present better saturation, reduce needs for supplemental oxygen support. Type I interferons seem to be well tolerated, and don't increase life threating adverse effects. Data on IFNs in HCoVs are limited, heterogenous and mainly observational., Conclusions: Current data do not allow making regarding robust commendations for the use of IFNs in HCoVs in general or in specific subtype. But we still recommend type I interferons serving as first-line antivirals in HCoVs infections within local protocols, and interferons may be adopted to the treatments of the SARS-CoV-2 as well. Well-designed large-scale prospective randomized control trials are greatly needed to provide more robust evidence on this topic., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020. Published by Elsevier B.V.)

Type I interferons (IFN) have long been recognised as mediators of innate immune defense mechanisms against viral threats. Robust evidence over the last 15 years revealed their significant role in the pathogenesis of systemic autoimmune diseases, including systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). Despite the progress, methods of detection, initial triggers, biological functions and clinical associations in the setting of autoimmunity remain to be fully clarified. As therapeutic options for SS are currently limited, neutralising specific targets of the type I IFN pathway seems a promising option. In this review we summarise the current evidence regarding the role of type I IFN in SS.

Type I interferons (IFNs) (IFN-α, IFN-β) and type III IFNs (IFN-λ) share many properties, including induction by viral infection, activation of shared signaling pathways, and transcriptional programs. However, recent discoveries have revealed context-specific functional differences. Here, we provide a comprehensive review of type I and type III IFN activities, highlighting shared and distinct features from molecular mechanisms through physiological responses. Beyond discussing canonical antiviral functions, we consider the adaptive immune priming, anti-tumor, and autoimmune functions of IFNs. We discuss a model wherein type III IFNs serve as a front-line defense that controls infection at epithelial barriers while minimizing damaging inflammatory responses, reserving the more potent type I IFN response for when local responses are insufficient. In this context, we discuss current therapeutic applications targeting these cytokine pathways and highlight gaps in understanding of the biology of type I and type III IFNs in health and disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In this brief review, the authors present a history of the different aspects of the scientific puzzle leading from pioneer animal studies and astute clinical experimental observations to a mature appreciation of the deleterious role of excess of a type I interferon in human pathology., (© 2019 médecine/sciences – Inserm.)

Many drugs have been reported to cause thrombotic microangiopathy (TMA), yet evidence supporting a direct association is often weak. In particular, TMA has been reported in association with recombinant type I interferon (IFN) therapies, with recent concern regarding the use of IFN in multiple sclerosis patients. However, a causal association has yet to be demonstrated. Here, we adopt a combined clinical and experimental approach to provide evidence of such an association between type I IFN and TMA. We show that the clinical phenotype of cases referred to a national center is uniformly consistent with a direct dose-dependent drug-induced TMA. We then show that dose-dependent microvascular disease is seen in a transgenic mouse model of IFN toxicity. This includes specific microvascular pathological changes seen in patient biopsies and is dependent on transcriptional activation of the IFN response through the type I interferon α/β receptor (IFNAR). Together our clinical and experimental findings provide evidence of a causal link between type I IFN and TMA. As such, recombinant type I IFN therapies should be stopped at the earliest stage in patients who develop this complication, with implications for risk mitigation., (© 2016 by The American Society of Hematology.)

The interferons (IFNs) are glycoproteins with strong antiviral activities that represent one of the first lines of host defense against invading pathogens. These proteins are classified into three groups, Type I, II and III IFNs, based on the structure of their receptors on the cell surface. Due to their ability to modulate immune responses, they have become attractive therapeutic options to control chronic virus infections. In combination with other drugs, Type I IFNs are considered as "standard of care" in suppressing Hepatitis C (HCV) and Hepatitis B (HBV) infections, while Type III IFN has generated encouraging results as a treatment for HCV infection in phase III clinical trials. However, though effective, using IFNs as a treatment is not without the need for caution. IFNs are such powerful cytokines that affect a wide array of cell types; as a result, patients usually experience unpleasant symptoms, with a percentage of patients suffering system wide effects. Thus, constant monitoring is required for patients treated with IFN in order to reach the treatment goals of suppressing virus infection and maintaining quality of life., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: To describe the psychometric properties and identify the minimally important difference (MID) of the hepatitis C virus patient-reported outcomes (HCV-PRO) instrument. Chronic HCV infection and associated treatments negatively affect PROs of function and well-being., Methods: In a phase 2 trial, HCV-infected patients received direct-acting antivirals (DAAs) for 12 weeks with peg-interferon/ribavirin (peg-IFN/RBV) for 48 weeks, or placebo plus peg-IFN/RBV. The HCV-PRO total score, SF-36 PCS and MCS scores, EQ-5D-3L, and EQ VAS were measured at baseline, week 8, end of DAA treatment (EODT), end of peg-IFN/RBV treatment (EOT), and posttreatment week 24 (SVR24). Convergent validity of the HCV-PRO was assessed by Pearson's correlation coefficients. Discriminant validity was assessed by analyzing mean HCV-PRO total scores by EQ-5D anxiety/depression and pain/discomfort domain scores (none vs. some) and presence/absence of depression or fatigue adverse events. MID was identified through effect size (ES) and receiver-operating characteristic (ROC) curve analyses (HCV-PRO response vs. SF-36 PCS/MCS and EQ VAS MID thresholds)., Results: In 74 patients (22 % female; 81 % White; 51 % ≥50 years), correlations (0.64-0.96) between HCV-PRO total scores, SF-36 PCS/MCS scores, and EQ VAS scores at all time points supported convergent validity. HCV-PRO total scores were reduced to 10-30 points in patients impaired by depression, pain, or fatigue symptoms. Impact of peg-IFN/RBV regimen on HCV-PRO ES increased over time (EODT -0.76; EOT -0.93). ES and ROC curve analyses indicated an MID of -10 points., Conclusion: The HCV-PRO was valid and responsive in the population studied. An MID of -10 points represented a threshold of clinical significance for the HCV-PRO.

