Molecular maps of synovial cells in inflammatory arthritis using an optimized synovial tissue dissociation protocol.

In this study, we optimized the dissociation of synovial tissue biopsies for single-cell omics studies and created a single-cell atlas of human synovium in inflammatory arthritis. The optimized protocol allowed consistent isolation of highly viable cells from tiny fresh synovial biopsies, minimizing the synovial biopsy drop-out rate. The synovium scRNA-seq atlas contained over 100,000 unsorted synovial cells from 25 synovial tissues affected by inflammatory arthritis, including 16 structural, 11 lymphoid, and 15 myeloid cell clusters. This synovial cell map expanded the diversity of synovial cell types/states, detected synovial neutrophils, and broadened synovial endothelial cell classification. We revealed tissue-resident macrophage subsets with proposed matrix-sensing (FOLR2+COLEC12high) and iron-recycling (LYVE1+SLC40A1+) activities and identified fibroblast subsets with proposed functions in cartilage breakdown (SOD2highSAA1+SAA2+SDC4+) and extracellular matrix remodeling (SERPINE1+COL5A3+LOXL2+). Our study offers an efficient synovium dissociation method and a reference scRNA-seq resource, that advances the current understanding of synovial cell heterogeneity in inflammatory arthritis.

The long non-coding RNA HOTAIR contributes to joint-specific gene expression in rheumatoid arthritis.

Although patients with rheumatoid arthritis (RA) typically exhibit symmetrical joint involvement, some patients develop alternative disease patterns in response to treatment, suggesting that different molecular mechanism may underlie disease progression depending on joint location. Here, we identify joint-specific changes in RA synovium and synovial fibroblasts (SF) between knee and hand joints. We show that the long non-coding RNA HOTAIR, which is only expressed in knee SF, regulates more than 50% of this site-specific gene expression in SF. HOTAIR is downregulated after stimulation with pro-inflammatory cytokines and is expressed at lower levels in knee samples from patients with RA, compared with osteoarthritis. Knockdown of HOTAIR in knee SF increases PI-Akt signalling and IL-6 production, but reduces Wnt signalling. Silencing HOTAIR inhibits the migratory function of SF, decreases SF-mediated osteoclastogenesis, and increases the recruitment of B cells by SF. We propose that HOTAIR is an important epigenetic factor in joint-specific gene expression in RA.

Early axial spondyloarthritis according to the ASAS consensus definition: characterisation of patients and effectiveness of a first TNF inhibitor in a large observational registry.

OBJECTIVE: To characterise the population fulfilling the Assessment of SpondyloArthritis international Society (ASAS) consensus definition of early axial spondyloarthritis (axSpA) and to determine the effectiveness of a first tumour necrosis factor inhibitor (TNFi) in early versus established axSpA in a large observational registry. METHODS: A total of 3064 patients with axSpA in the Swiss Clinical Quality Management registry with data on duration of axial symptoms were included (≤2 years=early axSpA, N=658; >2 years=established axSpA, N=2406). Drug retention was analysed in patients starting a first TNFi in early axSpA (N=250) versus established axSpA (N=874) with multiple-adjusted Cox proportional hazards models. Adjusted logistic regression analyses were used to determine the achievement of the ASAS criteria for 40% improvement (ASAS40) at 1 year. RESULTS: Sex distribution, disease activity, impairments of function and health-related quality of life were comparable between patients with early and established axSpA. Patients with established disease were older, had more prevalent axial radiographical damage and had a higher impairment of mobility. A comparable TNFi retention was found in early versus established disease after adjustment for age, sex, human leucocyte antigen-B27 status, education, body mass index, smoking, elevated C reactive protein and sacroiliac inflammation on MRI (HR 1.05, 95% CI 0.78 to 1.42). The adjusted ASAS40 response was similar in the two groups (OR 1.09, 95% CI 0.67 to 1.78). Results were confirmed in the population fulfilling the ASAS classification criteria. CONCLUSION: Considering the recent ASAS definition of early axSpA, TNFi effectiveness seems comparable in early versus established disease.

Impact of sex on spinal radiographic progression in axial spondyloarthritis: a longitudinal Swiss cohort analysis over a period of 10 years.

