Early spinal cord pseudoatrophy in interferon-beta-treated multiple sclerosis.

BACKGROUND AND PURPOSE: Brain pseudoatrophy has been shown to play a pivotal role in the interpretation of brain atrophy measures during the first year of disease-modifying therapy in multiple sclerosis. Whether pseudoatrophy also affects the spinal cord remains unclear. The aim of this study was to analyze the extent of pseudoatrophy in the upper spinal cord during the first 2 years after therapy initiation and compare this to the brain. METHODS: A total of 129 patients from a prospective longitudinal multicentric national cohort study for whom magnetic resonance imaging scans at baseline, 12 months, and 24 months were available were selected for brain and spinal cord volume quantification. Annual percentage brain volume and cord area change were calculated using SIENA (Structural Image Evaluation of Normalized Atrophy) and NeuroQLab, respectively. Linear mixed model analyses were performed to compare patients on interferon-beta therapy (n = 84) and untreated patients (n = 45). RESULTS: Patients treated with interferon-beta demonstrated accelerated annual percentage brain volume and cervical cord area change in the first year after treatment initiation, whereas atrophy rates stabilized to a similar and not significantly different level compared to untreated patients during the second year. CONCLUSIONS: These results suggest that pseudoatrophy occurs not only in the brain, but also in the spinal cord during the first year of interferon-beta treatment.

Thrombotic microangiopathy due to acquired complement factor I deficiency in a male receiving interferon-beta treatment for multiple sclerosis.

AIMS: Interferon-beta (IFNß), the most widely prescribed medication for multiple sclerosis, is generally considered safe. Nevertheless, rare serious and/or life-threatening side effects have been reported such as thrombotic microangiopathy. A few mechanisms have been proposed to explain how interferon causes thrombotic microangiopathy, but immunological studies have been unable to pin this phenomenon down to a single pathophysiologic pathway. The aim of this article was to report a new mechanism explaining Interferon beta related thrombotic microangiopathy. METHODS: We report thrombotic microangiopathy in a 28-year-old male receiving interferon-beta treatment for multiple sclerosis. RESULTS: After three years of starting interferon beta therapy, the patient presented with malignant hypertension causing seizures, rapidly progressive renal failure requiring haemodialysis and haemolytic anaemia. Corticosteroid and plasma exchange sessions permitted haemolysis control. Nonetheless, the patient remained hemodialysis-dependent. Exploration of the complement system found a complement factor I deficiency whose activity normalized at the control carried out after 2 years. CONCLUSION: IFNß treatment may cause complement factor I deficit, which can lead to thrombotic microangiopathy and severe renal failure.

Trial of Fingolimod versus Interferon Beta-1a in Pediatric Multiple Sclerosis.

BACKGROUND: Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population. METHODS: In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 µg per week for up to 2 years. The primary end point was the annualized relapse rate. RESULTS: Of a total of 215 patients, 107 were assigned to fingolimod and 108 to interferon beta-1a. The mean age of the patients was 15.3 years. Among all patients, there was a mean of 2.4 relapses during the preceding 2 years. The adjusted annualized relapse rate was 0.12 with fingolimod and 0.67 with interferon beta-1a (absolute difference, 0.55 relapses; relative difference, 82%; P<0.001). The key secondary end point of the annualized rate of new or newly enlarged lesions on T2-weighted magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in 88.8% of patients who received fingolimod and 95.3% of those who received interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in the fingolimod group and included seizures (in 4 patients), infection (in 4 patients), and leukopenia (in 2 patients). Serious adverse events occurred in 7 patients (6.5%) in the interferon beta-1a group and included infection (in 2 patients) and supraventricular tachycardia (in 1 patient). CONCLUSIONS: Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events. Longer studies are required to determine the durability and safety of fingolimod in pediatric multiple sclerosis. (Funded by Novartis Pharma; PARADIGMS ClinicalTrials.gov number, NCT01892722 .).

Tocilizumab for the treatment of adult patients with severe COVID-19 pneumonia: A single-center cohort study.

