Publications by authors named "Johan Askling"

233 Publications

Rheumatoid arthritis autoantibodies and their association with age and sex.

Clin Exp Rheumatol 2021 Mar 30. Epub 2021 Mar 30.

Department of Immunology, Genetics and Pathology, University of Uppsala, Sweden.

Objectives: To examine the association between individual rheumatoid arthritis (RA) autoantibodies, sex and age at RA onset.

Methods: Anti-CCP2, IgA-, IgG- and IgM-RF were analysed centrally in baseline sera from 1600 RA patients diagnosed within one year of RA symptom onset. Cut-offs for RF isotypes were determined at the 98th percentile based on RA-free controls, close to the 98.4% anti-CCP2 specificity.

Results: Anti-CCP2 was found in 1020 patients (64%), IgA RF in 692 (43%), IgG RF in 529 (33%) and IgM RF in 916 (57%) of the patients. When assessed one by one, anti-CCP2 and IgM RF were both associated with lower age at RA diagnosis. When assessed in one joint model, the association to IgM RF weakened and a strong association between IgA RF and higher age at RA diagnosis appeared. IgA RF and IgG RF associated with male sex, and IgM RF with female sex, with no difference for anti-CCP2. When the model was adjusted for sex, the association between IgM RF and age disappeared, whereas the strong associations between IgA RF and high age and between anti-CCP2 and low age at diagnosis remained. Further adjustments for smoking, shared epitope and inclusion year did not change the outcome. Univariate analyses stratified on anti-CCP2 and IgA RF status confirmed the findings.

Conclusions: Anti-CCP associate with low, and IgA RF with high age at RA onset. RFs and anti-CCP2 display opposing association with sex. These results underscore that studies on RA phenotypes in relation to autoantibodies should accommodate age and sex.
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March 2021

Tuberculosis in biologic-naïve patients with rheumatoid arthritis - risk factors and tuberculosis characteristics.

J Rheumatol 2021 Apr 1. Epub 2021 Apr 1.

Rheumatology Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden; Department of Health Sciences, Luleå University of Technology, Luleå, Sweden; Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Department of Infectious Diseases, Karolinska University Hospital, Stockholm Sweden; Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; Public Health Agency of Sweden, Stockholm, Sweden; Rheumatology Division, Department of Medicine, Karolinska Institutet, Stockholm, Sweden. Funding:No specific funding was received from any bodies in the public, commercial or notfor-profit sectors to carry out the work described in this article. J. Karlsson Sundbaum PhD, Assistant Professor Luleå University of Technology, E.V. Arkema PhD, Assistant Professor Karolinska institutet, J. Bruchfeld PhD, Senior consultant Karolinska University Hospital, J. Jonsson PhD, Senior consultant Public Health Agency of Sweden, J. Askling PhD professor Karolinska institutet, E. Baecklund PhD, Associate professor Uppsala University. Corresponding author: Johanna Sundbaum, Rheumatology Unit, Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, E-mail: Key words: rheumatoid arthritis, tuberculosis, biologic-naïve, risk factors.

Objective: To investigate risk factors and characteristics of active tuberculosis (TB) in biologics-naïve rheumatoid arthritis (RA) patients.

Methods: Population-based case-control study using the Swedish Rheumatology Quality Register, the National Patient Register and the Tuberculosis Register to identify RA cases with active TB and matched RA controls without TB 2001-2014. Clinical data were obtained from medical records. TB risk was estimated as adjusted (adj) odds ratios (OR) with 95% confidence intervals (CI) using univariate and multivariable logistic regression analyses.

Results: After validation of diagnoses, the study included 31 RA cases with TB, and 122 matched RA controls. All except three cases had reactivation of latent TB. Pulmonary TB dominated (84%). Ever use of methotrexate was not associated with increased TB risk (adj OR 0.8; 95% CI 0.3-2.0), whereas ever treatment with leflunomide (adj OR 6.0; 95% CI 1.5-24.6), azathioprine (adj OR 3.8; 95% CI 1.1-13.8) and prednisolone (adj OR 2.4 (95% CI 1.0-5.9) was. There were no significant differences of maximum dose of prednisolone, treatment duration with prednisolone before TB, or cumulative dose of prednisolone the year before TB diagnosis between cases and controls. Obstructive pulmonary disease was associated with an increased TB risk (adj OR 3.9; 95% CI 1.4-10.7).

Conclusion: Several RA-associated factors may contribute to the increased TB risk in biologics-naïve RA patients, making risk of TB activation difficult to predict in the individual patient. To further decrease TB in RA patients, the results suggest that screening for latent TB should also be considered in biologics-naïve patients.
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http://dx.doi.org/10.3899/jrheum.201251DOI Listing
April 2021

Effectiveness of a second biologic after failure of a non-tumor necrosis factor inhibitor as first biologic in rheumatoid arthritis.

J Rheumatol 2021 Mar 1. Epub 2021 Mar 1.

Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden; DANBIO and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopedics, Rigshospitalet, Copenhagen, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; On behalf of the DANBIO Registry, Copenhagen Denmark; Helsinki University and Hospital (ROB-FIN), Departments of Medicine and Rheumatology, Helsinki, Finland; Pharmaceuticals Pricing Board, Ministry of Social Affairs and Health, Helsinki, Finland. Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway; Centre for Rheumatology Research, University Hospital, and Faculty of Medicine, University of Iceland, Reykjavik, Iceland; Department of Rheumatology and Centre for Rheumatology Research, University Hospital, Reykjavik, Iceland; Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark; Department of Clinical Medicine, Aalborg University, Aalborg, Denmark; The Parker Institute, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen F, Denmark; Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. Address correspondence to Katerina Chatzidionysiou, MD, PhD. Rheumatology Unit, Karolinska University Hospital, D2:00, 171 76, Solna, Stockholm, Sweden.

Objective: In Rheumatoid Arthritis (RA), evidence regarding the effectiveness of a second biologic Disease Modifying Anti-Rheumatic Drugs (bDMARDs) in patients whose first ever bDMARD was a non-tumor-necrosis-factor-inhibitor (TNFi) bDMARD is limited. The objective of this study was therefore to assess the outcome of the second bDMARD (non-TNFi [rituximab, abatacept or tocilizumab, separately] and TNFi) after failure of a non-TNFi bDMARD as first bDMARD.

Methods: We identified RA patients from the five Nordic biologics registers started treatment with a non-TNFi as first ever bDMARD but switched to a second bDMARD. For the second bDMARD, we assessed survival-on-drug (at 6 and 12 months), and primary response (at 6 months).

