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Abstract

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. Acknowledgements
  7. REFERENCES

Progressive multifocal leukoencephalopathy (PML) is a rare brain disease caused by reactivation of the JC virus. Herein, a case of PML in association with rituximab treatment in a patient with chronic rheumatoid arthritis (RA) and Sjögren's syndrome is described. The patient received 4 courses of rituximab (2 1,000-mg infusions administered 2 weeks apart) over a period of ∼40 months, during a phase III trial and safety extension study. PML was diagnosed ∼18 months after the last rituximab course, and the patient died 1 month later. Determination of the cause of PML was confounded by the fact that the patient had developed oropharyngeal cancer, which was treated with chemoradiotherapy, 9 months prior to the development of PML. Although there was no direct evidence that linked rituximab to the development of PML, this case highlights the need to consider a diagnosis of PML in patients with RA who have been treated with rituximab and who subsequently develop new neurologic symptoms.

Progressive multifocal leukoencephalopathy (PML) is a rare, progressive, usually fatal demyelinating brain disease caused by reactivation of the JC virus (JCV) (1–3). Although the vast majority of PML cases occur in persons with severe immunosuppression due to human immunodeficiency virus [HIV]/acquired immunodeficiency syndrome (4), rare cases have been reported in association with various autoimmune disorders (2). Recently, attention has focused on a potential association between the onset of PML and monoclonal antibody therapy, including reports that PML occurred in patients being treated with natalizumab (5), efalizumab (6), and rituximab (7). Most cases of PML associated with rituximab therapy have occurred in patients undergoing treatment for hematologic malignancies, with the majority of these patients receiving rituximab in combination with multiagent chemotherapy or as part of hematopoietic stem cell transplantation (7). Two cases of PML have been reported recently in patients who had received rituximab for the treatment of systemic lupus erythematosus (SLE) (8, 9). Herein, the full details of a recent a case of PML (first reported by the manufacturer of rituximab [10]) occurring in a rheumatoid arthritis (RA) patient who had been receiving rituximab in a long-term safety extension study are presented.

CASE REPORT

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. Acknowledgements
  7. REFERENCES

The patient, a 51-year-old woman, participated in the open-label extension of the REFLEX (Randomized Evaluation of Long-Term Efficacy of Rituximab in RA) phase III trial, a study of placebo and methotrexate (MTX) versus rituximab and MTX (11). The patient was first diagnosed as having RA in 1994, with symptoms of polyarthritis involving the wrists, proximal interphalangeal joints, ankles, and feet; she also had dryness of the eyes and mouth, consistent with Sjögren's syndrome. Initial treatment of the RA consisted of etodolac, prednisone, and hydroxychloroquine.

The patient was first evaluated in our clinic in 2002. Laboratory results at that time were as follows: antinuclear antibody (ANA) titer 1:40 (speckled pattern), rheumatoid factor (RF) 384 units, SSA/Ro 1,521 units/ml, SSB/La 431 units/ml, C-reactive protein (CRP) 2 mg/dl, and erythrocyte sedimentation rate (ESR) 46 mm/hour. She was negative for anti-DNA, anti-Sm, and anti-RNP antibodies. Parotid gland swelling and lymphadenopathy were consistent with Sjögren's syndrome. Treatment with MTX (15 mg/week) and prednisone (5 mg/day) resulted in an incomplete response. Infliximab therapy (5 mg/kg every 8 weeks) was begun in March 2002, and resulted in clinical improvement for 1 year.

A sustained flare subsequently occurred, with a Disease Activity Score in 28 joints (DAS28) (12) of 6.5 and she was enrolled in the REFLEX study. Laboratory results at the time of study entry were as follows: RF 190 units, anti–cyclic citrullinated peptide antibody 22 mg/liter, ANA titer 1:640 (speckled pattern), ESR 63 mm/hour, CRP 87 mg/dl, CD4 398 cells/μl (normal 400–1,600), CD8 87 cells/μl (normal 200–1,346), C3 within the normal range, C2 10.4 mg/dl (normal 22–39), and C4 3.4 mg/dl (normal 11–39). (Her patient's C4 level remained low throughout the study.) Serum IgA, IgG, and IgM levels were within the normal range and remained so throughout the study (IgG 1,420–2,730 mg/dl, IgM 106–189 mg/dl, and IgA 226–302 mg/dl). Radiography showed advanced erosive disease consistent with RA.

