Oral nomegestrol acetate and transdermal 17-beta-estradiol for preventing post-partum relapses in multiple sclerosis: The POPARTMUS study.

BACKGROUND: Sex steroids could explain the course of multiple sclerosis (MS) in pregnancy. OBJECTIVE: To compare the annualized relapse rate (ARR) 12 weeks post-partum in women treated with nomegestrol acetate (NOMAc) and 17-beta-estradiol (E2) versus placebo. METHODS: POPARTMUS is a randomized, proof-of-concept trial in women with MS, receiving oral NOMAc 10 mg/day and transdermal estradiol 75 µg/week, or placebo. RESULTS: Recruitment was stopped prematurely due to slow inclusions (n = 202). No treatment effect was observed on ARR after 12 weeks (sex steroids = 0.90 (0.58-1.39), placebo = 0.97 (0.63-1.50) (p = 0.79)). CONCLUSION: POPARTMUS failed showing efficacy of a NOMAc-E2 combination in preventing post-partum relapses.

Neuraxial analgesia is not associated with an increased risk of post-partum relapses in MS.

BACKGROUND: Obstetrical analgesia remains a matter of controversy because of the fear of neurotoxicity of local anesthetics on demyelinated fibers or their potential relationship with subsequent relapses. OBJECTIVE: To assess the impact of neuraxial analgesia on the risk of relapse during the first 3 months post-partum, with a focus on women who experienced relapses during pregnancy. METHODS: We analyzed data of women followed-up prospectively during their pregnancies and at least 3 months post-partum, collected in the Pregnancy in Multiple Sclerosis (PRIMS) and Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPARTMUS) studies between 1992-1995 and 2005-2012, respectively. The association of neuraxial analgesia with the occurrence of a post-partum relapse was estimated by logistic regression analysis. RESULTS: A total of 389 women were included, 215 from PRIMS and 174 from POPARTMUS. In total, 156 women (40%) had neuraxial analgesia. Overall, 24% experienced a relapse during pregnancy and 25% in the 3 months post-partum. Women with a pregnancy relapse were more likely to have a post-partum relapse (odds ratio (OR) = 1.83, p = 0.02), independently of the use of neuraxial analgesia. There was no association between neuraxial analgesia and post-partum relapse (OR = 1.08, p = 0.78). CONCLUSION: Neuraxial analgesia was not associated with an increased risk of post-partum relapses, whatever multiple sclerosis (MS) activity during pregnancy.

Active CMV infection in two patients with multiple sclerosis treated with alemtuzumab.

Alemtuzumab is a humanized monoclonal antibody targeting the surface molecule CD52, resulting in a rapid depletion of innate and adaptive immune cells. Infection rates in multiple sclerosis (MS) treatment trials were higher in alemtuzumab than in interferon beta-treated patients. We report two MS patients who developed cytomegalovirus disease within 1 month after the first 5-day cycle of alemtuzumab. Upon identification and appropriate treatment of the infection, each recovered completely. Neurologists should be aware of this serious but treatable complication.

Natalizumab in Multiple Sclerosis: Long-Term Management.

Natalizumab is a monoclonal antibody highly effective in the treatment of relapsing remitting multiple sclerosis (RRMS) patients. Despite its effectiveness, there are growing concerns regarding the risk of progressive multifocal leukoencephalopathy (PML), a brain infection caused by John Cunningham virus (JCV), particularly after 24 doses and in patients who previously received immunosuppressive drugs. Long-term natalizumab treated, immunosuppressive-pretreated, and JCV antibody-positive patients are asked to rediscuss natalizumab continuation or withdrawal after 24 doses. Until now, there has not been a clear strategy that should be followed to avoid PML risk and in parallel reduce clinical and radiological rebound activity. In this review, we analyzed the results of clinical trials and case reports in relation to the following situations: natalizumab continuation, natalizumab discontinuation followed by full therapeutic suspension or switch to other first or second line MS treatments. Quitting all MS treatment after natalizumab increases MS activity occurrence. The results regarding the therapeutic switch are not homogeneous, so at the moment there are no established guidelines regarding natalizumab treatment after 24 administrations; the choice is currently based on the professional experience of the neurologist, and on patients' clinical features and preferences.

Epigenetic therapy for Friedreich ataxia.

