http://informahealthcare.com/mor ISSN 1439-7595 (print), 1439-7609 (online) Mod Rheumatol, 2013; Early Online: 1–3 © 2013 Japan College of Rheumatology DOI: 10.3109/14397595.2013.861333
CASE REPORT
Neuromyelitis optica spectrum disorder complicated with Sjogren syndrome successfully treated with tocilizumab: A case report Toshihiko Komai1, Hirofumi Shoda1, Kenichi Yamaguchi1, Keiichi Sakurai1, Mihoko Shibuya1, Kanae Kubo1, Toshiyuki Takahashi2, Keishi Fujio1, and Kazuhiko Yamamoto1
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1Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan and 2Department of Neurology,
Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan Abstract
Keywords
A 38-year-old woman with relapsing longitudinal extensive transverse myelitis and Sjogren’s syndrome (SS) was admitted with lower extremity muscle weakness. Studies showed high serum titer of anti-aquaporin4 antibody and gadolinium-enhanced-MRI T1-weighted lesions within thoracic cord. Clinical findings suggested neuromyelitis optica-spectrum disorder (NMO-SD). High-dose corticosteroids, plasma exchange and cyclophosphamide were not effective. After starting tocilizumab, her neurological findings gradually improved. This report describes the first evidence to show tocilizumab could be effective for NMO-SD with SS.
Anti-aquaporin4 antibody, Neuromyelitis optica, Sjogren’s syndrome, Tocilizumab, Transverse myelitis
Introduction Longitudinal extensive transverse myelitis (LETM) has been defined as a bilateral sensorimotor and autonomic spinal cord dysfunction, a clearly defined sensory level, progression to nadir of clinical deficits between 4 h and 21 days after symptom onset, demonstration of spinal cord inflammation with CSF pleocytosis and MRI revealing gadolinium-enhanced cord lesion that extends over three or more vertebral segments, and exclusion of compressive and neoplastic causes [1,2]. Neuromyelitis optica (NMO) is the most common underlying disease complicated by LETM, and many autoimmune diseases, such as systemic lupus erythematosus (SLE) and Sjogren’s syndrome (SS), also present the pathognomonic symptoms of LETM. Seropositivity to the anti-aquaporin 4 (anti-AQP4) antibody is an important marker for diagnosing NMO, and is associated with the pathogenesis of NMO, because it is an antigenic target of NMO-IgG [3]. Actually, NMO is defined to have optic neuritis, acute myelitis and at least two of three supportive data containing contiguous spinal cord MRI lesion extending over three vertebral segments, brain MRI not meeting criteria for multiple sclerosis and NMO-IgG seropositive status [4]. Limited forms of NMO, such as idiopathic single or recurrent events of LETM with the anti-AQP4 antibody, have been categorized in NMO spectrum disorders (SDs) [5]. Since the presence of the anti-AQP4 antibody in serum from SLE and Sjogren syndrome (SS) patients has been strongly correlated with neurological diseases including LETM [6], these patients may be regarded as having NMO-SDs. High-dose intravenous steroid, including steroid pulse therapy, and immunosuppressive agents, such as azathioprine, are typically Correspondence to: Hirofumi Shoda, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. Tel:⫹ 81-3-3815-5411. Fax: ⫹ 81-3-3815-5954. E-mail: [email protected]
History Received 27 August 2013 Accepted 29 October 2013 Published online 9 December 2013
used as an initial therapy for LETM or NMO [7], although there have been almost no randomized controlled trial for the treatment. Plasma exchange therapy is sometimes effective in patients, even those with steroid-resistant inflammatory demyelinating disease. Recent case reports have indicated the effectiveness of tocilizumab (TCZ) in NMO patients [8–10]. However, few have investigated NMO-SD with SS, and a therapy for patients with NMO-SD with SS has not yet been established. This case report firstly describes that TCZ could be effective for NMO-SD with SS, even unresponsive to other immunosuppressive therapies.
