| 1. |
- Bower, Hannah, et al.
(författare)
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Are JAKis more effective among elderly patients with RA, smokers and those with higher cardiovascular risk? A comparative effectiveness study of b/tsDMARDs in Sweden.
- 2023
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Ingår i: RMD open. - : BMJ Publishing Group Ltd. - 2056-5933. ; 9:4
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Tidskriftsartikel (refereegranskat)abstract
- To investigate whether the relative effectiveness of janus kinase inhibitors (JAKis) versus tumour necrosis factor inhibitors (TNFi) or other biological disease-modifying antirheumatic drugs in rheumatoid arthritis differ by the presence or absence of risk factors for cardiovascular (CV) disease, age, sex and smoking.Through Swedish registers, we identified 13493 individuals with 3166 JAKi, 5575 non-TNFi and 11 286 TNFi treatment initiations 2016-2022. All lines of therapy were included, with the majority in second line or higher. Treatment response was defined as the proportion reaching European Alliance of Associations for Rheumatology (EULAR) good response and Clinical Disease Activity Index (CDAI) remission, respectively, within 6 months. Crude percentage point differences in these proportions (JAKis, and non-TNFis, vs TNFis) overall and by risk factors were observed, and adjusted for confounders using linear regression models. Predicted probabilities of response and remission were estimated from adjusted Poisson models, and presented across CV risk and age.Overall, adjusted percentage point differences indicated higher response (+5.0%, 95% CI 2.2% to 7.9%) and remission (+5.8%, 95% CI 3.2% to 8.5%) with JAKis versus TNFis. The adjusted percentage point differences for response in those above 65, at elevated CV risk, and smokers were +5.9% (95% CI 2.7% to 9.0%), +8.3% (95% CI 5.3% to 11.4%) and +6.0% (95% CI 3.3% to 8.7%), respectively. The corresponding estimates for remission were +8.0% (95% CI 5.3% to 10.8%), +5.6% (95% CI 3.0% to 8.2%) and +7.6% (95% CI 5.5% to 9.7%).As used in clinical practice, response and remission at 6 months with JAKis are higher than with TNFi. Among patients with risk factors of concern, effectiveness is similar or numerically further increased. For individualised benefit-to-risk ratios to guide treatment choice, safety and effectiveness in specific patient segments should be considered.
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| 2. |
- Bower, Hannah, et al.
(författare)
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Impact of the COVID-19 pandemic on morbidity and mortality in patients with inflammatory joint diseases and in the general population : a nationwide Swedish cohort study
- 2021
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 80:8, s. 1086-1093
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To estimate absolute and relative risks for all-cause mortality and for severe COVID-19 in inflammatory joint diseases (IJDs) and with antirheumatic therapies.Methods: Through Swedish nationwide multiregister linkages, we selected all adult patients with rheumatoid arthritis (RA, n=53 455 in March 2020), other IJDs (here: spondyloarthropathies, psoriatic arthritis and juvenile idiopathic arthritis, n=57 112), their antirheumatic drug use, and individually matched population referents. We compared annual all-cause mortality March-September 2015 through 2020 within and across cohorts, and assessed absolute and relative risks for hospitalisation, admission to intensive care and death due to COVID-19 March-September 2020, using Cox regression.Results: During March-September 2020, the absolute all-cause mortality in RA and in other IJDs was higher than 2015-2019, but relative risks versus the general population (around 2 and 1.5) remained similar during 2020 compared with 2015-2019. Among patients with IJD, the risks of hospitalisation (0.5% vs 0.3% in their population referents), admission to intensive care (0.04% vs 0.03%) and death (0.10% vs 0.07%) due to COVID-19 were low. Antirheumatic drugs were not associated with increased risk of serious COVID-19 outcomes, although for certain drugs, precision was limited.Conclusions: Risks of severe COVID-19-related outcomes were increased among patients with IJDs, but risk increases were also seen for non-COVID-19 morbidity. Overall absolute and excess risks are low and the level of risk increases are largely proportionate to those in the general population, and explained by comorbidities. With possible exceptions, antirheumatic drugs do not have a major impact on these risks.