After several decades of intense clinical research, the great promise of Type I interferons (IFN1) as the anticancer wonder drugs that could cure or, at the very least, curb the progression of various oncological diseases has regrettably failed to deliver. Severe side effects and low efficacy of IFN1-based pharmaceutics greatly limited use of these drugs and further reduced the enthusiasm of clinical oncologists for future optimization of IFN1-based therapeutic modalities. Incredibly, extensive clinical studies to assess the efficacy of IFN1 alone or in combination with other anticancer drugs have not been paralleled by an equal scope in defining the determinants that confer cell sensitivity or refractoriness to IFN1. Given that all effects of IFN1 on malignant and benign cells alike are mediated by its receptor, the mechanisms regulating these receptor cell surface levels should play a paramount role in shaping the magnitude and duration of IFN1-elicited effects. These mechanisms and their role in controlling IFN1 responses, as well as an ability of a growing tumor to commandeer these events, are the focus of our review. We postulate that activation of numerous signaling pathways leading to elimination of IFN1 receptor occurs in cancer cells and benign cells that contribute to tumor tissue. We further hypothesize that activation of these eliminative pathways enables the escape from IFN1-driven suppression of tumorigenesis and elicits the primary refractoriness of tumor to the pharmaceutical IFN1.

Sjögren's syndrome is a chronic autoimmune disease characterized by lymphocytic infiltration of the salivary and lachrymal glands resulting in dry eyes and mouth. Genetic predisposition, pathogenic infections and hormones have been implicated in the pathogenesis of the disease. Studies in the last several years have revealed marked over-expression of the type I interferon (IFN)-inducible genes in the peripheral blood and salivary glands of patients with Sjögren's syndrome. The expression of the type I IFN-inducible genes in Sjögren's syndrome also positively correlates to titers of anti-Ro and anti-La autoantibodies, which are typical for this disease. Plasmacytoid dendritic cells (pDC) are the major source of type I IFN production and activated pDC are detected in minor salivary gland biopsies from patients with primary Sjögren's syndrome. In addition, polymorphisms in genes important both for the production and response to type I IFN are associated to increased risk for Sjögren's syndrome. Because type I IFN bears a variety of biological functions, such as defense against viral infections and activation of the immune system, these results suggest that the type I IFN system has an important role in the pathogenesis of Sjögren's syndrome. A variety of mechanisms causing an activation of the type I IFN system are discussed in this review. Given the pivotal role of type I IFN in the disease process, therapeutic interventions targeting the type I IFN signaling pathway have the potential to benefit the patients with elevated type I IFN status and such hypothesis needs to be carefully evaluated in clinical development., (Copyright © 2012 Elsevier B.V. All rights reserved.)

In multiple sclerosis, type I interferon (IFN) is considered immune-modulatory, and recombinant forms of IFN-β are the most prescribed treatment for this disease. This is in contrast to most other autoimmune disorders, because type I IFN contributes to the pathologies. Even within the relapsing-remitting multiple sclerosis (RRMS) population, 30-50% of MS patients are non-responsive to this treatment, and it consistently worsens neuromyelitis optica, a disease similar to RRMS. In this article, we discuss the recent advances in the field of autoimmunity and introduce the theory explain how type I IFNs can be pro-inflammatory in disease that is predominantly driven by a Th17 response and are therapeutic when disease is predominantly Th1., (© 2012 John Wiley & Sons A/S.)

This review summarizes and analyzes the clinical outcomes following treatment of a wide range of diseases with recombinant interferons (r-IFNs) and/or natural interferons (n-IFNs). The investigation focuses on the frequency of neutralizing antibodies (NABs) directed against IFN, which are formed during treatment and their clinical impact. r-IFNs (α-2a, α-2b, β-1a, and β-1b) induced seroconversion with generation of NABs in 17.2% of patients studied. The highest incidence of NABs occurred in macular degeneration (61.4%) with the lowest in multiple sclerosis (14.7%). The incidence of antibodies induced against n-IFNs was very low (<0.2%) and was significantly less than that seen for r-IFNs (P<0.0001). Overall, the fraction of relapsed and refractory patients is statistically greater in NAB positive patients compared to NAB negative patients (<0.0001), whereas the percentage of responding patients is higher in the NAB negative cohort (P<0.001). Finally, we also analyzed relapsed and refractory NAB positive patients who switched treatment to n-IFN, such as leukocyte derived Alferon N Injection® (α-n3) or Wellferon® (α-n1). Overall, in 33/40 (82%) of these relapsed or refractory patients, switching to n-IFNs restored the clinical response. This result is consistent with serology studies showing that the NABs directed against r-IFNs do not effectively cross-react with n-IFNs.

