Patients with systemic sclerosis (SSc) report loss of bowel control as one of the most distressing gastrointestinal (GI) manifestations of their disease. Nevertheless, despite the pivotal aspect of fecal incontinence (FI) care, our understanding of its prevalence and true impact on SSc patients remains elusive.
Objectives:
The study had three aims; (i) assess prevalence and burden of FI symptoms by two different patient-reported outcome measures, (ii) identify potential associations between FI symptoms and baseline SSc characteristics, and (iii) determine predictive factors for worsening of FI-related quality of life over time in SSc patients with lower GI disease.
Methods:
In the 20-week multicenter randomized clinical trial (ReSScue) [1] FI symptoms were assessed in 67 SSc patients with moderate to severe lower GI symptoms at baseline, 12 and 20 weeks using the Fecal Incontinence Quality of Life (FIQL) scale and University of California Los Angeles Scleroderma Clinical Trial Consortium GIT 2.0 (UCLA GIT) scale. Patients reporting presence of FI symptoms at all three timepoints were defined as having "severe FI". Using multivariable logistic regressions, we assessed associations between baseline FI and frequency of FI with patient characteristics. Next, we assessed associations between FI, by UCLA GIT fecal soilage score and FIQL subscales, as well as ScleroID, HAQ-DI, EuroEQ-5D, patient and physician global assessment and VAS fatigue scale, using Pearson's correlation analysis. Linear mixed-effect models were applied to unveil predictors of FIQL score behavior over time.
Results:
In the entire cohort, 72% (48/67) reported FI on the FIQL scale, in contrast to 33% (22/67) using the UCLA GIT. Altogether, 14 SSc patients met the definition of "severe" FI. Compared to the patients with no FI, the patients who reported FI symptoms were more often anti-centromere positive and had lower Body Mass Index (Table 1 and Figure 1A). We found that "severe" FI associated with Modified Rodnan Skin Score (Figure 1B), while recurrent FI episodes associated with digital ulcers (DU), loose stools and diarrhea (Figure 1C). Age and disease duration predicted FI worsening over time in all and the severe FI patients (Figure 1D), with no associations between baseline FI severity and score changes in either cohort. The FIQL subdomains, particularly coping (r=-0.74, p<.001) and embarrassment (r=-0.63, p<.001), correlated with both mild and moderate to severe UCLA fecal soilage scores, notably in "severe" FI patients. No correlation was found between FIQL subdomains and ScleroID lower GI domain and no other patient-reported outcome measures correlated with the severity of fecal soilage.
Conclusion:
In SSc patients with moderate to severe lower GI disease, reported prevalence of fecal incontinence symptoms is high. In this study, the FIQL scale identified more FI cases than the UCLA GIT score, probably indicating higher sensitivity of the FIQL scale. Recurrent FI episodes are associated with more severe SSc-related GI involvement. Although we have identified significant associations with various aspects of FI, early FI assessment appears key to prevent the considerable life restrictions patients face daily.
REFERENCES:
[1] Hoffmann-Vold AM, Fretheim HH, Sarna VK, Barua I, Carstens MN, Distler O, et al. Safety and efficacy of faecal microbiota transplantation by Anaerobic Cultivated Human Intestinal Microbiome (ACHIM) in patients with systemic sclerosis: study protocol for the randomised controlled phase II ReSScue trial. BMJ Open. 2021 Jun;11(6): e048541.
Objective. To examine the frequency of 6 definitions for remission and 4 definitions for low disease activity (LDA) after starting a disease-modifying antirheumatic drug (DMARD) in patients with rheumatoid arthritis (RA) in clinical practice, and to study whether predictors for achieving remission after 6 months are similar for these definitions. Methods. Remission and LDA were calculated according to the 28-joint Disease Activity Score (DAS28), the Clinical Disease Activity Index (CDAI), the Simplified Disease Activity Index (SDAI), the Routine Assessment of Patient Index Data (RAPID3), and both the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean remission definitions 3 and 6 months after 4992 DMARD prescriptions for patients enrolled in the NOR-DMARD, a 5-center Norwegian register. Prediction of remission after 6 months was also studied. Results. After 3 months, remission rates varied between definitions from 8.7% to 22.5% and for LDA from 35.5% to 42.7%, and increased slightly until 6 months of followup. DAS28 and RAPID3 gave the highest and ACR/EULAR, SDAI, and CDAI the lowest proportions for remission. Positive predictors for remission after 6 months were similar across the definitions and included lower age, male sex, short disease duration, high level of education, current nonsmoking, nonerosive disease, treatment with a biological DMARD, being DMARD-naive, good physical function, little fatigue, and LDA. Conclusion. In daily clinical practice, the DAS28 and RAPID3 definitions identified remission about twice as often as the ACR/EULAR Boolean, SDAI, and CDAI. Predictors of remission were similar across remission definitions. These findings provide additional evidence to follow treatment recommendations and treat RA early with a DMARD.
