Marinella Clerico

T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-β†

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‐β in MS patients.

Real-life impact of early interferonβ therapy in relapsing multiple sclerosis

Recent findings support greater efficacy of early vs. delayed interferon beta (IFNβ) treatment in patients with a first clinical event suggestive of multiple sclerosis (MS). We aimed to evaluate the effectiveness of early IFNβ treatment in definite relapsing‐remitting MS (RRMS) and to assess the optimal time to initiate IFNβ treatment with regard to the greatest benefits on disability progression.

Epigenetic therapy for Friedreich ataxia.

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.

MRI activity and neutralising antibody as predictors of response to interferon beta treatment in multiple sclerosis

Objective: To prospectively validate MRI activity and neutralising anti-interferon antibody (NAb) during the first 6 months of interferon β treatment as response indicators in multiple sclerosis (MS). Methods: Patients with relapsing–remitting MS were followed during the first 2 years of treatment. Neurological assessments were performed every 3 months or when a relapse was suspected. MRI scans performed at baseline and at 3, 4, 5 and 6 months after the start of treatment were assessed centrally for disease activity: new T2 or gadolinium enhancing T1 lesions. NAb were assessed using the MxA protein assay; positivity was defined as two consecutive titres ⩾20 NU/ml. We evaluated the predictivity of an active scan, NAb positivity, or both, during the first 6 months of treatment, on the occurrence of clinical disease activity in the following 18 months. Results: 147 patients were assessed at 16 centres. Predictivity parameters (with confidence intervals) were as follows: active scan, sensitivity (SN) 52% (34–69%), specificity (SP) 80% (65–91%), negative predictive value (NPV) 73% (58–77%), positive predictive value (PPV) 62% (42–79%), p = 0.002; NAb positivity, SN 71% (45–88%), SP 66% (55–76%), NPV 92% (82–97%), PPV 29% (16–45%), p = 0.01; active scan and NAb positivity, SN 71% (38–91%), SP 86% (73–94%), NPV 94% (86–98%), PPV 50% (29–70%), p = 0.0003. Conclusions: MRI activity and NAb occurrence during the first 6 months of interferon β treatment were reliable predictors of long term clinical response, particularly when combined. Patients with negative predictors showed a less than 10% risk of developing clinical activity. Patients with positive predictors showed a 50% risk of further clinical activity. These patients need to be followed carefully with further MRI and NAb tests.

Interferon-beta1a for the treatment of multiple sclerosis.

At present, two types of recombinant human interferon (IFN)-β are in clinical use. IFN-β1a is produced in genetically engineered Chinese hamster ovary cells, and its amino acid sequence and glycosylation pattern are identical to those of endogenous human IFN-β. The beneficial effect of IFN-β in multiple sclerosis (MS) probably results from different mechanisms of action, such as a direct effect on plasma cells modulating IgG synthesis, an increase of interleukin (IL)-10 levels, the inhibition of IL-1β and tumour necrosis factor α, the stimulation of IL-1 receptor antagonist production, the inhibition of proliferation of leukocytes, a decreased antigen presentation in microglia, a reduction of T cell migration into the brain by inhibition of the activity of T cell matrix metalloproteinases, and a downregulation of adhesion molecules. IFN-β1a has been shown by several multicenter controlled trials to be effective in relapsing-remitting MS. It reduces relapse rate by 30 – 50%, magnetic resonance imaging signs of disease activity in 30 – 80% and disability progression by 30%. It is also effective in preventing conversion to clinically definite MS when given at the time of a first demyelinating event (i.e., at the very beginning of the clinical disease). No clear evidence of the persistence of the efficacy over the long-term has stood out from a systematic analysis of published trials. A Cochrane review concluded that, in fact, the clinical effect beyond the first year of treatment is not clear. Finally, no efficacy has been shown in secondary progressive or primary progressive MS. However, IFN-β1a is very well tolerated and the most frequent side effects are mild (local skin reaction and flu-like symptoms) and decline in frequency or disappear after the first 3 – 6 months of treatment. Although the optimal frequency between once weekly or multiple weekly administrations is still controversial, all protocols require multiple monthly injections. Some patients might find it hard to cope with such a treatment regimen over the long term. Ongoing trials with new powerful immunomodulatory drugs, such as monoclonal antibodies, that require only monthly or bimonthly parenteral administrations will probably offer a better tolerated treatment option in the near future.

