A novel needle for subcutaneous injection of interferon beta-1a: effect on pain in volunteers and satisfaction in patients with multiple sclerosis

Background  

To reduce injection pain and improve satisfaction, a thinner (29-gauge [29G]), sharper (5-bevel) needle than the 27G/3-bevel needle used previously to inject interferon (IFN) beta-1a, 44 or 22 mcg subcutaneously (sc) three times weekly (tiw), was developed for use in multiple sclerosis (MS).     

Regulation by interferon beta-1a of reactive oxygen metabolites production by lymphocytes and monocytes and serum sulfhydryls in relapsing multiple sclerosis patients

The activation of lymphocytes and monocytes and the concentration of reduction equivalents in serum were studied in a cohort of multiple sclerosis (MS) patients undergoing weekly treatment with 30 microg intramuscular interferon beta-1a for 2 years. The degree of activation of monocytes and lymphocytes and reactive oxygen species (ROS) production was higher in MS patients than in healthy controls and decreased in the course of interferon beta-1a treatment approaching control values. The concentration of reduced sulfhydryls in the serum of MS patients was lower than in healthy controls and the treatment with interferon beta-1a (IFNbeta-1a) raised the levels approaching the values of healthy controls.     

The oxidation-reduction state of serum proteins in multiple sclerosis patients: effect of interferon beta-1b.

The concentration of reduction equivalents in serum was studied in a cohort of healthy individuals, in a group of multiple sclerosis (MS) patients undergoing treatment with interferon beta-1b and another group of MS patients who refused treatment with interferon beta-1b. Two classes of sulfhydryl groups were detectable in serum: (1) the uncovered sulfhydryls, accessible to the oxidation-reduction substrate 5,5-dithiobis-(-2-nitrobenzoic acid) (DTNB); and (2) the hidden sulfhydryls that required previous heat denaturation of serum proteins to become accessible to DTNB. The concentration of the reduced form of both the uncovered- and hidden-type of sulfhydryls was higher in the serum of MS patients than in healthy individuals. Interferon beta-1b lowered the plasma concentration of the uncovered reduced sulfhydryls after 3 months of treatment. This was in contrast to a minor effect of interferon beta-1b in the hidden-form of sulfhydryl groups. The results suggest that the concentration of reduced sulfhydryls is a biochemical marker of the in vivo oxidation/reduction reactions in MS.     

Adverse events of interferon beta-1a: a prospective multi-centre international ICH-GCP-based CRO-supported external validation study in daily practice

Background

Due to methodological shortcomings the available post-registration data on the adverse events (AEs) occurring in interferon beta-1a (INFb-1a)-treated patients fail to adequately validate phase III data and only partially inform on safety in daily practice. We assessed AEs in relapsing remitting multiple sclerosis (RRMS) patients treated with intramuscular (IM) INFb-1a in daily practice using data quality assurance measures similar to those in phase III trials.

Methods

A prospective, International Conference on Harmonization (ICH) - Good Clinical Practice (GCP)-based, clinical research organization (CRO)-supported study in 36 practices in the Netherlands, Belgium, the United Kingdom and Luxembourg. During 24 months after start of IM INFb-1a treatment 275 RRMS patients were assessed for AEs'' severity (mild, moderate, severe) and relationship to treatment (not, unlikely, likely, definite). Data were compared with those reported in the pivotal phase III trial.

Findings

75.3% of the patients experienced one or more AEs that were likely or definitely related to INFb-1a. Of all AEs 40.5% were likely or definitely treatment-related; 68.5% of these were mild, and 3% severe. 6.6% of the patients discontinued treatment because of an AE. Compared to the pivotal phase III trial, we found statistically significantly lower incidences for most of the common AEs: headache, muscle ache, fatigue, fever, chills, nausea. One patient died following two cerebral vascular events in study month 22, both AEs were assessed as not related to INFb-1a.

Conclusion

Three out of four RRMS patients treated with IM INFb-1a in daily practice experience treatment-related AEs, most of these being mild. Our data externally validate the favorable phase III safety profile of IM INFb-1a and suggest that the real-life incidence of treatment-related AEs is less than reported in the pivotal phase III trial. Larger studies are needed to detect rare, potentially hazardous AEs of IM INFb-1a.     