Introduction In the multisystem inflammatory disorder systemic sclerosis (SSc), gastrointestinal tract (GIT) affliction is highly prevalent. There are no known disease modifying therapies and the negative impact is substantial. Aiming for a new therapeutic principle, and inspired by recent work showing associations between gut microbiota changes and GIT symptoms in SSc, we performed a pilot study on faecal microbiota transplantation (FMT) with the single-donor bacterial culture ‘Anaerobic Cultivated Human Intestinal Microbiome (ACHIM)’. Motivated by positive pilot study signals, we designed the ReSScue trial as a phase II multicentre, placebo-controlled, randomised 20-week trial to evaluate safety and efficacy on lower GIT symptoms of FMT by ACHIM in SSc. Methods and analyses We aim to include 70 SSc participants with moderate to severe lower GIT symptoms, defined by the validated patient-reported University of California Los Angeles Scleroderma Clinical Trial Consortium GIT 2.0 2.0 questionnaire. The trial includes three parts. In part A1 (induction phase) lasting from week 0 to week 12, participants will be randomised 1:1 to repeat infusions of 30 mL ACHIM or placebo at week 0 and 2 by gastroduodenoscopy. In part A2, which is an 8-week subsequent maintenance phase, all study participants will receive 30 mL ACHIM at week 12 and followed until week 20 on continued blind. In part B, which will last until the last participant completes part A2, the participants will be followed through a maximum 16-week extended monitoring period, for longer-term data on safety and intervention effects. Primary endpoint is change from baseline to week 12 in UCLA GIT subscale scores of diarrhoea or bloating, depending on the worst symptom at baseline evaluated separately for each patient. Secondary endpoints are safety measures and changes in UCLA GIT scores (total, diarrhoea and bloating). Ethics and dissemination This protocol was approved by the Northern Norwegian Committee for Medical Ethics. Study findings will be published. Trial registration number NCT04300426 ; Pre-results. Protocol version V.3.1.
EULAR recommendations for cardiovascular disease (CVD) risk management include annual CVD risk assessments for patients with rheumatoid arthritis (RA). We evaluated the recording of CVD risk factors (CVD-RF) in a rheumatology outpatient clinic, where EULAR recommendations had been implemented. Further, we compared CVD-RF recordings between a regular rheumatology outpatient clinic (RegROC) and a structured arthritis clinic (AC).In 2012, 1142 RA patients visited the rheumatology outpatient clinic: 612 attended RegROC and 530 attended AC. We conducted a search in the patient journals to ascertain the rate of CVD-RF recording.The overall CVD-RF recording rate was 40.1% in the rheumatology outpatient clinic, reflecting a recording rate of 59.1% in the AC and 23.6% in the RegROC. The odds ratios for having CVD-RFs recorded for patients attending AC compared to RegROC were as follows: blood pressure: 12.4, lipids: 5.0-6.0, glucose: 9.1, HbA1c: 6.1, smoking: 1.4, and for having all the CVD-RFs needed to calculate the CVD risk by the systematic coronary risk evaluation (SCORE): 21.0.The CVD-RF recording rate was low in a rheumatology outpatient clinic. However, a systematic team-based model was superior compared to a RegROC. Further measures are warranted to improve CVD-RF recording in RA patients.
Introduction: Endothelial dysfunction is an early step in the atherosclerotic process and can be quantified by flow-mediated vasodilation (FMD).Our aim was to investigate the effect of long-term rosuvastatin therapy on endothelial function in patients with inflammatory joint diseases (IJD) with established atherosclerosis.Furthermore, to evaluate correlations between change in FMD (ΔFMD) and change in carotid plaque (CP) height, arterial stiffness [aortic pulse wave velocity (aPWV) and augmentation index (AIx)], lipids, disease activity and inflammation.Methods: Eighty-five statin-naïve patients with IJD and ultrasound-verified CP (rheumatoid arthritis: n = 53, ankylosing spondylitis: n = 24, psoriatic arthritis: n = 8) received rosuvastatin treatment for 18 months.Paired-samples t tests were used to assess ΔFMD from baseline to study end.Linear regression models were applied to evaluate correlations between ΔFMD and cardiovascular risk factors, rheumatic disease variables and medication.Results: The mean ± SD FMD was significantly improved from 7.10 ± 3.14 % at baseline to 8.70 ± 2.98 % at study end (p < 0.001).Improvement in AIx (p < 0.05) and CP height reduction (p = 0.001) were significantly associated with ΔFMD (dependent variable).Conclusions: Long-term lipid lowering with rosuvastatin improved endothelial function in IJD patients with established atherosclerotic disease.Reduced arterial stiffness and CP regression were longitudinally correlated with the improvement in endothelial function measured by FMD.
