Neurol Sci (2014) 35:307–316 DOI 10.1007/s10072-013-1616-1
HEALTHCARE ORGANIZATION
Guidelines on the clinical use for the detection of neutralizing antibodies (NAbs) to IFN beta in multiple sclerosis therapy: report from the Italian Multiple Sclerosis Study group Antonio Bertolotto • Marco Capobianco • Maria Pia Amato • Elisabetta Capello • Ruggero Capra • Diego Centonze • Maria Di Ioia • Antonio Gallo • Luigi Grimaldi • Luisa Imberti • Alessandra Lugaresi Chiara Mancinelli • Maria Giovanna Marrosu • Lucia Moiola • Enrico Montanari • Silvia Romano • Luigina Musu • Damiano Paolicelli • Francesco Patti • Carlo Pozzilli • Silvia Rossi • Marco Salvetti • Gioachino Tedeschi • Maria Rosaria Tola • Maria Troiano • Mauro Zaffaroni • Simona Malucchi
•
Received: 13 November 2013 / Accepted: 17 December 2013 / Published online: 29 December 2013 Ó Springer-Verlag Italia 2013
Abstract Interferon beta (IFNb) was the first specific disease-modifying treatment licensed for relapsing-remitting multiple sclerosis, and is still one of the most commonly prescribed treatments. A strong body of evidence supports the effectiveness of IFNb preparations in reducing the annual relapse rate, magnetic resonance (MRI) disease activity and disease progression. However, the development of binding/neutralizing antibodies (BAbs/ NAbs) during treatment negatively affects clinical and MRI outcomes. Therefore, guidelines for the clinical use for the detection of NAbs in MS may result in better treatment of these patients. In October 2012, a panel of
Italian neurologists from 17 MS clinics convened in Milan to review and discuss data on NAbs and their clinical relevance in the treatment of MS. In this paper, we report the panel’s recommendations for the use of IFNb Nabs detection in the early identification of IFNb non-responsiveness and the management of patients on IFNb treatment in Italy, according to a model of therapeutically appropriate care.
A. Bertolotto M. Capobianco S. Malucchi (&) Neurologia 2-CRESM, AOU San Luigi, Orbassano, Italy e-mail: [email protected]
L. Grimaldi U.O. di Neurologia, Fondazione Istituto San Raffaele ‘‘G. Giglio’’ di Cefalu`, Cefalu`, Pa, Italy
M. P. Amato Section Neurosciences, Department NEUROFARBA, University of Florence, Florence, Italy
L. Imberti CREA, Spedali Civili di Brescia, Brescia, Italy
E. Capello Departmento of Neuroscience, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy R. Capra Centro Sclerosi Multipla, Spedali Civili, Brescia, Italy D. Centonze S. Rossi Centro Sclerosi Multipla, Universita` Tor Vergata, Rome, Italy M. Di Ioia A. Lugaresi Dipartimento di Neuroscienze E Imaging, Centro Sclerosi Multipla, Universita` ‘‘G. d’Annunzio’’ Chieti, Chieti, Italy
Keywords Multiple sclerosis IFNb Neutralizing antibodies Immunogenicity Guidelines
C. Mancinelli C. Pozzilli MultipleSclerosis Center S.Andrea Hospital Dept. Neurology and Psychiatry, Sapienza University, Rome, Italy M. G. Marrosu L. Musu Dipartimento Sanita` Pubblica Medicina Clinica e Molecolare, Centro Sclerosi Multipla, ASL 8, Universita` di Cagliari, Cagliari, Italy L. Moiola Neurological Department, San Raffaele Scientific Institute, Milan, Italy E. Montanari Divisione di Neurologia, Ospedale Civile di Fidenza, Parma, Italy
A. Gallo G. Tedeschi II Division of Neurology, Second University of Naples, Naples, Italy
123
308
Background Interferon beta (IFNb) treatment favorably alters the shortand medium-term course of relapsing-remitting multiple sclerosis (RRMS), as shown in many randomized controlled trials (RCTs). It is the most commonly prescribed first-line disease-modifying treatment (DMT) for relapsingremitting multiple sclerosis (RRMS); it reduces the annualized relapse rate (ARR) and the brain magnetic resonance imaging (MRI) activity, and decreases disease progression [1]; however, up to 45 % of patients may develop neutralizing antibodies (NAbs) during the treatment [2, 3]. NAbs appearance has been associated with decreased therapeutic efficacy of IFNb, as exemplified by an increased ARR, disease activity on brain MRI and disability progression [3–5]. The risk of decreased efficacy in NAb-positive patients should be taken into high consideration in the early identification of non-responder patients, because of the availability of other treatment options as well as of the need for cost containment in the managed care of MS [6].
Consensus Conference: methodology The Consensus Conference is a participatory methodology to evaluate a medical process and develop practice guidelines. The aim of the Consensus Conference held in Milan in October 2012 was to define guidelines on the search, detection and use of NAbs in clinical practice, based on clinical, paraclinical and laboratory data. The Consensus Panel included MS neurologists with NAb expertise from 17 Italian MS Centers. The Consensus Panel is part of the MS study group of the Italian Neurological Society.
S. Romano M. Salvetti Neurology and Department of Neurosciences, Mental Health and Sensory Organs, Centre for Experimental Neurological Therapies (CENTERS), Sapienza University, S. Andrea Hospital-site, Rome, Italy D. Paolicelli M. Troiano Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy F. Patti Department of Neurosciences, University of Catania, Catania, Italy M. R. Tola U.O. di Neurologia, Dipartimento Neuroscienze/Riabilitazione, AOU di Ferrara, Ferrara, Italy M. Zaffaroni Centro Studi Sclerosi Multipla, Ospedale di Gallarate, Gallarate, Italy
123
Neurol Sci (2014) 35:307–316
The main issues discussed during the Consensus Meeting were: 1. 2. 3. 4. 5. 6. 7.
Therapeutic appropriateness Non-responsiveness to IFNb therapy Costs of non-responsiveness Immunogenic potential of IFNb preparations Clinical relevance of NAbs Impact of NAbs on MRI activity Biological markers of IFNb biological activity.
Therapeutic appropriateness in MS The concept of ‘‘appropriateness of care’’ was first used in an editorial published in the British Medical Journal in 1994 [7]. The author argued that healthcare is often delivered inappropriately: many patients overuse, while others underuse the available healthcare resources. A diagnostic/therapeutic intervention can be defined ‘‘appropriate’’ when fulfilling, as much as possible, efficacy, safety and effectiveness criteria. Appropriate care means delivering care ‘‘to the right patient, in the right moment, in the right measure, without any overuse or underuse of healthcare’’ [8]. In RRMS patients treated with IFNb, therapeutic appropriateness is strictly linked to identification of non-responder patients.
Responsiveness to IFNb treatment Early identification of IFNb non-responders is a critical clinical issue. Definition of treatment response in MS patients is not consistent across the literature, being based on a combination of clinical (i.e. relapses and disability progression) and MRI criteria after the first year of therapy [9, 10]. The main reasons of poor responsiveness to IFNb therapy include: (1) lack of biological activity of the drug even if correctly administered; (2) inability of the drug even if biologically active to control the disease; and (3) poor adherence. Biological activity has been defined as ‘‘the whole of pharmacological, physiological and biochemical effects, resulting from the interaction of a drug with its target receptor; it is a necessary but not sufficient condition for effectiveness of a drug’’ [11]. The main reason for reduced or suppressed biological activity of IFNb is the development of NAbs [12]. A subset of nonresponder patients, named ‘‘immuno-pharmacological nonresponders’’, develops Nabs against IFNb [13]. A second subset of non-responders to IFNb has a pathogenetic origin: even if the drug is biologically active, its therapeutic effect may be too weak to keep a highly active disease under control [14]. Breakthrough disease, defined as any
Neurol Sci (2014) 35:307–316
309
MS is associated with a substantial economic burden, as the disease affects young individuals at the beginning of their social and professional lives [18]. According to the World Health Organization (WHO), MS is among the most expensive diseases: in Italy, the cost to an MS patient is 38.845€/year, with DMT costs representing only 12.2 % of the total cost of MS general costs and all costs raising linearly as the EDSS score increases [18]. The growing number of patients under treatment and Italian National Health Service budget constraints call for highly cost-effective therapeutic choices, as well as evaluation of total costs per relapse and costs of disability avoided with each treatment [19]. In this context, therapeutic appropriateness and the research of early markers become essential to guarantee the wellbeing of patients, and to allow the full sustainability of the disease. Assessment of IFNb NAb has a great economic impact because (1) there are more than 20,000 patients on IFNb therapy in Italy; (2) the annual cost of IFNb therapy is about 10.000€/ patient; and (3) 10–15 % of patients become immunopharmacological non-responders because they develop NAbs. Therefore, it can be estimated that every year 20–30 million € are misallocated because of unnecessary treatment of NAb-positive patients.
IFNb is associated with the development of both binding antibodies (BAbs) and NAbs. BAbs may be detected since the first month of therapy, but they do not necessarily inhibit IFNb biological activity; however, in the long term, a subset of BAbs may transform into NAbs [20]. Longitudinal studies on the development of NAbs suggest that they may develop 4–6 months after beginning the therapy and generally within the first 2 years [21]. These antibodies prevent IFNb from binding to its receptor, as reflected by a decreased IFNb biological activity, thus negatively affecting responsiveness [22, 23]. NAbs development is independent of sex, age, duration of the disease and progression of the disease at the beginning of IFNb treatment [24]. Immunogenicity of IFN is due to drugrelated, treatment-related or patient-related factors [25]. Primary protein structure, absence of glycosylation, posttranslational modifications and the presence of aggregates have been identified among the drug-related factors that affect immunogenicity the most. IFNb-1b preparations show a greater immunogenic potential than IFNb-1a preparations, due to the absence of glycosylation, amino-acid substitution and the consequent development of aggregates [26]: in fact, intramuscular (i.m.) IFNb-1a is characterized by the lowest amount of aggregated proteins among all IFNb [27]. NAbs present cross reaction among different IFNb formulations [26]; as a consequence, NAb-positive patients do not benefit from switching to other IFNb formulations. Regarding treatment-related factors, the subcutaneous (s.c.) route seems more immunogenic than the i.m. route. A high frequency of injections also seems to increase the probability to develop NAbs, whereas evidence regarding its dosage is unclear [3]. Among patient-related factors, the general immune status of the patient and the genetic profile are most likely determinants; in particular, it has been suggested that HLADRB1*0401 and HLA-DRB1*0408 are strongly associated with the development of antibodies [28]. Reported rates of NAbs positivity while on treatment with different IFNb formulations vary between studies and could be influenced by the method of detection [29]. Nevertheless, on average, we can assume an immunogenic potential of 2–6 % for IFNb-1a i.m., 12–28 % for IFNb-1a s.c., and 28–47 % for IFNb-1b s.c. [30] (Table 1, 2). The new IFNb-1a s.c. formulation without albumin is expected to be less immunogenic (14.8 %) [31] compared to the old one, but there are yet no data for direct comparison.