Immunogenicity comparison of interferon beta-1a preparations using the BALB/c mouse model: assessment of a new formulation for use in multiple sclerosis

The in vivo immunogenicity of a new interferon (IFN) beta-1a product (Rebif New Formulation; RNF) was compared with that of two approved recombinant human IFN beta-1a products (Rebif and Avonex). Immunogenic potential was assessed based on time to development of neutralizing antibodies (NAbs) and NAb titer. Female BALB/c mice (six in each group) received RNF, Rebif or Avonex (1.0 microg/mL subcutaneously three times weekly), and serum samples collected on Days 7, 21, and 35 (Study 1), or 28, 42, 49, and 60 (Study 2) were assayed for NAbs. In Study 1, no mice had NAbs at Day 7, but by Day 21 one mouse in the RNF group had NAbs, compared with three and four mice in the Rebif and Avonex groups, respectively. Results were similar in Study 2. All control mice were NAb negative; all actively treated mice had NAbs by day 35 or 42. Throughout Study 1, NAb titers were lowest in the RNF group and highest in the Avonex group, and at day 35, NAb titers were significantly lower in the RNF group than the Rebif group (p = 0.037). Results indicate that, on a gram-for-gram basis, RNF appears less immunogenic than Rebif or Avonex.     

PEGylation of proteins in organic solution: a case study for interferon beta-1b

Conventional protein PEGylation is carried out in aqueous solution. However, some hydrophobic proteins seem to be stable in organic solution. In this study, a novel approach of PEGylating IFN-β-1b in an organic solution of 2-butanol (2-BuOH) was investigated. Compared with protein PEGylation in aqueous solution, the overall modification yields increased more than 37%, while the yield of mono-PEGylated products could be increased by 36%. Furthermore, the PEGylated IFN-β-1b, which was obtained in organic solution, demonstrated 18% more antiviral potency than those derived from aqueous solution. The PEGylation step could be directly connected to the previous protein separation step for process integration. Dynamic light scattering (DLS) and atomic force microscope (AFM) analysis revealed that IFN-β-1b formed aggregates both in water and in 2-BuOH solutions. However, the aggregates were much smaller and more homogeneous in 2-BuOH than those in aqueous solution, thereby providing larger solvent accessible protein surfaces, which resulted in a more productive PEGylation process. In addition, the results of circular dichroism (CD), fluorescence spectra, and peptide mapping suggested that the increased bioactivity came from the difference in PEGylation site distribution due to solution environment that induced conformational discrepancy. The results of this study show that PEGylation of IFN-β-1b in organic solution is a facile and efficient process, which might find applications for other hydrophobic proteins.     

Impact of natalizumab on cognitive performances and fatigue in relapsing multiple sclerosis: a prospective, open-label, two years observational study

Background and Objectives

Natalizumab reduces the relapse rate and magnetic resonance imaging activity in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). So far the influence of natalizumab on cognitive functions and fatigue in MS remains uncertain. The aim of this prospective, open-label, observational study was to evaluate the possible effects of natalizumab on cognition and fatigue measures in RRMS patients treated for up to two years.

Methods

Cognitive performances were examined by the Rao''s Brief Repeatable Battery (BRB), the Stroop test (ST) and the Cognitive Impairment Index (CII), every 12 months. Patients who failed in at least 3 tests of the BRB and the ST were classified as cognitively impaired (CI). Fatigue Severity Scale (FSS) was administered every 12 months to assess patient''s self-reported fatigue. One hundred and 53 patients completed 1 and 2 year-natalizumab treatment, respectively.

Results

After 1 year of treatment the percentage of CI patients decreased from 29% (29/100) at baseline to 19% (19/100) (p = 0.031) and the mean baseline values of CII (13.52±6.85) and FSS (4.01±1.63) scores were significantly reduced (10.48±7.12, p<0.0001 and 3.61±1.56, p = 0.008). These significant effects were confirmed in the subgroup of patients treated up to two years.

Conclusions

These results demonstrate that a short-term NTZ treatment may significantly improve cognitive performances and fatigue in RRMS patients.     

