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Research Letters |

Lack of Response to Monoclonal Antibody Therapy in Neuromyelitis Optica FREE

Peiqing Qian, MD; Anne H. Cross, MD; Robert T. Naismith, MD
[+] Author Affiliations

Author Affiliations: Department of Neurology, Washington University, St Louis, Missouri.


Arch Neurol. 2011;68(9):1207-1209. doi:10.1001/archneurol.2011.194.
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Published online

The article by Matiello et al1 regarding a relapse of neuromyelitis optica (NMO) after autologous hematopoietic stem cell transplantation highlights the need to further understand the role of the immune system in this disease. Immunosuppressive therapeutics targeting B and T cells are used to prevent disabling relapses in NMO.2 Rituximab is a monoclonal anti-CD20 antibody that is reported to be effective in NMO.3 Alemtuzumab is a monoclonal anti-CD52 antibody with preliminary phase II data in multiple sclerosis, but not in NMO.4 Here we describe a patient with 20 relapses in 5 years despite sequential treatment with 4 immunomodulatory therapeutics in combination with corticosteroids and plasma exchange for relapses. She appeared to paradoxically worsen, with profound weakness, after B cell depletion with rituximab and developed tumefactive cerebral lesions after alemtuzumab.

A 40-year-old African American woman presented with optic neuritis 5 years prior, with recovery of visual acuity to 20/20 after intravenous methylprednisolone (IVMP) (Figure). Three months later, dysesthesias in 4 extremities, mild sensory ataxia, and urinary incontinence developed. Cervical-spine magnetic resonance imaging revealed longitudinally extensive transverse myelitis and serum was positive for NMO-IgG antibodies (1:1920). Treatment included IVMP for this relapse. Treatment with azathioprine and daily prednisone were added. Azathioprine treatment was adjusted to lymphocyte counts of 500 000 to1 000 000/mm3.5 She relapsed 2 months later, and had 5 total episodes of transverse myelitis in the first year; each episode was treated with IVMP. Azathioprine treatment was discontinued and 1000 mg of mycophenolate mofetil twice per day with daily prednisone was used for 18 months. She experienced 4 additional sensory and bladder relapses, unaccompanied by urinary tract infection. Findings of motor testing were normal during the first 3 years.

Place holder to copy figure label and caption
Graphic Jump Location

Figure. A, Timeline of clinical events and treatments with Expanded Disability Status Scale. B, After treatment with alemtuzumab, brain magnetic resonance imaging revealed multiple large regions of T2 signal abnormality with patchy enhancement. This included a 1.5 × 1.5 × 4–cm lesion in the right temporal lobe, a 1.4 × 1.8 × 1.2–cm lesion in the right corona radiata, and a 5.5 × 2.5 × 2.4–cm lesion in the left occipital lobe. IVMP indicates intravenous methylprednisolone; NMO, neuromyelitis optica; PLEX, plasma exchange.

Owing to continued disease activity, rituximab was administered. Beginning 5 months after rituximab treatment, and with a confirmed count of 0 CD19+ cells, she experienced 4 additional relapses over 5 months, stabilizing after each. However, these culminated in persistent paraplegia.

Nine months following rituximab treatment, B cells began to return (CD19 cell count, 9/mm3; reference range, 79-545). Fourth-line treatment options were discussed owing to concern for quadriplegia and respiratory compromise. Mitoxantrone was not chosen owing to dose limitations and risks of cardiotoxicity and malignancy.6,7 Cyclophosphamide was not used owing to risk of infection among other adverse effects. Alemtuzumab was selected to suppress mononuclear immune system cells and because it is well tolerated, with promising early results in relapsing multiple sclerosis. She received 12 mg/kg/d of intravenous alemtuzumab for 5 days, with 5 days of IVMP.

Six weeks following alemtuzumab, a relapse manifested by worsening dysesthesias culminated in apnea and intubation. Magnetic resonance imaging showed an expansile, contrast-enhancing, longitudinally extensive transverse myelitis. Her CD4 count was 30 cells/mm3 (reference range, 393-1607). She received plasma exchange and was extubated. Four months after beginning treatment with alemtuzumab, aphasia, dysarthria, lethargy, and moderate right arm weakness developed. Brain magnetic resonance imaging revealed 3 large, discreet regions of T2 signal abnormality with patchy enhancement, the largest being 33 cm3 (Figure). The thoracic cord demonstrated an enhancing expansile T2 lesion. Brain biopsy, performed to exclude opportunistic infection and malignancy, confirmed a demyelinating process. The CD4 count was 133 cells/mm3, and the CD19 count was 115 cells/mm3. During the next 5 months, the patient had 2 confirmed relapses and received IVMP. Mycophenolate and low-dose prednisone were added, with no further clinical relapse after 8 months' follow-up. She currently resides in a nursing facility, transfers with a lift, and cannot feed herself.

This case, together with the article by Matiello et al, may be instructive, as NMO disease activity continued despite marked suppression of cellular immunity. Plasma cells are the primary source of antibodies, but CD20 is not expressed by plasma cells, and CD52 is only expressed by a fraction of plasma cells. Failure to eliminate anti–aquaporin 4 antibodies may be the reason for lack of therapeutic success in each case.

Correspondence: Dr Naismith, Department of Neurology, Washington University, Campus Box 8111, 660 S Euclid Ave, St Louis, MO 63110 (naismithr@neuro.wustl.edu).

Accepted for Publication: May 18, 2011.