OBJECTIVE: To investigate whether a histone deacetylase inhibitor (HDACi) would be effective in an in vitro model for the neurodegenerative disease Friedreich ataxia (FRDA) and to evaluate safety and surrogate markers of efficacy in a phase I clinical trial in patients. METHODS: We used a human FRDA neuronal cell model, derived from patient induced pluripotent stem cells, to determine the efficacy of a 2-aminobenzamide HDACi (109) as a modulator of FXN gene expression and chromatin histone modifications. FRDA patients were dosed in 4 cohorts, ranging from 30mg/day to 240mg/day of the formulated drug product of HDACi 109, RG2833. Patients were monitored for adverse effects as well as for increases in FXN mRNA, frataxin protein, and chromatin modification in blood cells. RESULTS: In the neuronal cell model, HDACi 109/RG2833 increases FXN mRNA levels and frataxin protein, with concomitant changes in the epigenetic state of the gene. Chromatin signatures indicate that histone H3 lysine 9 is a key residue for gene silencing through methylation and reactivation through acetylation, mediated by the HDACi. Drug treatment in FRDA patients demonstrated increased FXN mRNA and H3 lysine 9 acetylation in peripheral blood mononuclear cells. No safety issues were encountered. INTERPRETATION: Drug exposure inducing epigenetic changes in neurons in vitro is comparable to the exposure required in patients to see epigenetic changes in circulating lymphoid cells and increases in gene expression. These findings provide a proof of concept for the development of an epigenetic therapy for this fatal neurological disease.

Th17 cells in multiple sclerosis express higher levels of JAK2, which increases their surface expression of IFN-γR2.

IFN-ß inhibits the expansion of Th17 cells in active multiple sclerosis (AMS), and this might contribute to improve the clinical symptoms. The effectiveness of this inhibition, however, requires intact IFN-γ signaling in T cells. In this study, we report that both mRNA and cell surface expression of the signaling chain of the IFN-γ receptor (IFN-γR2) and its cognate tyrosine kinase JAK2 are enhanced in peripheral blood Th17 cells and clones from patients with AMS compared with those with inactive multiple sclerosis (IMS) or healthy subjects (HS). IFN-γ decreased the frequency of Th17 peripheral cells and proliferation of Th17 clones from AMS patients. Stimulation of PBMCs from HS in Th17-polarizing conditions resulted in the enhancement of JAK2 expression and accumulation of cell surface IFN-γR2. The role of JAK2 in the modulation of IFN-γR2 was demonstrated as its transduction prevented rapid internalization and degradation of IFN-γR2 in JAK2-deficient γ2A cells. In conclusion, these data identify JAK2 as a critical factor that stabilizes IFN-γR2 surface expression in Th17 cells from AMS patients, making them sensitive to IFN-γ. These data may have clinical implications for a better use of IFNs in multiple sclerosis and possibly other inflammatory diseases.

T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-beta.

OBJECTIVE: T-helper 1 (Th1) and Th17 lymphocytes are involved in experimental autoimmune encephalomyelitis, the model of multiple sclerosis (MS). We characterized the Th1/Th17 cell populations in peripheral blood (PB), their interferon (IFN) receptor expression sensitivity to IFN-beta in MS patients. METHODS: In 30 untreated patients with active MS (AMS) and 32 with inactive MS (IMS), and in 22 healthy subjects, we measured intracellular cytokine expression, interleukin-17-producing myelin basic protein-stimulated PB lymphocytes, surface IFN type I receptor chain1 (IFN-alphaR1) expression, IFN-beta-dependent signal transducer and activator of transcription 1 (STAT1) phosphorylation, and apoptosis of anti-CD3 monoclonal antibody-stimulated PB lymphocytes. RESULTS: Th17 cell percentage increased around sevenfold in AMS compared with IMS or healthy subjects, but there was no change in Th1 cells. Th17 cells in AMS were myelin basic protein specific. The longitudinal follow-up of 18 MS patients shifting between AMS and IMS showed that the percentage of Th17 but not Th1 cells always increased in AMS. IFN-alphaR1 expression, IFN-beta-induced STAT1 activation, and apoptosis were significantly greater in Th17 than Th1 cells. IFN-alphaR1 expression and IFN-beta-dependent STAT1 activation progressively increased in vitro with a highly significant positive correlation only in developing Th17 but not in Th0 or Th1 cells. INTERPRETATION: Evidence that an expansion of peripheral Th17 cells, a Th subset that can infiltrate brain parenchyma and damage cells, is associated with disease activity in MS. The greater IFN-alphaR1 level expressed by Th17 compared with Th1 cells might make them a selective target for IFN-beta therapy.