In July 2003, the patient received her first course of rituximab (2 1,000-mg infusions administered on day 1 and day 15, plus intravenous methylprednisone [100 mg] as premedication and prednisone [60 mg/day for 6 days, then 30 mg/day for 7 days]), and her DAS28 score decreased from 7.79 to 2.18 at week 24. She was then enrolled in the open-label extension and received 3 additional courses of rituximab in March 2004, December 2004, and November 2006, when her symptoms flared. The MTX dosage was increased to 20 mg/week in February 2005. Each course of rituximab was accompanied by a significant clinical response, with complete clinical remission of her RA, according to the American College of Rheumatology 20% improvement criteria (13) and a DAS28 score of DAS28 2.01. Peripheral B cell counts, which were within the normal range prior to the first course of rituximab (CD19+ cells 150/μl; normal 101–668), were completely depleted following each course, with B cell recovery evident after each course. Partial repletion occurred after the fourth course (CD19+ cells 34/μl at 7 months), but the extent of recovery was probably affected by the subsequent events described below.

In June 2007, ∼7 months after the final course of rituximab, the patient was diagnosed as having a superficial papillary squamous cell carcinoma of the oropharynx (clinical stage T3N0M0). Treatment involved 6 weeks of radiotherapy (66 Gy) plus carboplatin (45 mg/day for 5 days, every 2 weeks) and cetuximab (375 mg/m2 weekly), which was completed on September 24, 2007. Followup examinations indicated complete remission of the carcinoma. In August 2007, immediately following radiotherapy and chemotherapy, the patient's CD19+ cell count was 10/μl; subsequent measurements were 7 cells/μl in November 2007 and 19 cells/μl in February 2008, the final time the count was assessed. By early 2008, the patient was well enough to return to work. A routine study assessment showed remission of her RA (DAS28 2.31).

On April 24, 2008 (17 months after her last rituximab infusion), the patient was hospitalized because of severe malnutrition. A percutaneous endoscopic gastrostomy tube, which had been inserted during chemotherapy, was found to be leaking and infected with gram-negative bacteria (enterococci). The patient's condition was complicated by Enterococcus faecalis pneumonia (requiring ventilator support), respiratory failure (requiring tracheostomy), and pansinusitis. While in the hospital, the patient also developed new neurologic symptoms, including an inability to walk, depression, and a progressive decline in her functional and mental state.

Extensive investigations were conducted to determine whether there had been a possible recurrence of carcinoma. Magnetic resonance imaging (MRI) revealed a white matter lesion (diameter 4 cm) in the right frontal region of the brain and several small lesions in the right frontal, left frontal, and parietal subcortical regions (Figure 1A). Three days later, followup positron emission tomography showed abnormal 18F-fluorodeoxyglucose uptake in the right frontal region, consistent with metastatic neoplasia. On May 19, 2008, a brain biopsy revealed chronic inflammatory changes, with an increase in mononuclear cells (T and B lymphocytes, plasma cells, and macrophages) and reactive gliosis. Samples were negative for herpes simplex virus, varicella-zoster virus, cryptococcal antigen, cytomegalovirus, tuberculosis, and fungal infection, but were positive for JCV, as determined by in situ hybridization. A repeat MRI scan on May 21 showed progression of the white matter lesions in the left hemisphere and anterior and posterior to the dominant right frontal lesion, confirming the diagnosis of PML (Figure 1B).

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Figure 1. Magnetic resonance imaging scans. A, Scan obtained on May 5, 2008, showing the primary white matter lesion in the right frontal region (arrow). B, Repeat scan obtained on May 21, 2008, showing progression of the white matter lesions (arrow).

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The patient was discharged to a hospice, where she received palliative care and died on May 29, 2008. An autopsy was not performed.