Identification of coronin‐1a as a novel antibody target for clinically isolated syndrome and multiple sclerosis

Recently, we identified the mimotope UH‐CIS6 as a novel candidate antibody target for clinically isolated syndrome (CIS) and relapsing‐remitting (RR) multiple sclerosis (MS). The purpose of this study was to further validate UH‐CIS6 as an antibody target for CIS and MS and to identify the in vivo antibody target of UH‐CIS6. First, a UH‐CIS6 peptide ELISA was optimized. Next, we investigated the antibody response toward UH‐CIS6 in cerebrospinal fluid (CSF) from patients with CIS (n = 20), MS (n = 43) and other neurological diseases (n = 42). Immunoprecipitation of anti‐UH‐CIS6 antibodies on a normal human brain lysate was performed to identify the in vivo antibody target of UH‐CIS6. The cellular expression of an in vivo candidate target was investigated by immunohistochemistry using MS brain tissue sections. Antibody reactivity toward UH‐CIS6 was detected in a significantly increased proportion of CSF samples from CIS and RR‐MS patients as compared with neurological controls (p = 0.046). We identified and confirmed coronin‐1a as the in vivo antibody target for UH‐CIS6. Furthermore, coronin‐1a was expressed by T cells and macrophages in an active MS lesion. Together, these results demonstrate that coronin‐1a is a novel antibody target for CIS and MS.     

Serum pharmacokinetics and cerebrospinal fluid concentration analysis of the new IgG4 monoclonal antibody GNbAC1 to treat multiple sclerosis: A Phase 1 study

GNbAC1 is a humanized IgG4 monoclonal antibody antagonist of Mulitple Sclerosis Retrovirus Envelope (MSRV-Env), a protein that could play a critical role in multiple sclerosis. This randomized placebo-controlled dose-escalation study evaluated the safety and pharmacokinetics of GNbAC1 in 21 healthy volunteers after single intravenous infusion at doses of 6, 18 and 36 mg/kg. Lumbar punctures were performed at days 2, 15 or 29 to measure GNbAC1 concentrations in cerebrospinal fluid (CSF). GNbAC1 was well tolerated. Serum data show a dose-linear pharmacokinetics. A mean CSF/serum ratio of 0.12% was observed at Day 2, increasing to 0.39% at Day 15 and 0.42% at Day 29. Linear regression analysis shows a relationship between GNbAC1 CSF/serum ratio and albumin CSF/serum ratio and a relationship at the limit of statistical significance with the timing of CSF sampling.     

Effect of peginterferon beta-1a on MRI measures and achieving no evidence of disease activity: results from a randomized controlled trial in relapsing-remitting multiple sclerosis

Background

Subcutaneous peginterferon beta-1a provided clinical benefits at Year 1 (placebo-controlled period) of the 2-Year Phase 3 ADVANCE study in relapsing-remitting multiple sclerosis (RRMS). Here we report the effect of peginterferon beta-1a on brain magnetic resonance imaging (MRI) lesions, and no evidence of disease activity (NEDA; absence of clinical [relapses and 12-week confirmed disability progression] and MRI [gadolinium-enhancing, and new or newly-enlarging T2 hyperintense lesions] disease activity) during Year 1.

Methods

RRMS patients (18–65 years; Expanded Disability Status Scale score ≤5) were randomized to double-blind placebo or peginterferon beta-1a 125 μg every 2 or 4 weeks. Sensitivity analyses of last observation carried forward and composite disease activity (using minimal MRI allowance definitions) were conducted.

Results

1512 patients were randomized and dosed (placebo n?=?500; peginterferon beta-1a every 2 [n?=?512] or 4 [n?=?500] weeks). Every 2 week dosing significantly reduced, versus placebo and every 4 week dosing, the number of new or newly-enlarging T2 hyperintense lesions at Weeks 24 (by 61% and 51%, respectively) and 48 (secondary endpoint; by 67% and 54%, respectively); all p?<?0.0001. Every 2 week dosing also provided significant reductions versus placebo and every 4 week dosing in the number of new T1 hypointense, gadolinium-enhancing, and new active (gadolinium-enhancing plus non-enhancing new T2) lesions (all p?<?0.0001), as well as the volume of T2 and T1 lesions (p?<?0.05) at Weeks 24 and 48. Significantly more patients dosed every 2 weeks had NEDA versus placebo and every 4 weeks (all p?<?0.01) from baseline to Week 48 (33.9% versus 15.1% and 21.5%, respectively [odds ratios, ORs: 2.89 and 1.87]), from baseline to Week 24 (41.0% versus 21.9% and 30.7%, [ORs: 2.47 and 1.57]) and from Week 24 to Week 48 (60.2% versus 28.9% and 36.6%, [ORs: 3.71 and 2.62]). Consistent results were seen when allowing for minimal MRI activity.

Conclusion

During Year 1 of ADVANCE, significantly more RRMS patients receiving peginterferon beta-1a every 2 weeks had NEDA, and early and sustained improvements in all MRI endpoints, versus placebo and every 4 week dosing. NEDA sensitivity analyses align with switch strategies in clinical practice settings and provide insight into future responders/non-responders.

