Thrombotic Microangiopathy after a 15-year Treatment with Interferon Beta-1b in a Patient with Multiple Sclerosis: A Case Report and Review of Literature.

A 54-year-old woman with multiple sclerosis treated with interferon-ß (IFN-ß)-1b for 15 years presented with sustained hypertension (240/124 mmHg) and retinal bleeding. She had proteinuria, anemia, thrombocytopenia, elevated serum creatinine levels, and haptoglobin depletion. Intravenous nicardipine stabilized her blood pressure, but her renal function and platelet count deteriorated. The initial disintegrin-like metalloprotease with thrombospondin type 1 motifs 13 (ADAMTS13) activity was 28% of normal without its inhibitor. The subsequent peripheral appearance of schistocytes suggested thrombotic microangiopathy (TMA). After IFN-ß-1b cessation, the platelet count increased, and the blood pressure stabilized. The ADAMTS13 activity normalized, although the creatinine level did not. TMA may develop after the long-term use of IFN-ß without adverse events.

TnP Peptide Suppresses Experimental Autoimmune Encephalomyelitis (EAE) in a Preclinical Mouse Model.

TnP is a family of patented synthetic peptides which is in a preclinical development stage with valuable potential therapeutic indication for multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system (CNS). The use of a preclinical animal model, such as experimental autoimmune encephalomyelitis (EAE) has deepened our knowledge of the immunomodulatory functions of TnP as a drug. We have shown that TnP possesses a disease suppressive function in EAE, ameliorating disease severity by 40% and suppressing the accumulation of T helper (Th)1- and Th17-producing lymphocytes (by 55% and 60%, respectively) in CNS along with activated microglia/macrophages populations (by 33% and 50%, respectively), and also conferred a protective effect anticipating the remyelination process to day 66 compared to day 83 of untreated cuprizone-mice. Here we expanded our knowledge about its effects compared with current first-line disease-modifying therapies (DMT). We demonstrated that prophylactic treatment with TnP generated similar protection to betaseron (30%) or was more effective than glatiramer (44% versus 6%) or fingolimod (50% versus 19%) against the development of clinical symptoms. Although TnP controlled the leukocyte infiltration (87% versus 82%) into demyelinated areas of the spinal cord in the same way as betaseron and fingolimod, it was more effective (72% to 78% decrease) in the long-term control of neuronal degeneration compared to them. Also, when compared to glatiramer, TnP was more efficient in reversing leukocytes infiltration into the spinal cord (55% versus 24%), as well as induced a higher percentage of regulatory cells in spleen (2.9-fold versus 2.3-fold increase over vehicle-treated EAE mice) an in the spinal cord (8-fold versus 6-fold increase over vehicle-treated EAE mice). This specialized TnP profile for inducing immune tolerance and neuronal regeneration has significant therapeutic potential for the treatment of MS and other autoimmune diseases.

The Impact of Interferon Beta-1b Therapy on Thyroid Function and Autoimmunity Among COVID-19 Survivors.

Background: Some studies have indicated that interferon (IFN) may be valuable in COVID-19. We aimed to evaluate the impact of short-term IFN on incident thyroid dysfunction and autoimmunity among COVID-19 survivors. Methods: We included consecutive adults without known thyroid disorder admitted to Queen Mary Hospital for COVID-19 from July 2020 to January 2021 who had thyroid function tests (TFTs) and anti-thyroid antibodies measured both on admission and at three months. Results: 226 patients were included (median age 55.0 years; 49.6% men): 135 were IFN-treated. There tended to be more abnormal TFTs upon reassessment in IFN-treated patients (8.1% vs 2.2%, p=0.080). 179 patients (65.4% IFN-treated) had a complete reassessment of anti-thyroid antibodies. There were significant increases in titres of both anti-thyroid peroxidase antibodies (anti-TPO: baseline 29.21 units [IQR: 14.97 - 67.14] vs reassessment 34.30 units [IQR: 18.82 - 94.65], p<0.001) and anti-thyroglobulin antibodies (anti-Tg: baseline 8.23 units [IQR: 5.40 - 18.44] vs reassessment 9.14 units [IQR: 6.83 - 17.17], p=0.001) in the IFN-treated group but not IFN-naïve group. IFN treatment (standardised beta 0.245, p=0.001) was independently associated with changes in anti-TPO titre. Of the 143 patients negative for anti-TPO at baseline, 8 became anti-TPO positive upon reassessment (seven IFN-treated; one IFN-naïve). Incident anti-TPO positivity was more likely to be associated with abnormal TFTs upon reassessment (phi 0.188, p=0.025). Conclusion: IFN for COVID-19 was associated with modest increases in anti-thyroid antibody titres, and a trend of more incident anti-TPO positivity and abnormal TFTs during convalescence. Our findings suggest that clinicians monitor the thyroid function and anti-thyroid antibodies among IFN-treated COVID-19 survivors, and call for further follow-up studies regarding the clinical significance of these changes.

