Multiple Sclerosis (MS) involves inflammation of myelin sheaths coating the neurones of the brain and spinal cord. Treatment options for MS include immunosuppressive and immunomodulatory drugs that alter the body’s immune system, as well as treatments to reduce inflammation, thereby providing relief and preventing flare-ups and exacerbations. However, an immunosuppressed host is always vulnerable to opportunistic pathogen infections, which makes adequate supportive therapy necessary.
One of the premier drugs in treating relapsing and secondary progressive MS is Natalizumab (trade name: Tsyabri), which reduces the ability of pro-inflammatory immune cells to attach and pass through the cell layers in the blood brain barrier. Since its approval by the FDA in 2004, it was recommended to be injected intravenously along with another immunosuppressive drug and interferon-β-2a, which can lead to extreme immunosuppression in the host. This in turn led to John Cunningham Virus (JCV) infection, destroying myelin sheaths, causing Progressive Multifocal Leucoencephalopathy (PML).
After being withdrawn and renewed again in 2006, there have been rare but steady reports of PML, 440 to date to be exact. The main risk factors for the onset of PML include more than 24 injections of Natalizumab along with other immunosuppressive drugs, which have led to either JCV DNA (recent) or JCV Antibodies (for past) infections.
A study conducted by Elliot M. Frohman, MD, PhD, Department of Neurology and Opthalmology, and her team at the UT Southwestern Medical Center, Dallas, demonstrated the direct link between Natalizumab use and development of PML. A total of 49 volunteers with MS were selected, out of which 26 had just started with their Natalizumab therapy and the remaining 23 had been undergoing the same for a pan of 2 years or more. !8 healthy controls were also selected for the trial.
Blood samples (120 ml) were drawn from baseline from the lot of 26 volunteers, in 3 to 10 month intervals, and one sample was taken from the lot of 23 volunteers who had been undergoing therapy for 2 years or more. Control samples were taken from 18 healthy volunteers as well.
The samples were separated through flowcytometry and matched against CD34+, CD19+ and CD3+ marker subsets. DNA extraction and analysis showed that 13 of 26 (50%) of the newly Natalizumab treated patients were positive for JCV DNA in at least one subset or more. 10 out of 23 (44%) of the patients having undergone Natalizumab therapy for 24 months or more, had detectable viral DNA in one or more subsets and so did 3 of 18 (17%) healthy volunteers.
Summing up, out of the 49 patients with MS and having undergone Natalizumab therapy, 15 of them (31%) were detected positive for viral DNA in their CD34+ subsets, whereas 12 of them (24%) had it in their CD19+ cells.
It was thus concluded by the authors that in immunocompromised hosts treated with Natalizumab, JCV infected the CD34+ cells in the bone marrow, which differentiated and spread further to CD19+ cells and the peripheral circulation. This can thus be referred to as a direct link between Natalizumab use and Progressive Multifocal Leukoadenopathy (PML).