Trial registration

ClinicalTrials.gov: https://clinicaltrials.gov/ct2/show/NCT00906399

     

Evaluation of the efficacy of a novel electronic pain assessment device, the Pain Gauge, for measuring postoperative pain in rats

One of the major challenges for individuals working with laboratory animals is the recognition and alleviation of pain. The Pain Gauge is marketed as a pain assessment device that measures electrodermal activity. To establish whether the Pain Gauge is effective in assessing postoperative pain in laboratory rats, preoperative and postoperative pain gauge scores ('pain scores') were obtained from 67 rats. Rats were randomly assigned to one of three experimental groups (laparotomy, craniotomy or control) and to one of four analgesic groups (meloxicam [2 mg/kg s.c.] or parecoxib [1, 5 or 20 mg/kg i.v.]). Five consecutive 'pain scores' were obtained from each animal at each of five time points (preprocedure, and at 1, 2, 3 and 4 h postoperatively). Overall there was a significant difference between 'pain scores' at different time points; mainly a decrease at 1 h postoperatively compared with the preoperative scores. There was no overall increase in postoperative 'pain scores' in the rats that were most likely to suffer from postoperative pain (rats given a lower dose of analgesic that underwent a surgical procedure) compared with rats that did not undergo a potentially painful procedure (rats in anaesthesia-only/control group). Therefore it was concluded that the Pain Gauge is ineffective in assessing postoperative pain in rats in this study.     

Synthesis,electronic, and spectral properties of novel geranylated chalcone derivatives: a theoretical and experimental study

Novel chalcone derivatives with different substituents attached to A and B-rings: hydroxyl, methoxyl, geranyl, and prenyl groups were synthesized. The obtained compounds were characterized by NMR, HRMS, UV-Vis, IR, and MS. The theoretical analysis was carried out in all the compounds using density functional theory (DFT) with the B3LYP, PBE0, and M06-2X functionals in combination with the 6-311G(d,p) Pople-type basis set. The excited state properties were calculated by time dependent density functional theory (TD-DFT) using the same methodology applied for the ground state properties. The calculated vertical absorption wavelengths (λ_max) in gas phase and in ethanol as a solvent are consistent with the experimental ones, being the TD-DFT:B3LYP/6-311G(d,p) and PCM-TD-DFT:PBE0/6-311G(d,p) the best methodologies for these calculations with good approximation to the experimental values. The calculated reorganization energies indicated that, the four chalcone derivatives present an electron transfer character due to the smaller registered values. From these parameters it is proposed that these show an n-type semiconductor character. The localization of the frontier orbitals (HOMO and LUMO) shows that only the compound containing a hydroxyl group on the A-ring displays a marked delocalization favoring the charge-transfer process in this system. The HOMO-LUMO gap energies indicate that the inclusion of different donor groups in the rings does not improve the obtained values for this property.

Open image in new window

Graphical Abstract Relationship between spectroscopic and geometrical properties of chalcones were carried out using quantum-chemical calculations and compared with experimental values.

     

The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: a multicenter case-control study

Background

In the recently published meta-analysis of multiple sclerosis genome-wide association studies De Jager et al. identified three single nucleotide polymorphisms associated to MS: rs17824933 (CD6), rs1800693 (TNFRSF1A) and rs17445836 (61.5 kb from IRF8). To refine our understanding of these associations we sought to replicate these findings in a large more extensive independent sample set of 11 populations of European origin.

Principal Findings

We calculated individual and combined associations using a meta-analysis method by Kazeem and Farral (2005). We confirmed the association of rs1800693 in TNFRSF1A (p 4.19×10−7, OR 1.12, 7,665 cases, 8,051 controls) and rs17445836 near IRF8 (p 5.35×10−10, OR 0.84, 6,895 cases, 7,580 controls and 596 case-parent trios) The SNP rs17824933 in CD6 also showed nominally significant evidence for association (p 2.19×10−5, OR 1.11, 8,047 cases, 9,174 controls, 604 case-parent trios).

Conclusions

Variants in TNFRSF1A and in the vicinity of IRF8 were confirmed to be associated in these independent cohorts, which supports the role of these loci in etiology of multiple sclerosis. The variant in CD6 reached genome-wide significance after combining the data with the original meta-analysis. Fine mapping is required to identify the predisposing variants in the loci and future functional studies will refine their molecular role in MS pathogenesis.     

