Interferon Beta Treatment Research Articles

Thrombotic microangiopathy due to acquired ADAMTS13 deficiency in a patient receiving interferon-beta treatment for multiple sclerosis

Thrombotic microangiopathies (TMAs) can be due to inherited or acquired ADAMTS13 deficiency. Acquired deficiency is mainly associated with autoantibodies directed to ADAMTS13, including drug-induced forms. A few cases of TMA have been reported in association with interferon-alpha treatment and more rarely with interferon-beta. We report the case of a 52-year-old male with TMA-associated severe renal failure secondary to severe ADAMTS13 deficiency due to an anti-ADAMTS13 IgG antibody which developed after interferon-beta treatment for multiple sclerosis. Treatment included interferon-beta discontinuation, immediate plasma exchange therapy, corticosteroids, and hemodialysis. After an initial hematologic improvement, early hemolysis relapse led us to introduce rituximab allowing durable hematologic recovery. This is the first reported case of interferon-beta-induced TMA due to acquired ADAMTS13 deficiency that was treated by rituximab.

Oxidative Stress and Proinflammatory Cytokines Contribute to Demyelination and Axonal Damage in a Cerebellar Culture Model of Neuroinflammation

BackgroundDemyelination and axonal damage are critical processes in the pathogenesis of multiple sclerosis (MS). Oxidative stress and pro-inflammatory cytokines elicited by inflammation mediates tissue damage.Methods/Principal FindingsTo monitor the demyelination and axonal injury associated with microglia activation we employed a model using cerebellar organotypic cultures stimulated with lipopolysaccharide (LPS). Microglia activated by LPS released pro-inflammatory cytokines (IL-1β, IL-6 and TNFα), and increased the expression of inducible nitric oxide synthase (iNOS) and production of reactive oxygen species (ROS). This activation was associated with demyelination and axonal damage in cerebellar cultures. Axonal damage, as revealed by the presence of non-phosphorylated neurofilaments, mitochondrial accumulation in axonal spheroids, and axonal transection, was associated with stronger iNOS expression and concomitant increases in ROS. Moreover, we analyzed the contribution of pro-inflammatory cytokines and oxidative stress in demyelination and axonal degeneration using the iNOS inhibitor ethyl pyruvate, a free-scavenger and xanthine oxidase inhibitor allopurinol, as well as via blockage of pro-inflammatory cytokines using a Fc-TNFR1 construct. We found that blocking microglia activation with ethyl pyruvate or allopurinol significantly decreased axonal damage, and to a lesser extent, demyelination. Blocking TNFα significantly decreased demyelination but did not prevented axonal damage. Moreover, the most common therapy for MS, interferon-beta, was used as an example of an immunomodulator compound that can be tested in this model. In vitro, interferon-beta treatment decreased oxidative stress (iNOS and ROS levels) and the release of pro-inflammatory cytokines after LPS stimulation, reducing axonal damage.ConclusionThe model of neuroinflammation using cerebellar culture stimulated with endotoxin mimicked myelin and axonal damage mediated by the combination of oxidative stress and pro-inflammatory cytokines. This model may both facilitate understanding of the events involved in neuroinflammation and aid in the development of neuroprotective therapies for the treatment of MS and other neurodegenerative diseases.

Natural interferon-beta plus ribavirin therapy led to sustained virological response after seven unsuccessful courses of anti-viral treatment in a chronic hepatitis C patient

We describe a patient infected with hepatitis C virus (HCV) genotype 1 who failed to respond to interferon with or without ribavirin seven times but who then achieved sustained virological response by the combination of interferon-beta plus ribavirin treatment for 48weeks. He did not respond to stronger treatment such as prolonged peginterferon plus ribavirin treatment for 87weeks. It might be rare to treat a patient with interferon 8 times considering the cost and time, since patients failing interferon treatment several times are regarded to be refractory to interferon. It is possible that the difference in biological effects between interferon-alfa and interferon-beta might have resulted in a different outcome in our patient. Interferon-beta plus ribavirin therapy might be one of the treatment options for certain patients chronically infected with HCV who do not respond to standard care treatment.

