Aspects of methodology in assessing inflammation and damage in rheumatoid arthritis and axial spondyloarthritis

This thesis is two-fold focused on rheumatoid arthritis and axial spondyloarthritis. It covers outstanding aspects of research methodology in the assessment of inflammation and damage in patients with these diseases. The studies pertaining to the first part of the thesis focus on rheumatoid arthritis and may help to better understand the relationship between disease activity, radiographic damage and disability. More specifically, they evaluate which of the available tools (individual instruments or composite indices) is associated with radiographic damage and which of the different types of structural lesions detectable on radiographs is associated with disability. Additionally, these studies address methodological issues related to the optimal assessment of radiographic progression in clinical trials. The studies described in the second part of the thesis evaluate the benefit of supplementary tests reflecting inflammation, especially to help classifying (diagnosing) patients and to monitor disease activity. Among others, the studies described in this thesis provide data that allow a better usage of these tests in clinical practice. Overall, this thesis provide guidelines on how to assess properly rheumatoid arthritis and axial spondyloarthritis in clinical trials and in clinical practice. This precise way of assessment will lead to a better understanding and a better management of these diseases.UBL - phd migration 201

The 5-year data of the DESIR cohort

Funding Information: Acknowledgements the dESIr cohort was sponsored by the département de la recherche Clinique et du développement de l’Assistance publique–Hôpitaux de paris. this study is conducted under the umbrella of the French Society of rheumatology and InSErM (Institut national de la Santé et de la recherche Médicale). the database management is performed within the department of epidemiology and biostatistics (professor paul Landais, d.I.M., nîmes, France). An unrestricted grant from pfizer was allocated for the 10 years of the follow-up of the recruited patients. the authors would like to thank the different regional participating centres: pr Maxime dougados (paris – Cochin B), pr André Kahan (paris - Cochin A), pr olivier Meyer (paris - Bichat), pr pierre Bourgeois (paris - La pitié Salpetrière), pr Francis Berenbaum (paris - Saint Antoine), pr pascal Claudepierre (Créteil), pr Maxime Breban (Boulogne Billancourt), dr Bernadette Saint-Marcoux (Aulnay-sous-Bois), pr philippe Goupille (tours), pr Jean-Francis Maillefert (dijon), dr xavier puéchal, dr Emmanuel dernis (Le Mans), pr daniel Wendling (Besançon), pr Bernard Combe (Montpellier), pr Liana Euller-Ziegler (nice), pr philippe orcel, dr pascal richette (paris - Lariboisière), pr pierre Lafforgue (Marseille), dr patrick Boumier (Amiens), pr Jean-Michel ristori, pr Martin Soubrier (Clermont-Ferrand), dr nadia Mehsen (Bordeaux), pr damien Loeuille (nancy), pr rené-Marc Flipo (Lille), pr Alain Saraux (Brest), pr Corinne Miceli (Le Kremlin Bicêtre), pr Alain Cantagrel (toulouse), pr olivier Vittecoq (rouen). the authors would also like to thank UrC-CIC paris Centre for the coordination and monitoring of the study. Contributors All authors contributed and finally approved the current manuscript. Competing interests none declared. Patient consent obtained. ethics approval Comitte de protection des personnes Ile de France III. Provenance and peer review not commissioned; externally peer reviewed. Open Access this is an open Access article distributed in accordance with the Creative Commons Attribution non Commercial (CC BY-nC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/ licenses/by-nc/4.0/ © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. no commercial use is permitted unless otherwise expressly granted. Publisher Copyright: © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved.Objective To estimate sacroiliac joint radiographic (X-SIJ) progression in patients with axial spondyloarthritis (axSpA) and to evaluate the effects of inflammation on MRI (MRI-SIJ) on X-SIJ progression. Methods X-SIJ and MRI-SIJ at baseline and after 2 and 5 years in patients with recent onset axSpA from the DESIR cohort were scored by three central readers. Progression was defined as (1) the shift from non-radiographic (nr) to radiographic (r) sacroiliitis (by modified New York (mNY) criteria) or alternative criteria, (2) a change of at least one grade or (3) a change of at least one grade but ignoring a change from grade 0 to 1. The effects of baseline inflammation on MRI-SIJ on 5-year X-SIJ damage (mNY) were tested by generalised estimating equations. Results In 416 patients with pairs of baseline and 5-year X-SIJ present, net progression occurred in 5.1% (1), 13.0% (2) and 10.3% (3) respectively, regarding a shift from nr-axSpA to r-axSpA (1), a change of at least one grade (2) or a change of at least one grade but ignoring a change from grade 0 to 1 (3). Baseline MRI-SIJ predicted structural damage after 5 years in human leukocyte antigen-B27 (HLA-B27) positive (OR 5.39 (95% CI 3.25 to 8.94)) and in HLA-B27 negative (OR 2.16 (95% CI 1.04 to 4.51)) patients. Conclusions Five-year progression of X-SIJ damage in patients with recent onset axSpA is limited but present beyond measurement error. Baseline MRI-SIJ inflammation drives 5-year radiographic changes.publishersversionpublishe

