PML and Rituximab: What Rheumatologists Should Know

Prior to 2005, progressive multifocal leukoencephalopathy (PML) was the domain of HIV specialists, oncologists, or physicians caring for transplant recipients. Then, a tectonic change occurred. PML was discovered among patients taking the biologic agent natalizumab for multiple sclerosis. Within two years, we found that the disease occurred rarely with a variety of immunosuppressive agents, including rituximab.¹

As there is no simple and effective therapy for this often-fatal condition, it is important for physicians who prescribe biologics to remain informed. Here are the basics and the latest facts:

•  PML is a rare, typically fatal opportunistic infection secondary to JC virus (a polyoma virus originally called John Cunningham virus). Classically, it is seen in patients with compromised immune systems. Most patients (about 95%) have HIV infection, are on combination chemotherapy for cancer, or are transplant recipients. Approximately 2-5% of patients with PML have underlying autoimmune or autoinflammatory disorders, and are on or have been treated with immunosuppressives. PML occurs rarely in normal hosts and can also arise on rare occasions in the absence of iatrogenic immunosuppression, generally associated with a comorbidity such as sarcoidosis or chronic liver disease.¹ 

•  With approval of the biologic agent natalizumab for the treatment of multiple sclerosis, which represented a major clinical advance for that condition, PML re-emerged as an iatrogenic threat. In 2007, shortly after review of 24-month data on natalizumab,² cases of PML were identified, followed quickly by a third case. This led to temporary suspension of the drug.  Over time it was re-introduced with aggressive risk mitigation. Over 350 cases have been reported worldwide by now. As a result, there is now a much greater focus upon PML in the immunosuppressed patient in general, and more specifically in those patients on biologic therapies. (A second and small chapter in this history was the identification of 4 cases of PML associated with the T cell directed drug efalizumab, used to treat psoriasis. This agent was pulled from the market voluntarily.)

•  PML has also been associated with other immunosuppressive agents including rituximab, frequently in patients with systemic lupus erythematosus (SLE).  In 2007, our group found that the disease occurred rarely with a variety of immunosuppressive agents.² Of note, SLE patients appeared to be affected disproportionately. Two patients with SLE had been exposed to rituximab, and over time it was appreciated that rituximab was associated with PML. One systematic review that used a sophisticated search mechanism for rare diseases reported 57 cases.³ The majority were patients who had been prescribed rituximab along with chemotherapy to treat malignancy. 

•  It remains unexplained why PML arises as a rare complication of therapy with immunosuppressive agents. Since the original cases reporting PML in SLE patients, a total of 6 cases have been described in patients treated with rituximab for rheumatoid arthritis (RA), and summarized in a recent systematic review of the FDA Adverse reporting System.⁴  An analysis of several of these cases revealed no obvious cofactors associated with the development of PML, such as age, dose, or duration of treatment. In this analysis of all cases of PML occurring in patients with rheumatic diseases from 1997-2010, a total 34 confirmed cases  were described, including 14 exposed to rituximab. Again, SLE was the predominant underlying diagnosis.⁴ PML was found in only one instance of exposure to a TNF inhibitor. 

•  In terms of aggregate risk, PML remains a very rare complication in rheumatic diseases in general and in RA in particular.  For RA patients treated with rituximab, the risk is extremely low, with recent incidence estimates in the range of 5/100,000 patients exposed to the drug.  In comparison, the incidence of PML in natalizumab-exposed patients is approximately 1/1000. In the case of natalizumab, cofactors such as dose, duration, and co-therapy contribute to the risk. It can be calculated that for a JC virus-infected patient with MS treated with natalizumab for a long period (>24 months) who has a history of prior immunosuppressive exposure, the risk may approach 1/100.⁵ Clearly, these are significantly different magnitudes of risk.

From my perspective, PML is very rare prevalent risk for all patients who are on heavy immunosuppressives including rituximab, especially in the setting of SLE. Given the difference in levels of risk just described, I do not believe that a risk-mitigation strategy (such as serologic testing for underlying JC infection, being used to stratify risk in MS) can be justified for patients with rheumatic diseases.

While I advocate vigilance in terms of carefully evaluating new-onset suspicious focal and diffuse neurologic dysfunction, as we have summarized elsewhere,⁶ PML is not a reason to eschew effective therapy when needed.

Much remains to be learned about the biology and natural history of JC infection. Unfortunately, there is no effective therapy, short of reconstituting the immune system. So rheumatologists will have to stay tuned in.²
 

References:

REFERENCES

1. Molloy ES. PML and rheumatology: the contribution of disease and drugs.Cleve Clin J Med (2011) 78 Suppl 2:S28-S32
2. Calabrese LH, Molloy ES, Huang D, Ransohoff RM. Progressive multifocal leukoencephalopathy in rheumatic diseases: evolving clinical and pathologic patterns of disease.Arthritis & Rheumatism (2007) 56:2116-2128
3. Carson KR, Evens AM, Richey EA, et al.Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project.Blood (2009) 113:4834-4840
4. Molloy ES, Calabrese LH. Progressive multifocal leukoencephalopathy associated with immunosuppressive therapy in rheumatic diseases: evolving role of biologic therapies.Arthritis and Rheumatism (2012) 64:3043-3051
5. Fox R. Advances in the management of PML: focus on natalizumab.Cleve Clin J Med (2012) 78: Suppl 2:S33-S37
6. Berger JR. The clinical features of PML.Cleve Clin J Med (2011) 78: Suppl 2:S8-S12.