Real-world prevalence and consequences of potential drug-drug interactions in the first-wave COVID-19 treatments.

WHAT IS KNOWN AND OBJECTIVE: Initial treatment recommendations of COVID-19 were based on the use of antimicrobial drugs and immunomodulators. Although information on drug interactions was available for other pathologies, there was little evidence in the treatment of COVID-19. The objective of this study was to analyse the potential drug-drug interactions (pDDIs) derived from the medication used in COVID-19 patients in the first pandemic wave and to evaluate the real consequences of such interactions in clinical practice. METHODS: Cohort, retrospective and single-centre study carried out in a third-level hospital. Adult patients, admitted with suspected COVID-19, that received at least one dose of hydroxychloroquine, lopinavir/ritonavir, interferon beta 1-b or tocilizumab and with any pDDIs according to "Liverpool Drug Interaction Group" between March and May 2020 were included. The possible consequences of pDDIs at the QTc interval level or any other adverse event according to the patient's medical record were analysed. A descriptive analysis was carried out to assess possible factors that may affect the QTc interval prolongation. RESULTS AND DISCUSSION: Two hundred and eighteen (62.3%) patients of a total of 350 patients admitted with COVID-19 had at least one pDDI. There were 598 pDDIs. Thirty-eight pDDIs (6.3%) were categorized as not recommended or contraindicated. The mean value difference between baseline and pDDI posterior ECG was 412.3 ms ± 25.8 ms vs. 426.3 ms ± 26.7 ms; p < 0.001. Seven patients (5.7%) had a clinically significant alteration of QTc. A total of 44 non-cardiological events (7.3%) with a possible connection to a pDDI were detected. WHAT IS NEW AND CONCLUSION: The number of pDDIs in patients admitted for COVID-19 in the first pandemic wave was remarkably high. However, clinical consequences occurred in a low percentage of patients. Interactions involving medications that would be contraindicated for concomitant administration are rare. Knowledge of these pDDIs and their consequences could help to establish appropriate therapeutic strategies in patients with COVID-19 or other diseases with these treatments.

Interferon Beta-1b and Lopinavir-Ritonavir for Middle East Respiratory Syndrome.

BACKGROUND: Whether combined treatment with recombinant interferon beta-1b and lopinavir-ritonavir reduces mortality among patients hospitalized with Middle East respiratory syndrome (MERS) is unclear. METHODS: We conducted a randomized, adaptive, double-blind, placebo-controlled trial that enrolled patients at nine sites in Saudi Arabia. Hospitalized adults with laboratory-confirmed MERS were randomly assigned to receive recombinant interferon beta-1b plus lopinavir-ritonavir (intervention) or placebo for 14 days. The primary outcome was 90-day all-cause mortality, with a one-sided P-value threshold of 0.025. Prespecified subgroup analyses and safety analyses were conducted. Because of the pandemic of coronavirus disease 2019, the data and safety monitoring board requested an unplanned interim analysis and subsequently recommended the termination of enrollment and the reporting of the results. RESULTS: A total of 95 patients were enrolled; 43 patients were assigned to the intervention group and 52 to the placebo group. A total of 12 patients (28%) in the intervention group and 23 (44%) in the placebo group died by day 90. The analysis of the primary outcome, with accounting for the adaptive design, yielded a risk difference of -19 percentage points (upper boundary of the 97.5% confidence interval [CI], -3; one-sided P = 0.024). In a prespecified subgroup analysis, treatment within 7 days after symptom onset led to lower 90-day mortality than use of placebo (relative risk, 0.19; 95% CI, 0.05 to 0.75), whereas later treatment did not. Serious adverse events occurred in 4 patients (9%) in the intervention group and in 10 (19%) in the placebo group. CONCLUSIONS: A combination of recombinant interferon beta-1b and lopinavir-ritonavir led to lower mortality than placebo among patients who had been hospitalized with laboratory-confirmed MERS. The effect was greatest when treatment was started within 7 days after symptom onset. (Funded by the King Abdullah International Medical Research Center; MIRACLE ClinicalTrials.gov number, NCT02845843.).

