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We describe a 72-year-old white man with erosive rheumatoid arthritis in whom subacute neurologic and psychiatric symptoms developed after 3 years of treatment with infliximab, prednisone, and methotrexate. White matter demyelination was seen on magnetic resonance imaging of the brain, and progressive multifocal leukoencephalopathy (PML) was ultimately confirmed by brain biopsy. The patient was treated with supportive therapy and discontinuation of disease-modifying antirheumatic drugs, resulting in stabilization of the disease process. The patient survived, but neurologic and cognitive deficits persisted. The distribution and pathology of this patient's disease are unique from almost all reported incidents of oral methotrexate–associated leukoencephalopathy. The pathogenesis of disease may be linked to a T cell–mediated process that is potentially impacted by infliximab. This case provides the first reported evidence that PML can be seen in association with infliximab therapy.
Infliximab is a monoclonal chimeric antibody directed against soluble and membrane-bound tumor necrosis factor α (TNFα), preventing receptor binding and blocking gene transcription (1). It is approved by the US Food and Drug Administration (FDA) for the treatment of rheumatoid arthritis (RA), psoriasis, psoriatic arthritis, Crohn's disease, ulcerative colitis, and ankylosing spondylitis. Since its initial approval in 1998, infliximab has been widely used in the management of autoimmune disease and, by 2007, had been used to treat 1 million patients worldwide (2). Infliximab has been associated with lymphoma, reactivation of hepatitis B virus infection, reactivation of tuberculosis, drug-induced lupus, and serious infection.
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease resulting in subacute neurologic deficits associated with reactivation of the JC virus (JCV). This disease most often occurs in patients who are immunosuppressed or are receiving immunosuppressive medications. Monoclonal antibodies have been linked to the development of PML, but, to date, infliximab has not been reported to cause PML.
Here, we describe a patient with RA treated with infliximab who experienced classic, biopsy-proven PML.
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The patient, a 72-year-old, nonsmoking man, presented with symmetric joint pain and swelling of 6 months' duration affecting the knees, elbows, and hands, with evidence of bilateral knee effusions and metacarpophalangeal synovitis. Laboratory studies revealed a rheumatoid factor titer of 1:640, and erosive RA was ultimately diagnosed. The patient had a history of hypertension, benign prostatic hypertrophy, and chronic bronchitis. Treatment with prednisone at a dosage of 10 mg/day, hydroxychloroquine at a dosage of 200 mg twice daily, and weekly oral methotrexate (MTX) was begun, with the latter agent titrated to a dose of 17.5 mg over 6 months.
Three years after therapy was started, a routine ophthalmologic evaluation indicated hydroxychloroquine toxicity, and therapy was discontinued. The patient subsequently began treatment with infliximab at a dose of 3 mg/kg, with titration up to 4 mg/kg, administered every 2 months, and an excellent clinical response was achieved.
The patient did very well for ∼3 years while receiving a regimen of MTX, infliximab, and 7.5 mg prednisone, when he presented with a 2-week history of vertigo when leaning forward. The patient also described a 24-hour sensation of left hand “clumsiness” at the onset of vertigo that had self-resolved. At the time of examination, his symptoms had improved, and the results of a Dix-Hallpike test were unremarkable. The results of a neurologic examination performed during this evaluation were normal, and the patient was closely followed up, and infliximab treatment was continued.
Two years later, the patient presented with symptoms of memory loss, confusion, and occasional falls for 2.5 months. He had difficulty driving due to this confusion, and coordination difficulties with his right hand had developed, which made writing problematic. Right-sided weakness was observed on examination, with reduced right arm swing and dragging of the right leg in addition to pronator drift. The patient was admitted to the hospital based on the presumption of a stroke, and subsequent magnetic resonance imaging (MRI) revealed extensive patchy and confluent areas of increased fluid-attenuated inversion recovery (FLAIR) signal throughout the periventricular and deep white matter, with additional areas of subcortical increased FLAIR in the bilateral front lobes (Figure 1). The results of electroencephalography were unremarkable, and a lumbar puncture was performed, revealing a total of 16 nucleated cells, a protein level of 55 mg/dl, and a glucose level of 63 mg/dl. The antinuclear antibody titer was 1:80, and the results of serologic tests were negative, including those for Lyme disease and human immunodeficiency virus (HIV) infection, VDRL, and rapid plasma reagin. The patient experienced progressive symptoms of confusion and poor hand–eye coordination, prompting a repeat MRI that showed worsening white matter changes.
Figure 1. T2-weighted (A) and fluid-attenuated inversion recovery (B) signal enhancement observed in the periventricular and subcortical white matter bilaterally.
