Journal of the Neurological Sciences 353 (2015) 191–192
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Neuromyelitis optica overlapping systemic sclerosis with anti-centromere antibodies Keywords: Neuromyelitis optica Systemic sclerosis Anti-aquaporin-4 antibody Anti-centromere antibody Sjögren syndrome Good recovery
Dear Editor, Neuromyelitis optica (NMO) is characterized by positivity for antiaquaporin 4 (AQP4) antibody and is an idiopathic demyelinating disease associated with various systemic autoimmune diseases such as Sjögren syndrome (SS) and systemic lupus erythematosus [1]. It has been proposed that optic neuritis or longitudinal extensive transverse myelitis associated with systemic autoimmune disease should be categorized as NMO spectrum disorder (NMOSD) [2]. Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by excess collagen deposition in the skin and internal organs, [3] and is occasionally reported in cases of NMO/NMOSD [4–6]. It is unclear whether SSc triggers NMO/NMOSD. Herein, we report a case of NMO overlapping with anti-centromere antibody (ACA)-positive SSc and SS without other organ involvement. To investigate the relationship between SSc and NMO/NMOSD, we also investigated ACAs in sera from 16 patients with anti-AQP4 antibody-positive NMO/NMOSD who visited our hospital and we analyzed the clinical features of ACA-positive patients with NMO or NMOSD. A representative case is demonstrated below: In December 2013, a 51-year-old female was admitted to our hospital for weakness and numbness in the left leg two weeks after upper respiratory infection. She had a history of relapsing optic neuritis on four occasions and relapsing thoracic myelitis on three occasions from 1988 to 1994. She was diagnosed with opticospinal multiple sclerosis, and oral prednisolone and cyclophosphamide were administered. She remained relapse-free from 1994 to 2003, and thus the immunotherapy was withdrawn. One year later, she suffered from limbic skin sclerosis and Raynaud's phenomenon, and was diagnosed with limited cutaneous (lc)SSc at a local clinic. On examination at admission, the patient had left-dominant paraparesis, dysesthesia below the thoracic (Th) 6 level, and bowel–bladder dysfunction. Her visual activity was intact. She was not capable of walking
Abbreviations: AQP4, aquaporin4; lcSSc, limited cutaneous systemic sclerosis; CSF, cerebrospinal fluid; EDSS, Expanded Disability Scoring Scale; LETM, longitudinally extensive transverse myelitis; MRI, magnetic resonance imaging; NMO, neuromyelitis optica; NMOSD, NMO spectrum disorder; SS, Sjögren syndrome; SSc, systemic sclerosis; Th, thoracic.
http://dx.doi.org/10.1016/j.jns.2015.04.027 0022-510X/© 2015 Elsevier B.V. All rights reserved.
without bilateral support and her EDSS was 6.5. Spinal cord T2weighted magnetic resonance imaging (MRI) showed hyperintense Th3 to Th4 lesions with partial gadolinium (Gd) enhancement. Brain MRI findings were normal. A cerebrospinal fluid (CSF) examination showed 10 lymphocytes/μl, a normal protein concentration, and a high level of myelin basic protein (272 pg/ml). Oligoclonal band was absent. Serum was positive for anti-nuclear, anti-centromere, and anti-AQP4 antibodies, but negative for rheumatoid factor, SS-A and SS-B antibodies, anti-thyroglobulin and anti-thyroperoxidase antibodies, anti-dsDNA antibody, anti-neutrophil cytoplasmic antibodies, and anti-Scl-70 antibody. Since the patient also complained of dry eye and dry mouth, 99m TcO− 4 salivary gland scintigraphy and a fluorescein test were conducted and showed salivary and lacrimal hypofunction. Labial salivary biopsy revealed focal lymphocytic sialadenitis. There was no evidence of other organ involvement, including no pulmonary hypertension, renal failure, or esophageal dysfunction. The patient was diagnosed with NMO fulfilling the criteria proposed by Wingerchuk [7] and with SSc [8] and Sjögren syndrome [9] based on published criteria. Three courses of intravenous methylprednisolone pulse therapy (1 g/day × 3 days) were administered and