The OPTimization of interferon for MS study: 375 microg interferon beta-1b in suboptimal responders.

We aimed to evaluate the safety and MRI efficacy of interferon beta-1b (IFNbeta-1b) 375 microg (subcutaneously [sc] every other day [eod]) in relapsing-remitting multiple sclerosis (RRMS) patients with a suboptimal response to IFNbeta-1b 250 microg, i.e., with MRI activity or relapses. The OPTimization of Interferon for MS (OPTIMS) study was a prospective multicenter randomized phase 2 trial comprising a 6-month run-in phase (to identify suboptimal responders) and a 6-month randomized phase of open-label clinical and blinded MRI follow-up. During run-in all patients were treated with IFNbeta-1b 250 microg sc eod; during the study phase suboptimal treatment responders were randomized either to IFNbeta-1b 250 or 375 microg sc eod. Primary outcome was the proportion of patients without MRI activity during study Months 9-12 according to the intention-to-treat principle. 216 RRMS patients entered the study: 83 suboptimal responders were identified and randomized, 7 refused to continue treatment, 76 were included in the analysis. More patients treated with 375 microg had no MRI activity at Months 9-12 (30/36 vs.16/40; relative risk, 0.28; 95 % confidence interval, 0.08-0.47; p = 0.0001). Sensitivity analysis ("worst case scenario") confirmed the results. No new or unexpected adverse events were observed, but there was a trend towards more withdrawals in the 375 microg group. Increasing the dose of IFNbeta-1b from 250 microg to 375 microg is a successful strategy for reducing subclinical signs of disease activity in RRMS patients. Further studies are needed to show whether this dose may also improve clinical efficacy.

The therapy of multiple sclerosis with immune-modulating or immunosuppressive drug. A critical evaluation based upon evidence based parameters and published systematic reviews.

Today many different drugs are available for treatment of multiple sclerosis (MS). Interferons, glatiramer acetate, mitoxantrone, and natalizumab have been approved by the regulatory authorities of many countries for the treatment of MS. Evidence based medicine (EBM) principles allow physicians to better address the correct treatment for patients. This article aimed to review all the clinical trials on immune-modulating and immunosuppressive drugs on the basis of the EBM principles. Based on the evidence to date interferon beta represents the best therapeutic option, particularly if given at high doses and with multiple injections per week. Due to its lower efficacy, glatiramer acetate should be used as a second choice in case of intolerable side effects or toxicity of interferon beta. Great efficacy has been demonstrated for mitoxantrone and natalizumab. These drugs should be, however, used with particular attention for their potential toxic effects.

Pregnancy Epigenetic Signature in T Helper 17 and T Regulatory Cells in Multiple Sclerosis.

Increasing evidence supports the anti-inflammatory role of estrogens in Multiple Sclerosis (MS), originating from the observation of reduction in relapse rates among women with MS during pregnancy, but the molecular mechanisms are still not completely understood. Using an integrative data analysis, we identified T helper (Th) 17 and T regulatory (Treg) cell-type-specific regulatory regions (CSR) regulated by estrogen receptor alpha (ERα). These CSRs were validated in polarized Th17 from healthy donors (HD) and in peripheral blood mononuclear cells, Th17 and Treg cells from relapsing remitting (RR) MS patients and HD during pregnancy. 17ß-estradiol induces active histone marks enrichment at Forkhead Box P3 (FOXP3)-CSRs and repressive histone marks enrichment at RAR related orphan receptor C (RORC)-CSRs in polarized Th17 cells. A disease-associated epigenetic profile was found in RRMS patients during pregnancy, suggesting a FOXP3 positive regulation and a RORC negative regulation in the third trimester of pregnancy. Altogether, these data indicate that estrogens act as immunomodulatory factors on the epigenomes of CD4+ T cells in RRMS; the identified CSRs may represent potential biomarkers for monitoring disease progression or new potential therapeutic targets.

Adherence to interferon-beta treatment and results of therapy switching.

Adherence to long-term therapy has always been a problem in all fields of medicine. In multiple sclerosis (MS), treatment consists of parenteral administration of immune-modulating drugs once or several times weekly for an as yet undetermined length of time. Different studies on the MS patients' compliance showed that the most frequent cause of stopping treatment is the perceived lack of efficacy and that most treatment withdrawals occur during the first year of treatment. A trial aimed to identify the minimum effective IFNbeta dose showed that some patients had disease activity after switching to a lower IFNbeta dose. OPTIMS (OPTimization of Interferon dose for MS study) was a multicenter study, involving 24 Italian MS centers, 216 patients, aimed to identify a treatment response indicator allowing the early identification of poorly responding patients. A single active scan during the first 6 months of IFN treatment had a significant positive predictability of 59% (95% confidence interval, 41-76; p=0.05) on the presence of clinical signs of disease activity during the further 2-year follow-up.

