Jens Kristian Pedersen

To describe antibiotic use in patients with inflammatory arthritis (IA) and in the background population (BP) within one year before and after IA diagnosis. Using data from Danish nationwide registries, we identified all adults with a first-time diagnosis of RA, PsA, or AS/spondyloarthritis (AS/SpA) from 2010 through 2018. For each IA patient, we randomly sampled 10 persons from the BP, matched on sex and birthdate. We calculated the prevalence (n [%]) of any antibiotic dispensing and the total antibiotic dispensing in the year before and after diagnosis. We identified 28 504 new-onset IA patients (RA, n = 16 130; PsA, n = 5988; AS/SpA, n = 6386) and 285 040 BP individuals. Within one year before diagnosis, the total amount of dispensed antibiotics was higher in both RA, PsA and As/SpA compared with the BP (prevalence rate ratios [PRR], 1.48 [1.46; 1.51]; 1.67 [1.62; 1.72]; 1.52 [1.47; 1.56], respectively). The amount increased with 22% in IA patients three months before diagnosis compared with the preceding three-month period. Although the prevalence of any antibiotic dispensing in IA patients decreased in the year following the diagnosis (IA; 40.6%), the total one-year antibiotic dispensing remained constant in RA (PRR 0.99 [0.97; 1.01]), decreased in PsA (0.91 [0.87; 0.94]) and increased in AS/SpA (1.08 [1.04; 1.12]) patients after diagnosis compared with before. Antibiotics are more frequently dispensed to individuals developing IA compared with the BP. Antibiotic utilization patterns change after IA diagnosis with marked differences among IA subgroups.

Background Metabolite profiling of biofluids has an emergent role in exploring the contribution of host-microbiome interactions to the treatment response of immune-mediated arthritis.[1] Objectives As part of the FLORA trial (exploring the impact of gut microbiome manipulation upon response to methotrexate [MTX]),[2] we investigated plasma metabolomic profiles of adults with psoriatic arthritis (PsA) and whether they correlated with the primary trial outcome, which was clinical response to MTX (responder vs failure) following one faecal microbiota transplant (FMT) or sham transplant. Methods Thirty-one PsA patients with active peripheral disease, despite at least 3 months of steady-state dose MTX, were included in the 26-week, double-blind, parallel-group, 1:1 randomised, sham-controlled, superiority trial (FLORA trial; NCT03058900).[2] Patients were randomly allocated to receive either one gastroscopic-guided FMT (n = 15) or sham transplant (n = 16). Each FMT product encompassed 50 g of processed faeces obtained from one of four healthy, thoroughly screened donors. Patients continued MTX throughout the trial. The primary trial endpoint was the proportion of treatment failures through 26 weeks, defined as need for treatment escalation (in most cases instigation of TNF inhibitors) due to insufficient improvement of disease activity or disease worsening.[2] Li-Hep plasma samples were collected at baseline, week 4, 12, and 26. The metabolic profiles were measured using ¹H Nuclear Magnetic Resonance (NMR). We used a supervised multivariate orthogonal partial least squares-discriminant analysis (OPLS-DA) to model metabolic differences among groups. Results Twenty women and eleven men with a mean age of 50.7 years (SD = 13.6) and a mean swollen joint count of 7.1 (SD = 2.8) were included in the trial.[2] We were able to annotate 40 plasma metabolites in the baseline samples. No differences in baseline plasma profiles were observed between patients allocated to FMT and sham (OPLS-DA model; Q2 = -0.452, p = 1). However, the OPLS-DA analysis revealed a significant model for treatment responders (n = 19) vs failures (n = 12) among all patients, Figure 1. Correlations between metabolites and the primary trial outcome with a correlation coefficient (r) ≥0.50 are presented in Table 1. When patients were stratified for intervention type, the models continued to show significant separation (FMT arm: Q2 = 0.383, p < 0.0001; sham arm: Q2 = 0.260, p = 0.002). In both the FMT and the sham models, glucose (r = 0.67 and r = 0.63) correlated positively with treatment failure while lysine (r = -0.83 and r = -0.65) and phenylacetate (r = -0.66 and r = -0.51) correlated with successful treatment response. OPLS-DA model that significantly separates treatment responders (n = 19) from failures (n = 12) based on their plasma metabolomic profiles. Plot includes ¹H-NMR plasma profile for all patients at all timepoints. Plasma metabolites associated with successful treatment response (green) vs failure (blue) in the Figure 1 model. Conclusion In the FLORA trial, plasma metabolomic profiles of patients with active, peripheral PsA significantly discriminated between treatment responders and failures. This discriminatory power was the case for the entire trial population as well as for each of the two treatment arms (FMT vs sham). References [1]Rizzo C, et al. Metabolomics: An Emerging Approach to Understand Pathogenesis and to Assess Diagnosis and Response to Treatment in Spondyloarthritis. Cells 2022;11(3):549. [2]Kragsnaes MS, et al. Safety and efficacy of faecal microbiota transplantation for active peripheral psoriatic arthritis: an exploratory randomised placebo-controlled trial. Ann Rheum Dis 2021; 80: 1158-1167. Acknowledgements: NIL. Disclosure of Interests None Declared.