Coronavirus disease 2019 (COVID-19) can lead to a massive cytokine release. The use of the anti-interleukin-6 receptor monoclonal antibody tocilizumab (TCZ) has been proposed in this hyperinflammatory phase, although supporting evidence is limited. We retrospectively analyzed 88 consecutive patients with COVID-19 pneumonia that received at least one dose of intravenous TCZ in our institution between 16 and 27 March 2020. Clinical status from day 0 (first TCZ dose) through day 14 was assessed by a 6-point ordinal scale. The primary outcome was clinical improvement (hospital discharge and/or a decrease of ≥2 points on the 6-point scale) by day 7. Secondary outcomes included clinical improvement by day 14 and dynamics of vital signs and laboratory values. Rates of clinical improvement by days 7 and 14 were 44.3% (39/88) and 73.9% (65/88). Previous or concomitant receipt of subcutaneous interferon-ß (adjusted odds ratio [aOR]: 0.23; 95% confidence interval [CI]: 0.06-0.94; P = .041) and serum lactate dehydrogenase more than 450 U/L at day 0 (aOR: 0.25; 95% CI: 0.06-0.99; P = .048) were negatively associated with clinical improvement by day 7. All-cause mortality was 6.8% (6/88). Body temperature and respiratory and cardiac rates significantly decreased by day 1 compared to day 0. Lymphocyte count and pulse oximetry oxygen saturation/FiO2 ratio increased by days 3 and 5, whereas C-reactive protein levels dropped by day 2. There were no TCZ-attributable adverse events. In this observational single-center study, TCZ appeared to be useful and safe as immunomodulatory therapy for severe COVID-19 pneumonia.

Quantifying the risk of disease reactivation after interferon and glatiramer acetate discontinuation in multiple sclerosis: The VIAADISC score.

BACKGROUND AND PURPOSE: There is a lack of evidence guiding discontinuation of disease-modifying therapy (DMT) in relapsing multiple sclerosis (RMS). Thus, the objective of this study was to generate and validate a risk score for disease reactivation after DMT discontinuation in RMS. METHODS: We drew a generation and validation dataset from two separate prospectively collected observational databases including RMS patients who received interferon-ß or glatiramer acetate for ≥12 months, then discontinued DMT for ≥6 months and had ≥2 years of follow-up available. In the generation sample (n = 168), regression analysis was performed to identify clinical or magnetic resonance imaging (MRI) variables independently predicting disease reactivation after DMT discontinuation. A predictive score was calculated using the variables included in the multivariable model and applied to the validation sample (n = 98). RESULTS: The variables included in the final model as independent predictors of disease reactivation were age at discontinuation, MRI activity at discontinuation, and duration of clinical stability (all p < 0.001). The resulting score was able to robustly identify patients at high (83%-85%), moderate (36%-38%), and low risk (7%) of disease reactivation within 5 years after DMT discontinuation in both cohorts. CONCLUSIONS: The composite VIAADISC score is a valuable tool to inform and support patients and neurologists in the process of decision making to discontinue injectable DMTs.

Manifestation of Susac syndrome during interferon beta-1a and glatiramer acetate treatment for misdiagnosed multiple sclerosis: a case report.

BACKGROUND: Susac syndrome (SS) is characterized by the triad of encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss. However, the diagnosis of SS remains difficult because the clinical triad rarely occurs at disease onset, and symptom severity varies. SS symptoms often suggest other diseases, in particular multiple sclerosis (MS), which is more common. Misdiagnosing SS as MS may cause serious complications because MS drugs, such as interferon beta-1a, can worsen the course of SS. This case report confirms previous reports that the use of interferon beta-1a in the course of misdiagnosed MS may lead to exacerbation of SS. Moreover, our case report shows that glatiramer acetate may also exacerbate the course of SS. To the best of our knowledge, this is the first reported case of exacerbation of SS by glatiramer acetate. CASE PRESENTATION: We present a case report of a patient with a primary diagnosis of MS who developed symptoms of SS during interferon beta-1a treatment for MS; these symptoms were resolved after the discontinuation of the treatment. Upon initiation of glatiramer acetate treatment, the patient developed the full clinical triad of SS. The diagnosis of MS was excluded, and glatiramer acetate therapy was discontinued. The patient's neurological state improved only after the use of a combination of corticosteroids, intravenous immunoglobulins, and azathioprine. CONCLUSIONS: The coincidence of SS signs and symptoms with treatment for MS, first with interferon beta-1a and then with glatiramer acetate, suggests that these drugs may influence the course of SS. This case report indicates that treatment with glatiramer acetate may modulate or even exacerbate the course of SS.

