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Letters
A case report of progressive multifocal leucoencephalopathy (PML) associated with adalimumab CASE REPORT Progressive multifocal leucoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by polyomavirus JC. It results from lytic infection of glial cells and is often fatal.1 2 A common risk factor for PML is immunosuppression due to HIV infection or malignancy (or its treatment). PML has also been reported in those using immunomodulation therapies.3 A previous study estimated incidence of PML at 0.2/100 000 among patients with autoimmune diseases who did not have HIV or malignancy. Based on the single case of PML exposed to a biological agent, another study reported the incidence rate (IR) of PML was 2.3 (95% CI 0.1 to 71) per 100 000 person-years in patients who were exposed to biological agents and 0.8 (95% CI 0.2 to 2.5) per 100 000 person-years in those not exposed to biological agents.4 Cases of PML associated with use of certain monoclonal antibody therapies and other immunosuppressive agents have raised concerns about the safety of these agents.5 Reported monoclonal antibodies associated with PML and used for treatment of rheumatological diseases include efalizumab, infliximab and rituximab,3 5 6 which have led to Food and Drug Administration (FDA) alerts and warning letters regarding immunosuppressive agents (natalizumab, rituximab, efalizumab and mycophenolate).7 We report here a patient with rheumatoid arthritis treated with adalimumab who developed PML. To our knowledge this is the first case of PML associated with use of adalimumab in the USA. During our background literature search we identified one additional case of PML associated with use of adalimumab. This case was reported in the WHO adverse event databases, but no details are available.8 A 66 year-old white woman with long-standing rheumatoid arthritis presented with coordination problems of 3 months duration which later progressed to impaired writing, gait and dysarthria. At time of onset of symptoms associated with PML the patient had been receiving adalimumab for 2 years, the only biological she had ever received. When symptoms arose she was changed to methotrexate 20 mg weekly. She was not receiving corticosteroids. A brain MRI revealed bilateral cerebellar non-enhancing white matter lesions bordering the dentate nuclei, with extension into the middle cerebellar peduncles. The left posterior superior
Figure 1 MRI of brain showing bilateral cerebellar non-enhancing white matter lesions. Ann Rheum Dis July 2014 Vol 73 No 7
1429
Downloaded from ard.bmj.com on September 27, 2014 - Published by group.bmj.com
Letters parietal white matter also showed signal abnormality suspicious for PML (figure 1). HIV serology was negative; there was no evidence of sarcoidosis, multiple sclerosis, diabetes or malignancy. Cerebrospinal fluid (CSF) for JC virus was initially negative (ViraCor Laboratories; limit of detection 100 copies/mL and limit of quantitation 800 copies/mL). However, because of suspicion for PML, a second CSF sample was tested at the National Institutes of Health and was positive ( JC virus 364 copies/mL). She developed worsening neurological symptoms during the next month. A repeat MRI 4 months later showed significant worsening of the bilateral cerebellar white matter extending into the middle cerebellar peduncles and the pons. The previous left parietal confluent subcortical white matter lesions had worsened and progressed towards the frontal lobe. New right frontal and parietal confluent subcortical white matter lesions were present. Her follow-up after 4 months is not known. With older PCR techniques the sensitivity of detection is 75%; however, the sensitivity with newer ultrasensitive techniques is >95%. Most diagnostic laboratories are able to detect JC virus DNA if at least >200 copies are present in CSF; the National Institutes of Health test is able to reliably detect up to 10 copies/mL of JC virus.2 Clinicians should be aware of the association of PML with newer treatment modalities and the clinical presentation of PML. Availability of ultrasensitive PCR technology may be useful as an adjunctive diagnostic test in patients with clinical findings consistent with PML.
Received 26 November 2013 Revised 31 January 2014 Accepted 16 February 2014 Published Online First 11 March 2014 Ann Rheum Dis 2014;73:1429–1430. doi:10.1136/annrheumdis-2013-204978
REFERENCES 1
2 3
4
5 6 7 8
Tan CS, Koralnik IJ, et al. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 2010;9:425–37. Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology 2013;80:1430–8. Bharat A, Xie F, Baddley JW, et al. Incidence and risk factors for progressive multifocal leukoencephalopathy among patients with selected rheumatic diseases. Arthritis Care Res (Hoboken) 2012;64:612–15. Arkema EV, van Vollenhoven RF, Askling J. Incidence of progressive multifocal leukoencephalopathy in patients with rheumatoid arthritis: a national population-based study. Ann Rheum Dis 2012;71:1865–7. Berger JR, et al. Progressive multifocal leukoencephalopathy and newer biological agents. Drug Saf 2010;33:969–83. Kuhle J, Gosert R, Bühler R, et al. Management and outcome of CSF-JC virus PCRnegative PML in a natalizumab-treated patient with MS. Neurology 2011;77:2010–6. Molloy ES, et al. PML and rheumatology: the contribution of disease and drugs. Cleve Clin J Med 2011;78(Suppl 2):S28–32. Keene DL, Legare C, Taylor E, et al. Monoclonal antibodies and progressive multifocal leukoencephalopathy. Can J Neurol Sci 2011;38:565–71.