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| 3. |
- Cordtz, Rene Lindholm, et al.
(författare)
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Haematological malignancies in patients with psoriatic arthritis overall and treated with TNF inhibitors : a Nordic cohort study
- 2022
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Ingår i: RMD Open. - : BMJ Publishing Group Ltd. - 2056-5933. ; 8:2
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To evaluate the risk of haematological malignancies in patients with psoriatic arthritis (PsA) overall, and in relation to treatment with tumour necrosis factor inhibitors (TNFi).Methods We identified that patients with PsA starting a first TNFi from the clinical rheumatology registers (CRR) in the five Nordic countries (n=10 621) and biologics-naive PsA patients from (1) the CRR (n=18 705) and (2) the national patient registers (NPR, n=27 286, Sweden and Denmark) from 2006 through 2019. For Sweden and Denmark, general population comparators were matched 5:1 to PsA patients on birth year, year at start of follow-up and sex. By linkage to the national cancer registers in all countries, we collected information on haematological malignancies overall, and categorised into lymphoid or myeloid types. We estimated incidence rate ratios (IRRs) with 95% CIs using modified Poisson regression for TNFi-treated versus biologics-naive PsA patients and versus the general population adjusted for age, sex, calendar period and country.Results During 59 827 person-years, 40 haematological malignancies occurred among TNFi-treated patients with PsA resulting in a pooled IRR of 0.96 (0.68-1.35) versus biologics-naive PsA from CRR and an IRR of 0.84 (0.64-1.10) versus biologics-naive PsA from NPR. The IRR of haematological malignancies in PsA overall versus general population comparators was 1.35 (1.17-1.55). The estimates were largely similar for lymphoid and myeloid malignancies.Conclusions Treatment with TNFi in patients with PsA was not associated with an increased incidence of haematological malignancies. Conversely, a moderately increased underlying risk was seen in patients with PsA compared with the general population.
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| 4. |
- Delcoigne, Bénédicte, et al.
(författare)
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Blood neurofilament light levels segregate treatment effects in multiple sclerosis
- 2020
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Ingår i: Neurology. - 1526-632X. ; 94
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Tidskriftsartikel (refereegranskat)abstract
- Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. OBJECTIVE: To determine factors (including the role of specific disease modulatory treatments [DMTs]) associated with (1) baseline, (2) on-treatment, and (3) change (from treatment start to on-treatment assessment) in plasma neurofilament light chain (pNfL) concentrations in relapsing-remitting multiple sclerosis (RRMS). METHODS: Data including blood samples analyses and long-term clinical follow-up information for 1,261 Swedish patients with RRMS starting novel DMTs were analyzed using linear regressions to model pNfL and changes in pNfL concentrations as a function of clinical variables and DMTs (alemtuzumab, dimethyl fumarate, fingolimod, natalizumab, rituximab, and teriflunomide). RESULTS: The baseline pNfL concentration was positively associated with relapse rate, Expanded Disability Status Scale score, Age-Related MS Severity Score, and MS Impact Score (MSIS-29), and negatively associated with Symbol Digit Modalities Test performance and the number of previously used DMTs. All analyses, which used inverse propensity score weighting to correct for differences in baseline factors at DMT start, highlighted that both the reduction in pNfL concentration from baseline to on-treatment measurement and the on-treatment pNfL level differed across DMTs. Patients starting alemtuzumab displayed the highest reduction in pNfL concentration and lowest on-treatment pNfL concentrations, while those starting teriflunomide had the smallest decrease and highest on-treatment levels, but also starting from lower values. Both on-treatment pNfL and decrease in pNfL concentrations were highly dependent on baseline concentrations. CONCLUSION: Choice of DMT in RRMS is significantly associated with degree of reduction in pNfL, which supports a role for pNfL as a drug response marker.
