Angele Cucci

Terminal latency index in polyneuropathy with IgM paraproteinemia and anti‐MAG antibody

Criteria for the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) are met by the polyneuropathy associated with immunoglobulin M (IgM) paraproteinemia and anti‐myelin–associated glycoprotein (MAG) antibody (MAG‐CIDP). However, MAG‐CIDP differs from other types of CIDP, mainly in its poorer response to treatment. The utility of terminal latency index (TLI) as an electrophysiological marker for MAG‐CIDP has been debated. In this study we confirmed its diagnostic usefulness and evaluated TLI threshold values for motor nerves investigated in routine nerve conduction studies. Median, ulnar, peroneal, and tibial TLIs of 11 subjects with MAG‐CIDP, 18 with CIDP, and 76 healthy controls were compared, and threshold values for MAG‐CIDP evaluated as the lowest value with a likelihood ratio higher than 10. Mean TLI values and TLIs of all but the peroneal nerve were significantly lower in MAG‐CIDP. Median nerve TLI of 0.26 and ulnar nerve TLI of 0.33 were identified as the threshold TLI values for MAG‐CIDP.

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.

Pro-inflammatory cytokine and chemokine mRNA blood level in multiple sclerosis is related to treatment response and interferon-beta dose

Of 37 multiple sclerosis patients, 19 suboptimal responders were randomized to 375 (n=12) or 250µg (n=7) interferon (IFN)-β-1b. mRNA levels of 23 cytokines, chemokines, and chemokine receptors were quantified by TaqMan low-density array (TLDA) real-time polymerase chain reaction. Better treatment responses or increased IFN-β doses were associated with elevated IL-10 and TGF-β and decreased CXCL10, IL-18, IFN-γ, and TNF-α transcript levels. Adjusting for dose, poor treatment responses resulted in a 4-fold increase in CXCL10 and IFN-γ expression (Mantel-Haenszel RR=3.74, p<0.0001). CXCL10 and IFN-γ mRNA levels were reliable indicators of treatment response. TLDA can be used to tailor IFN-β-1b therapy.

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–β 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.

Neutralizing antibodies in multiple sclerosis patients treated with 375 μg interferon-β-1b

Background: Neutralizing antibodies (NAbs) to IFN-β may have a detrimental effect on treatment response, but increasing IFN-β dose could reduce their occurrence. The OPTimization of Interferon for MS (OPTIMS) study was a multicenter trial investigating clinical and MRI outcomes with the approved IFN-β-1b dose (250 μg) and a higher dose (375 μg), s.c. every other day. Objective: To analyze the occurrence of NAbs and their effect on clinical and MRI response over a long-term (4-year) follow-up using cross-sectional and longitudinal statistical analysis. Methods: Relapses or disease progression was assessed open-label and MRI scans were performed serially during the first year of the study. Neutralizing antibodies were measured using the MxA protein production neutralization assay. Results: A total of 145 patients with relapsing-remitting multiple sclerosis from 14 centers participated in the study. Neutralizing antibody frequency was negatively associated with MRI treatment response, but no detrimental effect of NAbs on the clinical response was observed. Results obtained using cross-sectional or longitudinal statistical approaches were similar. Over the 4-year period, NAb-positive patients treated with 375 μg had a significantly greater probability of NAb disappearance (hazard ratio: 3.41; 95% confidence interval: 1.78 – 6.43; p < 0.01). Conclusion: Use of an IFN-β-1b dose higher than the currently approved 250-μg dose is associated with an increased probability of NAb disappearance. The OPTIMS study was registered at ClinicalTrials.gov: NCT00473213.