Interferon ß-1b in treatment of severe COVID-19: A randomized clinical trial.

In this study, efficacy and safety of interferon (IFN) ß-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 ß-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 ß-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 ß-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 ß-1b.

Effectiveness of Interferon Beta 1a, compared to Interferon Beta 1b and the usual therapeutic regimen to treat adults with moderate to severe COVID-19: structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: We will investigate the effectiveness of Interferon Beta 1a, compared to Interferon Beta 1b and the usual therapeutic regimen in COVID-19 in patients that have tested positive and are moderately to severely ill. TRIAL DESIGN: This is a single center, open label, randomized, controlled, parallel group, clinical trial that will be conducted at Loghman Hakim Medical Education Center in conjunction with Shahid Beheshti University of Medical Sciences. PARTICIPANTS: Sixty COVID-19 confirmed cases (using the RT-PCR test) will be enrolled in the trial between April 9th to April 14th 2020. Patients will be randomly assigned to the intervention groups or the control group with the following eligibility criteria: ≥ 18 years of age AND (oxygen saturation (SPO2) ≤ 93% OR respiratory rate ≥ 24) AND at least one of the following: Contactless infrared forehead thermometer temperature of ≥37.8, cough, sputum production, nasal discharge, myalgia, headache or fatigue on admission, and time of onset of the symptoms should be acute (Days ≤ 14). Although Hydroxychloroquine will be administered in a single dose, patients with heart problems (prolonged QT or PR intervals, second- or third-degree heart block, and arrhythmias including torsade de pointes) will be excluded. Other exclusion criteria include using drugs with potential interaction with Hydroxychloroquine + Lopinavir/Ritonavir, Interferon-ß 1a, Interferon-ß 1b, pregnant or lactating women, history of alcohol or drug addiction in the past 5 years, blood ALT/AST levels > 5 times the upper limit of normal on laboratory results and refusal to participate. This study will be undertaken at the Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences and Health Services. INTERVENTION AND COMPARATOR: COVID-19 confirmed patients will be randomly assigned to one of three groups, with 20 patients in each. The first group (Arm 1) will receive Hydroxychloroquine + Lopinavir / Ritonavir (Kaletra) + Interferon-ß 1a (Recigen), the second group (Arm 2) will be administered Hydroxychloroquine + Lopinavir / Ritonavir (Kaletra) + Interferon-ß 1b (Ziferon), and the control group (Arm 3) will be treated by Hydroxychloroquine + Lopinavir / Ritonavir (Kaletra). MAIN OUTCOMES: Time to clinical improvement is our primary outcome measure. This is an improvement of two points on a seven-category ordinal scale (recommended by the World Health Organization: Coronavirus disease (COVID-2019) R&D. Geneva: World Health Organization) or discharge from the hospital, whichever comes first. Secondary outcomes include mortality from the date of randomization until the last day of the study which will be the day all of the patients have had at least one of the following outcomes: 1) Improvement of two points on a seven-category ordinal scale. 2) Discharge from the hospital 3) Death. If any patient dies, we have reached an important secondary outcome. SpO2 Improvement between the last and first day of hospitalization, using pulse-oximetry. Duration of hospitalization from date of randomization until the date of hospital discharge or date of death from any cause, whichever comes first. Incidence of new mechanical ventilation uses from date of randomization until the last day of the study. Please note that we are trying to add further secondary outcomes and this section of the protocol is still evolving. Statistical analysis will be performed by R version 3.6.1 software. We will use Kaplan-Meier to analyze the time to clinical improvement (compared with a log-rank test). Hazard ratios with 95% confidence intervals will be calculated using the Cox proportional-hazards model in crude and adjusted analysis. RANDOMIZATION: Eligible patients will be randomly assigned in a 1:1:1 ratio to receive either Interferon Beta 1a, Interferon Beta 1b or standard care only. Patients will be randomly allocated to three therapeutic arms using permuted, block-randomization to balance the number of patients allocated to each group. The permuted block (three or six patients per block) randomization sequence will be generated, using Package 'randomizeR' in R software version 3.6.1. and placed in individual sealed and opaque envelopes by the statistician. The investigator will enroll the patients and only then open envelopes to assign patients to the different treatment groups. This method of allocation concealment will result in minimum selection and confounding biases. BLINDING (MASKING): The present research is open-label (no masking) of patients and health care professionals who are undertaking outcome assessment of the primary outcome - time to clinical improvement. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): Of the 60 patients who underwent randomization, 20 patients were assigned to receive Interferon beta-1a, 20 patients were assigned to receive Interferon beta 1b plus standard care and the rest of patients were assigned to receive the standard care alone. TRIAL STATUS: Protocol version 1.2.1. Recruitment is finished, the start date of recruitment was on 9th April 2020 and the end date was on 14th April 2020. Last point of data collection will be the last day on which all of the 60 participants have had an outcome of clinical improvement or death, completing the study's follow-up time window. TRIAL REGISTRATION: This study was registered with National Institutes of Health Clinical trials (www.clinicaltrials.gov; identification number NCT04343768, registered April 8, 2020 and first available online April 13, 2020). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Active Pulmonary Tuberculosis Triggered by Interferon Beta-1b Therapy of Multiple Sclerosis: Four Case Reports and a Literature Review.

