Management of IFN-beta-induced flu-like symptoms with Chinese herbal medicine in a patient with multiple sclerosis: A case report.

OBJECTIVE: The purpose of this case report was to elucidate how Chinese herbal medicine (CHM) was used safely in this patient undergoing interferon beta (IFNß-1a) treatment and was associated with reduction in the side effects the patient had experienced when using IFNß-1a treatment alone. CLINICAL FEATURES AND OUTCOME: A 30-year-old man was diagnosed with MS in December 2014. For two years, he suffered from severe flu-like symptoms as side effects of IFNß-1a treatment. He subsequently received treatment with Chinese herbal medicine. During a two-month period of treatment with CHM, the patient responded well, with most of the symptoms induced by IFNß-1a ameliorated. The fever subsided. Incidence rates of dizziness and headaches were reduced. The health condition compared to the prior year increased by 50%. According to CCMQ and SF-36 assessments, CHM had the beneficial effects of recovering the yin-yang balance, harmonizing the qi, and regulating the blood state; essentially, improving the patient's comfort level and quality of life. CONCLUSIONS: IFNß-1a injections will damage qi and cause blood stasis in MS patients, thereby causing various side effects and weakening the body's immune system. Bu-Zhong-Yi-Qi-Tang, associated with Salvia miltiorrhiza, Ligusticum chuanxiong, Angelica dahurica and Polygonum multiflorum Thunb., is an effective prescription to ameliorate such symptoms and signs in patients with MS.

Hepatitis tóxica tras tratamiento concomitante con interferón beta y aloe vera en un paciente con esclerosis múltiple: a propósito de un caso / Toxic hepatitis after concomitant interferon beta and aloe vera treatment in a patient with multiple sclerosis: A case report

No disponible

Fumaric acid esters in psoriasis and multiple sclerosis.

Fumaric acid esters (FAEs) are effective in patients with moderate to severe psoriasis. Recent studies also report the efficacy of one FAE component, dimethylfumarate, in relapsing forms of multiple sclerosis (MS). We describe the case of a patient with MS who developed severe plaque psoriasis during interferon-ß-1a treatment for MS. The psoriasis was unresponsive to usual topical treatments and phototherapy. The patient was started on FAE 720 mg daily, with complete remission of the psoriatic lesions and neurological stabilization at follow-up at 24 months. Our case suggests that FAEs could represent a therapeutic option for patients with MS who develop plaque psoriasis following exposure to immune-modulating agents.

Vitamin D supplementation for patients with multiple sclerosis treated with interferon-beta: a randomized controlled trial assessing the effect on flu-like symptoms and immunomodulatory properties.

BACKGROUND: Flu-like symptoms (FLS) are common side effects of interferon beta (IFN-ß) treatment in patients with Multiple Sclerosis (PwMS) and are associated with post-injection cytokine surge. We hypothesized that vitamin D3 supplementation would ameliorate FLS by decreasing related serum cytokines' levels. METHODS: In a randomized, double blind study of 45 IFNß-treated PwMS, 21 patients were assigned to 800 IU of vitamin D3 per day (low dose), while 24 patients received 4,370 IU per day (high dose) for one year. FLS were assessed monthly by telephonic interviews. Serum levels of 25-hydroxy-D (25-OH-D), calcium, PTH, IL-17, IL-10 and IFN-γ were measured periodically. EDSS, relapses, adverse events and quality of life (QoL) were documented. RESULTS: 25-OH-D levels increased to a significantly higher levels and PTH levels decreased in the high dose group. There was no significant change in FLS. IL-17 levels were significantly increased in the low dose group, while patients receiving high dose vitamin D had a heterogeneous IL-17 response. No significant differences in relapse rate, EDSS, QoL, serum IL-10 and IFNγ were found. Hypercalcemia or other potential major adverse events were not observed. CONCLUSION: Vitamin D supplementation to IFN-ß treated PwMS, at the doses used, seems safe and associated with dose-dependent changes in IL-17 serum levels, while not affecting IFN-ß related FLS. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT01005095.

Alpha-tocopherol and MRI outcomes in multiple sclerosis--association and prediction.

OBJECTIVE: Alpha-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. METHODS: Prospective 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. RESULTS: During 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. CONCLUSION: During treatment with IFNB, increasing serum concentrations of alpha-tocopherol were associated with reduced odds for simultaneous and subsequent MRI disease activity in RRMS patients.

Severe liver dysfunction possibly caused by the combination of interferon beta-1b therapy and melilot (sweet clover) supplement.

WHAT IS KNOWN AND OBJECTIVE: We report a case of severe liver dysfunction exacerbated after interferon beta (IFNB)-1b injection in a patient with multiple sclerosis (MS) who had been taking a melilot (sweet clover) supplement. Although IFNB-1b therapy for MS can cause mild liver dysfunction, severe hepatotoxicity attributable to supplement use has been reported. CASE SUMMARY: A 23-year-old Japanese woman taking a melilot supplement containing coumarin at 10 mg/day for 3 years was admitted to our hospital to receive IFNB-1b therapy for MS. Fourteen days after subcutaneous injection of IFNB-1b every other day, her aspartate transaminase (AST) and alanine aminotransferase (ALT) levels were elevated at 235 and 681 IU/L, respectively. After the discontinuation of IFNB-1b therapy and supplement intake, AST and ALT returned to normal levels. Later, she started receiving an intramuscular injection of IFNB-1a weekly without supplement intake. She was able to continue IFNB-1a therapy this time, showing a slight elevation of AST level at 61 IU/L. WHAT IS NEW AND CONCLUSION: The combination of IFNB-1b therapy and melilot supplement intake may cause severe liver dysfunction in patients with MS. Given the doubtful value of the supplement, we suggest that it should be avoided by patients receiving interferon therapy.

PEGylation of interferon-ß-1a: a promising strategy in multiple sclerosis.

Achieving optimal patient benefit from biological therapies can be hindered by drug instability, rapid clearance requiring frequent dosing or potential immune reactions. One strategy for addressing these challenges is drug modification through PEGylation, a well established process by which one or more molecules of polyethylene glycol (PEG) are covalently attached to a biological or small-molecule drug, effectively transforming it into a therapy with improved pharmacokinetic and pharmacodynamic properties. Numerous PEGylated therapeutics are currently available, all of which have at least comparable efficacy, safety and tolerability to their unmodified forms. A PEGylated form of interferon-ß-1a (PEG-IFNß-1a) is being developed to address an unmet medical need for safer, more effective and more convenient therapies for multiple sclerosis (MS). Phase I study data suggest that PEG-IFNß-1a should provide patients with a first-line therapy with a more convenient dosing regimen while maintaining the established efficacy, safety and tolerability of presently available IFNß-1a. The ongoing global ADVANCE phase III study will determine the clinical efficacy of PEG-IFNß-1a in patients with relapsing MS.

Atorvastatin combined to interferon to verify the efficacy (ACTIVE) in relapsing-remitting active multiple sclerosis patients: a longitudinal controlled trial of combination therapy.

A large body of evidence suggests that, besides their cholesterol-lowering effect, statins exert anti-inflammatory action. Consequently, statins may have therapeutic potential in immune-mediated disorders such as multiple sclerosis. Our objectives were to determine safety, tolerability and efficacy of low-dose atorvastatin plus high-dose interferon beta-1a in multiple sclerosis patients responding poorly to interferon beta-1a alone. Relapsing-remitting multiple sclerosis patients, aged 18-50 years, with contrast-enhanced lesions or relapses while on therapy with interferon beta-1a 44 microg (three times weekly) for 12 months, were randomized to combination therapy (interferon + atorvastatin 20 mg per day; group A) or interferon alone (group B) for 24 months. Patients underwent blood analysis and clinical assessment with the Expanded Disability Status Scale every 3 months, and brain gadolinium-enhanced magnetic resonance imaging at screening, and 12 and 24 months thereafter. Primary outcome measure was contrast-enhanced lesion number. Secondary outcome measures were number of relapses, EDSS variation and safety laboratory data. Forty-five patients were randomized to group A (n = 21) or B (n = 24). At 24 months, group A had significantly fewer contrast-enhanced lesions versus baseline (p = 0.007) and significantly fewer relapses versus the two pre-randomization years (p < 0.001). At survival analysis, the risk for a 1-point EDSS increase was slightly higher in group B than in group A (p = 0.053). Low-dose atorvastatin may be beneficial, as add-on therapy, in poor responders to high-dose interferon beta-1a alone.

Cognitive dysfunction evaluation in multiple sclerosis patients treated with interferon beta-1b: an open-label prospective 1 year study.

BACKGROUND: The cognitive impairment (frontal, parietal) in many patients with multiple sclerosis does not correlate with the degree of neurological disability and disease duration. Frontal/prefrontal cognitive impairment requires neuropsychological diagnostic tools. OBJECTIVES: To evaluate the clinical effect of IFNbeta-1b (Betaferon) treatment on cognitive function and event-related potential as compared to the clinical course (EDSS) in MS patients during 1 year of follow-up. METHODS: This prospective open-label design study included 16 consecutive patients with relapsing forms of MS attending the MS outpatient clinic. Mean EDSS score was calculated prior to starting treatment. Parietal lobe event-related potential P300 was elicited using an auditory physical stimulus to an alert subject. Mean P300 amplitude and latency were calculated for the group before treatment. The Wisconsin Card Sorting Test, which measures frontal lobe functions, was performed before the treatment. After 1 year of treatment a second P300 and Wisconsin test were performed and the mean change between visit 1 and baseline was calculated for each parameter. Correlation between the change in P300 and the Wisconsin test score at baseline was measured using the paired t-test. RESULTS: There was a significant reduction in P300 amplitude and latency after 1 year of treatment with IFNbeta-1b: from 20.3 +/- 8.3 microv to 13.1 +/- 10.6 microv (P = 0.026) for amplitude, and from 312.9 +/- 15.6 msec to 302.0 +/- 17.0 msec (P = 0.002) for latency. The Perseverative Response (raw score) and the Perseverative Response U.S. Census age-matched standard score showed a significant improvement--from 20.7 +/- 30.7 to 13.1 +/- 10.6 (P = 0.001) and 96.7 +/- 15.7 to 100.1 +/- 11.1 (P = 0.0025) respectively--after 1 year of treatment. A mild but not significant improvement was observed on the EDSS after 1 year of treatment: 2.9 +/- 0.5 to 2.8 +/- 1.1. CONCLUSIONS: A cognitive decline in MS patients may have a negative impact on the quality of life, affecting all active daily living domains. IFNbeta-1b, a disease-modifying therapy, has demonstrated a positive therapeutic effect on cognitive dysfunction, unrelated to its effect on the EDSS score and course of the disease.

Abdominal wall ulceration and mucinosis secondary to recombinant human interferon-beta-1b.

46-year-old woman developed painful ulcers over her lower abdomen in the form of reticulate erythema after injecting interferon beta-1b subcutaneously for multiple sclerosis. Skin biopsy revealed multiple superficial thrombosed vessels with focal epidermal necrosis as well as prominent interstitial mucinosis. Treatment with low-molecular-weight heparin followed by a heparinoid resulted in slow healing of the ulcers but also allowed the subcutaneous interferon injections to be continued.

A randomized open label study of pain medications (naproxen, acetaminophen and ibuprofen) for controlling side effects during initiation of IFN beta-1a therapy and during its ongoing use for relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) patients initiating IFN beta-1a, Avonex, therapy (Group 1, n = 30) or experiencing side effects after 6 months on therapy (Group 2, n = 30) were randomized for 5 weeks open label adjunct therapy to naproxen (Aleve), acetaminophen (Tylenol) or ibuprofen (Advil). Our hypothesis was that non-prescription pain medications are effective in decreasing or alleviating the side effects associated with IFN beta-1a therapy. Contrary to the hypothesis, most patients in both groups continued to report side effects on all pain medications. After 5 weeks, headache, fever, chills and injection site pain were low in < or = 50% of patients. Moderate to significant fatigue, muscle or joint pain continued in most patients. As a quality of life measure, the Modified Fatigue Impact Scale (mFIS) improved for Group 1 on naproxen or ibuprofen with greatest improvement in physical subset (P = 0.002 for naproxen and P<0.01 for ibuprofen). Total mFIS for Group 1 on acetaminophen improved (P = 0.04) due to improved cognitive subset rather than physical subset. Group 2, with side effects initially, reported less significant fatigue (severity 5-10) but more moderate fatigue (severity 2-4) at study end for all three medications. All medications improved cognitive subset (P = 0.05). Physical mFIS subset did not improve for Group 2 on acetaminophen, but did with naproxen (P = 0.05) or ibuprofen (P = 0.03). Naproxen and ibuprofen were more effective than acetaminophen in minimizing physical side effects of IFN beta-1a. None of the three pain medications tested were as effective as hypothesized for minimizing fatigue or muscle and joint pain.

The effect of a herbal medicine (Mao-to) for the prevention of interferon-induced psychiatric complications in chronic hepatitis C: a pilot study.

OBJECTIVE: To evaluate the efficacy of a herbal medicine (Mao-to) on psychiatric complications caused by IFN, and to examine the relationship between depression and microcirculation. METHODS: Twelve patients with chronic hepatitis C and a past history of IFN-induced depression were enrolled in this study. Their mental state was evaluated by the self-rating depression scale (SDS)> or =40, or M-R of the Cornell medical index (CMI)> or =10. Each patient received a daily dose of 6 million units of IFN-beta for 8 weeks, and Mao-to was given orally four times a day during the IFN-beta course. RESULTS: All patients in this study completed a full course of IFN. Mean CMI scores (M-R) had significantly decreased at the end of the treatment. Mean erythrocyte aggregability and erythrocyte deformability had also significantly decreased at the end of treatment. CONCLUSION: Mao-to might be useful for preventing the incidence of depression in patients with chronic hepatitis C being treated with IFN. The mechanism by which Mao-to prevents depression is suggested to be through the improvement of microcirculation.

Hepatic reactions during treatment of multiple sclerosis with interferon-beta-1a: incidence and clinical significance.

BACKGROUND: Hepatic dysfunction, manifested as liver enzyme elevations, occurs frequently in patients who are treated with interferon, however, data for patients with multiple sclerosis are limited. OBJECTIVE: To retrospectively assess the safety profile of interferon-beta-1a therapy with respect to liver function during clinical trials and postmarketing surveillance in the treatment of multiple sclerosis. PATIENTS AND METHODS: Adverse effects and laboratory abnormalities were analysed from six randomised, controlled clinical trials (five of which were placebo-controlled) that assessed the use of interferon-beta-1a in patients with multiple sclerosis. Treatment data were collected for 2819 patients for up to 12 months, of whom 1995 received interferon-beta-1a (337 [12%] received Avonex intramuscular therapy, and 1658 [59%] received Rebif subcutaneous therapy), and 824 (29%) received placebo. Data for 2 years were collated for 1178 patients (from two studies). Total weekly interferon doses were 22-132 microg. Postmarketing surveillance data were also analysed. RESULTS: In patients receiving interferon-beta-1a, there were significant elevations of alanine aminotransferase (ALT) levels, of all grades of severity, in up to 59% of patients at 6 months, up to 64% of patients at 12 months and up to 67% of patients at 24 months; ALT elevations were asymptomatic and dose related. More than 50% of elevations in liver enzymes occurred during the first 3 months of treatment, and more than 75% occurred during the first 6 months. Elevated enzyme levels resolved spontaneously or with dosage adjustment. Although the overall incidence of liver enzyme elevation was high during the early months of therapy, after 2 years, the proportion of patients with abnormal liver enzyme levels was 11% of those receiving Rebif 44 microg three times weekly compared with 6% of placebo-treated patients. Only 0.4% of patients discontinued interferon-beta-1a treatment because of hepatic adverse effects. Serious symptomatic interferon-related hepatic toxicity occurs, but is uncommon. Concomitant medication use was not associated with increased risk. CONCLUSION: Asymptomatic hepatic dysfunction is common in patients with multiple sclerosis who are treated with interferon-beta-1a, and is dose related. Adverse effects are mainly mild and transient, with little impact on adherence to therapy, although rare serious events can occur. Regular liver function monitoring during the first 6 months is recommended.