Results: We included 620 patients starting a second bDMARD (ABA 86, RTX 40, TCZ 67 and TNFi 427) following failure of a first non-TNFI bDMARD. At 6 and 12 months after start of their second bDMARD, around 70% and 50%, respectively, remained on treatment, and at 6 months less than one third of patients were still on their second bDMARD and had reached low disease activity or remission according to DAS28. For those patients whose second bMDARD was a TNFI, the corresponding proportion was slightly higher (40%).

Conclusion: The survival-on-drug and primary response of a second bDMARD in RA patients switching due to failure of a non-TNFi bDMARD as first bDMARD is modest. Some patients may benefit from TNFi when used after failure of a non-TNFi as first bDMARD.
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http://dx.doi.org/10.3899/jrheum.201467DOI Listing
March 2021

Hepatobiliary Cancer Risk in Patients with Inflammatory Bowel Disease: A Scandinavian Population-Based Cohort Study.

Cancer Epidemiol Biomarkers Prev 2021 May 24;30(5):886-894. Epub 2021 Feb 24.

Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark.

Background: Inflammatory bowel disease (IBD) has been associated with hepatobiliary cancer, but existing evidence is poor. We evaluated risk of death from hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (ECC) among patients with IBD.

Methods: This Swedish/Danish population-based cohort study (1969-2017) followed patients with IBD and 1:10 matched population comparators from their diagnosis/match date until death, emigration, or end of follow-up.

Results: Among the 97,496 patients with ulcerative colitis/963,026 comparators, we found 66/390 HCC-deaths, 120/173 ICC-deaths, and 91/220 ECC-deaths (median follow-up 10 years); the 10-year-mortality was 0.5‰ (per mille) for HCC, 0.6‰ for ICC, and 0.4‰ for ECC, which decreased to 0.3‰, 0.4‰, and 0.2‰, respectively, in 2003-2017. Overall hazard ratios (HR) were 1.83 [95% confidence interval (CI), 1.41-2.38] for HCC-, 7.33 (95% CI, 5.81-9.25) for ICC-, and 4.46 (95% CI, 3.49-5.70) for ECC-deaths. A total of 22/66 HCC-deaths, 87/120 ICC-deaths, and 55/91 ECC-deaths occurred among patients with ulcerative colitis with primary sclerosing cholangitis (PSC), corresponding to 10-year-mortality of 6.7‰, 26.2‰, and 17.2‰, respectively. Among 47,399 patients with Crohn's disease (median follow-up 11 years), 10-year-mortality from HCC ( = 28), ICC ( = 28), and ECC ( = 24) were 0.3‰, 0.1‰, and 0.3‰, respectively, and corresponding HRs were 1.96 (95% CI, 1.31-2.93), 3.33 (95% CI, 2.19-5.09), and 3.10 (95% CI, 1.97-4.87). One of 28 HCC-deaths, 14/28 ICC-deaths (10-year-mortality 19‰), and 12/24 ECC-deaths (10-year-mortality 14‰) occurred after PSC.

Conclusions: Risk of HCC-, ICC-, and ECC-deaths was low in patients with IBD and decreased over time. However, a large proportion of deaths occurred after PSC.

Impact: Guidelines on specific surveillance strategies for patients with IBD with PSC, but not those without PSC, are needed.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1241DOI Listing
May 2021

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.

Ann Rheum Dis 2021 Feb 23. Epub 2021 Feb 23.

Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

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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http://dx.doi.org/10.1136/annrheumdis-2021-219845DOI Listing
February 2021

Adaptation of the Charlson Comorbidity Index for Register-Based Research in Sweden.

Clin Epidemiol 2021 12;13:21-41. Epub 2021 Jan 12.

Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Purpose: Comorbidity indices are often used to measure comorbidities in register-based research. We aimed to adapt the Charlson comorbidity index (CCI) to a Swedish setting.

Methods: Four versions of the CCI were compared and evaluated by disease-specific experts.

Results: We created a cohesive coding system for CCI to 1) harmonize the content between different international classification of disease codes (ICD-7,8,9,10), 2) delete incorrect codes, 3) enhance the distinction between mild, moderate or severe disease (and between diabetes with and without end-organ damage), 4) minimize duplication of codes, and 5) briefly explain the meaning of individual codes in writing.

Conclusion: This work may provide an integrated and efficient coding algorithm for CCI to be used in medical register-based research in Sweden.
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http://dx.doi.org/10.2147/CLEP.S282475DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812935PMC
January 2021

Morbidity, risk of cancer and mortality in 3645 HFE mutations carriers.

Liver Int 2021 03 26;41(3):545-553. Epub 2021 Jan 26.

Division of Hepatology, Department of Upper GI diseases, Karolinska University Hospital, Stockholm, Sweden.

Background & Aims: Mutations in the HFE gene can lead to hereditary haemochromatosis (HH) and have been suggested to increase the risk of extra-hepatic diseases, especially breast and colorectal cancer. Here we investigated long-term outcomes of Swedish patients with HFE mutations.

Methods: We identified 3645 patients with a homozygous p.C282Y (62%) or a compound heterozygous p.C282Y/p.H63D (38%) mutation from eight centres in Sweden between 1997 and 2017. These were matched 1:10 by age, sex and county of residence to reference individuals from the general population. We ascertained incident outcomes until the end of 2017 by linkage to national registers. Studied outcomes were HH, cirrhosis, hepatocellular carcinoma (HCC), breast cancer (in women), colorectal cancer, type 1 and 2 diabetes, hypothyroidism, Parkinson's disease and mortality. Cox proportional hazards regression was used to estimate hazard ratios for these outcomes.

Results: Median age at diagnosis was 52 years, 44% were females. During a mean follow-up of 7.9 years, we found an increased risk for HCC, HH, cirrhosis, type 2 diabetes, osteoarthritis and death. Excess mortality was only seen in men. No increased risk was seen for colorectal or breast cancer. Liver-related outcomes were rare, with a cumulative incidence of <1%.

Conclusions: Individuals found to be HFE mutation carriers in a university hospital setting had an increased risk for mortality in men, along with increased risks of cirrhosis, HCC, diabetes type 2, and osteoarthritis. In general, the absolute risk for adverse outcomes was low and no increased risk for colon or breast cancer was observed.
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http://dx.doi.org/10.1111/liv.14792DOI Listing
March 2021

Risk of solid cancers overall and by subtypes in patients with psoriatic arthritis treated with TNF inhibitors - a Nordic cohort study.

Rheumatology (Oxford) 2021 Jan 5. Epub 2021 Jan 5.

Bispebjerg and Frederiksberg, The Parker Institute, Copenhagen University Hospital.

