A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases

Objectives: Informing an international task force updating the consensus statement on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) selectively targeting interleukin-6 (IL-6) pathway in the context of immune-mediated inflammatory diseases. Methods: A systematic literature research of all publications on IL-6 axis inhibition with bDMARDs published between January 2012 and December 2020 was performed using MEDLINE, EMBASE and Cochrane CENTRAL databases. Efficacy and safety outcomes were assessed in clinical trials including their long-term extensions and observational studies. Meeting abstracts from ACR, EULAR conferences and results on clinicaltrials.gov were taken into consideration. Results: 187 articles fulfilled the inclusion criteria. Evidence for positive effect of IL-6 inhibition was available in various inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still’s disease, cytokine release syndrome due to chimeric antigen receptor T cell therapy and systemic sclerosis-associated interstitial lung disease. Newcomers like satralizumab and anti-IL-6 ligand antibody siltuximab have expanded therapeutic approaches for Castleman’s disease and neuromyelitis optica, respectively. IL-6 inhibition did not provide therapeutic benefits in psoriatic arthritis, ankylosing spondylitis and certain connective tissue diseases. In COVID-19, tocilizumab (TCZ) has proven to be therapeutic in advanced disease. Safety outcomes did not differ from other bDMARDs, except higher risks of diverticulitis and lower gastrointestinal perforations. Inconsistent results were observed in several studies investigating the risk for infections when comparing TCZ to TNF-inhibitors. Conclusion: IL-6 inhibition is effective for treatment of several inflammatory diseases with a safety profile that is widely comparable to other bDMARDs

Consensus statement on blocking interleukin-6 receptor and interleukin-6 in inflammatory conditions: an update

Background: Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway. Methods: A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document. Results: The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still’s disease, Castleman’s disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring. Conclusions: The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers

Langzeitverlauf nach stationärer Therapie eines Kopfschmerzes durch übermäßigen Medikamentengebrauch - eine follow-up Studien

Hintergrund: Der Kopfschmerz bei Medikamentenübergebrauch („medication-overuse headache“ MOH) stellt eine relativ neue und zunehmend wachsende Problematik dar, dessen Häufigkeit nach dem Kopfschmerz vom Spannungstyp und der Migräne in Europa den dritten Platz einnimmt. Der MOH ist das Ergebnis eines exzessiven Medikamentengebrauchs bei einer empfänglichen Person mit einer ursprünglich bestehenden primären Kopfschmerzform. Bei manifestem MOH hat sich eine Entzugsbehandlung als Mittel der Wahl profiliert. Ziel der Studie: Die Ziele dieser Studie liegen neben der Eruierung des Langzeitverlaufes und MOH-Rückfalls nach stationärer Entzugstherapie in der Erforschung von Faktoren, die den Verlauf beeinflussen. Methodik: In die Studie wurden alle 493 Patienten eingeschlossen, die sich in dem Zeitraum vom 01.01.2000 bis 31.12.2015 unter der Diagnose „Arzneimittelbedingter Kopfschmerz“ nach ICHD-3 beta an der Universitätsklinik für Neurologie am Allgemeinen Krankenhaus der Stadt Wien einer stationären Entzugsbehandlung unterzogen haben. Die Daten zum stationären Aufenthalt wurden den Entlassungsbriefen entnommen, die Daten zum Langzeitverlauf wurden anhand identisch strukturierter Telefoninterviews erhoben. Zur Quantifizierung psychiatrischer Komorbiditäten sowie funktioneller Beeinträchtigungen durch Kopfschmerzen wurden validierte Fragebögen verwendet (Severity of Dependence Scale, SDS; Beck Anxiety Inventory, BAI; Beck Depression Inventory II, BDI II; Migraine Disability Assessment, MIDAS). In allen Fragenbögen sind höhere Werte ungünstig. Patienten und Patientinnen wurden als ungünstiger Langzeitverlauf klassifiziert, wenn 15 Kopfschmerztage/Monat, eine Medikamenteneinnahme an 10 Tagen pro Monat und eine mittelstarke bis starke Schmerzintensität gemeinsam zu irgendeinem Zeitpunkt in der Nachbeobachtung zusammentrafen. Resultate: Bei 82% (n=403) konnte mangels Interview kein Studieneinschlusss erfolgen, wobei 7 der insgesamt 90 Befragten nicht die Einschlusskriterien erfüllten. 17% (n=83) der PatientInnen erfüllen alle Einschlusskriterien und konnten in die vorliegende Studie inkludiert werden. Im Hinblick auf die Baselinevariablen für Alter, Geschlecht, Dauer des primären ursprünglichen Kopfschmerzes (KS) und Dauer des MOH zwischen den in die Studie eingeschlossenen 83 Patienten und Patientinnen und den insgesamt 410 nicht eingeschlossenen Personen zeigte sich kein statistisch signifikanter Unterschied. Der Beobachtungszeitraum vom letzten stationären Entzug bis zum follow-up lag im Durchschnitt bei 7,8 Jahren. Bei 34 (41%) Probanden lag ein ungünstiger Verlauf vor; 37,3% zeigten hinsichtlich ihrer Kopfschmerzen einen ungünstigen Verlauf, 36% einen rekurrenten Medikamentenübergebrauch und etwa ein Drittel erfüllte im definierten Beobachtungszeitraum die MOH-Kriterien. PatientInnen mit ungünstigem Verlauf wiesen in puncto SDS, BAI, BDI-II und MIDAS signifikant höhere Werte auf; die Verwendung einer Akutmedikation und subjektive Einschätzung der stationären Therapie erwiesen sich Faktoren, die mit einem ungünstigen Langzeitverlauf in Zusammenhang standen. In den Korrelationsuntersuchungen wiesen Patienten und Patientinnen mit zunehmendem Alter tendenziell weniger ungünstige Verlaufsformen auf. PatientInnen, welche die MOH-Rückfall erlitten, hatten hinsichtlich SDS und MIDAS signifikant höhere Werte als PatientInnen ohne Rückfall. Als Faktoren für einen Rückfall konnten das Bestehen anderer chronischer Schmerzen und ebenso die subjektive Einschätzung des Behandlungserfolgs identifiziert werden. Konklusion: Diese Studie untersucht anhand multipler Parameter den Langzeitverlauf nach stationärer Therapie eines Kopfschmerzes durch übermäßigen Medikamentengebrauch und liefert erstmals Daten für Österreich über einen überdurchschnittlichen langen Beobachtungszeitraum. Die ermittelten Resultate sind mit der bisherigen Literatur vergleichbar und implizieren, dass bei komplizierten MOH-Fällen die stationäre Entzugsstrategie vorzuziehen ist. Eine suffiziente Nachsorge und Betreuung unmittelbar nach stationärer Therapie ist unabdingbar.Background: Medication-overuse headache (MOH) is a relatively new and growing problem and the third-leading cause of headaches after tension-type headache and migraine in Europe. MOH is the result of excessive drug use in susceptible persons with a pre-existing headache. In overt MOH, withdrawal therapy has emerged as the treatment of choice. Aim: The aims of this study are to investigate the long-term outcome and MOH relapse after inpatient withdrawal therapy as well as the assessment of influential factors for therapeutic outcome. Methods: The study included all 493 patients who previously underwent inpatient withdrawal in the period from 01/01/2000 to 31/12/2015 under the diagnosis of "medication overuse headache" according to ICHD-3 beta at the Department of Neurology, General Hospital of Vienna. For assessing the long-course, we performed standardized telephone interviews. In order to quantify potential psychiatric comorbidities and functional impairments due to headaches respectively we used validated questionnaires (Severity of Dependence Scale, SDS; Beck Anxiety Inventory, BAI; Beck Depression Inventory II, BDI-II; Migraine Disability Assessment, MIDAS). In all quastionnaires higher values are unfavorable. Patients were classified as an unfavorable long-term outcome if 15 headache days/month, 10 days of medication use, and moderate to severe pain intensity came together at some point in the follow-up. Results: For 82% (n = 403) no study inclusion was possible due to lack of interview; 7 out of 90 respondents failed to meet the inclusion criteria. 17% (n = 83) of the patients met all inclusion criteria and could therefore be included in the present study. There were no statistically significant differences in the baseline variables for age, sex, primary headache duration and duration of MOH between the 83 patients enrolled in the study and the total of 410 non-included patients. The observation period from the last inpatient withdrawal to follow-up averaged 7.8 years. 41% (n = 34) of the respondents were classified as unfavorable long-term outcome; 37.3% had an unfavorable outcome with regard to their headaches, 36% had a recurrent medication overuse and about one third fulfilled the MOH criteria during the defined observation period. Patients with unfavorable outcome had significantly higher scores for SDS, BAI, BDI and MIDAS; the use of acute medication intake and subjective evaluation of inpatient treatment were factors associated with unfavorable long-term outcome. In the correlation examinations, patients tended to show less unfavorable forms of progression with increasing age. Apart from that, patients who suffered MOH relapse had significantly higher scores for SDS and MIDAS than non-relapsed patients; the co-existence of other chronic pain as well as the subjective evaluation of the success of the treatment could be identified as promoting factors for a relapse. Conclusion: Using multiple parameters, this study examines the long-term course after inpatient treatment of MOH and for the first time provides data for Austria on an above-average long observation period. The results obtained are comparable to the previous literature and imply that in complex MOH cases the inpatient withdrawal strategy is preferable. Sufficient aftercare and care immediately after inpatient therapy is indispensable.eingereicht von Kastriot KastratiAbweichender Titel laut Übersetzung der Verfasserin/des VerfassersMedizinische Universität Wien, Diplomarb., 2018(VLID)253362

A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases

Objectives: Informing an international task force updating the consensus statement on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) selectively targeting interleukin-6 (IL-6) pathway in the context of immune-mediated inflammatory diseases. Methods: A systematic literature research of all publications on IL-6 axis inhibition with bDMARDs published between January 2012 and December 2020 was performed using MEDLINE, EMBASE and Cochrane CENTRAL databases. Efficacy and safety outcomes were assessed in clinical trials including their long-term extensions and observational studies. Meeting abstracts from ACR, EULAR conferences and results on clinicaltrials.gov were taken into consideration. Results: 187 articles fulfilled the inclusion criteria. Evidence for positive effect of IL-6 inhibition was available in various inflammatory diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, cytokine release syndrome due to chimeric antigen receptor T cell therapy and systemic sclerosis-associated interstitial lung disease. Newcomers like satralizumab and anti-IL-6 ligand antibody siltuximab have expanded therapeutic approaches for Castleman's disease and neuromyelitis optica, respectively. IL-6 inhibition did not provide therapeutic benefits in psoriatic arthritis, ankylosing spondylitis and certain connective tissue diseases. In COVID-19, tocilizumab (TCZ) has proven to be therapeutic in advanced disease. Safety outcomes did not differ from other bDMARDs, except higher risks of diverticulitis and lower gastrointestinal perforations. Inconsistent results were observed in several studies investigating the risk for infections when comparing TCZ to TNF-inhibitors. Conclusion: IL-6 inhibition is effective for treatment of several inflammatory diseases with a safety profile that is widely comparable to other bDMARDs

Consensus statement on blocking interleukin-6 receptor and interleukin-6 in inflammatory conditions: an update

Background: Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway. Methods: A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document. Results: The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring. Conclusions: The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers