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Fatal Varicella-Zoster Virus Vasculopathy Associated With Adalimumab Therapy FREE

Wonki Baek, MD; Sang-Gon Lee, MD; Young Seo Kim, MD; Jae-Hoon Kim, MD; Jae-Bum Jun, MD, PhD; Hyun Young Kim, MD, PhD
[+] Author Affiliations

Author Affiliations: Department of Neurology, College of Medicine (Drs Baek, Lee, Y. S. Kim, and H. Y. Kim), and Hospital for Rheumatic Diseases (Drs J.-H. Kim and Jun), Hanyang University, Seoul, Republic of Korea.


Arch Neurol. 2012;69(9):1193-1196. doi:10.1001/archneurol.2011.3741.
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Published online

ABSTRACT

Objective To describe the case of a patient who had been receiving adalimumab for rheumatoid arthritis and died of varicella-zoster virus vasculopathy with multifocal cerebral hemorrhage.

Design Case report.

Setting Hanyang University Hospital, Seoul, Republic of Korea.

Patient A 66-year-old woman with adalimumab therapy for rheumatoid arthritis followed by stuporous mental changes.

Results Magnetic resonance imaging scans showed multifocal parenchymal lesions and hemorrhage in the brainstem and supratentorial areas. Polymerase chain reaction analysis of the cerebrospinal fluid was positive for varicella-zoster virus. The patient died of multifocal vasculopathy despite intensive antiviral and antibacterial medication.

Conclusions Varicella-zoster virus multifocal vasculopathy with encephalitis may be associated with adalimumab therapy. Clinicians should be aware of the possibility of fatal varicella-zoster virus vasculopathy with encephalitis in patients undergoing adalimumab therapy for rheumatoid arthritis.

Figures in this Article

Monoclonal antibodies, which are often considered “magic bullets,” are effective in autoimmune diseases where they can specifically block anti-inflammatory cytokines. Tumor necrosis factor α (TNF-α) antagonists (infliximab, etanercept, adalimumab), most of which are monoclonal antibodies, have come into widespread use in autoimmune diseases such as rheumatoid arthritis and spondyloarthritis.1 However, opportunistic infections and other drug-related adverse effects have been reported.2 Even the most recently developed TNF-α antagonist, adalimumab, has been associated with skin infections, paranasal sinus infections, and aggravation of tuberculosis.3 In addition, several neurological complications have been reported.4 However, these events have tended to be transient and not fatal.2 Herein, we describe a serious case of adalimumab-associated varicella-zoster virus (VZV) multifocal vasculopathy with encephalitis.

