Unmet needs in axial spondyloarthritis. Proceedings of the French spondyloarthritis taskforce workshop.

The progress observed over the last 30 years in the field of axial spondyloarthritis (axSpA) has not made it possible to answer all the current questions. This manuscript represents the proceedings of the meeting of the French spondyloArthitiS Task force (FAST) in Besançon on September 28 and 29, 2023. Different points of discussion were thus individualized as unmet needs: biomarkers for early diagnosis and disease activity, a common electronic file dedicated to SpA nationwide, a better comprehension of dysbiosis in the disease, a check-list for addressing to the rheumatologist, adapt patient reported outcomes thresholds for female gender, implementation of comorbidities screening programs, new imaging tools, in research cellular and multi omics approaches, grouping, at a nationwide level, different cohorts and registries, therapeutic strategy studies, consensual definition of difficult to treat disease and management, preclinical stage of the disease, mastering AI as a tool in the various aspects of research. These elements may represent a framework for the research agenda in axSpA for the years to come.

Standardized reporting for systematic global evaluation of axial spondyloarthritis: An evidence-based and consensus-driven initiative.

INTRODUCTION: National and international scientific societies advocate for a regular, systematic, and standardized global evaluation of axial spondyloarthritis (axSpA) patients. However, there are no recommendations specifying the content of this global evaluation. This initiative aimed to propose a standardized reporting framework, using evidence-based and consensus approaches, to collect data on all domains of axSpA. METHODS: A literature review and consensus process involved a steering committee and an expert panel of 37 rheumatologists and health professionals. The first steering committee took place in March 2022 and identified the main domains for inclusion in the standardized report. A hierarchical literature review was conducted to identify items within these domains and tools for assessment. The items and tools for assessment were discussed and consensus was reached through a vote session during an expert meeting that took place in March 2023. RESULTS: The steering committee identified four main domains to include in the standardized reporting framework: disease assessment, comorbidities, lifestyle, and quality of life. Items and tools for assessment were adopted after the expert meeting. Additionally, recommendations regarding digital tools (websites, apps, social media) were provided. CONCLUSION: This initiative led to a consensus, based on evidence and expertise, on a reporting framework for use during periodic systematic global evaluations of axSpa in daily practice.

Serum calprotectin and renal function decline in ANCA-associated vasculitides: a post hoc analysis of MAINRITSAN trial.

OBJECTIVE: Serum calprotectin appears to be an interesting biomarker associated with renal vascular disease activity in antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). The aim of this study was to assess whether serum calprotectin levels can predict decline in renal function in AAV patients receiving maintenance therapy. METHODS: Serum calprotectin levels were assessed at inclusion and month 6 in AAV patients, in complete remission after induction therapy, randomly assigned to rituximab or azathioprine. Renal function decline was defined as a 25% decrease in estimated glomerular filtration rate (eGFR) and a change in the eGFR category, or a decrease of 15 mL/min/1.73 m2. Relapse was defined as a Birmingham Vasculitis Activity Score >0 attributable to active vasculitis. RESULTS: Seventy-six AAV were included. Serum calprotectin increased from baseline to month 6 in patients with renal function decline (7940 (-226.0, 28 691) ng/ml vs -4800 (-18 777, 3708) ng/ml; p<0.001). An increase of calprotectin level was associated with a higher risk of subsequent renal function decline even after adjustment (OR 6.50 (95% CI 1.7 to 24.9) p=0.006). A significantly higher risk of relapse was observed in proteinase 3- AAV patients with an increase of serum calprotectin levels (OR 5.6 (95% CI 1.0 to 31.2), p=0.03). CONCLUSION: An increase in serum calprotectin by month 6 compared with inclusion during remission-maintenance therapy in AAV was associated with a higher risk of renal function decline in the following 12 months. TRIAL REGISTRATION NUMBER: NCT00748644.

Heterogeneity of antibody-secreting cells infiltrating autoimmune tissues.