Fish possess multiple copies of fgfrl1, the gene for a novel FGF receptor

FGFRL1 is a novel FGF receptor that lacks the intracellular tyrosine kinase domain. While mammals, including man and mouse, possess a single copy of the FGFRL1 gene, fish have at least two copies, fgfrl1a and fgfrl1b. In zebrafish, both genes are located on chromosome 14, separated by about 10 cM. The two genes show a similar expression pattern in several zebrafish tissues, although the expression of fgfrl1b appears to be weaker than that of fgfrl1a. A clear difference is observed in the ovary of Fugu rubripes, which expresses fgfrl1a but not fgfrl1b. It is therefore possible that subfunctionalization has played a role in maintaining the two fgfrl1 genes during the evolution of fish. In human beings, the FGFRL1 gene is located on chromosome 4, adjacent to the SPON2, CTBP1 and MEAEA genes. These genes are also found adjacent to the fgfrl1a gene of Fugu, suggesting that FGFRL1, SPON2, CTBP1 and MEAEA were preserved as a coherent block during the evolution of Fugu and man.     

Geomagnetic disturbances may be environmental risk factor for multiple sclerosis: an ecological study of 111 locations in 24 countries

Background

We noticed that a hypothesis based on the effect of geomagnetic disturbances (GMD) has the ability to explain special features of multiple sclerosis (MS). Areas around geomagnetic 60 degree latitude (GM60L) experience the greatest amount of GMD. The easiest way to evaluate our hypothesis was to test the association of MS prevalence (MSP) with angular distance to geomagnetic 60 degree latitude (AMAG60) and compare it with the known association of MS with geographical latitude (GL). We did the same with angular distance to geographic 60 degree latitude (AGRAPH60) as a control.

Methods

English written papers with MSP keywords, done in Europe (EUR), North America (NA) or Australasia (AUS) were retrieved from the PubMed. Geomagnetic coordinates were determined for each location and AMAG60 was calculated as absolute value of numerical difference between its geomagnetic latitude from GM60L. By an ecological study with using meta-regression analyses, the relationship of MSP with GL, AMAG60 and AGRAPH60 were evaluated separately. MSP data were weighted by square root of number of prevalent cases. Models were compared by their adjusted R square (AR²) and standard error of estimate (SEE).

Results

111 MSP data were entered in the study. In each continent, AMAG60 had the best correlation with MSP, the largest AR² (0.47, 0.42 and 0.84 for EUR, NA and AUS, respectively) and the least SEE. Merging both hemispheres data, AMAG60 explained 56% of MSP variations with the least SEE (R?=?0.75, AR²?=?0.56, SEE?=?57), while GL explained 17% (R?=?0.41, AR²?=?0.17, SEE?=?78.5) and AGRAPH60 explained 12% of that variations with the highest SEE (R?=?0.35, AR²?=?0.12, SEE?=?80.5).

Conclusions

Our results confirmed that AMAG60 is the best describer of MSP variations and has the strongest association with MSP distribution. They clarified that the well-known latitudinal gradient of MSP may be actually a gradient related to GM60L. Moreover, the location of GM60L can elucidate why MSP has parabolic and linear gradient in the north and south hemisphere, respectively. This preliminary evaluation supported that GMD can be the mysterious environmental risk factor for MS. We believe that this hypothesis deserves to be considered for further validation studies.     

区域种植业气候适宜度及其对种植活动的响应——以四川省盐亭县为例

在分析盐亭县近63年来(1950—2012)种植业生产发展的基础上,选取该县农村社会经济条件相对稳定的近32年(1981—2012)为研究时段。运用农业生态气候适宜度方法,依据水稻、红薯、玉米、小麦和油菜等5种主要作物生育期的光、热、水等气候条件,分别估算各种作物的资源适宜指数、效能适宜指数和利用指数,构建小尺度区域种植业气候适宜度模型和种植活动对区域种植业气候适宜度的影响度模型,进行小尺度区域种植业气候适宜度以及种植活动对种植业气候适宜度的影响度估算,并对种植业生产对气候变化的适应进行探讨。研究结果表明,(1)近32年来盐亭县大春作物的平均资源适宜指数、效能适宜指数和利用指数(分别为0.578、0.281和48.37%)均大于小春作物(分别为0.304、0.128和42.24%),大春作物的气候适宜度高于小春作物,且作物间的气候适宜度差异较大。(2)受季风气候波动的影响,该县作物气候适宜度有明显的年际波动;该县近32年来气候变化对大春作物气候适宜度有轻微不利影响,而对小春作物气候适宜度趋于有利。(3)盐亭县近32年来种植业平均的资源适宜指数为0.466、效能适宜指数为0.212、利用指数为45.49%;受5种作物资源适宜指数、效能适宜指数,以及作物播种面积与产量年际波动的综合影响,该县种植业气候适宜度亦有明显的年际波动;气候变化对该县种植业气候适宜度总体上有不利影响。(4)近32年来该县种植活动对种植业气候适宜度的影响度平均值为0.00092,其年际波动较大。通过作物种植组合结构的调整,在20世纪90年代中期前对种植业气候适宜度的提高有微弱的正向影响,对气候变化有一定程度的适应;而后期则有负向作用。     