Case report A 38-year-old woman was admitted to our department with exacerbating muscle weakness and paresthesia, especially in the left lower extremity, with nausea and abdominal pain. She had a previous experience of lower extremity muscle weakness, nausea and urinary incontinence 10 years before being admitted. She was diagnosed with LETM based on spinal MRI and cerebrospinal fluid (CSF) tests, and symptoms improved following methylprednisolone (mPSL) pulse therapy. The recurrence of LETM was noted eight times in 10 years of steroid tapering, and was treated each time using mPSL pulse therapy and high-dose corticosteroids. As steroid sparing medications, methotrexate, azathioprine, and tacrolimus were not effective in preventing the recurrence of her symptoms, even though the doses of these medications were limited by adverse effects. The patient was diagnosed with SS due to xerostomia, keratoconjunctivitis, serum anti SS-A and SS-B antibodies, and massive lymphocyte infiltration in a lip biopsy specimen 9 years before her admission. On admission, she had lower extremity muscle weakness, hyperreflexia in the lower limbs, hypesthesia beneath Th5, and bladder and rectal disturbances. She had not had any ocular symptoms, no visual field loss and no difficulty of ocular movements. Manual Muscle Testing showed decreased muscle power
2
T. Komai et al.
Mod Rheumatol, 2013; Early Online: 1–3
Mod Rheumatol Downloaded from informahealthcare.com by University of Calgary on 04/02/15 For personal use only.
Table 1. Laboratory findings on admission. Hematology WBC Neu Lym Mono Eos RBC Hb Ht Plt Coagulation PT-INR APTT Fibrinogen D-dimer Biochemistry & serology TP Alb BUN Cr T-Bil AST ALT LDH ALP Na K Cl Ca CK Ferritin CRP ESR IL-6 RF IgG ANA Anti-dsDNA Ab Anti-ssDNA Ab Anti-SS-A Ab Anti-SS-B Ab Anti-AQP4 Ab MPO ANCA PR-3 ANCA Cerebrospinal fluid Cell Neu Lym Protein Alb Glu IgG IL-6 IgG index
15000 /uL 93.0% 5.0% 2.0% 0.0% 4.8 million/uL 14.3 g/dL 43.3% 280 thousand/mL 0.98 27.1 sec 428 mg/dL 0.5 ug/mL 7.1 g/dL 4.0 g/dL 8.1 mg/dL 0.37 mg/dL 0.8 mg/dL 21 U/L 30 U/L 294 U/L 126 U/L 137 mEq/L 3.9 mEq/L 102 mEq/L 8.4 mg/dL 122 U/L 28 ng/mL 2.77 mg/dL 25 mm 126 pg/mL Negative 1049 mg/dL 1: 320 Speckled Negative Negative 121.6 index 108.7 index 8.0 U/mL Negative Negative 65 /uL 69.0% 31.0% 196 mg/dL 93.7 mg/dL 61 mg/dL 224.2 ug/mL 11500 pg/mL 0.912
to 3/1 on iliopsoas muscle, 3/1 on quadriceps muscle, 3/1 on tibial anterior muscle and 2/1 on triceps surae muscle. The Expanded Disability Status Scale (EDSS) [11], which was used in previous reports associated with NMO as a method of quantifying disability, was estimated as 8.5. C-reactive protein (2.77 mg/dL) and interleukin-6 (126 pg/mL) levels were serologically elevated, and the serum anti-nuclear antibody with a speckled pattern (1:320), anti-SS-A antibody (121.6 Index), and anti-SS-B antibody (108.7 Index) were positive. The serum titer of anti-AQP4 IgG antibody was 8.0 U/mL (ELISA, cut off ⬍ 5.0) [12]. Serum anti-AQP4 IgG antibody was also positively detected (more than ⫻ 16) by another method (immunofluorescence assay) [13]. A CSF test revealed pleiocytosis, and elevated IL-6 levels (11500 pg/mL) and IgG index (0.912). Her laboratory findings on admission are listed on Table 1. T1-weighted gadolinium-enhanced MRI showed diffuse highly contrasted lesions between the first and eighth thoracic vertebral
Figure 1. Gadolinium-enhanced T1-weighted spinal cord MRI. On admission, diffuse high contrast T1-weighted enhanced area within cord between the first and the eighth thoracic vertebra.
cords (Figure 1). Since she met all of the criteria of LETM [1,2], and the anti-AQP4 antibody in the serum was highly suggestive of the classification [1,5], she was diagnosed with NMO-SD with SS. High-dose steroid therapy, including mPSL pulse, intravenous cyclophosphamide pulse and plasma exchange, was performed, and her IL-6 levels were reduced to lower than detectable levels in the serum (1.8 pg/mL) and CSF (1.2 pg/mL). However, her symptoms did not improve thoroughly. Therefore, we administered TCZ, which led to the gradual amelioration of her neurological symptoms to better than was expected as shown in Figure 2. In addition, not only motor disability, but also sensory deficits were gradually improved. No relapse was observed during the clinical course, and prednisolone was safely tapered to less than 20 mg/ day, though her anti-AQP4 antibody on Day 253 was still detected (11.5 U/mL). She continues to receive 8 mg/kg of TCZ once a month.
