Hydroxychloroquine as treatment for progressive multiple sclerosis? Maybe!
Hydroxychloroquine for Primary Progressive Multiple Sclerosis
Marcus W Koch, Sharanjit Kaur, Kayla Sage, Janet Kim, Myriam Levesque-Roy, Graziela Cerchiaro, V Wee Yong, Gary R Cutter, Luanne M Metz
Ann Neurol; 2021 Sep 30. doi: 10.1002/ana.26239
Hydroxychloroquine, originally used as anti-malarial drug and then as a treatment for rheumatologic illness, garnered a bad reputation when touted as treatment for COVID-19. A new study, described in the above paper, may repurpose hydroxychloroquine as a potential treatment for persons with progressive multiple sclerosis.
Persons with primary progressive multiple sclerosis have a gradual onset of increasing neurologic difficulties without relapses. While initially considered a different disease than relapsing forms of multiple sclerosis, multiple studies have shown that disease progression unrelated to relapses occurs frequently, even in early relapsing MS. The tissue changes associated with such progression in both primary progressive MS and relapsing MS are similar, and implicate a major role for a population of cells found only in the central nervous system called microglia.
Microglia have multiple functions, both destructive (stripping myelin from nerve fibers) and restorative (removing myelin debris). Since microglia are relatively “hidden” in the body behind the blood-brain barrier, finding drugs that can access these cells is challenging. Hydroxychloroquine may be one such drug.
Initial experiments with animal models of MS showed that hydroxychloroquine affected microglial cells. In this context the drug was tested in a single center Phase 2 trial involving forty persons with primary progressive multiple sclerosis. Participants were given hydroxychloroquine and tested for the time it took to walk 25 feet. Results were compared to changes noted in other individuals with progressive MS. While the average walking speed of all participants slowly declined over the 18 months of the study, only 8 of 35 final participants (23%) had more than a 20% worsening of the time needed to walk 25 feet. This was less than the expected number (~40%) observed in two untreated groups of persons with progressive MS. Based on finding this reduced progression of disability the authors propose to test hydroxychloroquine in a larger, randomized, placebo-controlled clinical trial.
This is an important and interesting study, suggesting a new approach to the treatment of progressive multiple sclerosis, but there are caveats that must be considered. Several are described below.
Key Points Related to the Above Article:
1. The tissue changes in the central nervous systems of persons with progressive multiple sclerosis are also present, albeit to a lesser degree, in persons with relapsing forms of multiple sclerosis. While drugs have been approved to treat progressive MS, they are only modestly effective, and then mainly in individuals who also have acute brain inflammation.
2. One of the major brain cells involved in progressive tissue destruction are microglia. They are found only in the central nervous system and are relatively protected from circulating drugs by the blood-brain barrier. The chronic brain inflammation that microglia produce is thus “compartmentalized.”
3. As with lymphocytes, microglia can have multiple functions. They also can change functions based on their local tissue environment. Under some conditions microglia are tissue-destructive, releasing toxic substances (cytokines) that effect and disrupt myelin and nerve fibers (axons). Under other conditions microglia promote healing, with removal of myelin debris and release of cytokines that promote regeneration.
4. The blood-brain barrier prevents large molecules from leaving the circulation and entering the brain. Hydroxychloroquine is small enough to pass through the blood-brain barrier and decrease the activity of activated microglia. Studies of human microglia in tissue cultures, and studies in mouse models of MS, such as experimental autoimmune encephalomyelitis, showed that addition of hydroxychloroquine resulted in decreased microglial activation and less severe disease.
5. Based on these findings the authors of the above article studied the effects of hydroxychloroquine on the time it took persons with primary progressive multiple sclerosis to walk 25 feet.
6. The researchers excluded individuals with active lesions on central nervous system MRIs as well as those on drugs known to improve walking, such as dalfampridine and baclofen. None of the participants were on a disease-modifying therapy.
7. Participants were tested at the start of the study, and then at 6-month intervals to allow hydroxychloroquine to act. Results were compared to populations of persons with primary progressive multiple sclerosis that had received placebos in other clinical trials.
8. In those other studies more than 40% of individuals had a >20% worsening of their 25-foot timed walk. In the present study, while all participants had some decline in their walking speed, only 23% (8 out of 35 final subjects) had a >20% increase in their 25-foot timed walk.
9. Overall, hydroxychloroquine was well tolerated, with mild side effects, though some participants did withdraw because of them.
10. This “proof of concept” study is important in that is raises the possibility of treating progressive MS by affecting a major “player” in the process, namely microglia. Hydroxychloroquine has multiple mechanisms of action that may affect cells other than microglia. Nevertheless, the results described in this paper are still important. There are, however, several caveats that need to be considered.
11. Microglia are different in different regions of the central nervous system, and may have different functions and responses to drugs. The authors of the above study focused on walking speed as an outcome. This is mainly related to spinal cord dysfunction and the possible effects on microglia in that anatomic region. Effects of hydroxychloroquine on other functions such as cognitive decline (affecting microglia in cerebral cortex and thalamus) or coordination (affecting microglia in the cerebellum) may be different and need to be determined.
12. Most importantly is the question of how specific the microglial-inhibiting properties of hydroxychloroquine are. Do they only inhibit tissue-destructive microglia, or do they inhibit all microglia? While inhibiting the function of destructive microglia may be of benefit, microglia can change function and become reparative. A most unfortunate consequence of hydroxychloroquine action could be a limitation of tissue repair by also inhibiting the actions of tissue-repairing microglia.
13. Even with the above uncertainties, the above paper is a step forward in advancing the concept of altering microglia function to delay and even prevent progressive forms of multiple sclerosis. As the authors note, much work still needs to be done.
Most persons with MS develop the relapsing form of the disease, with acute bouts of central nervous system inflammation resulting in attacks or relapses. However, several recent studies demonstrated that tissue changes characteristic of those seen in progressive multiple sclerosis are also present early in relapsing forms of multiple sclerosis and that progression can occur in relapsing forms of multiple sclerosis in the absence of acute inflammation.
There are multiple disease-modifying therapies for MS that greatly reduce the acute central nervous system inflammation characteristic of relapsing forms of multiple sclerosis. However, while two current disease-modifying therapies are FDA approved for progressive multiple sclerosis their effects are, at best, only modest. Thus, there is a great need for a more robustly effect drug for progressive multiple sclerosis.
As noted above, microglia appear to play a major role in progressive multiple sclerosis, being found in large numbers at the edges of chronically inflamed lesions. Reducing microglial activity reduced disease severity in an animal model of MS, experimental autoimmune encephalomyelitis. The above paper is one of the first to suggest that modifying microglial activity in progressive multiple sclerosis may be of clinical benefit. While there are uncertainties regarding hydroxychloroquine’s exact mechanism of action, and potential negative consequences, more definitive studies of hydroxychloroquine as a treatment for progressive multiple sclerosis should be strongly encouraged.