Results of the worldwide, cross-sectional ASAS-PerSpA study

Objectives: To characterise peripheral musculoskeletal involvement in patients with spondyloarthritis (SpA) including psoriatic arthritis (PsA), across the world. Methods: Cross-sectional study with 24 participating countries. Patients with a diagnosis of axial SpA (axSpA), peripheral SpA (pSpA) or PsA according to their rheumatologist were included. The investigators were asked which diagnosis out of a list of six (axSpA, PsA, pSpA, inflammatory bowel disease-associated SpA, reactive arthritis or juvenile SpA (Juv-SpA)) fitted the patient best. Peripheral manifestations (ie, peripheral joint disease, enthesitis, dactylitis and root joint disease), their localisation and treatments were evaluated. Results: A total of 4465 patients were included (61% men, mean age 44.5 years) from four geographic areas: Latin America (n=538), Europe plus North America (n=1677), Asia (n=975) and the Middle East plus North Africa (n=1275). Of those, 78% had ever suffered from at least one peripheral musculoskeletal manifestation; 57% had peripheral joint disease, 44% had enthesitis and 15% had dactylitis. Latin American had far more often peripheral joint disease (80%) than patients from other areas. Patients with PsA had predominantly upper limb and small joint involvement (52%). Hip and shoulder involvement was found in 34% of patients. The prevalence of enthesitis ranged between 41% in patients with axSpA and 65% in patients with Juv-SpA. Dactylitis was most frequent among patients with PsA (37%). Conclusion: These results suggest that all peripheral features can be found in all subtypes of SpA, and that differences are quantitative rather than qualitative. In a high proportion of patients, axial and peripheral manifestations coincided. These findings reconfirm SpA clinical subtypes are descendants of the same underlying disease, called SpA.publishersversionpublishe

A cluster analysis in the worldwide ASAS-PerSpA study

Objective To identify clusters of peripheral involvement according to the specific location of peripheral manifestations (ie, arthritis, enthesitis and dactylitis) in patients with spondyloarthritis (SpA) including psoriatic arthritis (PsA), and to evaluate whether these clusters correspond with the clinical diagnosis of a rheumatologist. Methods Cross-sectional study with 24 participating countries. Consecutive patients diagnosed by their rheumatologist as PsA, axial SpA or peripheral SpA were enrolled. Four different cluster analyses were conducted: one using information on the specific location from all the peripheral manifestations, and a cluster analysis for each peripheral manifestation, separately. Multiple correspondence analyses and k-means clustering methods were used. Distribution of peripheral manifestations and clinical characteristics were compared across the different clusters. Results The different cluster analyses performed in the 4465 patients clearly distinguished a predominantly axial phenotype (cluster 1) and a predominantly peripheral phenotype (cluster 2). In the predominantly axial phenotype, hip involvement and lower limb large joint arthritis, heel enthesitis and lack of dactylitis were more prevalent. In the predominantly peripheral phenotype, different subgroups were distinguished based on the type and location of peripheral involvement: a predominantly involvement of upper versus lower limbs joints, a predominantly axial enthesitis versus peripheral enthesitis, and predominantly finger versus toe involvement in dactylitis. A poor agreement between the clusters and the rheumatologist € s diagnosis as well as with the classification criteria was found. Conclusion These results suggest the presence of two main phenotypes (predominantly axial and predominantly peripheral) based on the presence and location of the peripheral manifestations.publishersversionpublishe

Looking through the window of opportunity in axial spondyloarthritis?

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that affects the spine and sacroiliac joints, that can lead to irreversible structural damage. Early detection and timely intervention are crucial for preventing long-term structural damage, improving quality of life, and reducing the burden of the disease. The concept of a window of opportunity suggests that an early intervention in the reversible stage of the disease can lead to improved long-term outcomes. However, it is unclear whether this concept applies in axSpA. Recent advances in axSpA management, including the use of diagnostic techniques such as magnetic resonance imaging as well as the use of advanced therapies, have shown promise in improving outcomes. However, studies investigating the potential window of opportunity in axSpA by assessing the impact of an early treatment on clinical outcomes have yielded inconclusive results. One of the reasons behind this is the lack of a standardized definition of early axSpA. The Assessment of Spondyloarthritis International Society (ASAS)-SPEAR (SPondyloarthritis EARly) project has set the ground for it by working on a consensus definition of early axSpA. Randomized controlled trials specifically focused on the comparison between treating axSpA in the early and late stages of the disease and using the standardised definition of early axSpA are essential to understand better the potential benefits of an early treatment on clinical outcomes. Additionally, it would be relevant to assess the long-term outcomes of early axSpA treatment, especially regarding structural damage, to better grasp the concept of the window of opportunity in axSpA.& COPY; 2023 Socie & PRIME;te & PRIME; franc,aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved

Relationship between types of radiographic damage and disability in patients with rheumatoid arthritis in the EURIDISS cohort: a longitudinal study