Immunogenicity of IFNb formulations
Clinical relevance of NAbs
Immunogenicity of biopharmaceuticals is a well-known phenomenon and is one of the main reasons for impaired efficacy. Like other recombinant protein therapeutics,
The impact of NAbs on IFNb therapeutic efficacy has been difficult to assess for several reasons: (1) most of the studies have been underpowered and/or of short
ongoing clinical or MRI activity [15] while on IFNb therapy and often regarded as a treatment failure, may be observed despite a NAb-negative status, due to a spontaneous variation of the underlying disease [16]. Poor treatment adherence may also negatively affect clinical response [17]. Therefore, correct and detailed patient information should be part of an appropriate therapeutic approach. MRI or clinical approaches alone may present some limitations in the responsiveness assessment. The limitations of a clinical-based assessment, which can be easily performed at every appointment, are the difficulty in defining the criteria of clinical response and the late recognition of a non-responder status. An MRI-based assessment is more sensitive compared to a clinical assessment, but it presents limitations as the timing of scanning, technical procedure and definition of MRI non-responders have to be defined.
Economic and psychosocial costs of non-responsiveness in relapsing-remitting MS
123
310
Neurol Sci (2014) 35:307–316
Table 1 Impact of NABs on clinical and MRI parameters in randomized clinical trials Study
Type of IFNb
Definition of positivity
% pts Nabs positive
Week or years
Nabs effect
Note
RR
EDSS
MRI activity
MRI BOD
The IFNB MS study Group [34]
Betaferon
2 consecutive NABs? titers
35
3 years
?*
- (ns)
–
? (ns)
Rudick et al. [39]
Avonex
At least one positive sample
17
2 years
? (ns)
? (ns)
?*
–
SPECTRIMS, Li et al. [54, 65]
Rebif 22 Rebif 44
At least one positive sample
21.6 (Re22)
3 years
? (ns)
- (ns)
? (ns)
? (ns)
Panitch et al. EVIDENCE (Panitch et al. [55])
Avonex Rebif 44
Any positive antibody value
25 (Re44)
48 weeks
ns
–
?***
–
Durelli et al. (INCOMIN) [56]
Avonex Betaferon
Any positive antibody value
7 (Av)
2 years
? (ns)
–
–
–
Polman et al. European Study on IFNb 1b SPMS [57]
Betaferon
Once positive always positive; all switches considered
27.8
3 years
?**
? (ns)
–
?**
The North American Study Group on IFNb 1b in SPMS [58]
Betaferon 250mcg and 160 mcg
Once positive always positive; all switches considered
23 (250 mcg)
3 years
ns
ns
ns
ns
Primary outcome = confirmed EDSS progression: no difference in IFNb vs placebo groups.
PRISMS (Francis et al. [35])
Rebif 22 Rebif 44
Anytime positive or interval positive
24 (Re22)
4 years
?***
?*
?***
?***
NAbs impact during 3–4 years
Kappos et al. [36]
Avonex 30mcg and 60mcg
2 consecutive NABs? titer
1.8 (30 mcg), 4.8 (60 mcg)
4 years
?**
?*
?*
?*
BENEFIT study, Hartung et al. [59]
Betaferon
At least one positive value 2 consecutive positive values
31.8,
5 years
ns
ns
?***
?***
14.7 (Re44)
Primary outcome, time to confirmed EDSS progression not significantly affected by IFNB treatment
2 (Av)
30 (Be)
32 (160 mcg)
14 (Re44)
26.7
NAb? associated with higher risk of McDonald MS P \ 0.001
AV, Avonex; Be, Betaferon; Re22, Rebif 22; Re44, Rebif 44; BOD, burden of disease; ?, outcome worse in NAbs-positive group than in NAbnegative group; -, outcome worse in NAbs-negative group than in NAb-positive group; ns, not significant; –, not done * P \ 0.05; ** P \ 0.01; *** P \ 0.001
duration (i.e. \2 years), therefore not taking into account the late appearance of NABs and the time they need to exert a negative impact on clinical parameters; (2) studies have used different laboratory tests for NAbs detection and quantification; (3) the timing of sampling was different, thus making results less comparable; (4) a crucial issue has also been the differences in study designs and statistical approaches used for investigating the impact of NAbs on clinical and/or MRI outcomes
123
[32], which should consider that many of the NAbpositive patients revert to a NAb-negative status over time [33]. The cut-off points for low, medium and high titer are different among the studies and set-up arbitrarily; in the present Consensus, the cut-off for high-titer NAb is [100 TRU because 96 % of the samples with [100 TRU showed the absence of biological activity [12].
Any IFNb
Any IFNb
Betaferon
Avonex Betaferon
Any IFNb
Boz et al. [63]
Malucchi et al. [49]
Durelli et al. [64]
Sato et al. [66]
Paolicelli et al. [5]
2 consecutive positive samples
1 positive sample
1 positive sample at 6 months
Positive sample at 12 months of therapy
1 positive sample
1 positive sample at 1 year of treatment
1 positive sample
14 %
35.5 %
34 %
12.4 %
13 %
25.4 %
24 %
37 %
17 %
From 9 to 46 %
% pts Nabs positive
5 years
4 years
2 years
?**
?***
?**
?**
?*
[3 years 3 years
–
?***
–
?***
?**
RR
? (ns)
–
? (ns)
–
ns
?**
?**
–
?*
? (ns)
EDSS
NAbs effect
6 years
4 years
2.5 years
3 years
5y
Week or years
–
?**
–
–
–
–
–
?**
–
–
MRI activity
–
–
–
–
–
–
–
?**
–
? (ns)
MRI BOD
Negative trend on time to EDSS 4 (IRR = 2.94; P = 0.0879)
NAbs? predicts risk of relapse or EDSS progression
MxA and NAbs predict time to first relapse
NAbs impact during 3–4 years
NAbs? predicts EDSS progression (5 years follow-up)
NAbs impact only at high titer
Significantly reduced time to first relapse
Note
* P \ 0.05; ** P \ 0.01; *** P \ 0.001
AV, Avonex; Re22, Rebif 22; Re44, Rebif 44; BOD, burden of disease; ?, outcome worse in NAbs-positive group than in NAb-negative group; -, outcome worse in NAbs-negative group than in NAb-positive group; ns, not significant; – not done
Rebif 11 or 33mcg x 3–w
Tomassini et al. [62]
2 consecutive NAB? samples
Betaferon
Any IFNb
Frank et al. [60]
Perini et al. [61]
2 consecutive NAB? samples
Any IFNb
Malucchi et al. [22]
Positive sample at 12 months of therapy
Any IFNb
Sorensen et al. [24]
Definition of positivity
Type of IFNb
Study
Table 2 Impact of NABs on clinical and MRI parameters in observational studies
Neurol Sci (2014) 35:307–316 311
123
312
Neurol Sci (2014) 35:307–316
Fig. 1 Flow chart of NAbs quantification
Data coming from clinical trials of C3 years’ duration, non-randomized prospective and real-world propensity score studies indicate that NAbs reduced or abolished the therapeutic efficacy of IFNb on relapse, independently of the type of IFNb used (Tables 1, 2). In the pivotal trial on IFNb 1-b, 35 % of treated patients developed NAbs and in the NAbs-positive group, the relapse rate during years 2 and 3 was significantly higher than in the NAbs-negative group and comparable with the placebo arm [34]. In the IFNb1-a s.c. PRISMS-4 study, NAbs-positive patients had a significantly higher RR than NAbs-negative patients RR during years 3 and 4 [35]. The two-dosage IFNb 1-a i.m. study showed that NAbs-positive patients had higher RR from months 12 to 48 and higher rate of worsening in EDSS from baseline to month 48 than NAbs-negative patients [36]. Data of phase III clinical trials are in line with prospective non-randomized studies (Tables 1, 2), such as the large Danish MS study, that enrolled more than 500 patients treated with all IFNb preparations. In this study, NAb-positive patients showed significantly higher RR, shorter time to first relapse and higher EDSS score at 42 and 48 months than NAbs-negative patients [24]. The impact of NAbs on clinical outcomes has also been recently evaluated in a large cohort of Italian RRMS patients. In this 5-year observational study, a significant increase in relapse rate (IRR = 1.39; P = 0.0076) and a shorter time to first relapse (IRR = 1.71; P = 0.0038) were found during the NAb-positivity period. Propensity score analysis in a selected cohort of patients revealed a negative impact of NAbs on disability progression (milestone EDSS = 4) as well [5].
123
Impact of NAbs on MRI activity A number of reports and meta-analysis of clinical trials demonstrated that patients developing new MRI lesions while on DMT or placebo show higher risk of relapses and poor clinical outcomes over time [9, 10, 37]. The DMT impact on MRI measures is more pronounced and precocious than clinical measures; therefore, MRI measures can help evaluate the negative impact of NAbs on MS course earlier and more consistently than clinical signs and symptoms. All the Randomized Clinical Trials in relapsing-remitting MS, with each of the 3 IFNb products, have clearly demonstrated the negative effects of NAbs on MRI measures of disease activity (Table 1). Compared with patients who remained NAb negative, NAbs-positive patients showed a higher number of T1 gadolinium-enhanced lesions and/or greater accrual of new or enlarging T2 lesions.
Biological markers of IFNb biological activity: Myxovirus resistant protein A (MxA) monitoring strategy Even though NAbs may appear after 3 months of treatment, the lack of MRI efficacy may not be evident before 12–18 months, while the clinical detrimental effect may require up to 3–4 years to reach statistical significance (Table 1) [3, 36, 38]. Monitoring markers of biological activity may provide instead an early, objective and reliable indication of biological response to IFNb that,
Neurol Sci (2014) 35:307–316
following the binding of IFNb with its receptor (IFNAR) on cell surface, activated the biochemical intracellular pathway. A large number of proteins have been proposed as IFNb biomarkers: b-2-microglobulin and neopterin [39], MxA protein [40] and MxA mRNA [41], oligoadenylate synthetase [42], TRAIL [43, 44], viperin [45], IFI27, CCL2 and CXCL10 [46]. Among the biomarkers reflecting in vivo response to IFNb, MxA is the best validated and increasingly used one in clinical practice [4, 12, 47, 48]. The level of MxA mRNA after 1 year of IFNb treatment is a stronger predictor of relapses than NAbs [49], and low levels of MxA mRNA before IFNb treatment are reported to be associated with occurrence of relapses and contrastenhancing lesions on MRI, whereas a high MxA mRNA seems to be associated with a longer time to a new relapse and reduction of CELs [50]. MxA mRNA has demonstrated important advantages such as specificity, as it is induced only by IFNb type 1 and some viruses and not by IFNc, sensitivity, as it can be quantified in every patient, and reliability. Moreover, its short half-life avoids accumulation and every single IFNb injection can be assessed [42]. Many studies have demonstrated that administration of IFNb leads to a large increase in the amount of MxA mRNA, whereas the presence of NAbs is associated with a decrease or abolition of MxA mRNA and protein increase [40, 51]. There is no consensus regarding the exact definition of biologically relevant MxA gene expression, and some patients show MxA mRNA expression in the presence of NAbs [52]; however, an inverse correlation between titers of NAbs and MxA level have been demonstrated [12]. Choice of relevance thresholds can be different across studies and this may influence sensitivity or specificity of the method. Higher specificity could be more adequate for the identification of non-responder patients after 1-year treatment; the ?3SD or 99th percentile cut-offs are suggested to increase the efficiency of screening and prevent unnecessary treatment switches in patients still presenting some bioactivity of the drug [12, 52].