Author Contributions: The corresponding author takes full responsibility for the data, the analyses and interpretation, and the conduct of the research. All coauthors reviewed the manuscript. Acquisition of data: Qian, Cross, and Naismith. Analysis and interpretation of data: Qian, Cross, and Naismith. Critical revision of the manuscript for important intellectual content: Qian, Cross, and Naismith. Administrative, technical, and material support: Qian, Cross, and Naismith.

Financial Disclosure: Dr Qian has received speaking honoraria from Teva Neurosciences. Dr Cross has received research funding, clinical trial funding, honoraria, or consulting fees from the National Institutes of Health (NIH), National Multiple Sclerosis Society USA, Consortium of Multiple Sclerosis Centers, Genentech Inc, Bayer Healthcare, Biogen-Idec, Hoffmann-La Roche Inc, Teva Neuroscience, Acorda Therapeutics, Serono, Pfizer, and BioMS. Dr Naismith has received consulting fees and speaking honoraria from Acorda Therapeutics, Bayer Healthcare, Biogen Idec, EMD Serono, Genzyme Corporation, and Teva Neurosciences.

Funding/Support: This study was supported by the NIH (grants T32NS007205 to PQ, K23NS052430-01A1 to Dr Naismith and K24 RR017100 to Dr Cross); Manny and Rosalyn Rosenthal–Dr John L. Trotter Chair in Neuroimmunology (Dr Cross). This publication was made possible by Grant No. UL1 RR024992 from the National Center for Research Resources, a component of the NIH and NIH Roadmap for Medical Research.

Disclaimer: The contents of the study are solely the responsibility of the authors and do not necessarily represent the official view of the National Center for Research Resources or NIH.

Additional Information: The corresponding author has full access to all the data and has the right to publish any and all data, separate and apart from the attitudes of the sponsor.

Matiello M, Pittock SJ, Porrata L, Weinshenker BG. Failure of autologous hematopoietic stem cell transplantation to prevent relapse of neuromyelitis optica [published online March 14, 2011].  Arch Neurol. 2011;68(7):953-955
Link to Article
Wingerchuk DM, Weinshenker BG. Neuromyelitis optica: clinical predictors of a relapsing course and survival.  Neurology. 2003;60(5):848-853
PubMed   |  Link to Article
Jacob A, Weinshenker BG, Violich I,  et al.  Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients.  Arch Neurol. 2008;65(11):1443-1448
PubMed   |  Link to Article
Coles AJ, Compston DA, Selmaj KW,  et al; CAMMS223 Trial Investigators.  Alemtuzumab vs. interferon beta-1a in early multiple sclerosis.  N Engl J Med. 2008;359(17):1786-1801
PubMed   |  Link to Article
Bichuetti DB, Lobato de Oliveira EM, Oliveira DM, Amorin de Souza N, Gabbai AA. Neuromyelitis optica treatment: analysis of 36 patients.  Arch Neurol. 2010;67(9):1131-1136
PubMed   |  Link to Article
Weinstock-Guttman B, Ramanathan M, Lincoff N,  et al.  Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease).  Arch Neurol. 2006;63(7):957-963
PubMed   |  Link to Article
Kim S-H, Kim W, Park MS, Sohn EH, Li XF, Kim HJ. Efficacy and safety of mitoxantrone in patients with highly relapsing neuromyelitis optica.  Arch Neurol. 2011;68(4):473-479
Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure. A, Timeline of clinical events and treatments with Expanded Disability Status Scale. B, After treatment with alemtuzumab, brain magnetic resonance imaging revealed multiple large regions of T2 signal abnormality with patchy enhancement. This included a 1.5 × 1.5 × 4–cm lesion in the right temporal lobe, a 1.4 × 1.8 × 1.2–cm lesion in the right corona radiata, and a 5.5 × 2.5 × 2.4–cm lesion in the left occipital lobe. IVMP indicates intravenous methylprednisolone; NMO, neuromyelitis optica; PLEX, plasma exchange.

Tables

References

Matiello M, Pittock SJ, Porrata L, Weinshenker BG. Failure of autologous hematopoietic stem cell transplantation to prevent relapse of neuromyelitis optica [published online March 14, 2011].  Arch Neurol. 2011;68(7):953-955
Link to Article
Wingerchuk DM, Weinshenker BG. Neuromyelitis optica: clinical predictors of a relapsing course and survival.  Neurology. 2003;60(5):848-853
PubMed   |  Link to Article
Jacob A, Weinshenker BG, Violich I,  et al.  Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients.  Arch Neurol. 2008;65(11):1443-1448
PubMed   |  Link to Article
Coles AJ, Compston DA, Selmaj KW,  et al; CAMMS223 Trial Investigators.  Alemtuzumab vs. interferon beta-1a in early multiple sclerosis.  N Engl J Med. 2008;359(17):1786-1801
PubMed   |  Link to Article
Bichuetti DB, Lobato de Oliveira EM, Oliveira DM, Amorin de Souza N, Gabbai AA. Neuromyelitis optica treatment: analysis of 36 patients.  Arch Neurol. 2010;67(9):1131-1136
PubMed   |  Link to Article
Weinstock-Guttman B, Ramanathan M, Lincoff N,  et al.  Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease).  Arch Neurol. 2006;63(7):957-963
PubMed   |  Link to Article
Kim S-H, Kim W, Park MS, Sohn EH, Li XF, Kim HJ. Efficacy and safety of mitoxantrone in patients with highly relapsing neuromyelitis optica.  Arch Neurol. 2011;68(4):473-479
Link to Article

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