Interferon Beta Use and Disability Prevention in Relapsing-Remitting Multiple Sclerosis

Context: Interferon beta is widely prescribed to treat multiple sclerosis (MS); however, its relationship with disability progression has yet to be established. Objective: To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS. Design, Setting, and Patients: Retrospective cohort study based on prospectively collected data (1985-2008) from British Columbia, Canada. Patients with relapsing-remitting MS treated with interferon beta (n = 868) were compared with untreated contemporary (n = 829) and historical (n = 959) cohorts. Main Outcome Measures: The main outcome measure was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained score of 6 (requiring a cane to walk 100 m; confirmed at >150 days with no measurable improvement) on the Expanded Disability Status Scale (EDSS) (range, 0-10, with higher scores indicating higher disability). A multivariable Cox regression model with interferon beta treatment included as a time-varying covariate was used to assess the hazard of disease progression associated with interferon beta treatment. Analyses also included propensity score adjustment to address confounding by indication. Results: The median active follow-up times (first to last EDSS measurement) were as follows: for the interferon beta–treated cohort, 5.1 years (interquartile range [IQR], 3.0-7.0 years); for the contemporary control cohort, 4.0 years (IQR, 2.1-6.4 years); and for the historical control cohort, 10.8 years (IQR, 6.3-14.7 years). The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8%, 5.3%, and 23.1% in the 3 cohorts, respectively. After adjustment for potential baseline confounders (sex, age, disease duration, and EDSS score), exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort (hazard ratio, 1.30; 95% CI, 0.92-1.83; P = .14) or the historical control cohort (hazard ratio, 0.77; 95% CI, 0.58-1.02; P = .07) were considered. Further adjustment for comorbidities and socioeconomic status, where possible, did not change interpretations, and propensity score adjustment did not substantially change the results. Conclusion: Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability.

Alpha-tocopherol and MRI Outcomes in Multiple Sclerosis – Association and Prediction

ObjectiveAlpha-tocopherol is the main vitamin E compound in humans, and has important antioxidative and immunomodulatory properties. The aim of this study was to study alpha-tocopherol concentrations and their relationship to disease activity in Norwegian multiple sclerosis (MS) patients.MethodsProspective cohort study in 88 relapsing-remitting MS (RRMS) patients, originally included in a randomised placebo-controlled trial of omega-3 fatty acids (the OFAMS study), before and during treatment with interferon beta. The patients were followed for two years with repeated 12 magnetic resonance imaging (MRI) scans and nine serum measurements of alpha-tocopherol.ResultsDuring interferon beta (IFNB) treatment, each 10 µmol/L increase in alpha-tocopherol reduced the odds (CI 95%) for simultaneous new T2 lesions by 36.8 (0.5–59.8) %, p = 0.048, and for combined unique activity by 35.4 (1.6–57.7) %, p = 0.042, in a hierarchical regression model. These associations were not significant prior to IFNB treatment, and were not noticeably changed by gender, age, body mass index, HLA-DRB1*15, treatment group, compliance, or the concentrations of 25-hydroxyvitamin D, retinol, neutralising antibodies against IFNB, or the omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid. The corresponding odds for having new T1 gadolinium enhancing lesions two months later was reduced by 65.4 (16.5–85.7) %, p = 0.019, and for new T2 lesions by 61.0 (12.4–82.6) %, p = 0.023.ConclusionDuring treatment with IFNB, increasing serum concentrations of alpha-tocopherol were associated with reduced odds for simultaneous and subsequent MRI disease activity in RRMS patients.

Rare MEFV variants are not associated with risk to develop multiple sclerosis and severity of disease

Background: Recent studies suggest an association between rare variants in Mediterranean fever (MEFV), the gene underlying the auto-inflammatory disorder Familial Mediterranean Fever (FMF), the risk to develop multiple sclerosis (MS) and severity of MS. Objective: The objective of this study is to investigate these findings in a Belgian MS population and to test for association with additional clinical parameters such as treatment response. Methods: MEFV was sequenced in a cohort of MS patients (N=94) suffering from auto-inflammatory symptoms, systemic side-effects upon interferon-beta (IFN-β) treatment, or patients in whom glatiramer acetate was started as first choice due to severe fatigue. Five rare non-synonymous variants were detected in this cohort and subsequently genotyped in 915 MS patients and 763 healthy controls. Results: We observed no association between these alleles and susceptibility to MS (p-value=0.99) or disease severity (p-value=0.78). However, we did observe a correlation between carrying an MEFV variant and the development of systemic side-effects upon IFN-β treatment (p-value=0.022). Conclusion: In contrast to recent smaller studies, we did not find an association between carrying a rare variant in the MEFV gene and the risk to develop MS or disease severity. However, carrying rare variants in MEFV was associated with the development of severe systemic side-effects upon IFN-β treatment.