The efficacy of herbal medicine (kampo) in reducing the adverse effects of IFN-beta in chronic hepatitis C.

The purpose of this study was to determine if the adverse effects of interferon (IFN) in hepatitis C patients could be reduced by treatment with Japanese Oriental (Kampo) medicine. Twelve patients with chronic hepatitis C were treated with a combination of IFN-beta and either Mao-to or Dai-seiryu-to (groups A and B), and 16 patients were treated with IFN-beta alone (group C). Mao-to was administered to eight patients and Dai-seiryu-to was administered to four in groups A and B, respectively. Adverse effects were evaluated by clinical and laboratory examinations. The severity of symptoms was daily self-classified into four categories (1: none, 2: very slight, 3: moderate, and 4: serious), using a questionnaire consisting of 29 items. Scores of symptom such as discomfort and fever in group A, and discomfort, general malaise, paresthesia and arthralgia in group B were significantly lower than those in group C (p < 0.05). In all patients, HCV-RNA was negative at the end of the treatment, and serum alanine aminotransferase (ALT) levels had normalized transiently in all group A and B patients with genotype 1b by 2 weeks after cessation of IFN treatment. This study indicates that Kampo medicines are useful for reducing the adverse effects accompanying IFN treatment in patients with chronic hepatitis C without reducing the antiviral effects.

Safety and systemic absorption of pulmonary delivered human IFN-beta1a in the nonhuman primate: comparison with subcutaneous dosing.

Safety and bioavailability of pulmonary delivered interferon-beta 1a (IFN-beta1a, AVONEX, Biogen, Inc., Cambridge, MA) was evaluated in the nonhuman primate. Pulmonary bioavailability following intratracheal (i.t.) instillation of 50 microg/kg IFN-beta1a to rhesus macaques was approximately 10%. To evaluate pulmonary safety, IFN-beta1a was administered intrabronchially to rhesus and cynomolgus macaques at a dose of 60 microg/dose one, three, or seven times per week for 4 weeks. At scheduled termination, lungs were evaluated for gross and histomorphologic changes. IFN-beta1a or vehicle (human serum albumin [HSA] in phosphate-buffered saline [PBS]) treatment resulted in minimal to mild subchronic alveolitis, located primarily near the instillation sites. These responses were considered nonspecific and consistent with either instillation of a foreign protein or minor injury associated with the instillation procedure. In one rhesus macaque treated every day for 4 weeks, IFN-beta1a induced mild to moderate eosinophilic alveolitis, considered possibly an isolated type I hypersensitivity response to HSA or IFN-beta1a. Partial resolution of pulmonary lesions was seen in all recovery animals killed 2 weeks after cessation of treatment. In conclusion, this study shows that pulmonary administration of human IFN-beta1a is safe and that the pulmonary route of administration is a possible alternate route for the systemic delivery of IFN-beta1a.