A 60-year-old woman developed type 1 diabetes mellitus and anti-aquaporin-4 antibody positive optic neuritis during type 1 interferon therapies for chronic hepatitis C. The diabetes mellitus was elicited by interferon-α plus ribavirin therapy, while the optic neuritis was induced after interferon-β treatment, followed by interferon-α and ribavirin therapy. It is possible that type 1 interferons lead to the onset of the two autoimmune diseases by inducing disease-specific autoantibodies. Autoimmune disease is an infrequent complication of type 1 interferon treatment; however, once it has occurred, it may result in severe impairments. Patients undergoing type 1 interferon therapy should therefore be carefully monitored for any manifestations of autoimmune diseases.

Background: Adverse events attributed to the treatment of chronic hepatitis C patients with pegylated interferon (PEG-IFN) and ribavirin have been widely discussed. Lung disorders have been described, but the respiratory function of these patients during treatment has not been well studied. The aim of this study was to investigate the incidence of dyspnoea and possible changes in lung function associated with the use of PEG-IFN and ribavirin., Methods: We evaluated clinical data and spirometry in 31 patients with chronic hepatitis C infections prior to treatment, in the 2(nd) week of treatment and in the 12(th) week of treatment., Results: During the follow-up period, 19 patients (61.3%) had dyspnoea. Decreased haemoglobin levels were observed during the study, but there was no significant association with dyspnoea. However, patients with a body mass index (BMI) greater than 25 had a higher incidence of dyspnoea. No significant difference was detected between the values of forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), or forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) ratio measured during the investigation. However, a significant decrease in FEV1 and FEV1/FVC ratio was observed in patients with later stages of liver fibrosis., Conclusions: Dyspnoea is a frequently occurring respiratory symptom during chronic hepatitis C treatment, and it is not associated with changes in spirometric parameters in the first 12 weeks of treatment. However, changes in FEV1 and FEV1/FVC can be observed in patients with advanced liver disease in the first 12 weeks of treatment with PEG-IFN and ribavirin.

The limited effects of current treatments of primary myelofibrosis (PM) led us to prospectively evaluate recombinant interferon-α (rIFNα) in "early" PM patients with residual hematopoiesis and only grade 1 or 2 myelofibrosis. Seventeen patients meeting World Health Organization PM diagnostic criteria received either rIFNα-2b 500 000 to 3 million units 3 times weekly, or pegylated rIFNα-2a 45 or 90 μg weekly. International Working Group for Myelofibrosis Research and Treatment criteria for prognosis and response were used. Eleven patients were women and 6 were men. Their median age at diagnosis was 57 years. Eleven patients were low risk and 6 were intermediate-1 risk. Two achieved complete remission, 7 partial, 1 clinical improvement, 4 stable disease, and 3 had progressive disease. Thus, more than 80% derived clinical benefit or stability. Improvement in marrow morphology occurred in 4. Toxicity was acceptable. These results, with documented marrow reversion because of interferon treatment, warrant expanded evaluation.

Objectives: To report the results from the Brazilian database on multiple sclerosis (MS) and pregnancy., Methods: Retrospective data from MS patients who became pregnant at any time of their disease were sent to a Brazilian database, using a specific file for this purpose., Results: Data on 128 women (142 pregnancies) from 30 neurologists working in 21 cities in Brazil were collected. Patients' average age at pregnancy was 29.8 years (range 16-42). EDSS at start of pregnancy was 1.5±1.4; and the relapse rate in the year preceding pregnancy was 1.2±1.5. Exposure to medication at any time during pregnancy was high (69.7%): 48.6% to interferon beta; 14.1% to glatiramer acetate; and 7% to other immunomodulatory and immunosuppressive drugs. There was a significant decrease in relapse rate during pregnancy. The prevalence of complications was relatively low, with 4.9% of obstetric and 1.4% neonatal unfavorable outcomes., Conclusions: Our patients had low degrees of disability, short histories of disease, high drug exposure, and relatively high relapse rate in the year previous to pregnancy. Obstetric and neonatal outcomes were successful in over 90% of our patients., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Although it is recommended that interferon-beta (IFNβ) injections be administered in the evening, it is possible that morning injections could more effectively decrease interleukin 6 secretion., Methods: This study evaluated the effects of switching from an evening injection of IFNβ to a morning injection on the intensity of flu-like syndrome in patients with multiple sclerosis (MS). We performed an intervention study that consisted of a quantitative evaluation of IFNβ-related flu-like syndrome in a cohort of 105 MS patients. Patients with persistent flu-like reactions who injected IFNβ in the evening were encouraged to switch to morning injections. After one month, we evaluated various quantitative and qualitative changes (e.g., severity of flu-like syndrome, sleep quality, antipyretic drug use)., Results: Of the 98 patients (93%) who injected IFNβ in the evening, 88 (85%) had a persistent flu-like syndrome (the severity score was 3.92±0.26). A total of 50 (57%) patients switched to morning injections. One month after changing the injection time, 29 patients (58%) reported that their flu-like syndrome was decreased, 11 (24%) thought that it was unchanged and 9 (18%) thought that it was increased (p=0.014). In addition, 23 patients (48%) reported improved sleep (p=0.001), and 33 (68%) patients chose to continue morning injections, whereas 17 (32%) patients switched back to evening injections (p=0.024). Quantitative measures, however, indicated that there was no change in the severity of flu-like syndrome or the number of antipyretic doses taken for its management., Conclusion: Morning injections qualitatively improved IFNβ-related flu-like syndrome and sleep. A change in IFNβ injection time from evening to morning could benefit a significant proportion of patients with MS., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Chronic hepatitis C (CHC) affects over 170 million individuals worldwide and is a growing public health concern. Despite the availability of CHC treatment, specifically interferon-α and ribavirin, treatment of CHC is limited by concerns about psychiatric side effects including risks of suicide. Although depression has been the focus of neuropsychiatric complications from interferon-alpha (IFNα), emerging evidence has contributed to our understanding of IFNα-induced suicidal ideation and attempts. Using Pubmed, we performed a literature review of all English articles published between 1989 and April 1, 2010 on suicide in untreated and IFNα-treated patients with CHC. References in all identified review articles were scanned and included in our review. A total of 17 articles were identified. Studies have suggested that the first 12 weeks of IFNα therapy are the high-risk period. Moreover, the emergence of suicidal ideation can be linked to neuropsychiatric abnormalities, specifically serotonin depletion. Pretreatment with antidepressant treatment should be reserved for high-risk groups, as this may reduce the risk of depression and thus decrease the suicide risk indirectly. Although there is a paucity of literature on suicide and suicide risk during IFNα therapy for CHC, recent studies on IFNα-induced depression have provided some potential insights into suicide in this patient population. Further research examining the effects of pharmacological and nonpharmacological interventions on suicide risk during IFNα treatment is needed., (© 2010 Blackwell Publishing Ltd.)