A case of exacerbated multiphasic disseminated encephalomyelitis after interferon beta treatment

Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disorder of the central nervous system (CNS), which can be monophasic or with repeated episodes. Relapsing ADEM can be misdiagnosed as multiple sclerosis (MS). We describe here a 16-year-old female patient with multiphasic disseminated encephalomyelitis (MDEM), which was exacerbated after an interferon beta (INF-β) treatment. The patient presented with polysymptomatic and encephalopathic features at the first attack and was definitively diagnosed with ADEM. During the following 28months, she had two relapses, with the lesions spatially disseminated in time and space, but without encephalopathy. She was diagnosed with MS and started on treatment with IFN-β injection. A severe relapse occurred 5months after starting IFN-β treatment, with both the clinical and MRI characteristics worse than during the former 2 relapses, meeting the diagnostic criteria for MDEM. Treatment with IFN-β was halted, with no new relapses observed over the following 9months. These findings suggest that treating MDEM patients with IFN-β may exacerbate the disease, similar to that observed during IFN-β treatment of patients with neuromyelitis optica. Caution should be exercised when treating these patients with IFN-β.

The Effect of Methylprednisolone, Interferon Beta and Glatiramer Acetate Treatment on the Levels of Leptin, Adiponectin and Resistin in Multiple Sclerosis Patients

Objective: Adipocytokines are cytokine-like mediators that link adipose tissue function with inflammatory and autoimmune processes, and have a suggested role in the pathogenesis of multiple sclerosis (MS). The aim of this study was to analyze the effects of methylprednisolone, interferon-1b (INF) and glatiramer acetate (GA) on leptin, resistin, and adiponectin concentrations in relapsing-remitting MS (RRMS) patients. Methods: The study included 154 RRMS patients who were hospitalized in the Department of Neurology, Poznan University of Medical Sciences. The comparison group included 31 patients with myasthenia gravis (MG) and 39 healthy controls. Serum levels of leptin, adiponectin, and resistin were evaluated before treatment initiation. In the RRMS patients treated with methylprednisolone, adipocytokine evaluation was performed one day after the therapy. Patients treated with INF or GA were evaluated at 1 month and 6 months. Routine neurological examination and expanded disability status scale (EDSS) scoring were performed, and MRI scans were analyzed for the localization of demyelinating plaques. Body mass index, glycemia, and insulin levels were evaluated and homeostatic model assessment insulin resistance index (HOMA-IR) was calculated. Results: Adiponectin and resistin levels in RRMS and MG patients were increased compared to controls, but adiponectin levels were lower in RRMS than MG patients. Intravenous methylprednisolone in RRMS with relapse caused an elevation of leptin concentration. INF treatment caused a significant, time-dependent effect on resistin concentration. GA administration influenced only resistin concentration as a long-term effect. No relationship between adipocytokines and metabolic status or insulin resistance was found. Conclusions: We identified resistin as the most important adipocytokine associated with RRMS. Its concentrations are reduced by first line immunomodulatory treatment, which produces a milieu of beneficial inflammatory and metabolic processes. On the other hand, the routine treatment of MS relapses with methylprednisolone induces harmful metabolic and inflammatory effects that may be mediated by elevated leptin levels.

Longitudinal interferon-β effects in multiple sclerosis: Differential regulation of IL-10 and IL-17A, while no sustained effects on IFN-γ, IL-4 or IL-13

BackgroundRecent studies in experimental models and in vitro indicate lowering of IL-17/Th17 as an important mechanism of interferon-beta (IFN-β) treatment in multiple sclerosis (MS). Material and methodsIn this longitudinal study of MS patients (n=25), spontaneous and myelin antigen-induced secretion of IL-4, IFN-γ and IL-10 (ELISPOT), mitogen stimulated secretion of IL-13 and IL-17A (ELISA) and circulating cytokine levels (Luminex) were recorded at inclusion and after 1.5, 3, 6 and 12months of IFN-β treatment. ResultsEarly changes were noted for IL-4, while after one year of treatment the only recorded significant effects were a decrease in secreted IL-17A levels and an increase in IL-10 secreting cells. While IL-17A levels tended to be higher in non-responders (n=8), the decrease in IL-17A levels seemed to be more pronounced in responders (n=17) showing significantly lower IL-17A levels after one year as compared with non-responders. ConclusionIFN-β treatment seems to mainly affect IL-17/IL-10-associated pathways rather than the IFN-γ/IL-4 axis.

Treatment With Interferon Beta for Multiple Sclerosis

TotheEditor:DrShirani andcolleagues suggested that interferonbeta treatmentwasnotassociatedwithareductioninprogression of long-term disability in patients with multiple sclerosis (MS). In contrast, long-term follow-up of a randomized controlled trialof interferonbeta-1breporteda60%to70%reduction in long-term disability and a 46% to 47% reduction in mortality. Although Shirani et al did not cite these studies, both reports used bias-reduction methods. Time zero was the same for all patients (either eligibility for interferon beta treatmentortrialentry)sothattherewasnoimmortaltimebias, andbothanalysesusedpropensityscore(covariate)adjustment. Through their study design, Shirani et al introduced an important source of selection bias. Although covariate adjustment was undertaken at time zero, this method does not adjust adequately for subsequent treatment decisions. Every patient who ultimately chose not to receive treatment began this option immediately after becoming eligible. If such a patient deteriorated, however, they may have been treated. Thus, only clinically stable patients would remain untreated whereas treated patients would begin therapy at staggered times after eligibility, depending on their clinical status. This bias cannot be overcome by using time-dependent covariates or covariate adjustment because, by definition, the no treatment group must survive the observation period untreated. This bias is indicated by the reversal in the hazard ratio (HR) direction when using the historical control group. Although interferon beta treatment was not statistically significantly associated with reaching an Expanded Disability Status Scale (EDSS) score of 6, the HR was increased compared with the contemporary controls (HR, 1.30; 95% CI, 0.921.83) and decreased compared with the historical controls (HR, 0.77; 95% CI, 0.58-1.02). Similarly, this selection bias in the contemporary control group is also suggested by the observed increase in HRs for the treatment and posttreatment intervals compared with the pretreatment interval (eFigure 5 in article). This pattern suggests that patients may have been followed up without interferon beta treatment until they worsened or that treatment may have been discontinued in those who progressed further. To avoid this bias, controls without access to treatment are necessary. Unfortunately, almost 20% of the historical controls in the study were excluded for having received interferon beta therapy during follow-up. Thus, even within the historical control group, untreated patients may have been selected for doing well without therapy.

MHC2TA mRNA levels and human herpesvirus 6 in multiple sclerosis patients treated with interferon beta along two-year follow-up

BackgroundIn previous studies we found that MHC2TA +1614 genotype frequency was very different when MS patients with and without human herpesvirus 6 (HHV-6) in serum samples were compared; a different clinical behavior was also described. The purpose of the study was: 1. To evaluate if MHC2TA expression in MS patients was influenced by interferon beta (IFN-beta) treatment. 2. To study MHC2TA expression in MS patients with and without minor allele C. 3. To analyze the relation between MHC2TA mRNA levels and HHV-6 active infection in MS patients.MethodsBlood and serum samples of 154 MS patients were collected in five programmed visits: basal (prior to beginning IFN-beta treatment), six, twelve, eighteen and twenty-four months later. HHV-6 in serum and MHC2TA mRNA levels were evaluated by PCR and RT-PCR, respectively. Neutralizing antibodies (NAbs) against IFN-beta were analyzed by the cytopathic effect assay.ResultsWe found that MHC2TA mRNA levels were significantly lower among MS patients with HHV-6 active infection at the basal visit (without treatment) than in those MS patients without HHV-6 active infection at the basal visit (p = 0.012); in all the positive samples we only found variant A. Furthermore, 58/99 (58.6%) MS patients without HHV-6 along the five programmed visits and an increase of MHC2TA expression after two-years of IFN-beta treatment were clinical responders vs. 5/21 (23.8%) among those MS patients with HHV-6 and a decrease of MHC2TA mRNA levels along the two-years with IFN-beta treatment (p = 0.004); no differences were found between patients with and without NAbs.ConclusionsMHC2TA mRNA levels could be decreased by the active replication of HHV-6; the absence of HHV-6 in serum and the increase of MHC2TA expression could be further studied as markers of good clinical response to IFN-beta treatment.

Suspected autoimmune hepatitis and primary biliary cirrhosis unmasked by interferon-beta in a multiple sclerosis patient

The use of interferon-beta in multiple sclerosis is associated with various forms of hepatotoxicity, including autoimmune hepatitis and liver failure. We describe a case with features of autoimmune liver disease and primary biliary cirrhosis occurring during long-term treatment with interferon-beta in a patient with relapsing-remitting multiple sclerosis. This case highlights the importance of monitoring biochemical liver test results throughout interferon-beta treatment of multiple sclerosis.

Efficacy and safety of beta-interferon in Thai patients with demyelinating diseases

Background: The efficacy of beta-interferon (IFN-β) treatment in Thai patients with demyelinating diseases has not been reported. Objectives: To evaluate the efficacy and any adverse drug reactions of IFN-β therapy in Thai patients, for each group of demyelinating diseases. Methods: We retrospectively reviewed data of Thai patients with multiple sclerosis (MS), neuromyelitis optica (NMO) and NMO spectrum disorders (NMOSDs) who attended the MS Clinic at Siriraj Hospital, Thailand from March 2000 to October 2011. We reviewed those 73 patients who received IFN-β. We evaluated the drug’s efficacy over 2 years and any adverse drug reactions among these patients. Results: Of the 40 MS patients who received IFN-β, 26 adhered to the medication for at least 2 years. In addition, 27 NMO/NMOSDs patients who had been diagnosed with MS were treated as such with IFN-β. In the true MS group, the pre- and post-treatment annualized relapse rates (ARR) were 1.25 and 0.59, respectively, so there was a reduction of 52.8% (p = 0.004). In addition, in 69.2% of the patients, IFN-β also showed beneficial effects by prolonging the time to first relapse to 15.9 months and stabilizing or decreasing progression of the disease. In contrast, no significant benefit was seen in the NMO/NMOSDs group. On the contrary, an increase in EDSS was seen in 53.3 % of them. The most common side effects seen were local skin reactions and flu-like symptoms. Conclusions: Treatment with IFN-β was effective in reducing both ARR and disability progression in Thai patients with MS. In contrast, we observed that giving IFN-β treatment to NMO/NMOSDs patients may lead to a worsening of symptoms.

Association Between Use of Interferon Beta and Progression of Disability in Patients With Relapsing-Remitting Multiple Sclerosis

Interferon beta is widely prescribed to treat multiple sclerosis (MS); however, its relationship with disability progression has yet to be established. To investigate the association between interferon beta exposure and disability progression in patients with relapsing-remitting MS. Retrospective cohort study based on prospectively collected data (1985-2008) from British Columbia, Canada. Patients with relapsing-remitting MS treated with interferon beta (n = 868) were compared with untreated contemporary (n = 829) and historical (n = 959) cohorts. The main outcome measure was time from interferon beta treatment eligibility (baseline) to a confirmed and sustained score of 6 (requiring a cane to walk 100 m; confirmed at >150 days with no measurable improvement) on the Expanded Disability Status Scale (EDSS) (range, 0-10, with higher scores indicating higher disability). A multivariable Cox regression model with interferon beta treatment included as a time-varying covariate was used to assess the hazard of disease progression associated with interferon beta treatment. Analyses also included propensity score adjustment to address confounding by indication. The median active follow-up times (first to last EDSS measurement) were as follows: for the interferon beta-treated cohort, 5.1 years (interquartile range [IQR], 3.0-7.0 years); for the contemporary control cohort, 4.0 years (IQR, 2.1-6.4 years); and for the historical control cohort, 10.8 years (IQR, 6.3-14.7 years). The observed outcome rates for reaching a sustained EDSS score of 6 were 10.8%, 5.3%, and 23.1% in the 3 cohorts, respectively. After adjustment for potential baseline confounders (sex, age, disease duration, and EDSS score), exposure to interferon beta was not associated with a statistically significant difference in the hazard of reaching an EDSS score of 6 when either the contemporary control cohort (hazard ratio, 1.30; 95% CI, 0.92-1.83; P = .14) or the historical control cohort (hazard ratio, 0.77; 95% CI, 0.58-1.02; P = .07) were considered. Further adjustment for comorbidities and socioeconomic status, where possible, did not change interpretations, and propensity score adjustment did not substantially change the results. Among patients with relapsing-remitting MS, administration of interferon beta was not associated with a reduction in progression of disability.

