Incidence and risk factors for Progressive Multifocal Leukoencephalopathy among patients with selected rheumatic diseases




To ascertain the incidence of progressive multifocal leukoencephalopathy (PML) in patients with selected rheumatic diseases, to describe the characteristics of PML cases occurring in this setting, and to evaluate the extent to which such cases occurred in the context of biologic therapies such as rituximab or tumor necrosis factor antagonists.


We conducted a large population-based study to describe the incidence and risk factors for PML among patients with rheumatoid arthritis, psoriatic arthritis, psoriasis, juvenile idiopathic arthritis, inflammatory bowel disease, and ankylosing spondylitis using national inpatient and outpatient administrative data from the entire Center for Medicare and Medicaid Services from 2000–2009. Suspected PML cases were identified using hospital discharge diagnosis codes. Risk factors for PML were evaluated using outpatient data ≥6 months prior to PML diagnosis.


Among 2,030,578 patients with autoimmune diseases of interest, a total of 53 PML cases were identified (2.6 per 100,000 patients). Most PML cases had human immunodeficiency virus (HIV) and/or cancer. Nine PML cases had evidence for biologic use prior to PML hospitalization, of which 3 had neither HIV nor malignancy and were exposed to biologics within 12 (rituximab) or 6 months (all other biologics) prior to PML diagnosis. PML occurred at an estimated incidence of 0.2 per 100,000 patients with autoimmune diseases who did not have HIV or malignancy.


PML occurs at a very low incidence among patients with rheumatic diseases but can occur even in the absence of HIV or malignancy.


Progressive multifocal leukoencephalopathy (PML) is a rare and serious infection caused by the JC virus (1, 2) and characterized by progressive inflammation and demyelination of the white matter of the brain at multiple locations. Most humans have been exposed to the JC virus during their lifetimes, and infection typically occurs during the first several decades of life; approximately 50–80% of adults have serologic evidence of prior exposure. Following initial infection, the virus remains latent in multiple tissues in healthy individuals, with reactivation and clinical disease occurring in severely immunosuppressed states. PML has been most commonly observed among patients with human immunodeficiency virus (HIV), those with malignancies, and organ transplant recipients. PML has also been reported rarely in patients with inflammatory autoimmune disorders, including rheumatoid arthritis (RA) (3, 4), and other rheumatic conditions (5–9), particularly in those receiving cytotoxic and biologic therapies, including rituximab (10–13), natalizumab (14), efalizumab (15), and less commonly tumor necrosis factor (TNF) inhibitors (16, 17). At present, the contribution of biologic therapies to the development of PML is unclear, and the epidemiology of PML has been poorly characterized among patients with rheumatic diseases. Case series and data from spontaneous reports suggest that PML may occur more commonly in systemic lupus erythematosus (SLE) than in other rheumatic diseases (6), but little population-based data exist evaluating PML incidence and risk factors in the rheumatic disease setting.

Accordingly, we conducted a large population-based study to ascertain the incidence of PML in patients with selected rheumatic diseases, to describe the characteristics of PML cases occurring in this setting, and to evaluate the extent to which such cases occurred in the context of biologic therapies such as rituximab or TNF antagonists.

Patients and methods

We used person-level inpatient and outpatient administrative data from the Center for Medicare and Medicaid Services (CMS) for the period 2000–2009 and for the entire US. Prior to 2006, the data were restricted to all Medicaid only and “dual eligible” (Medicare and Medicaid) enrollees. From 2006 onward, the entire US Medicare population was included. Individuals with ≥1 physician diagnosis of RA, psoriatic arthritis, psoriasis, juvenile idiopathic arthritis, inflammatory bowel disease (IBD), and ankylosing spondylitis were identified. Suspected hospitalized cases of PML were identified among these patients using hospital discharge diagnosis codes (International Classification of Diseases, Ninth Revision, Clinical Modification 046.3). The date of hospital admission was considered the PML “case date.”