In this paper, we reported on four cases of severe pulmonary active tuberculosis in patients with multiple sclerosis (MS) undergoing interferon beta-1b (IFNß-1b) therapy. Disease-modifying therapies (DMTs) in MS may increase the risk of developing active tuberculosis (TB) due to their impact on cellular immunity. Screening for latent infection with Mycobacterium tuberculosis (LTBI) should be performed, not only for the newer DMTs (alemtuzumab, ocrelizumab) but also for IFNß-1b, alongside better supervision of these patients.

Treatment of Middle East respiratory syndrome with a combination of lopinavir/ritonavir and interferon-ß1b (MIRACLE trial): statistical analysis plan for a recursive two-stage group sequential randomized controlled trial.

The MIRACLE trial (MERS-CoV Infection tReated with A Combination of Lopinavir/ritonavir and intErferon-ß1b) investigates the efficacy of a combination therapy of lopinavir/ritonavir and recombinant interferon-ß1b provided with standard supportive care, compared to placebo provided with standard supportive care, in hospitalized patients with laboratory-confirmed MERS. The MIRACLE trial is designed as a recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The aim of this article is to describe the statistical analysis plan for the MIRACLE trial. The primary outcome is 90-day mortality. The primary analysis will follow the intention-to-treat principle. The MIRACLE trial is the first randomized controlled trial for MERS treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02845843. Registered on 27 July 2016.

Cutaneous necrotic lesion: A wonderful delay adverse effect of interferon beta-1b injection for multiple sclerosis treatment.

Multiple sclerosis (MS) is a chronic and inflammatory autoimmune disease. These patients may manifest severe inflammatory cutaneous reactions after using interferon beta-1b. This article describes a 55-year-old man with severe injection site reactions after 10 years administration of interferon beta-1b. The biopsy specimens revealed skin and subcutaneous tissue necrosis. Histologic evaluation revealed nonspecific inflammatory reactions with no evidence of vasculitis or granulomatous reactions. Based on clinical and pathological findings, the diagnosis of skin and soft tissue necrosis due to interferon injection was given. The injection of interferon beta-1b in the affected areas was stopped, and the patient's clinical condition improved by wound care. This report is aimed to increase awareness about severe adverse skin reactions, which may infrequently occur with subcutaneous interferon beta-1b injection after several years. Early diagnosis of this reaction can help to prevent associated complications.

Morphea secondary to interferon beta1b injection: a case and review of the literature.