313
3.
4.
5. 6.
7. 8.
9. 10.
11.
12.
patients do not benefit from switching to other IFNb formulations. According to EFNS Task Force’s guidelines [3], the Consensus Panel recommends testing the patients treated with IFNb for the presence of NAbs after 12 and 24 months of treatment. If positive, the patient should be retested for confirmation after 3 months (Fig. 1). Measurement of NAbs can be discontinued in patients remaining NAbs negative during the first 2 years of treatment, but it should be resumed if disease activity increases. Persistently high NAb titers ([100 TRU) reduce or abolish biological activity of IFN b. Persistently high NAb titers have a significant negative impact on MRI parameters of disease activity. Persistently high NAbs titers have a significant negative impact on the RR. A negative effect of NAbs on disability progression has been suggested; however, further studies are needed to confirm this observation. NAbs testing has a prognostic value on IFNb therapeutic efficacy. In patients with a clinically active disease and with persistently high NAb titer (C100 TRU), IFNb should be discontinued. In patients doing clinically well and with a persistently high NAb titer, switching therapy should be considered, as high NAb titers can represent an early predictor of poor MRI and clinical response. Absence of biological activity can support switching. MxA mRNA measurement provides important information about IFNb biological activity. However, since MxA quantification is not a widely performed test in clinical laboratory, at present it is principally used in clinically challenging cases requiring deeper characterization.
Conclusions Consensus reached by the Consensus Panel There was consensus among members of the Panel regarding the following key points: 1.
2.
There are differences among IFNb formulations with the IFNb 1a i.m. being less immunogenic and IFNb 1b more immunogenic. NAbs present cross reaction among different IFNb formulations. As a consequence, NAb-positive
The current economic scenario requires the optimization of resources, especially in the management of chronic diseases like MS, affecting young persons who have to face long years of disease. The guidelines proposed by the panel for the management of NAbs in IFNb-treated patients will probably make the clinical management of NAbs more homogeneous as well as improve the appropriateness of therapy and cost effectiveness of DMTs (Fig. 1).
123
314
Quantification of immunogenicity of IFNb is an extremely relevant issue, particularly within the context of improving the appropriateness of MS management. The approach should be individually tailored to the patient, encouraging the discontinuation of ineffective treatments, while offering other potentially valid therapeutic alternative. Maintaining IFNb therapy in patients with high-titer NAbs or lacking MxA mRNA induction can constitute a clinical risk to the patient, who is virtually untreated, as well as an economic burden for society through unnecessary waste of resources [53]. Early identification of non-responders should be a multidisciplinary process, based on the evaluation of the clinical course of the disease, MRI activity, presence of NAb and, when available, the assessment of IFNb biological activity through MxA quantification. The present Consensus is part of the commitment of the Italian neurological community to continuous improvement of management of neurological patients, combining the best treatment option with optimization of financial resources. Acknowledgments This Consensus Paper, aimed at providing Italian neurologists with National Recommendations for anti-IFNb NAb testing, is the result of a Consensus Meeting held in Milan on October 24, 2012. The Italian Society of Neurology (Societa` Italiana di Neurologia, SIN) was the official sponsor of the meeting. Biogen Idec Italia provided unrestricted support to the logistics of the meeting with no influence on the content of the manuscript.
References 1. Trojano M, Pellegrini F, Fuiani A, Paolicelli D, Zipoli V, Zimatore GB, Di Monte E, Portaccio E, Lepore V, Livrea P, Amato MP (2007) New natural history of interferon-beta-treated relapsing multiple sclerosis. Ann Neurol 61:300–306 2. Bertolotto A, Malucchi S, Sala A, Orefice G, Carrieri PB, Capobianco M, Milano E, Melis F, Giordana MT (2002) Differential effects of three interferon betas on neutralising antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory. J Neurol Neurosurg Psychiatry 73:148–153 3. Sorensen PS, Deisenhammer F, Duda P, Hohlfeld R, Myhr KM, Palace J, Polman C, Pozzilli C, Ross C (2005) Guidelines on use of anti-IFN beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 12:817–827 4. Polman CH, Bertolotto A, Deasenhammer F, Giovannoni G, Hartung HP, Hemmer B, Killestein J, McFarland HF, Oger J, Pachner AR, Petkau J, Reder AT, Reingold SC, Schellekeng H, Sorensen PS (2010) Recommendations for clinical use of data on neutralizing antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol 9(7):740–750 5. Paolicelli D, D’Onghia M, Pellegrini F, Direnzo V, Iaffaldano P, Lavolpe V, Trojano M (2013) The impact of neutralizing antibodies on the risk of disease worsening in interferon b-treated relapsing multiple sclerosis: a 5 year post-marketing study. J Neurol 260(6):1562–1568
123
Neurol Sci (2014) 35:307–316 6. Noyes K, Bajorska A, Chapel A, Schwid SR, Mehta LR, Weinstock-Guttman B, Holloway RG, Dick AW (2011) Cost-effectiveness of disease modifying therapy for multiple sclerosis. A population-based study. Neurology 77:355–363 7. Brook RH (1994) Appropriateness of care: the new frontier. BMJ 308:218–219 8. Fuchs VR (2011) The doctor’s dilemma—what is ‘‘appropriate’’ care ? NEJM 365(7):585–587 9. Rio J, Comabella M, Montalban X (2009) Predicting responders to therapies for multiple sclerosis. Nat Rev Neurol 5(10):533–560 10. Sormani MP, De Stefano N (2013) Defining and scoring response to IFN b in multiple sclerosis. Nat Rev Neurol 9:504–512 11. Hardman JG, Limbird LE, Gilman AG (1996) The pharmacological basis of therapeutics. McGraw-Hill, New York 12. Malucchi S, Gilli F, Caldano M, Sala A, Capobianco M, di Sapio A, Granieri L, Bertolotto A (2011) One-year evaluation of factors affecting the biological activity of interferon beta in multiple sclerosis patients. J Neurol 258:895–903 13. Bertolotto A, Gilli F (2008) Interferon-beta responders and nonresponders. A biological approach. Neurol Sci 29:S216–S217 14. Sbardella E, Tomassini V, Gasperini C, Bellomi F, Cefano LA, Morra VB, Antonelli G, Pozzilli C (2009) Neutralizing antibodies explain the poor clinical response to interferon beta in a small proportion of patients with Multiple Sclerosis: retrospective study. BMC Neurol 9:54 15. Rudick RA, Polman CH (2009) Current approaches to the identification and management of breakthrough disease in patients with multiple sclerosis. Lancet Neurol 8(6):545–559 16. Hesse D, Krakauer M, Lund H, Sondegaard HB, Langkilde A, Ryder LP, Sorensen PS, Sellebjerg F (2010) Breakthrough disease during interferon-beta therapy in MS: no signs of impaired biologic response. Neurol 4;74(18):1455–1462 17. Steinberg SC, Faris RJ, Chang CF, Cham A, Tankersley MA (2010) Impact of adherence to interferons in the treatment of multiple sclerosis: a non-experimental, retrospective, cohort study. Clin Drug Investig 30(2):89–100 18. Kobelt G, Berg J, Lindgren P, Battaglia M, Lucioni C, Uccelli A (2006) Costs and quality of life of multiple sclerosis in Italy. Eur J Health Econ 7(Suppl 2):S45–S54 19. Goldberg LD, Edwards NC, Fincher C, Doan QV, Al-Sabbagh A, Meletiche DM (2009) Comparing the cost-effectiveness of disease-modifying drugs for the first-line treatment of relapsingremitting multiple sclerosis. J Manag Care Pharm 15(7):543–555 20. Hegen H, Millonig A, Bertolotto A, Comabella M, Giovanonni G, Guger M, Hoelzl M, Khalil M, Killestein J, Lindberg R, Malucchi S, Mehling M, Montalban X, Polman C, Rudzki D, Schautzer F, Sellebjerg F, Sørensen P, Deisenhammer F (2013) Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development. Mult Scler [Epub ahead of print] 21. Sorensen PS, Koch-Henriksen N, Ross C, Clemmesen KM, Bendtsen K (2005) Appearance and disappearance of neutralizing antibodies during interferon-beta therapy. Neurology 65(1):33–39 22. Malucchi S, Sala A, Gilli F, Bottero R, Di Sapio A, Capobianco M, Bertolotto A (2004) Neutralizing antibodies reduce the efficacy of beta IFN during treatment of multiple sclerosis. Neurology 62:2031–2037 23. Creeke PI, Farrell RA (2013) Clinical testing for neutralizing antibodies to interferon-b in multiple sclerosis. Ther Adv Neurol Disord 6(1):3–17 24. Sorensen PS, Ross C, Clemmensen KM, Bendtzen K, Frederiksen JL, Jensen K, Kristensen O, Petersen T, Rasmussen S, Ravnoborg M, Stenager E, Koch-Henriksen N, the Danish Multiple Sclerosis Study Group (2003) Clinical importance of neutralizing antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis. Lancet 362:1184–1191
Neurol Sci (2014) 35:307–316 25. Farrell RA, Marta M, Gaeguta AJ, Souslova V, Giovannoni G, Creeke PI (2012) Understanding drug resistance to biologic therapy. Development of resistance to biologic therapies with reference to IFN-b. Rheumatology 51(4):590–599 26. Bertolotto A, Malucchi S, Milano E, Castello A, Capobianco M, Mutani R (2000) Interferon beta neutralizing antibodies in multiple sclerosis: neutralizing activity and cross-reactivity with three different preparations. Immunopharmacology 48:95–100 27. Barnard JG, Babcock K, Carpenter JF (2012) Characterization and quantitation of aggregates and particles in interferon-b products: Potential links between product quality attributes and immunogenicity. J Pharm Sci Dec 11. doi:10.1002/jps.23415. [Epub ahead of print] 28. Hoffmann S, Cepok S, Grummel V, Lehmann-Horn K, Hackermu¨ller J, Stadler PF, Hartung HP, Berthele A, Deisenhammer F, Wassmuth R, Hemmer B (2008) HLA-DRB1*0401 and HLADRB1*0408 are strongly associated with the development of antibodies against interferon-beta therapy in multiple sclerosis. Am J Hum Genet 83(2):219–227 29. Deisenhammer F, Schellekens H, Bertolotto A (2004) Measurement of neutralizing antibodies to interferon beta in patients with multiple sclerosis. J Neurol 251(Suppl 2):II31–II39 30. Bertolotto A, Deisenhammer F, Gallo P, Soelberg Sorensen P (2004) Immunogenicity of interferon beta. Differences among products. J Neurol 251(suppl 2):II15–II24 31. Comi G, De Stefano N, Freedman MS, Barkhof F, Polman CH, Kitdehaag BM, Casset-Semanaz F, Hennessy B, Moraga MS, Rocak S, Stubinski B, Kappos L (2012) Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomized controlled trial. Lancet Neurol 11(1):33–41 32. Cutter G (2003) Statistical issues in neutralizing antibodies. Neurology 61(Suppl 5):S38–S39 33. Hesse D, Sørensen PS (2007) Using measurements of neutralizing antibodies: the challenge of IFN-beta therapy. Eur J Neurol 14(8):850–859 34. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group (1996) Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first 3 years. Neurology 47:889–894 35. The PRISMS (Prevention of Relapses and Disability by Interferon-b-1a Subcutaneously in Multiple Sclerosis) Study Group and the University of British Columbia MS/MRI Analysis Group (2001) PRISMS-4: long-term efficacy of interferon-b-1a in relapsing MS. Neurology 56:1628–1636 36. Kappos L, Clanet M, Sandberg W, Radue EW, Hartung HP, Hohlfeld R, Xu J, bennett D, Sandrock A, Goelz S and European Interferon beta-1a IM Dose-Comparison Study Investigators (2005) Neutralizing antibodies and efficacy of interferon b-1a: a 4 year controlled study. Neurology 65:40–47 37. Sormani MP, Bruzzi P (2013) MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials. Lancet Neurol 12(7):669–676 38. Francis GS, Rice GP, Alsop JC, PRISMS Study Group (2005) Interferon beta-1a in MS: results following development of neutralizing antibodies in PRISMS. Neurology 65:48–55 39. Rudick RA, Simonian NA, Alam JA, Campion M, Scaramucci JO, Jones W, Coats ME, Goodkin DE, Weinstock-Guttman B, Herndon RM, Mass MK, Richert JR, Salazar AM, Munschauer FF 3rd, Cookfair DL, Simon JH, Jacobs LD (1998) Incidence and significance of neutalizing antibodies to interferon beta 1a in multiple sclerosis. Neurology 50:1266–1272
315 40. Deisenhammer F, Reindel M, Harvey J, Gasse T, Dilitz E, Berger T (1999) Bioavailability of interferon beta 1b in MS patients with and without neutralizing antibodies. Neurology 52:1239–1243 41. Bertolotto A, Gilli F, Sala A, Audano L, Castello A, Magliola U, Melis F, Giordana MT (2001) Evaluation of bioavalability of three types of IFN beta in multiple sclerosis patients by a new quantitative-competitive-PCR method for MxA quantification. J Immunol Methods 256:141–152 42. Pachner A, Narayan K, Price N, Hurd M, Dail D (2003) MxA gene expression analysis as an interferon-beta bioactivity measurement in patients with multiple sclerosis and the identification of antibody-mediated decreased bioactivity. Mol Diagn 7:17–25 43. Wandinger KP, Lu¨nemann JD, Wengert O, Bellmann-Strobl J, Aktas O, Weber A, Grundstrom E, Ehrlich S, Wernecke KD, Volk HD, Zipp F (2003) TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis. Lancet 361:2036–2043 44. Gilli F, Marnetto F, Caldano M, Sala A, Malucchi S, Capobianco M, Bertolotto A (2006) Biological markers of IFNb therapy: comparison among interferon-stimulated-genes MxA, TRAIL, and XAF-1. Mult Scler 12:1–11 45. Pachner AR, Warth JD, Pace A, Goelz S, INSIGHT investigators (2009) Effect of neutralizing antibodies on biomarker responses to interferon beta. The INSIGHT study. Neurology 73:1493–1500 46. Sellebjerg F, Krakauer M, Hesse D, Ryder LP, Alsing I, Jensen PE, Koch-Henriksen N, Svejgaard A, Soelberg Sørensen P (2009) Identification of new sensitive biomarkers for the in vivo response to interferon-beta treatment in multiple sclerosis using DNA-array evaluation. Eur J Neurol 16(12):1291–1298 47. Hesse D, Sellbjerg F, Sorensen PS (2009) Absence of MxA induction by interferon b in patients with MS reflects complete loss of bioactivity. Neurology 73:372–377 48. Zanotti C, Ghidini C, Lamorgese C, Caimi L, Capra R, Imberti L (2010) Transfer of myxovirus-protein-A mRNA assay for interferon-b bioactivity measurement in multiple sclerosis patients to routine laboratory practice. A 4-year experience. Clin Chem Lab Med 48(9):1235–1238 49. Malucchi S, Gilli F, Caldano M, Marnetto F, Valentino P, Granieri L, Sala A, Capobianco M, Bertolotto A (2008) Predictive markers for response to interferon therapy in patients with multiple sclerosis. Neurology 70(13 Pt 2):119–127 50. Van der Voort, LF, Vennegoor A, Visser A, Knol DL, Kitdehaag BM, Barkhof F, Oudejans CB, Polman CH, Killestein J (2010) Spontaneous MxA mRNA level predicts relapses in patients with recently diagnosed MS. Neurol 5,75(14):1228–1233 51. Bertolotto A, Gilli F, Sala A, Capobianco M, Malucchi S, Milano E, Melis F, Marnetto F, Linberg RL, Bottero R, Di Sapio A, Giordana MT (2003) Persistent neutralizing antibodies abolish the interferon b bioavailability in MS patients. Neurology 60:634–639 52. Capra R, Sottini A, Cordioli C, Serana F, Chiarini M, Caimi L, Padovani A, Bergamaschi R, Imberti L (2007) IFNbeta bioavailability in multiple sclerosis patients: MxA versus antibodydetecting assays. J Neuroimmunol 189(1–2):102–110 53. Fitzgerald S (2009) Antibodies block effect of interferon on MS. Neurology Today 9(15):14 54. Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group (2001) Randomized controlled trial of interferon-beta-1a in secondary progressive MS: Clinical results. Neurology 56:1496–1504 55. Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O’Connor P, Monaghan E, Li D, Weinshenker B for the EVIDENCE (Evidence of Interferon Dose-Response: European North American Comparative Efficacy) Study Group and the University of
123
316
56.
57.
58.
59.
60.
Neurol Sci (2014) 35:307–316 British Columbia MS/MRI Research Group (2002) Randomized, comparative study of interferonb-1a treatment regimens in MS. The EVIDENCE Trial. Neurol 59:1496–1506 Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Chezzi A, Montanari E, Zaffaroni M, the Independent COMparison of Interferon (INCOMIN) Trial Study Group (2002) Every-otherday interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 359:1453–1460 Polman C, Kappos L, White R, Dahlke F, beckmann K, Pozzilli C, Thompson A, Petkau J, Miller D (2003) Neutralizing antibodies during treatment of secondary progressive MS with interferon beta-1b. Neurology 60:37–43 The North American Study Group on Interferon beta-1b in Secondary Progressive MS (2004) Interferon beta-1b in secondary progressive MS. Results from a 3-year controlled study. Neurology 3:1788–1795 Hartung H-P, Freedman MS, Polman CH, Edan G, Kappos L, Miller DH, Montalban X, Barkhof F, Petkau J, White R, Sahajpal V, Knappertz V, Beckmann K, Lanius V, Sandbrink R, Pohl C, For the BENEFIT Study Group (2011) Interferon b-1b—neutralizing antibodies 5 years after clinically isolated syndrome. Neurology 77:835–843 Frank JA, Richert N, Bash C, Stone L, Calabresi PA, Lewis B, Stone R, Howard T, McFarland HF (2004) InterferonB-1b slows progression of atrophy in RRMS. Three-year follow-up in NAb and Nab patients. Neurology 62:719–725
123
61. Perini P, Calabrese M, Biasi G, Gallo P (2004) The clinical impact of interferon beta antibodies in relapsing-remitting MS. J Neurol 251:305–309 62. Tomassini V, Paolillo A, Russo P, Giugni E, Prosperini L, Gasperini C, Antonelli G, Bastianello S, Pozzilli C (2006) Predictors of long-term clinical response to interferon beta therapy in relapsing multiple sclerosis. J Neurol 253:287–293 63. Boz C, Oger J, Gibbs E, Grossberg SE (2007) Reduced effectiveness of long-term interferon-treatment on relapses in neutralizing antibody-positive multiple sclerosis patients: a Canadian multiple sclerosis clinic-based study. Mult Scler 13:1127–1137 64. Durelli L, Barbero P, Berqui M, Versino E, Bassano MA, Verdun E, Rivoiro C, Ferrero C, Picco E, Ripellino P, Giuliani G, Montanari E, Clerico M (2008) MRI activity and neutralising antibody as predictors of response to interferon b treatment in multiple sclerosis. J Neurol Neurosurg Psychiatry 79:646–651 65. Li DK, Zhao GJ, Paty DW, University of British Columbia MS/ MRI Analysis Research Group, The SPRECTRIMS Study Group (2001) Randomized controlled trial of interferon-beta 1a in secondary progressive MS: MRI results. Neurology 56(11): 1505–1513 66. Sato DK, Nakashima I, Fukazawa T, Shimizu Y, Tomizawa Y, Yokoyama K, Misu T, Creeke PI, Farrell R, Giovannoni G, Itoyama Y, Fujihara K, Aoki M (2012) Neutralizing antibodies are associated with a reduction of Interferon-b efficacy during the treatment of Japanese Multiple sclerosis patients. Tohoky J Exp Med 228:85–92
HEALTHCARE ORGANIZATION
Guidelines on the clinical use for the detection of neutralizing antibodies (NAbs) to IFN beta in multiple sclerosis therapy: report from the Italian Multiple Sclerosis Study group Antonio Bertolotto • Marco Capobianco • Maria Pia Amato • Elisabetta Capello • Ruggero Capra • Diego Centonze • Maria Di Ioia • Antonio Gallo • Luigi Grimaldi • Luisa Imberti • Alessandra Lugaresi Chiara Mancinelli • Maria Giovanna Marrosu • Lucia Moiola • Enrico Montanari • Silvia Romano • Luigina Musu • Damiano Paolicelli • Francesco Patti • Carlo Pozzilli • Silvia Rossi • Marco Salvetti • Gioachino Tedeschi • Maria Rosaria Tola • Maria Troiano • Mauro Zaffaroni • Simona Malucchi
•
Received: 13 November 2013 / Accepted: 17 December 2013 / Published online: 29 December 2013 Ó Springer-Verlag Italia 2013
Abstract Interferon beta (IFNb) was the first specific disease-modifying treatment licensed for relapsing-remitting multiple sclerosis, and is still one of the most commonly prescribed treatments. A strong body of evidence supports the effectiveness of IFNb preparations in reducing the annual relapse rate, magnetic resonance (MRI) disease activity and disease progression. However, the development of binding/neutralizing antibodies (BAbs/ NAbs) during treatment negatively affects clinical and MRI outcomes. Therefore, guidelines for the clinical use for the detection of NAbs in MS may result in better treatment of these patients. In October 2012, a panel of
Italian neurologists from 17 MS clinics convened in Milan to review and discuss data on NAbs and their clinical relevance in the treatment of MS. In this paper, we report the panel’s recommendations for the use of IFNb Nabs detection in the early identification of IFNb non-responsiveness and the management of patients on IFNb treatment in Italy, according to a model of therapeutically appropriate care.
A. Bertolotto M. Capobianco S. Malucchi (&) Neurologia 2-CRESM, AOU San Luigi, Orbassano, Italy e-mail: [email protected]
L. Grimaldi U.O. di Neurologia, Fondazione Istituto San Raffaele ‘‘G. Giglio’’ di Cefalu`, Cefalu`, Pa, Italy
M. P. Amato Section Neurosciences, Department NEUROFARBA, University of Florence, Florence, Italy
L. Imberti CREA, Spedali Civili di Brescia, Brescia, Italy
E. Capello Departmento of Neuroscience, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy R. Capra Centro Sclerosi Multipla, Spedali Civili, Brescia, Italy D. Centonze S. Rossi Centro Sclerosi Multipla, Universita` Tor Vergata, Rome, Italy M. Di Ioia A. Lugaresi Dipartimento di Neuroscienze E Imaging, Centro Sclerosi Multipla, Universita` ‘‘G. d’Annunzio’’ Chieti, Chieti, Italy
Keywords Multiple sclerosis IFNb Neutralizing antibodies Immunogenicity Guidelines
C. Mancinelli C. Pozzilli MultipleSclerosis Center S.Andrea Hospital Dept. Neurology and Psychiatry, Sapienza University, Rome, Italy M. G. Marrosu L. Musu Dipartimento Sanita` Pubblica Medicina Clinica e Molecolare, Centro Sclerosi Multipla, ASL 8, Universita` di Cagliari, Cagliari, Italy L. Moiola Neurological Department, San Raffaele Scientific Institute, Milan, Italy E. Montanari Divisione di Neurologia, Ospedale Civile di Fidenza, Parma, Italy
A. Gallo G. Tedeschi II Division of Neurology, Second University of Naples, Naples, Italy
123
308
Background Interferon beta (IFNb) treatment favorably alters the shortand medium-term course of relapsing-remitting multiple sclerosis (RRMS), as shown in many randomized controlled trials (RCTs). It is the most commonly prescribed first-line disease-modifying treatment (DMT) for relapsingremitting multiple sclerosis (RRMS); it reduces the annualized relapse rate (ARR) and the brain magnetic resonance imaging (MRI) activity, and decreases disease progression [1]; however, up to 45 % of patients may develop neutralizing antibodies (NAbs) during the treatment [2, 3]. NAbs appearance has been associated with decreased therapeutic efficacy of IFNb, as exemplified by an increased ARR, disease activity on brain MRI and disability progression [3–5]. The risk of decreased efficacy in NAb-positive patients should be taken into high consideration in the early identification of non-responder patients, because of the availability of other treatment options as well as of the need for cost containment in the managed care of MS [6].
Consensus Conference: methodology The Consensus Conference is a participatory methodology to evaluate a medical process and develop practice guidelines. The aim of the Consensus Conference held in Milan in October 2012 was to define guidelines on the search, detection and use of NAbs in clinical practice, based on clinical, paraclinical and laboratory data. The Consensus Panel included MS neurologists with NAb expertise from 17 Italian MS Centers. The Consensus Panel is part of the MS study group of the Italian Neurological Society.
S. Romano M. Salvetti Neurology and Department of Neurosciences, Mental Health and Sensory Organs, Centre for Experimental Neurological Therapies (CENTERS), Sapienza University, S. Andrea Hospital-site, Rome, Italy D. Paolicelli M. Troiano Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, Bari, Italy F. Patti Department of Neurosciences, University of Catania, Catania, Italy M. R. Tola U.O. di Neurologia, Dipartimento Neuroscienze/Riabilitazione, AOU di Ferrara, Ferrara, Italy M. Zaffaroni Centro Studi Sclerosi Multipla, Ospedale di Gallarate, Gallarate, Italy
123
Neurol Sci (2014) 35:307–316
The main issues discussed during the Consensus Meeting were: 1. 2. 3. 4. 5. 6. 7.
Therapeutic appropriateness Non-responsiveness to IFNb therapy Costs of non-responsiveness Immunogenic potential of IFNb preparations Clinical relevance of NAbs Impact of NAbs on MRI activity Biological markers of IFNb biological activity.
Therapeutic appropriateness in MS The concept of ‘‘appropriateness of care’’ was first used in an editorial published in the British Medical Journal in 1994 [7]. The author argued that healthcare is often delivered inappropriately: many patients overuse, while others underuse the available healthcare resources. A diagnostic/therapeutic intervention can be defined ‘‘appropriate’’ when fulfilling, as much as possible, efficacy, safety and effectiveness criteria. Appropriate care means delivering care ‘‘to the right patient, in the right moment, in the right measure, without any overuse or underuse of healthcare’’ [8]. In RRMS patients treated with IFNb, therapeutic appropriateness is strictly linked to identification of non-responder patients.
Responsiveness to IFNb treatment Early identification of IFNb non-responders is a critical clinical issue. Definition of treatment response in MS patients is not consistent across the literature, being based on a combination of clinical (i.e. relapses and disability progression) and MRI criteria after the first year of therapy [9, 10]. The main reasons of poor responsiveness to IFNb therapy include: (1) lack of biological activity of the drug even if correctly administered; (2) inability of the drug even if biologically active to control the disease; and (3) poor adherence. Biological activity has been defined as ‘‘the whole of pharmacological, physiological and biochemical effects, resulting from the interaction of a drug with its target receptor; it is a necessary but not sufficient condition for effectiveness of a drug’’ [11]. The main reason for reduced or suppressed biological activity of IFNb is the development of NAbs [12]. A subset of nonresponder patients, named ‘‘immuno-pharmacological nonresponders’’, develops Nabs against IFNb [13]. A second subset of non-responders to IFNb has a pathogenetic origin: even if the drug is biologically active, its therapeutic effect may be too weak to keep a highly active disease under control [14]. Breakthrough disease, defined as any
Neurol Sci (2014) 35:307–316
309
MS is associated with a substantial economic burden, as the disease affects young individuals at the beginning of their social and professional lives [18]. According to the World Health Organization (WHO), MS is among the most expensive diseases: in Italy, the cost to an MS patient is 38.845€/year, with DMT costs representing only 12.2 % of the total cost of MS general costs and all costs raising linearly as the EDSS score increases [18]. The growing number of patients under treatment and Italian National Health Service budget constraints call for highly cost-effective therapeutic choices, as well as evaluation of total costs per relapse and costs of disability avoided with each treatment [19]. In this context, therapeutic appropriateness and the research of early markers become essential to guarantee the wellbeing of patients, and to allow the full sustainability of the disease. Assessment of IFNb NAb has a great economic impact because (1) there are more than 20,000 patients on IFNb therapy in Italy; (2) the annual cost of IFNb therapy is about 10.000€/ patient; and (3) 10–15 % of patients become immunopharmacological non-responders because they develop NAbs. Therefore, it can be estimated that every year 20–30 million € are misallocated because of unnecessary treatment of NAb-positive patients.
IFNb is associated with the development of both binding antibodies (BAbs) and NAbs. BAbs may be detected since the first month of therapy, but they do not necessarily inhibit IFNb biological activity; however, in the long term, a subset of BAbs may transform into NAbs [20]. Longitudinal studies on the development of NAbs suggest that they may develop 4–6 months after beginning the therapy and generally within the first 2 years [21]. These antibodies prevent IFNb from binding to its receptor, as reflected by a decreased IFNb biological activity, thus negatively affecting responsiveness [22, 23]. NAbs development is independent of sex, age, duration of the disease and progression of the disease at the beginning of IFNb treatment [24]. Immunogenicity of IFN is due to drugrelated, treatment-related or patient-related factors [25]. Primary protein structure, absence of glycosylation, posttranslational modifications and the presence of aggregates have been identified among the drug-related factors that affect immunogenicity the most. IFNb-1b preparations show a greater immunogenic potential than IFNb-1a preparations, due to the absence of glycosylation, amino-acid substitution and the consequent development of aggregates [26]: in fact, intramuscular (i.m.) IFNb-1a is characterized by the lowest amount of aggregated proteins among all IFNb [27]. NAbs present cross reaction among different IFNb formulations [26]; as a consequence, NAb-positive patients do not benefit from switching to other IFNb formulations. Regarding treatment-related factors, the subcutaneous (s.c.) route seems more immunogenic than the i.m. route. A high frequency of injections also seems to increase the probability to develop NAbs, whereas evidence regarding its dosage is unclear [3]. Among patient-related factors, the general immune status of the patient and the genetic profile are most likely determinants; in particular, it has been suggested that HLADRB1*0401 and HLA-DRB1*0408 are strongly associated with the development of antibodies [28]. Reported rates of NAbs positivity while on treatment with different IFNb formulations vary between studies and could be influenced by the method of detection [29]. Nevertheless, on average, we can assume an immunogenic potential of 2–6 % for IFNb-1a i.m., 12–28 % for IFNb-1a s.c., and 28–47 % for IFNb-1b s.c. [30] (Table 1, 2). The new IFNb-1a s.c. formulation without albumin is expected to be less immunogenic (14.8 %) [31] compared to the old one, but there are yet no data for direct comparison.
Immunogenicity of IFNb formulations
Clinical relevance of NAbs
Immunogenicity of biopharmaceuticals is a well-known phenomenon and is one of the main reasons for impaired efficacy. Like other recombinant protein therapeutics,
The impact of NAbs on IFNb therapeutic efficacy has been difficult to assess for several reasons: (1) most of the studies have been underpowered and/or of short
ongoing clinical or MRI activity [15] while on IFNb therapy and often regarded as a treatment failure, may be observed despite a NAb-negative status, due to a spontaneous variation of the underlying disease [16]. Poor treatment adherence may also negatively affect clinical response [17]. Therefore, correct and detailed patient information should be part of an appropriate therapeutic approach. MRI or clinical approaches alone may present some limitations in the responsiveness assessment. The limitations of a clinical-based assessment, which can be easily performed at every appointment, are the difficulty in defining the criteria of clinical response and the late recognition of a non-responder status. An MRI-based assessment is more sensitive compared to a clinical assessment, but it presents limitations as the timing of scanning, technical procedure and definition of MRI non-responders have to be defined.
Economic and psychosocial costs of non-responsiveness in relapsing-remitting MS
123
310
Neurol Sci (2014) 35:307–316
Table 1 Impact of NABs on clinical and MRI parameters in randomized clinical trials Study
Type of IFNb
Definition of positivity
% pts Nabs positive
Week or years
Nabs effect
Note
RR
EDSS
MRI activity
MRI BOD
The IFNB MS study Group [34]
Betaferon
2 consecutive NABs? titers
35
3 years
?*
- (ns)
–
? (ns)
Rudick et al. [39]
Avonex
At least one positive sample
17
2 years
? (ns)
? (ns)
?*
–
SPECTRIMS, Li et al. [54, 65]
Rebif 22 Rebif 44
At least one positive sample
21.6 (Re22)
3 years
? (ns)
- (ns)
? (ns)
? (ns)
Panitch et al. EVIDENCE (Panitch et al. [55])
Avonex Rebif 44
Any positive antibody value
25 (Re44)
48 weeks
ns
–
?***
–
Durelli et al. (INCOMIN) [56]
Avonex Betaferon
Any positive antibody value
7 (Av)
2 years
? (ns)
–
–
–
Polman et al. European Study on IFNb 1b SPMS [57]
Betaferon
Once positive always positive; all switches considered
27.8
3 years
?**
? (ns)
–
?**
The North American Study Group on IFNb 1b in SPMS [58]
Betaferon 250mcg and 160 mcg
Once positive always positive; all switches considered
23 (250 mcg)
3 years
ns
ns
ns
ns
Primary outcome = confirmed EDSS progression: no difference in IFNb vs placebo groups.
PRISMS (Francis et al. [35])
Rebif 22 Rebif 44
Anytime positive or interval positive
24 (Re22)
4 years
?***
?*
?***
?***
NAbs impact during 3–4 years
Kappos et al. [36]
Avonex 30mcg and 60mcg
2 consecutive NABs? titer
1.8 (30 mcg), 4.8 (60 mcg)
4 years
?**
?*
?*
?*
BENEFIT study, Hartung et al. [59]
Betaferon
At least one positive value 2 consecutive positive values
31.8,
5 years
ns
ns
?***
?***
14.7 (Re44)
Primary outcome, time to confirmed EDSS progression not significantly affected by IFNB treatment
2 (Av)
30 (Be)
32 (160 mcg)
14 (Re44)
26.7
NAb? associated with higher risk of McDonald MS P \ 0.001
AV, Avonex; Be, Betaferon; Re22, Rebif 22; Re44, Rebif 44; BOD, burden of disease; ?, outcome worse in NAbs-positive group than in NAbnegative group; -, outcome worse in NAbs-negative group than in NAb-positive group; ns, not significant; –, not done * P \ 0.05; ** P \ 0.01; *** P \ 0.001
duration (i.e. \2 years), therefore not taking into account the late appearance of NABs and the time they need to exert a negative impact on clinical parameters; (2) studies have used different laboratory tests for NAbs detection and quantification; (3) the timing of sampling was different, thus making results less comparable; (4) a crucial issue has also been the differences in study designs and statistical approaches used for investigating the impact of NAbs on clinical and/or MRI outcomes
123
[32], which should consider that many of the NAbpositive patients revert to a NAb-negative status over time [33]. The cut-off points for low, medium and high titer are different among the studies and set-up arbitrarily; in the present Consensus, the cut-off for high-titer NAb is [100 TRU because 96 % of the samples with [100 TRU showed the absence of biological activity [12].
Any IFNb
Any IFNb
Betaferon
Avonex Betaferon
Any IFNb
Boz et al. [63]
Malucchi et al. [49]
Durelli et al. [64]
Sato et al. [66]
Paolicelli et al. [5]
2 consecutive positive samples
1 positive sample
1 positive sample at 6 months
Positive sample at 12 months of therapy
1 positive sample
1 positive sample at 1 year of treatment
1 positive sample
14 %
35.5 %
34 %
12.4 %
13 %
25.4 %
24 %
37 %
17 %
From 9 to 46 %
% pts Nabs positive
5 years
4 years
2 years
?**
?***
?**
?**
?*
[3 years 3 years
–
?***
–
?***
?**
RR
? (ns)
–
? (ns)
–
ns
?**
?**
–
?*
? (ns)
EDSS
NAbs effect
6 years
4 years
2.5 years
3 years
5y
Week or years
–
?**
–
–
–
–
–
?**
–
–
MRI activity
–
–
–
–
–
–
–
?**
–
? (ns)
MRI BOD
Negative trend on time to EDSS 4 (IRR = 2.94; P = 0.0879)
NAbs? predicts risk of relapse or EDSS progression
MxA and NAbs predict time to first relapse
NAbs impact during 3–4 years
NAbs? predicts EDSS progression (5 years follow-up)
NAbs impact only at high titer
Significantly reduced time to first relapse
Note
* P \ 0.05; ** P \ 0.01; *** P \ 0.001
AV, Avonex; Re22, Rebif 22; Re44, Rebif 44; BOD, burden of disease; ?, outcome worse in NAbs-positive group than in NAb-negative group; -, outcome worse in NAbs-negative group than in NAb-positive group; ns, not significant; – not done
Rebif 11 or 33mcg x 3–w
Tomassini et al. [62]
2 consecutive NAB? samples
Betaferon
Any IFNb
Frank et al. [60]
Perini et al. [61]
2 consecutive NAB? samples
Any IFNb
Malucchi et al. [22]
Positive sample at 12 months of therapy
Any IFNb
Sorensen et al. [24]
Definition of positivity
Type of IFNb
Study
Table 2 Impact of NABs on clinical and MRI parameters in observational studies
Neurol Sci (2014) 35:307–316 311
123
312
Neurol Sci (2014) 35:307–316
Fig. 1 Flow chart of NAbs quantification
Data coming from clinical trials of C3 years’ duration, non-randomized prospective and real-world propensity score studies indicate that NAbs reduced or abolished the therapeutic efficacy of IFNb on relapse, independently of the type of IFNb used (Tables 1, 2). In the pivotal trial on IFNb 1-b, 35 % of treated patients developed NAbs and in the NAbs-positive group, the relapse rate during years 2 and 3 was significantly higher than in the NAbs-negative group and comparable with the placebo arm [34]. In the IFNb1-a s.c. PRISMS-4 study, NAbs-positive patients had a significantly higher RR than NAbs-negative patients RR during years 3 and 4 [35]. The two-dosage IFNb 1-a i.m. study showed that NAbs-positive patients had higher RR from months 12 to 48 and higher rate of worsening in EDSS from baseline to month 48 than NAbs-negative patients [36]. Data of phase III clinical trials are in line with prospective non-randomized studies (Tables 1, 2), such as the large Danish MS study, that enrolled more than 500 patients treated with all IFNb preparations. In this study, NAb-positive patients showed significantly higher RR, shorter time to first relapse and higher EDSS score at 42 and 48 months than NAbs-negative patients [24]. The impact of NAbs on clinical outcomes has also been recently evaluated in a large cohort of Italian RRMS patients. In this 5-year observational study, a significant increase in relapse rate (IRR = 1.39; P = 0.0076) and a shorter time to first relapse (IRR = 1.71; P = 0.0038) were found during the NAb-positivity period. Propensity score analysis in a selected cohort of patients revealed a negative impact of NAbs on disability progression (milestone EDSS = 4) as well [5].
123
Impact of NAbs on MRI activity A number of reports and meta-analysis of clinical trials demonstrated that patients developing new MRI lesions while on DMT or placebo show higher risk of relapses and poor clinical outcomes over time [9, 10, 37]. The DMT impact on MRI measures is more pronounced and precocious than clinical measures; therefore, MRI measures can help evaluate the negative impact of NAbs on MS course earlier and more consistently than clinical signs and symptoms. All the Randomized Clinical Trials in relapsing-remitting MS, with each of the 3 IFNb products, have clearly demonstrated the negative effects of NAbs on MRI measures of disease activity (Table 1). Compared with patients who remained NAb negative, NAbs-positive patients showed a higher number of T1 gadolinium-enhanced lesions and/or greater accrual of new or enlarging T2 lesions.
Biological markers of IFNb biological activity: Myxovirus resistant protein A (MxA) monitoring strategy Even though NAbs may appear after 3 months of treatment, the lack of MRI efficacy may not be evident before 12–18 months, while the clinical detrimental effect may require up to 3–4 years to reach statistical significance (Table 1) [3, 36, 38]. Monitoring markers of biological activity may provide instead an early, objective and reliable indication of biological response to IFNb that,
Neurol Sci (2014) 35:307–316
following the binding of IFNb with its receptor (IFNAR) on cell surface, activated the biochemical intracellular pathway. A large number of proteins have been proposed as IFNb biomarkers: b-2-microglobulin and neopterin [39], MxA protein [40] and MxA mRNA [41], oligoadenylate synthetase [42], TRAIL [43, 44], viperin [45], IFI27, CCL2 and CXCL10 [46]. Among the biomarkers reflecting in vivo response to IFNb, MxA is the best validated and increasingly used one in clinical practice [4, 12, 47, 48]. The level of MxA mRNA after 1 year of IFNb treatment is a stronger predictor of relapses than NAbs [49], and low levels of MxA mRNA before IFNb treatment are reported to be associated with occurrence of relapses and contrastenhancing lesions on MRI, whereas a high MxA mRNA seems to be associated with a longer time to a new relapse and reduction of CELs [50]. MxA mRNA has demonstrated important advantages such as specificity, as it is induced only by IFNb type 1 and some viruses and not by IFNc, sensitivity, as it can be quantified in every patient, and reliability. Moreover, its short half-life avoids accumulation and every single IFNb injection can be assessed [42]. Many studies have demonstrated that administration of IFNb leads to a large increase in the amount of MxA mRNA, whereas the presence of NAbs is associated with a decrease or abolition of MxA mRNA and protein increase [40, 51]. There is no consensus regarding the exact definition of biologically relevant MxA gene expression, and some patients show MxA mRNA expression in the presence of NAbs [52]; however, an inverse correlation between titers of NAbs and MxA level have been demonstrated [12]. Choice of relevance thresholds can be different across studies and this may influence sensitivity or specificity of the method. Higher specificity could be more adequate for the identification of non-responder patients after 1-year treatment; the ?3SD or 99th percentile cut-offs are suggested to increase the efficiency of screening and prevent unnecessary treatment switches in patients still presenting some bioactivity of the drug [12, 52].
313
3.
4.
5. 6.
7. 8.
9. 10.
11.
12.
patients do not benefit from switching to other IFNb formulations. According to EFNS Task Force’s guidelines [3], the Consensus Panel recommends testing the patients treated with IFNb for the presence of NAbs after 12 and 24 months of treatment. If positive, the patient should be retested for confirmation after 3 months (Fig. 1). Measurement of NAbs can be discontinued in patients remaining NAbs negative during the first 2 years of treatment, but it should be resumed if disease activity increases. Persistently high NAb titers ([100 TRU) reduce or abolish biological activity of IFN b. Persistently high NAb titers have a significant negative impact on MRI parameters of disease activity. Persistently high NAbs titers have a significant negative impact on the RR. A negative effect of NAbs on disability progression has been suggested; however, further studies are needed to confirm this observation. NAbs testing has a prognostic value on IFNb therapeutic efficacy. In patients with a clinically active disease and with persistently high NAb titer (C100 TRU), IFNb should be discontinued. In patients doing clinically well and with a persistently high NAb titer, switching therapy should be considered, as high NAb titers can represent an early predictor of poor MRI and clinical response. Absence of biological activity can support switching. MxA mRNA measurement provides important information about IFNb biological activity. However, since MxA quantification is not a widely performed test in clinical laboratory, at present it is principally used in clinically challenging cases requiring deeper characterization.
Conclusions Consensus reached by the Consensus Panel There was consensus among members of the Panel regarding the following key points: 1.
2.
There are differences among IFNb formulations with the IFNb 1a i.m. being less immunogenic and IFNb 1b more immunogenic. NAbs present cross reaction among different IFNb formulations. As a consequence, NAb-positive
The current economic scenario requires the optimization of resources, especially in the management of chronic diseases like MS, affecting young persons who have to face long years of disease. The guidelines proposed by the panel for the management of NAbs in IFNb-treated patients will probably make the clinical management of NAbs more homogeneous as well as improve the appropriateness of therapy and cost effectiveness of DMTs (Fig. 1).
123
314
Quantification of immunogenicity of IFNb is an extremely relevant issue, particularly within the context of improving the appropriateness of MS management. The approach should be individually tailored to the patient, encouraging the discontinuation of ineffective treatments, while offering other potentially valid therapeutic alternative. Maintaining IFNb therapy in patients with high-titer NAbs or lacking MxA mRNA induction can constitute a clinical risk to the patient, who is virtually untreated, as well as an economic burden for society through unnecessary waste of resources [53]. Early identification of non-responders should be a multidisciplinary process, based on the evaluation of the clinical course of the disease, MRI activity, presence of NAb and, when available, the assessment of IFNb biological activity through MxA quantification. The present Consensus is part of the commitment of the Italian neurological community to continuous improvement of management of neurological patients, combining the best treatment option with optimization of financial resources. Acknowledgments This Consensus Paper, aimed at providing Italian neurologists with National Recommendations for anti-IFNb NAb testing, is the result of a Consensus Meeting held in Milan on October 24, 2012. The Italian Society of Neurology (Societa` Italiana di Neurologia, SIN) was the official sponsor of the meeting. Biogen Idec Italia provided unrestricted support to the logistics of the meeting with no influence on the content of the manuscript.
References 1. Trojano M, Pellegrini F, Fuiani A, Paolicelli D, Zipoli V, Zimatore GB, Di Monte E, Portaccio E, Lepore V, Livrea P, Amato MP (2007) New natural history of interferon-beta-treated relapsing multiple sclerosis. Ann Neurol 61:300–306 2. Bertolotto A, Malucchi S, Sala A, Orefice G, Carrieri PB, Capobianco M, Milano E, Melis F, Giordana MT (2002) Differential effects of three interferon betas on neutralising antibodies in patients with multiple sclerosis: a follow up study in an independent laboratory. J Neurol Neurosurg Psychiatry 73:148–153 3. Sorensen PS, Deisenhammer F, Duda P, Hohlfeld R, Myhr KM, Palace J, Polman C, Pozzilli C, Ross C (2005) Guidelines on use of anti-IFN beta antibody measurements in multiple sclerosis: report of an EFNS Task Force on IFN-beta antibodies in multiple sclerosis. Eur J Neurol 12:817–827 4. Polman CH, Bertolotto A, Deasenhammer F, Giovannoni G, Hartung HP, Hemmer B, Killestein J, McFarland HF, Oger J, Pachner AR, Petkau J, Reder AT, Reingold SC, Schellekeng H, Sorensen PS (2010) Recommendations for clinical use of data on neutralizing antibodies to interferon-beta therapy in multiple sclerosis. Lancet Neurol 9(7):740–750 5. Paolicelli D, D’Onghia M, Pellegrini F, Direnzo V, Iaffaldano P, Lavolpe V, Trojano M (2013) The impact of neutralizing antibodies on the risk of disease worsening in interferon b-treated relapsing multiple sclerosis: a 5 year post-marketing study. J Neurol 260(6):1562–1568
123
Neurol Sci (2014) 35:307–316 6. Noyes K, Bajorska A, Chapel A, Schwid SR, Mehta LR, Weinstock-Guttman B, Holloway RG, Dick AW (2011) Cost-effectiveness of disease modifying therapy for multiple sclerosis. A population-based study. Neurology 77:355–363 7. Brook RH (1994) Appropriateness of care: the new frontier. BMJ 308:218–219 8. Fuchs VR (2011) The doctor’s dilemma—what is ‘‘appropriate’’ care ? NEJM 365(7):585–587 9. Rio J, Comabella M, Montalban X (2009) Predicting responders to therapies for multiple sclerosis. Nat Rev Neurol 5(10):533–560 10. Sormani MP, De Stefano N (2013) Defining and scoring response to IFN b in multiple sclerosis. Nat Rev Neurol 9:504–512 11. Hardman JG, Limbird LE, Gilman AG (1996) The pharmacological basis of therapeutics. McGraw-Hill, New York 12. Malucchi S, Gilli F, Caldano M, Sala A, Capobianco M, di Sapio A, Granieri L, Bertolotto A (2011) One-year evaluation of factors affecting the biological activity of interferon beta in multiple sclerosis patients. J Neurol 258:895–903 13. Bertolotto A, Gilli F (2008) Interferon-beta responders and nonresponders. A biological approach. Neurol Sci 29:S216–S217 14. Sbardella E, Tomassini V, Gasperini C, Bellomi F, Cefano LA, Morra VB, Antonelli G, Pozzilli C (2009) Neutralizing antibodies explain the poor clinical response to interferon beta in a small proportion of patients with Multiple Sclerosis: retrospective study. BMC Neurol 9:54 15. Rudick RA, Polman CH (2009) Current approaches to the identification and management of breakthrough disease in patients with multiple sclerosis. Lancet Neurol 8(6):545–559 16. Hesse D, Krakauer M, Lund H, Sondegaard HB, Langkilde A, Ryder LP, Sorensen PS, Sellebjerg F (2010) Breakthrough disease during interferon-beta therapy in MS: no signs of impaired biologic response. Neurol 4;74(18):1455–1462 17. Steinberg SC, Faris RJ, Chang CF, Cham A, Tankersley MA (2010) Impact of adherence to interferons in the treatment of multiple sclerosis: a non-experimental, retrospective, cohort study. Clin Drug Investig 30(2):89–100 18. Kobelt G, Berg J, Lindgren P, Battaglia M, Lucioni C, Uccelli A (2006) Costs and quality of life of multiple sclerosis in Italy. Eur J Health Econ 7(Suppl 2):S45–S54 19. Goldberg LD, Edwards NC, Fincher C, Doan QV, Al-Sabbagh A, Meletiche DM (2009) Comparing the cost-effectiveness of disease-modifying drugs for the first-line treatment of relapsingremitting multiple sclerosis. J Manag Care Pharm 15(7):543–555 20. Hegen H, Millonig A, Bertolotto A, Comabella M, Giovanonni G, Guger M, Hoelzl M, Khalil M, Killestein J, Lindberg R, Malucchi S, Mehling M, Montalban X, Polman C, Rudzki D, Schautzer F, Sellebjerg F, Sørensen P, Deisenhammer F (2013) Early detection of neutralizing antibodies to interferon-beta in multiple sclerosis patients: binding antibodies predict neutralizing antibody development. Mult Scler [Epub ahead of print] 21. Sorensen PS, Koch-Henriksen N, Ross C, Clemmesen KM, Bendtsen K (2005) Appearance and disappearance of neutralizing antibodies during interferon-beta therapy. Neurology 65(1):33–39 22. Malucchi S, Sala A, Gilli F, Bottero R, Di Sapio A, Capobianco M, Bertolotto A (2004) Neutralizing antibodies reduce the efficacy of beta IFN during treatment of multiple sclerosis. Neurology 62:2031–2037 23. Creeke PI, Farrell RA (2013) Clinical testing for neutralizing antibodies to interferon-b in multiple sclerosis. Ther Adv Neurol Disord 6(1):3–17 24. Sorensen PS, Ross C, Clemmensen KM, Bendtzen K, Frederiksen JL, Jensen K, Kristensen O, Petersen T, Rasmussen S, Ravnoborg M, Stenager E, Koch-Henriksen N, the Danish Multiple Sclerosis Study Group (2003) Clinical importance of neutralizing antibodies against interferon beta in patients with relapsing-remitting multiple sclerosis. Lancet 362:1184–1191
Neurol Sci (2014) 35:307–316 25. Farrell RA, Marta M, Gaeguta AJ, Souslova V, Giovannoni G, Creeke PI (2012) Understanding drug resistance to biologic therapy. Development of resistance to biologic therapies with reference to IFN-b. Rheumatology 51(4):590–599 26. Bertolotto A, Malucchi S, Milano E, Castello A, Capobianco M, Mutani R (2000) Interferon beta neutralizing antibodies in multiple sclerosis: neutralizing activity and cross-reactivity with three different preparations. Immunopharmacology 48:95–100 27. Barnard JG, Babcock K, Carpenter JF (2012) Characterization and quantitation of aggregates and particles in interferon-b products: Potential links between product quality attributes and immunogenicity. J Pharm Sci Dec 11. doi:10.1002/jps.23415. [Epub ahead of print] 28. Hoffmann S, Cepok S, Grummel V, Lehmann-Horn K, Hackermu¨ller J, Stadler PF, Hartung HP, Berthele A, Deisenhammer F, Wassmuth R, Hemmer B (2008) HLA-DRB1*0401 and HLADRB1*0408 are strongly associated with the development of antibodies against interferon-beta therapy in multiple sclerosis. Am J Hum Genet 83(2):219–227 29. Deisenhammer F, Schellekens H, Bertolotto A (2004) Measurement of neutralizing antibodies to interferon beta in patients with multiple sclerosis. J Neurol 251(Suppl 2):II31–II39 30. Bertolotto A, Deisenhammer F, Gallo P, Soelberg Sorensen P (2004) Immunogenicity of interferon beta. Differences among products. J Neurol 251(suppl 2):II15–II24 31. Comi G, De Stefano N, Freedman MS, Barkhof F, Polman CH, Kitdehaag BM, Casset-Semanaz F, Hennessy B, Moraga MS, Rocak S, Stubinski B, Kappos L (2012) Comparison of two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX): a phase 3 randomized controlled trial. Lancet Neurol 11(1):33–41 32. Cutter G (2003) Statistical issues in neutralizing antibodies. Neurology 61(Suppl 5):S38–S39 33. Hesse D, Sørensen PS (2007) Using measurements of neutralizing antibodies: the challenge of IFN-beta therapy. Eur J Neurol 14(8):850–859 34. The IFNB Multiple Sclerosis Study Group and the University of British Columbia MS/MRI Analysis Group (1996) Neutralizing antibodies during treatment of multiple sclerosis with interferon beta-1b: experience during the first 3 years. Neurology 47:889–894 35. The PRISMS (Prevention of Relapses and Disability by Interferon-b-1a Subcutaneously in Multiple Sclerosis) Study Group and the University of British Columbia MS/MRI Analysis Group (2001) PRISMS-4: long-term efficacy of interferon-b-1a in relapsing MS. Neurology 56:1628–1636 36. Kappos L, Clanet M, Sandberg W, Radue EW, Hartung HP, Hohlfeld R, Xu J, bennett D, Sandrock A, Goelz S and European Interferon beta-1a IM Dose-Comparison Study Investigators (2005) Neutralizing antibodies and efficacy of interferon b-1a: a 4 year controlled study. Neurology 65:40–47 37. Sormani MP, Bruzzi P (2013) MRI lesions as a surrogate for relapses in multiple sclerosis: a meta-analysis of randomised trials. Lancet Neurol 12(7):669–676 38. Francis GS, Rice GP, Alsop JC, PRISMS Study Group (2005) Interferon beta-1a in MS: results following development of neutralizing antibodies in PRISMS. Neurology 65:48–55 39. Rudick RA, Simonian NA, Alam JA, Campion M, Scaramucci JO, Jones W, Coats ME, Goodkin DE, Weinstock-Guttman B, Herndon RM, Mass MK, Richert JR, Salazar AM, Munschauer FF 3rd, Cookfair DL, Simon JH, Jacobs LD (1998) Incidence and significance of neutalizing antibodies to interferon beta 1a in multiple sclerosis. Neurology 50:1266–1272
315 40. Deisenhammer F, Reindel M, Harvey J, Gasse T, Dilitz E, Berger T (1999) Bioavailability of interferon beta 1b in MS patients with and without neutralizing antibodies. Neurology 52:1239–1243 41. Bertolotto A, Gilli F, Sala A, Audano L, Castello A, Magliola U, Melis F, Giordana MT (2001) Evaluation of bioavalability of three types of IFN beta in multiple sclerosis patients by a new quantitative-competitive-PCR method for MxA quantification. J Immunol Methods 256:141–152 42. Pachner A, Narayan K, Price N, Hurd M, Dail D (2003) MxA gene expression analysis as an interferon-beta bioactivity measurement in patients with multiple sclerosis and the identification of antibody-mediated decreased bioactivity. Mol Diagn 7:17–25 43. Wandinger KP, Lu¨nemann JD, Wengert O, Bellmann-Strobl J, Aktas O, Weber A, Grundstrom E, Ehrlich S, Wernecke KD, Volk HD, Zipp F (2003) TNF-related apoptosis inducing ligand (TRAIL) as a potential response marker for interferon-beta treatment in multiple sclerosis. Lancet 361:2036–2043 44. Gilli F, Marnetto F, Caldano M, Sala A, Malucchi S, Capobianco M, Bertolotto A (2006) Biological markers of IFNb therapy: comparison among interferon-stimulated-genes MxA, TRAIL, and XAF-1. Mult Scler 12:1–11 45. Pachner AR, Warth JD, Pace A, Goelz S, INSIGHT investigators (2009) Effect of neutralizing antibodies on biomarker responses to interferon beta. The INSIGHT study. Neurology 73:1493–1500 46. Sellebjerg F, Krakauer M, Hesse D, Ryder LP, Alsing I, Jensen PE, Koch-Henriksen N, Svejgaard A, Soelberg Sørensen P (2009) Identification of new sensitive biomarkers for the in vivo response to interferon-beta treatment in multiple sclerosis using DNA-array evaluation. Eur J Neurol 16(12):1291–1298 47. Hesse D, Sellbjerg F, Sorensen PS (2009) Absence of MxA induction by interferon b in patients with MS reflects complete loss of bioactivity. Neurology 73:372–377 48. Zanotti C, Ghidini C, Lamorgese C, Caimi L, Capra R, Imberti L (2010) Transfer of myxovirus-protein-A mRNA assay for interferon-b bioactivity measurement in multiple sclerosis patients to routine laboratory practice. A 4-year experience. Clin Chem Lab Med 48(9):1235–1238 49. Malucchi S, Gilli F, Caldano M, Marnetto F, Valentino P, Granieri L, Sala A, Capobianco M, Bertolotto A (2008) Predictive markers for response to interferon therapy in patients with multiple sclerosis. Neurology 70(13 Pt 2):119–127 50. Van der Voort, LF, Vennegoor A, Visser A, Knol DL, Kitdehaag BM, Barkhof F, Oudejans CB, Polman CH, Killestein J (2010) Spontaneous MxA mRNA level predicts relapses in patients with recently diagnosed MS. Neurol 5,75(14):1228–1233 51. Bertolotto A, Gilli F, Sala A, Capobianco M, Malucchi S, Milano E, Melis F, Marnetto F, Linberg RL, Bottero R, Di Sapio A, Giordana MT (2003) Persistent neutralizing antibodies abolish the interferon b bioavailability in MS patients. Neurology 60:634–639 52. Capra R, Sottini A, Cordioli C, Serana F, Chiarini M, Caimi L, Padovani A, Bergamaschi R, Imberti L (2007) IFNbeta bioavailability in multiple sclerosis patients: MxA versus antibodydetecting assays. J Neuroimmunol 189(1–2):102–110 53. Fitzgerald S (2009) Antibodies block effect of interferon on MS. Neurology Today 9(15):14 54. Secondary Progressive Efficacy Clinical Trial of Recombinant Interferon-beta-1a in MS (SPECTRIMS) Study Group (2001) Randomized controlled trial of interferon-beta-1a in secondary progressive MS: Clinical results. Neurology 56:1496–1504 55. Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O’Connor P, Monaghan E, Li D, Weinshenker B for the EVIDENCE (Evidence of Interferon Dose-Response: European North American Comparative Efficacy) Study Group and the University of
123
316
56.
57.
58.
59.
60.
Neurol Sci (2014) 35:307–316 British Columbia MS/MRI Research Group (2002) Randomized, comparative study of interferonb-1a treatment regimens in MS. The EVIDENCE Trial. Neurol 59:1496–1506 Durelli L, Verdun E, Barbero P, Bergui M, Versino E, Chezzi A, Montanari E, Zaffaroni M, the Independent COMparison of Interferon (INCOMIN) Trial Study Group (2002) Every-otherday interferon beta-1b versus once-weekly interferon beta-1a for multiple sclerosis: results of a 2-year prospective randomised multicentre study (INCOMIN). Lancet 359:1453–1460 Polman C, Kappos L, White R, Dahlke F, beckmann K, Pozzilli C, Thompson A, Petkau J, Miller D (2003) Neutralizing antibodies during treatment of secondary progressive MS with interferon beta-1b. Neurology 60:37–43 The North American Study Group on Interferon beta-1b in Secondary Progressive MS (2004) Interferon beta-1b in secondary progressive MS. Results from a 3-year controlled study. Neurology 3:1788–1795 Hartung H-P, Freedman MS, Polman CH, Edan G, Kappos L, Miller DH, Montalban X, Barkhof F, Petkau J, White R, Sahajpal V, Knappertz V, Beckmann K, Lanius V, Sandbrink R, Pohl C, For the BENEFIT Study Group (2011) Interferon b-1b—neutralizing antibodies 5 years after clinically isolated syndrome. Neurology 77:835–843 Frank JA, Richert N, Bash C, Stone L, Calabresi PA, Lewis B, Stone R, Howard T, McFarland HF (2004) InterferonB-1b slows progression of atrophy in RRMS. Three-year follow-up in NAb and Nab patients. Neurology 62:719–725
123
61. Perini P, Calabrese M, Biasi G, Gallo P (2004) The clinical impact of interferon beta antibodies in relapsing-remitting MS. J Neurol 251:305–309 62. Tomassini V, Paolillo A, Russo P, Giugni E, Prosperini L, Gasperini C, Antonelli G, Bastianello S, Pozzilli C (2006) Predictors of long-term clinical response to interferon beta therapy in relapsing multiple sclerosis. J Neurol 253:287–293 63. Boz C, Oger J, Gibbs E, Grossberg SE (2007) Reduced effectiveness of long-term interferon-treatment on relapses in neutralizing antibody-positive multiple sclerosis patients: a Canadian multiple sclerosis clinic-based study. Mult Scler 13:1127–1137 64. Durelli L, Barbero P, Berqui M, Versino E, Bassano MA, Verdun E, Rivoiro C, Ferrero C, Picco E, Ripellino P, Giuliani G, Montanari E, Clerico M (2008) MRI activity and neutralising antibody as predictors of response to interferon b treatment in multiple sclerosis. J Neurol Neurosurg Psychiatry 79:646–651 65. Li DK, Zhao GJ, Paty DW, University of British Columbia MS/ MRI Analysis Research Group, The SPRECTRIMS Study Group (2001) Randomized controlled trial of interferon-beta 1a in secondary progressive MS: MRI results. Neurology 56(11): 1505–1513 66. Sato DK, Nakashima I, Fukazawa T, Shimizu Y, Tomizawa Y, Yokoyama K, Misu T, Creeke PI, Farrell R, Giovannoni G, Itoyama Y, Fujihara K, Aoki M (2012) Neutralizing antibodies are associated with a reduction of Interferon-b efficacy during the treatment of Japanese Multiple sclerosis patients. Tohoky J Exp Med 228:85–92