Discussion Plasmablasts (PBs) are believed to play important roles in the pathogenesis of NMO. PBs are a major source of the anti-AQP4 antibody, which plays a direct pathogenic role in astrocyte damage. IL-6 signaling was previously shown to be crucial in enhancing the cell survival of PB and anti-AQP4 antibody production [14]. According to these findings, suppressing anti-AQP4-antibodyproducing PBs is supposed to be one of the most important therapeutic mechanisms of TCZ for NMO. In the present case, IL-6 levels were reduced to lower than detectable levels in the serum and CSF due to previous immunosuppressive therapies before the administration of TCZ. Nevertheless, her neurological symptoms gradually improved with TCZ. According to a previous report, which described the effectiveness of TCZ in a patient with NMO [8], although serum IL-6 levels were low, the number of PBs was markedly decreased after TCZ. Since the serum anti-AQP4 antibody remained highly detectable before TCZ therapy in our case, anti-AQP4 antibody-producing PBs would continue to exist.
Mod Rheumatol Downloaded from informahealthcare.com by University of Calgary on 04/02/15 For personal use only.
DOI 10.3109/14397595.2013.861333
Neuromyelitis optica spectrum disorder complicated with Sjogren syndrome 3
Figure 2. Clinical course and changes of neurological findings. TCZ could lead to the gradual amelioration of her neurological symptoms.
TCZ could regulate polyclonal PBs and improve the patient’s symptoms, or there would be other important NMO-associated autoantibody. Unfortunately, we had no chance to analyze the number of PBs in this patient. Although a few case reports have previously described the effectiveness of TCZ in patients with NMO, this is the first one to show that TCZ could be effective in patients with NMO-SD with SS who were an unresponsive case to other immunosuppressive therapies. Further studies are required to confirm the effectiveness of TCZ in patients with NMO-SD with SS.
Conflict of interest None.
References 1. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106–12. 2. Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology. 2002; 59(4):499–505. 3. Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med. 2005;202(4):473–7. 4. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66(10):1485–9. 5. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6(9):805–15.
6. Wandinger KP, Stangel M, Witte T, Venables P, Charles P, Jarius S, et al. Autoantibodies against aquaporin-4 in patients with neuropsychiatric systemic lupus erythematosus and primary Sjogren’s syndrome. Arthritis Rheum. 2010;62(4):1198–200. 7. Wingerchuk DM, Weinshenker BG. Neuromyelitis Optica. Curr Treat Options Neurol. 2005;7(3):173–82. 8. Araki M, Aranami T, Matsuoka T, Nakamura M, Miyake S, Yamamura T. Clinical improvement in a patient with neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab. Mod Rheumatol. 2013;23(4):827–31. 9. Kieseier BC, Stuve O, Dehmel T, Goebels N, Leussink VI, Mausberg AK, et al. Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses. JAMA Neurol. 2013;70(3):390–3. 10. Ayzenberg I. Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy. JAMA Neurol. 2013;70(3):394–7. 11. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983; 33(11):1444–52. 12. Jarius S, Franciotta D, Paul F, Bergamaschi R, Rommer PS, Ruprecht K, et al. Testing for antibodies to human aquaporin-4 by ELISA: sensitivity, specificity, and direct comparison with immunohistochemistry. J Neurol Sci. 2012;320(1–2):32–7. 13. Takahashi T, Fujihara K, Nakashima I, Misu T, Miyazawa I, Nakamura M, et al. Establishment of a new sensitive assay for antihuman aquaporin-4 antibody in neuro- myelitis optica. Tohoku J Exp Med 2006;210(4):307–13. 14. Chihara N, Aranami T, Sato W, Miyazaki Y, Miyake S, Okamoto T, et al. Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. Proc Natl Acad Sci U S A. 2011;108(9):3701–6.