Pathophysiology and treatment of rheumatic disease

Quality indicators in rheumatoid arthritis: results from the METEOR database

OBJECTIVE: To test the feasibility of collecting, storing, retrieving and analysing necessary information to fulfil a preliminary set of quality indicators (QIs) that have been proposed by an international task force in a large multinational clinical practice database of patients with RA. METHODS: Data from all 12 487 patients with 46 005 visits in the Measurement of Efficacy of Treatment in the Era of Outcome in Rheumatology database from January 2008 until January 2012 were analysed to test the feasibility of collecting information on 10 QIs: time to diagnosis; frequency of visits; assessment of autoantibodies and radiographs, disease activity and function; disease remission, low disease activity, normal function; time to first DMARD and type of first DMARD. For each QI, two aspects were assessed: information availability and target achievement. RESULTS: Information was available for \u3c 50% of patients regarding the following QIs: time to diagnosis, assessment of ACPAs or radiographs, time to first DMARD and type of first DMARD. Information was available for function assessment in 49% of visits and 67% of patients and for disease activity assessment in 85% of visits and 86% of patients. Information relevant to the QI frequency of visits was available for all patients. Relevant information to calculate the proportion of patients who achieved a defined target could be obtained for all QIs. CONCLUSION: Collecting storing, retrieving and analysing the core data necessary to meaningfully assess quality of care is feasible in a multinational, practice-based electronic database

International Map of Axial Spondyloarthritis (IMAS): results from the perspective of 5557 patients from 27 countries around the globe

Background: The International Map of Axial Spondyloarthritis (IMAS) is a global initiative aimed to assess the impact and burden of axial spondyloarthritis (axSpA) and identify the unmet needs from the patient’s perspective. Method: IMAS is a collaboration between the Axial Spondyloarthritis International Federation (ASIF), the University of Seville, Novartis Pharma AG and steered by a scientific committee. IMAS collected information through an online cross-sectional survey (2017–2022) from unselected patients with axSpA from Europe, Asia, North America, Latin America and Africa who completed a comprehensive questionnaire containing over 120 items. Results: 5557 patients with axSpA participated in IMAS. Mean age was 43.9 ±12.8 years, 55.4% were female, 46.2% had a university education and 51.0% were employed. The mean diagnostic delay was 7.4 ±9.0 years (median: 4.0), and the mean symptom duration was 17.1 ±13.3 years. 75.0% of patients had active disease (Bath Ankylosing Spondylitis Disease Activity Index ≥4), and 59.4% reported poor mental health (12-item General Health Questionnaire ≥3). In the year before the survey, patients had visited primary care physicians 4.6 times and the rheumatologist 3.6 times. 78.6% had taken non-steroidal anti-inflammatory drug ever, 48.8% biological disease-modifying antirheumatic drugs and 43.6% conventional synthetic disease-modifying antirheumatic drugs. Patients’s greatest fear was disease progression (55.9%), while the greatest hope was to be able to relieve pain (54.2%). Conclusions: IMAS shows the global profile of patients with axSpA, highlighting unmet needs, lengthy delays in diagnosis and high burden of disease in patients with axSpA worldwide. This global information will enable more detailed investigations to obtain evidence on the critical issues that matter to patients around the world to improve their care and quality of life

An Exploratory Analysis of the Potential Disconnect Between Objective Inflammatory Response and Clinical Response Following Certolizumab Pegol Treatment in Patients with Active Axial Spondyloarthritis

Rudwaleit M, Van den Bosch F, Marzo-Ortega H, et al. An Exploratory Analysis of the Potential Disconnect Between Objective Inflammatory Response and Clinical Response Following Certolizumab Pegol Treatment in Patients with Active Axial Spondyloarthritis. In: American College of Rheumatology, ed. ABSTRACT SUPPLEMENT ACR Convergence 2022, November 10–14, 2022, Philadelphia, PA. Arthritis & Rheumatology. Vol 74. Hoboken: Wiley; 2022: 1097-1100

Therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal disease: A systematic literature review informing EULAR points to consider

The objectives of this review were to collect and summarise evidence on therapeutic drug monitoring (TDM) of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases and to inform the EULAR Task Force for the formulation of evidence-based points to consider. A systematic literature review (SLR) was performed, covering technical aspects and (clinical) utility of TDM, to answer 13 research questions. MEDLINE, Embase and Cochrane were searched until July 2020. American College of Rheumatology and EULAR abstracts were also considered for inclusion. Data were extracted in evidence tables and risk of bias assessment was performed. For the search on technical aspects, 678 records were identified, of which 22 papers were selected. For the clinical utility search, 3846 records were identified, of which 108 papers were included. Patient-related factors associated with biopharmaceutical blood concentrations included body weight, methotrexate comedication and disease activity. The identification of a target range was hampered by study variability, mainly disease activity measures and study type. Evidence was inconsistent for multiple clinical situations in which TDM is currently applied. However, for some particular scenarios, including prediction of future treatment response, non-response to treatment, tapering and hypersensitivity reactions, robust evidence was found. There is currently no evidence for routine use of proactive TDM, in part because published cost-effectiveness analyses do not incorporate the current landscape of biopharmaceutical costs and usage. This SLR yields evidence in favour of TDM of biopharmaceuticals in some clinical scenarios, but evidence is insufficient to support implementation of routine use of TDM