Treatment of Relapsing-Remitting Multiple Sclerosis After 24 Doses of Natalizumab: Evidence From an Italian Spontaneous, Prospective, and Observational Study (the TY-STOP Study)

IMPORTANCE The evaluation of therapeutic choices is needed after 24 doses of natalizumab in patients with multiple sclerosis (MS). OBJECTIVE To evaluate the effect of therapeutic choices on the mean annualized relapse rate and on magnetic resonance imaging MS activity after 24 doses of natalizumab in patients with relapsing-remitting MS. DESIGN, SETTING, AND PARTICIPANTS The TY-STOP study, which recruited participants between October 22, 2010, and October 22, 2012, at 8 Italian MS centers (secondary care outpatient clinics) among 124 adult patients who demonstrated no clinical or magnetic resonance imaging MS activity after 24 doses of natalizumab. INTERVENTIONS Natalizumab, no treatment, interferon beta, glatiramer acetate, or fingolimod. MAIN OUTCOMES AND MEASURES The primary end point was the mean annualized relapse rate. Statistical analyses were performed in 124 patients with complete follow-up data among 130 patients who were recruited and stratified into study groups. In the intent-to-treat group, the decision was made to continue or interrupt natalizumab after 24 doses. In the as-treated group, natalizumab continuers received natalizumab, natalizumab switchers changed to different therapies, and natalizumab quitters discontinued natalizumab during the study year. RESULTS No significant differences in demographic or baseline clinical characteristics were found among the study participants. In the intent-to-treat group (n = 124), clinical (P = .004) and radiologic (P = .02) MS activity was significantly lower in patients continuing natalizumab (n = 43) than in patients interrupting natalizumab (n = 81), with a protective effect of natalizumab continuation on both outcomes (odds ratio [OR], 0.33; 95% CI, 0.15-0.70 for clinical activity and OR, 0.35; 95% CI, 0.15-0.79 for radiologic activity). In the as-treated group (n = 124), clinical (P = .003) and radiologic (P = .03) MS activity was significantly lower in natalizumab continuers than in natalizumab switchers or quitters, confirming a protective effect of natalizumab on the risk of relapse in natalizumab continuers compared with natalizumab quitters (OR, 4.40; 95% CI, 1.72-11.23) and natalizumab switchers (OR, 3.28; 95% CI, 0.99-10.79). No disease rebound was observed in natalizumab quitters. After natalizumab discontinuation, 1 patient developed progressive multifocal leukoencephalopathy during the observation period, with complete recovery. CONCLUSIONS AND RELEVANCE This study provides class III evidence of an increased risk of MS activity resumption after natalizumab discontinuation. Therapy discontinuation after 24 doses in natalizumab-responding patients should be considered only if the risk of progressive multifocal leukoencephalopathy is high and outweighs the benefits of continuing the drug. TRIAL REGISTRATION Osservatorio Nazionale Sulla Sperimentazione Clinica dei Medicinali No. 131/2010.

Every-other-day interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis (INCOMIN Trial) II: analysis of MRI responses to treatment and correlation with NAb

Background In RRMS, clinical exacerbations are usually associated with different types of active lesions at MRI, including: hyperintense lesions on T1-weighted post-gadolinium sequences; new hyperintense lesions or enlarging old lesions on PD/T2-weighted scans; or new hypointense lesions on T1-weighted pre-Gd sequences. Objective/methods Primary outcome was the occurrence of patients with at least one active MRI lesion of the different types indicated above during treatment with 250 mg every other day (EOD) interferon beta (IFNβ)-1b or 30 mg once weekly (OW) IFNβ-1a in outpatients with RRMS (INCOMIN Trial). Results The number of patients with at least one ‘active’ lesion, evaluated over the two-year follow-up, was significantly (P=0.014) lower in the EOD IFNβ-1b arm (13/76, 17%) then in the OW IFNβ-1a arm (25/73, 34%). NAb frequency over two-year follow-up was 22/65 (33.8%) in the EOD IFNβ-1b arm and 4/62 (6.5%) in the OW IFNβ-1a arm, significantly greater in the EOD IFNβ-1b arm. Conclusions The development of MRI active lesions is strongly reduced by EOD-IFNβ-1b compared with OW-IFNβ-1a, indicating that EOD-IFNβ-1b is more effective than OW-IFNβ-1a in reducing ongoing inflammation and demyelination in MS. Logistic regression showed that NAb status did not affect the risk of MRI activity.