paraparesis gradually improved and Gd-enhanced lesions in spinal cord MRI diminished. One-year oral administration of 10 mg/day prednisolone was followed by improvement of her illness. Medical records were reviewed for 16 patients with anti-AQP4 antibody-positive NMO or NMOSD who visited our hospital from January 2010 to January 2014. They were all patients positive for anti-AQP4 antibodies in our hospital. All patients suspected of NMO were tested for serum anti-AQP4 antibodies by cell based assay and patients negative for anti-AQP4 antibodies were excluded in this study. Besides the representative case, 2 of the 15 patients (13%) had ACAs. In one patient, serum ACA was negative at the onset of NMOSD and became positive 5 years after onset of NMOSD. All patients were negative for anti-Scl-70 antibodies. The clinical features of the ACA-positive and ACA-negative groups are shown in Table 1. There were no significant differences in age (51 ± 7.3 vs. 54 ± 12 years), disease duration (17 ± 9.1 vs. 12 ± 9.0 years), and Expanded Disability Scoring Scale (EDSS) (4.7 ± 0.85 vs. 5.0 ± 3.1) between the two groups. At the time of sampling, six patients had been taking steroid only, and ten steroid and immunosuppressants (seven azathioprine, two cyclosporine, and one tacrolimus). The etiology of NMO is not clearly understood and it is uncertain if SSc is an etiological factor in NMO. In the case described above, the patient developed optic neuritis and myelitis 26 years ago, had no relapse for over 2 decades, and was drug-free in the last decade until relapse following onset of lcSSc. A diagnosis of NMO was made based on her history, MRI findings, and the presence of serum anti-AQP4 antibody. Plasmapheresis was not performed because Gd-enhanced lesions and the IgG index decreased after oral administration of corticosteroids. The dose of prednisolone was determined based on the possibility of scleroderma renal crisis, [10] but there were no signs of renal dysfunction or recurrence in the present case. Of three NMO patients with ACAs, one developed SSc and two had no clinical symptoms, which may have been due to treatment with oral steroids and immunosuppressants over
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Letter to the Editor
Table 1 Clinical features of NMO/NMOSD with and without anti-centromere antibodies. Anti-centromere antibody
Positive (n = 3)
Negative (n = 13)
Female:male Age (mean ± SD) Optic neuritis LETM Disease duration EDSS
3:0 51 ± 7.3 2 2 17 ± 9.1 4.7 ± 0.85
10:3 54 ± 12 8 10 12 ± 9.0 5.0 ± 3.1
LETM, longitudinally extensive transverse myelitis; EDSS, Expanded Disability Scoring Scale.
many years. Of note, our results show that ACAs can emerge under longterm treatment even if the ACA status is negative at the onset of NMO/ NMOSD. Therefore, careful observation including regular examination of autoantibodies such as ACAs is required in patients with NMO/ NMOSD as well as SS. To our knowledge, this is the first case series study of NMO/NMOSD with ACAs. In previous reports [3–5] of anti-AQP4 antibody-positive NMOSD associated with SSc, two of three cases were positive for ACAs and none were positive for anti-Scl-70 antibodies. All cases had mild systemic organ involvement and two of three were complicated by SS. All cases were relapsing myelitis and two were LETM. All cases were treated with corticosteroids only and showed good recovery in shortterm follow-up. The clinical features of patients with ACA-positive NMO/NMOSD remain unclear, but our cases and previous reports suggest that these patients have a good response to corticosteroids and mild disease severity. Accumulation of cases and clinicoserological analyses of a larger population of patients are required to determine whether an ACA-positive status is a marker of good prognosis. Conflict of interest statement The authors have no conflict of interest to disclose. Acknowledgment This work was supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grant-in-Aid for Scientific Research (C), KAKENHI; Grant Number 24591282).
