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Few long-term follow-up data are available on thyroid dysfunction (TD) in multiple sclerosis (MS) patients treated with glatiramer acetate (GA) or with interferon-beta (IFNb). In a cohort of 787 relapsing-remitting MS (RRMS) patients whom were followed up for 8 years, we observed an increased prevalence of TD and thyroid autoimmunity (TA) within the first year of IFNb treatment, regardless of the dose or frequency of administration, while no change was observed with GA treatment. The increased prevalence of TD and TA within the first year of IFNb treatment suggested the need for close monitoring of thyroid function and autoimmunity, though only during the first year of IFNb treatment., (© The Author(s) 2014.)

Background: Glatiramer acetate (GA) in multiple sclerosis acts through the induction of GA-specific T-helper 2 cells. Nevertheless, the phenomenon is not universal in patients, explaining individual differences in clinical response., Objective: The objective of this article was to categorize GA-treated patients., Method: An enhanced quantitative PCR assay was used for measuring ex-vivo GA-induced IFNγ and IL4 mRNA responses in mononuclear cells from 23 healthy donors, 27 untreated patients, 33 short-term (≤6 months) and 77 long-term (>6 months) GA-treated patients. Thresholds for IFNγ and IL4 transcriptional response were calculated by ROC analysis and long-term treated patients were compared in terms of prognostic stratification., Results: Thresholds for IFNγ and IL4 transcriptional response were calculated at 5.36 and 1.41 relative expression (RE). Finally, 67% of long-term treated patients scored above both response thresholds. These patients had a higher proportion of relapse-free subjects (74% vs 40% when compare to patients who scored below both thresholds) and a significantly better relapse-free survival rate (p=0.006; CI 0.29-0.75). The negative predictive value to predict adverse clinical outcome was 79% (CI 0.63-0.90), meaning that by a positive response, there is a 79% chance that the patient will not experience a negative outcome at 3 years., Conclusions: Our enhanced quantitative PCR assay produced clinically significant results for GA-treated patients. As such, if patients have a positive response, it means they have less chance of a relapse, while patients with a negative response have a greater probability of a worse outcome.

Neutralizing antibodies (NAb) against interferon-beta (IFN-beta) develop in about a third of treated multiple sclerosis patients and are believed to reduce therapeutic efficacy of IFN-beta on clinical and MRI measures. The expression of the interferon acute-response protein, myxovirus resistance protein A (MxA) is a sensitive measure of the biological activity of therapeutically applied IFN-beta and of its reduced bioavailability due to NAb. However, MxA may not be operative in the pathogenesis of multiple sclerosis or the therapeutic effect of IFN-beta. Instead, matrix metalloproteinases (MMPs) are increased in brain tissue, CSF and blood circulation of multiple sclerosis patients and function as effector molecules in several steps of multiple sclerosis pathogenesis. One of the molecular mechanisms by which IFN-beta exerts its beneficial effect in multiple sclerosis is reduction of MMP-9 expression and increase of its endogenous tissue inhibitor, TIMP-1. Quantitative PCR measurements of MMP-2 and MMP-9, TIMP-1 and TIMP-2, and MxA were performed in peripheral mononuclear cells from clinically stable multiple sclerosis patients with relapsing remitting disease course after short-term and long-term treatment with IFN-beta. IFN-beta therapy down-regulated the expression of MMP-9 and abolished that of MMP-2 in long-term, but not short-term treated multiple sclerosis, while levels of MxA were increased in both instances. The presence of NAb reversed these effects, i.e. led to reduced MxA and increased MMP-2/MMP-9 expression levels compared with NAb- patients. In contrast, expression of TIMPs in peripheral blood mononuclear cells remained unaffected by IFN-beta therapy and the presence of NAb. While MxA is able to detect the biological action and reduced bioavailability of IFN-beta on the basis of single injections, only MMP-9 shows quantitative correlation with the NAb titre. Together with evidence that an imbalance between MMP and TIMP expression is a crucial pathogenetic feature in multiple sclerosis, these findings support the concept of a significant role of NAb in reducing the therapeutic efficacy of IFN-beta.