Th22 cells are expanded in multiple sclerosis and are resistant to IFN-β

Th1 and Th17 cells have been considered as effectors in mouse EAE and in the human counterpart, MS. Recently, IL‐22, a Th17‐related, proinflammatory cytokine, has been associated with a new Th cell subset, defined as Th22, involved in chronic inflammatory conditions, such as psoriasis; the role of IL‐22 in MS has not yet been elucidated. Here, we report that similar to Th17 cells, the number of Th22 cells increased in the PB and the CSF of RR MS patients, especially during the active phases of the disease. However, as opposed to Th17 cells, the expansion of Th22 cells occurred before the active phases of the disease. Th22 cells were found to be specific for the autoantigen MBP and also expressed high levels of CCR6 and T‐bet, as for Th17 cells, indicating that Th22 self‐reactive cells could have CNS‐homing properties and be pathogenic in active RRMS patients. Conversely to Th17 cells, Th22 cells displayed lower levels of IFNAR1 and were insensitive to IFN‐β inhibition. These data suggest that expansion of Th22 cells in MS could be one of the factors that critically influence resistance to IFN‐β therapy.

Interferon-β1a for the treatment of multiple sclerosis

At present, two types of recombinant human interferon (IFN)-β are in clinical use. IFN-β1a is produced in genetically engineered Chinese hamster ovary cells, and its amino acid sequence and glycosylation pattern are identical to those of endogenous human IFN-β. The beneficial effect of IFN-β in multiple sclerosis (MS) probably results from different mechanisms of action, such as a direct effect on plasma cells modulating IgG synthesis, an increase of interleukin (IL)-10 levels, the inhibition of IL-1β and tumour necrosis factor α, the stimulation of IL-1 receptor antagonist production, the inhibition of proliferation of leukocytes, a decreased antigen presentation in microglia, a reduction of T cell migration into the brain by inhibition of the activity of T cell matrix metalloproteinases, and a downregulation of adhesion molecules. IFN-β1a has been shown by several multicenter controlled trials to be effective in relapsing-remitting MS. It reduces relapse rate by 30 – 50%, magnetic resonance imaging signs of disease activity in 30 – 80% and disability progression by 30%. It is also effective in preventing conversion to clinically definite MS when given at the time of a first demyelinating event (i.e., at the very beginning of the clinical disease). No clear evidence of the persistence of the efficacy over the long-term has stood out from a systematic analysis of published trials. A Cochrane review concluded that, in fact, the clinical effect beyond the first year of treatment is not clear. Finally, no efficacy has been shown in secondary progressive or primary progressive MS. However, IFN-β1a is very well tolerated and the most frequent side effects are mild (local skin reaction and flu-like symptoms) and decline in frequency or disappear after the first 3 – 6 months of treatment. Although the optimal frequency between once weekly or multiple weekly administrations is still controversial, all protocols require multiple monthly injections. Some patients might find it hard to cope with such a treatment regimen over the long term. Ongoing trials with new powerful immunomodulatory drugs, such as monoclonal antibodies, that require only monthly or bimonthly parenteral administrations will probably offer a better tolerated treatment option in the near future.

High-dose, frequently administered interferon beta therapy for relapsing–remitting multiple sclerosis must be maintained over the long term: the interferon beta dose-reduction study

Long-term trials have demonstrated the continued efficacy of interferon (IFN) beta treatment in patients with relapsing-remitting (RR) multiple sclerosis (MS) during prolonged administration. The objective of the work was to evaluate the effects of reducing IFN beta administration frequency and total weekly dose in patients with RR MS who have achieved clinical and MRI disease activity stabilization during long-term IFN beta-1b treatment. Prospective 1-year follow-up of 27 RR MS patients on long-term 250 microg every other day (standard dose) IFN beta-1b treatment were randomized either to gradually reduce dose to 30 microg once-a-week IFN beta-1a (13 patients), or to continue on IFN beta-1b standard dose (14 patients). We found significant differences in the two group of patients. In the group of patients continuously treated with IFN beta-1b standard dose, 79% remained relapse free compared to 23% in the group receiving once-weekly IFN beta-1a (p=0.006). The number of patients without new PD/T2 lesions was higher in the group of patients continuously treated with IFN beta-1b standard dose (77%) compared to the once-weekly IFN beta-1a group (23%) (p=0.04). IFN beta is a long-term treatment for MS. The reduction of IFN beta-1b administration frequency and dose is not advisable even in patients free from clinical and MRI disease activity for many years.