Objectives: To investigate whether TNF inhibitors (TNFi) are associated with increased risk of solid cancer in patients with psoriatic arthritis (PsA).

Methods: From the Nordic clinical rheumatology registers (CRR) here: SRQ/ARTIS (Sweden), DANBIO (Denmark), NOR-DMARD (Norway), ROB-FIN (Finland) and ICEBIO (Iceland) we identified PsA patients who started a first TNFi 2001-2017 (n = 9655). We identified patients with PsA not treated with biologics from (i) the CRR (n = 14 809) and (ii) the national patient registers (PR, n = 31 350). By linkage to the national cancer registers, we collected information on incident solid cancer overall and for eight cancer types. We used Cox regression to estimate hazard ratio (HR) with 95% CI of cancer (per country and pooled) in TNFi-exposed vs biologics-naïve, adjusting for age, sex, calendar period, comorbidities and disease activity. We also assessed standardized incidence ratios (SIR) in TNFi-exposed PsA vs the general population (GP).

Results: We identified 296 solid cancers among the TNFi-exposed PsA patients (55 850 person-years); the pooled adjusted HR for solid cancer overall was 1.0 (0.9-1.2) for TNFi-exposed vs biologics-naïve PsA from the CRR, and 0.8 (0.7-1.0) vs biologics-naïve PsA from the PRs. There were no significantly increased risks for any of the cancer types under study. The pooled SIR of solid cancer overall in TNFi treated PsA vs GP was 1.0 (0.9-1.1).

Conclusion: In this large cohort study from five Nordic countries, we found no increased risk of solid cancer in TNFi-treated PsA patients, neither for solid cancer overall nor for eight common cancer types.
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http://dx.doi.org/10.1093/rheumatology/keaa828DOI Listing
January 2021

Infection risk in sarcoidosis patients treated with methotrexate compared to azathioprine: A retrospective 'target trial' emulated with Swedish real-world data.

Respirology 2021 May 4;26(5):452-460. Epub 2021 Jan 4.

Clinical Epidemiology Division, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

Background And Objective: No clinical trial has examined the risk of infection associated methotrexate and azathioprine, two advocated treatments for sarcoidosis. We aimed to compare the 6-month risk of infection after the initiation of methotrexate or azathioprine.

Methods: We conducted a retrospective target trial emulation using Swedish pre-existing data. We searched for eligible participants who were dispensed methotrexate or azathioprine in the Prescribed Drug Register (PDR) every day between January 2007 and June 2013. Adults were eligible if they had ≥2 ICD-coded visits for sarcoidosis in the National Patient Register (NPR) and were dispensed ≥1 systemic corticosteroid but no methotrexate or azathioprine in the past 6 months (PDR). Within 6 months of methotrexate or azathioprine initiation, diagnosis of infectious disease was identified (visit in the NPR where infectious disease was the primary diagnosis). We estimated RR and risk differences comparing methotrexate (n = 667) to azathioprine initiations (n = 259) using targeted maximum likelihood estimation (TMLE) adjusting for demographic factors, comorbidity and sarcoidosis severity proxies.

Results: There were 43 infections in the methotrexate group (adjusted 6-month risk 6.8%) and 29 infections in the azathioprine group (12.0%). The RR for infectious disease at 6 months associated with methotrexate compared to azathioprine initiation was 0.57 (95% CI: 0.39, 0.82) and the risk difference was -5.2% (95% CI: -8.5%, -1.8%). The RR at 9 months was attenuated to 0.77 (95% CI: 0.52, 1.14).

Conclusion: Methotrexate appears to be associated with a lower risk of infection in sarcoidosis than azathioprine, but randomized trials should confirm this finding.
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http://dx.doi.org/10.1111/resp.14001DOI Listing
May 2021

Comparison of treatment retention and response to secukinumab versus tumour necrosis factor inhibitors in psoriatic arthritis.

Rheumatology (Oxford) 2020 Dec 26. Epub 2020 Dec 26.

Parker Institute, Copenhagen University Hospital, Bispebjerg and Frederiksberg, Copenhagen, Denmark.

Objectives: To compare treatment retention and response to secukinumab vs adalimumab, including the other four TNF inhibitors (TNFi) as comparators, in PsA.

Methods: All patients with PsA starting secukinumab or a TNFi in 2015-2018 were identified in the biologic registers of the Nordic countries. Data on comorbidities were linked from national registers. One-year treatment retention and hazard ratios (HRs) for treatment discontinuation were calculated. The proportion achieving a 6 month 28-joint Disease Activity Index for Psoriatic Arthritis (DAPSA28) remission was determined together with odds ratios (ORs) for remission (logistic regression). Both HRs and ORs were calculated with adalimumab as the reference and adjusted for baseline characteristics and concurrent comorbidities. All analyses were stratified by the line of biologic treatment (first, second, third+).

Results: We identified 6143 patients contributing 8307 treatment courses (secukinumab, 1227; adalimumab, 1367). Secukinumab was rarely used as the first biologic, otherwise baseline characteristics were similar. No clinically significant differences in treatment retention or response rates were observed for secukinumab vs adalimumab. The adjusted HRs for discontinuation per the first, second and third line of treatment were 0.98 (95% CI 0.68, 1.41), 0.94 (0.70, 1.26) and 1.07 (0.84, 1.36), respectively. The ORs for DAPSA28 remission in the first, second and third line of treatment were 0.62 (95% CI 0.30, 1.28), 0.85 (0.41, 1.78) and 0.74 (0.36, 1.51), respectively. In the subset of patients previously failing a TNFi due to ineffectiveness, the results were similar.

Conclusion: No significant differences in treatment retention or response were observed between secukinumab and adalimumab, regardless of the line of treatment. This suggests that even in patients who have failed a TNFi, choosing either another TNFi or secukinumab may be equally effective.
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http://dx.doi.org/10.1093/rheumatology/keaa825DOI Listing
December 2020

Comorbidities at diagnosis of rheumatoid arthritis: a population-based case-control study.

Rheumatology (Oxford) 2020 Dec 17. Epub 2020 Dec 17.

Division of Clinical Epidemiology, Department of Medicine, Solna, Stockholm, Karolinska Institutet, Sweden.

Objectives: Comorbidities contribute to the morbidity and mortality in rheumatoid arthritis (RA), and are thus important to capture and treat early. In contrast to the well-studied comorbidity risks in established RA, less is known about the comorbidity pattern up until diagnosis of RA. We therefore compared if the occurrence of defined conditions, and the overall comorbidity burden at RA diagnosis, is different from that in the general population, and if it differs between seropositive and seronegative RA.