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis.

BACKGROUND: B cells influence the pathogenesis of multiple sclerosis. Ocrelizumab is a humanized monoclonal antibody that selectively depletes CD20+ B cells. METHODS: In two identical phase 3 trials, we randomly assigned 821 and 835 patients with relapsing multiple sclerosis to receive intravenous ocrelizumab at a dose of 600 mg every 24 weeks or subcutaneous interferon beta-1a at a dose of 44 µg three times weekly for 96 weeks. The primary end point was the annualized relapse rate. RESULTS: The annualized relapse rate was lower with ocrelizumab than with interferon beta-1a in trial 1 (0.16 vs. 0.29; 46% lower rate with ocrelizumab; P<0.001) and in trial 2 (0.16 vs. 0.29; 47% lower rate; P<0.001). In prespecified pooled analyses, the percentage of patients with disability progression confirmed at 12 weeks was significantly lower with ocrelizumab than with interferon beta-1a (9.1% vs. 13.6%; hazard ratio, 0.60; 95% confidence interval [CI], 0.45 to 0.81; P<0.001), as was the percentage of patients with disability progression confirmed at 24 weeks (6.9% vs. 10.5%; hazard ratio, 0.60; 95% CI, 0.43 to 0.84; P=0.003). The mean number of gadolinium-enhancing lesions per T1-weighted magnetic resonance scan was 0.02 with ocrelizumab versus 0.29 with interferon beta-1a in trial 1 (94% lower number of lesions with ocrelizumab, P<0.001) and 0.02 versus 0.42 in trial 2 (95% lower number of lesions, P<0.001). The change in the Multiple Sclerosis Functional Composite score (a composite measure of walking speed, upper-limb movements, and cognition; for this z score, negative values indicate worsening and positive values indicate improvement) significantly favored ocrelizumab over interferon beta-1a in trial 2 (0.28 vs. 0.17, P=0.004) but not in trial 1 (0.21 vs. 0.17, P=0.33). Infusion-related reactions occurred in 34.3% of the patients treated with ocrelizumab. Serious infection occurred in 1.3% of the patients treated with ocrelizumab and in 2.9% of those treated with interferon beta-1a. Neoplasms occurred in 0.5% of the patients treated with ocrelizumab and in 0.2% of those treated with interferon beta-1a. CONCLUSIONS: Among patients with relapsing multiple sclerosis, ocrelizumab was associated with lower rates of disease activity and progression than interferon beta-1a over a period of 96 weeks. Larger and longer studies of the safety of ocrelizumab are required. (Funded by F. Hoffmann-La Roche; OPERA I and II ClinicalTrials.gov numbers, NCT01247324 and NCT01412333 , respectively.).

Severe Necrosis and Cellulitis Complicating Treatment with Interferon ß-1a.

PURPOSE: A case report with a review of the current literature concerning cutaneous necrosis has occasionally been reported in interferon therapy. CASE REPORT: We report a 19-year-old woman diagnosed multiple sclerosis for three years. She selfinjected the standard dose of recombinant interferonß-1a (12 million units) subcutaneously three times a week. Severe necrotizing cutaneous reactions over abdomen Happened and she must receive parental antibiotics and surgical debridement. CONCLUSION: Our observation emphasizes the importance of educating patients on the proper selfadministration of subcutaneous injections of interferon ß.

[PROGNOSTIC VALUE OF BIOMARKERS OF MULTIPLE SCLEROSIS ACTIVITY].

About 30-40% of multiple sclerosis (MS) patients treated with interferon-beta (IFN-ß) develop neutralizing antibodies (NABs) to IFN-ß. NABs reduce bioavailability of IFN-ß, which leads to a decrease in the therapy effectiveness. The introduction of IFN-ß induce production of several proteins, which are used as markers of the therapy effectiveness. In this study, we assessed the prognostic significance of MS activity biomarkers in relation to the clinical data of MS patients treated with IFN-ß. The study involved 30 MS patients receiving IFN-ß. The average duration of therapy was 3.5 (3.4-5.3) years. The study showed the prevalence of NAbs formation in MS patients was 13% of cases, a year later - 30%. The level of viperin in patients without exacerbations during the observation period was lower than in patients with exacerbations. The study revealed the prognostic significance of viperin in relation to the frequency of exacerbations: viperin concentration above 0.2 ng / ml is a risk factor for exacerbation of MS. The results of this study suggest that viperin concentration in the serum could be used a prognostic marker in MS patients treated with interferons.

