Efficacy, Safety and Clinical Outcomes of Biologic Drugs in the Treatment of Rheumatoid Arthritis

Rheumatoid Arthritis (RA) is an autoimmune disease, which is treated with anti-inflammatory and immunosuppressive medication comprising synthetic disease-modifying anti-rheumatic (sDMARDs) and biologic drugs. In this thesis all published randomized controlled trials studying the efficacy and safety of biologic drugs based on the inhibition of tumor necrosis factor (TNF) were identified, evaluated and pooled in using a systematic review including a meta-analysis. Then we pursued a cross-sectional overview on disease activity and medical treatment of patients with RA treated wthin the Finnish specialized healthcare. Finally, we executed two cohort studies in which we combined longitudinal patient data with information on the incidence of serious infections, malignancies and joint replacement operations retrieved from national registers. Forty-one articles reporting on 26 RCTs of TNF-inhibitors were included in the systematic review and meta-analysis. TNF-inhibitors as a monotherapy were more efficacious than placebo but comparable to methotrexate (MTX). TNF-inhibitor and MTX combination was superior to either MTX or TNF-inhibitor alone. TNF-inhibitors were relatively safe as compared to either MTX or placebo. The cross-sectional study revealed 91%, 58% and 21% of patients as concurrent users of (sDMARDs), glucocorticoids and biologics, respectively. The cohort studies showed that the adjusted incidence rate ratios (aIRRs) of infections compared to sDMARD users were 0.9 (95% CI 0.6-1.4) and 1.1 (95% CI 0.59-1.9) for the users of TNF-inhibitors and rituximab, respectively. The aIRRs of malignancies were similar between the sDMARD and biologics users. There were more primary joint replacement operations per 100 patient years among the users of biologic drugs (3.89, 95% CI 3.41 4.41) vs. DMARD (2.63, 2.35 2.94) users but slightly fewer revisions (0.65, 0.46 0.88 vs. 0.83, 0.68 1.01). Efficacy and safety of TNF-inhibitors are comparable to MTX and only few differences were observed between individual agents. Currently, more than 20% of Finnish RA patients are using biologic drugs, with a majority of them in combination therapy with sDMARDs. The incidence of serious infections and malignancies is comparable between the users of sDMARDs, TNF-inhibitors and rituximab. Compared to sDMARD users, biologic drugs users had a higher incidence of joint replacement operations while the durability of the prostheses were similar.Nivelreuma on autoimmuunisairaus, jonka oireisiin kuuluu reumatulehduksesta johtuvaa nivelarkuutta- ja turvotusta erityisesti käsissä ja jaloissa. Nivelreuman diagnoosi perustuu lääkärin tekemään arvioon potilaan voinnista, potilaan omaan arvioon oireistaan sekä laboratorio- ja kuvantamistutkimuksiin. Nivelreuman hoito perustuu tulehdusreaktion hillintään ja sen tavoitteena on oireeton tauti. Suomalaisten hoitosuositusten mukaisesti lääkehoito aloitetaan metotreksaatilla tai tarvittaessa metotreksaatin, sulfasalatsiinin ja hydroksiklorokiinin sekä pieniannoksisen prednisolonin yhdistelmähoidolla. Mikäli näillä tavanomaisilla reumalääkkeillä ei saavuteta riittävää hoitovastetta tai ne ovat vasta-aiheisia potilaalla, voidaan hoitoa jatkaa biologisilla lääkkeillä. Väitöskirjatutkimuksen ensimmäisessä vaiheessa etsittiin, arvioitiin ja yhdistettiin kaikki Tuumorinekroosifaktorin estoon perustuvia biologisen lääkkeitä koskevat satunnaistetut kontrolliryhmän sisältävät tutkimukset niiden tehon ja turvallisuuden selvittämiseksi. Seuraavaksi tehtiin poikkileikkaustutkimus erikoissairaanhoidon piirissä olevista nivelreumapotilaista, jotta tiedettäisiin suomalaisten nivelreumapotilaiden tyypillinen tautiaktiivisuus ja heillä käytetty lääkitys. Lopuksi tehtiin kaksi kohorttitutkimusta, joissa selvitettiin biologisen lääkehoidon aikaisten vakavien infektioiden ja syöpien ilmaantuvuutta sekä biologisen lääkehoidon vaikutusta tekonivelkururgian tarpeeseen ja uusintaleikkaustarpeeseen. Tulosten perusteella biologiset lääkkeet ovat satunnaistetuissa verrokkiryhmän sisältävissä tutkimuksissa olleet vähintään yhtä tehokkaita ja turvallisia kuin metotreksaatti. Yhdistelmähoitona metotreksaatin kanssa ne ovat tehokkaampia, mutta yhtä turvallisia kuin kumpikaan vaihtoehto yksinään. Biologisilla lääkkeillä hoidetut suomalaiset nivelreumapotilaat eivät saaneet enempää vakavia infektioita tai syöpiä kuin pelkästään tavanomaisilla reumalääkkeillä hoidetut potilaatkaan. Biologista lääkehoitoa saavilla potilailla oli enemmän tekonivelleikkauksia kuin tavanomaisten reumalääkkeiden käyttäjillä, mikä saattoi johtua biologisten lääkkeiden käyttäjien vaikeammasta taudista ja pidemmälle edenneistä niveleroosiosta