References [1] Pittock SJ, Lennon VA, de Seze J, Vermersch P, Homburger HA, Wingerchuk DM, et al. Neuromyelitis optica and non-organ-specific autoimmunity. Arch Neurol 2008;65: 78–83. [2] Wingerchuk DM, Lennon VA, Lucchinetti FC, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6:805–15. [3] Wingerchuk DM, Lennon VA, Lucchinetti FC, Pittock SJ, Weinshenker BG. Immunologic rheumatic disorders. J Allergy Immunol 2010;125:S204–15. [4] Franciotta D, Zardini E, Caporali R, Piccolo L, Alberici E, Romani A, et al. Systemic sclerosis in aquaporin-4 antibody-positive longitudinally extensive transverse myelitis. J Neurol Sci 2011;303:139–41. [5] Iwanaga Y, Hayashi S, Kawamura N, Ohyagi Y, Kira J. A case of neuromyelitis optica spectrum disorder associated with a limited cutaneous systemic sclerosis and Sjögren syndrome. Clin Neurol 2013;53:695–700. [6] Takahashi M, Nagata R, Ozaki A, Kaneko S, Saiki H, Matsumoto S. A case of anti-AQP4 antibody-positive recurrent myelitis overlapped with autoimmune disorders including incomplete CREST syndrome revealed multiple discontinuous cord lesions. Clin Neurol 2009;49:115–8. [7] Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1485–9. [8] LeRoy EC, Medsger Jr TA. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28:1573–6. [9] Shiboski SC, Shiboski CH, Criswell LA, Baer A, Challacombe S, Lanfranchi H, et al. American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 2012;64:475–87. [10] Steen VD, Medsger Jr TA. Case–control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum 1998;41:1613–9.
Kota Moriguchi Kenichi Kaida⁎ Naohiko Togashi Hiroyuki Onoue Katsunori Ikewaki Division of Neurology, Department of Internal Medicine 3, National Defense Medical College, Saitama, Japan ⁎Corresponding author at: Division of Neurology, Department of Internal Medicine 3, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. Tel.: +81 42 2995 1617; fax: +81 42 2996 5202. E-mail address: [email protected] (K. Kaida). 20 February 2015
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor Neuromyelitis optica overlapping systemic sclerosis with anti-centromere antibodies Keywords: Neuromyelitis optica Systemic sclerosis Anti-aquaporin-4 antibody Anti-centromere antibody Sjögren syndrome Good recovery
Dear Editor, Neuromyelitis optica (NMO) is characterized by positivity for antiaquaporin 4 (AQP4) antibody and is an idiopathic demyelinating disease associated with various systemic autoimmune diseases such as Sjögren syndrome (SS) and systemic lupus erythematosus [1]. It has been proposed that optic neuritis or longitudinal extensive transverse myelitis associated with systemic autoimmune disease should be categorized as NMO spectrum disorder (NMOSD) [2]. Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by excess collagen deposition in the skin and internal organs, [3] and is occasionally reported in cases of NMO/NMOSD [4–6]. It is unclear whether SSc triggers NMO/NMOSD. Herein, we report a case of NMO overlapping with anti-centromere antibody (ACA)-positive SSc and SS without other organ involvement. To investigate the relationship between SSc and NMO/NMOSD, we also investigated ACAs in sera from 16 patients with anti-AQP4 antibody-positive NMO/NMOSD who visited our hospital and we analyzed the clinical features of ACA-positive patients with NMO or NMOSD. A representative case is demonstrated below: In December 2013, a 51-year-old female was admitted to our hospital for weakness and numbness in the left leg two weeks after upper respiratory infection. She had a history of relapsing optic neuritis on four occasions and relapsing thoracic myelitis on three occasions from 1988 to 1994. She was diagnosed with opticospinal multiple sclerosis, and oral prednisolone and cyclophosphamide were administered. She remained relapse-free from 1994 to 2003, and thus the immunotherapy was withdrawn. One year later, she suffered from limbic skin sclerosis and Raynaud's phenomenon, and was diagnosed with limited cutaneous (lc)SSc at a local clinic. On examination at admission, the patient had left-dominant paraparesis, dysesthesia below the thoracic (Th) 6 level, and bowel–bladder dysfunction. Her visual activity was intact. She was not capable of walking
Abbreviations: AQP4, aquaporin4; lcSSc, limited cutaneous systemic sclerosis; CSF, cerebrospinal fluid; EDSS, Expanded Disability Scoring Scale; LETM, longitudinally extensive transverse myelitis; MRI, magnetic resonance imaging; NMO, neuromyelitis optica; NMOSD, NMO spectrum disorder; SS, Sjögren syndrome; SSc, systemic sclerosis; Th, thoracic.