Intralesional immunotherapy for the treatment of warts: A network meta-analysis.

BACKGROUND: Without clear evidence, selecting among the existing immunotherapeutic options for warts remains challenging. OBJECTIVE: Through network meta-analyses, we aimed to evaluate the comparative efficacy of different intralesional immunotherapeutic modalities. METHODS: We included randomized controlled trials comparing intralesional immunotherapeutic modalities to cryotherapy, placebo, or imiquimod. All outcomes were presented as odds ratios (ORs) with 95% confidence intervals. Both conventional and network meta-analyses (with a frequentist approach) were conducted on R software. The P-score was used to rank different treatments. RESULTS: Network meta-analysis of 17 randomized controlled trials (1676 patients) showed that PPD (purified protein derivative vaccine, OR 39.56), MMR (measles, mumps, rubella vaccine, OR 17.46) and interferon ß (OR 15.55) had the highest efficacy in terms of complete recovery at the primary site compared with placebo. Regarding complete recovery at the distant site, autoinoculation (OR 79.95), PPD (OR 42.95), and MMR (OR 15.39) were all statistically superior to placebo. According to the P-score, MMR was more effective than other modalities in reducing the recurrence rate at the same site. LIMITATIONS: Relatively small sample size in some comparisons and variability in baseline characteristics. CONCLUSION: PPD and MMR were the most effective in achieving complete primary and distant recovery (along with autoinoculation for distant recovery) and reducing the recurrence rate at the same site compared with cryotherapy and other immunotherapeutic modalities.

Use and safety of disease-modifying therapy in pregnant women with multiple sclerosis.

PURPOSE: The purpose of this study is to describe dispensing patterns and comparative safety of disease-modifying therapies (DMTs) during pregnancy in women with multiple sclerosis (MS). METHODS: We identified pregnancies from the Truven Health Marketscan® Commercial Claims and Encounters Database (2011-2015) and ascertained MS before delivery from inpatient and outpatient claims. We computed the proportion of women with DMT dispensing claims around pregnancy and estimated risk ratios of spontaneous abortion, infections, cesarean section, preterm delivery, poor fetal growth, preeclampsia, and major structural malformations by DMT exposure. RESULTS: Of 984 058 pregnancies, 1649 were to women with MS. Thirty-five percent of women with MS filled a prescription for a DMT in the 90 days before pregnancy. DMT use declined during pregnancy but increased again after delivery. Glatiramer acetate and interferon beta were most commonly dispensed. Pregnancies with and without early DMT exposure had similar risks of outcomes to one another and to pregnancies in women without MS. Small numbers did not allow evaluation of specific DMTs. CONCLUSIONS: Approximately one third of commercially insured women with MS in the United States uses DMTs before conception. Neither MS itself nor early pregnancy use of DMTs overall seems to be associated with a substantial risk of adverse pregnancy outcomes.

Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis.

BACKGROUND: Daclizumab high-yield process (HYP) is a humanized monoclonal antibody that binds to CD25 (alpha subunit of the interleukin-2 receptor) and modulates interleukin-2 signaling. Abnormalities in interleukin-2 signaling have been implicated in the pathogenesis of multiple sclerosis and other autoimmune disorders. METHODS: We conducted a randomized, double-blind, active-controlled, phase 3 study involving 1841 patients with relapsing-remitting multiple sclerosis to compare daclizumab HYP, administered subcutaneously at a dose of 150 mg every 4 weeks, with interferon beta-1a, administered intramuscularly at a dose of 30 µg once weekly, for up to 144 weeks. The primary end point was the annualized relapse rate. RESULTS: The annualized relapse rate was lower with daclizumab HYP than with interferon beta-1a (0.22 vs. 0.39; 45% lower rate with daclizumab HYP; P<0.001). The number of new or newly enlarged hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) over a period of 96 weeks was lower with daclizumab HYP than with interferon beta-1a (4.3 vs. 9.4; 54% lower number of lesions with daclizumab HYP; P<0.001). At week 144, the estimated incidence of disability progression confirmed at 12 weeks was 16% with daclizumab HYP and 20% with interferon beta-1a (P=0.16). Serious adverse events, excluding relapse of multiple sclerosis, were reported in 15% of the patients in the daclizumab HYP group and in 10% of those in the interferon beta-1a group. Infections were more common in the daclizumab HYP group than in the interferon beta-1a group (in 65% vs. 57% of the patients, including serious infection in 4% vs. 2%), as were cutaneous events such as rash or eczema (in 37% vs. 19%, including serious events in 2% vs. <1%) and elevations in liver aminotransferase levels that were more than 5 times the upper limit of the normal range (in 6% vs. 3%). CONCLUSIONS: Among patients with relapsing-remitting multiple sclerosis, daclizumab HYP showed efficacy superior to that of interferon beta-1a with regard to the annualized relapse rate and lesions, as assessed by means of MRI, but was not associated with a significantly lower risk of disability progression confirmed at 12 weeks. The rates of infection, rash, and abnormalities on liver-function testing were higher with daclizumab HYP than with interferon beta-1a. (Funded by Biogen and AbbVie Biotherapeutics; DECIDE ClinicalTrials.gov number, NCT01064401.).

