Migraine, interferon ß1a and siponimod immunomodulator therapies.

BACKGROUND: Autoimmunity seems to play a great role in the pathogenesis of migraine headache pain. There is far more evidence that interferon can exacerbate migraines. We report a case where remission of severe comorbid migraine attacks happened with the start of interferon ß1a (Merck, Netherlands) immunomodulation therapy. Therapy for multiple sclerosis was decided according to the severity of the debilitating comorbid migraine headache pain rather than the evolution of multiple sclerosis the far more serious disease. CASE PRESENTATION: A 63-years old patient suffered for 30-years from migraine headache of severe disability assessment scale (MIDAS) Grade-IV = 27. He also suffered for 25-years from optic-sensory relapsing remitting multiple sclerosis (RRMS). Subcutaneous interferon ß1a 44-µg immunomodulation therapy for 4-years resulted in multiple sclerosis complete remission. The start of interferon ß1a therapy for multiple sclerosis seemed to help resolving the comorbid migraine attacks. The visual aura premonitory symptom preceding migraine headache would end up with a feeling of post visual aura clearer field of vision and a feeling of wellbeing. As the patient developed secondary progressive multiple sclerosis (SPMS), oral siponimod 2 mg (Novartis, Ireland), currently the only available therapy for SPMS, replaced his interferon therapy. This was associated with a relapse of migraine severe attacks. Reverting back to interferon therapy was again associated with migraine headache remission. CONCLUSIONS: Interferon ß1a might be an efficic therapy for "autoimmune migraine". With numerous immunomodulators currently available for other systemic autoimmune diseases associated with comorbid migraine; examining the effect of these immunomodulatory therapies on comorbid migraine headache could be beneficial in finding a specific immunomodulator therapy for "autoimmune migraine".

No evidence of disease activity status in patients treated with early vs. delayed subcutaneous interferon ß-1a.

BACKGROUND: Clinically isolated syndrome (CIS) is defined as a monophasic clinical episode highly suggestive of multiple sclerosis (MS). Regardless, studies have shown that treatment at this early stage of MS can delay a second event and prolong the transition to clinically diagnosed MS. The objective of this post-hoc analysis was to determine the effect of early CIS treatment with once weekly (qw) or three times weekly (tiw) subcutaneous interferon (scIFN) ß-1a vs. delayed treatment (DT) on the composite endpoint of no evidence of disease activity (NEDA)-3. METHODS: In REFLEX, patients with CIS were randomized to double-blind scIFN ß-1a 44 µg tiw, qw, or placebo for 24 months. Upon clinically-definite MS, patients switched to open-label scIFN ß-1a tiw. Patients who completed REFLEX entered an extension (REFLEXION). Patients initially randomized to placebo switched to tiw (DT); scIFN ß-1a patients continued their initial qw/tiw regimen for up to 60-months post-randomization. This post-hoc analysis was conducted in the integrated intent-to-treat REFLEX plus REFLEXION population (tiw, n = =171; qw, n = =175; DT, n = =171). All p values are nominal. CIS was defined using the McDonald 2010 criteria. RESULTS: Patients receiving early treatment (ET) with scIFN ß-1a tiw and qw were more likely to achieve NEDA-3 than DT at year 2 (tiw vs. DT: OR 4.26, 95% CI 2.02-8.98, p = =0.0001; qw vs. DT: OR 2.99, 95% CI 1.39-6.43, p = =0.005). Compared with DT, ET with scIFN ß-1a tiw was more likely to achieve NEDA-3 at year 3 (OR 3.73, 95% CI 1.63-8.55, p = =0.002) and year 5 (OR 12.96, 95% CI 1.66-101.04, p = =0.015). Between ET regimens, the odds of achieving NEDA-3 were not significantly improved by scIFN ß-1a 44 µg tiw at year 2 (OR 1.42, 95% CI 0.81-2.50, p = =0.22) but were at year 3 (OR 2.26, 95% CI 1.11-4.60, p = =0.024) and year 5 (OR 3.22, 95% CI 1.01-10.22, p = =0.048), indicating that the beneficial effects of more frequent scIFN ß-1a dosing become more apparent over time in patients with CIS. In the subgroup of patients with Gd+ lesions at baseline the odds for achieving NEDA-3 were higher for ET up to year 2 compared with DT (tiw: OR 10.21, 95% CI 1.23-84.82, p = =0.03; qw: OR 8.97, 95% CI 1.08-74.28, p = =0.04). In patients without Gd+ lesions at baseline, those receiving ET were more likely to achieve NEDA-3 at year 2 (OR 3.56, 95% CI 1.56-8.10, p = =0.003), year 3 (OR 2.54, 95% CI 1.05-6.18, p = =0.04) and year 5 (OR 9.63, 95% CI 1.19-77.79, p = =0.034) than patients who received DT. CONCLUSIONS: ET with scIFN ß-1a tiw was associated with a higher likelihood of achieving NEDA-3 not only at 2 but also at 3 and 5 years.

GPIHBP1 autoantibody syndrome during interferon ß1a treatment.

BACKGROUND: Autoantibodies against glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) cause chylomicronemia by blocking the ability of GPIHBP1 to bind lipoprotein lipase (LPL) and transport the enzyme to its site of action in the capillary lumen. OBJECTIVE: A patient with multiple sclerosis developed chylomicronemia during interferon (IFN) ß1a therapy. The chylomicronemia resolved when the IFN ß1a therapy was discontinued. Here, we sought to determine whether the drug-induced chylomicronemia was caused by GPIHBP1 autoantibodies. METHODS: We tested plasma samples collected during and after IFN ß1a therapy for GPIHBP1 autoantibodies (by western blotting and with enzyme-linked immunosorbent assays). We also tested whether the patient's plasma blocked the binding of LPL to GPIHBP1 on GPIHBP1-expressing cells. RESULTS: During IFN ß1a therapy, the plasma contained GPIHBP1 autoantibodies, and those autoantibodies blocked GPIHBP1's ability to bind LPL. Thus, the chylomicronemia was because of the GPIHBP1 autoantibody syndrome. Consistent with that diagnosis, the plasma levels of GPIHBP1 and LPL were very low. After IFN ß1a therapy was stopped, the plasma triglyceride levels returned to normal, and GPIHBP1 autoantibodies were undetectable. CONCLUSION: The appearance of GPIHBP1 autoantibodies during IFN ß1a therapy caused chylomicronemia. The GPIHBP1 autoantibodies disappeared when the IFN ß1a therapy was stopped, and the plasma triglyceride levels fell within the normal range.