CASE REPORT
Neuromyelitis optica spectrum disorder complicated with Sjogren syndrome successfully treated with tocilizumab: A case report Toshihiko Komai1, Hirofumi Shoda1, Kenichi Yamaguchi1, Keiichi Sakurai1, Mihoko Shibuya1, Kanae Kubo1, Toshiyuki Takahashi2, Keishi Fujio1, and Kazuhiko Yamamoto1
Mod Rheumatol Downloaded from informahealthcare.com by University of Calgary on 04/02/15 For personal use only.
1Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan and 2Department of Neurology,
Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan Abstract
Keywords
A 38-year-old woman with relapsing longitudinal extensive transverse myelitis and Sjogren’s syndrome (SS) was admitted with lower extremity muscle weakness. Studies showed high serum titer of anti-aquaporin4 antibody and gadolinium-enhanced-MRI T1-weighted lesions within thoracic cord. Clinical findings suggested neuromyelitis optica-spectrum disorder (NMO-SD). High-dose corticosteroids, plasma exchange and cyclophosphamide were not effective. After starting tocilizumab, her neurological findings gradually improved. This report describes the first evidence to show tocilizumab could be effective for NMO-SD with SS.
Anti-aquaporin4 antibody, Neuromyelitis optica, Sjogren’s syndrome, Tocilizumab, Transverse myelitis
Introduction Longitudinal extensive transverse myelitis (LETM) has been defined as a bilateral sensorimotor and autonomic spinal cord dysfunction, a clearly defined sensory level, progression to nadir of clinical deficits between 4 h and 21 days after symptom onset, demonstration of spinal cord inflammation with CSF pleocytosis and MRI revealing gadolinium-enhanced cord lesion that extends over three or more vertebral segments, and exclusion of compressive and neoplastic causes [1,2]. Neuromyelitis optica (NMO) is the most common underlying disease complicated by LETM, and many autoimmune diseases, such as systemic lupus erythematosus (SLE) and Sjogren’s syndrome (SS), also present the pathognomonic symptoms of LETM. Seropositivity to the anti-aquaporin 4 (anti-AQP4) antibody is an important marker for diagnosing NMO, and is associated with the pathogenesis of NMO, because it is an antigenic target of NMO-IgG [3]. Actually, NMO is defined to have optic neuritis, acute myelitis and at least two of three supportive data containing contiguous spinal cord MRI lesion extending over three vertebral segments, brain MRI not meeting criteria for multiple sclerosis and NMO-IgG seropositive status [4]. Limited forms of NMO, such as idiopathic single or recurrent events of LETM with the anti-AQP4 antibody, have been categorized in NMO spectrum disorders (SDs) [5]. Since the presence of the anti-AQP4 antibody in serum from SLE and Sjogren syndrome (SS) patients has been strongly correlated with neurological diseases including LETM [6], these patients may be regarded as having NMO-SDs. High-dose intravenous steroid, including steroid pulse therapy, and immunosuppressive agents, such as azathioprine, are typically Correspondence to: Hirofumi Shoda, Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. Tel:⫹ 81-3-3815-5411. Fax: ⫹ 81-3-3815-5954. E-mail: [email protected]
History Received 27 August 2013 Accepted 29 October 2013 Published online 9 December 2013
used as an initial therapy for LETM or NMO [7], although there have been almost no randomized controlled trial for the treatment. Plasma exchange therapy is sometimes effective in patients, even those with steroid-resistant inflammatory demyelinating disease. Recent case reports have indicated the effectiveness of tocilizumab (TCZ) in NMO patients [8–10]. However, few have investigated NMO-SD with SS, and a therapy for patients with NMO-SD with SS has not yet been established. This case report firstly describes that TCZ could be effective for NMO-SD with SS, even unresponsive to other immunosuppressive therapies.
Case report A 38-year-old woman was admitted to our department with exacerbating muscle weakness and paresthesia, especially in the left lower extremity, with nausea and abdominal pain. She had a previous experience of lower extremity muscle weakness, nausea and urinary incontinence 10 years before being admitted. She was diagnosed with LETM based on spinal MRI and cerebrospinal fluid (CSF) tests, and symptoms improved following methylprednisolone (mPSL) pulse therapy. The recurrence of LETM was noted eight times in 10 years of steroid tapering, and was treated each time using mPSL pulse therapy and high-dose corticosteroids. As steroid sparing medications, methotrexate, azathioprine, and tacrolimus were not effective in preventing the recurrence of her symptoms, even though the doses of these medications were limited by adverse effects. The patient was diagnosed with SS due to xerostomia, keratoconjunctivitis, serum anti SS-A and SS-B antibodies, and massive lymphocyte infiltration in a lip biopsy specimen 9 years before her admission. On admission, she had lower extremity muscle weakness, hyperreflexia in the lower limbs, hypesthesia beneath Th5, and bladder and rectal disturbances. She had not had any ocular symptoms, no visual field loss and no difficulty of ocular movements. Manual Muscle Testing showed decreased muscle power