Tumour necrosis factor inhibitors (TNFi) have revolutionized treatment of axial spondylarthritis (axSpa). The five different available TNFi have not been compared directly, and whether effectiveness differs between agents is unknown. In Norway national authorities consider the different TNFi equivalent, and since 2009 the least expensive drug following an annual national tender has been the drug-of-choice in the publicly funded healthcare system. This has lead to variations across different years in drug use where choice of TNFi has been predominantly based on national price policy and not clinical characteristics.
Objectives
Comparing response to TNFi during the first year of treatment of axSpA in biologics-naïve patients over years with highly varying uptake of different TNFi.
Methods
We included the 981 biologics-naïve patients with axSpA from the NOR-DMARD register who started their first TNFi from 2009 through 2015. The preferred drugs in national recommendations were: 2009 adalimumab, 2010 golimumab, 2011 etanercept, 2012 etanercept, 2013 golimumab, 2014 certolizumab, 2015 certolizumab/biosimilar infliximab (CT-P13). We compared the estimated change in Ankylosing Spondylitis Disease Activity Score (ASDAS) between treatment years at 3, 6 and 12 months after treatment start using a mixed model with subject-specific random intercept, adjusting for baseline disease activity, age, sex and treatment centre.
Results
Demographics, drug uptake and baseline characteristics for each year 2009–2015 are listed in table 1. The preferred drug was started in 57–91% of patients. There was a trend towards lower ASDAS and disease duration over time. There were no differences in treatment effectiveness between the years, regardless of the substantial differences in type of TNFi used (figure).
Conclusions
Real-life data do not show differences in response to TNFi despite large annual variation in type of TNFi prescribed, indicating similar effectiveness of the available TNFi in patients with axSpA. This supports the practice of selecting drug based on cost and feasibility of use, as is the current practice in Norway. Further adoption of this principle can provide access to TNFi treatment to more patients, as it reduces costs and healthcare resources are limited.
Disclosure of Interest
E. K. Kristianslund: None declared, K. M. Fagerli: None declared, E. Lie Consultant for: AbbVie, Celgene, Hospira, Pfizer, UCB., A. Wierød: None declared, S. Kalstad: None declared, E. Rødevand: None declared, F. Krøll: None declared, P. Mielnik: None declared, T. K. Kvien Consultant for: AbbVie, Biogen, BMS, Boehringer Ingelheim, Celltrion, Eli Lilly, Epirus, Janssen, Merck-Serono, MSD, Mundipharma, Novartis, Oktal, Orion Pharma, Hospira/Pfizer, Roche, Sandoz, UCB, I. C. Olsen: None declared
The NOR-SWITCH main and extension trials demonstrated that switching from originator to biosimilar infliximab (CT-P13) is efficacious and safe across six diseases. However, a subgroup analysis of Crohn's disease (CD) in the main trial displayed a close to significant difference favouring originator infliximab, and more scientific data have therefore been requested. The aim was to assess treatment efficacy, safety, and immunogenicity in an explorative subgroup analysis in CD and ulcerative colitis (UC) in the NOR-SWITCH trials. The 52-week, randomised, non-inferiority, double-blind, multicentre, phase 4 NOR-SWITCH study was followed by a 26-week open extension trial where all patients received treatment with CT-P13. Treatment efficacy, safety, and immunogenicity in CD and UC were assessed throughout the 78-week study period. The main and extension trials included 155 and 93 patients with CD and 93 and 80 patients with UC, respectively. Demographic and baseline characteristics were comparable in both treatment arms within patient groups. There were no differences in the main and extension trials regarding changes in activity indices, C-reactive protein, faecal calprotectin, patient's and physician's global assessment of disease activity and patient-reported outcome measures in CD and UC. Moreover, comparable results were also demonstrated for trough serum levels, presence of anti-drug antibodies, and reported adverse events. Efficacy, safety, and immunogenicity of both the originator and biosimilar infliximab were comparable in CD and UC in the NOR-SWITCH main and extension trials. These explorative subgroup analyses confirm that there are no significant concerns related to switching from originator infliximab to CT-P13 in CD and UC. ClinicalTrials.gov, number NCT02148640.
Background: The oral, selective Janus kinase 1/2 inhibitor baricitinib has shown efficacy in mixed populations of hospitalised participants with COVID-19. Bari-SolidAct is the first trial in the investigator-initiated, adaptive platform trial EU-SolidAct, and is a multinational, phase 3, randomised, double-blind, placebo-controlled trial of baricitinib in hospitalised patients with confirmed SARS-CoV-2 infection. We aimed to evaluate the efficacy and safety of baricitinib plus standard of care in hospitalised adults with severe or critical COVID-19.Methods: The study was conducted in 39 clinical sites (hospital wards and intensive care units) across 10 European countries. Participants (aged ≥18 years) hospitalised with laboratory-confirmed SARS-CoV-2 infection and severe or critical illness were randomly assigned in combination with standard of care (1:1) to baricitinib (4 mg) or matching placebo once daily for up to 14 days The primary end point was all-cause mortality within 60 days, and patients were remotely followed up to day 90 for safety and patient related outcome measures. The efficacy and safety analyses were completed in all randomised participants receiving at least one treatment dose of study drug (modified intention to treat population). The trial was stopped for immunocompetent participants before reaching the planned sample size of 1,900 due to external evidence from the Recovery trial indicating survival benefit of baricitinib in the trial population. The Bari-SolidAct trial is registered with ClinicalTrials.gov, NCT04891133.Findings: Between 3 rd June 2021 and 7 th March 2022, 299 patients were screened, 284 randomised, and 275 participants received study drugs (139 baricitinib and 136 placebo). There were 21 deaths in each group, with a proportion of death at day 60 of 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI -0·1% [-8·3 to 8·0]). There were no differences between the study groups with regard to changes in viral load, lymphocyte count, neutrophil count, lactate dehydrogenase, D-Dimer, CRP, procalcitonin or ferritin levels. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. There were 54 serious adverse events in 32 participants (23%) in the baricitinib group and 60 in 34 participants (25%) in the placebo group. In a post-hoc analysis, there was a significant interaction between vaccination status and treatment allocation on serious adverse events (interaction p-value = 0.003), with an increased occurrence of respiratory complications and severe infections in vaccinated participants treated with baricitinib.Interpretation: We found no difference in participants treated with baricitinib for the primary mortality endpoint at day 60. There was a potential interaction between vaccination status and treatment allocation on mortality and occurrence of serious adverse events, although our findings are not conclusive. Real-world data and subgroup analyses according to vaccination status and disease severity in larger trials, are warranted to assess the precise risk/benefit ratio of baricitinib in vaccinated patients with severe/critical COVID-19. Trial Registration: EU-SolidAct/Bari-SolidAct is registered at www.clinicaltrials.gov (NCT04891133) and euclinicaltrials.eu (EU CTIS number 2022-500385-99-00).Funding: European Commission.Declaration of Interest: MT has been member of scientific advisory board for Lilly. MT has been member of scientific advisory board for Lilly. JP reports lecture fees from Gilead; support for attending meetings from Gilead, Eumedica, Merck Sharp & Dohme, outside the submitted work. ARH reports personal fee from Pfizer (2021) for lectures outside the submitted work. MH(it) has received funding for other trials on COVID-19 from the Federal Belgian Center for Knowledge and the joint Université Libre de Bruxelles-Fonds Erasme-COVID-19 projects (2020-21), personal fees from Gilead (2020) and Pfizer (2021) for editing and lectures outside the submitted work, and travel/congress grants from Pfizer (2020, 2021), and Gilead (2022). MJ reports consulting or speakers fees from Baxter, Gilead, CLS Behring, AM-Pharma, Novartis, Fresenius and grant support from Fresenius, Baxter, outside the submitted work. JAP reports fees for lectures and advisory boards from MSD, Pfizer, Astra-Zeneca, Jansen, Gilead, AOP Orphan Pharmaceuticals, Cepheid MB reports an unrestricted grant for Moderna (2022) outside the submitted work. MB reports an unrestricted grant for Moderna (2022) outside the submitted work. KL reports personal fees from Gilead, MSD, Janssen and ViiV Healthcare for advisory boards and lectures outside of the submitted work. JM reports personal fees from Pfizer (2017) for lectures outside the submitted work and travel fees from Pfizer (2022) and Menarini (2021). JCR reports a grant from Hamilton medical (2019-2020) outside the submitted work FLJ reports Helse Sør-Øst grant for developing COVID-19 serology (2020-2021) and Grant from CEPI to monitor responses in patients (2021-2023) DC reports an HIV grant from Janssen (2019-2020), personal fees from Gilead (2020) and Pfizer (2022) for lectures outside the submitted work. All ther authors have nothing to declare. Ethical Approval: The trial was conducted in accordance with ICH E6 (R2) Good Clinical Practice and the ethical principles of the Declaration of Helsinki. Informed consent by the study participant or legally authorised representative was given prior to inclusion in the study. This is an international trial conducted in several European countries, with approval from ethics committees and national competent authority in each country, and in some countries also regional and site specific ethics approvals. The trial was initially submitted through the volunteer harmonized procedure (VHP) in the CTFG system, with first ethical approvals in France and Norway, followed by approval in all other countries in the trial. The trial has been transferred to CTIS and is now accepted under the Clinical Trial Regulation (CTR), euclinicaltrials.eu (EU CTIS number 2022-500385-99-00). EU-SolidAct/Bari-SolidAct is also registered at www.clinicaltrials.gov (NCT04891133).
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