http://dx.doi.org/10.1016/j.jns.2015.04.027 0022-510X/© 2015 Elsevier B.V. All rights reserved.
without bilateral support and her EDSS was 6.5. Spinal cord T2weighted magnetic resonance imaging (MRI) showed hyperintense Th3 to Th4 lesions with partial gadolinium (Gd) enhancement. Brain MRI findings were normal. A cerebrospinal fluid (CSF) examination showed 10 lymphocytes/μl, a normal protein concentration, and a high level of myelin basic protein (272 pg/ml). Oligoclonal band was absent. Serum was positive for anti-nuclear, anti-centromere, and anti-AQP4 antibodies, but negative for rheumatoid factor, SS-A and SS-B antibodies, anti-thyroglobulin and anti-thyroperoxidase antibodies, anti-dsDNA antibody, anti-neutrophil cytoplasmic antibodies, and anti-Scl-70 antibody. Since the patient also complained of dry eye and dry mouth, 99m TcO− 4 salivary gland scintigraphy and a fluorescein test were conducted and showed salivary and lacrimal hypofunction. Labial salivary biopsy revealed focal lymphocytic sialadenitis. There was no evidence of other organ involvement, including no pulmonary hypertension, renal failure, or esophageal dysfunction. The patient was diagnosed with NMO fulfilling the criteria proposed by Wingerchuk [7] and with SSc [8] and Sjögren syndrome [9] based on published criteria. Three courses of intravenous methylprednisolone pulse therapy (1 g/day × 3 days) were administered and paraparesis gradually improved and Gd-enhanced lesions in spinal cord MRI diminished. One-year oral administration of 10 mg/day prednisolone was followed by improvement of her illness. Medical records were reviewed for 16 patients with anti-AQP4 antibody-positive NMO or NMOSD who visited our hospital from January 2010 to January 2014. They were all patients positive for anti-AQP4 antibodies in our hospital. All patients suspected of NMO were tested for serum anti-AQP4 antibodies by cell based assay and patients negative for anti-AQP4 antibodies were excluded in this study. Besides the representative case, 2 of the 15 patients (13%) had ACAs. In one patient, serum ACA was negative at the onset of NMOSD and became positive 5 years after onset of NMOSD. All patients were negative for anti-Scl-70 antibodies. The clinical features of the ACA-positive and ACA-negative groups are shown in Table 1. There were no significant differences in age (51 ± 7.3 vs. 54 ± 12 years), disease duration (17 ± 9.1 vs. 12 ± 9.0 years), and Expanded Disability Scoring Scale (EDSS) (4.7 ± 0.85 vs. 5.0 ± 3.1) between the two groups. At the time of sampling, six patients had been taking steroid only, and ten steroid and immunosuppressants (seven azathioprine, two cyclosporine, and one tacrolimus). The etiology of NMO is not clearly understood and it is uncertain if SSc is an etiological factor in NMO. In the case described above, the patient developed optic neuritis and myelitis 26 years ago, had no relapse for over 2 decades, and was drug-free in the last decade until relapse following onset of lcSSc. A diagnosis of NMO was made based on her history, MRI findings, and the presence of serum anti-AQP4 antibody. Plasmapheresis was not performed because Gd-enhanced lesions and the IgG index decreased after oral administration of corticosteroids. The dose of prednisolone was determined based on the possibility of scleroderma renal crisis, [10] but there were no signs of renal dysfunction or recurrence in the present case. Of three NMO patients with ACAs, one developed SSc and two had no clinical symptoms, which may have been due to treatment with oral steroids and immunosuppressants over
192
Letter to the Editor
Table 1 Clinical features of NMO/NMOSD with and without anti-centromere antibodies. Anti-centromere antibody
Positive (n = 3)
Negative (n = 13)
Female:male Age (mean ± SD) Optic neuritis LETM Disease duration EDSS
3:0 51 ± 7.3 2 2 17 ± 9.1 4.7 ± 0.85
10:3 54 ± 12 8 10 12 ± 9.0 5.0 ± 3.1
LETM, longitudinally extensive transverse myelitis; EDSS, Expanded Disability Scoring Scale.