OBJECTIVE: To investigate sex differences in spinal radiographic progression in axial spondyloarthritis (axSpA). METHODS: AxSpA patients in the Swiss Clinical Quality Management cohort with available spinal radiographs every 2 years were included. Paired radiographs were scored by two readers according to the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Progression was defined as an increase of ≥2 mSASSS units in 2 years. The relationship between sex and progression was investigated with binomial generalised estimating equation models, considering baseline spinal damage as an intermediate covariate. Additional analyses included adjustments for explanatory variables and multiple imputations for missingness. RESULTS: In a total of 505 axSpA patients (317 men and 188 women), mean±SD radiographic progression over 2 years was 1.0±2.8 years in men and 0.3±1.1 years in women (p<0.001). Male sex was associated with enhanced progression in a small model not including baseline damage (OR 3.41, 95% CI 1.87 to 6.21). Both a direct effect of male sex on spinal progression, and an indirect effect, via enhancement of baseline spinal damage were significant (OR 2.06, 95% CI 1.15 to 3.67 and OR 1.04, 95% CI 1.01 to 1.07, respectively). A significant impact of male sex on spinal radiographic progression was still demonstrated after multiple adjustments for covariates known to potentially affect spinal radiographic progression (OR 1.97, 95% CI 1.04 to 3.71). CONCLUSIONS: Spinal radiographic progression in axSpA is more severe in men than in women, with three times higher odds of progression in male patients and an effect that is mediated in part through an increase in baseline radiographic damage.

Characterisation of patients with axial psoriatic arthritis and patients with axial spondyloarthritis and concomitant psoriasis in the SCQM registry.

BACKGROUND: Within the spectrum of spondyloarthritides, axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) present with overlapping features. Axial involvement in PsA (axial PsA) is treated according to recommendations for axSpA, as specific studies in axial PsA are scarce. We compared characteristics of patients with axSpA (particularly of patients with axSpA and concomitant psoriasis (pso)) with those of patients with axial PsA. METHODS: Patients with axSpA and PsA in the Swiss Clinical Quality Management (SCQM) registry were included if information on pso and axial involvement was available. Patients with AxSpA were stratified by axSpA with and without pso (axSpA±pso) and patients with PsA were stratified to axial PsA or strictly peripheral PsA. RESULTS: Previous or current psoriasis was observed in 479/4489 patients with axSpA (10.7%). Of 2631 patients with PsA, 1153 (43.8%) presented with axial involvement (opinion of the treating rheumatologist). Compared with patients with axSpA+pso, patients with axial PsA were older at symptom onset and at inclusion in SCQM, were less frequently HLA-B27 positive, had back pain less frequently and a higher prevalence of dactylitis and peripheral arthritis. A positive family history of pso or PsA was more frequent in axial PsA, while a positive family history of axSpA was more frequent in patients with axSpA+pso. Disease activity, function and mobility were comparable in axSpA+pso versus axial PsA. CONCLUSION: Patients with axial PsA differ from patients with axSpA+pso in important demographic and clinical characteristics, and genetically, but present with a comparable disease burden. Treatment studies specifically dedicated to axial PsA seem warranted.

Anaemia is associated with higher disease activity in axial spondyloarthritis but is not an independent predictor of spinal radiographic progression: data from the Swiss Clinical Quality Management Registry.

OBJECTIVE: As anaemia represents a biomarker for increased radiographic damage in rheumatoid arthritis, we aimed to investigate whether it independently predicts spinal radiographic progression in axial spondyloarthritis (axSpA). METHODS: AxSpA patients with available haemoglobin levels from the prospective Swiss Clinical Quality Management Registry were included for comparison of patients with and without anaemia. Spinal radiographic progression was assessed according to the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) in patients with ankylosing spondylitis (AS) if ≥ 2 sets of spinal radiographs were available every 2 years. The relationship between anaemia and progression (defined as an increase ≥ 2 mSASSS units in 2 years) was analysed with generalized estimating equation models after adjustment for the Ankylosing Spondylitis Disease Activity Score (ASDAS) and potential confounding, as well as after multiple imputations of missing values. RESULTS: A total of 212/2522 axSpA patients presented with anaemia (9%). Anaemic patients had higher clinical disease activity, higher acute phase reactants and more severe impairments in physical function, mobility and quality of life. In the subgroup of patients with AS (N = 433), a comparable mSASSS progression was found in anaemic and non-anaemic patients (OR 0.69, 95% CI 0.25 to 1.96, p = 0.49). Age, male sex, baseline radiographic damage and ASDAS were associated with enhanced progression. The results were confirmed in complete case analyses and with progression defined as the formation of ≥ 1 syndesmophyte in 2 years. CONCLUSION: Although anaemia was associated with higher disease activity in axSpA, it did not additionally contribute to the prediction of spinal radiographic progression. Key Points • Anaemia is associated with higher disease activity and more severely impaired physical function, mobility and quality of life in axSpA. • Anaemia does not provide an additional value to ASDAS for prediction of spinal radiographic progression.