Background: There have been conflicting reports of the role of Type I interferons (IFN) in inflammatory bowel disease (IBD). Clinical trials have shown potent efficacy of systemic interferon-beta (IFN-β) in inducing remission of ulcerative colitis. Likewise, IFNAR1(-/-) mice display an increased sensitivity to dextran sulfate sodium (DSS)-induced colitis, suggesting Type I IFN play a protective role during inflammation of the gut. Curiously, however, there have also been reports detailing the spontaneous development of IBD in patients receiving systemic IFN-β therapy for multiple sclerosis or hepatitis., Methodology/principal Findings: To investigate the effects of local administration of IFN-β on a murine model of colitis, we developed a transgenic Lactobacillus acidophilus strain that constitutively expresses IFN-β (La-IFN-β). While pretreatment of mice with control Lactobacillus (La-EV) provided slight protective benefits, La-IFN-β increased sensitivity to DSS. Analysis showed colitic mice pretreated with La-IFN-β had increased production of TNF-α, IFN-γ, IL-17A and IL-13 by intestinal tissues and decreased regulatory T cells (Tregs) in their small intestine. Examination of CD103(+) dendritic cells (DCs) in the Peyer's patches revealed that IFNAR1 expression was dramatically reduced by La-IFN-β. Similarly, bone marrow-derived DCs matured with La-IFN-β experienced a 3-fold reduction of IFNAR1 and were impaired in their ability to induce Tregs., Conclusions/significance: Our IFNAR1 expression data identifies a correlation between the loss/downregulation of IFNAR1 on DCs and exacerbation of colitis. Our data show that Lactobacillus secreting IFN-β has an immunological effect that in our model results in the exacerbation of colitis. This study underscores that the selection of therapeutics delivered by a bacterial vehicle must take into consideration the simultaneous effects of the vehicle itself.

We report a 48-year-old man who developed rheumatoid arthritis (RA) after a successful treatment with peg-IFN-alpha plus ribavirin for chronic hepatitis C virus (HCV) infection. He had a history of smoking and a single copy of the HLA-DRB1 shared epitope (SE). In a retrospective analysis, he exhibited the anti-CCP antibodies before the start of IFN plus ribavirin treatment. However, the titers of anti-CCP antibodies and BAFF levels were elevated by the IFN plus ribavirin therapy. These observations suggest that IFN plus ribavirin therapy may work as a "trigger" for RA in genetically and environmentally predisposed individuals by affecting the cytokine network.

Background: Interferon (IFN) beta is a safe and efficient drug for treating multiple sclerosis (MS). It is widely accepted that previously depressed patients may get worse when using IFN-beta. There are few reports on the association of IFN-beta and severe depression among patients without previous psychiatric history., Methods: Discussion of a case of a patient with MS who developed severe depression and attempted suicide while using IFN-beta encouraged us to review the subject. A group of neurologists in Brazil retrospectively gathered together their similar cases for the present paper., Results: The present paper reports on 11 cases of severe depression with suicide attempts or ideation among patients with MS who were using IFN-beta. These patients had no previous history of any psychiatric disease. Nine patients developed the symptoms over a relatively short period (4 months, on average). Two patients developed severe depression after more than 1 year of treatment with IFN-beta. Phobic, aggressive, behavioral, psychotic, and manic symptoms also were observed in these patients, thus suggesting the existence of a complex mood-behavior disorder associated with this drug. Interferon beta withdrawal led to complete remission of symptoms. The Naranjo algorithm established a highly probable association between IFN-beta and this adverse reaction in these patients., Conclusions: Although uncommon, severe depression with suicide ideation or attempts may be observed during treatment of MS with IFN-beta. This association should not discourage the use of this drug, but physicians need to be aware of this possible adverse event from IFN-beta.