Disease-modifying drugs for multiple sclerosis and infection risk: a cohort study.

OBJECTIVE: Little is known about disease-modifying treatments (DMTs) for multiple sclerosis (MS) and infection risk in clinical practice. We examined the association between DMTs and infection-related medical encounters. METHODS: Using population-based administrative data from British Columbia, Canada, we identified MS cases and followed them from their first demyelinating event (1996-2013) until emigration, death or study end (December 2013). Associations between DMT exposure (by DMT generation or class) and infection-related physician or hospital claims were assessed using recurrent time-to-events models, adjusted for age, sex, socioeconomic status, index year and comorbidity count. Results were reported as adjusted HRs (aHRs). RESULTS: Of 6793 MS cases, followed for 8.5 years (mean), 1716 (25.3%) were DMT exposed. Relative to no DMT, exposure to any first-generation DMT (beta-interferon or glatiramer acetate) was not associated with infection-related physician claims (aHR: 0.96; 95% CI 0.89 to 1.02), nor was exposure to these drug classes when assessed separately. Exposure to any second-generation DMT (oral DMT or natalizumab) was associated with an increased hazard of an infection-related physician claim (aHR: 1.47; 95% CI 1.16 to 1.85); when assessed individually, the association was significant for natalizumab (aHR: 1.59; 95% CI 1.19 to 2.11) but not the oral DMTs (aHR: 1.17; 95% CI 0.88 to 1.56). While no DMTs were associated with infection-related hospital claims, these hospitalisations were also uncommon. CONCLUSION: Exposure to first-generation DMTs was not associated with an altered infection risk. However, exposure to the second-generation DMTs was, with natalizumab associated with a 59% increased risk of an infection-related physician claim. Continued pharmacovigilance is warranted, including an investigation of the DMT-associated infection burden on patient outcomes.

Localized pigmentation disorder after subcutaneous pegylated interferon beta-1a injection.

We report the case of a 42-year-old female patient who developed peculiar skin lesions due to subcutaneous polyethylene glycol (PEG) interferon beta-1a. The dermatological examination showed hypochromic macules that had coalesced into a 10-cm-diameter patch. On the abdomen injection sites, there was a greyish diffuse hyperpigmentation arranged irregularly in annular macules. Fungal infection, vitiligo and pityriasis alba were excluded. After 6 months, the lesions had worsened. This is the first case of localized pigmentation disorder reported with interferon beta, and while the clinical findings are not ascribable to vitiligo or interferon-related facial/mucosal hyperpigmentation, they may partially share the underlining mechanisms.

JCOG0911 INTEGRA study: a randomized screening phase II trial of interferonß plus temozolomide in comparison with temozolomide alone for newly diagnosed glioblastoma.

