Hydroxychloroquine was originally cast as the big saviour against COVID-19 and is now being cast as a way to control progressive MS. It was originally suggested that hydroxychloroquine was anti-viral, however, the story in COVID-19 was put to the sword and it was questioned where there were unwanted side effects associated with its use ( Zhanel et al. . Can J Infect Dis Med Microbiol. 2021;2021:5942366)
Hydroxychloroquine, is a medication used to prevent and treat malaria in areas where malaria remains sensitive to chloroquine and is used in the treatment of rheumatoid arthritis, and lupus, Can it be used in multiple sclerosis?.
Koch et al. Hydroxychloroquine for Primary Progressive Multiple Sclerosis. Anals of Neurology. 2021 Sep 30. doi: 10.1002/ana.26239.
Objective: Primary progressive multiple sclerosis (PPMS) does not respond well to immunomodulatory or immunosuppressive treatment. Chronic activation of microglia has been implicated in the pathophysiology of PPMS. The anti-malarial drug hydroxychloroquine (HCQ) reduces the activity of human microglia and has neuroprotective effects in vitro.
Methods: We conducted a single-arm, phase 2 futility trial of 200mg oral HCQ twice daily for 18 months (NCT02913157). In an effort to investigate disability worsening in the absence of overt focal inflammation, we excluded participants with contrast enhancing lesions on a screening MRI. The primary endpoint was ≥20% worsening on the timed 25-foot walk measured between 6 and 18 months of follow-up.
Results: Based on original trial data, 40% of the cohort were expected to worsen…..HCQ treatment would be deemed successful if fewer than 10 of 35 participants experienced clinically significant worsening. The study met its primary endpoint, as only 8 of 35 participants worsened between 6 and 18 months. HCQ was overall well tolerated, with adverse events in 82% and serious adverse events in 12% of participants. All serious adverse events were unlikely related to HCQ use.
Interpretation: HCQ treatment was associated with reduced disability worsening in people with PPMS. HCQ is a promising treatment candidate in PPMS and should be investigated further in randomized controlled clinical trials.
It was reported that mega hydrochloroquine could inhibit microglia and mega amounts (100mg/kg) inhibited attack based EAE in animals.
Koch MW, Zabad R, Giuliani F, Hader W Jr, Lewkonia R, Metz L, Wee Yong V. Hydroxychloroquine reduces microglial activity and attenuates experimental autoimmune encephalomyelitis. J Neurol Sci. 2015 Nov 15;358(1-2):131
Human doses are around 200-400mg/day (about 2-6mg/kg) and this prompted a trial. They did a futility trial which means it asks the question would it be futile to keep on going? The answer in 18 months was that you should keep trying, however it does not say it works. This was not a placebo controlled trial. The THC trial in MS was considered a failure… but the control group did not worsen as predicted and so it was not possible to show an effect and we know the placebo effect can be very strong. Therefore the futility trial is fraught with dangers. It will need to be done again
However if it does something in arthritis it has a chance of doing something in MS. One thing it does do is that it gets rid of tumour necrosis factor and it does appear to be able to get in the brain. Richardson et al. J Neurol. 2020;267:1880. We suggested this may be desirable. This is a mechanism that works with IBUDILAST and we know this shows promise as will be shown in ECTRIMS2021.
H. Ehrhardt et al 151 – Ibudilast slows retinal atrophy in progressive multiple sclerosis: post-hoc analyses of the SPRINT-MS Phase II randomized controlled trial
Introduction: Inner retinal layer thinning (in particular of the composite ganglion cell + inner plexiform layer [GCIPL]) as measured by optical coherence tomography (OCT) reflects global neurodegeneration across multiple sclerosis (MS) subtypes, including progressive MS (PMS). Atrophy of the inner (INL) and outer nuclear layer (ONL) have also been shown to be prominent in PMS. Unlike in relapsing-remitting MS, rates of GCIPL, INL or ONL appear to be unaffected by conventional therapies in PMS. The SPRINT-MS trial, however, has demonstrated slower macular volume loss with ibudilast treatment, as well as varying effects on brain substructure measures, by PMS subtype.
(1) To determine the effects of ibudilast on retinal layer atrophy in PMS,
(2) To investigate differences in retinal atrophy response to ibudilast in primary PMS (PPMS) and secondary PMS (SPMS), and
(3) To evaluate associations between changes in OCT and MRI measures in the SPRINT-MS PMS cohort.
Methods: Participants (PPMS: n=134, SPMS: n=121) were randomized to ibudilast or placebo. OCT and MRI data were collected every 24 weeks for 96 weeks. OCT scans underwent extensive quality control before and after segmentation using a Johns Hopkins University algorithm which produces consistent results across Cirrus HD-OCT and Spectralis devices. Longitudinal data were analyzed using linear mixed-effects regression models adjusted for age, sex, disease duration, and subtype. Similarly adjusted partial Pearson correlations are also reported.
Results: GCIPL atrophy was slower in the ibudilast (-0.020±0.20 µm/year, n=129) than the placebo group (-0.27±0.20 µm/year, n=126, p=0.003). This difference in GCIPL atrophy rates was pronounced in the PPMS cohort (Ibudilast: -0.08±0.29 µm/year vs Placebo: -0.60±0.29 µm/year, p<0.001), but was not significant in the SPMS cohort (Ibudilast: -0.20±0.28 µm/year vs Placebo: -0.12±0.28 µm/year, p=0.54). Rates of brain parenchymal fraction (BPF) decline and atrophy of the GCIPL (r=0.31), INL (r=0.25), and ONL (r=0.17) were each significantly associated (p<0.001).
Conclusions: In the SPRINT-MS trial ibudilast treatment in PMS decreased GCIPL atrophy. Similar to previous MRI findings, the difference appeared to be primarily driven by response in the PPMS cohort. Atrophy of retinal layers, particularly the GCIPL, correlate with whole brain atrophy in PMS. Further OCT analyses are underway examining relationships with clinical outcomes and serum neurofilament.