Long-term safety evaluation of natalizumab for the treatment of multiple sclerosis.

INTRODUCTION: Natalizumab is a humanized monoclonal antibody highly effective in relapsing-remitting multiple sclerosis (MS). Important concerns about its safety have been pointed out mainly because of the risk of progressive multifocal leukoencephalopathy (PML), caused by the opportunistic John-Cunningham virus (JCV). Areas covered: This review analyzes all the safety aspects related to the use and safety of natalizumab in MS patients. Other than PML, post-marketing, safety red-flags have been reported, as liver or haematological serious adverse events. Pregnancy evidences will be pointed out. The risk of PML depends on: concomitant or previous immunosuppression, exposure duration, anti-JCV antibody level. In natalizumab-related PML the average survival is 77%; prognostic features and information for the earliest identification of PML have been identified to maximally reduce its incidence, mortality and morbidity. Expert opinion: Natalizumab is a highly effective drug for MS patients but its safety issues represent a relevant limitation and impose strict clinical surveillance of treated patients. Some post-marketing safety red-flags have been pointed out, with higher attention to severe liver failures and limphoma cases. If PML and its consequences are considered the most relevant issues, a continuous surveillance must be maintained also regarding other possible SAEs like liver diseases and malignancies.

Lack of CD4+ T cell percent decrease in alemtuzumab-treated multiple sclerosis patients with persistent relapses.

Alemtuzumab, a highly effective treatment for relapsing remitting multiple sclerosis (RRMS), induces lymphopenia especially of CD4+ T cells. Here, we report the atypical CD4+ T population behaviour of two patients with persistent disease activity despite repeated alemtuzumab treatments. Whereas lymphocytes count decreased and fluctuated accordingly to alemtuzumab administration, their CD4+ cell percentage was not or just mildly affected and was slightly below the lowest normal limit already before alemtuzumab. These cases anticipate further studies aimed to investigate whether the evaluation of the CD4+ cell percentage could represent a helpful tool to address the individual clinical response to alemtuzumab.

Ultrasound-guided Botulinum Toxin-A Injections: A Method of Treating Sialorrhea.

Neurological diseases can be complicated by sialorrhea, an excessive flow of saliva. Patients suffering from moderate to severe sialorrhea have an impaired quality of life, often worsened by correlated complications such as aspiration pneumonia, oral infections, dental caries, and maceration of the skin. Diverse therapeutic approaches have been proposed for the treatment of sialorrhea, including surgery and the use of anticholinergic agents, with limited results and the possible occurrence of serious adverse events. Recently, botulinum toxin (BoNT) injection within the major salivary glands has been proposed in patients refractory to anticholinergic therapy, with the aim of inhibiting local acetylcholine release and gland activity. In order to obtain a better outcome in terms of reduction of saliva production, efficacy, duration, and avoidance of major adverse events, we developed an ultrasound-guided BoNT-type A injection technique accurately described in the text. Here we present a method of treating sialorrhea with bilateral parotid and submandibular gland BoNT-type A injections under ultrasound guidance. Four quadrants of the parotid gland and two quadrants of the submandibular gland are visualized and injected using two accesses and one access, respectively. The ultrasound-guided procedure provides a simple, non-invasive, real-time visualization of the muscular and glandular tissues and their surrounding structures, optimizing treatment efficacy and safety.

Alemtuzumab long-term immunologic effect: Treg suppressor function increases up to 24 months.