Interferon beta (IFNß) is a drug used successfully in the treatment of multiple sclerosis (MS). Although IFNß is a safe and well-tolerated drug, dermatological side effects are common. The most common dermatological adverse effect is a local reaction at the injection site. It may also cause inflammatory and immune-mediated dermatological side effects. However, morphea induced by IFNß1b injection is very rare.

Treatment of Middle East Respiratory Syndrome with a combination of lopinavir-ritonavir and interferon-ß1b (MIRACLE trial): study protocol for a randomized controlled trial.

BACKGROUND: It had been more than 5 years since the first case of Middle East Respiratory Syndrome coronavirus infection (MERS-CoV) was recorded, but no specific treatment has been investigated in randomized clinical trials. Results from in vitro and animal studies suggest that a combination of lopinavir/ritonavir and interferon-ß1b (IFN-ß1b) may be effective against MERS-CoV. The aim of this study is to investigate the efficacy of treatment with a combination of lopinavir/ritonavir and recombinant IFN-ß1b provided with standard supportive care, compared to treatment with placebo provided with standard supportive care in patients with laboratory-confirmed MERS requiring hospital admission. METHODS: The protocol is prepared in accordance with the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines. Hospitalized adult patients with laboratory-confirmed MERS will be enrolled in this recursive, two-stage, group sequential, multicenter, placebo-controlled, double-blind randomized controlled trial. The trial is initially designed to include 2 two-stage components. The first two-stage component is designed to adjust sample size and determine futility stopping, but not efficacy stopping. The second two-stage component is designed to determine efficacy stopping and possibly readjustment of sample size. The primary outcome is 90-day mortality. DISCUSSION: This will be the first randomized controlled trial of a potential treatment for MERS. The study is sponsored by King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. Enrollment for this study began in November 2016, and has enrolled thirteen patients as of Jan 24-2018. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02845843 . Registered on 27 July 2016.

Eficacia y seguridad del uso de interferon beta 1A 30 mg intramuscular para el tratamiento de esclerosis múltiple recurrente remitente que ha presentado eventos adversos a tratamiento previo con interferón beta 1b / Efficacy and safety of the use of intramuscular interferon beta 1A 30 mg for the treatment of relapsing-remitting multiple sclerosis that has presented adverse events to previous treatment with interferon beta 1b