Methods: Using Swedish national clinical and demographic registers, we identified new-onset RA patients (n = 11 086), and matched (1:5) to general population controls (n = 54 813). Comorbidities prior to RA diagnosis were identified in the Patient and Prescribed Drug Registers, and compared using logistic regression.

Results: At diagnosis of RA, respiratory (OR = 1.58, 95% CI = 1.44-1.74), endocrine (OR = 1.39, 95% CI = 1.31-1.47), and certain neurological diseases (OR = 1.73, 95% CI = 1.59-1.89) were more common in RA vs controls, with a similar pattern in seropositive and seronegative RA. In contrast, psychiatric disorders (OR = 0.87, 95% CI = 0.82-0.92) and malignancies (OR = 0.88, 95% CI = 0.79-0.97) were less commonly diagnosed in RA vs controls. The comorbidity burden was slightly higher in RA patients compared with controls (p< 0.0001).

Conclusion: We found several differences in comorbidity prevalence between patients with new-onset seropositive and seronegative RA compared with matched controls from the general population. These findings are important both for our understanding of the evolvement of comorbidities in established RA and for early detection of these conditions.
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http://dx.doi.org/10.1093/rheumatology/keaa856DOI Listing
December 2020

Findings on coronary angiographies in patients with rheumatoid arthritis and ischemic heart disease: different from patients without rheumatoid arthritis?

Arthritis Care Res (Hoboken) 2020 Dec 7. Epub 2020 Dec 7.

Clinical Epidemiology Division, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.

Background: Patient with rheumatoid arthritis (RA) are at increased risk of coronary artery disease (CAD) and seem to develop more severe acute coronary syndromes (ACS) than the general population. Whether this is due to a different distribution and severity of coronary stenoses (vs. non-RA)) resulting in clinical manifest CAD remains unknown, as few studies have investigated the CAD distribution in the context of acute or stable CAD in RA.

Methods: We performed a population-based study using linkages of nationwide clinical-, health- and demographics registers. We compared one cohort of patients with RA, and one matched cohort of patients without RA, undergoing a first coronary angiography 2006 through 2015. Cardiovascular characteristics, presence and distribution of clinically significant stenoses were compared (through odds ratios (OR)), stratified by indication (stable CAD/ST-elevation myocardial infarction [STEMI]/non-ST ACS [NSTACS]), using logistic regression.

Results: We identified 2,985 patients with RA and 10,290 patients without RA who underwent a first coronary angiography. A higher proportion of patients with RA (75% vs. 69%) had STEMI and NSTACS as indication for angiography. We found no difference in the presence and distribution of clinically significant coronary stenoses in RA compared with the patients without RA, regardless of CAD-type (OR for having any significant stenosis in stable CAD = 0.9, STEMI OR=0.8, NSTACS OR=1.1), stratification by RA duration, sex, or burden of concomitant CV risk factors.

Conclusions: Although RA may accelerate the development of clinical CAD events, the underlying angiographic characteristics are similar to those in patients without RA.
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http://dx.doi.org/10.1002/acr.24214DOI Listing
December 2020

One-year treatment outcomes of secukinumab versus tumor necrosis factor inhibitors in Spondyloarthritis.

Arthritis Care Res (Hoboken) 2020 Nov 30. Epub 2020 Nov 30.

Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Objective: To describe baseline characteristics and to compare treatment effectiveness of secukinumab versus tumor necrosis factor inhibitors (TNFi), in patients with spondyloarthritis (SpA) using adalimumab as the main comparator.

Methods: Observational, prospective cohort study. Patients with SpA (clinical ankylosing spondylitis/non-radiographic axial SpA/undifferentiated SpA) starting secukinumab or a TNFi during 2015-2018 were identified from five Nordic clinical rheumatology registries. Comorbidities and extra-articular manifestations (psoriasis/uveitis/inflammatory bowel disease) were captured from national registries (data available in 94% of patients) and included in multivariable analyses. We assessed 1-year treatment retention (crude survival curves, adjusted hazard ratios (HR) for treatment discontinuation) and 6-months' response-rates (ASDAS<2.1/BASDAI<40mm, crude/LUNDEX-adjusted, adjusted logistic-regression analyses with odds-ratio(OR)), stratified by line of biological treatment (1 /2 /3 +).

Results: In total, 10,853 treatment courses (842 secukinumab/10,011 TNFi whereof 1,977 adalimumab) were included. The proportion treated with secukinumab during 1 /2 /3 + was 1%/6%/22%). Extra-articular manifestations varied across treatments, while other baseline characteristics were largely similar. Secukinumab had a one-year retention comparable to adalimumab as 1 or 2 , but poorer as 3 + line of therapy (secukinumab 56% (51%-61%) versus adalimumab 70% (64%-75%)), adjusted HR 1.43 (1.12-1.81). Across treatment lines, secukinumab had poorer estimates for 6-months response rates than adalimumab, statistically significantly so only for 3 + line (adjusted analyses: ASDAS<2.1 OR=0.56 (0.35-0.90), BASDAI<40mm OR=0.62 (0.41-0.95)). Treatment outcomes varied across the five TNFi.

Conclusion: Secukinumab was mainly used in biologically experienced SpA patients. Secukinumab and adalimumab performed similar in patients who had failed a first biological, although with increasing prior biological exposure, adalimumab was superior.
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http://dx.doi.org/10.1002/acr.24523DOI Listing
November 2020

Women's earnings are more affected by inflammatory bowel disease than men's: a register-based Swedish cohort study.

J Crohns Colitis 2020 Nov 27. Epub 2020 Nov 27.

Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.

Background/aim: Patients with inflammatory bowel disease (IBD) have more work disability than the general population. We aimed to estimate the monetary cost of IBD for the individual through assessment of earnings in relation to diagnosis.

Methods: Through linkage of national registers we identified patients aged 30-55 years at first IBD diagnosis in Sweden 2002-2011, and same-sex IBD-free siblings. We estimated taxable earnings and disposable income from 5 years before to 5 years after diagnosis.

Results: The 5,961 patients (27% Crohn's disease, 68% ulcerative colitis, 4.3% IBD unclassified) had similar taxable earnings as their 7,810 siblings until the year of diagnosis, when earnings decreased and remained lower than in siblings during follow-up. The adjusted difference in earnings over the entire 5-year period after diagnosis was -5% (-8,212€; 95%CI: -11,458 to-4,967). The difference was larger in women than in men, and larger in Crohn's disease than in ulcerative colitis. When stratifying for sex and IBD subtype and comparing earnings during each year of follow-up, the median annual earnings were lower in women with Crohn's disease and ulcerative colitis than in their sisters during all years of follow-up, whereas the men had similar annual taxable earnings as their brothers. The disposable income was similar between patients and siblings during the investigated time period.