The humoral response is frequently dysfunctioning in autoimmunity with a frequent rise in total serum immunoglobulins, among which are found autoantibodies that may be pathogenic by themselves and/or propagate the inflammatory reaction. The infiltration of autoimmune tissues by antibody-secreting cells (ASCs) constitutes another dysfunction. The known high dependency of ASCs on the microenvironment to survive combined to the high diversity of infiltrated tissues implies that ASCs must adapt. Some tissues even within a single clinical autoimmune entity are devoid of infiltration. The latter means that either the tissue is not permissive or ASCs fail to adapt. The origin of infiltrated ASCs is also variable. Indeed, ASCs may be commonly generated in the secondary lymphoid organ draining the autoimmune tissue, and home at the inflammation site under the guidance of specific chemokines. Alternatively, ASCs may be generated locally, when ectopic germinal centers are formed in the autoimmune tissue. Alloimmune tissues with the example of kidney transplantation will also be discussed own to their high similarity with autoimmune tissues. It should also be noted that antibody production is not the only function of ASCs, since cells with regulatory functions have also been described. This article will review all the phenotypic variations indicative of tissue adaptation described so for at the level of ASC-infiltrating auto/alloimmune tissues. The aim is to potentially define tissue-specific molecular targets in ASCs to improve the specificity of future autoimmune treatments.

Translation and French Linguistic Validation of the Bath Ankylosing Spondylitis Functional Index and the Bath Ankylosing Spondylitis Global Score in Patients with Axial Spondyloarthritis.

BACKGROUND: Axial spondyloarthritis (axSpA) may lead to functional and physical disturbances. Self-administered questionnaires can measure functional limitations associated to axSpA. If these questionnaires are currently used in clinical practice and research, the French version of these questionnaires has not been validated. The aim of this study was to translate and perform a linguistic validation of the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Global score (BAS-G) in French. METHODS: The study has been approved by local ethic committee and is registered in Clinical Trial (NCT04212806). The translation process was performed through a forward/backward validation process, followed by clinician experts validation and patient cognitive interviews. RESULTS: The two questionnaires were translated into a French version by two independent translators. Translators then agreed on sentences being different between the two translations. The backward translation was equivalent to the initial English version except for two questions. Five French clinician experts on rheumatology made essential changes in sentences constructions of the translated questionnaire. The last version of the questionnaires was presented to 5 patients with axSpA which all found them clear and understandable. CONCLUSION: BASFI and BAS-G would be a generally reliable instrument for patients with axSpA. These questionnaires can be widely used in clinical practice and research in French-speaking population. The use of these questionnaires is expected to have a positive impact on patient care to better understand physical consequences of axSpA.

Spine abnormalities associated with bone edema on sacroiliac joints MRI in patients with non-inflammatory chronic back pain.

OBJECTIVE: To investigate whether bone marrow edema (BME) fulfilling the ASAS definition of magnetic resonance imaging (MRI) sacroiliitis is associated with non-inflammatory spine abnormalities in patients with definite mechanical chronic back pain (CBP). METHODS: Patients with definite mechanical CBP, according to the physician, started before the age of 45 and be lasting for more than 3months but less than 3years underwent a protocolized MRI and radiographs of sacroiliac joint (SIJ) and spine. BME and structural changes were scored, by three readers, for SIJ as well as non-inflammatory abnormalities for spine, including degenerative lesions and static disorders. Univariate analysis by Chi2 test was performed to search a statistical association between BME fulfilling the ASAS definition of MRI sacroiliitis and the presence of at least one non-inflammatory spine abnormality. RESULTS: A total of 94 patients were analyzed, 27 (29%) patients had BME and 16 (17%) patients had BME fulfilling the ASAS definition of MRI sacroiliitis; 86 (91.5%) patients had at least one non-inflammatory spine abnormality which are associated into 3 distinct clusters. BME was slightly more frequent at the lower and posterior part of the SIJ. MRI sacroiliitis was associated with interspinous bursitis, facet joint effusion and lateral spinal deviation and was more likely in patients with at least one non-inflammatory spine abnormality (OR: 4.96, 95% CI [1.47; 16.72]). CONCLUSIONS: BME fulfilling the ASAS definition of MRI sacroiliitis is significantly associated with non-inflammatory spine abnormalities in patients with mechanical CBP.

Systematic assessment of heart valves and cardiac function by echocardiography in axial spondyloarthritis: A systematic review and meta-analysis.