64 pisteen riski ja kuinka sitä pienennetään

Riskinarviointi auttaa varautumaan muutosten tuomiin uhkiin. Vaikutukset potilasturvallisuuteenkannattaa arvioida numeerisesti vertailun ja seurannan helpottamiseksi

The Cost-Effectiveness of Biologics for the Treatment of Rheumatoid Arthritis : A Systematic Review

Background and Objectives Economic evaluations provide information to aid the optimal utilization of limited healthcare resources. Costs of biologics for Rheumatoid arthritis (RA) are remarkably high, which makes these agents an important target for economic evaluations. This systematic review aims to identify existing studies examining the cost-effectiveness of biologics for RA, assess their quality and report their results systematically. Methods A literature search covering Medline, Scopus, Cochrane library, ACP Journal club and Web of Science was performed in March 2013. The cost-utility analyses (CUAs) of one or more available biological drugs for the treatment of RA in adults were included. Two independent investigators systematically collected information and assessed the quality of the studies. To enable the comparison of the results, all costs were converted to 2013 euro. Results Of the 4890 references found in the literature search, 41 CUAs were included in the current systematic review. While considering only direct costs, the incremental cost-effectiveness ratio (ICER) of the tumor necrosis factor inhibitors (TNFi) ranged from 39,000 to 1 273,000 (sic)/quality adjusted life year (QALY) gained in comparison to conventional disease-modifying antirheumatic drugs (cDMARDs) in cDMARD naive patients. Among patients with an insufficient response to cDMARDs, biologics were associated with ICERs ranging from 12,000 to 708,000 (sic)/QALY. Rituximab was found to be the most cost-effective alternative compared to other biologics among the patients with an insufficient response to TNFi. Conclusions When 35,000 (sic)/QALY is considered as a threshold for the ICER, TNFis do not seem to be cost-effective among cDMARD naive patients and patients with an insufficient response to cDMARDs. With thresholds of 50,000 to 100,000 (sic)/QALY biologics might be cost-effective among patients with an inadequate response to cDMARDs. Standardization of multiattribute utility instruments and a validated standard conversion method for missing utility measures would enable better comparison between CUAs.Peer reviewe

Effectiveness and drug survival of TNF-inhibitors in the treatment of psoriatic arthritis : A prospective cohort study

Background and objectives: Tumor necrosis factor (TNF)-inhibitors are used to treat psoriatic arthritis (PsA), but only a limited number of observational studies on this subject have been published thus far. The aim of this research was to analyze the effectiveness and drug survival of TNF-inhibitors in the treatment of PsA. Methods: PsA patients identified from the National Register for Biologic Treatment in Finland (ROB-FIN) starting their first, second, or third TNF-inhibitor treatment between 2004 and 2014 were included. Effectiveness was measured using ACR and EULAR response criteria and modeled using ordinal logistic regression. Treatment persistence was analyzed using Kaplan-Meier survival analysis and Cox proportional hazards model. Results: The study comprised 765 patients and 990 TNF-inhibitor treatment courses. EULAR moderate treatment responses at 6 months were achieved by 68% and 37% of the users of the first and the second or the third biologic, respectively. The probabilities of discontinuing the treatment within 12 and 24 months were 20% and 28%, respectively. Adjusted treatment responses to all TNF-inhibitors were similar; however, co-therapy with conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) was not associated with better effectiveness. Adalimumab [hazard ratio (HR) = 0.62; 95% confidence interval (CD: 0.44-0.88] was superior to infliximab in drug survival while etanercept (HR = 0.77, 95% CI: 0.55-1.1) and golimumab (HR = 0.75, 95% CI: 0.46-1.2) did not differ from it. Co-medication with csDMARDs did not statistically improve drug survival. Conclusion: All available TNF-inhibitors showed similar treatment responses with or without csDMARDs. Adalimumab was associated with better drug survival when compared to infliximab. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe

Systematic Review and Meta-Analysis of the Efficacy and Safety of Existing TNF Blocking Agents in Treatment of Rheumatoid Arthritis

Background and Objectives: Five-tumour necrosis factor (TNF)-blockers (infliximab, etanercept, adalimumab, certolizumab pegol and golimumab) are available for treatment of rheumatoid arthritis. Only few clinical trials compare one TNF-blocker to another. Hence, a systematic review is required to indirectly compare the substances. The aim of our study is to estimate the efficacy and the safety of TNF-blockers in the treatment of rheumatoid arthritis (RA) and indirectly compare all five currently available blockers by combining the results from included randomized clinical trials (RCT). Methods: A systematic literature review was conducted using databases including: MEDLINE, SCOPUS (including EMBASE), Cochrane library and electronic search alerts. Only articles reporting double-blind RCTs of TNF-blockers vs. placebo, with or without concomitant methotrexate (MTX), in treatment of RA were selected. Data collected were information of patients, interventions, controls, outcomes, study methods and eventual sources of bias. Results: Forty-one articles reporting on 26 RCTs were included in the systematic review and meta-analysis. Five RCTs studied infliximab, seven etanercept, eight adalimumab, three golimumab and three certolizumab. TNF-blockers were more efficacious than placebo at all time points but were comparable to MTX. TNF-blocker and MTX combination was superior to either MTX or TNF-blocker alone. Increasing doses did not improve the efficacy. TNF-blockers were relatively safe compared to either MTX or placebo. Conclusions No single substance clearly rose above others in efficacy, but the results of the safety analyses suggest that etanercept might be the safest alternative. Interestingly, MTX performs nearly identically considering both efficacy and safety aspects with a margin of costs.Peer reviewe

Cost-effectiveness of abatacept, tocilizumab and TNF-inhibitors compared with rituximab as second-line biologic drug in rheumatoid arthritis

Objectives The objective of this study was to evaluate the cost-effectiveness of abatacept, tocilizumab, and tumor necrosis factor (TNF) inhibitors as compared with rituximab in Finnish rheumatoid arthritis patients, who have previously been treated with TNF inhibitors. Methods A patient-level simulation model was developed to predict costs and outcomes associated with four biological drugs (abatacept, tocilizumab, rituximab and TNF inhibitors) in the treatment of rheumatoid arthritis. Following lack of efficacy or adverse events, the patients were switched to another biological drug until all four options were exhausted. After that, the patients were assumed to receive a 6th line treatment until death. The patients' baseline characteristics and regression models used in the simulation were based on observational data from the National Register for Biological Treatments in Finland. Direct costs comprised drug costs, administration costs, costs of switching, and outpatient and inpatient care, while indirect costs included disability pension and sick leaves due to rheumatoid arthritis. Several subgroup and deterministic sensitivity analyses were conducted. Results Drug costs were the lowest for rituximab, but when administration costs and costs of switching were included, drug costs were the lowest for TNF inhibitors. Abatacept was associated with the highest drug costs, whereas rituximab was associated with the highest healthcare costs. In total, TNF inhibitors had the lowest direct costs, while rituximab had the highest direct costs. The amount of quality-adjusted life years (QALY) gained ranged from 9.405 for rituximab to 9.661 for TNF inhibitors. TNF inhibitors, abatacept, and tocilizumab were dominant in comparison to RTX. Conclusions TNF inhibitors, abatacept, and tocilizumab had lower costs and higher QALYs than rituximab, and therefore, they were dominant in comparison to rituximab. As TNF inhibitors had the lowest costs and highest QALYs, they were the most cost-effective treatment option.Peer reviewe

Opportunities and challenges for real-world studies on chronic inflammatory joint diseases through data enrichment and collaboration between national registers : the Nordic example

RMD Open 2018;4:e000655. doi:10.1136/ rmdopen-2018-000655Peer reviewe

Treatment retention of infliximab and etanercept originators versus their corresponding biosimilars : Nordic collaborative observational study of 2334 biologics naive patients with spondyloarthritis

Objective Although clinical trials support equivalence of originator products and biosimilars for etanercept and infliximab, real-world studies among biologics-naive patients with spondyloarthritis (SpA) are lacking. The objectives were to compare treatment retention in biologics-naive patients with SpA starting either the originator product or a biosimilar of infliximab and etanercept, and to explore the baseline characteristics of these patients. Methods Patients with SpA (ankylosing spondylitis/non-radiographical axial SpA/undifferentiated SpA), starting infliximab or etanercept as their first-ever biological disease-modifying antirheumatic drug during January 2014-June 2017 were identified in five Nordic biologics-rheumatology registers. Baseline characteristics were retrieved from each registry; comorbidity data were identified through linkage to national health registers. Country-specific data were pooled, and data on infliximab and etanercept were analysed separately. Comparisons of treatment retention between originators and biosimilars were assessed through survival probability curves, retention rates (2 years for infliximab/1 year for etanercept) and Hazard Ratios (HR). Results We included 1319 patients starting infliximab (24% originator/76% biosimilar), and 1015 patients starting etanercept (49% originator/51% biosimilar). Baseline characteristics were largely similar for the patients treated with the originators compared with the corresponding biosimilars. Survival probability curves were highly similar for the originator and its biosimilar, as were retention rates: infliximab 2-year retention originator, 44% (95% CI 38% to 50%)/biosimilar, 46% (95% CI: 42% to 51%); and etanercept 1-year retention originator, 66% (95% CI 61% to 70%)/biosimilar, 73% (95% CI 68% to 78%). HRs were not statistically significant. Conclusion This observational study of biologics-naive patients with SpA from five Nordic countries showed similar baseline characteristics and very similar retention rates in patients treated with originators versus biosimilars, for both infliximab and etanercept, indicating comparable effectiveness in clinical practice.Peer reviewe

Exposure to specific tumour necrosis factor inhibitors and risk of demyelinating and inflammatory neuropathy in cohorts of patients with inflammatory arthritis : a collaborative observational study across five Nordic rheumatology registers

Funding Information: This work was supported by NordForsk and the Foundation for Research in Rheumatology (Foreum) and Vinnova. The research infrastructure was supported by funds from the Swedish Research Council, the Swedish Heart Lung Foundation and the Swedish Cancer Society, and funds from Region Stockholm-Karolinska Institutet (ALF). The Center for Treatment of Rheumatic and Musculoskeletal Diseases (REMEDY) (Norway) is funded as a Centre for Clinical Treatment Research by the Research Council of Norway (project 328657). Publisher Copyright: © 2023 Author(s) (or their employer(s)). Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Objective To compare incidences of neuroinflammatory events, including demyelinating disease (DML), inflammatory polyneuropathies (IPN) and multiple sclerosis (MS), in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA; including psoriatic arthritis) starting a tumour necrosis factor inhibitor (TNFi), investigating whether monoclonal TNFi antibodies (other TNFis (oTNFis)) confer higher risk than etanercept. Methods This is an observational cohort study including patients from the five Nordic countries starting a TNFi in 2001-2020. Time to first neuroinflammatory event was identified through register linkages. We calculated crude incidence rates (cIR) per 1000 person-years and used multivariable-adjusted Cox regression to compare incidences of neuroinflammatory events overall and for DML, IPN and MS with oTNFi versus etanercept. We further examined individual TNFis and indications. Results 33 883 patients with RA and 28 772 patients with SpA were included, initiating 52 704 and 46 572 treatment courses, respectively. In RA, we observed 135 neuroinflammatory events (65% DML) with cIR of 0.38 with oTNFi and 0.34 with etanercept. The HR of oTNFi versus etanercept was 1.07 (95% CI 0.74 to 1.54) for any neuroinflammatory event, 0.79 (95% CI 0.51 to 1.22) for DML, 2.20 (95% CI 1.05 to 4.63) for IPN and 0.73 (95% CI 0.34 to 1.56) for MS. In SpA, we observed 179 events (78% DML) with cIR of 0.68 with oTNFi and 0.65 with etanercept. The HR for any neuroinflammatory event, DML, IPN and MS was 1.06 (95% CI 0.75 to 1.50), 1.01 (95% CI 0.68 to 1.50), 1.28 (95% CI 0.61 to 2.69) and 0.94 (95% CI0.53 to 1.69), respectively. Conclusion The cIRs of neuroinflammatory events are higher in SpA than in RA, but the choice of specific TNFi does not seem to play an important role in the risk of neuroinflammatory events.Peer reviewe