Objectives: In patients with RA, the association between mortality and depression has been investigated only in patients with prevalent RA. In this study, we estimated the mortality risk associated with depression, defined as the first filling of a prescription for antidepressants, in patients with incident RA and background population comparators. Methods: From 2008 to 2018, we identified patients with incident RA in the nationwide Danish rheumatologic database, DANBIO. For each patient, we randomly selected five comparators. Participants were not treated with antidepressants or diagnosed with depression 3 years prior to the index date. From other registers we collected data on socioeconomic status, mortality and cause of death using unique personal identifiers. Using Cox models, we calculated hazard rate ratios (HRR) with 95% CI. Results: In depressed patients with RA vs patients without depression, adjusted HRR for all-cause mortality was 5.34 (95% CI 3.02, 9.45) during 0–2 years and 3.15 (95% CI 2.62, 3.79) during the total follow-up period, and highest in patients <55 years with HRR 8.13 (95% CI 3.89, 17.02). In comparators with depression vs comparators without depression, the association with mortality was similar to that in patients with RA. There were no unnatural causes of death among depressed patients with RA. The most frequent natural causes of death were cancer, cardiovascular disease, stroke and pneumonia. Conclusion: In patients with RA, depression was a predictor of death but with a strength similar to that in matched comparators.

Objective: To explore anxiety and self-isolation in patients with inflammatory rheumatic disease (IRD)15 months into the coronavirus disease 2019 (COVID-19) pandemic, including attitudes toward and effects of SARS-CoV-2 vaccination.Methods: A nationwide online survey was conducted at 3 timepoints: May 2020, November 2020, and May 2021. Patients with IRD followed in the Danish Rheumatology Quality Registry (DANBIO) were asked about the effects of the pandemic, including SARS-CoV-2 infection and their behavior, anxiety, and concerns. The May 2021 survey included attitudes toward SARS-CoV-2 and influenza vaccination. Characteristics associated with self-isolation in May 2021 were explored with adjusted logistic regression analyses that included patient characteristics and SARS-CoV-2 vaccination status.Results: Respondents to surveys 1, 2, and 3 included 12,789; 14,755; and 13,921 patients, respectively; 64% had rheumatoid arthritis and 63% were female. Anxiety and concerns were highest in May 2020 and decreased to stable levels in November 2020 and May 2021; 86%, 50%, and 52% of respondents reported self-isolation, respectively. In May 2021, 4% of respondents self-reported previous SARS-CoV-2 infection. The SARS-CoV-2 vaccine acceptance rate was 86%, and the proportion of patients vaccinated against influenza had increased from 50% in winter 2019-2020 to 64% in winter 2020-2021. The proportion of patients with anxiety appeared similar among those vaccinated and unvaccinated against SARS-CoV-2. In multivariable analyses, being unvaccinated, female gender, receiving biologic drugs, and poor quality of life were independently associated with self-isolation.Conclusion: Levels of anxiety and self-isolation decreased after the initial lockdown period in patients with IRD. Half of the patients reported self-isolation in May 2021, a phase that included widespread reopening of society and large-scale vaccination. The lack of prepandemic data prevented a full understanding of the long-term effects of the pandemic on anxiety and self-isolation in patients with IRD.

Objectives In 2018, a nationwide mandatory switch from originator to biosimilar adalimumab was conducted in Denmark. The available biosimilar was GP2017 (Hyrimoz) in Eastern regions and SB5 (Imraldi) in Western regions. We aimed to assess the comparative effectiveness of GP2017 versus SB5 in patients with rheumatoid arthritis (RA)/psoriatic arthritis (PsA)/axial spondyloarthritis (AxSpA). Methods Observational cohort study based on the DANBIO registry with geographical cluster pseudo-randomisation, analysed by emulating a randomised clinical trial. Main outcome was adjusted 1-year treatment retention (Cox regression). Furthermore, 6 months’ remission rates (logistic regression), reasons for withdrawal and back-switching to originator were investigated (overall and stratified by indication). Results Overall, of 1570 eligible patients, 1318 switched and were included (467 RA/321 PsA/530 AxSpA); 623 (47%) switched to GP2017, 695 (53%) to SB5. Baseline characteristics of the two clusters were largely similar, but some differences in registration practice were observed. The combined 1-year retention rate for the two biosimilars was 89.5%. Compared with SB5, estimated risk of withdrawal for GP2017 was lower (HR 0.60; 95% CI 0.42 to 0.86) and 6 months’ remission rate was higher (OR 1.72; 95% CI 1.25 to 2.37). Stratified analyses gave similar results (statistically significant for RA). During 1 year, 8.5% and 12.9% withdrew GP2017 and SB5, respectively (primarily lack of effect and adverse events), of whom 48 patients (3.6%) back-switched. Conclusion This head-to-head comparison of GP2017 versus SB5 following a mandatory switch from the originator indicated differences in effectiveness in routine care. This may reflect a true difference, but other explanations, for example, differences in excipients, differences between clusters and residual confounding cannot be ruled out.

Objectives Although causality remains to be established, targeting dysbiosis of the intestinal microbiota by faecal microbiota transplantation (FMT) has been proposed as a novel treatment for inflammatory diseases. In this exploratory, proof-of-concept study, we evaluated the safety and efficacy of FMT in psoriatic arthritis (PsA). Methods In this double-blind, parallel-group, placebo-controlled, superiority trial, we randomly allocated (1:1) adults with active peripheral PsA (≥3 swollen joints) despite ongoing treatment with methotrexate to one gastroscopic-guided FMT or sham transplantation into the duodenum. Safety was monitored throughout the trial. The primary efficacy endpoint was the proportion of participants experiencing treatment failure (ie, needing treatment intensification) through 26 weeks. Key secondary endpoints were change in Health Assessment Questionnaire Disability Index (HAQ-DI) and American College of Rheumatology (ACR20) response at week 26. Results Of 97 screened, 31 (32%) underwent randomisation (15 allocated to FMT) and 30 (97%) completed the 26-week clinical evaluation. No serious adverse events were observed. Treatment failure occurred more frequently in the FMT group than in the sham group (9 (60%) vs 3 (19%); risk ratio, 3.20; 95% CI 1.06 to 9.62; p=0.018). Improvement in HAQ-DI differed between groups (0.07 vs 0.30) by 0.23 points (95% CI 0.02 to 0.44; p=0.031) in favour of sham. There was no difference in the proportion of ACR20 responders between groups (7 of 15 (47%) vs 8 of 16 (50%)). Conclusions In this first preliminary, interventional randomised controlled trial of FMT in immune-mediated arthritis, we did not observe any serious adverse events. Overall, FMT appeared to be inferior to sham in treating active peripheral PsA. Trial registration number NCT03058900.

To explore the impact of the COVID-19 pandemic on treat-to-target strategies (disease activity, remission rates) and access to physical consultations in patients with inflammatory rheumatic disease, as well as to explore characteristics of patients with/without physical consultations in the clinic and the impact of early vs established disease. Patients with RA, PsA or axial SpA (axSpA) prospectively followed in the nationwide DANBIO registry answered online questionnaires and reported patient-reported outcomes (PROs) in June and November 2020. Patient characteristics, disease activity and physical consultations in the clinic before and during the pandemic were identified in DANBIO [all patients and subgroups with early disease (disease duration ≤2 years)]. In individual patients, changes in PROs before and during the pandemic were calculated. Characteristics of patients with/without physical consultations were described (age, gender, education level, comorbidities, disease duration, treatment). We included 7836 patients (22% of eligible patients), 12% of which had early disease. PROs were stable before and during the pandemic, with median changes approximating zero, as well as in patients with early disease. Remission rates were stable. The relative decrease in the number of patients with physical consultations was 21–72%, which was highest in axSpA. Characteristics of patients with/without physical consultations were similar. Self-reported satisfaction with treatment options and access was >70%; the preferred contact form was physical consultation (66%). In this nationwide study performed during the first 8 months of the pandemic, patient satisfaction was high and the PROs and remission rates remained stable despite the remarkable reduction in physical consultations, as well as in patients with early disease. Characteristics of patients with/without physical consultations appeared similar.

