Progressive Multifocal Leukoencephalopathy is a life-threatening, progressive demyelinating disease affecting the white matter tracts of the brain. It is caused by reactivation of the John Cunningham (JC) virus. Although JC virus infects 80 – 90% of the world’s population, PML is exceptionally rare and almost exclusively occurs in people who are immunosuppressed, either due to a disease such as HIV/AIDS or due to medication.
In the MS world, cases of PML have been linked to the use of natalizumab, a highly-effective disease-modifying drug which prevents entry of immune cells into the central nervous system. PML was thought to occur in around 0.5% of people treated with natalizumab. Given that there is no effective treatment for PML, it is crucial that we have a method for working out who is at risk of developing PML and who can be safely treated with natalizumab.
We knew already that the three risk factors for PML in people getting natalizumab are:
1. The presence of antibodies against the JC virus (implying prior infection)
2. Previous immunosuppressive treatment
3. Duration of natalizumab therapy
To clarify how an individual’s risk of PML depends on these factors, Chang et al did some excellent digging: they collected data from participants treated with natalizumab in 4 big studies (STRATA, STRATIFY-2, TOP, and TYGRIS). Altogether this produced a cohort of 37,249 people treated with natalizumab.
They found that 0.4% of the cohort were diagnosed with PML. Of these people, 120 had antibody results available. 119/120 (99%) of these people tested positive for anti-JCV antibodies in the 6 months preceding PML diagnosis. Out of 13,996 people who were negative for anti-JCV antibodies, only 1 developed PML within 6 months of the test. This shows that the presence of antibodies against JC virus is extremely sensitive for detecting PML risk. I.e. if you don’t have antibodies against the JC virus, you’re incredibly unlikely to get PML.
Among people with anti-JCV antibodies, the cumulative probability of developing PML over 6 years was 2.7% if they had had prior immunosuppression, and 1.7% if they had not. The cumulative risk was relatively stable throughout the first 2 years of treatment, but increased after year 2. This confirms what we knew, i.e. that immunosuppression and a longer duration of treatment increase the risk of PML.
Lastly, they found that the amount of anti-JCV antibody correlated with the risk of developing PML in people who had not had immunosuppression. Interestingly, the amount of anti-JCV antibody did not correlate clearly with PML risk in people who had had immunosuppression (see figure). This implies that antibody titres are not a reliable guide to PML risk in people who have been previously immunosuppressed. A possible explanation for this is that immunosuppressive drugs may ‘clear up’ antibodies in the blood but not touch antibodies in the CNS.
This study is excellent – it extends and confirms what we understood about the factors that predispose people to PML. It also provides pwMS and clinicians with a way of calculating an individual’s risk. This kind of evidence is invaluable when people are deciding with their neurologist whether to pursue treatment with natalizumab or switch to another DMT.
Previous estimates of risk of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis receiving natalizumab were stratified by three risk factors: anti-John Cunningham virus (JCV) antibodies in serum, previous immunosuppressant use, and treatment duration, which were estimated using population-based assumptions. We aimed to calculate PML risk estimates from patient-level risk-factor data and to stratify risk by concentrations of anti-JCV antibody in serum (anti-JCV antibody index).
Data on natalizumab-treated patients were pooled from four large, observational, open-label studies: STRATIFY-2, STRATA, TOP, and TYGRIS. Data were analysed with and without imputation for missing values of anti-JCV antibody status and previous immunosuppressant use. For anti-JCV antibody-positive patients in this pooled cohort, cumulative PML risk with or without previous immunosuppressant use was estimated using Kaplan-Meier analysis. Annual PML risks (per 12 natalizumab infusions) for patients without PML in the preceding year were estimated using conditional probability based on the life table method. For anti-JCV antibody-positive patients without previous immunosuppressant use, risk estimates were further stratified using a probability distribution for anti-JCV antibody index values, separately for patients with or without PML. Anti-JCV antibody index cutoffs were selected via sensitivity and specificity assessments for identifying PML cases in an index cohort.
156 (<1%) of 37 249 patients in the pooled cohort had PML. We imputed missing values on anti-JCV antibody status (3912 patients) and on previous immunosuppresant use (544 patients) using a multiple imputation method. For anti-JCV antibody-negative patients (n=13 996), estimated PML risk was less than 0·07 per 1000 patients (95% CI 0·00–0·40). In anti-JCV antibody-positive patients (n=21 696), estimated cumulative PML probability over 6 years (72 infusions of natalizumab) was 2·7% (95% CI 1·8–4·0) in patients with previous immunosuppressant use and 1·7% (1·4–2·1) in those without. In patients without previous immunosuppressant use (n=18 616), estimated annual PML risks per 1000 patients, conditional on having no PML before that year, ranged from 0·01 (0·00–0·03) in year 1 (1–12 infusions) to 0·6 (0·0–1·5) in year 6 (61–72 infusions) for people with an index of 0·9 or less; from 0·1 (0·0–0·2) in year 1 to 3·0 (0·2–5·8) in year 6 for those with an index of more than 0·9 up to and including 1·5; and from 0·2 (0·0–0·5) in year 1 to 10·0 (5·6–14·4) in year 6 for those with an index of more than 1·5.
Our risk estimates calculated from patient-level clinical data allow individualised annual prediction of risk of PML in patients receiving natalizumab for multiple sclerosis, supporting yearly benefit–risk re-evaluation in clinical practice. Further, our estimates are generally consistent with previously calculated estimates. Incorporating anti-JCV antibody index allows further risk stratification for anti-JCV antibody-positive patients who have not previously taken immunosuppressants.