INTRODUCCIÓN: El presente dictamen expone la evaluación de tecnología de la eficacia y seguridad de interferón beta-1a (IFNß-1a) vía intramuscular para el tratamiento de pacientes adultos con esclerosis múltiple recurrente remitente (EMRR), quienes han presentado reacción adversa en el punto de inyección secundaria al uso de interferón beta-1b (IFNß-1b) por vía subcutánea, sin pérdida de respuesta al tratamiento. La esclerosis múltiple es una enfermedad crónica inflamatoria autoinmune del sistema nervioso central. Se caracteriza por el daño de la vaina de mielina que recubre a los axones de las neuronas en el sistema nervioso central, el cual puede tener distintos niveles de severidad. La esclerosis múltiple puede producir un grado creciente de discapacidad a lo largo de su evolución, con consecuente disminución de la calidad de vida y de la productividad en quienes la padecen. METODOLOGIA: Se llevó a cabo una búsqueda sistemática de la literatura con respecto a la eficacia y seguridad del uso de IFNß-1a IM para el tratamiento de pacientes adultos con esclerosis múltiple recurrente remitente, que ha presentado reacción adversa en el punto de inyección secundaria al uso de IFNß-1b SC, sin pérdida de respuesta al tratamiento. La búsqueda se inició revisando la información sobre el uso del medicamento de acuerdo con entidades reguladoras como la Food and Drug Administration (FDA), la European Medicines Agency (EMA) y la Dirección General de Medicamentos y Drogas (DIGEMID). Posteriormente, se revisaron las bases de datos de PubMed, Cochrane Library, TRIPDATABASE y www.clinicaltrials.gov. Adicionalmente, se realizó una búsqueda de evaluaciones de tecnologías y guías de práctica clínica en las páginas web de grupos dedicados a la investigación y educación en salud en general como The National Institute for Health and Care Excellence (NICE); y especializados en enfermedades neurológicas como la Sociedad Americana de Neurología (AAN). RESULTADOS: De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de IFNß-1a. En la presente sinopsis se describe la evidencia disponible. CONCLUSIONES: La presente evaluación de tecnología sanitaria tuvo por objetivo la evaluación de la eficacia y seguridad del uso de Interferón beta 1a 30 mcg en pacientes con esclerosis múltiple recurrente remitente, que han presentado eventos adversos en el sitio de inyección secundario al uso de Interferón beta 1b SC. Así, a la fecha, no se encontró ensayos clínicos en la población de interés, es decir, que evalúen el uso subsecuente de IFNß-1a IM después del uso de IFNß-1b SC para el tratamiento de EMRR, en pacientes que presentan eventos adversos en el lugar de inyección. Por lo tanto, se incluyó el ECAs fase III pivotal donde se evaluó la eficacia y seguridad del uso de IFNß -1a IM comparado con placebo, como evidencia indirecta. Los resultados del ECA pivotal mostraron que el tratamiento con IFNß - 1a IM podía retrasar la progresión de la discapacidad en pacientes con esclerosis múltiple recurrente en comparación con placebo. Esto significa que ante la ausencia de opciones en el petitorio farmacológico de EsSalud, el IFNß -1a IM sería una opción válida de tratamiento para dicho tipo de pacientes. Esto se condice con la opinión del experto, quien refiere que además de existir plausibilidad biológica para el uso subsecuente de interferones beta, en la institución se ha utilizado el IFNß -1a IM en un grupo de pacientes con EMRR presentando una evolución satisfactoria. Además, estas conclusiones fueron avaladas por la opinión de experto quien refiere que la institución cuenta con más de 10 años de experiencia con el uso de IFNß-1a IM, que ha mostrado ser eficaz y seguro en esta población; teniendo en cuenta además que no hay alternativa en el petitorio. Por lo tanto, el IFNß -1a IM vendría a ser la mejor terapia alternativa disponible en el mercado peruano ante el escenario de haber reacción adversa importante en el lugar de aplicación por el uso de interferón beta 1b subcutáneo, sin pérdida de la respuesta al tratamiento. Por lo expuesto, el Instituto de Evaluaciones de Tecnologías en Salud e Investigación - IETSI, aprueba el uso de IFNß -1a para el manejo de los pacientes con diagnóstico de esclerosis múltiple recurrente remitente que ha presentado eventos adversos en el sitio de inyección secundario al uso de IFNß -1b, sin pérdida de respuesta al tratamiento, según lo establecido en el Anexo No 1. La vigencia del presente dictamen preliminar es de un año, la continuación de dicha aprobación estará sujeta a los resultados obtenidos de los pacientes que se beneficien con dicho tratamiento y a nueva evidencia que pueda surgir en el tiempo.

Interferon beta-1b-induced postmenopausal bleeding in a patient with multiple sclerosis.

OBJECTIVE: Postmenopausal bleeding must always be evaluated to rule out endometrial carcinoma, although there are many benign etiologies. There have been rare reports of premenopausal bleeding with interferon beta-1b, used to treat multiple sclerosis, but no prior reports in postmenopausal women. METHODS: Literature searches were performed using PubMed and Medline for articles with content related to premenopausal and postmenopausal bleeding while taking interferon beta-1b. The searches were restricted to the English language. Search terms included interferon beta-1b and/or uterine hemorrhage and/or vaginal bleeding and/or postmenopausal and/or menopause. RESULTS: The literature review found no related articles for postmenopausal bleeding while taking interferon beta-1b. We present a case of a patient with postmenopausal bleeding attributed to elevation of serum estradiol in association with interferon beta-1b therapy. CONCLUSION: It is important for patients and providers to be aware of the association between postmenopausal bleeding with the use of interferon beta-1b therapy which could be due to elevated serum estradiol levels.

[Experience of application of Russian biosimilar of interferon beta-1b for treatment of pediatric multiple sclerosis]. / Opyt primeneniya rossiiskogo bioanaloga interferona beta-1b v lechenii detskogo rasseyannogo skleroza.