Background: About one-half of patients with hepatitis C genotype 1 and one-third with genotype 2/3 have treatment failure with peginterferon alpha and ribavirin. Consensus interferon (CIFN) is an option for retreatment of these patients., Objective: To summarize comparative safety and efficacy of different regimens of CIFN for the treatment of patients with chronic hepatitis C infection., Data Source: Medline, Scopus, ISI, and Cochran Central Register of Clinical Trials were used., Study Eligibility Criteria: Randomized clinical trials (RCTs) were eligible for inclusion in the study., Participants: HIV and HBV seronegative patients with positive HCV-RNA during the 6 months before the start of the study were eligible for inclusion., Interventions: Different regimens of CIFN were studied., Study Appraisal and Synthesis Methods: Studies were appraised based on methods of random sequence generation, allocation concealment, and blinding. The random effects model of DerSimonian and Laird was employed to run the meta-analysis. The end-point was sustained virological response (SVR)., Results: Data of 10 RCTs including 1,600 subjects were extracted. High daily induction dose regimen of CIFN did not yield a higher rate of SVR than low daily induction dose treatment regimen, RR = 0.83 (95% CI 0.58-1.17). A dose of 9 μg thrice weekly (tiw) was associated with a significantly higher rate of SVR compared with 3 μg [RR = 3.14 (95% CI 1.68-5.58)][Symbol: see text]. Withdrawal rate was similar [RR = 1.28 (95% CI 0.65-2.50)] but dose modification was higher in 9 μg [RR = 3.22 (95% CI 1.08-9.60)]. A dose of 18/15 μg tiw was not more effective than 9 μg over a similar treatment duration [RR = 1.02 (95% CI 0. 87-1.19)]., Limitations: Limitations include inadequate reporting of methodological information and side effects, lack of publication bias assessment due to the small number of studies in each analysis., Conclusions: High dose daily induction therapy with CIFN is not superior to low dose therapy in terms of SVR. It seems that 9 μg tiw is the optimal treatment dose of CIFN for treatment of HCV infection. Optimal duration and safety profile of CIFN therapy have yet been elucidated.

Purpose: To study the influence of protein aggregation on the immunogenicity of recombinant human interferon beta (rhIFNbeta) in wild-type mice and transgenic, immune-tolerant mice, and to evaluate the induction of immunological memory., Methods: RhIFNbeta-1b and three rhIFNbeta-1a preparations with different aggregate levels were injected intraperitoneally in mice 15x during 3 weeks, and the mice were rechallenged with rhIFNbeta-1a. The formation of binding (BABs) and neutralizing antibodies (NABs) was monitored., Results: Bulk rhIFNbeta-1a contained large, mainly non-covalent aggregates and stressed rhIFNbeta-1a mainly covalent, homogeneous (ca. 100 nm) aggregates. Reformulated rhIFNbeta-1a was essentially aggregate-free. All products induced BABs and NABs in wild-type mice. Immunogenicity in the transgenic mice was product dependent. RhIFNbeta-1b showed the highest and reformulated rhIFNbeta-1a the lowest immunogenicity. In contrast with wild-type mice, transgenic mice did not show NABs, nor did they respond to the rechallenge., Conclusions: The immunogenicity of the products in transgenic mice, unlike in wild-type mice, varied. In the transgenic mice, neither NABs nor immunological memory developed. The immunogenicity of rhIFNbeta in a model reflecting the human immune system depends on the presence and the characteristics of aggregates.

The discovery that type I interferon (IFN-alpha/beta) inhibited tumor cell growth was welcomed initially with great excitement as it rapidly became a U.S. Food and Drug Administration-approved drug to treat several forms of cancer. In time, this enthusiasm diminished as severe toxicity associated with IFN-alpha administration, resistance to the therapy, or less than optimal responses became evident in cancer patients, thus restricting its clinical use and reducing its potential as an anticancer drug. The recent discovery of a third type of IFN [IFN-lambda/interleukin (IL)-29/IL-28], which shares the same biological properties of type I IFNs, opens the door for evaluating the therapeutic potential of IFN-lambda as it uses a distinct receptor complex whose expression, unlike type I IFN receptors, is restricted to cells of specific lineage. It is unclear whether the mechanism by which type III IFNs restrict tumor cell proliferation is different or the same from the one utilized by type I IFN. Nevertheless, accumulating evidence as described in this review suggests that, in contrast to IFN-alpha therapy, IFN-lambda therapy could be less toxic and suitable for certain types of malignancies as not all cells are responsive to this cytokine.

Type I interferons are pleiotropic cytokines with antiviral, antitumor and immunoregulatory functions. An aspect of their complex biology is the paradox that, depending on context, type I interferons can be anti-inflammatory and tissue protective or can be proinflammatory and promote autoimmunity. Along these lines, the activation of type I interferon pathways is effective in suppressing disease activity in patients with multiple sclerosis and in animal models of arthritis and colitis, while there is an expectation that blockade of the same pathways will be beneficial in the treatment of patients with systemic lupus erythematosus.