OBJECTIVE: To analyze changes in T-helper (Th) subsets, T-regulatory (Treg) cell percentages and function, and mRNA levels of immunologically relevant molecules during a 24-month follow-up after alemtuzumab treatment in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: Multicenter follow-up of 29 alemtuzumab-treated patients with RRMS in the Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS) I and CARE-MS II trials. Peripheral blood (PB) samples were obtained at months 0, 6, 12, 18, and 24. We evaluated (1) mRNA levels of 26 immunologic molecules (cytokines, chemokines, chemokine receptors, and transcriptional factors); (2) Th1, Th17, and Treg cell percentages; and (3) myelin basic protein (MBP)-specific Treg suppressor activity. RESULTS: We observed 12 relapses in 9 patients. mRNA levels of the anti-inflammatory cytokines interleukin (IL)-10, IL-27, and transforming growth factor-ß persistently increased whereas those of proinflammatory molecules related to the Th1 or Th17 subsets persistently decreased after alemtuzumab administration throughout the follow-up period. PB CD4+ cell percentage remained significantly lower than baseline while that of Th1 and Th17 cells did not significantly change. A significant increase in Treg cell percentage was observed at month 24 and was accompanied by an increase in Treg cell suppressive activity against MBP-specific Th1 and Th17 cells. CONCLUSIONS: The long-lasting therapeutic benefit of alemtuzumab in RRMS may involve a shift in the cytokine balance towards inhibition of inflammation associated with a reconstitution of the PB CD4+ T-cell subsets that includes expansion of Treg cells with increased suppressive function.

Immunodetection of anti-MAG IgM antibody by cross-reactivity to LA-N-1 neuroblastoma cells.

Demyelinating polyneuropathiy associated with IgM paraproteinemia and high titers of anti-MAG IgM antibodies (MAG-PN) is considered different from chronic inflammatory demyelinating polyneuropathy, particularly because of the poorer response to treatment of MAG-PN patients. Therefore, anti-MAG anitbodies may have relevant prognostic value. Available anti-MAG antibody assays require central nervous system myelin proteins from autopsied human brains. This study investigated the feasibility of detecting anti-MAG antibody by immunofluorescence and flow cytometry using a panel of human neuroblastoma cell lines as targets. We report here on the evaluation of the LA-N-1 cell line as an appropriate substrate for the detection of anti-MAG antibody by indirect immunoflourescence.

The importance of maintaining effective therapy in multiple sclerosis.

The INCOMIN study (INdependent COMparison of INterferons) lends further support to the growing body of evidence that both dose and frequency of interferon beta (IFNbeta) administration are important in the treatment of multiple sclerosis (MS). High-dose, high-frequency IFNbeta (IFNbeta-1b 250 microg eod sc and IFNbeta-1a 44 microg sc) treatment offers greater therapeutic benefit, in terms of clinical and magnetic resonance imaging (MRI) outcome measures, compared with low-dose, once-weekly administration of IFNbeta. The importance of maintaining the most effective treatment regimen has been shown in another study. The data from this study suggested that patients who have 'stable' disease (i. e. no evidence of clinical or MRI disease activity) during long-term treatment with IFNbeta-1b 250 microg, who are subsequently treated with low-dose, once-weekly IFNbeta-1a 30 microg, are more likely to experience relapses, disease progression or MRI activity compared with those remaining on IFNbeta-1b 250 microg. These data clearly indicate that frequently administered therapy must be maintained to achieve the optimal therapeutic benefit for patients. Those patients who had their IFNbeta-1b 250 microg therapy reduced to low-dose, once-weekly IFNbeta-1a and experienced a resumption of disease activity were returned to their previous regimen. However, after 1 year of additional follow-up, many of these patients still had clinical or MRI signs of disease activity, highlighting further the risks associated with the reduction of IFNbeta dose and frequency of administration. Taking into consideration the evidence supporting the greater efficacy of IFNbeta-1b 250 microg or IFNbeta-1a 44 microg in MS it is of considerable interest to examine whether it is useful to increase the dose of IFNbeta-1b in patients who do not respond satisfactorily to the approved standard dose. This is the rationale for the recently completed OPTIMS (OPTimization of Interferon for MS) study, in which partially responding patients were randomised to IFNbeta-1b 250 or 375 microg every other day. An interim safety analysis of OPTIMS patients has not raised any safety or tolerability concerns. In summary, there is consistent evidence to support the importance of maintaining frequently administered IFNbeta (IFNbeta-1b 250 microg or IFNbeta-1a 44 microg) for the treatment of MS.

Long-term follow-up of ultrasound-guided botulinum toxin-A injections for sialorrhea in neurological dysphagia.