OBJECTIVES: Axial Spondyloarthritis (ax-SpA) is associated with increased risk of cardiovascular disease (CVD)-specific deaths. We aimed to assess the prevalence of left ventricular (LV) systolic and diastolic dysfunction and valvular heart disease (VHD) by transthoracic echocardiography (TTE) in ax-SpA patients without history of CVD. METHODS: A systematic literature review was performed in PUBMED, Embase, Cochrane Library databases published before April 2020. We included all controlled studies assessing myocardial function and heart valve by TTE in ax-SpA without history of CVD. A meta-analysis was performed with random or fixed effects model estimating mean differences (MD) and odds ratio (OR). RESULTS: Literature search selected 189 abstracts and 28 articles were included (1471 ax-SpA and 1115 controls). ax-SpA had a statistically slight alteration of LV ejection fraction (MD=0.64%, 95%CI: 0.14-1.14). ax-SpA had more frequently LV diastolic dysfunction (OR=3.43, 95%CI: 1.78-6.59) and an alteration of E/A ratio (MD=0.15, 95%CI: 0.08-0.21), deceleration time (MD=13.07ms, 95%CI: 7.75-18.40), isovolumetric relaxation time (MD=7.90ms, 95%CI: 4.50-11.30), left-ventricular end diastolic (MD=0.57mm, 95%CI: 0.19-0.95) and systolic (MD=0.77mm, 95%CI: 0.36-1.17) diameters. Three studies (15%) used a combination of TTE parameters to diagnose LV diastolic dysfunction. Prevalence of mitral regurgitation and aortic regurgitation were similar in ax-SpA patients and healthy individuals. CONCLUSION: ax-SpA have a non-clinically relevant alteration of LV ejection fraction and similar prevalence of VHD compared to healthy individuals. LV diastolic TTE parameters are altered in ax-SpA. However, most studies do not combine set of parameters to recognize diastolic dysfunction. The clinical relevance of diastolic dysfunction observed by TTE remains to be determined in future longitudinal studies.

Gout and Levodopa: An unknown adverse effect?

We report the case of a 77-year-old man with Parkinson's disease (PD) who experimented for the first time gout crisis after the initiation of levodopa. Levodopa was withdrawn, and colchicine and allopurinol were initiated to treat the gout crisis. Because of PD progression, levodopa was reintroduced, and the patient presented relapse of gout flare. To further explore the association between gout and levodopa, we extracted and synthetized all Individual Case Safety Reports of gout associated with levodopa in the World Health Organization pharmacovigilance database, VigiBase® , up to April 2021. 43 cases of gout were reported in VigiBase® with drugs from N04BA ATC class. Levodopa was suspected in fifteen cases among which improvement was noticed in six cases (two after levodopa withdrawal, two despite treatment continuation, and two cases lacking details about action taken with levodopa); three cases did not recover; in the remaining six cases, evolution was not known. "Hyperuricemia" was not mentioned in the Summary of Product Characteristics of medicine containing levodopa; however, "abnormality biologics test with uric acid" was mentioned. Despite few cases of recovery after reduced doses of levodopa, the above-described case of positive reintroduction was an argument in favor of the role of levodopa in gout flare. This study highlights a potential association between levodopa and gout through an analysis of the cases reported in the WHO pharmacovigilance database.

Gait and Axial Spondyloarthritis: Comparative Gait Analysis Study Using Foot-Worn Inertial Sensors.