Risk factors for PML were evaluated using inpatient and outpatient data prior to the case date. Therefore, patients hospitalized with a diagnosis of PML were required to be observable (e.g., enrolled in Medicare part A + part B, but not enrolled in a Medicare advantage plan) in the month of hospitalization and for at least the previous 6 months. Relevant comorbidities and medication exposures were determined using health care encounter–coded diagnoses, procedures, and pharmacy fill records. Additionally, we described mortality within 4 months following the case date. Two study investigators (JRC and AB) manually reviewed the claims data to ascertain the validity and features of each suspected PML case with a history of exposure to biologic therapies and without other risk factors such as HIV or malignancy. Because the data available in this report were not derived from a review of medical records but only from inpatient physician diagnoses/hospital discharge diagnoses, all identified cases of PML were therefore considered as “suspected PML.” Written clearance was obtained from the CMS to describe the data, and the study was approved by the local Institutional Review Board at the University of Alabama at Birmingham.


A total of 2,030,578 rheumatic disease patients with at least 6 months of observability (median 40 months, range 6–120 months) in the claims data were included. Among these individuals, 53 patients were hospitalized with a PML diagnosis, yielding an estimated incidence proportion of 2.6 PML cases per 100,000 patients with rheumatic disease.

Among these 53 cases, and using all of the data prior to hospitalization available (median 38 months, range 8–105 months), 35 (66%) had an HIV diagnosis and 16 (30%) had at least 1 cancer diagnosis (with or without HIV). Only 11 PML cases (21%) had neither HIV nor cancer diagnoses; all of these individuals were observable in the CMS data for more than 1 year (median 36 months, range 14–85 months) prior to the case date. Among patients without any HIV or cancer diagnosis, the estimated incidence proportion was 0.2 PML case per 100,000 patients with rheumatic disease.

Among those receiving biologics, we identified 9 cases with evidence for use of a biologic prior to PML hospitalization; of these 9 cases, 4 had no HIV or malignancy diagnoses. Next, we describe the 3 PML cases that had evidence of biologic use within 6 months prior to PML hospitalization. We also searched the 1 year prior to PML hospitalization for rituximab use, given its more prolonged period of effect.

The first case was a white man in the seventh decade of life who had a history of IBD diagnosed for at least 3 years prior to the date of PML hospitalization. He had frequent episodes of upper respiratory tract infection and renal calculi and a diagnosis of peptic ulcer disease. He had been receiving infliximab at a dose of 300–350 mg per infusion every 8 weeks for at least 3 years. The most recent dose of infliximab was administered 6 weeks before the PML hospitalization. He was not receiving oral glucocorticoids at the time of the hospitalization for PML (most recent dose 32 months prior to hospitalization). At the time of admission with PML, the coded diagnoses submitted by his physicians included loss of coordination, abnormal gait, dizziness, cerebellar ataxia, autonomic neuropathy, and encephalopathy. Magnetic resonance imaging (MRI) of the brain (plain and with contrast) was performed, although the results of the MRI were not available in the data source. A search of the procedure codes during the hospitalization revealed no evidence of a brain biopsy being performed. PML was listed as the primary diagnosis code on hospital discharge. Subsequently, the patient died 12 days from the date of the hospital admission.

We identified 2 additional patients hospitalized with PML with prior use of rituximab. One was a white woman in her early 70s with RA for at least 2.5 years before PML diagnosis. The patient had a history of diabetes mellitus, ileus, and hypertension. The patient manifested altered consciousness, lack of coordination, abnormal gait, and peripheral neuropathy as an outpatient. She had received a total of 10 infusions of 1,000 mg of intravenous (IV) rituximab. MRI of the brain and a lumbar puncture were performed; the patient then was diagnosed with PML as an outpatient. The last dose of rituximab was administered 2 months before PML was diagnosed. She was hospitalized 3 months after the first outpatient PML diagnosis for 2 weeks with a primary diagnosis of PML and secondary diagnoses of sepsis and heart failure. Three months later, she died of cardiac arrest and pulmonary embolism. In total, from the date of the first PML diagnosis until the patient's death, the diagnosis code for PML was reported 22 times by a physician.