2
T. Komai et al.
Mod Rheumatol, 2013; Early Online: 1–3
Mod Rheumatol Downloaded from informahealthcare.com by University of Calgary on 04/02/15 For personal use only.
Table 1. Laboratory findings on admission. Hematology WBC Neu Lym Mono Eos RBC Hb Ht Plt Coagulation PT-INR APTT Fibrinogen D-dimer Biochemistry & serology TP Alb BUN Cr T-Bil AST ALT LDH ALP Na K Cl Ca CK Ferritin CRP ESR IL-6 RF IgG ANA Anti-dsDNA Ab Anti-ssDNA Ab Anti-SS-A Ab Anti-SS-B Ab Anti-AQP4 Ab MPO ANCA PR-3 ANCA Cerebrospinal fluid Cell Neu Lym Protein Alb Glu IgG IL-6 IgG index
15000 /uL 93.0% 5.0% 2.0% 0.0% 4.8 million/uL 14.3 g/dL 43.3% 280 thousand/mL 0.98 27.1 sec 428 mg/dL 0.5 ug/mL 7.1 g/dL 4.0 g/dL 8.1 mg/dL 0.37 mg/dL 0.8 mg/dL 21 U/L 30 U/L 294 U/L 126 U/L 137 mEq/L 3.9 mEq/L 102 mEq/L 8.4 mg/dL 122 U/L 28 ng/mL 2.77 mg/dL 25 mm 126 pg/mL Negative 1049 mg/dL 1: 320 Speckled Negative Negative 121.6 index 108.7 index 8.0 U/mL Negative Negative 65 /uL 69.0% 31.0% 196 mg/dL 93.7 mg/dL 61 mg/dL 224.2 ug/mL 11500 pg/mL 0.912
to 3/1 on iliopsoas muscle, 3/1 on quadriceps muscle, 3/1 on tibial anterior muscle and 2/1 on triceps surae muscle. The Expanded Disability Status Scale (EDSS) [11], which was used in previous reports associated with NMO as a method of quantifying disability, was estimated as 8.5. C-reactive protein (2.77 mg/dL) and interleukin-6 (126 pg/mL) levels were serologically elevated, and the serum anti-nuclear antibody with a speckled pattern (1:320), anti-SS-A antibody (121.6 Index), and anti-SS-B antibody (108.7 Index) were positive. The serum titer of anti-AQP4 IgG antibody was 8.0 U/mL (ELISA, cut off ⬍ 5.0) [12]. Serum anti-AQP4 IgG antibody was also positively detected (more than ⫻ 16) by another method (immunofluorescence assay) [13]. A CSF test revealed pleiocytosis, and elevated IL-6 levels (11500 pg/mL) and IgG index (0.912). Her laboratory findings on admission are listed on Table 1. T1-weighted gadolinium-enhanced MRI showed diffuse highly contrasted lesions between the first and eighth thoracic vertebral
Figure 1. Gadolinium-enhanced T1-weighted spinal cord MRI. On admission, diffuse high contrast T1-weighted enhanced area within cord between the first and the eighth thoracic vertebra.
cords (Figure 1). Since she met all of the criteria of LETM [1,2], and the anti-AQP4 antibody in the serum was highly suggestive of the classification [1,5], she was diagnosed with NMO-SD with SS. High-dose steroid therapy, including mPSL pulse, intravenous cyclophosphamide pulse and plasma exchange, was performed, and her IL-6 levels were reduced to lower than detectable levels in the serum (1.8 pg/mL) and CSF (1.2 pg/mL). However, her symptoms did not improve thoroughly. Therefore, we administered TCZ, which led to the gradual amelioration of her neurological symptoms to better than was expected as shown in Figure 2. In addition, not only motor disability, but also sensory deficits were gradually improved. No relapse was observed during the clinical course, and prednisolone was safely tapered to less than 20 mg/ day, though her anti-AQP4 antibody on Day 253 was still detected (11.5 U/mL). She continues to receive 8 mg/kg of TCZ once a month.