Conclusion: From the year of diagnosis and at least 5 years onwards, patients with IBD had 5% lower earnings than siblings, mainly explained by differences between women with IBD and their sisters. However, there were no differences in disposable income.
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http://dx.doi.org/10.1093/ecco-jcc/jjaa238DOI Listing
November 2020

Is rheumatoid arthritis a risk factor for acute coronary syndrome also among individuals at elevated risk, such as individuals presenting with acute chest pain?

RMD Open 2020 11;6(3)

Department of Medicine Solna, Karolinska Institutet, Sweden.

Background: Patients with rheumatoid arthritis (RA) are, on average, at increased risk of acute coronary syndrome (ACS) compared to the general population, but it remains unknown whether RA remains an ACS risk factor also in settings where the ACS risk is already high elevated, such as among individuals presenting to the emergency department (ED) with chest pain.

Methods And Results: We included 49 283 individuals (514 (1.0%) had RA) presenting with chest pain at the four hospital EDs in Stockholm, Sweden, 2013-2016 in a cohort study. Information on exposure (RA), outcome (ACS) and comorbidities was provided through national registers. The association between RA and ACS was assessed, overall and by levels of high-sensitivity cardiac troponin T (hs-cTnT) and number of ACS risk factors, using logistic regression models adjusted for age, sex, hospital, calendar year and cardiovascular risk factors. ACS was more common in patients with (8.2%) than without (4.6%) RA, adjusted OR =1.4, 95% CI 1.0 to 2.0. This association was particularly strong in individuals with initial hs-cTnT levels between 5 and 14 ng/L, or no additional ACS risk factors (adjusted ORs above 2), but no longer detectable in those with hs-cTnT >14 ng/L or with three or more additional ACS risk factors.

Conclusion: RA is a risk factor for ACS also among patients at the ED with chest pain. This association is not explained by traditional ACS risk factors, and most pronounced in patients with normal hs-cTnT and few other ACS risk factors, prompting particular ACS vigilance in this RA patient group.
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http://dx.doi.org/10.1136/rmdopen-2020-001463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856117PMC
November 2020

Incidence of extra-articular manifestations in ankylosing spondylitis, psoriatic arthritis and undifferentiated spondyloarthritis: results from a national register-based cohort study.

Rheumatology (Oxford) 2020 Nov 20. Epub 2020 Nov 20.

Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg.

Objectives: To estimate the incidence and strength of association of extra-articular manifestations [EAMs, here: anterior uveitis (AU), IBD and psoriasis] in patients with AS, undifferentiated SpA (uSpA) and PsA, compared with controls.

Methods: Three mutually exclusive cohorts of patients aged 18-69 years with AS (n = 8517), uSpA (n = 10 245) and PsA (n = 22 667) were identified in the Swedish National Patient Register 2001-2015. Age-, sex- and geography-matched controls were identified from the Swedish Population Register. Follow-up began 1 January 2006, or six months after the first SpA diagnosis, whichever occurred later, and ended at the first date of the EAM under study, death, emigration, 70 years of age, and 31 December 2016. Incidence rates (IRs) and incidence rate ratios were calculated for each EAM, and stratified by sex and age.

Results: Incidence rate ratios for incident AU, IBD and psoriasis were significantly increased in AS (20.2, 6.2, 2.5), uSpA (13.6, 5.7, 3.8) and PsA (2.5, 2.3, n.a) vs controls. Men with AS and uSpA had significantly higher IRs per 1000 person-years at risk for incident AU than women with AS (IR 15.8 vs 11.2) and uSpA (IR 10.1 vs 6.0), whereas no such sex difference was demonstrated in PsA or for the other EAMs.

Conclusions: AU, followed by IBD and psoriasis, is the EAM most strongly associated with AS and uSpA. Among the SpA subtypes, AS and uSpA display a largely similar pattern of EAMs, whereas PsA has a considerably weaker association with AU and IBD.
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http://dx.doi.org/10.1093/rheumatology/keaa692DOI Listing
November 2020

Mortality over 14 years in MTX-refractory patients randomized to a strategy of addition of infliximab or sulfasalazine and hydroxychloroquine.

Rheumatology (Oxford) 2020 Nov 12. Epub 2020 Nov 12.

Department of Medicine Solna, Karolinska Institutet, Stockholm.

Objective: To compare mortality risk over up to 14 years of follow-up in methotrexate-refractory patients with early RA randomized to a strategy starting with addition of infliximab vs addition of SSZ and HCQ.

Methods: Data was from the two-arm, parallel, randomized, active-controlled, open-label Swefot trial in which patients with early RA (symptom duration <1 y) were recruited from 15 rheumatology clinics in Sweden (2002-2005). Patients who did not achieve low disease activity after 3-4 months of MTX were randomized to addition of infliximab (n = 128) or SSZ and HCQ (n = 130). Participants were followed until death, emigration, or end of follow-up, whichever came first. Analyses were by intention-to-treat.

Results: Over an average follow-up of 13 years, there were 13 and 16 deaths, respectively [8.8 vs 10.6 deaths per 1000 person-years; mortality hazard ratio 1.2 (95% CI: 0.6, 2.5); P =0.62]. The 1-year mortality was 0.8% in both treatment arms, the 5-year mortality was 2.3% for the infliximab arm compared with 1.5% for the conventional combination treatment arm, while the 10-year mortality was 7.8% and 7.7%, respectively. After 5 years, ∼50% of patients in the conventional combination therapy arm had switched to biologic treatment, and 50% in the biologic arm had discontinued treatment with a biologic DMARD.

Conclusion: No difference in mortality risk could be observed over up to 14 years of follow-up between treatment strategy groups. At 5 years (3 years after trial cessation), 50% of patients remained on their assigned therapy, reflecting that DMARD combination is an adequate treatment strategy in 50% of patients.

Trial Registration: clinicaltrials.gov, identifier: NCT00764725.
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http://dx.doi.org/10.1093/rheumatology/keaa553DOI Listing
November 2020

Risk of venous thromboembolism in rheumatoid arthritis, and its association with disease activity: a nationwide cohort study from Sweden.

Ann Rheum Dis 2021 02 8;80(2):169-175. Epub 2020 Oct 8.

Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden.

Objective: To assess the incidence of venous thromboembolism (VTE) in rheumatoid arthritis (RA) relative to individuals without RA, and to investigate the relationship between aspects of clinical disease activity in RA and the risk of VTE.