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| 5. |
- Delcoigne, Bénédicte
(författare)
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Efficient design and analysis of extended case-control studies
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The nested case-control design is widely used in epidemiology for its efficiency, as it combines the advantages of both cohort and case-control designs. This design is an extension of the matched case-control design, where the matching variable is the time of occurrence of the outcome. Consequently, the nested case-control data are usually analysed with conditional logistic regression; however, this analysis suffers from various limitations. Several authors have developed novel statistical methods for alternative analyses of nested case-control data using basic information from the underlying cohort. Among these methods, one approach consists of ignoring the matching, weighting the sampled individuals to recover a representation of the underlying cohort and analysing the data by maximising a weighted partial likelihood. This method can be considered when two conditions are fulfilled: 1) the sampling was performed in a well-defined underlying cohort for which basic information is available, and 2) the exact sampling procedure is known. This thesis aimed to refine and extend the scope of the weighted likelihood approach in nested case-control data analysis by investigating the advantages of this method as an alternative to the traditional conditional logistic regression in several situations. The reuse of nested case-control data to address a research question regarding a new outcome, the calculation of absolute risk, the mitigation of the problem of overmatching, the maximisation of the data exploitation in case of clustered data and the analysis of subgroups of nested case-control data were addressed in this thesis. While Studies I and III were motivated by an actual epidemiological question for which data were available, simulation studies were the main approach used in Studies II and IV. Reusing nested case-control data to address a research question regarding another outcome was the central point of interest in Study I. Addressing an epidemiological question regarding the risk factors for contralateral breast cancer, for which data on contralateral breast cancer case patients were available, the feasibility of reusing nested case-control data from a previous study as the control dataset was studied. Practical aspects of the approach were highlighted, such as the consequences of reusing data which have narrow inclusion criteria, the restriction in the choice of the type of weights which can be calculated and the importance of having information on censoring dates for controls. In addition, we found that an imperfect reconstruction of the study base led to similar estimates in the analysis compared to an appropriate study base reconstruction; moreover, we confirmed that using unstratified weights (in cases of stratified sampling) provided similar exposure estimates than stratified weights, provided that adjustments were made on the confounder variables which drove the sampling. We also confirmed that using a naïve unweighted method instead of an appropriate method led to biased estimates. Absolute risk estimation was studied in Study II. Two methods were compared with both simulation studies and a real data application. The ability of each method to provide valid absolute risk estimates was investigated, in particular in cases of matched study designs. Both the Langholz-Borgan and weighted methods provided valid estimates in most situations, the latter showing slightly higher levels of precision than the former. In case of fine matching, the Langholz-Borgan method was more prone to be biased than the weighted method and had larger standard errors. In Study III, we handled nested case-control data, which had been collected to address an epidemiological question regarding how radiation therapy and smoking interact in their association with lung cancer in female breast cancer patients. Data on paired organs (breast and lungs) were collected for exposure and outcome variables, which provided clustered data at the individual level. The collected data was also characterised by the problem of overmatching which arose at the design stage. Using weighted partial likelihood allowed mitigation of the problem of overmatching and better exploited the collected data, compared to conditional logistic regression. In addition, a further advantage of the weighted approach was to enable calculating the absolute risk for a lung to develop cancer given the radiation therapy dose received for breast cancer treatment and the smoking habits of the patient. In Study IV, we compared the conditional logistic regression and weighted likelihood methods in terms of validity and efficiency of nested case-control data subgroup analyses, with subgroups defined by different variables measured at baseline. All investigated subgroup analyses provided valid estimates with both analyses. The advantages of weighted likelihood compared to conditional logistic regression were highlighted for the estimate’s precision. In addition, we showed that the weighting system enabled, on average, the reconstruction of the correct number of individuals at risk over time, for the whole cohort and in subgroups. In conclusion, the weighted likelihood approach showed several advantages compared to the traditional conditional logistic regression in nested case-control data analysis, which reinforces, refines and extends what has been previously shown in the literature.
