Substituting one disease for another. A large number of you argue that by treating MS, a disabling disease, with immunosuppressive therapies we simply create another ticking time bomb and swap one disease, MS, for another disease, immunosuppression. The difference between these two diseases is that MS-related disability is in general irreversible and associated with loss of quality of life. Immunosuppression on the other hand can be derisked to some extent and its consequences, in particular the opportunistic infections, treated.
The poster-child for derisking opportunistic infections must be natalizumab-associated PML. We now know that pwMS who are JCV-seropositive need to come off natalizumab because of the risk of PML. In high-risk subjects who decide to stay on natalizumab, against our advice, we offer them 3-monthly MRI studies to look for asymptomatic PML, which has a better prognosis than symptomatic PML. The problem with PML is that you need immune reconstitution to clear the virus from the brain and herein lies the problem. When you wash out natalizumab with either plasma exchange, or by waiting for it to wash-out spontaneously, when your immune cells start re-trafficking into the brain you develop and encephalitis. This is called IRIS (immune reconstitution inflammatory syndrome). IRIS in itself is very dangerous. Therefore in patients with a large PML burden, or PML in strategic brain areas such as the brainstem, we tend to give steroids to try and dampen down the damage associated with IRIS. Anecdotal experience suggests steroids work. Is there another strategy we can try?
Two case reports below describe the anti-HIV drug, maviroc, which blocks a particular chemokine receptor CCR5 on lymphocytes, may help prevent or dampen down IRIS. T-cells, including cytotoxic CD8+ T-cells, use CCR5 to cross the blood-brain-barrier. Blocking CCR5 dampens down IRIS and appeared to prevent IRIS-related damage in these two cases. Clearly maviroc as a monotherapy is not enough to stop the immune system clearing the JC virus from the CNS. The question that arises is whether or not maviroc is better than steroids in achieving this? The latter will require a clinical trial.
In reality I hope the number of cases of natalizumab-associated PML drops to become a very rare complication of this treatment. Now that we have derisking strategies, and other highly-effective DMTs which are safer do we really need to continue to put pwMS at such a high risk of PML?
Please note that until we get a drug that clears JCV from the body we will never derisk the PML problem completely. As you are aware PML is a complication of immunosuppression and therefore it will remain a very rare complication of our MS treatments.
Steiner & Benninger. Maraviroc in PML-IRIS: A separate ball game under HIV infection and natalizumab? Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e331. doi: 10.1212/NXI.0000000000000331.
The pathogen is a ubiquitous DNA virus that infects only humans. Subclinical infection often takes place within the first decade of life.
While HAART has a significant beneficial impact on the prognosis of PML in patients with HIV, it remains one of the 4 most common CNS opportunistic infections affecting patients with AIDS.
However, the introduction of HAART and the discontinuation of natalizumab led to the recognition of the immune reconstitution inflammatory syndrome (IRIS), an entity that is not unique to PML and has been observed also with mycobacterial diseases, leprosy, fungal infections, and herpes viruses.
Thus, diagnosis of PML in an immune-compromised patient is associated with a 2-edge challenge and risk: clearing the JC virus from the brain, which requires normalisation of the immune state, and reconstitution of immune surveillance while minimising infiltration of the brain with activated T cells that attempt to control an underlying CNS opportunistic infection.
Maraviroc is drug developed to protect against HIV. HIV infects human T cells via recognition of the CD4 and notably the chemokine receptor CCR5. Maraviroc blocks CCR5.
It has been reported that the CD8 T cells that target the JC-virus infected cells express CCR5, and maraviroc can inhibit the accumulation of CD8 T cells.
Bsteh et al. Severe early natalizumab-associated PML in MS: Effective control of PML-IRIS with maraviroc. Neurol Neuroimmunol Neuroinflamm. 2017;4(2):e323.