We document 4 additional cases of rituximab-associated PML occurring in the setting of underlying RA, extending the information available from the prior single published case report.18
Given the rarity of RA-associated PML, these cases support the hypothesis that rituximab increases the risk of PML in this setting. Rheumatoid arthritis has not been commonly associated with PML, although patients living with it commonly take other immunosuppressive drugs that have been associated with this condition.23
Calabrese and Molloy15–17
used the Nationwide Inpatient Sample data to document that the rate of PML in patients with RA is 0.4 per 100 000 discharges, compared with 0.2 for the general population (excluding acknowledged high-risk conditions of HIV, malignancy, and organ transplant) while another incidence study found no cases of RA-associated PML.23
With 5 described cases of rituximab-associated PML in patients with RA and an estimated 129 000 exposed (A. Kelman, MD, Genentech, Inc, written communication, May 20, 2010), incidence is probably at least 1 in 25 000 exposed patients, especially given that not all involved patients may have been accurately diagnosed or reported. While this evidence suggests that risk is increased, it is less than the apparent risk of PML with natalizumab treatment, which is about 1 in 1000 patients exposed for more than 24 months,10,11
or for efalizumab, where risk may have been as high as 1 in 400 exposed patients.24
Risk of PML associated with rituximab has been particularly difficult to characterize. While many cases of PML are reported,14
in most cases they have occurred in individuals with a well-known concomitant risk of PML. This factor, as well as the absence of a clear denominator for exposure, and probable missed cases of PML have made it challenging even for interested professionals collecting all available data to decide if any increased risk exists. To our knowledge, the present series of cases is the most decisive evidence available, documenting a growing number of cases in a setting where PML was very rare, including 1 case (case 1) where there were minimal other significant risks outside the recent exposure to rituximab.
This case series is instructive in an additional way, since PML in this setting differs from that seen in the case of malignancy or untreated HIV by the common occurrence of PML with IRIS. This factor is critical for clinicians, since it impacts diagnosis and management. Detection of JC virus DNA in CSF was insensitive for PML diagnosis early in the disease onset. This may reflect low copy numbers, a phenomenon recently reported in natalizumab-associated PML cases.11,25
If PML presents during IRIS, CSF viral loads are likely to be low or undetectable, making a brain biopsy necessary to confirm the diagnosis. If inflammatory changes are under way, the lesions may transform, accounting for the appearance of gadolinium enhancement, which is atypical for PML in other settings. This inflammatory component may exacerbate neurological signs and symptoms and cause a further decline in the patient’s status. Immune reconstitution inflammatory syndrome associated with PML can be a life-threatening complication requiring therapy such as corticosteroids to optimize survival and best functional outcomes.
The mechanism of increased risk of PML in association with rituximab remains unknown. The immune deficiency experience in AIDS, where the greatest risk for PML occurs, is typified by cellular immune deficiency with progressive loss of CD4 lymphocytes but with relative preservation of humoral immunity. Given the routine presence of antibody to JC virus when PML develops, and the important association of JC virus–specific CD8 cells to the prognosis for survival from PML, the humoral immune system has generally been thought to be of secondary importance in this disorder.26,27
Lymphopenia was chronic in 75% of our cases, providing a prolonged setting in which JC virus may have spread and transformed to enhance neurovirulence. Therapy that targets CD20 cells and the humoral immune system was thought theoretically to carry less risk for PML. Our cases suggest that optimal control of JC virus requires both intact B and T cells. An alternative possibility may be that B-cell precursors, believed to be a site of infection in the marrow, may be critical to activation and spread of the virus with subsequent risk of PML. Depletion and reconstitution of CD20 cells occurring during rituximab therapy may enhance the spread of virus from marrow to the brain. It is interesting that our cases appear to occur during immune reconstitution following rituximab therapy, rather than when CD20 cells are at their nadir.
It is now apparent that a modest increase in the risk of PML should be considered with the use of rituximab, and potentially other agents that target CD20 cells. Given the benefit that this drug provides many patients, it reinforces the need to find means of detecting those at increased risk for this complication and ways to prevent its occurrence. In the case of natalizumab treatment, it has been suggested that patients who are JC virus sero-negative prior to therapy are likely at reduced risk of developing PML, and a similar situation is likely to occur in the setting of rituximab treatment.3
Progressive multifocal leukoencephalopathy is presumed to result from reactivation of latent JC virus rather than from primary exposure. The presence of antibodies is indicative of past exposure to virus and probably identifies a higher-risk population. Conversely, the absence of antibodies likely indicates that primary infection with JC virus has not occurred and that risk of reactivation is therefore theoretically nonexistent.3,27
In the absence of prevention, early diagnosis of PML should be enhanced by clinical vigilance; education of practitioners, patients, and their families; and appropriate diagnostic efforts. Early discontinuation of therapy may allow for earlier immune reconstitution and improved outcomes. Effective direct antiviral treatment for the JC virus has not been demonstrated. An urgent need exists to find active drugs for treating PML. This includes both cytosine arabinoside28
which are still occasionally tried in spite of significant evidence that they are not effective. Mefloquine hydrochloride was used in several of our cases and has in vitro activity against this virus. However, a recent clinical trial was stopped for lack of demonstrable efficacy.30
Similarly, clinicians continue to prescribe mirtazapine on a theoretical basis related to its potential efficacy in blocking serotonin receptors used for viral entry, despite absence for documented clinical efficacy.31
Assuming that rituximab contributes to PML in these cases, reversal of the drug’s effect would be appropriate. Plasma exchange has become a standard practice with natalizumab-associated PML.32
Rituximab is given infrequently in RA since CD20 counts remain depressed for 6 to 9 months after each treatment. While rituximab may remain detectable in plasma for 2 to 3 months, PLEX is unlikely to speed immune recovery after this period. However, if PML is discovered shortly after an infusion of rituximab, PLEX could be considered in this setting, as was performed in case 4 in our series. The apparent brisk increase in inflammatory changes of lesions following PLEX in this case and survival of the patient suggest the possibility this intervention may have been of benefit.
Immune reconstitution inflammatory syndrome, which occurred in our cases, provides an additional potential therapeutic avenue. While controlled trials are not available, the most commonly used treatment for inflammatory PML has been high-dose corticosteroid pulses, often 1 g of intravenous methylprednisolone daily for 5 days, which is repeated if symptoms respond and then recur. Steroid infusions have been reported to stop neurological decline in the setting of IRIS and initiate recovery, without evidence of increased risk.33
Physicians should be aware that this may be required even when the CD20 count suggests ongoing immune compromise on the basis of the prior rituximab therapy. The present cases support the possibility that with early diagnosis and careful management, patients may survive this complication, some with modest deficits. Until more experience is acquired, it is reasonable to encourage support and therapy for these patients, since the dire prognosis of PML acquired when associated with advanced malignancy or AIDS may be exaggerated when considering this disease in other settings. Indeed, current experience with natalizumab suggests survival of as many as 70% to 80% of patients with PML with concentrated efforts for early detection and reversal of immunosuppression (medinfo.biogenidec.com).11
Physicians considering the use of rituximab treatment of rheumatic diseases including RA should be aware that there is a potential, albeit modest risk of developing PML. Because of the morbidity and mortality of PML, however, it is important to consider this in the choice of treatments and to inform patients that this possibility must be considered with therapy including rituximab. In patients treated with rituximab, aggressive evaluation of new and progressing neurological deficits is very important to allow early diagnosis. No further rituximab should be used if a suspicious neurological symptom or sign appears until the diagnosis is successfully excluded.