REPORT OF A CASE

A 66-year-old woman with a 5-year history of rheumatoid arthritis was admitted with mental obtundation. Six hours before admission, headache with fever developed. She had been given 40 mg of adalimumab every other week for 22 months prior to presentation, in addition to prednisolone (10 mg/d) and methotrexate (17.5 mg/wk). Urosepsis from a renal abscess due to Enterobacter aerogenas had occurred 4 months earlier. As a result, adalimumab, which inhibits TNF-α, a component of the immune system that protects the body from infection, and methotrexate as an immunosuppressant, had been stopped to control the infection. The urosepsis had improved but her symptoms of arthritis became aggravated. So, about 6 weeks before admission, adalimumab therapy was restarted. Her clinical symptoms of rheumatoid arthritis had improved, but 1 week before admission, small erythematous papules had developed on her left gluteal region. On admission, these skin lesions were positive for the Tzanck test. On presentation, her mental state was confusional, without focal neurological deficits. Body temperature was 39°C, and there was neck stiffness and Kernig signs. No papilledema was observed. At that time, cerebrospinal fluid (CSF) analysis revealed lymphocytic pleocytosis (150 cells/mm3, 72% lymphocytes), a red blood cell count of 3810 cells/mm3, a glucose level of 60 mg/dL (serum glucose level, 127 mg/dL [to convert to millimoles per liter, multiply by 0.0555]), and a protein level of 330 mg/dL. Serum biochemistry findings, urine analysis results, and chest radiograph were all normal. Brain magnetic resonance imaging, performed at admission, indicated multifocal parenchymal lesions and hemorrhage in the brainstem and supratentorial areas (Figure 1). Based on these findings, acyclovir (10 mg/kg every 8 hours) and empirical broad-spectrum antibiotics (piperacillin/tazobactam) were given immediately, and adalimumab and prednisolone were stopped. The CSF polymerase chain reaction test results were initially negative for herpes simplex viruses 1 and 2, VZV, cytomegalovirus, Epstein-Barr virus, and mycobacterium tuberculosis. The patient's neurological status continued to deteriorate to stuporous mentation, and both eyeballs started to deviate downward, with sluggish light and corneal reflexes. On the fifth day, follow-up brain magnetic resonance imaging demonstrated worsening of the multiple bilateral parenchymal involvement, with multifocal hemorrhage and hydrocephalus in addition to the preexisting lesions (Figure 2). The CSF analysis revealed aggravated pleocytosis (1130 cells/mm3, 47% lymphocytes), a red blood cell count of 12 120 cells/mm3, a glucose level of 171 mg/dL (serum glucose level, 255 mg/dL), and a protein level of 290 mg/dL. The second CSF polymerase chain reaction test results were positive for VZV but negative for herpes simplex viruses 1 and 2, Epstein-Barr virus, cytomegalovirus, and mycobacterium tuberculosis. At that time, CSF test results were positive for anti-VZV IgM antibody. Despite intensive antiviral medication, the patient's clinical status deteriorated, with serious neurological deficits. Although VZV was detected in her CSF, antibacterial agents were continued because of newly developed pneumonia. The patient died of VZV multifocal vasculopathy and sepsis, possibly aggravated by coinfection with Klebsiella pneumonia, on the 13th day.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Magnetic resonance images on the day of symptom onset. T2-weighted image showing hyperintensities in the dorsal midbrain (A) with lower intensities (arrow). The diffusion-weighted image (B) reveals a ring-shaped restriction, and the T2 gradient-echo image (C) represents a hemorrhagic focus in the left midbrain tectal region.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Magnetic resonance images on the fifth day after symptom onset. The lesions appear as hyperintense foci, especially in the left ventral pons and midbrain extending to the contralateral medial temporal lobe (A). On T2 gradient-echo images (B and C), the lesions are accompanied by intraparenchymal hemorrhage and multiple microbleeds.

COMMENT

We report a rare case of VZV multifocal vasculopathy with encephalitis subsequent to adalimumab therapy for rheumatoid arthritis. Because of their ability to bind selectively to abnormal cells and molecules, monoclonal antibodies have been widely and successfully used as a new generation of biological agents.1 In particular, TNF-α antagonists, one group of monoclonal antibodies, are proving themselves to be effective in autoimmune diseases such as rheumatoid arthritis and spondylarthritis. Their use is based on the idea that blockade of TNF-α, which plays an important role in T cell–mediated immunity,5 leads to inhibition of downstream inflammatory agents and cytokines.6 Adalimumab, a recombinant human IgG monoclonal antibody specific for human TNF-α, is the most recently developed TNF-α antagonist.

Since the approval of adalimumab by the US Food and Drug Administration for rheumatoid arthritis, adverse effects have been reported. However, it is recommended that adalimumab should be considered because its adverse effect profile is favorable compared with traditional immunosuppressants.2 The most common adverse effect is injection site reaction, increasing the risk of rare serious infections, and the most notable adverse effect is reactivation of tuberculosis.7 Several neurological adverse events, including Guillain-Barre syndrome,8,9 chronic inflammatory demyelinating polyneuropathy,10 multiple motor neuropathy with conduction block,11 and multiple sclerosis,12 have been reported. Recently, a case of VZV encephalitis with good recovery was reported during adalimumab treatment.13 However, our patient followed an intractable fatal course with massive hemorrhage and hydrocephalus.