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The lumbar puncture was repeated, and 100 cells were seen, with a predominance of lymphocytes, a protein level of 52 mg/dl, and a glucose level of 75 mg/dl. The results of polymerase chain reaction (PCR) for JCV in cerebrospinal fluid were negative, as were those for acid-fast bacilli, Gram staining, and culture. Due to the inability to serologically identify the patient's disease, he ultimately underwent a brain biopsy.
On pathologic evaluation of the white matter, as seen in Figure 2, perivascular and parenchymal inflammation with a prominent macrophage component was seen. Reactive astrocytes and nuclei showed purple-stained nucleoplasm, consistent with intranuclear inclusions. Numerous enlarged oligodendroglial nuclei showed homogenation of their nucleoplasm, with chromatin margination. CD3 and CD68 immunostaining showed parenchymal and perivascular positivity. Solochrome–eosin staining revealed focal areas devoid of myelin, and immunostaining for neurofilament showed relative preservation of axons within the areas devoid of myelin, consistent with demyelination. Sections immunostained with an antibody for polyomavirus showed positive staining within the enlarged oligodendroglial nuclei. The morphologic and immunohistochemical features of this biopsy specimen were consistent with PML caused by polyomavirus. Treatment with MTX and infliximab was discontinued, supportive therapy was administered, and the patient was eventually discharged to home in stable condition.
Figure 2. A, Demyelinated area (left of broken line), showing no blue-staining myelin in brain tissue. B, Brown-staining axons in the demyelinated area (left of broken line), showing relative preservation of axons in the demyelinated area. C, Positive staining (brown) within multiple oligodendroglial nuclei within an area of demyelination. Inset, Histologic section stained with antibody for polyomavirus.
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Following hospitalization, the patient continued to experience deficits, with cognitive impairment limiting orientation to time and persistent symptoms of weakness, with only three-fifths strength in the upper and lower extremities of his right side, not including his face. At his most recent followup visit, he had spontaneous speech and was alert, with a mini-mental state examination score of 16/30 and comparative improvement in his symptoms of confusion and cognitive slowing compared with his initial presentation of disease. The patient has remained wheelchair-bound, and his RA has been controlled by daily treatment with low-dose prednisone.
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PML is a demyelinating disease of the central nervous system that occurs as a consequence of JCV replication in oligodendrocytes, resulting in cell lysis and myelin sheath breakdown in the cerebral subcortex. In the process of active disease, cells lyse and release virus to neighboring cells, resulting in plaque formation (3). The clinical manifestations of PML are largely related to white matter involvement, with classic forms resulting in subacute neurologic deficits. These can include mental status changes, motor deficits, limb ataxia, gait abnormalities, and cortical symptoms including aphasia, seizures, and blindness. The diagnosis of PML is classically made based on the results of cerebrospinal fluid PCR, radiologic features, and brain biopsy.
Our patient represents the first reported case of PML associated with the use of infliximab in combination with methotrexate. MTX-associated leukoencephalopathy has been described previously, mostly in cases in which the drug was administered intrathecally or intravenously.
PML is commonly observed in immunocompromised hosts and was initially described in patients with lymphoproliferative or myeloproliferative disease. In a review of drug-induced PML, investigators revealed that PML was observed in patients being treated with monoclonal antibodies, anti-HIV drugs, conventional immunosuppressants, and a variety of chemotherapeutic agents. HIV was noted to be the most common underlying disease associated with PML, followed by lymphoproliferative disorders and autoimmune disease (most typically multiple sclerosis) (4).
Only 5 cases of leukoencephalopathy resulting from oral MTX treatment have been described, with a variety of disease manifestations (5–9). Yokoo et al described liquefactive necrosis occurring in bilateral occipital lobes with progressive expansion and death (5). Renard et al described a patient who had a prolonged 5-month course with occipitotemporal and parietal white matter changes that regressed following discontinuation of medication (6). Raghavendra et al described another case that showed a biphasic course with bilateral parieto-occipital hyperintensity (7). After the initial discontinuation of MTX, that patient experienced improvement, but experienced a recurrence of disease 4 months later, with hyperintense lesions in the posterior limb of the internal capsule to the midbrain pons and lower medulla.
The distribution of MTX-associated lesions described in the literature has been almost entirely posterior, with only 1 report in 2008 describing a hyperintense lesion in the supratentorial and infratentorial brain with extension of frontal lobe lesions to the cerebellar peduncle (9). In that case, pathology findings were consistent with classic PML, with multiple foci of demyelination, atypical astrocytes, and oligodendrocytes with enlarged nuclei. The cases that were described by Yokoo et al and Raghavendra et al illustrated pathology with foamy macrophages and demyelination, which are features that have also been described in animal models of MTX toxicity showing axonal degeneration, perivascular fibrin exudation, and foamy cells (7).
In many of these cases, the patients were receiving multiple immunosuppressant medications, which makes the isolation of blame to a single agent challenging. This observation was made by Piccinni et al, who noted that most immunosuppressive and anti-HIV drugs implicated in the development of PML were being used in patients receiving combination therapy (4).
The distribution of intracranial lesions observed in our patient is clearly distinct from that observed in the majority of cases of oral MTX–associated leukoencephalopathy described in the literature. The patient demonstrated confluent white matter changes in the bilateral frontal lobes, and pathologic findings were also classic for PML, with enlarged oligodendroglial nuclei, astrocytes with intranuclear inclusions, and antibody positivity for polyomavirus. Although JCV was not isolated in the CSF, previous reports have indicated that JCV positivity can occur months after the onset of disease (3). It is our belief that infliximab, if not alone at least in combination therapy, was responsible for the manifestation of PML in our patient.
The specific mechanism for the development of PML is not completely understood, although T cell mobilization has been generally implicated in the pathogenesis of disease. Clues to this pathogenesis may come from understanding the mechanisms of action of drugs that have been associated with the development of PML. Natalizumab has been shown to decrease the number of dendritic cells and T lymphocytes in the central nervous system, which can result in reduced immunosurveillance. Efalizumab is a humanized IgG monoclonal antibody to CD11a that targets T cell trafficking and was withdrawn from the market due to association with PML. Rituximab has no clearly defined association with T lymphocyte depletion, so its relationship with PML is uncertain, although Fleischmann (10) confirmed the disease in a patient with RA who was treated in the rituximab clinical trial program, also noting a previous case of PML in a patient with RA that was reported through the MedWatch program of the FDA (11). Regarding pathogenesis, Carson et al suggested that the expansion of pre-B lymphocytes harboring latent JCV occurs after rituximab-mediated B cell depletion (3). Those investigators also reference the work of Cross et al, who noted the depletion of cerebrospinal T lymphocytes in patients with multiple sclerosis treated with rituximab (12).
Providing further evidence of a T cell–mediated process, Koralnik and colleagues demonstrated that peripheral blood CD8 cytotoxic T lymphocytes (CTLs) directed against JCV epitopes were seen in 71% of the survivors of PML studied and in none of those who experienced progressive disease (13–15). It has also been suggested that these cells may control viral replication and help prevent the development of PML in healthy individuals (16). These findings were corroborated by Marzocchetti et al, who concluded that JCV CTLs were associated with longer survival in patients with PML (17). To date, no conclusive evidence of a discrete genetic risk factor for the development of PML has been identified.
Infliximab is an IgG1 chimeric monoclonal antibody to soluble and transmembrane forms of TNFα. The primary mode of action is at the macrophage site of TNFα production. Suppression of TNFα results in reduced expression of interleukin-6 (IL-6) and IL-1, with a subsequent reduction in inflammation. A reduction in cell recruitment occurs through reduced expression of CD3+, CD68+, vascular cell adhesion molecule 1, intercellular adhesion molecule, and E-selectin. Infliximab also impairs angiogenesis through reduced expression of vascular endothelial growth factor. A reduction in T cell activity has been theorized to occur through a reduction in interferon-γ, STAT-1, granzyme B, and T cell inflammatory gene expression as well as a reduction in dendritic cell–mediated T cell activation (18). TNF blockade has also been shown to reduce the expansion of cytotoxic CD28− T cells and subsequently restore T cell homeostasis in patients with RA (19). This broad involvement in immune modulation, particularly the affect on T cell activation, could have direct implications on the risk of PML.
Currently, there is no cogent explanation for why certain medications appear to predispose some patients to PML. JCV is a relatively ubiquitous, latent infection, and the extensive use of these medications would normally suggest a greater prevalence of disease. It is quite possible, due to the indolent presentation of PML, that this is an underdiagnosed phenomenon. Certainly, the identification of PML can be challenging, and the extensive work-up that our patient underwent, including brain biopsy, is likely neither attempted nor available for many patients in the same clinical scenario. Regardless, this case represents the first reported association of PML with infliximab, a previously unrecognized adverse reaction to such therapy. T cell–mediated processes may underlie this process, and we believe that infliximab-associated PML should be considered in any patient undergoing this therapy in whom a similar, subacute neurologic decline develops.