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| 6. |
- Delcoigne, Bénédicte, et al.
(författare)
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How does current disease activity in rheumatoid arthritis affect the short-term risk of acute coronary syndrome? : A clinical register based study from Sweden and Norway
- 2023
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Ingår i: European journal of internal medicine. - 0953-6205 .- 1879-0828. ; 115, s. 55-61
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To estimate short-term risks of acute coronary syndrome (ACS) in patients with rheumatoid arthritis (RA) as a function of current RA disease activity including remission.Methods: Data from clinical visits of RA patients in Sweden (SE) and Norway (NO) between January 1st 2012 until December 31st 2020 were used. At each visit, patient's disease activity was assessed including remission status (measured with several metrics). Through linkage to national health and death registers, patients were followed up for incident ACS up to six months from each visit. We compared the short-term risk of ACS in patients not in remission vs. in remission using Cox regression analyses with robust standard errors, adjusted for country and covariates (e.g., age, sex, prednisolone use, comorbidities). We also explored disease activity categories as exposure.Results: We included 212,493 visits (10,444 from Norway and 202,049 from Sweden) among 41,250 patients (72% women, mean age at visit 62 years). During the 6-month follow-ups, we observed 524 incident ACS events. Compared to patients in remission, patients currently not in remission had an increased rate of ACS: adjusted hazard ratio (95% confidence interval) 1.52 (1.24–1.85) with DAS28 metric. The crude absolute six-month risks were 0.2% for patients in remission vs. 0.4% for patients with DAS28 high disease activity. The use of alternative RA disease activity and remission metrics provided similar results.Conclusion: Failure to reach remission is associated with elevated short-term risks of ACS, underscoring the need for CV risk factor optimization in these patients.
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| 7. |
- Delcoigne, Benedicte, et al.
(författare)
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Short-term, intermediate-term and long-term risks of acute coronary syndrome in cohorts of patients with RA starting biologic DMARDs : Results from four Nordic countries
- 2022
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 81:6, s. 789-797
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Tidskriftsartikel (refereegranskat)abstract
- Objectives: To compare the 1-year, 2-year and 5-year incidences of acute coronary syndrome (ACS) in patients with rheumatoid arthritis (RA) starting any of the biologic disease-modifying antirheumatic drugs (bDMARDs) currently available in clinical practice and to anchor these results with a general population comparator.Methods: Observational cohort study, with patients from Denmark, Finland, Norway and Sweden starting a bDMARD during 2008-2017. Time to first ACS was identified through register linkages. We calculated the 1-year, 2-year and 5-year incidence rates (IR) (on drug and ever since treatment start) and used Cox regression (HRs) to compare ACS incidences across treatments taking ACS risk factors into account. Analyses were further performed separately in subgroups defined by age, number of previous bDMARDs and history of cardiovascular disease. We also compared ACS incidences to an individually matched general population cohort.Results: 24 083 patients (75% women, mean age 56 years) contributing 40 850 treatment courses were included. During the maximum (5 years) follow-up (141 257 person-years (pyrs)), 780 ACS events occurred (crude IR 5.5 per 1000 pyrs). Overall, the incidence of ACS in RA was 80% higher than that in the general population. For all bDMARDs and follow-up definitions, HRs were close to 1 (etanercept as reference) with the exception of the 5-year risk window, where signals for abatacept, infliximab and rituximab were noted.Conclusion: The rate of ACS among patients with RA initiating bDMARDs remains elevated compared with the general population. As used in routine care, the short-term, intermediate-term and longer-term risks of ACS vary little across individual bDMARDs.
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| 8. |
- Delcoigne, Benedicte, et al.