Varicella-zoster virus encephalitis is rare, although latent VZV infection is common even in normal individuals.14 Our patient had the most serious adverse neurological effects of all the previously reported cases in patients receiving adalimumab therapy (Table). In our case, adalimumab caused the reactivation of latent VZV resulting in a skin rash, and the reactivated virus may have then been disseminated to the intracranial space. Despite prompt and intensive antiviral and bacterial medication, the clinical status of the patient continued to deteriorate inexorably. It is possible that the VZV vasculopathy with encephalitis was the result of the prolonged traditional immunosuppressive medication. However, there are clear indications that it was associated with the adalimumab: (1) The VZV vasculopathy with encephalitis occurred shortly after restarting adalimumab therapy. (2) The clinical symptoms of the rheumatoid arthritis were definitely improved by the adalimumab therapy, whereas they had hardly responded, if at all, to the traditional therapy. (3) Viral encephalitis is plausible as a result of exposure to a long-term TNF-α antagonist, based on its mechanism of action. (4) Other cases of VZV meningitis have been reported after adalimumab therapy. On the basis of published criteria,22 we conclude that the VZV vasculopathy with encephalitis in our case was an adalimumab-associated adverse effect.22

Table Graphic Jump LocationTable. Adalimumab-Associated Neurological Disorders

A patient with VZV encephalitis after adalimumab therapy has been described previously.3 However, because of the absence of any evidence of frank encephalitis, a diagnosis of VZV meningitis would have been more appropriate. That is the reason why the patient recovered well after antiviral therapy, unlike our patient. It is possible that involvement of the brainstem with VZV multifocal vasculopathy was responsible for the poor outcome in our patient. The use of corticosteroids and methotrexate along with the adalimumab may have contributed to the adverse outcome. Finally, the long-term use of adalimumab may have been another factor contributing to the adverse neurological effect associated with the adalimumab therapy.

In summary, we describe a case of serous VZV multifocal vasculopathy with encephalitis associated with adalimumab. Clinicians should be aware of the possibility of fatal VZV vasculopathy and encephalitis in patients undergoing adalimumab therapy for rheumatoid arthritis.

ARTICLE INFORMATION

Correspondence: Hyun Young Kim, MD, PhD, Department of Neurology, College of Medicine, Hanyang University, 17 Haengdang-dong, Seongdong-gu, Seoul 133-792, Republic of Korea (hyoungkim1@hanyang.ac.kr).

Accepted for Publication: December 29, 2011.

Published Online: June 25, 2012. doi:10.1001/archneurol.2011.3741

Author Contributions: Drs Jun and H. Y. Kim contributed equally to this work. Study concept and design: Baek, Jun, and H. Y. Kim. Acquisition of data: Baek, Lee, Y. S. Kim, and J.-H. Kim. Analysis and interpretation of data: Baek. Drafting of the manuscript: Baek, Lee, J.-H. Kim, Jun, and H. Y. Kim. Critical revision of the manuscript for important intellectual content: Y. S. Kim. Administrative, technical, and material support: Baek, Lee, Y. S. Kim, J.-H. Kim, Jun, and H. Y. Kim.

Financial Disclosure: None reported.