Glatiramer Acetate Induced Hepatotoxicity

Glatiramer acetate (Copaxone), a polypeptide has been approved for treating patients with active relapsing-remitting multiple sclerosis. We report the first case of severe acute hepatitis after commencing treatment for multiple sclerosis with glatiramer acetate. A 31-year-old female with multiple sclerosis presented with anorexia, lethargy and jaundice five weeks after commencing glatiramer acetate. She had never received beta-interferon treatment. Investigations revealed a bilirubin of 0.109 mmol/L (0.002-0.02 mmoL/L) and prothrombin time of 21 secs (9-15 secs). Her liver function tests were normal before commencing glatiramer acetate. A liver biopsy performed approximately 6 weeks after commencement of glatiramer acetate showed predominantly centrilobular hepatocyte necrosis with portal-venous bridging, along with mild portal and interface hepatitis. The necrosis was not accompanied by an acute inflammatory or chronic inflammatory infiltrate. The features were not suggestive of autoimmune hepatitis but consistent with drug toxicity. The liver tests returned to normal within 2 months after cessation of glatiramer acetate. Physicians should be aware that glatiramer acetate can be associated with uncommon but yet significantly severe liver toxicity.

Immunoregulatory T cells in multiple sclerosis and the effect of interferon beta and glatiramer acetate treatment on T cell subpopulations

IntroductionMultiple sclerosis (MS) is a chronic disease characterized by demyelination and chronic inflammation of the central nervous system (CNS). Many of the immune cells including T and B cells seem to be involved in disease pathogenesis by inducing or controlling the immune responses in the nervous system of MS patients. The objective of this study was to evaluate the differences in subpopulations of T cells between MS patients and healthy controls and the effects of interferon beta (INF-beta) and glatiramer acetate (GA) treatment on T cell subpopulations. Material and methodsWe have investigated the frequency of subpopulations of T cells using flow cytometry in 84 relapsing-remitting MS patients; forty-five patients started treatment with INF-beta and eighteen patients with GA, twenty-one patients were not treated. We collected blood samples at the beginning and after 6 and 12months. ResultsWe observed a significant decrease in CD4+CD25+ Treg cells (p=0.03) and a significant increase in T helper cells (p=0.002) and central memory T cells (p=0.03) in MS patients compared to healthy controls. After INF-beta therapy, we demonstrated a significant increase in naive T cells (p=0.008), a decline in central memory T cells (p=0.01). After GA therapy, we observed a significant increase in naive T cells (p=0.04), a decrease in central memory T cells (p=0.03) and an increase in T-suppressor cells (p=0.008). ConclusionIn conclusion, we demonstrated the imbalance of T-cell subpopulations in MS patients and the potential benefit of DMD (disease modifying drugs) treatment on its restoration.

Thrombotic microangiopathy associated with use of interferon-beta

Interferon-beta is widely used for the treatment of relapsing multiple sclerosis. The drug is usually well tolerated, but autoimmune adverse effects, including kidney disease, have been reported. Only a few cases of hemolytic uremic syndrome-thrombotic microangiopathy associated interferon-alpha have been described so far, and even fewer with beta-interferon. We report a patient who developed thrombotic microangiopathy during treatment with interferon-beta and improved after discontinuation and steroid therapy. Complement cascade and antiphospholipid antibodies are investigated. The spectrum of renal diseases associated with interferon-beta treatment is also reviewed.

Sarcoidosis Triggered by Interferon-Beta Treatment of Multiple Sclerosis: A Case Report and Focused Literature Review

To report a rare case of sarcoidosis induced by chronic interferon-beta (a type I interferon) therapy of multiple sclerosis and to review previously reported cases. We describe a patient with a prior diagnosis of multiple sclerosis, who developed noncaseating granulomas in her skin and pulmonary lymph nodes, consistent with sarcoidosis, while being treated with recombinant interferon-beta. A retrospective review of the literature was performed using the PubMed database. In our patient, sarcoidosis developed after 3 years of continuous recombinant interferon-beta therapy, dosed 3 times a week. The patient presented with progressive dyspnea on exertion, diffuse arthralgias, low-grade fevers, with an acute onset of rash. The diagnosis of sarcoidosis was secured by finding typical, well-formed, noncaseating granulomas on skin and endobronchial biopsies, with other possible etiologies for granulomatous conditions excluded beforehand. Following the withdrawal of recombinant interferon-beta and a course of corticosteroids combined with disease-modifying anti-rheumatic drug therapy, the patient's clinical presentation resolved. Excluding ours, only 4 additional cases of sarcoidosis developing after interferon-beta therapy have been reported, with 2 of those cases in the context of underlying multiple sclerosis. Developing sarcoidosis during treatment of multiple sclerosis with recombinant interferon-beta represents an exceedingly rare and paradoxical adverse event. The occurrence of sarcoidosis with the use of this agent is perhaps due to a dysregulation in the modulatory role played by interferon-beta (and more generally type I interferon) expression in chronic inflammation.