many years. Of note, our results show that ACAs can emerge under longterm treatment even if the ACA status is negative at the onset of NMO/ NMOSD. Therefore, careful observation including regular examination of autoantibodies such as ACAs is required in patients with NMO/ NMOSD as well as SS. To our knowledge, this is the first case series study of NMO/NMOSD with ACAs. In previous reports [3–5] of anti-AQP4 antibody-positive NMOSD associated with SSc, two of three cases were positive for ACAs and none were positive for anti-Scl-70 antibodies. All cases had mild systemic organ involvement and two of three were complicated by SS. All cases were relapsing myelitis and two were LETM. All cases were treated with corticosteroids only and showed good recovery in shortterm follow-up. The clinical features of patients with ACA-positive NMO/NMOSD remain unclear, but our cases and previous reports suggest that these patients have a good response to corticosteroids and mild disease severity. Accumulation of cases and clinicoserological analyses of a larger population of patients are required to determine whether an ACA-positive status is a marker of good prognosis. Conflict of interest statement The authors have no conflict of interest to disclose. Acknowledgment This work was supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (Grant-in-Aid for Scientific Research (C), KAKENHI; Grant Number 24591282).
References [1] Pittock SJ, Lennon VA, de Seze J, Vermersch P, Homburger HA, Wingerchuk DM, et al. Neuromyelitis optica and non-organ-specific autoimmunity. Arch Neurol 2008;65: 78–83. [2] Wingerchuk DM, Lennon VA, Lucchinetti FC, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol 2007;6:805–15. [3] Wingerchuk DM, Lennon VA, Lucchinetti FC, Pittock SJ, Weinshenker BG. Immunologic rheumatic disorders. J Allergy Immunol 2010;125:S204–15. [4] Franciotta D, Zardini E, Caporali R, Piccolo L, Alberici E, Romani A, et al. Systemic sclerosis in aquaporin-4 antibody-positive longitudinally extensive transverse myelitis. J Neurol Sci 2011;303:139–41. [5] Iwanaga Y, Hayashi S, Kawamura N, Ohyagi Y, Kira J. A case of neuromyelitis optica spectrum disorder associated with a limited cutaneous systemic sclerosis and Sjögren syndrome. Clin Neurol 2013;53:695–700. [6] Takahashi M, Nagata R, Ozaki A, Kaneko S, Saiki H, Matsumoto S. A case of anti-AQP4 antibody-positive recurrent myelitis overlapped with autoimmune disorders including incomplete CREST syndrome revealed multiple discontinuous cord lesions. Clin Neurol 2009;49:115–8. [7] Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1485–9. [8] LeRoy EC, Medsger Jr TA. Criteria for the classification of early systemic sclerosis. J Rheumatol 2001;28:1573–6. [9] Shiboski SC, Shiboski CH, Criswell LA, Baer A, Challacombe S, Lanfranchi H, et al. American College of Rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort. Arthritis Care Res (Hoboken) 2012;64:475–87. [10] Steen VD, Medsger Jr TA. Case–control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum 1998;41:1613–9.
Kota Moriguchi Kenichi Kaida⁎ Naohiko Togashi Hiroyuki Onoue Katsunori Ikewaki Division of Neurology, Department of Internal Medicine 3, National Defense Medical College, Saitama, Japan ⁎Corresponding author at: Division of Neurology, Department of Internal Medicine 3, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. Tel.: +81 42 2995 1617; fax: +81 42 2996 5202. E-mail address: [email protected] (K. Kaida). 20 February 2015