REFERENCES

Waldmann TA. Immunotherapy: past, present and future.  Nat Med. 2003;9(3):269-277
PubMed   |  Link to Article
Scheinfeld N. Adalimumab: a review of side effects.  Expert Opin Drug Saf. 2005;4(4):637-641
PubMed
Efde MN, Houtman PM, Spoorenberg JP, Jansen TL. Tonsillar tuberculosis in a rheumatoid arthritis patient receiving anti-TNFalpha (adalimumab) treatment.  Neth J Med. 2005;63(3):112-114
PubMed
Lozeron P, Denier C, Lacroix C, Adams D. Long-term course of demyelinating neuropathies occurring during tumor necrosis factor-alpha-blocker therapy.  Arch Neurol. 2009;66(4):490-497
PubMed
Cope AP, Liblau RS, Yang XD,  et al.  Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling.  J Exp Med. 1997;185(9):1573-1584
PubMed
Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis.  Annu Rev Immunol. 1996;14:397-440
PubMed
Fleischmann R, Yocum D. Does safety make a difference in selecting the right TNF antagonist?  Arthritis Res Ther. 2004;6:(suppl 2)  S12-S18
PubMed
Shin IS, Baer AN, Kwon HJ, Papadopoulos EJ, Siegel JN. Guillain-Barré and Miller Fisher syndromes occurring with tumor necrosis factor alpha antagonist therapy.  Arthritis Rheum. 2006;54(5):1429-1434
PubMed
Faivre A, Franques J, De Paula AM,  et al.  Acute motor and sensory axonal neuropathy and concomitant encephalopathy during tumor necrosis factor-alpha antagonist therapy.  J Neurol Sci. 2010;291(1-2):103-106
PubMed
Richez C, Blanco P, Lagueny A, Schaeverbeke T, Dehais J. Neuropathy resembling CIDP in patients receiving tumor necrosis factor-alpha blockers.  Neurology. 2005;64(8):1468-1470
PubMed
Paolazzi G, Peccatori S, Cavatorta FP, Morini A. A case of spontaneously recovering multifocal motor neuropathy with conduction blocks (MMNCB) during anti-TNF alpha therapy for ankylosing spondylitis.  Clin Rheumatol. 2009;28(8):993-995
PubMed
Bensouda-Grimaldi L, Mulleman D, Valat JP, Autret-Leca E. Adalimumab-associated multiple sclerosis.  J Rheumatol. 2007;34(1):239-240
PubMed
Buccoliero G, Lonero G, Romanelli C, Loperfido P, Resta F. Varicella zoster virus encephalitis during treatment with anti-tumor necrosis factor-alpha agent in a psoriatic arthritis patient.  New Microbiol. 2010;33(3):271-274
PubMed
Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, Mahalingam R, Cohrs RJ. Neurologic complications of the reactivation of varicella-zoster virus.  N Engl J Med. 2000;342(9):635-645
PubMed
Ahmed M, Luggen M, Herman JH,  et al.  Hypertrophic pachymeningitis in rheumatoid arthritis after adalimumab administration.  J Rheumatol. 2006;33(11):2344-2346
PubMed
Makol A, Grover M. Adalimumab induced mononeuritis multiplex in a patient with refractory rheumatoid arthritis: a case report.  Cases J. 2008;1(1):287
PubMed
Chung JH, Van Stavern GP, Frohman LP, Turbin RE. Adalimumab-associated optic neuritis.  J Neurol Sci. 2006;244(1-2):133-136
PubMed
Berthelot CN, George SJ, Hsu S. Distal lower extremity paresthesia and foot drop developing during adalimumab therapy.  J Am Acad Dermatol. 2005;53(5):(suppl 1)  S260-S262
PubMed
Brunasso AM, Scocco GL, Massone C. Dermatomyositis during adalimumab therapy for rheumatoid arthritis.  J Rheumatol. 2010;37(7):1549-1550
PubMed
Azevedo VF, Parchen C, Coelho SA, Lacerda DC, Hirth CG. Tuberculous myositis in a patient with ankylosing spondylitis treated with adalimumab.  Rheumatol Int. 2009;29(11):1381-1384
PubMed
Liozon E, Ouattara B, Loustaud-Ratti V, Vidal E. Severe polymyositis and flare in autoimmunity following treatment with adalimumab in a patient with overlapping features of polyarthritis and scleroderma.  Scand J Rheumatol. 2007;36(6):484-486
PubMed
Miller FW, Hess EV, Clauw DJ,  et al.  Approaches for identifying and defining environmentally associated rheumatic disorders.  Arthritis Rheum. 2000;43(2):243-249
PubMed

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Magnetic resonance images on the day of symptom onset. T2-weighted image showing hyperintensities in the dorsal midbrain (A) with lower intensities (arrow). The diffusion-weighted image (B) reveals a ring-shaped restriction, and the T2 gradient-echo image (C) represents a hemorrhagic focus in the left midbrain tectal region.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Magnetic resonance images on the fifth day after symptom onset. The lesions appear as hyperintense foci, especially in the left ventral pons and midbrain extending to the contralateral medial temporal lobe (A). On T2 gradient-echo images (B and C), the lesions are accompanied by intraparenchymal hemorrhage and multiple microbleeds.