(författare)
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The influence of patient demographics on disease activity measurments in theumatoid arthritis
- 2019
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 78, s. 1423-1424
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background: Several indexes have been constructed for the measurement of disease activity in rheumatoid arthritis (RA) patients, including the Disease Activity Score 28-joint count, which either includes the Erythrocyte Sedimentation Rate (DAS28ESR) or the C-reactive protein concentration (DAS28CRP), and the Clinical Disease Activity Index (CDAI). The categorization of the results of these three indexes into levels of disease activity (Remission, Low, Moderate and High) is used to assess patient outcomes, and to guide medical decisions regarding treatment. However, the different indexes can lead to somewhat different classification, and hence influence treatment decisions.1 Objectives: To investigate how DAS28ESR, DAS28CRP and CDAI indexes are associated to age and sex in RA patients. To investigate the agreement between indexes and between categories of disease activity levels.Methods: We identified a cohort of RA patients, registered in the Swedish Rheumatology Quality Register between January 1st2014 and December 31st2017. The indexes were obtained from the first visit at the time point of RA diagnosis, and at the visit registered at the start of a first ever biological treatment prescription. Linear models were used to investigate the correlation between the indexes, age and sex. The agreement between the indexes was explored with Bland-Altman plots. The agreement between disease activity levels was evaluated through kappa statistics.Results: Data were analyzed for 3855 RA patients (2576 women, mean age ±SD=60±15) at their first diagnosis visit and for 3062 RA patients (2313 women, mean age ±SD=57±14) at the start of their first biologic. Similar results for all subsequently described analyses were obtained at both time points. The correlation coefficient and 95% confidence interval (95%CI) between the indexes and age were 0.093 (0.063-0.124) for DAS28ESR and 0.055 (0.025-0.085) for DAS28CRP at the first visit, while CDAI was not correlated to age. There was no difference between men and women for CDAI and DAS28CRP, while DAS28ESR presented a mean difference of 0.1 unit between men and women. The agreement between categories of disease activity was moderate: at the RA diagnosis visit, the kappa statistics and 95% CI were: 0.63 (0.61-0.65) between DAS28ESR and DAS28CRP, 0.59 (0.57-0.61) between DAS28ESR and CDAI, and 0.55 (0.53-0.57) between DAS28CRP and CDAI. About 25% of the patients were classified differently. The Bland-Altman plot revealed that the difference between DAS28ESR and DAS28CRP depended on sex and slightly increased with age.Conclusion: Factors related to patient demographics might influence the results of disease activity indexes. This has a potential to affect clinical decisions, as the definition into disease activity categories can differ depending on the score used. This suggests the need to consider sex and age when defining such categories and interpreting results from these indexes.
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| 9. |
- Gedeborg, Rolf, et al.
(författare)
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Federated analyses of multiple data sources in drug safety studies
- 2023
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Ingår i: Pharmacoepidemiology and Drug Safety. - : John Wiley & Sons. - 1053-8569 .- 1099-1557. ; 32:3, s. 279-286
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Forskningsöversikt (refereegranskat)abstract
- PurposeStudies of rare side effects of new drugs with limited exposure may require pooling of multiple data sources. Federated Analyses (FA) allow real-time, interactive, centralized statistical processing of individual-level data from different data sets without transfer of sensitive personal data.MethodsWe review IT-architecture, legal considerations, and statistical methods in FA, based on a Swedish Medical Products Agency methodological development project.ResultsIn a review of all post-authorisation safety studies assessed by the EMA during 2019, 74% (20/27 studies) reported issues with lack of precision in spite of mean study periods of 9.3 years. FA could potentially improve precision in such studies. Depending on the statistical model, the federated approach can generate identical results to a standard analysis. FA may be particularly attractive for repeated collaborative projects where data is regularly updated. There are also important limitations. Detailed agreements between involved parties are strongly recommended to anticipate potential issues and conflicts, document a shared understanding of the project, and fully comply with legal obligations regarding ethics and data protection. FA do not remove the data harmonisation step, which remains essential and often cumbersome. Reliable support for technical integration with the local server architecture and security solutions is required. Common statistical methods are available, but adaptations may be required.ConclusionsFederated Analyses require competent and active involvement of all collaborating parties but have the potential to facilitate collaboration across institutional and national borders and improve the precision of postmarketing drug safety studies.
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