DISCUSSION

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. Acknowledgements
  7. REFERENCES

This report describes the first case of PML associated with RA in a patient enrolled in the rituximab clinical trial program. Whether rituximab contributed to the development of PML in this case is difficult to determine because of the following confounding factors: the patient's complex medical history, including Sjögren's syndrome with evidence of immune dysregulation (low or undetectable levels of C2 and C4, lymphopenia, and hypergammaglobulinemia, although no evidence of concomitant SLE was found), the time period between the last dose of rituximab and the onset of PML (almost 18 months), and the development of papillary squamous cell carcinoma of the oropharynx, with subsequent chemoradiotherapy.

Peripheral CD19+ cells remain undetectable for at least 4–5 months in RA patients receiving rituximab; the timing of B cell recovery varies among patients but may start as early as 16 weeks after the final rituximab infusion (14). In the case described in this report, CD19+ counts 7 months after the final dose of rituximab indicated that B cell repletion had started; however, full recovery appeared to have been affected by the chemoradiotherapy required for the patient's cancer (2 months prior to the onset of PML, the CD19+ cell count was 19/μl). Even after B cells return to pretreatment levels, the possibility of longer-lasting immunomodulatory effects cannot be discounted, although the limited current data indicate that the long-term impact of rituximab on the patient's ability to fight infection is similar to that observed with other biologic agents used to treat RA (15, 16).

The timing of the cancer therapy in this case is clearly a confounding factor, with treatment instituted 9 months before the onset of PML and continuing for ∼6 weeks. As well as chemoradiotherapy, the patient received high-dose steroids during and after her cancer treatment and would therefore have been further immunosuppressed at that point. Although PML has not been reported in patients with papillary squamous cell carcinoma of the oropharynx, it has been reported in patients immunosuppressed by chemotherapy. In addition, PML has been reported in patients with RA who were treated with disease-modifying antirheumatic drugs, including leflunomide (17), MTX (in combination with leucovorin) (18), and chlorambucil (19).

Another case of PML in an RA patient in the postmarketing setting had been reported through the MedWatch Program of the Food and Drug Administration. That patient was a 73-year-old woman with longstanding RA who had a medical history that was notable because it included sustained lymphopenia (20). Prior to treatment with rituximab, her RA treatment included MTX, etanercept, and adalimumab. A total of 5 courses of rituximab (2 infusions of 1,000 mg, 2 weeks apart) were administered between May 2006 and September 2008. Neurologic symptoms (balance problems and ataxia) began in July 2008, and in November 2008, PML was confirmed by polymerase chain reaction, which identified the presence of JCV. That patient is reportedly recovering. As in the present case, there were potential contributing risk factors for the development of PML, including lymphopenia and a history of long-term immunosuppressive therapy.

The 2 confirmed cases of PML in RA have been reported among the ∼90,700 RA patients worldwide who were treated with rituximab between 2004 and 2008. This corresponds to a cumulative reporting rate of 2.2 cases of PML per 100,000 RA patients treated with rituximab (95% confidence interval 0.3–8.0). The cumulative incidence rate of PML in the RA population has been estimated at 1/100,000 RA admissions in an analysis limited to hospitalized patients with SLE and other rheumatic diseases (including 25 patients with RA), a majority of whom had concomitant risk factors, including HIV, malignancy, or transplantation of bone marrow or another organ (21). PML has previously been reported in patients receiving rituximab treatment for hematologic malignancies and autoimmune disorders other than RA (1, 7).

In conclusion, although there is no direct evidence of a causal relationship, this first published report of PML in an RA patient who had received multiple courses of rituximab highlights the need for physicians to consider PML as a possible diagnosis in patients with RA who have been treated with rituximab and who subsequently develop new neurologic symptoms.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. Acknowledgements
  7. REFERENCES

Dr. Fleischmann drafted the article, revised it critically for important intellectual content, and approved the final version to be published. Dr. Fleischmann 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. Fleischmann.

Acquisition of data. Fleischmann.

Analysis and interpretation of data. Fleischmann.

Acknowledgements

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. Acknowledgements
  7. REFERENCES

Third-party writing assistance for the manuscript was funded by Genentech and Biogen Idec.

REFERENCES

  1. Top of page
  2. Abstract
  3. CASE REPORT
  4. DISCUSSION
  5. AUTHOR CONTRIBUTIONS
  6. Acknowledgements
  7. REFERENCES