Tables

Table Graphic Jump LocationTable. Adalimumab-Associated Neurological Disorders

References

Waldmann TA. Immunotherapy: past, present and future.  Nat Med. 2003;9(3):269-277
PubMed   |  Link to Article
Scheinfeld N. Adalimumab: a review of side effects.  Expert Opin Drug Saf. 2005;4(4):637-641
PubMed
Efde MN, Houtman PM, Spoorenberg JP, Jansen TL. Tonsillar tuberculosis in a rheumatoid arthritis patient receiving anti-TNFalpha (adalimumab) treatment.  Neth J Med. 2005;63(3):112-114
PubMed
Lozeron P, Denier C, Lacroix C, Adams D. Long-term course of demyelinating neuropathies occurring during tumor necrosis factor-alpha-blocker therapy.  Arch Neurol. 2009;66(4):490-497
PubMed
Cope AP, Liblau RS, Yang XD,  et al.  Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling.  J Exp Med. 1997;185(9):1573-1584
PubMed
Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis.  Annu Rev Immunol. 1996;14:397-440
PubMed
Fleischmann R, Yocum D. Does safety make a difference in selecting the right TNF antagonist?  Arthritis Res Ther. 2004;6:(suppl 2)  S12-S18
PubMed
Shin IS, Baer AN, Kwon HJ, Papadopoulos EJ, Siegel JN. Guillain-Barré and Miller Fisher syndromes occurring with tumor necrosis factor alpha antagonist therapy.  Arthritis Rheum. 2006;54(5):1429-1434
PubMed
Faivre A, Franques J, De Paula AM,  et al.  Acute motor and sensory axonal neuropathy and concomitant encephalopathy during tumor necrosis factor-alpha antagonist therapy.  J Neurol Sci. 2010;291(1-2):103-106
PubMed
Richez C, Blanco P, Lagueny A, Schaeverbeke T, Dehais J. Neuropathy resembling CIDP in patients receiving tumor necrosis factor-alpha blockers.  Neurology. 2005;64(8):1468-1470
PubMed
Paolazzi G, Peccatori S, Cavatorta FP, Morini A. A case of spontaneously recovering multifocal motor neuropathy with conduction blocks (MMNCB) during anti-TNF alpha therapy for ankylosing spondylitis.  Clin Rheumatol. 2009;28(8):993-995
PubMed
Bensouda-Grimaldi L, Mulleman D, Valat JP, Autret-Leca E. Adalimumab-associated multiple sclerosis.  J Rheumatol. 2007;34(1):239-240
PubMed
Buccoliero G, Lonero G, Romanelli C, Loperfido P, Resta F. Varicella zoster virus encephalitis during treatment with anti-tumor necrosis factor-alpha agent in a psoriatic arthritis patient.  New Microbiol. 2010;33(3):271-274
PubMed
Gilden DH, Kleinschmidt-DeMasters BK, LaGuardia JJ, Mahalingam R, Cohrs RJ. Neurologic complications of the reactivation of varicella-zoster virus.  N Engl J Med. 2000;342(9):635-645
PubMed
Ahmed M, Luggen M, Herman JH,  et al.  Hypertrophic pachymeningitis in rheumatoid arthritis after adalimumab administration.  J Rheumatol. 2006;33(11):2344-2346
PubMed
Makol A, Grover M. Adalimumab induced mononeuritis multiplex in a patient with refractory rheumatoid arthritis: a case report.  Cases J. 2008;1(1):287
PubMed
Chung JH, Van Stavern GP, Frohman LP, Turbin RE. Adalimumab-associated optic neuritis.  J Neurol Sci. 2006;244(1-2):133-136
PubMed
Berthelot CN, George SJ, Hsu S. Distal lower extremity paresthesia and foot drop developing during adalimumab therapy.  J Am Acad Dermatol. 2005;53(5):(suppl 1)  S260-S262
PubMed
Brunasso AM, Scocco GL, Massone C. Dermatomyositis during adalimumab therapy for rheumatoid arthritis.  J Rheumatol. 2010;37(7):1549-1550
PubMed
Azevedo VF, Parchen C, Coelho SA, Lacerda DC, Hirth CG. Tuberculous myositis in a patient with ankylosing spondylitis treated with adalimumab.  Rheumatol Int. 2009;29(11):1381-1384
PubMed
Liozon E, Ouattara B, Loustaud-Ratti V, Vidal E. Severe polymyositis and flare in autoimmunity following treatment with adalimumab in a patient with overlapping features of polyarthritis and scleroderma.  Scand J Rheumatol. 2007;36(6):484-486
PubMed
Miller FW, Hess EV, Clauw DJ,  et al.  Approaches for identifying and defining environmentally associated rheumatic disorders.  Arthritis Rheum. 2000;43(2):243-249
PubMed

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