Discussion Plasmablasts (PBs) are believed to play important roles in the pathogenesis of NMO. PBs are a major source of the anti-AQP4 antibody, which plays a direct pathogenic role in astrocyte damage. IL-6 signaling was previously shown to be crucial in enhancing the cell survival of PB and anti-AQP4 antibody production [14]. According to these findings, suppressing anti-AQP4-antibodyproducing PBs is supposed to be one of the most important therapeutic mechanisms of TCZ for NMO. In the present case, IL-6 levels were reduced to lower than detectable levels in the serum and CSF due to previous immunosuppressive therapies before the administration of TCZ. Nevertheless, her neurological symptoms gradually improved with TCZ. According to a previous report, which described the effectiveness of TCZ in a patient with NMO [8], although serum IL-6 levels were low, the number of PBs was markedly decreased after TCZ. Since the serum anti-AQP4 antibody remained highly detectable before TCZ therapy in our case, anti-AQP4 antibody-producing PBs would continue to exist.
Mod Rheumatol Downloaded from informahealthcare.com by University of Calgary on 04/02/15 For personal use only.
DOI 10.3109/14397595.2013.861333
Neuromyelitis optica spectrum disorder complicated with Sjogren syndrome 3
Figure 2. Clinical course and changes of neurological findings. TCZ could lead to the gradual amelioration of her neurological symptoms.
TCZ could regulate polyclonal PBs and improve the patient’s symptoms, or there would be other important NMO-associated autoantibody. Unfortunately, we had no chance to analyze the number of PBs in this patient. Although a few case reports have previously described the effectiveness of TCZ in patients with NMO, this is the first one to show that TCZ could be effective in patients with NMO-SD with SS who were an unresponsive case to other immunosuppressive therapies. Further studies are required to confirm the effectiveness of TCZ in patients with NMO-SD with SS.
Conflict of interest None.
References 1. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106–12. 2. Transverse Myelitis Consortium Working Group. Proposed diagnostic criteria and nosology of acute transverse myelitis. Neurology. 2002; 59(4):499–505. 3. Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med. 2005;202(4):473–7. 4. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66(10):1485–9. 5. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The spectrum of neuromyelitis optica. Lancet Neurol. 2007;6(9):805–15.
6. Wandinger KP, Stangel M, Witte T, Venables P, Charles P, Jarius S, et al. Autoantibodies against aquaporin-4 in patients with neuropsychiatric systemic lupus erythematosus and primary Sjogren’s syndrome. Arthritis Rheum. 2010;62(4):1198–200. 7. Wingerchuk DM, Weinshenker BG. Neuromyelitis Optica. Curr Treat Options Neurol. 2005;7(3):173–82. 8. Araki M, Aranami T, Matsuoka T, Nakamura M, Miyake S, Yamamura T. Clinical improvement in a patient with neuromyelitis optica following therapy with the anti-IL-6 receptor monoclonal antibody tocilizumab. Mod Rheumatol. 2013;23(4):827–31. 9. Kieseier BC, Stuve O, Dehmel T, Goebels N, Leussink VI, Mausberg AK, et al. Disease amelioration with tocilizumab in a treatment-resistant patient with neuromyelitis optica: implication for cellular immune responses. JAMA Neurol. 2013;70(3):390–3. 10. Ayzenberg I. Interleukin 6 receptor blockade in patients with neuromyelitis optica nonresponsive to anti-CD20 therapy. JAMA Neurol. 2013;70(3):394–7. 11. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983; 33(11):1444–52. 12. Jarius S, Franciotta D, Paul F, Bergamaschi R, Rommer PS, Ruprecht K, et al. Testing for antibodies to human aquaporin-4 by ELISA: sensitivity, specificity, and direct comparison with immunohistochemistry. J Neurol Sci. 2012;320(1–2):32–7. 13. Takahashi T, Fujihara K, Nakashima I, Misu T, Miyazawa I, Nakamura M, et al. Establishment of a new sensitive assay for antihuman aquaporin-4 antibody in neuro- myelitis optica. Tohoku J Exp Med 2006;210(4):307–13. 14. Chihara N, Aranami T, Sato W, Miyazaki Y, Miyake S, Okamoto T, et al. Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica. Proc Natl Acad Sci U S A. 2011;108(9):3701–6.