Monthly Pulse Adrenocorticotropic Hormone (ACTH) or Methylprednisolone Therapy for Long-Term Treatment of Multiple Sclerosis as an Add-On Therapy to beta-Interferons: Current Status of the Pilot Study (P04.147)

Objective: This pilot study is designed to evaluate the efficacy and safety of monthly adrenocorticotropic hormone (ACTH) treatment added to beta-interferon in breakthrough multiple sclerosis (MS) compared with monthly methylprednisolone (MP), the most commonly used therapy. Background ACTH gel is approved for treatment of MS relapses. There is mounting evidence that ACTH may have a variety of immune-modulating mechanisms relevant to the MS disease course. However, no clinical studies have evaluated ACTH pulse therapy for MS. Design/Methods: This single-center, examiner-blinded study enrolled MS patients receiving ongoing beta-interferon treatment with Expanded Disability Status Scale (EDSS) scores of 3.0-6.5 and ≥1 relapse or new T2 or Gadolinium-enhanced lesion within the previous year. Patients were randomly assigned to open-label ACTH (80 units intramuscularly once/day x 3 consecutive days) or MP (1 gram IV x 1 dose) monthly for 12 months, with assessments every 3 months. Outcomes include relapse rate (primary); EDSS, MS Functional Composite, and MS Quality of Life scores; MRI; bone density; and side effects. We report the current status of the study. Results: Of 26 patients enrolled (ACTH: n=14, mean±SD EDSS 4.4±1.4; MP: n=12, mean EDSS 4.7±1.4), 18 have ≥6 months of data (ACTH: n=10, MP: n=8). During 6 months of pulse therapy, there were 0 relapses in the ACTH group and 4 relapses (in 2 patients) in the MP group. Mean EDSS score at month 3 was 3.9±2.0 (p=0.028; n=12) for ACTH and 3.9±1.6 (p=0.058; n=10) for MP. EDSS at month 6 was 4.4±1.8 (p=0.075) for ACTH and 4.2±2.0 (p=0.401) for MP. Seventeen side effects were reported from 9 patients in the ACTH group and 13 side effects were reported by 6 patients in the MP group. Conclusions: These data suggest a potential role for ACTH pulse therapy in treating breakthrough MS. Supported by: Questcor Pharmaceuticals, Inc. Disclosure: Dr. Berkovich has received personal compensation for activities with Acorda Therapeutics, Bayer Pharmaceuticals Corporation, Biogen Idec, Teva Neuroscience and Questcor Inc. as a speaker. Dr. Berkovich has received research support from Questcor Inc. Dr. Amezcua has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Teva Neuroscience, and Serono/Pfizer Inc. Dr. Fernandez has nothing to disclose. Dr. Subhani has nothing to disclose. Dr. Kravtsova has nothing to disclose.

Long-term adherence to interferon-beta treatment in a cohort of RRMS patients in Belgrade, Serbia

ObjectiveLong-term adherence to interferon-beta (IFNβ) treatment in patients with multiple sclerosis (MS) varies considerably in daily clinical practice. The aim of the present study was to assess the frequency and reasons for stopping the INFβ treatment in our relapsing-remitting (RR) MS patients’ cohort. Patients and methodAll patients with RRMS initiating treatment with IFNβ at the Clinic of neurology, CCS, in Belgrade, from January 2004 to June 2009, were included in the study. Treatment was initiated in RRMS patients with at least two relapses in the previous two years, and EDSS score at entry ≤3.5. During the follow-up, patients underwent regular detailed clinical evaluation performed by MS specialists. ResultsThe study comprised a total of 290 RRMS patients. During the 6-year follow up period (mean 3.5±2.1years), 18% of patients stopped the treatment. The main reason for treatment discontinuation was lack of efficacy (54%); 21% of patients stopped therapy because of pregnancy and only 17% because of AE. ConclusionThe frequency of treatment discontinuation in our study pointed to the low permanent termination rate reflecting good adherence to IFNβ in our RRMS patients. Our results support the notion that long-term adherence to IFNβ treatment might be significantly influenced by optimizing the benefits to be achieved from therapy, adequate patient selection and easy accessibility of MS health professionals.