Manoj Ray,1 Jeffrey R Curtis,2 John W Baddley1 1
Department of Medicine/Division of Infectious Diseases, University of Alabama at Birmingham, 1900 University Boulevard, Birmingham, Alabama, USA 2 Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA Correspondence to Dr John W Baddley, Department of Medicine/Division of Infectious Diseases, University of Alabama at Birmingham, 1900 University Boulevard, 229 THT, Birmingham, AL 35294-0006, USA; [email protected] Contributors MR and JWB provided the study concept and drafting of the manuscript. JWB and JRC supervised the study and critically revised the manuscript for important intellectual content. Competing interests JWB: He is a consultant for Merck, Pfizer and Astellas. Pending research grant from Bristol-Myers Squibb (BMS). JRC: He receives salary support from National Institutes of Health (AR053351) and Agency for Healthcare Research and Quality (AHRQ) (R01 R01HS018517). He is a consultant and has received research support from Amgen, Janssen, Consortium of Rheumatology Researchers of North America (CORRONA), Pfizer, Roche/Genentech, Abbvie and UCB. Provenance and peer review Not commissioned; externally peer reviewed.
To cite Ray M, Curtis JR, Baddley JW. Ann Rheum Dis 2014;73:1429–1430.
1430
Ann Rheum Dis July 2014 Vol 73 No 7
Downloaded from ard.bmj.com on September 27, 2014 - Published by group.bmj.com
A case report of progressive multifocal leucoencephalopathy (PML) associated with adalimumab Manoj Ray, Jeffrey R Curtis and John W Baddley Ann Rheum Dis 2014 73: 1429-1430 originally published online March 11, 2014
doi: 10.1136/annrheumdis-2013-204978
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References
This article cites 8 articles, 2 of which can be accessed free at: http://ard.bmj.com/content/73/7/1429.full.html#ref-list-1
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Letters
A case report of progressive multifocal leucoencephalopathy (PML) associated with adalimumab CASE REPORT Progressive multifocal leucoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by polyomavirus JC. It results from lytic infection of glial cells and is often fatal.1 2 A common risk factor for PML is immunosuppression due to HIV infection or malignancy (or its treatment). PML has also been reported in those using immunomodulation therapies.3 A previous study estimated incidence of PML at 0.2/100 000 among patients with autoimmune diseases who did not have HIV or malignancy. Based on the single case of PML exposed to a biological agent, another study reported the incidence rate (IR) of PML was 2.3 (95% CI 0.1 to 71) per 100 000 person-years in patients who were exposed to biological agents and 0.8 (95% CI 0.2 to 2.5) per 100 000 person-years in those not exposed to biological agents.4 Cases of PML associated with use of certain monoclonal antibody therapies and other immunosuppressive agents have raised concerns about the safety of these agents.5 Reported monoclonal antibodies associated with PML and used for treatment of rheumatological diseases include efalizumab, infliximab and rituximab,3 5 6 which have led to Food and Drug Administration (FDA) alerts and warning letters regarding immunosuppressive agents (natalizumab, rituximab, efalizumab and mycophenolate).7 We report here a patient with rheumatoid arthritis treated with adalimumab who developed PML. To our knowledge this is the first case of PML associated with use of adalimumab in the USA. During our background literature search we identified one additional case of PML associated with use of adalimumab. This case was reported in the WHO adverse event databases, but no details are available.8 A 66 year-old white woman with long-standing rheumatoid arthritis presented with coordination problems of 3 months duration which later progressed to impaired writing, gait and dysarthria. At time of onset of symptoms associated with PML the patient had been receiving adalimumab for 2 years, the only biological she had ever received. When symptoms arose she was changed to methotrexate 20 mg weekly. She was not receiving corticosteroids. A brain MRI revealed bilateral cerebellar non-enhancing white matter lesions bordering the dentate nuclei, with extension into the middle cerebellar peduncles. The left posterior superior
Figure 1 MRI of brain showing bilateral cerebellar non-enhancing white matter lesions. Ann Rheum Dis July 2014 Vol 73 No 7
1429
Downloaded from ard.bmj.com on September 27, 2014 - Published by group.bmj.com
Letters parietal white matter also showed signal abnormality suspicious for PML (figure 1). HIV serology was negative; there was no evidence of sarcoidosis, multiple sclerosis, diabetes or malignancy. Cerebrospinal fluid (CSF) for JC virus was initially negative (ViraCor Laboratories; limit of detection 100 copies/mL and limit of quantitation 800 copies/mL). However, because of suspicion for PML, a second CSF sample was tested at the National Institutes of Health and was positive ( JC virus 364 copies/mL). She developed worsening neurological symptoms during the next month. A repeat MRI 4 months later showed significant worsening of the bilateral cerebellar white matter extending into the middle cerebellar peduncles and the pons. The previous left parietal confluent subcortical white matter lesions had worsened and progressed towards the frontal lobe. New right frontal and parietal confluent subcortical white matter lesions were present. Her follow-up after 4 months is not known. With older PCR techniques the sensitivity of detection is 75%; however, the sensitivity with newer ultrasensitive techniques is >95%. Most diagnostic laboratories are able to detect JC virus DNA if at least >200 copies are present in CSF; the National Institutes of Health test is able to reliably detect up to 10 copies/mL of JC virus.2 Clinicians should be aware of the association of PML with newer treatment modalities and the clinical presentation of PML. Availability of ultrasensitive PCR technology may be useful as an adjunctive diagnostic test in patients with clinical findings consistent with PML.
