Safety of alemtuzumab in a nationwide cohort of Finnish multiple sclerosis patients

Background Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice. Objectives To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients. Methods In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files. Results Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1-3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented. Conclusions SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.Peer reviewe

Safety of alemtuzumab in a nationwide cohort of Finnish multiple sclerosis patients

Background Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice. Objectives To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients. Methods In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files. Results Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1-3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented. Conclusions SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised.</p

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Primaarisprogressiivinen MS-tauti, kliininen, immunologinen ja radiologinen kuva

Ensisijaisesti etenevän MS-taudin kliininen, immunologinen ja radiologinen kuva Multippeliskleroosi (MS-tauti) on yleisin keskushermoston tulehduksellinen sairaus, jonka oireet voivat olla hyvin monimuotoisia. Taudin yleisin ilmenemismuoto on aaltomainen MS-tauti (relapsoiva-remittoiva MS, RRMS), joka useimmilla muuttuu vuosien kuluessa toissijaisesti etenevään tautimuotoon (sekudaarisprogressiivinen MS, SPMS). Ensisijaisesti etenevä MS-tauti (primaarisprogressiivinen, PPMS) on harvinainen MS-taudin alatyyppi, jossa oireet ja invaliditeetti lisääntyy tasaisesti sairauden alusta alkaen ilman selviä pahenemisvaiheita. PPMS-tautia on tutkittu aiemmin vähän, ja tautiin vaikuttavat tekijät ovat edelleen epäselvät. PPMS-tautiin ei ole käytössä taudin kulkuun vaikuttavia lääkehoitoja. Tämän väitöskirjatutkimuksen tarkoituksena on selvittää PPMS-taudin kliinisiä ilmentymiä, keskushermoston kuvantamislöydöksiä ja immunologisia piirteitä sekä verrata niitä SPMS-tautiin. Tutkimukseen osallistui 28 PPMS- ja 28 SPMS-potilasta sekä verrokkeina 20 tervettä henkilöä. Heille kaikille tehtiin kliininen neurologinen tutkimus ja laaja neropsykologinen kartoitus ja osalle tehtiin selkäydinnestenäytetutkimus (likvor). Selkäydinnestenäytteestä ja verestä tutkittiin tulehdusprosessiin osallistuvia adheesiomolekyylejä, sytokiinejä ja kemokiinejä. PPMS-potilaille ja terveille kontrolleille tehtiin koko keskushermoston magneettitutkimus (MRI) ja PPMS-potilaille tehtiin lisäksi laaja virtsausoireita kartoittava (urodynaaminen) tutkimus. PPMS-potilailla yleisimmät taudin alkuoireet olivat motoriset-, pikkuaivo- ja tuntohäiriöt. Motorisen toiminnan häiriöt olivat yleisimmät löydökset kliinisessä neurologisessa tutkimuksessa. Kaikilla PPMS-potilailla oli virtsaustoiminnan häiriöitä, joista tihentynyt virtsaamistarve ja siihen liittyvä virtsan karkailu olivat yleisimmät oireet. Urodynaamisen tutkimuksen yleisimmät löydökset olivat virtsarakon seinämälihaksen yliaktiivisuus (detrusor hyperrefleksia) sekä seinämälihaksen ja virtsaputken sulkijalihaksen koordinoimaton supistelu (detrusor sphinkterin dyssynergia, DSD). Neuropsykologisessa kartoituksessa todettiin PPMS-potilailla heikentymistä useilla eri osa-alueilla verrattuna terveisiin verrokkeihin, mutta tilastollisesti merkitseviä eroja PPMS- ja SPMS-potilaiden välillä ei ollut. Vertailussa kolmen eri tutkimusryhmämme välillä, todettiin että adheesiomolekyylien ilmentymistä immuunisolujen pinnalla esiintyi eniten PPMS-potilailla, mutta merkitseviä eroja sytokiinien tai kemokiinien esiintymisessä ei ollut. PPMS-potilailla esiintyi enemmän keskushermoston atrofialöydöksiä kuin terveillä verrokeilla. MRI-löydökset eivät kuitenkaan korreloineet MS-potilaan kokonaistoimintakykyä mittaavaan EDSS (expanded disability status scale)- pistetykseen. Aivojen T2-painotteisten leesioiden tilavuus ja diffuusien leesioiden määrä korreloivat tilastollisesti merkitsevästi PPMS-potilaiden neuropsykologisiin muutoksiin. Urodynaamisista löydöksistä detrusor hyperrefleksia ja DSD korreloivat aivojen T2-painotteisten leesioiden tilavuuteen ja hypotonisella detrusor-löydöksellä oli yhteys rintarangan plakkien määrään. Adheesiomolekyyleista ainoastaan VLA-4:n ilmentyminen veressä ja selkäydinnestenäytteessä korreloi aivoleesioiden kokonaistilavuuteen ja diffuusien leesioiden määrään. Sytokiinien tai kemokiinien osalta ei todettu merkitseviä korrelaatioita MRI-muutoksiin. Yhteenvetona voidaan todeta, että PPMS-potilaiden MRI-löydökset korreloivat vain heikosti kliinisiin löydöksiin. PPMS-potilailla todettiin heikentymistä useilla eri osa-alueilla kognitiivisissa toiminnoissa, mutta merkitseviä eroja verrattuna SPMS-potilaihin ei löydetty. Virtsaustoiminnan häiriöt ovat erittäin yleisiä PPMS-potilailla. Adheesiomolekyylien ja joidenkin sytokiinien ilmentymisen lisääntyminen viittaa siihen, että tulehduksellista aktiviteettia esiintyy pidemmälle edenneessä PPMS-taudissakin.Multiple sclerosis (MS) that is the most frequent demyelinating disease of the central nervous system (CNS) has very heterogeneous clinical presentations. The majority of patients have relapsing-remitting disease course characterized by episodes of acute exacerbation. Primary progressive MS (PPMS) is a rare subtype of MS which is characterized by a steady progression of irreversible disability from the onset of the disease. The main goal of this thesis was to identify clinical and immunological features of PPMS and correlate them with magnetic resonance imaging (MRI) findings. The specific aims were the following: 1) to characterize the neurological, cognitive and urological abnormalities in PPMS; 2) to test whether there are specific immunological abnormalities in progressive subtypes of MS; 3) to characterize the volumes of MRI abnormalities in brain and spinal cord in PPMS and 4) to evaluate whether the volumes of focal, diffuse and atrophic central nervous system (CNS) abnormalities in MRI are associated with clinical and immunological features of PPMS. The study included patients with PPMS (n=28), secondary progressive (SP) MS (22) and healthy subjects (n=20). All patients and controls underwent detailed neurological examination, MR imaging and neuropsychological examinations. Expressions of adhesion molecules (AMs) and the levels of different 17 cytokines/chemokines were measured in blood and cerebrospinal fluid (CSF). MRI was made to patients with PPMS and healthy controls. Furthermore, an urodynamic investigation was made to patients with PPMS. The most common symptoms in PPMS at the onset of disease included motor, cerebellar or sensory disturbances. The disturbances in motor functions predominated over other neurological dysfunction involving cerebellar, brain stem, sensory, cerebral and visual problems. All patients with PPMS had at least one micturition complaint with urgency and urge incontinence being the most common among them. Urodynamic abnormalities were found in the majority of patients and the most common findings were detrusor sphinkter dyssynergia (DSD) and detrusor hyperreflexia. According to neuropsychological examination the patients with PPMS performed better than those with SPMS in the visual learning test but other significant differences were not found. According to immunological examinations, the expressions of most AMs on blood and CSF immune cells were higher in PPMS than in SPMS or healthy subjects, but no marked differences were detected in the levels of cytokines and chemokines. Based on MRI, the atrophic changes were pronounced in patients with PPMS compared to healthy controls. Clinicoradiological correlation revealed weak but some correlations between disability measures including ambulation index, arm index and higher cerebral disturbances and MRI findings. Any of the MRI findings did not correlate with expanded disability status scale (EDSS). The number of diffuse brain lesions correlated with attention and information processing, concept formation, reasoning and executive functions, verbal production and learning, visuoperceptual and –constructive functions. All other domains except attention and information processing correlated also with the volume of T2 lesions in brain. The atrophic changes in CNS did not correlated with any of those tests. Among urodynamic findings, detrusor hyperreflexia and DSD correlated with T2 lesion load in brain and hypotonic detrusor was associated with increased numbers of thoracic plaques and with the decreased brain volume. The expression of adhesion molecule VLA-4 on blood lymphocytes and on CSF lymphocytes and monocytes correlated with the total volume of brain lesions and the number of diffuse brain lesions. In summary, this thesis focusing on the identification of clinical, immunological and radiological characteristics of PPMS, showed only weak correlation between clinical parameters and MRI. Patients with PPMS have decline in several cognitive domains that did not differ markedly from those in SPMS. Micturition problems are very common in PPMS and typical urodynamic findings are DSD and detrusor hyperrefleksia. Upregulated expressions of AMs and some cytokines in blood and CSF compared to controls indicate the presence of persistent inflammation even in neurodegenerative subtypes of MS

Safety of alemtuzumab in a nationwide cohort of Finnish multiple sclerosis patients

Abstract Background:Alemtuzumab is an effective disease-modifying therapy (DMT) for highly active multiple sclerosis (MS). However, safety concerns limit its use in clinical practice. Objectives:To evaluate the safety of alemtuzumab in a nationwide cohort of Finnish MS patients. Methods:In this retrospective case series study, we analyzed the data of all but two MS patients who had received alemtuzumab in Finland until 2019. Data were systematically collected from patient files. Results:Altogether 121 patients were identified, most of whom had received previous DMTs (82.6%). Median follow-up time after treatment initiation was 30.3 months and exceeded 24 months in 78 patients. Infusion-associated reactions (IARs) were observed in 84.3%, 57.3%, and 57.1% of patients during alemtuzumab courses 1–3, respectively. Serious adverse events (SAEs) were observed in 32.2% of patients, serious IARs in 12.4% of patients, and SAEs other than IARs in 23.1% of patients. Autoimmune adverse events were observed in 30.6% of patients. One patient died of hemophagocytic lymphohistiocytosis, and one patient died of pneumonia. A previously unreported case of thrombotic thrombocytopenic purpura was documented. Conclusions:SAEs were more frequent in the present cohort than in previous studies. Even though alemtuzumab is a highly effective therapy for MS, vigorous monitoring with a long enough follow-up time is advised