Journal of the Neurological Sciences 339 (2014) 52–56

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Antibodies against interferon-beta in neuromyelitis optica patients Nasrin Asgari a,b,c,⁎, Kirsten Ohm Kyvik c,d, Troels Steenstrup e, Egon Stenager c,f, Soeren Thue Lillevang g a

Department of Neurology, Vejle Hospital, Odense University Hospital, Denmark Institute of Molecular Medicine, Odense University Hospital, Denmark c Institute of Regional Health Research, University of Southern Denmark, Odense University Hospital, Denmark d Odense Patient Data Explorative Network, Odense University Hospital, Denmark e Department of Biostatistics, University of Southern Denmark, Odense, Odense University Hospital, Denmark f The Multiple Sclerosis Clinic of Southern Jutland (Vejle, Esbjerg, Soenderborg), Department of Neurology, Odense University Hospital, Soenderborg, Denmark g Department of Clinical Immunology, Odense University Hospital, Denmark b

a r t i c l e

i n f o

Article history: Received 30 June 2013 Received in revised form 8 January 2014 Accepted 13 January 2014 Available online 17 January 2014 Keywords: Anti-aquaporin-4 antibody Multiple sclerosis Neuromyelitis optica Autoimmunity Magnetic resonance imaging Interferon-neutralizing antibodies

a b s t r a c t Neuromyelitis optica (NMO) is an antibody-mediated autoimmune inflammatory disease of the CNS. A poor response to treatment with recombinant interferon beta (IFN-ß) in NMO patients has been suggested, although the precise mechanisms remain uncertain. We analyzed occurrence and clinical consequences of IFNneutralizing antibodies (NAbs) in 15 IFN-ß treated NMO-patients from a population-based retrospective case series cohort. NMO patients not treated with IFN-ß acted as a reference group. IFN-ß antibody determinations included binding antibodies (BAbs) measured by immunoassay and NAbs measured by a neutralization bioassay. Antibodies were determined 6–36 months after initiation of IFN-β therapy and NAbs additionally 5–10 years post-therapy. BAbs were detected in 14/15 NMO patients; 6/15 were NAbs-positive (3 at 5–10 years posttherapy) two of those anti-AQP4 antibody-positive; seven of the nine NAbs-negative patients were anti-AQP4 antibody-positive. Eleven patients (three NAbs-positive, eight NAbs-negative) developed cerebral lesions and 12 patients (four NAbs-positive, eight NAbs-negative) spinal cord lesions on magnetic resonance imaging as gadolinium positive lesions or T2-weighted lesions, at significantly higher frequencies than NMO reference group (p b 0.009). Exacerbation occurred within 90 days in four and 6–36 months in eight patients. Progression of disease activity in NMO patients occurred during IFN-β treatment, irrespective of IFN-neutralizing antibody status. © 2014 Elsevier B.V. All rights reserved.

1. Introduction Neuromyelitis optica is an antibody-mediated autoimmune inflammatory disease of the central nervous system (CNS). After multiple sclerosis (MS) NMO is probably the most common demyelinating disease in CNS [1]. Unlike MS, NMO involves autoantibodies directed against the water channel aquaporin-4 (AQP4), expressed by astrocytes [2,3]. Immunoglobulin G (IgG) anti-AQP4 antibody (NMO-IgG) is a serum biomarker for NMO, suggesting that the precursors of the antibodyproducing plasma cells i.e. B cells, play a major role in NMO pathogenesis [4]. Immunomodulatory treatment with the cytokine interferon beta

Abbreviations: AQP4, aquaporin-4; BAbs, binding antibodies; CNS, central nervous system; EDSS, Expanded Disability Status Scale; IFN-ß, interferon beta; LETM, longitudinally extensive transverse myelitis; MS, multiple sclerosis; MRI, magnetic resonance imaging; NAbs, neutralizing antibodies; NMO, neuromyelitis optica. ⁎ Corresponding author at: Department of Neurology, Vejle Hospital, 7100 Vejle Denmark, Institute of Molecular Medicine, University of Southern Denmark, J.B. Winsloewsvej 25, 2, 5000 Odense C, Denmark. Tel.: +45 6550 3951; fax: +45 6550 3950. E-mail address: [email protected] (N. Asgari). 0022-510X/$ – see front matter © 2014 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2014.01.019

(IFN-β) which belongs to the type I IFN family is an established therapy for relapsing–remitting MS (RR-MS) [5]. Therapeutic action of IFN-β in MS reflects immunomodulatory effects [6]. Large-scale clinical trials have established the clinical efficacy of IFN-β in MS patients including a reduction in the frequency of relapses, disability progression and lesion load as visualized by magnetic resonance imaging (MRI) [5]. NMO can present with a clinical phenotype similar to MS and may initially be diagnosed as MS leading to treatment with IFN-β. Contrary to its effect in MS, IFN-β treatment of NMO appears to be ineffective for preventing relapse and may even increase the relapse rate [7–9]. Induction of IFN-β antibodies has been reported in patients treated with interferons [10]. The presence of such antibodies detected as neutralizing antibodies (NAbs) can lead to reduced clinical efficacy and disease progression in RR-MS patients [11–13]. It may be hypothesized that IFN-ß therapy facilitate the production of various autoantibodies, among them NAbs via increased B cell activity, consequently leading to reduction of the effect of IFN-ß and disease progression in NMO patients. The aim of the present study was to determine whether administration of IFN-ß was accompanied by development of NAbs and the clinical consequences of NAbs in NMO patients.

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2. Materials and methods

53

tested at dilutions of 20, 100, 1000, and 2000 and evaluated at the lowest dilution [10,17,19].

2.1. Patients 2.3. Determination of AQP4 antibody and other autoantibodies Patients originated from a population based cohort as a retrospective case series with clinical and radiological follow-up as reported previously [14]. Based on early diagnostic considerations of MS, 15/42 NMO patients received IFN-ß therapy before the diagnosis of NMO was established. A total of nine patients had IFN-β treatment for up to three years before discontinuation, and six patients had IFN-β treatment for up to two years and were on IFN-ß therapy at the time of NMO diagnosis, when it was discontinued. All NMO patients fulfilled the Wingerchuk 2006 criteria [15] for the diagnosis of definite NMO. Additional information was obtained by means of review of medical records, a questionnaire, a clinical examination, a re-evaluation of previous MRIs of CNS, an examination of supplementary MRIs and serum autoantibody determinations. Disability score was measured by Expanded Disability Status Scale (EDSS) and retrieved from the medical records [16]. Non-responding patients were defined either by clinical relapse as an increase of EDSS of at least 1.0 or by findings on a new MRI with gadolinium-enhancement or T2-weighted lesions, while on IFN-ß treatment. A group of NMO patients who were not treated with IFN-ß were included as a reference group with similar distribution of gender, age, disease duration and anti-AQP4 antibodies positivity as the IFN treated group. The clinical disease activity in IFN-beta treated NMO patients and non-IFN-beta treated NMO patients were described for the total length of IFN-treatment during up to 36 months of observation. The clinical presentation included optic neuritis (ON), transverse myelitis (TM), longitudinally extensive TM and brainstem syndrome. A total of nine patients were AQP4 antibody positive in the IFN-beta treated NMO patients and 10 in the non-IFN-beta treated NMO patients. The female:male ratio was 4:1 and mean age at onset was 33.5 years (range 15–64 years). 2.2. Determination of anti-IFN-β binding and neutralizing antibodies Two different classes of antibodies, binding and neutralizing antibodies were determined. Briefly, IFN-ß binding antibodies (BAbs) were measured by a radioimmuno-assay [10,17], based on the inhibition of binding of 125I-IFN-ß to IgG eluted by protein G columns. The test is considered positive at ≥ 16% binding capacity. IFN-ß neutralizing antibodies (NAbs) were measured by an antiviral neutralization bioassay based on the antiviral effect of IFN-ß added to MC-5 cells infected by encephalomyocarditis virus [10,17]. For re-analysis of NAbs a semiquantitative bioassay was used (Biomonitor, Copenhagen) [18]. The assay utilizes a human PIL5 cell line carrying the luciferase reporter gene under the control of an IFN-responsive chimeric promoter [18,19]. The test is considered NAbs-positive at ≥20% neutralizing capacity in the absence of endogenous IFN activity. High endogenous IFN in serum is known to be a limitation of Nab detection [10,17,19]. To diminish interference by such activity in serum, individual sera were

IgG AQP4 antibodies were measured as described previously [20] with an immunofluorescence assay using HEK293 cells transfected with recombinant human full-length AQP4 gene (Euroimmun, Lubeck, Germany) [21]. Patient sera were screened at a 1:10 dilution. Screening for other autoantibodies was performed using standard methods. Briefly, screening for antinuclear antibodies (ANA) was done by indirect immunofluorescence using HEp2 cells as substrate; IgM rheuma factor, IgG anti-CCP, IgA anti-tissue transglutaminase and anti-TPO antibodies were determined by enzyme linked immunosorbent assay (ELISA); acetylcholine receptor antibodies were determined by radioimmunoassay. Antibodies against gall canaliculi and mitochondria were determined by indirect immunofluorescence using ox tissue as substrate. 2.4. Statistics p-Values were estimated using Fisher's exact test. The 95% Confidence Intervals (CI) for the Odds Ratios (ORs) are exact. Statistical analyses were performed using Stata 11 (StataCorp LP, College Station, Texas, USA). A level of p b 0.05 was used as limit of significance. 3. Results 3.1. Occurrence of IFN-ß antibodies BAbs and NAbs were measured 6–36 months after the start of IFN-ß treatment as the first part of the study (Table 1). BAbs and NAbs capacities were classified into three levels: low 20–50%, moderate 60–80% and high 80–100%. BAbs were present in 14/15 of patients and NAbs were observed in six patients. Of those two were anti-AQP4 antibody positive. NAbs were negative in nine patients, eight of whom were positive for BAbs and seven positive for anti-AQP4 antibodies. 3.2. NAbs-positive patients and other autoimmune diseases Three NAbs-positive patients had a family history of autoimmune disease such as type 1 diabetes mellitus (two patients), NMO (one patient) and two patients had serum anti-nuclear antibody (ANA). Two NAbs-negative patients had a family history of autoimmune thyroid disease and MS, one patient had rheumatoid factor (RF) and one ANA antibodies. 3.3. NAbs 5–10 years after cessation of treatment Semi-quantitative determination of NAbs antibodies was performed in the serum of the same 15 NMO patients 5–10 years (median 7 years)

Table 1 Anti-interferon beta (IFNß) antibodies in neuromyelitis optica patients. Retrospective analysis of binding antibodies (BAbs) and neutralizing antibodies (NAbs) (during 6–36 months treatment with IFN-β) No. patients = 15

Prospective semi-quantitative determination of NAbs (5-10 years post-therapy) No. patients = 15

Characteristics

Positive 3

Female/male Anti-AQP4 antibody positive Other autoantibodies: anti-nuclear antibody rheumatoid factor Exacerbation by MRI and/or EDSS

Nabs negative No. patients = 9

Nabs positive No. patients = 6

low BAbs 4

Endogenous IFN-β activity 1

Moderate to high BAbs 4

High BAbs, low NAbs 2

High BAbs + NAbs 4

3/1 3 1

1/0 1 0

4/0 3 1

2/0 1 1

2/2 1 1

4

1

3

1

3

Negative 12 Negative 10

Endogenou-s IFN-β activity 2

2/1 2 1

8/2 6 1

2/0 1 2

2

8

2

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after cessation of treatment. Three patients were NAbs-positive, two patients who were high NAbs-positive in the previous analysis persisted as NAbs-positive and one, who was BAbs-positive, became NAbs-positive in the second analysis (Table 1). None had other autoimmune diseases. Two (2/3) were anti-AQP4 antibody seropositive. Of the 12 NAbsnegative patients seven were anti-AQP4 antibody positive. 3.4. Endogenous interferon activity Three NMO patients, who were treated with recombinant IFN-β earlier and were seronegative for NAbs, had high endogenous IFN in serum (see Section 2). All were female, two anti-AQP4 antibody positive. 3.5. Patient characteristics Clinical and serological characteristics are depicted in Tables 1 and 2. All 15 patients who received IFN-ß therapy failed to respond to IFN-β treatment. A total of eight (8/9) NAbs-negative and four (4/6) NAbspositive patients exacerbated as evaluated by disease activity (EDSS and MRI) after the initiation of IFN-β treatment (Table 2). Exacerbation occurred within 90 days in four (one NAbs-positive) and within 6–36 months in eight patients (three NAbs-positive) after the initiation of IFN-β therapy. A total of 11 patients, three NAbs-positive and eight NAbs-negative, developed cerebral lesions measured by MRI as gadolinium positive lesions or T2- lesions, in a significantly higher frequency as compared to controls (p b 0.009) (Fig. 1). Spinal cord MRI demonstrated relapse of transverse myelitis in 12 patients, four NAbspositive and eight NAbs-negative, of those three had longitudinally extensive transverse myelitis (LETM), and additionally recurrent LETM was observed in two patients during IFN-β treatment. A significantly higher frequency of spinal cord lesions were observed in NMO patients with IFN-β therapy (12/15) than in non- IFN-β therapy NMO patients (4/15) (p b 0.009) (Fig. 2). The EDSS scores increased in 12 of the IFNbeta treated NMO patients and in 7 of the non-IFN-beta treated NMO patients, the groups not being significantly different (Table 2). A total of nine patients had IFN-β treatment discontinued within three years due to exacerbation in five patients and due to persistently high titers of NAbs in four patients. 4. Discussion In the present retrospective case series from a population-based cohort 15 NMO patients received IFN-β therapy before the diagnosis of NMO was established [14]. Induction of BAbs was observed in the majority of patients, whereas only few patients developed high titer NAbs. All the NMO patients failed to respond to IFN-β treatment and 80% of the patients significantly exacerbated as evaluated by clinical

disease activity (MRI) after the initiation of IFN-β treatment. Remarkably, this clinical deterioration occurred during IFN-β treatment even in the absence of NAbs, thus the analysis of occurrence and clinical consequences of NAbs in IFN-β treated NMO-patients could not explain the lack of effect of IFN-β therapy. The marked differences in therapeutic response [7–9] to IFN-β treatment likely reflect differences between the disease mechanisms of NMO and MS. Similarly, several clinical studies indicate that other MS therapies such as natalizumab or fingolimod may cause disease exacerbation in NMO patients, when misdiagnosed as MS [22–24]. The present study was limited in the number of patients (15). A further limitation was the lack of randomized treatment due to the retrospective design of the study. However, the study does allow drawing tentative conclusions as to the role of NAbs in NMO due to a populationbased design with the strength of high representativity. International guidelines for MS patients recommend determining NAbs during IFN-β therapy [13]. A study from a large cohort of Danish RR-MS patients reported frequencies of NAbs in MS from 7–42% and of BAbs in up to 78% of patients after IFN-β treatment [10]. Furthermore, a positive correlation between high concentrations of NAbs and reduced clinical IFN-ß efficacy and disease progression was reported [11,12,25]. These authors observed in RR-MS patients that the clinically important NAbs appeared after only 9–18 months of IFN-ß treatment [10,13]. However, the clinical relevance and importance of BAbs is still unclear in RR-MS patients [10], as the reported frequencies and titers of antiIFN-β NAbs vary considerably depending on IFN preparations, dosage, and route of administration [10]. In this study of NMO patients variation in such factors could not be evaluated due to the small sample size. The large cohort of RR-MS patients mentioned above may be used for evaluation of the frequency of Nabs in MS patients, as the population background and antibody methodologies were identical. On this basis the occurrence of Nabs did not seem to be different between MS and NMO patients, in spite of differences in sample size. Several studies of clinical trials of IFN-β therapy for NMO indicate that IFN-β is ineffective for prevention of NMO relapse and may even increase the relapse rate [7–9]. NMO has been reported to have frequent co-existence of autoimmune diseases and of autoantibody production [20,26–28] and B cells probably play a major role in NMO pathogenesis with AQP4-antibodies as a main autoimmune element. Non-responsiveness and exacerbation could be explained by the hypothesis that IFN-β therapy is followed by increased B cell activity, induction of B-cell-activating factor (BAFF) and antibody production (Anti-AQP4 antibodies), and consequently aggravation of NMO disease activity [29,30]. Due to the retrospective nature of the present study we could not measure the level of BAFF and anti-AQP4 antibodies in consecutive samples, 7/9 of the NAbs negative and 2/6 of the NAbs positive NMO patients had anti-AQP4 antibodies. Other serum autoantibodies,

Table 2 Clinical characteristics of patients with neuromyelitis optica (NMO) who received IFN-ß therapy and NMO reference patients. Clinical characteristics

NMO + IFN-ß n = 15

NMO − IFN-ß n = 15

P-value

OR (95%)

Female Duration of disease (years): 2–4 year 5–10 year Positive anti-aquaporin-4 antibody EDSS: Unchanged with initial EDSS 3–5 Increased during study: Initial/Follow-up 3–5/6–7 6–7/8–9 MRI of Brain: New Lesions MRI of Spinal cord: New lesions: ≥3 vertebral segments b3 vertebral segments

12

12

1.000

1.0 (0.110–9.06)

9 6 9

10 5 10

1.000 1.000 1.000

0.75 (0.130–4.23) 1.3 (0.237–7.67) 0.75 (0.130–4.23)

3 12

8 7

0.128 0.128

0.22 (.0293–1.38) 4.6 (0.726–34.1)

6 6

5 2

1.000 0.215

1.3 (0.237–7.67) 4.3 (0.566–50.9)

11

3

0.009

11 (1.59–87. 3)

12 3 9

4 1 3

0.009 0.598 0.060

11 (1.59–87. 3) 3.5 (0.234–197) 6.0 (0.942–44.9)

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Fig. 1. Progression of brain lesions. Fluid-attenuated inversion recovery (FLAIR) MR-images of brain in a NMO-patient with progression of brain lesions during one year after the start of IFN-β treatment. The patient was anti-AQP4 antibody positive and NAbs negative.

mostly ANA, as well as family histories of autoimmunity were present in both the NAbs-positive and NAbs-negative group. Thus, the data do not suggest that the administration of IFN-β and subsequent development of NAbs was accompanied by development of anti-AQP4-antibodies or of other autoantibodies in NMO patients. Technically, a prerequisite for the detection of NAbs independent of the type of assays is the absence of high endogenous IFN activity in the patient's serum [10,17,19]. In the present study 60% (9) were NAbseronegative and of those three had endogenous interferon activity despite precautions to dilute and consequently to prevent endogenous interferon to influence the detection of Nabs. The presence of high endogenous IFN activity may then lead to occurrence of false negative results [10,17,19] reducing the frequency of patients with detected Nabs, consequently the data analysis will become more complex and difficult to interpret. In conformity with this observation, clinical and experimental data have suggested that interferon beta non-responders have elevated levels of endogenous type I IFN prior to treatment [31,32].

Inflammatory infiltrates seen within NMO lesions include granulocytes dominated by neutrophils, which are rarely seen in MS [33]. Type I IFN has a pro-inflammatory effect on granulocytes that are found in Th17 driven pathologies [34]. Interestingly, high level of Th17 cells in the blood and high concentrations of IL-17 and the granulocyte chemo-attractant, IL-8/CXCL8 in the cerebrospinal fluid were found in NMO patients compared with RR-MS [35–37]. Recently our group (Owens group) in an experimental mouse model of NMO has shown that NMO-like lesions were reduced in mice deficient in type I IFN receptor (IFNAR) signaling compared to wild type mice [38]. These data may provide a mechanistic explanation for the negative effect of IFN-β treatment in NMO and indicate a role for type I IFN signaling in NMO pathogenesis. In conclusion we have evaluated the occurrence and clinical importance of neutralizing antibodies against IFN-β in patients with NMO. The administration of IFN-β in NMO patients was accompanied by lack of response or progression of disease even in the absence of NAbs. In few

Fig. 2. Recurrent longitudinally extensive transverse myelitis. Sagittal T2-weighted (A–C) and T1-weighted images (D) of the spinal cord in an NMO-patient with recurrent cervical cord longitudinally extensive transverse myelitis (LETM) during 2–36 months after the initiation of IFN-β therapy. A) Primary image showing transverse myelitis. B) LETM relapse with extension to brainstem. C and D) Another acute LETM relapse in the cervical cord with contrast enhancement. The patient was anti-AQP4 antibody positive and NAbs negative.

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NMO Nabs-positive patients this effect may at least partly be explained by poor bioavailability of IFN-β due to development of NAbs, but this effect could not account for aggravation of NMO disease activity. There may be disease mechanisms in NMO patients that result in lack of effect of IFN-β treatment and the disease progression may be due to Th17 deviation via a pro-inflammatory effect on granulocytes by IFN-β. It could be speculated that NMO patients have high endogenous IFN-β expression prior to treatment, which is accompanied by false negative NAbs results. Standard protocol approvals, registrations, and patient consent The study was approved by The Committee on Biomedical Research Ethics for the Region of Southern Denmark (Ref. no. S-20080142) and The Danish Data Protection Agency (Ref. no. 2008-41-2826). All patients provided written informed consent. Conflicts of interest Egon Stenager has received support for congress participation from Novartis and BiogenIdec and unrestricted research grants from MerckSerono and BiogenIdec. The other authors report no disclosures. Author contributions N. Asgari: study concept and design, acquisition of data, analysis of data and interpretation of results, and writing of manuscript. K.O. Kyvik: interpretation of results, revision of the manuscript and approval of the final version. T. Steenstrup: statistical analysis of data, revision of the manuscript, and approval of the final revision. E. Stenager: interpretation of results, revision of the manuscript, and approval of the final version. S.T. Lillevang: concept of study, antibody determinations, interpretation of results, revision of the manuscript and approval of the final version. Acknowledgment The authors thank Professor Trevor Owens for valuable advice for the manuscript, consultant neuroradiologist Hanne Pernille Bro Skejoe for the evaluation of MRI and Carsten Bisgaard, MD, Head of Neurology Department at Vejle Hospital, Denmark for the support for antibody analysis. The Ole Jacobsen Commemoration Foundation and The Region of Southern Denmark Health Research Fund are thanked for economical support. References [1] Jacob A, Matiello M, Wingerchuk DM, Lucchinetti CF, Pittock SJ, Weinshenker BG. Neuromyelitis optica: changing concepts. J Neuroimmunol 2007;187:126–38. [2] Asgari N, Owens T, Frokiaer J, Stenager E, Lillevang ST, Kyvik KO. Neuromyelitis optica (NMO) — an autoimmune disease of the central nervous system (CNS). Acta Neurol Scand 2011;123:369–84. [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;202:473–7. [4] Weinshenker BG, Wingerchuk DM, Pittock SJ, Lucchinetti CF, Lennon VA. NMO-IgG: a specific biomarker for neuromyelitis optica. Dis Markers 2006;22:197–206. [5] Arnason BG. Immunologic therapy of multiple sclerosis. Annu Rev Med 1999;50: 291–302. [6] Benveniste EN, Qin H. Type I interferons as anti-inflammatory mediators. Sci STKE 2007;2007:pe70. [7] Kim SH, Kim W, Li XF, Jung IJ, Kim HJ. Does interferon beta treatment exacerbate neuromyelitis optica spectrum disorder? Multiple sclerosis, 18. Basingstoke, England: Houndmills; 2012 1480–3. [8] Palace J, Leite MI, Nairne A, Vincent A. Interferon beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers. Arch Neurol 2010; 67:1016–7. [9] Tanaka M, Tanaka K, Komori M. Interferon-beta(1b) treatment in neuromyelitis optica. Eur Neurol 2009;62:167–70.

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Antibodies against interferon-beta in neuromyelitis optica patients.

Neuromyelitis optica (NMO) is an antibody-mediated autoimmune inflammatory disease of the CNS. A poor response to treatment with recombinant interfero...
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