Methods: We conducted a nationwide register-based cohort study 2006 through 2018 using the Swedish Rheumatology Quality Register linked to other national patient registers to identify all patients with RA with at least one registered rheumatologist visit during the study period (n=46 316 patients, 322 601 visits). The Disease Activity Score 28 erythrocyte sedimentation rate (ESR) (DAS28 ESR) and its components served as the exposure, and a VTE event within the year following the visit was the main outcome. We also included general population referents (1:5) matched on age, sex and residential area.

Results: Based on 2241 incident VTE events within 1 year of each included visit, and 5301 VTE events in the general population cohort, the risk ratio for VTE in RA was 1.88 (95% CI 1.65 to 2.15). Among patients with RA, the risk (and risk ratio) increased with increasing RA disease activity, from 0.52% following visits in remission to 1.08% following visits with DAS28 ESR high disease activity, RR compared with remission=2.03, 95% CI 1.73 to 2.38. Compared with the general population, also patients with RA in DAS28 ESR remission were at elevated VTE risk.

Conclusions: This study demonstrates a strong association between clinical RA disease activity measured by DAS28 ESR and the risk of VTE. RA disease activity can be used as an additional tool for VTE risk stratification in patients with RA.
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http://dx.doi.org/10.1136/annrheumdis-2020-218419DOI Listing
February 2021

Validity of administrative codes associated with cirrhosis in Sweden.

Scand J Gastroenterol 2020 Oct 22;55(10):1205-1210. Epub 2020 Sep 22.

Division of Hepatology, Department of Upper GI, Karolinska University Hospital, Stockholm, Sweden.

Objectives: Although cirrhosisis a major cause of liver-related mortality globally, validation studies of the administrative coding for diagnoses associated with cirrhosis are scarce. We aimed to determine the validity of the International Classification of Diseases, 10th revision (ICD-10) codes corresponding to cirrhosis and its complications in the Swedish National Patient Register (NPR).

Methods: We randomly selected 750 patients with ICD codes for either alcohol-related cirrhosis (K70.3), unspecified cirrhosis (K74.6) oesophageal varices (I85.0/I85.9), hepatocellular carcinoma (HCC, C22.0) or ascites (R18.9) registered in the NPR from 72 healthcare centres in 2000-2016. Hospitalisation events and outpatient visits in specialised care were included. Positive predictive values (PPVs) were calculated using the information in the patient charts as the gold standard.

Results: Complete data were obtained for 630 (of 750) patients (84%). For alcohol-related cirrhosis, 126/136 cases were correctly coded, corresponding to a PPV of 93% (95% confidence interval, 95%CI: 87-96). The PPV for cirrhosis with unspecified aetiology was 91% (121/133, 95%CI: 85-95) and 96% for oesophageal varices (118/123, 95%CI: 91-99). The PPV was lower for HCC, 84% (91/109, 95%CI: 75-90). The PPV for liver-related ascites was low, 43% (56/129, 95%CI: 35-52), as this category often consisted of non-hepatic ascites. When combining the ascites code with a code for chronic liver disease, the PPV for liver-related ascites increased to 93% (50/54, 95%CI: 82-98).

Conclusions: The validity of ICD-10 codes for cirrhosis, oesophageal varices and HCC is high. However, coding for ascites should be combined with a code of chronic liver disease to have an acceptable validity.
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http://dx.doi.org/10.1080/00365521.2020.1820566DOI Listing
October 2020

Drug retention, inactive disease and response rates in 1860 patients with axial spondyloarthritis initiating secukinumab treatment: routine care data from 13 registries in the EuroSpA collaboration.

RMD Open 2020 09;6(3)

Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre for Head and Orthopedics, Rigshospitalet Glostrup, Copenhagen, Denmark.

Objectives: To explore 6-month and 12-month secukinumab effectiveness in patients with axial spondyloarthritis (axSpA) overall, as well as across (1) number of previous biologic/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs), (2) time since diagnosis and (3) different European registries.

Methods: Real-life data from 13 European registries participating in the European Spondyloarthritis Research Collaboration Network were pooled. Kaplan-Meier with log-rank test, Cox regression, χ² and logistic regression analyses were performed to assess 6-month and 12-month secukinumab retention, inactive disease/low-disease-activity states (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) <2/<4, Ankylosing Spondylitis Disease Activity Score (ASDAS) <1.3/<2.1) and response rates (BASDAI50, Assessment of Spondyloarthritis International Society (ASAS) 20/40, ASDAS clinically important improvement (ASDAS-CII) and ASDAS major improvement (ASDAS-MI)).

Results: We included 1860 patients initiating secukinumab as part of routine care. Overall 6-month/12-month secukinumab retention rates were 82%/72%, with significant (p<0.001) differences between the registries (6-month: 70-93%, 12-month: 53-86%) and across number of previous b/tsDMARDs (b/tsDMARD-naïve: 90%/73%, 1 prior b/tsDMARD: 83%/73%, ≥2 prior b/tsDMARDs: 78%/66%). Overall 6-month/12-month BASDAI<4 were observed in 51%/51%, ASDAS<1.3 in 9%/11%, BASDAI50 in 53%/47%, ASAS40 in 28%/22%, ASDAS-CII in 49%/46% and ASDAS-MI in 25%/26% of the patients. All rates differed significantly across number of previous b/tsDMARDs, were numerically higher for b/tsDMARD-naïve patients and varied significantly across registries. Overall, time since diagnosis was not associated with secukinumab effectiveness.

Conclusions: In this study of 1860 patients from 13 European countries, we present the first comprehensive real-life data on effectiveness of secukinumab in patients with axSpA. Overall, secukinumab retention rates after 6 and 12 months of treatment were high. Secukinumab effectiveness was consistently better for bionaïve patients, independent of time since diagnosis and differed across the European countries.
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http://dx.doi.org/10.1136/rmdopen-2020-001280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539854PMC
September 2020

Healthcare use, work loss and total costs in incident and prevalent Crohn's disease and ulcerative colitis: results from a nationwide study in Sweden.

Aliment Pharmacol Ther 2020 08 3;52(4):655-668. Epub 2020 Jul 3.

Stockholm, Sweden.

Background: There are limited data on population-wide assessment of cost in Crohn's disease (CD) and ulcerative colitis (UC).

Aim: To estimate the societal cost of actively treated CD and UC in Sweden.

Methods: We identified 10 117 prevalent CD and 19 762 prevalent UC patients, aged ≥18 years on 1 January 2014 and 4028 adult incident CD cases and 8659 adult incident UC cases (2010-2013) from Swedish Patient Register. Each case was matched to five population comparators. Healthcare costs were calculated from medications, outpatient visits, hospitalisations and surgery. Cost of productivity losses was derived from disability pension and sick leave.