Background and Objectives: For patients with advanced cancers, it is important that treatment improves the quality as well as the quantity of survival. This quality-adjusted time without symptoms of progression or toxicity (Q-TWiST) analysis provides a combined measure of both the overall survival interval and the quality of survival for patients with advanced renal cell carcinoma (RCC) receiving temsirolimus, interferon (IFN)-alpha or the combination of these agents, using data from a phase III clinical trial., Methods: Overall survival was partitioned into three distinct health states: time with serious toxicity (TOX), time after progression (REL) and time without symptoms of progression or toxicity (TWiST). Health states were quality weighted by patient-reported EQ-5D measures collected while receiving treatment., Results: All 626 patients from the trial were included in computation of health-state durations. EQ-5D questionnaires were obtained from 260 patients upon progression and from 230 after a grade 3 or 4 adverse event, and from 278 patients in the TWiST state. Patients receiving temsirolimus had 38% longer TWiST than those receiving IFNalpha (6.5 vs 4.7 months, respectively; p = 0.0005). Patients receiving temsirolimus had 25% longer quality-adjusted survival in terms of Q-TWiST than those receiving IFNalpha (7.0 vs 5.6 months, respectively; p = 0.0015). Differences between the combination (temsirolimus + IFNalpha) and IFNalpha groups were not statistically significant. Threshold utility analysis indicated that temsirolimus was the preferred alternative for all possible utility weights for REL and TOX health states., Conclusion: Temsirolimus resulted in significantly longer Q-TWiST (quality-adjusted survival) in patients with advanced RCC than IFNalpha therapy.

Depression and fatigue are frequent side effects of interferon-alpha (IFN-alpha) treatment, and there is compelling evidence that the inflammatory response system (including interleukin-6, IL-6) and the serotonergic system is important in the pathophysiology of such symptoms. Functional polymorphisms in the promoter region of the IL-6 gene (rs1800795) and serotonin transporter gene (5-HTTLPR) have been identified as regulating these systems. The present study aimed to determine if these polymorphisms were associated with the development of depression and fatigue during IFN-alpha and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN-alpha and ribavirin treatment for chronic hepatitis C virus at King's College Hospital, London, and Emory University Hospital, Atlanta, participated in this prospective cohort study. Symptoms of depression and fatigue were measured before treatment and at weeks 4, 8, 12 and 24 during treatment. The 'low IL-6' synthesizing genotype (CC) was associated with significantly fewer symptoms of depression (effect size = 0.7 at week 24; F = 9.4, d.f. = 436, P = 0.002). The 'high transcription' serotonin transporter (5-HTT) genotype (LL) was also associated with significantly fewer symptoms of depression, but with a much smaller effect (effect size = 0.2 at week 24; F = 4.5, d.f. = 436, P = 0.03). Neither polymorphisms were associated with symptoms of fatigue (IL-6: F = 1.2, d.f. = 430, P = 0.2; 5-HTT: F = 0.5, d.f. = 430, P = 0.5). The smaller effects of the 5-HTT polymorphism on depression may be explained by an interaction between the genes (F = 5.0, d.f. = 434, P = 0.02): the 'protective' effect of the 5-HTTLPR polymorphism was evident only in the presence of the 'low IL-6' genotype (F = 5.4, d.f. = 64, P = 0.02), not in the presence of the 'high IL-6' genotype (F = 2.2, d.f. = 369, P = 0.1). The association between the IL-6 polymorphism and reduced risk of depressive symptoms confirms the role of the inflammatory response system in the pathophysiology of IFN-alpha-induced depression; in contrast, the effect of the 5-HTT gene was small and perhaps dependent on the status of the inflammatory response.

This double-blind controlled study assessed whether reduced doses of omega interferon (rFeIFN-omega) (Virbagen Omega) could improve the clinical signs of canine atopic dermatitis (CAD) over a 6-month period, in comparison with cyclosporin. Thirty-one dogs diagnosed with CAD were entered in the study. Complicating infections were treated prior to entry. Dogs received 10 injections of rFeIFN-omega (1-5 million units according to bodyweight) or placebo over 6 months, and placebo capsules or cyclosporin (5 mg/kg) once daily for 2 months and then twice weekly for 4 months in groups 1 and 2 respectively. Flea control, non-medicated shampooing and ear cleansing were performed regularly. If a bacterial infection or Malassezia overgrowth developed, it was treated with oral cephalexin or with 3% chlorhexidine shampoo respectively. Oral prednisolone was used before day 90 to relieve pruritus when required for humane reasons (1 mg/kg once daily for 7 days). The CADESI-03 and a pruritus index were evaluated on day (D) 0, D14, D35, D56, D90, D120 and D180. No significant difference was detected between the groups for the time courses of lesions or pruritus over 6 months. On D90, the proportions of dogs with > or =50% improvement of pruritus and lesion scores were 56% and 72% respectively with interferon, 75% and 75% respectively with cyclosporin. Five dogs from group 1 and two dogs from group 2 were withdrawn from the study for treatment failure. Both products were well tolerated. Treatment with rfeIFN-omega at low doses may help for the long-term management of CAD.

Background: Interferon beta has been approved for the treatment of multiple sclerosis (MS). It is believed that immunomodulatory rather than antiviral activity of interferon beta is responsible for disease amelioration. The impact of interferon beta on the chemoattraction of immune cells has not been fully addressed., Objective: To address the influence of interferon beta on the expression of chemokines and their receptors in a standardized setting., Design: The expression of 14 chemokines and 14 chemokine receptor genes was determined by quantitative real-time polymerase chain reaction from fresh blood samples., Setting: Outpatient units in Germany. Patients Untreated and interferon beta-treated patients with MS who tested positive and negative for neutralizing antibodies (NABs) were recruited from August 24, 2006, through December 15, 2006, for the initial study and from March 12, 2007, through April 2, 2007, for the validation study., Main Outcome Measures: Gene expression and serum chemokine protein levels., Results: CCL1, CCL2, CCL7, CXCL10, CXCL11, and CCR1 gene expression was strongly upregulated in interferon beta-treated, NAB-negative MS patients. In contrast, gene expression in interferon beta-treated, NAB-positive MS patients did not differ from untreated control donor individuals. Antibody titers inversely correlated with chemokine and chemokine receptor gene expression. Accordingly, serum chemokine protein levels of interferon beta-treated, NAB-negative MS patients were significantly higher than in untreated or interferon beta-treated, NAB-positive MS patients., Conclusions: We demonstrate that interferon beta strongly upregulates a set of chemokines and CCR1 in peripheral immune cells. The peripheral upregulation of these chemokines may reduce the chemoattraction of immune cells to the central nervous system and thus add to the therapeutic effects of interferon beta.

Pregnancy is a high-risk event in women with essential thrombocythemia (ET). This observational study evaluated pregnancy outcome in ET patients focusing on the potential impact of aspirin (ASA) or interferon alpha (IFN) treatment during pregnancy. We retrospectively analyzed 122 pregnancies in 92 women consecutively observed in the last 10 years in 17 centers of the Italian thrombocythemia registry (RIT). The live birth rate was 75.4% (92/122 pregnancies). The risk of spontaneous abortion was 2.5-fold higher than in the control population (P < 0.01). ASA did not affect the live birth rate (71/93, 76.3% vs. 21/29, 72.4%, P = 0.67). However, IFN treatment during pregnancy was associated with a better outcome than was management without IFN (live births 19/20, 95% vs. 73/102, 71.6%, P = 0.025), and this finding was supported by multivariate analysis (OR: 0.10; 95% CI: 0.013-0.846, P = 0.034). The JAK2 V617F mutation was associated with a poorer outcome (fetal losses JAK2 V617F positive 9/25, 36% vs. wild type 2/24, 8.3%, P = 0.037), and this association was still significant after multivariate analysis (OR: 6.19; 95% CI: 1.17-32.61; P = 0.038). No outcome concordance between first and second pregnancies was found (P = 0.30). Maternal complications occurred in 8% of cases. In this retrospective study, in consecutively observed pregnant ET patients, IFN treatment was associated with a higher live birth rate, while ASA treatment was not. In addition, the JAK2 V617F mutation was confirmed to be an adverse prognostic factor., ((c) 2009 Wiley-Liss, Inc.)

Background: Because of the poor outcomes for patients with recurrent glioblastoma multiforme (GBM), and some laboratory and clinical evidence of efficacy using interferon in GBM, we assessed the toxicity and efficacy of temozolomide (TMZ) combined with either short-acting (IFN) or long-acting (pegylated) interferon alpha2b (PEG) in two single-arm phase II studies, and compared the results to 6-month progression-free survival (PFS-6) data from historical controls., Methods: Two single-arm phase II studies were carried out in adults with GBM. Patients were treated with the standard regimen of TMZ (150-200 mg m(-2) per day x 5 days every month) combined with either 4 million units per m(2) subcutaneously (SQ) three times weekly of IFN or 0.5 microg kg(-1) SQ weekly of PEG. Physical exams and imaging evaluations were carried out every 8 weeks., Results: On the IFN study, 34 adults (74% men) were enrolled, and 29 adults (55% men) on the PEG study; median Karnofsky performance status was 80 and 90 for the IFN and PEG studies, respectively. Grade 3 or 4 toxicities were common, leucopoenia and thrombocytopoenia occurring in 35-38% and 18-21% of patients, respectively. Grade 3 or 4 fatigue occurred in 18% of patients on both studies. Lymphopoenia was infrequent. PFS-6 was 31% for 29 evaluable patients in the IFN study and 38% for 26 evaluable patients in the PEG study., Conclusion: In recurrent GBM patients, both studies of standard dose TMZ with either IFN or PEG showed improved efficacy when compared to historical controls, or reports using TMZ alone. Even though the TMZ+PEG study met criteria for further study, the results of both of these studies must be considered in light of the standard of care (TMZ plus radiotherapy) for newly diagnosed GBM, which has evolved since the inception of these studies. Despite the results of the current studies being eclipsed by the new GBM standard of care, these results can still inform the development of newer approaches for GBM, either in an earlier, upfront setting, or by extrapolation of the results and consideration of the use of PEG or IFN in conjunction with other antiglioma strategies.

Interferon-beta (IFNbeta) is an extra-cellular protein mediator of host defense and homeostasis. IFNbeta has well-established direct antiviral, antiproliferative and immunomodulatory properties. Recombinant IFNbeta is approved for the treatment of relapsing-remitting multiple sclerosis. The immunomodulatory effects of IFNbeta administration failed to demonstrate consistent benefit during treatment of various autoimmune neuromuscular diseases. Existing studies were flawed due to the often uncontrolled and unblinded nature of protocols, small patient numbers per study, the undetermined optimum dose and schedule of IFNbeta therapy, and the relatively brief periods of IFNbeta administration and clinical follow-up for mostly chronic inflammatory disorders. Additional, controlled, prospective studies are needed to definitely establish the full potential of this cytokine for this group of diseases. IFNbeta therapy may trigger autoantibody production, but only rarely clinically overt autoimmune disease. Anecdotal reports hint at the exceptional association between IFNbeta treatment and the induction or exacerbation of a variety of immune-mediated neuromuscular diseases, likely in genetically predisposed individuals. Thus, recombinant IFNbeta has the theoretical potential to either treat or cause autoimmune neuromuscular disorders by altering the complicated and delicate balances within the immune system networks.

Background: Since their initial use in the 1980s, IFNs have become an essential component of the therapy for many diseases such as hepatitis and multiple sclerosis. Although they have been extremely useful in conditions that pose therapeutic challenges, complications associated with their use have been widely reported including emerging reports of several autoimmune diseases. Many of these reports have shed light on the pathogenesis of autoimmune disorders and helped to highlight not only the critical role of type I IFNs in defense against viral infections but also the pivotal role they occupy in the interface between innate and adaptive immunity. Many patients with autoimmune disease have increased responsiveness to type I IFNs (alpha/beta), and therapy with these cytokines has induced or unmasked autoimmune disease in many additional patients., Objective: The objective of this paper is to discuss the role of type I IFNs in autoimmunity., Methods: The literature regarding type I IFNs and autoimmunity was reviewed using the Medline database from 1950 to 2009. Search terms included 'interferon alpha' and 'autoimmune disease' and 'interferon beta' and 'autoimmune disease'. Case reports, case series, reviews and prospective studies were included in the analysis., Results/conclusions: In the literature a variety of autoimmune disorders have reportedly been induced by the use of type I IFNs, being used, although these are primarily in the form of case reports and case series. Nevertheless, there is a growing body of molecular evidence to support the clinical association. The role of IFNs in the induction of autoimmunity is complex with interplay of many genetic and environmental factors that influence the balance between normal and aberrant immune responsiveness, ultimately leading to the observed clinical manifestations.

Background and Aim: Thyroid disorders represent a common side effect of antiviral therapy in patients with chronic hepatitis C (CHC). However, there is strong evidence for a higher prevalence of thyroidal antibodies (TA) and nonorgan-specific autoantibodies (NOSA) even before interferon (IFN) administration. Here, we report for the first time on the distribution and occurrence of TA and NOSA before, during, and after treatment with daily highdosed IFN alfacon-1 [consensus IFN (CIFN)]., Methods: Thyrotropin (TSH) levels and antibodies to different autoantigens were analyzed in 217 patients with CHC (29.8% females) who were treated with CIFN induction therapy (27 or 18 mg q.d.)., Results: Pretreatment abnormal TSH levels (TSH>3.0 mU/L or <0.4 mU/L) were detected in 15.6% and occurred significantly more often in females (24.6%; P=0.018). TA could be detected only in 2.6%, NOSA in up to 29.9% (47.4% females vs. 24.2% males). During CIFN induction therapy, low TSH levels were detected in 14.1% whereas elevated TSH levels occurred later (week 48) in up to 15.5%, again preferentially in females (42%, P=0.005). In 1.4% of all patients, treatment had to be discontinued because of symptomatic hyperthyroidism. TAs were detected in 10.5% (30.5% females) and NOSA up to 58% during CIFN treatment., Conclusions: During CIFN induction therapy, alterations in TSH levels and an increased prevalence of TA and NOSA are quite common, especially in females. Clinically relevant symptoms occur, however, only in a small number (1.4%). Thus, treatment with daily and high-dose CIFN does not appear to increase the incidence of (severe) thyroidal or other autoimmune disorders compared with standard IFN in patients with CHC.

In this essay, we draw attention to some recent downsides and surprises of multiple sclerosis (MS) therapeutics. These include experiences with recent head-to-head trials of interferon-beta and glatiramer acetate, dose escalation trials, frustrating efforts with progressive MS trials, failures of smart concepts and designer therapies, and harsh lessons from newly observed adverse reactions.

Purpose: The case of a patient with hepatitis C who developed elevated hepatic transaminase levels associated with the use of interferon alfacon-1 and ribavirin is described., Summary: A 55-year-old Caucasian man arrived at a hepatitis C clinic to discuss alternative treatment options for his hepatitis C virus (genotype 1a) infection, which did not respond to a 48-week course of peginterferon and ribavirin therapy. He was subsequently treated with interferon alfacon-1 9 microg subcutaneously daily plus ribavirin 200 mg orally twice daily. During treatment with interferon alfacon-1, he developed elevated hepatic transaminase levels despite a decrease in viral load. His hepatic transaminase levels returned to baseline when interferon alfacon-1 was discontinued and rose again upon rechallenge. Ribavirin was not the likely cause of the increase in transaminases since the patient previously tolerated it in combination with peginterferon. While activation of autoimmune hepatitis is a potential cause of acute decompensation in patients treated with interferons, it was not believed to be the case in this patient. Interferon alfacon-1 was determined to be the probable cause of the rise in hepatic transaminase levels in this patient, since his levels declined when therapy was discontinued and rose dramatically once it was restarted. This case illustrates the importance of monitoring both viral loads and hepatic transaminase levels in patients with hepatitis C being treated with interferon therapy., Conclusion: A patient with hepatitis C developed elevated hepatic transaminase levels despite showing an improvement in viral load after receiving interferon alfacon-1 and ribavirin.