The other patient receiving rituximab was a white woman in her early 70s who had been diagnosed with RA at least 3 years before PML diagnosis. She had a history of leflunomide use, colonic polyps, and stroke. Within 1 month prior to PML diagnosis, she had symptoms of speech disorder and aphasia, idiopathic peripheral neuropathy, abnormal gait, lack of coordination, and hemiplegia. The patient had received prednisone for at least 2.5 years. A total of 2 infusions of 1,000 mg of IV rituximab at 2-week intervals were given 8 months before PML diagnosis. When she presented to the hospital, she underwent a lumbar puncture, was diagnosed with PML, and was discharged 11 days after admission to the hospital. Within 4 days of discharge, the patient was hospitalized again for 9 days with diagnosis codes for urinary tract infection, esophageal reflux, cerebrovascular accident, and PML. The patient died 50 days after the date of the first PML diagnosis. The diagnosis code for PML was recorded 24 times (both inpatient and outpatient diagnoses) from the day of the first PML diagnosis to the patient's death.


Among hospitalized cases of suspected PML occurring among individuals with selected rheumatic and autoimmune diseases, we identified 3 patients with RA or IBD that had been exposed to either infliximab or rituximab within the several months prior to hospitalization for PML. The overall estimated incidence of PML was 0.2 per 100,000 persons for rheumatic disease patients without HIV or cancer.

While our data suggest that PML occurs very rarely in patients with autoimmune disease without HIV, our 3 reported cases occurring in patients without HIV join at least 7 other published cases occurring in patients with autoimmune or rheumatic disease receiving biologic therapy. Most of these have occurred while rituximab therapy was being given in the context of other immunosuppressive therapies (18). Besides the case we reported here, the only other PML case receiving infliximab that has been previously reported (16) was a 72-year-old white man with RA and subacute neurologic and psychiatric symptoms that developed after 3 years of infliximab, prednisone, and methotrexate. The PML diagnosis for this case was established and confirmed by MRI of the brain and a brain biopsy, respectively. Discontinuation of antirheumatic drugs and supportive therapy led to stabilization of PML with continuation of neurologic and cognitive deficits. Given a lack of other risk factors, it was suggested that infliximab might have been casually associated with the development of PML. At least 6 additional PML cases have occurred in those receiving rituximab (18, 19); however, in only one instance was such a patient lacking other risk factors for PML (e.g., history of other cytotoxic drugs, other biologics, or documented cancer).

We were limited in not being able to review the medical records of our reported cases, making it difficult to judge whether other explanatory factors existed beyond biologic or other immunosuppressive therapy. Additionally, while the data contained evidence of multiple neurologic deficits compatible with PML, provided by physicians who cared for the patient during the hospitalization, we lacked detailed clinical information (e.g., laboratory or MRI results) that would further confirm the PML diagnosis. Finally, although most of the 53 cases of suspected PML had much more than 8 months of data available prior to hospitalization for PML, the differential availability of information prior to the case date could favor ascertainment of risk factors in patients with longer observable periods. Reassuringly, all of the PML cases without HIV or cancer were observable in the data for more than 2 years prior to hospitalization, making it unlikely that we missed relevant risk factors for these individuals.

In summary, we report population-based estimates of PML incidence using longitudinal inpatient and outpatient data among patients with selected autoimmune and rheumatic diseases (albeit not including SLE) who do not have HIV or cancer. Our findings suggest that PML occurs exceedingly rarely among such individuals, at less than 1 per 100,000 patients during the study period. However rare, such catastrophic cases do occur, and our study and others suggest that they can occur in the context of biologic therapies such as infliximab and rituximab, although a causal role for biologic agents remains uncertain.


All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Curtis had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Baddley, Beukelman, Chen, Delzell, Saag, Winthrop, Curtis.

Acquisition of data. Bharat, Patkar.

Analysis and interpretation of data. Bharat, Xie, Baddley, Beukelman, Chen, Calabrese, Delzell, Grijalva, Saag, Winthrop, Curtis.