Received 26 November 2013 Revised 31 January 2014 Accepted 16 February 2014 Published Online First 11 March 2014 Ann Rheum Dis 2014;73:1429–1430. doi:10.1136/annrheumdis-2013-204978
REFERENCES 1
2 3
4
5 6 7 8
Tan CS, Koralnik IJ, et al. Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 2010;9:425–37. Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology 2013;80:1430–8. Bharat A, Xie F, Baddley JW, et al. Incidence and risk factors for progressive multifocal leukoencephalopathy among patients with selected rheumatic diseases. Arthritis Care Res (Hoboken) 2012;64:612–15. Arkema EV, van Vollenhoven RF, Askling J. Incidence of progressive multifocal leukoencephalopathy in patients with rheumatoid arthritis: a national population-based study. Ann Rheum Dis 2012;71:1865–7. Berger JR, et al. Progressive multifocal leukoencephalopathy and newer biological agents. Drug Saf 2010;33:969–83. Kuhle J, Gosert R, Bühler R, et al. Management and outcome of CSF-JC virus PCRnegative PML in a natalizumab-treated patient with MS. Neurology 2011;77:2010–6. Molloy ES, et al. PML and rheumatology: the contribution of disease and drugs. Cleve Clin J Med 2011;78(Suppl 2):S28–32. Keene DL, Legare C, Taylor E, et al. Monoclonal antibodies and progressive multifocal leukoencephalopathy. Can J Neurol Sci 2011;38:565–71.
Manoj Ray,1 Jeffrey R Curtis,2 John W Baddley1 1
Department of Medicine/Division of Infectious Diseases, University of Alabama at Birmingham, 1900 University Boulevard, Birmingham, Alabama, USA 2 Division of Clinical Immunology & Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA Correspondence to Dr John W Baddley, Department of Medicine/Division of Infectious Diseases, University of Alabama at Birmingham, 1900 University Boulevard, 229 THT, Birmingham, AL 35294-0006, USA; [email protected] Contributors MR and JWB provided the study concept and drafting of the manuscript. JWB and JRC supervised the study and critically revised the manuscript for important intellectual content. Competing interests JWB: He is a consultant for Merck, Pfizer and Astellas. Pending research grant from Bristol-Myers Squibb (BMS). JRC: He receives salary support from National Institutes of Health (AR053351) and Agency for Healthcare Research and Quality (AHRQ) (R01 R01HS018517). He is a consultant and has received research support from Amgen, Janssen, Consortium of Rheumatology Researchers of North America (CORRONA), Pfizer, Roche/Genentech, Abbvie and UCB. Provenance and peer review Not commissioned; externally peer reviewed.
To cite Ray M, Curtis JR, Baddley JW. Ann Rheum Dis 2014;73:1429–1430.
1430
Ann Rheum Dis July 2014 Vol 73 No 7
Downloaded from ard.bmj.com on September 27, 2014 - Published by group.bmj.com
A case report of progressive multifocal leucoencephalopathy (PML) associated with adalimumab Manoj Ray, Jeffrey R Curtis and John W Baddley Ann Rheum Dis 2014 73: 1429-1430 originally published online March 11, 2014
doi: 10.1136/annrheumdis-2013-204978
Updated information and services can be found at: http://ard.bmj.com/content/73/7/1429.full.html
These include:
References
This article cites 8 articles, 2 of which can be accessed free at: http://ard.bmj.com/content/73/7/1429.full.html#ref-list-1
Email alerting service
Receive free email alerts when new articles cite this article. Sign up in the box at the top right corner of the online article.
Notes
To request permissions go to: http://group.bmj.com/group/rights-licensing/permissions
To order reprints go to: http://journals.bmj.com/cgi/reprintform
To subscribe to BMJ go to: http://group.bmj.com/subscribe/