Subacute herpes simplex virus type 1 encephalitis as an initial presentation of chronic lymphocytic leukemia and multiple sclerosis: a case report

Introduction

Herpes simplex virus type 1 encephalitis presents acutely in patients who are immunocompetent. We report what we believe to be the first published case of a subacute course of herpes simplex virus type 1 encephalitis in a patient with asymptomatic chronic lymphocytic leukemia who subsequently developed multiple sclerosis.

Case presentation

A 49-year-old Caucasian woman with a history of fever blisters presented to the emergency department with a history of left temporal headache for four weeks, and numbness of the left face and leg for two weeks. A complete blood count revealed white blood cell count of 11,820 cells/mL, with an absolute lymphocyte count of 7304 cells/mL. The cerebrospinal fluid contained 6 white blood cells/μL, 63 red blood cells/μL, 54 mg glucose/dL, and 49 mg total protein/dL. Magnetic resonance imaging of the brain revealed meningoencephalitis and bilateral ventriculitis. Cerebrospinal fluid polymerase chain reaction for herpes simplex virus type 1 was positive, and the patient's symptoms resolved after ten days of treatment with parenteral aciclovir. Incidental findings on peripheral blood smear and flow cytometry testing confirmed chronic lymphocytic leukemia. One month later, she developed bilateral numbness of the hands and feet; a repeat cerebrospinal fluid polymerase chain reaction for herpes simplex virus type 1 at this time was negative. A repeat magnetic resonance imaging scan showed an expansion of the peri-ventricular lesions, and the cerebrospinal fluid contained elevated oligoclonal bands and myelin basic protein. A brain biopsy revealed gliosis consistent with multiple sclerosis, and the patient responded to treatment with high-dose parenteral steroids.

Conclusion

Herpes simplex virus type 1 encephalitis is a rare presentation of chronic lymphocytic leukemia. Our patient had an atypical, subacute course, presumably due to immunosuppression from chronic lymphocytic leukemia. This unusual case of herpes simplex virus type 1 encephalitis emphasizes the importance of T cell function in diseases of immune dysregulation and autoimmunity such as chronic lymphocytic leukemia and multiple sclerosis. It raises the question of whether atypical presentations of herpes simplex virus encephalitis warrant deliberations on immunocompetence. The development of multiple sclerosis in our patient so soon after she received treatment for herpes simplex virus type 1 encephalitis raises the possibility that herpes simplex virus type 1 encephalitis in an immunosuppressed patient may trigger multiple sclerosis.

     

Short-term treatment of relapsing remitting multiple sclerosis patients with interferon (IFN)-beta1B transiently increases the blood levels of interleukin (IL)-6, IL-10 and IFN-gamma without significantly modifying those of IL-1beta, IL-2, IL-4 and tumour necrosis factor-alpha

We have studied the impact of short-term treatment with interferon (IFN)-beta1b of relapsing remitting (RR) multiple sclerosis (MS) patients' blood levels of type 1 and type 2 cytokines such as IFN-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10 and tumour necrosis factor (TNF)-alpha. These cytokines were measured by solid-phase ELISA. Serum samples were obtained prior to, and 2 and 12 hours after beginning of the treatment and 48 h after the last of 5 s.c. injections with 8 million IU IFN-beta1b given on alternate days for 10 days. The treatment was found to increase the circulating levels of IL-2, IL-6, IL-10 and IFN-gamma at some of the time points considered, with the effect acquiring statistical significance for IL-6, IL-10 and IFN-gamma. The blood levels of IL-1beta, IL-4 and TNF-alpha remained below the limit of sensitivity of the assays at any of the time points considered. If this in vivo study mirrors the impact of IFN-beta1b on MS patients' immune cells, these data demonstrate an activation of the immune system upon early treatment with the drug that does not lead to either type 1 or type 2 cytokine prevalence.