PURPOSE: This study explored the superiority of temozolomide (TMZ) + interferonß (IFNß) to standard TMZ as treatment for newly diagnosed glioblastoma (GBM) via randomized phase II screening design. EXPERIMENTAL DESIGN: Eligibility criteria included histologically proven GBM, with 50% of the tumor located in supratentorial areas, without involvement of the optic, olfactory nerves, and pituitary gland and without multiple lesions and dissemination. Patients in the TMZ + radiotherapy (RT) arm received RT (2.0 Gy/fr/day, 30 fr) with TMZ (75 mg/m2, daily) followed by TMZ maintenance (100-200 mg/m2/day, days 1-5, every 4 weeks) for 2 years. Patients in the TMZ + IFNß + RT arm intravenously received IFNß (3 MU/body, alternative days during RT and day 1, every 4 weeks during maintenance period) and TMZ + RT. The primary endpoint was overall survival (OS). The planned sample size was 120 (one-sided alpha 0.2; power 0.8). RESULTS: Between Apr 2010 and Jan 2012, 122 patients were randomized. The median OS with TMZ + RT and TMZ + IFNß + RT was 20.3 and 24.0 months (HR 1.00, 95% CI 0.65-1.55; one-sided log rank P = 0.51). The median progression-free survival times were 10.1 and 8.5 months (HR 1.25, 95% CI 0.85-1.84). The incidence of neutropenia with the TMZ + RT and the TMZ + IFNß + RT (grade 3-4, CTCAE version 3.0) was 12.7 versus 20.7% during concomitant period and was 3.6 versus 9.3% during maintenance period. The incidence of lymphopenia was 54.0 versus 63.8% and 34.5 versus 41.9%. CONCLUSIONS: TMZ + IFNß + RT is not considered as a candidate for the following phase III trial, and TMZ + RT remained to be a most promising treatment. This trial was registered with the UMIN Clinical Trials Registry: UMIN000003466.

Pharmacological interventions for acute hepatitis C infection.

BACKGROUND: Hepatitis C virus (HCV) is a single-stranded RNA (ribonucleic acid) virus that has the potential to cause inflammation of the liver. The traditional definition of acute HCV infection is the first six months following infection with the virus. Another commonly used definition of acute HCV infection is the absence of HCV antibody and subsequent seroconversion (presence of HCV antibody in a person who was previously negative for HCV antibody). Approximately 40% to 95% of people with acute HCV infection develop chronic HCV infection, that is, have persistent HCV RNA in their blood. In 2010, an estimated 160 million people worldwide (2% to 3% of the world's population) had chronic HCV infection. The optimal pharmacological treatment of acute HCV remains controversial. Chronic HCV infection can damage the liver. OBJECTIVES: To assess the comparative benefits and harms of different pharmacological interventions in the treatment of acute HCV infection through a network meta-analysis and to generate rankings of the available pharmacological treatments according to their safety and efficacy. However, it was not possible to assess whether the potential effect modifiers were similar across different comparisons. Therefore, we did not perform the network meta-analysis and instead we assessed the comparative benefits and harms of different interventions versus each other or versus no intervention using standard Cochrane methodology. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded, World Health Organization International Clinical Trials Registry Platform, and randomised controlled trials registers to April 2016 to identify randomised clinical trials on pharmacological interventions for acute HCV infection. SELECTION CRITERIA: We included only randomised clinical trials (irrespective of language, blinding, or publication status) in participants with acute HCV infection. We excluded trials which included previously liver transplanted participants and those with other coexisting viral diseases. We considered any of the various pharmacological interventions compared with placebo or each other. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We calculated the odds ratio (OR) and rate ratio with 95% confidence intervals (CI) using both fixed-effect and random-effects models based on the available-participant analysis with Review Manager 5. We assessed risk of bias according to Cochrane, controlled risk of random errors with Trial Sequential Analysis, and assessed the quality of the evidence using GRADE. MAIN RESULTS: We identified 10 randomised clinical trials with 488 randomised participants that met our inclusion criteria. All the trials were at high risk of bias in one or more domains. Overall, the evidence for all the outcomes was very low quality evidence. Nine trials (467 participants) provided information for one or more outcomes. Three trials (99 participants) compared interferon-alpha versus no intervention. Three trials (90 participants) compared interferon-beta versus no intervention. One trial (21 participants) compared pegylated interferon-alpha versus no intervention, but it did not provide any data for analysis. One trial (41 participants) compared MTH-68/B vaccine versus no intervention. Two trials (237 participants) compared pegylated interferon-alpha versus pegylated interferon-alpha plus ribavirin. None of the trials compared direct-acting antivirals versus placebo or other interventions. The mean or median follow-up period in the trials ranged from six to 36 months.There was no short-term mortality (less than one year) in any group in any trial except for one trial where one participant died in the pegylated interferon-alpha plus ribavirin group (1/95: 1.1%). In the trials that reported follow-up beyond one year, there were no further deaths. The number of serious adverse events was higher with pegylated interferon-alpha plus ribavirin than with pegylated interferon-alpha (rate ratio 2.74, 95% CI 1.40 to 5.33; participants = 237; trials = 2; I2 = 0%). The proportion of people with any adverse events was higher with interferon-alpha and interferon-beta compared with no intervention (OR 203.00, 95% CI 9.01 to 4574.81; participants = 33; trials = 1 and OR 27.88, 95% CI 1.48 to 526.12; participants = 40; trials = 1). None of the trials reported health-related quality of life, liver transplantation, decompensated liver disease, cirrhosis, or hepatocellular carcinoma. The proportion of people with chronic HCV infection as indicated by the lack of sustained virological response was lower in the interferon-alpha group versus no intervention (OR 0.27, 95% CI 0.09 to 0.76; participants = 99; trials = 3; I2 = 0%). The differences between the groups were imprecise or not estimable (because neither group had any events) for all the remaining comparisons.Four of the 10 trials (40%) received financial or other assistance from pharmaceutical companies who would benefit from the findings of the research; the source of funding was not available in five trials (50%), and one trial (10%) was funded by a hospital. AUTHORS' CONCLUSIONS: Very low quality evidence suggests that interferon-alpha may decrease the incidence of chronic HCV infection as measured by sustained virological response. However, the clinical impact such as improvement in health-related quality of life, reduction in cirrhosis, decompensated liver disease, and liver transplantation has not been reported. It is also not clear whether this finding is applicable in the current clinical setting dominated by the use of pegylated interferons and direct-acting antivirals, although we found no evidence to support that pegylated interferons or ribavirin or both are effective in people with acute HCV infection. We could find no randomised trials comparing direct-acting antivirals with placebo or other interventions for acute HCV infection. There is significant uncertainty in the benefits and harms of the interventions, and high-quality randomised clinical trials are required.