Literature provides reports only of a limited follow-up single injection of botulinum toxin-A (BoNT-A) in patients with sialorrhea. The aim of our study is to evaluate the long-lasting efficacy and safety of ultrasound-guided BoNT-A injections for severe sialorrhea secondary to neurological dysphagia. We enrolled 38 severe adult sialorrhea patients referred consecutively to the neurology unit and performed bilateral parotid and submandibular gland BoNT-A injections under ultrasound guidance. The outcomes of the study were reduction of sialorrhea, duration of therapeutic effect, and subjective patient- and caregiver-reported satisfaction. A total of 113 BoNT-A administrations were given during the study period with a mean duration of follow-up of 20.2 ± 4.4 months. We observed a significant decrease from baseline in mean number of daily aspirations and a significant improvement in patient- and caregiver-reported outcomes following ultrasound-guided BoNT-A injections (p < 0.001 vs baseline for all comparisons) and the mean duration of the efficacy was 5.6 ± 1 months. No major treatment-related adverse events occurred and a low incidence of minor adverse events was reported. This study confirms the long-lasting efficacy and safety of ultrasound-guided BoNT-A injections for sialorrhea, regardless of the causative neurological disorder. These results should encourage the use of BoNT-A in the treatment of severe sialorrhea and highlight the role of ultrasound guidance to obtain optimal results in terms of safety and reproducible outcomes.

Anti-interferon antibodies in multiple sclerosis. Molecular basis and their impact on clinical efficacy.

Low levels of naturally-occurring, high-affinity antibodies directed against cytokines can be found in the circulation of individuals who have never been exposed to exogenously-supplied cytokines. These antibodies are thought to play a regulatory role in the intensity and duration of immune response. Interferon (IFN) beta has been shown to attenuate both relapsing-remitting multiple sclerosis (MS) and secondary progressive MS in several well-powered, randomized, controlled clinical trials. IFN therapy can induce the production of anti-IFN neutralizing antibodies (NAb), usually in the second 6 months of treatment, in 3 to 45% of treated patients. This variation in the proportion of NAb-positive patients is probably due to the immunogenicity of different formulations of IFN beta, as well as the assay used, which are not currently standardized. The occurrence of NAb appears to be directly correlated with the dose of therapeutic IFN administered, up to a certain dose threshold. If the dose is increased beyond this threshold, the levels of NAb decrease. The biological significance of anti-IFN NAb is not yet known, nor has it been proven conclusively that they affect the clinical response to IFN beta therapy. The presence of NAb is therefore not an indication that treatment should be changed. Indeed, any treatment decision should be based only on the clinical response to therapy.

Dose and frequency of interferon treatment matter--INCOMIN and OPTIMS.

Three different interferon beta (IFN beta) products are currently approved for the treatment of patients with relapsing-remitting multiple sclerosis (RRMS). However, the recommended method of administration, the dosage and the frequency of administration differ widely between each of the three products. Although controlled clinical trials have demonstrated the efficacy of both alternate-day IFN beta-1b (Betaferon/Betaseron) and once-weekly IFN beta-1a (Avonex) compared with placebo, it is likely that patient compliance, efficacy and tolerability are affected by the dosage regimen used. There are several issues to consider. Once-weekly administration may be associated with fewer adverse events and greater convenience, and it has been suggested that this may increase compliance. Conversely, frequent administration may be associated with increased overall efficacy. There is a convincing pharmacological rationale indicating that frequent dosing, with an interval of less than 72 h, is necessary to sustain the activity of intracellular molecular signalling pathways responsible for regulating IFN beta-induced gene expression. However, there was a need to explore the overall effectiveness of the two administration protocols in a comparative trial. The INCOMIN (Independent Comparison of Interferon) study compared clinical and magnetic resonance imaging (MRI) efficacy of IFN beta-1b 250 microg (8 MIU) subcutaneously (s.c.) on alternate days and IFN beta-1a 30 microg (6 MIU) intramuscularly (i.m.) once weekly in patients with RRMS. INCOMIN demonstrated convincingly that clinical and MRI outcome measures were significantly better in the IFN beta-1b-treated group. Blinded MRI evaluation confirmed the clinical results. Despite some limitations of the study design, imposed by the ethical and practical challenges of conducting comparative trials of injectable therapies, the concordance of the clinical and MRI findings indicate that frequently administered IFN beta-1b reduced evidence of disease activity more effectively than once-weekly administered IFN beta-1a, with the clinical benefits for patients becoming more pronounced over time. Given that the response to IFN beta appears to be dose dependent, the question that might be asked is whether greater efficacy can be obtained by increasing doses beyond those currently approved. OPTIMS (Optimization of Interferon dose for MS) is currently examining the safety and efficacy of a dose of IFN beta-1b that is higher than any currently marketed IFN beta. While OPTIMS is still underway, preliminary safety analyses indicate that higher doses are well tolerated.