Background: In the DANBIO quality registry in Denmark, patients with rheumatoid arthritis (RA) psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA) have reported Patient Reported Outcomes (PROs) including the Stanford Health Assessment Questionnaire Disability Index (HAQ-DI) for nearly twenty years as part of routine care. Patients’ feedback have stressed a need for a shorter registration of disability (1). While the shorter Multidimensional Health Assessment Questionnaire (MDHAQ) is preferred by patients, the original HAQ-DI is the preferred tool in observational studies. Thus, a conversion algorithm between the MDHAQ and HAQ-DI scores is warranted. Objectives: To develop and validate a simple conversion algorithm between MDHAQ and HAQ-DI scores in RA, PsA and axSpA patients. Methods: Patients registered in DANBIO with a diagnosis of RA, PsA or axSpA who had completed both HAQ-DI and MDHAQ simultaneously at a visit +/- 30 days from start of conventional synthetic (cs)DMARD or biological (b)DMARD were eligible for the analysis, and randomly divided into development and validation cohorts stratified by diagnosis. The conversion algorithm was developed in the RA development cohort using linear regression with HAQ-DI as the dependent variable and MDHAQ as the independent variable. The predicted HAQ (pHAQ) scores were then calculated by applying the conversion algorithm to the MDHAQ scores in the RA, PsA and axSpA validation cohorts. The pHAQ was validated against the HAQ-DI in the validation cohorts regarding criterion, correlational and construct validity. Results: We included 8983/4410/1760 patients with RA/PsA/axSpA, respectively. The conversion algorithm pHAQ=0.15+MDHAQ*1.08 had the best fit (R²=0.83) in the RA development cohort. Criterion validity: The correlation coefficients between HAQ-DI/pHAQ and patient global score at baseline were 0.66/0.65. In groups of patients with high and low disability (defined as patient global score ≥50), standardized mean difference was -1.4 for HAQ-DI, and -1.4 for pHAQ. Correlational validity: Correlation coefficients between HAQ-DI/pHAQ and ΔHAQ-DI/ΔpHAQ between baseline and first follow-up visit were r=0.91 and r=0.87, respectively. Correlation coefficients between HAQ-DI/pHAQ and pain score, DAS28CRP and physician global score were 0.63/0.64, 0.55/0.55 and 0.34/0.34, respectively. A Bland-Altman plot showed good agreement of HAQ-DI and pHAQ across all functional states. Construct validity: HAQ-DI/pHAQ at the first follow-up visit after baseline was comparable between Patient Acceptable Symptom State groups (PASS=No: mean 1.17 vs 1.18/PASS=Yes: 0.55 vs 0.60). Similar results were seen for the external anchor (Figure 1). In PsA and axSpA validation cohorts, similar results were found. Conclusion: A conversion algorithm from MDHAQ to HAQ-DI was developed in ≈ 4500 RA patients. In separate large validation cohorts of RA, PsA and axSpA patients, the predicted HAQ calculated from the MDHAQ scores showed good criterion, correlational and construct validity comparable to the original HAQ-DI. The results suggest that for research purposes the MDHAQ can be converted to HAQ-DI if a full HAQ-DI has not been performed. References: [1] Primdahl J. et al. Arthritis Care Res 2019 (in press). Acknowledgments: The authors thank all Danish patients and Departments of Rheumatology, who conscientiously report to the DANBIO registry. Disclosure of Interests: Elisabeth Svensson: None declared, Katja Løngaard: None declared, Lykke Midtbøll Ørnbjerg Grant/research support from: Novartis, Rikke Meincke: None declared, Jens Kristian Pedersen: None declared, Lene Dreyer: None declared, Niels Steen Krogh: None declared, Dorte Vendelbo Jensen: None declared, Merete L. Hetland Grant/research support from: BMS, MSD, AbbVie, Roche, Novartis, Biogen and Pfizer, Consultant of: Eli Lilly, Speakers bureau: Orion Pharma, Biogen, Pfizer, CellTrion, Merck and Samsung Bioepis