Pharmacogenetic study of long-term response to interferon-ß treatment in multiple sclerosis.

The aim of the study is the identification of genetic factors that influence the long-term response to interferon-ß (IFNß) (4-year follow-up). We performed a genome-wide association study in 337 IFNß-treated Italian multiple sclerosis patients at the extreme of treatment response, and we meta-analyzed association effects, integrating results with pathway analysis, gene-expression profiling of IFNß-stimulated peripheral blood mononuclear cells from 20 healthy controls (HC) and expression quantitative locus (eQTL) analyses. From meta-analysis, 43 markers were associated at P<10-4, and two of them (rs7298096 and rs4726460) pointed to two genes, NINJ2 and TBXAS1, that were significantly downregulated after IFNß stimulation in HC (P=3.1 × 10-9 and 5.6 × 10-10). We also observed an eQTL effect for the allele associated with favorable treatment response (rs4726460A); moreover, TBXAS1 appeared downregulated upon IFNß administration (ß=-0.39; P=0.02). Finally, we found an enrichment of pathways related to inflammatory processes and presynaptic membrane, the latter with involvement of genes related to glutamatergic system (GRM3 and GRIK2), confirming its potential role in the response to IFNß.

The impact of drugs for multiple sclerosis on sleep.

Although there is a growing literature on the presence of sleep disorders in multiple sclerosis (MS), few studies have specifically addressed the impact of drugs on sleep of these patients. Moreover, even when sleep is considered, quantitative assessment by standardized questionnaires or polysomnography is lacking. The studies that have been done highlight that interferon-beta and some symptomatic medications may affect sleep, thus contributing to fatigue, depression, and poor quality of life; conversely, natalizumab and cannabinoids may improve sleep. Common limitations of the literature reviewed here are small sample size, selection bias, and often a lack of objective outcome measures. Clinicians need to remember to ask about sleep in all MS patients and intervene when appropriate. A systematic approach that takes sleep into account is recommended to enhance recognition and appropriate management of sleep disruption, including disorders related to medication. Consideration of the impact on sleep should also be part of the design of trials of new therapies.

Rhabdomyolysis and interferon-ß: case report and short review.

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

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