Results: The mean annual societal costs per working-age patient (18-64 years) with CD and UC were $22 813 (vs $7533 per comparator) and $14 136 (vs $7351 per comparator), respectively. In patients aged ≥65 years, the mean annual costs of CD and UC were $9726 and $8072 vs $3875 and $4016 per comparator, respectively. The majority of cost for both CD (56%) and UC (59%) patients originated from productivity losses. Higher societal cost of working-age CD patients as compared to UC patients was related to greater utilisation of anti-TNF (22.2% vs 7.4%) and increased annual disability pension (44 days vs 25 days). Among incident CD and UC patients, the mean total cost over the first year per patient was over three times higher than comparators.

Conclusion: In Sweden, the societal cost of incident and prevalent CD and UC patients was consistently two to three times higher than the general population.
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http://dx.doi.org/10.1111/apt.15889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490827PMC
August 2020

Reply: Survival in Crohn's disease-associated small bowel adenocarcinoma.

Gut 2021 May 1;70(5):998. Epub 2020 Sep 1.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.1136/gutjnl-2020-322450DOI Listing
May 2021

Concordance in survival among first-degree relatives diagnosed with indolent lymphoid malignancies including chronic lymphocytic leukemia.

Eur J Haematol 2020 Dec 29;105(6):779-785. Epub 2020 Sep 29.

Department of Medicine Solna, Clinical Epidemiology Division, Karolinska Institutet, Stockholm, Sweden.

Objectives: To investigate concordance in survival time among first-degree relatives with lymphoid malignancies.

Methods: By linkage of national Swedish registers, we identified 66 430 patients diagnosed with a lymphoid malignancy 1958-2016 with information on first-degree relationships and follow-up until 2017. Among these, we identified pairs of first-degree relatives with any (N = 3326) or a similar (N = 690) lymphoid malignancy subtype. We defined survival in the first-degree relative as good, expected, or poor based on tertiles of deviance residuals from a multivariable Cox regression model. Next, we used Cox regression to estimate hazard ratios (HR) of death with 95% confidence intervals (CI) among patients, using the survival of their first-degree relative as exposure and adjusting for confounders.

Results: There was no concordance in survival among first-degree relatives with any lymphoid malignancy (HR  = 1.00 (reference), HR  = 1.02, 95% CI: 0.89-1.17, HR  = 1.12, 95% CI: 0.98-1.27, P  = .08). Among first-degree relatives with indolent lymphoma, including chronic lymphocytic leukemia, those with a first-degree relative to an expected or poor survival had worse outcome compared to those with a first-degree relative with good survival (HR  = 1.44, 95% CI: 0.82-2.53, HR  = 1.79, 95% CI: 1.07-3.00, P  = .03).

Conclusion: Our results support a role of inherited factors in the outcome of indolent lymphoma, including chronic lymphocytic leukemia.
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http://dx.doi.org/10.1111/ejh.13510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702025PMC
December 2020

Characteristics and outcome of a first acute myocardial infarction in patients with ankylosing spondylitis.

Clin Rheumatol 2021 Apr 26;40(4):1321-1329. Epub 2020 Aug 26.

Department of Rheumatology and Inflammation Research, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

Objectives: To study clinical characteristics, mortality, and secondary prevention, after a first incident acute myocardial infarction (AMI) in patients with ankylosing spondylitis (AS) compared with the general population.

Methods: In total, 292 subjects with AS and a first AMI between Jan 2006 and Dec 2014 were identified using the Swedish national patient register. Each subject was matched with up to 5 general population comparators per AS-patient (n = 1276). Follow-up started at the date of admission for AMI and extended until death or 365 days of follow-up. Cox regression was used to assess mortality in two time intervals: days 0-30 and days 31-365. For a subgroup with available data, clinical presentation at admission, course, treatment for AMI, and secondary prevention were compared.

Results: During the 365-day follow-up, 56/292 (19%) AS patients and 184/1276 (14%) comparators died. There were no difference in mortality due to cardiovascular-related causes, although the overall mortality day 31-365 was increased among patients with AS compared with comparators (HR [95% CI] = 2.0 [1.3;3.0]). At admission, AS patients had a higher prevalence of cardiovascular comorbidities compared with comparators. At discharge, patients with AS were less often prescribed lipid-lowering drugs and non-aspirin antiplatelet therapy.

Conclusions: Patients with AS tend to have a higher comorbidity burden at admission for first AMI. The mortality after a first AMI due to cardiovascular-related causes does not seem to be elevated, despite an increased overall mortality during days 31-365 among patients with AS compared with the general population. Key Points • The all-cause mortality after a first AMI was higher in patients with AS. • Mortality after a first AMI due to CVD-related causes does not seem to be elevated for patients with AS. • In patients with AS suffering a first AMI, more attention should be given to other comorbidities causing an excess in mortality.
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http://dx.doi.org/10.1007/s10067-020-05354-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943508PMC
April 2021

The impact of seropositivity on the effectiveness of biologic anti-rheumatic agents: results from a collaboration of 16 registries.

Rheumatology (Oxford) 2021 02;60(2):820-828

Rheumatology, University Hospitals of Geneva, Geneva, Switzerland.

Objectives: RF and ACPA are used as diagnostic tools and their presence has been associated with clinical response to some biologic DMARDs (bDMARDs) in RA. This study compared the impact of seropositivity on drug discontinuation and effectiveness of bDMARDs in patients with RA, using head-to-head comparisons in a real-world setting.

Methods: We conducted a pooled analysis of 16 observational RA registries. Inclusion criteria were a diagnosis of RA, initiation of treatment with rituximab (RTX), abatacept (ABA), tocilizumab (TCZ) or TNF inhibitors (TNFis) and available information on RF and/or ACPA status. Drug discontinuation was analysed using Cox regression, including drug, seropositivity, their interaction, adjusting for concomitant and past treatments and patient and disease characteristics and accounting for country and calendar year of bDMARD initiation. Effectiveness was analysed using the Clinical Disease Activity Index evolution over time.

Results: Among the 27 583 eligible patients, the association of seropositivity with drug discontinuation differed across bDMARDs (P for interaction <0.001). The adjusted hazard ratios for seropositive compared with seronegative patients were 1.01 (95% CI 0.95, 1.07) for TNFis, 0.89 (0.78, 1.02)] for TCZ, 0.80 (0.72, 0.88) for ABA and 0.70 (0.59, 0.84) for RTX. Adjusted differences in remission and low disease activity rates between seropositive and seronegative patients followed the same pattern, with no difference in TNFis, a small difference in TCZ, a larger difference in ABA and the largest difference in RTX (Lundex remission difference +5.9%, low disease activity difference +11.6%).

Conclusion: Seropositivity was associated with increased effectiveness of non-TNFi bDMARDs, especially RTX and ABA, but not TNFis.
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http://dx.doi.org/10.1093/rheumatology/keaa393DOI Listing
February 2021

Lymphoma risks in patients with rheumatoid arthritis treated with biological drugs-a Swedish cohort study of risks by time, drug and lymphoma subtype.

Rheumatology (Oxford) 2021 02;60(2):809-819

Unit of Rheumatology, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.

Objectives: To estimate the association between biological DMARDs (bDMARDs; overall and by drug) as used in RA and the risk of malignant lymphomas including subtypes.

Methods: By linking nationwide Swedish registers we identified cohorts of patients with RA initiating treatment with a bDMARD (n = 16 392), bDMARD-naïve (n = 55 253), an age- and sex-matched general population comparator cohort (n = 229 047), and all incident lymphomas 2001-16. We used Cox regression to calculate hazard ratios (HRs) of lymphoma taking calendar period and other factors into account.

Results: There were 82 lymphomas among the bDMARD-treated patients with RA, crude incidence rate 76/100 000 person-years, and 310 lymphomas among the bDMARD-naïve patients with RA, crude incidence rate 90/100 000 person-years. This resulted in an adjusted HR (aHR) associated with bDMARD treatment (vs not) of 1.08 (95% CI: 0.83, 1.41). The corresponding aHR for bDMARD-treated and bDMARD-naïve vs the general population was 1.65 (95% CI: 1.31, 2.08) and 1.56 (95% CI: 1.37, 1.78) respectively. Restricting follow-up period to after 2006, the aHR of lymphoma for patients with RA starting a first bDMARD vs bDMARD-naïve was 0.69 (95% CI: 0.47, 1.00), and for bDMARD treated vs patients with RA switching from one conventional synthetic DMARDs to another, aHR was 0.46 (95% CI: 0.28, 0.73). There were no signals of different risks with any particular TNF inhibitor (TNFi) agent. We found no different lymphoma subtype pattern following bDMARD therapy.

Conclusion: Treatment with bDMARDs, including both TNFi and non-TNFi bDMARDs, does not further increase the lymphoma risk in RA; instead, bDMARD treatment may actually reduce the excess lymphoma risk in RA.
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http://dx.doi.org/10.1093/rheumatology/keaa330DOI Listing
February 2021

Respiratory Diseases as Risk Factors for Seropositive and Seronegative Rheumatoid Arthritis and in Relation to Smoking.

Arthritis Rheumatol 2021 01 4;73(1):61-68. Epub 2020 Dec 4.

Karolinska Institutet, Stockholm, Sweden.

Objective: The link and interplay between different airway exposures and rheumatoid arthritis (RA) risk are unclear. This study was undertaken to determine whether respiratory disease is associated with development of RA, and specifically to examine this relationship by RA serostatus and smoking exposure.

Methods: Using data from the Epidemiological Investigation of Rheumatoid Arthritis study, this analysis included 1,631 incident RA cases and 3,283 matched controls recruited from 2006 to 2016. Linking these individuals to the National Patient Register provided information on past acute or chronic, upper or lower respiratory disease diagnoses. For each disease group, we estimated adjusted odds ratios (OR ) with 95% confidence intervals (95% CI) for RA, using logistic regression models adjusted for age, sex, residential area, body mass index, and education both overall and stratified by anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) status and by smoking status.

Results: Respiratory disease diagnoses were associated with risk of RA, with an OR of 1.2 for acute upper respiratory disease (95% CI 0.8-1.7), 1.4 for chronic upper respiratory disease (95% CI 1.1-1.9), 2.4 for acute lower respiratory disease (95% CI 1.5-3.6), and 1.6 for chronic lower respiratory disease (95% CI 1.5-3.6). These associations were present irrespective of RF or ACPA status, though the association was somewhat stronger for ACPA/RF-positive than ACPA/RF-negative RA. The association between any respiratory disease and RA was stronger for nonsmokers (OR 2.1 [95% CI 1.5-2.9]) than for smokers (OR 1.2 [95% CI 0.9-1.5]).

Conclusion: Respiratory diseases increase the risk for both seropositive and seronegative RA, but only among nonsmokers. These findings raise the hypothesis that smoking and airway disease are associated with RA development through partly different mechanisms.
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http://dx.doi.org/10.1002/art.41491DOI Listing
January 2021

Does autoimmune thyroid disease affect rheumatoid arthritis disease activity or response to methotrexate?

RMD Open 2020 07;6(2)

Division of Clinical Epidemiology Unit, Department of Medicine, Solna, Karolinska Institutet, Stockholm, Sweden.

Objective: To investigate if autoimmune thyroid disease (AITD) impacts rheumatoid arthritis (RA) disease activity or response to methotrexate.

Methods: A nationwide register-based cohort study of 9 004 patients with new-onset RA from the Swedish Rheumatology Quality Register year 2006-2016, with linkage to other nationwide registers to identify comorbidity with AITD defined as thyroxine prescription before RA diagnosis, excluding non-autoimmune causes. We compared RA disease activity using 28-joint Disease Activity Score (DAS28) and its components, and EULAR response, between patients with and without AITD, using logistic regression.

Results: At diagnosis, patient reported outcome measures (PROMs; patient global, Health Assessment Questionnaire Disability Index and pain) but not objective disease activity measures (erythrocyte sedimentation rate and swollen joint count) were significantly higher (p<0.05 for all PROMs) among RA patients with AITD compared with those without. The level of DAS28 was 5.2 vs 5.1. By contrast, AITD had little influence on EULAR response to methotrexate at 3 months (OR of non/moderate response=0.95, 95% CI 0.8 to 1.1), nor at 6 months. When stratified by age, however, AITD was more common among EULAR non/moderate responders at 3 and 6 months in patients below 45 years resulting in ORs of non/moderate response of 1.44 (0.76-2.76) and 2.75 (1.04-7.28).

Conclusion: At diagnosis, RA patients with concomitant AITD score worse on patient reported but not on objective RA disease activity measures, while DAS28 was only marginally elevated. The overall chance of achieving a EULAR good response at 3 or 6 months remains unaffected, although among a limited subgroup of younger patients, AITD may be a predictor for an inferior primary response.
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http://dx.doi.org/10.1136/rmdopen-2020-001282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425184PMC
July 2020