AIM: To evaluate efficacy and safety of biosimilars of interferon beta-1b (Infibeta) in patients aged 14 to 17 years. MATERIAL AND METHODS: Interferon beta 1b (Infibeta) was appointed 9 children and adolescents (4 boys and 5 girls) between the ages of 14 to 17 years (mean age of onset of therapy 16.22±1.09). RESULTS: In the course of therapy there was a significant decrease in the annualrelapse rate (ARR) to 0.33±0.5 (from 0 to 1, r≤0,0001) and the of regression of neurological deficit on the EDSS scale up to ±1.94±0.68 (1.5 to 3, p≤0.05). No cases of cancellation was not recorded due to poor tolerability or inefficiency. CONCLUSION: Although numerically small so far, but quite successful results on the use of Russian interferon beta-1b biosimilar (Infibeta) in children, we can recommend this treatment as sufficiently safe and effective.

Adherence to Long-Term Interferon Beta-1b Injection Therapy in Patients with Multiple Sclerosis Using an Electronic Diary.

INTRODUCTION: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system requiring long-term treatment, which is often hampered by non-adherence to self-applicable therapies, provoking continued disease activity and health care system burdens. This study assessed the influence of a personal digital assistant (PDA) with diary function (n = 339 patients) on persistence and adherence to an interferon beta treatment regimen in comparison to a paper patient diary (n = 330 patients). METHODS: Patients who recently started with subcutaneous injections of interferon beta-1b were recruited in this prospective, non-interventional, national cohort study for an observational period of 2 years after successful completion of the initial dose escalation. RESULTS: Therapy persistence as assessed by the drop-out rate within 104 weeks was about 50% in both study cohorts. In male patients, the drop-out rate was 10% lower when using a PDA compared to the non-PDA group. Use of a PDA with an injection reminder function increased adherence to the injection schedule (every other day) by a mean of 24.5 injections over 24 months in comparison to use of a PDA without injection reminder function. CONCLUSION: Persistence in this study was in the published range of observational MS studies. Furthermore, in male patients continuation of therapy might be positively influenced by use of a PDA, and both female and male patients might benefit from an integrated reminder function. In conclusion, electronic diaries reminding patients of upcoming injections can promote an improved adherence to MS therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00902135. FUNDING: Bayer Vital GmbH.

Betaferon in chronic viral cardiomyopathy (BICC) trial: Effects of interferon-ß treatment in patients with chronic viral cardiomyopathy.

BACKGROUND: Chronic viral infections of the heart are considered one antecedent event leading to progressive dysfunction of the myocardium, often with an impaired prognosis due to a virus- or immune-mediated myocardial injury. Symptomatic treatment does not influence the viral cause of heart failure, and the effect of antiviral treatment has not been determined, yet. METHODS AND RESULTS: In this phase II study 143 patients with symptoms of heart failure and biopsy-based confirmation of the enterovirus (EV), adenovirus, and/or parvovirus B19 genomes in their myocardial tissue were randomly assigned to double-blind treatment, and received either placebo (n = 48) or 4 × 10(6) (n = 49) and 8 × 10(6) IU (n = 46) interferon beta-1b (IFN-ß-1b) for 24 weeks, in addition to standard heart failure treatment. Patients with active myocarditis or other specific causes of heart failure were excluded. Compared to placebo, virus elimination and/or virus load reduction was higher in the IFN-ß-1b groups (odds ratio 2.33, p = 0.048), similarly in both interferon groups and both strata. IFN-ß-1b treatment was associated with favourable effects on NYHA functional class (p = 0.013 at follow-up week 12), improvement in quality of life (Minnesota Heart Failure score; p = 0.032 at follow-up week 24) and patient global assessment (follow-up week 12 to follow-up week 24; p = 0.039). The frequency of adverse cardiac events was not higher in the IFN-ß-1b groups compared to the placebo group. CONCLUSIONS: Immunomodulatory IFN-ß-1b treatment is a well-tolerated and safe treatment option, leading to effective virus clearance or reduction of the virus load in patients with chronic viral cardiomyopathy. Favourable clinical effects assess quality of life, NYHA functional class, and patient global assessment. ClinicalTrials.gov identifier: NCT001185250.

A 10-year follow-up of the European multicenter trial of interferon ß-1b in secondary-progressive multiple sclerosis.

OBJECTIVES: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). METHODS: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. RESULTS: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R(2): 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R(2): 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. CONCLUSIONS: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed.