Risk factors for reactivation of clinical disease activity in multiple sclerosis after natalizumab cessation

Risk factors for reactivation of clinical disease activity in multiple sclerosis after natalizumab cessation Mustonen, Tiina, BMa,#; Rauma, Ilkka, MDb,#,*; Hartikainen, Päivi, MD, PhDa,c; Krüger, Johanna, MD, PhDd,e; Niiranen, Marja, MDa; Selander, Tuomas, M.Sc.f; Simula, Sakari, MD, PhDg; Remes, Anne M, MD, PhDd,e; Kuusisto, Hanna, MD, PhDb,h aKuopio University Hospital, Department of Neurology, Puijonlaaksontie 2, P.O. Box 100, 70029 KYS, Finland bTampere University Hospital, Department of Neurology, Teiskontie 35, 33520 Tampere, Finland cUniversity of Eastern Finland, Department of Neurology, Yliopistonranta 1, 70210 Kuopio, Finland dUniversity of Oulu, Research Unit of Clinical Neuroscience, P.O. Box 8000, 90014 University of Oulu, Finland eNorthern Ostrobothnia Hospital District, MRC Oulu, P.O. Box 8000, 90014 University of Oulu, Finland fKuopio University Hospital, Science Service Center, Puijonlaaksontie 2, P.O. Box 100, 70029 KYS, Finland gMikkeli Central Hospital, Department of Neurology, Porrassalmenkatu 35-37, 50100 Mikkeli, Finland hUniversity of Eastern Finland, Department of Health and Social Management, Yliopistonranta 1, 70210 Kuopio, Finland #Equal contribution / shared first authorship *Corresponding author (E-mail address: [email protected]) This is the accepted manuscript of the article, which has been published in Multiple Sclerosis and Related Disorders. 2020, 38,101498. https://doi.org/10.1016/j.msard.2019.101498 Highlights of the study - Clinical relapses were documented in 36 % of patients between 0-12 months - Corticosteroid-treated relapses occurred in 30 % of patients between 0-12 months - High disease activity and EDSS ≥ 5.5 before natalizumab predicted reactivation - Subsequent treatments failed to prevent reactivation - Washout time > 3 months was associated with an increased reactivation risk Abstract Background Natalizumab (NTZ) is widely used for highly active relapsing-remitting multiple sclerosis (MS). Inflammatory disease activity often returns after NTZ treatment discontinuation. We aimed to identify predictive factors for such reactivation in a real-life setting. Methods We conducted a retrospective survey in four Finnish hospitals. A computer-based search was used to identify all patients who had received NTZ for multiple sclerosis. Patients were included if they had received at least six NTZ infusions, had discontinued treatment for at least three months, and follow-up data was available for at least 12 months after discontinuation. Altogether 89 patients were analyzed with Cox regression model to identify risk factors for reactivation, defined as having a corticosteroid-treated relapse. Results At 6 and 12 months after discontinuation of NTZ, a relapse was documented in 27.0 % and 35.6 % of patients, whereas corticosteroid-treated relapses were documented in 20.2 % and 30.3 % of patients, respectively. A higher number of relapses during the year prior to the introduction of NTZ was associated with a significantly higher risk for reactivation at 6 months (Hazard Ratio [HR] 1.65, p<0.001) and at 12 months (HR 1.53, p<0.001). Expanded NTZ = natalizumab, MS = multiple sclerosis, HR = hazard ratio, EDSS = Expanded Disability Status Scale, DMD = disease-modifying drug, RRMS = relapsing-remitting multiple sclerosis, VCAM-1 = vascular-cell adhesion molecule 1, CNS = central nervous system, PML = progressive multifocal leukoencephalopathy, SPMS = secondary-progressive multiple sclerosis, MRI = magnetic resonance imaging, CI = confidence interval, SD = standard deviation Disability Status Scale (EDSS) of 5.5 or higher before NTZ initiation was associated with a higher reactivation risk at 6 months (HR 3.70, p=0.020). Subsequent disease-modifying drugs (DMDs) failed to prevent reactivation of MS in this cohort. However, when subsequent DMDs were used, a washout time longer than 3 months was associated with a higher reactivation risk at 6 months regardless of whether patients were switched to first-line (HR 7.69, p=0.019) or second-line therapies (HR 3.94, p=0.035). Gender, age, time since diagnosis, and the number of NTZ infusions were not associated with an increased risk for reactivation. Conclusion High disease activity and a high level of disability prior to NTZ treatment seem to predict disease reactivation after treatment cessation. When switching to subsequent DMDs, the washout time should not exceed 3 months. However, subsequent DMDs failed to prevent the reactivation of MS in this cohort. Keywords Multiple sclerosis; natalizumab; discontinuation; reactivation; rebound 1. Introduction Natalizumab (NTZ) is a humanized monoclonal antibody used in the treatment of relapsingremitting multiple sclerosis (RRMS)(Clerico et al., 2017). It is administered intravenously in every four weeks. NTZ has been proven effective in reducing the recurrence of relapses in multiple sclerosis (MS), and it is generally used in patients with a highly active course of disease or a poor response to the first-line therapies of MS(Kappos et al., 2011; Tramacere et al., 2015). By binding to the 4 subunit on 41 integrin, NTZ blocks the binding of these integrins to the vascular-cell adhesion molecule 1 (VCAM-1), which is expressed on the endothelial cells of blood vessels in the central nervous system (CNS)(Léger et al., 1997; Yednock et al., 1992). As a result, the migration of T-lymphocytes from the circulation to the CNS is prevented. The therapeutic effect of NTZ is mostly explained by this regulation of Tlymphocyte adhesion and migration across the blood-brain barrier, but other α4-mediated effects of NTZ have also been suggested(Rice et al., 2005). The use of NTZ is limited due to the risk of progressive multifocal leukoencephalopathy (PML)(Tan and Koralnik, 2010). The risk of PML is increased in patients with long treatment periods, prior immunosuppressive treatment, and positive status with respect to anti-JC virus antibodies(Bloomgren et al., 2012). If the risk is considered too high, switching to an alternative disease-modifying drug (DMD) should be considered. In Finland, national treatment guidelines are followed when selecting DMDs for MS(Multiple Sclerosis: Current Care Guidelines, 2019). In the Finnish national guidelines, NTZ is positioned either as a first-line or second-line therapy for highly active RRMS with no antiJC virus antibodies. Cessation of treatment is advised if seroconversion occurs. NTZ is officially licensed only for RRMS in Finland, but it is sometimes used in secondary- progressive multiple sclerosis (SPMS) patients who experience clinical relapses(Multiple Sclerosis: Current Care Guidelines, 2019). NTZ is cleared from circulation in approximately two months after discontinuation of treatment, but some residual effects may persist for up to 6 months(O’Connor et al., 2011; Stüve et al., 2006). As expected, reactivation of MS has been shown to occur during the first year after discontinuation of NTZ in some patients(Fox et al., 2014; Gueguen et al., 2014; Havla et al., 2011; Iaffaldano et al., 2015; Kerbrat et al., 2011; Lo Re et al., 2015; O’Connor et al., 2011; Salhofer-Polanyi et al., 2014; West and Cree, 2010). A recent systematic review and meta-analysis of six studies demonstrated that younger age, higher number of relapses and gadolinium-enhancing lesions before initiation of treatment as well as fewer NTZ infusions were associated with an increased risk for disease reactivation after cessation of treatment(Prosperini et al., 2019). There are no established guidelines on how to treat MS patients discontinuing NTZ therapy, but recent reports have suggested that subsequent treatment with other DMDs should be initiated within 3 months after discontinuation in order to prevent disease reactivation(Iaffaldano et al., 2015; Jokubaitis et al., 2014; Kappos et al., 2015; Lo Re et al., 2015; Salhofer-Polanyi et al., 2014). However, most of the current evidence comes from observatory studies with heterogeneous study settings, and only few randomized trials have been published(Fox et al., 2014; Kappos et al., 2015; O’Connor et al., 2011). Our purpose was to evaluate the predictive factors for post-NTZ disease reactivation in an unselected clinical cohort of MS patients in a real-life setting. 2. Material and methods 2.1 Study population This retrospective study was carried out using data from four Finnish hospitals covering a catchment area of 1.3 million residents. Three university hospitals (Kuopio University Hospital, Tampere University Hospital and Oulu University Hospital) from different parts of Finland and one medium-sized central hospital (Central Hospital of Mikkeli) were chosen to represent MS treatment in Finland. The study was approved by the Research Ethics Committee of the Northern Savo Hospital District, Kuopio, Finland, and had an institutional approval from each participating hospital. MS patients were identified by a computer-based search using the ICD-8, -9 or -10 diagnosis of MS and treatment with NTZ as search criteria. Patients were included in the study if they had received at least six consecutive infusions of NTZ before the treatment was discontinued and follow-up data was available for at least 12 months after the last infusion. A discontinuation was defined as a three-month period without any NTZ infusions. Shorter gaps between infusions were not considered relevant. We identified a total of 101 MS patients who had discontinued NTZ treatment in years 2009-2016, and 89 of them met the inclusion criteria. A flowchart displaying the selection of the study cohort is shown in Figure 1. 2.2 Methods The patient records were systematically reviewed from the time of the first symptom to the latest available contact with the hospital. Data was collected from both paper archives and the hospital districts’ electronic patient information systems. The following variables were collected: gender; onset symptom of MS; time from diagnosis to the initiation of NTZ treatment; existence of gadolinium-enhancing lesions in the pre-NTZ magnetic resonance imaging (MRI) scan; number of NTZ infusions; adverse events during NTZ treatment; primary reason for the discontinuation of NTZ; prior and subsequent DMDs; washout time between DMDs; and all courses of corticosteroid treatment. Age was collected both at the time of diagnosis and at NTZ initiation. Expanded Disability Status Scale (EDSS) was collected at diagnosis, at NTZ initiation, and at NTZ discontinuation. The number of relapses during the year before NTZ initiation and the year after NTZ discontinuation were collected. In our analysis, the onset symptom of MS was also regarded as a relapse. Relapses were collected in two categories. First, all reported relapses were collected regardless of whether they required corticosteroid treatment or not. Second, only relapses which required corticosteroid treatment were collected. The latter were used to define reactivation in the statistical analysis. Reactivation was defined as having experienced at least one corticosteroid-treated relapse after NTZ discontinuation. Rebound was defined as an increase in the yearly number of all relapses after the discontinuation of NTZ treatment when compared to the year before the initiation of NTZ. Washout time was defined as the time between the last infusion of NTZ and the initiation of the following treatment. In the analysis, EDSS was categorized into two groups with a cut point of 5.5. 2.3 Statistical analysis Univariate Cox regression model was first used to identify individual variables associated with the risk of reactivation at 6 and 12 months of follow-up. Variables with statistically significant associations in the univariate model were then re-analyzed with multivariate Cox regression. The effect of subsequent DMDs administered after the cessation of NTZ treatment was analyzed using univariate Cox regression with patient as a random effect, and subgroup analysis was performed to determine whether a washout of 0-3 months or longer than 3 months was associated with the risk of reactivation. Results of the Cox regression analyses are shown as hazard ratios (HR) with 95 % confidence intervals (CI). Statistical analysis for the risk of rebound was not performed, as there were only few cases representing possible rebound in the cohort. Data was expressed as means with standard deviations (SD) or frequencies with percentages. Statistical analysis was performed using SPSS Statistics 24.0 and R version 3.5.1. Statistical significance was defined as two-tailed p < 0.05. confirmed its existence(O’Connor et al., 2011). We defined rebound as an increase in the number of yearly relapses after discontinuation of NTZ when compared to the year before NTZ initiation and discovered that 9 % of our patients had experienced rebound activity. This is somewhat lower than what has been reported in the majority of earlier reports(Gueguen et al., 2014; Kerbrat et al., 2011; Lo Re et al., 2015), but almost similar to what was reported in two earlier studies(Salhofer-Polanyi et al., 2014; Sangalli et al., 2014). The study has limitations that should be noted. Due to the retrospective setting, some data were missing. Although it is a common custom in Finland for patients using DMDs to attend regular follow-up visits with neurological examinations, EDSS was not always documented. Furthermore, a substantial part of MRI data was missing. Therefore, we could not use it in the regression analysis. When describing pre-NTZ MRI, we only reported whether gadoliniumenhancing lesions were present, as the exact number of lesions was not reported for every patient. We find the strength of this study to be its coverage of a large catchment area, the inclusion of four hospitals from different parts of Finland, and the use of an unselected real-life case series. The existence of our national treatment guidelines makes our data uniform and well representative of the actual treatment that Finnish MS patients received in years 2009-2016. Due to our national treatment guidelines, the indications for using different DMDs for reducing disease activity and prescribing corticosteroids for relapses in MS are concordant between different study centers. Since approximately a fifth of MS patients discontinuing NTZ seem to suffer from reactivation regardless of the duration of their treatment, we suggest that NTZ should only be initiated with the purpose of using the treatment for long periods. None of the therapeutic strategies used in this cohort were able to control the return of disease activity. In the future, the efficacy of the more recently approved DMDs in preventing post-NTZ disease reactivation should be evaluated. Until then, close attention should be paid on patient selection, regarding fertile women with family plans in particular. Washout times should be kept as short as possible after NTZ cessation. 5. Conclusions Discontinuation of NTZ treatment may lead to a marked reactivation of MS. 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NTZ = natalizumab. 101 patients who had discontinued NTZ treatment between years 2009-2016 89 patients included in the analysis 13 treatment-naive patients 76 patients switched from other treatments 9 patients excluded for receiving < 6 infusions of NTZ 3 patients excluded for having < 12 months of follow-up Table 1. Clinical characteristics of the study cohort (n=89). SD = standard deviation, NTZ = natalizumab, EDSS = Expanded Disability Status Scale, PML = progressive multifocal leukoencephalopathy. *Positive anti-JC virus antibodies, long treatment period and/or prior immunosuppressive treatment Patients with at least one relapse at 6 months after cessation (n=24) Patients with no relapses at 6 months after cessation (n=65) All patients (n=89) Female gender, n (%) 17 (70.8 %) 46 (70.8 %) 63 (70.8 %) Age at the time of diagnosis, years, range (mean ±SD) 17-50 (27.9 9.2) 15-55 (31.48.9) 15-55 (30.4 ±9.0) Age at NTZ initiation, years, range (mean ±SD) 21-63 (34.511.2) 20-56 (36.69.6) 20-63 (36.0 ±10.1) Time from diagnosis at NTZ initiation, years, range (mean ±SD) 0-21 (6.25.8) 0-25 (5.35.6) 0-25 (5.5 ±5.6) EDSS at the time of diagnosis, range (mean ±SD) 1.0-6.0 (2.61.6) 0-5.0 (2.01.3) 0-6.0 (2.2 ±1.4) EDSS at NTZ initiation, range (mean ±SD) 1.0-7.5 (4.01.8) 0-7.0 (3.41.8) 0-7.5 (3.6 ±1.8) Duration of NTZ treatment < 12 months, n (%) 12-36 months, n (%) > 36 months, n (%) 4 (16.7 %) 15 (62.5 %) 5 (20.8 %) 9 (13.8 %) 38 (58.5%) 18 (27.7 %) 13 (14.6 %) 53 (59.6 %) 23 (25.8 %) Primary reason for the cessation of NTZ treatment, Risk of PML considered too high*, n (%) Inefficacy of treatment, n (%) Pregnancy plans or pregnancy, n (%) Adverse events, n (%) Difficulties with peripheral venous cannulation, n (%) Patient’s own wish to discontinue treatment, n (%) 11 (45.8 %) 7 (29.2%) 4 (16.7%) 1 (4.2 %) 1 (4.2%) 0 (0 %) 50 (76.9 %) 9 (13.8%) 3 (4.6%) 2 (3.1 %) 0 (0 %) 1 (1.5 %) 61 (68.5 %) 16 (18.0 %) 7 (7.9 %) 3 (3.4 %) 1 (1.1 %) 1 (1.1 %)