BACKGROUND: Axial spondyloarthritis (axSpA) can lead to spinal mobility restrictions associated with restricted lower limb ranges of motion, thoracic kyphosis, spinopelvic ankylosis, or decrease in muscle strength. It is well known that these factors can have consequences on spatiotemporal gait parameters during walking. However, no study has assessed spatiotemporal gait parameters in patients with axSpA. Divergent results have been obtained in the studies assessing spatiotemporal gait parameters in ankylosing spondylitis, a subgroup of axSpA, which could be partly explained by self-reported pain intensity scores at time of assessment. Inertial measurement units (IMUs) are increasingly popular and may facilitate gait assessment in clinical practice. OBJECTIVE: This study compared spatiotemporal gait parameters assessed with foot-worn IMUs in patients with axSpA and matched healthy individuals without and with pain intensity score as a covariate. METHODS: A total of 30 patients with axSpA and 30 age- and sex-matched healthy controls performed a 10-m walk test at comfortable speed. Various spatiotemporal gait parameters were computed from foot-worn inertial sensors including gait speed in ms-1 (mean walking velocity), cadence in steps/minute (number of steps in a minute), stride length in m (distance between 2 consecutive footprints of the same foot on the ground), swing time in percentage (portion of the cycle during which the foot is in the air), stance time in percentage (portion of the cycle during which part of the foot touches the ground), and double support time in percentage (portion of the cycle where both feet touch the ground). RESULTS: Age, height, and weight were not significantly different between groups. Self-reported pain intensity was significantly higher in patients with axSpA than healthy controls (P<.001). Independent sample t tests indicated that patients with axSpA presented lower gait speed (P<.001) and cadence (P=.004), shorter stride length (P<.001) and swing time (P<.001), and longer double support time (P<.001) and stance time (P<.001) than healthy controls. When using pain intensity as a covariate, spatiotemporal gait parameters were still significant with patients with axSpA exhibiting lower gait speed (P<.001), shorter stride length (P=.001) and swing time (P<.001), and longer double support time (P<.001) and stance time (P<.001) than matched healthy controls. Interestingly, there were no longer statistically significant between-group differences observed for the cadence (P=.17). CONCLUSIONS: Gait was significantly altered in patients with axSpA with reduced speed, cadence, stride length, and swing time and increased double support and stance time. Taken together, these changes in spatiotemporal gait parameters could be interpreted as the adoption of a so-called cautious gait pattern in patients with axSpA. Among factors that may influence gait in patients with axSpA, patient self-reported pain intensity could play a role. Finally, IMUs allowed computation of spatiotemporal gait parameters and are usable to assess gait in patients with axSpA in clinical routine. TRIAL REGISTRATION: ClinicalTrials.gov NCT03761212; https://clinicaltrials.gov/ct2/show/NCT03761212. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1007/s00296-019-04396-4.

The effects of a secondary task on gait in axial spondyloarthritis.

Studies on the effects of dual tasking in patients with chronic inflammatory rheumatic diseases are limited. The aim of this study was to assess dual tasking while walking in patients with axial spondyloarthritis (axSpA) in comparison to healthy controls. Thirty patients with axSpA and thirty healthy controls underwent a 10-m walk test at a self-selected comfortable walking speed in single- and dual-task conditions. Foot-worn inertial sensors were used to compute spatiotemporal gait parameters. Analysis of spatiotemporal gait parameters showed that the secondary manual task negatively affected walking performance in terms of significantly decreased mean speed (p < 0.001), stride length (p < 0.001) and swing time (p = 0.008) and increased double support (p = 0.002) and stance time (p = 0.008). No significant interaction of group and condition was observed. Both groups showed lower gait performance in dual task condition by reducing speed, swing time and stride length, and increasing double support and stance time. Patients with axSpA were not more affected by the dual task than matched healthy controls, suggesting that the secondary manual task did not require greater attention in patients with axSpA. Increasing the complexity of the walking and/or secondary task may increase the sensitivity of the dual-task design to axial spondyloarthritis.

Immunomodulation with IL-17 and TNF-α in spondyloarthritis: focus on the eye and the central nervous system.

Tumor necrosis factor alpha (TNF-α) and interleukin-17 (IL-17) are two pro-inflammatory cytokines involved in the pathophysiology of spondyloarthritis (SpA). Therapies targeting TNF-α or IL-17 are used as a second line among SpA patients failing non-steroidal anti-inflammatory drugs. The choice of such treatment has to take into account the patient's comorbidities. Neurologic diseases are common and their association with SpA deserves to be studied. Therefore, the role of TNF-α and IL-17 cytokines is worth investigating in these neuropsychiatric diseases. This review aimed to explore the role of TNF-α and IL-17 in the pathogenesis of uveitis, multiple sclerosis, neuromyelitis optica, Alzheimer's disease, Parkinson's disease and depression. This update is critical to guide the therapeutic management of these co-morbidities in SpA patients.