HLA-B27 as a predictor of effectiveness of treatment with TNF inhibitors in axial spondyloarthritis: data from the Swiss Clinical Quality Management Registry.

OBJECTIVE: To explore the impact of the human leucocyte antigen (HLA)-B27 on the effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA). METHODS: A total of 1109 patients with available HLA-B27 status (831 B27+ patients and 278 B27- patients) fulfilling the Assessment of Spondyloarthritis international Society classification criteria for axSpA from the prospective Swiss Clinical Quality Management Registry initiating a first TNFi were included. Drug retention was investigated with multiple adjusted Cox proportional hazard models with imputation of missing values. Multiple-adjusted logistic regression analyses were used to assess the proportion of patients reaching 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) at 1 year. RESULTS: B27+ and B27- patients differed with regard to age, sex, BASDAI, C-reactive protein (CRP), body mass index, enthesitis, uveitis, and classification status. After adjustment for potential confounders for the relationship between HLA-B27 and drug effectiveness (sex and family history of spondyloarthritis), a higher risk of drug discontinuation was found in B27- patients (HR 1.53, 95% CI 1.27-1.83). This difference decreased after additional adjustment for parameters which may act as mediators (HR 1.30, 95% CI 1.30-1.55). Male sex and elevated C-reactive protein (CRP) levels were consistently associated with longer retention. Comparable results were obtained for BASDAI50 responses. CONCLUSION: The HLA-B27 genotype is an important predictor of treatment effectiveness. Male sex and CRP seem, however, to better describe variability of response in individual patients. This data may help avoiding potential discrimination of B27- individuals with regard to TNFi initiation. Key Points • HLA-B27 is a predictor of effectiveness of TNF inhibitors in axial spondyloarthritis. • Variability of response in individual patients is better defined by sex and objective markers of disease activity, such as C-reactive protein.

Sacroiliac joint radiographic progression in axial spondyloarthritis is retarded by the therapeutic use of TNF inhibitors: 12-year data from the SCQM registry.

OBJECTIVES: To analyse the effect of tumour necrosis factor inhibitors (TNFi) on sacroiliac joint (SIJ) radiographic progression in axial spondyloarthritis (axSpA). METHODS: Patients with axSpA in the Swiss Clinical Quality Management cohort with up to 12 years of follow-up and radiographic assessments every 2 years were included. SIJs were scored by two readers according to the modified New York criteria blinded to chronology. The relationship between TNFi use before or during a 2-year radiographic interval and SIJ progression was investigated using generalised estimating equation models with adjustment for potential confounding. Progression was defined as worsening of ≥1 grade in ≥1 SIJ and ignoring a change from 0 to 1 over 2 years, if both readers agreed. A third reading of radiographs was integrated in sensitivity analyses. RESULTS: A total of 515 patients with axSpA contributed to data for 894 radiographic intervals (24 progression events). In patients with complete covariate data, prior use of TNFi reduced the odds of progression (OR 0.21, 95% CI 0.07 to 0.65). A comparable effect was found for use of TNFi for ≥1 year within a 2-year radiographic interval (OR 0.21, 95% CI 0.08 to 0.55). The inhibitory impact of TNFi was confirmed if progression was demonstrated in 2/3 readings: OR 0.50, 95% CI 0.28 to 0.89 and OR 0.46, 95% CI 0.27 to 0.78 for TNFi treatment before and for ≥1 year within the interval, respectively. CONCLUSION: TNFi are associated with deceleration of SIJ radiographic progression in patients with axSpA if treatment is continued for ≥1 year.

An Optimized Tissue Dissociation Protocol for Single-Cell RNA Sequencing Analysis of Fresh and Cultured Human Skin Biopsies.

We present an optimized dissociation protocol for preparing high-quality skin cell suspensions for in-depth single-cell RNA-sequencing (scRNA-seq) analysis of fresh and cultured human skin. Our protocol enabled the isolation of a consistently high number of highly viable skin cells from small freshly dissociated punch skin biopsies, which we use for scRNA-seq studies. We recapitulated not only the main cell populations of existing single-cell skin atlases, but also identified rare cell populations, such as mast cells. Furthermore, we effectively isolated highly viable single cells from ex vivo cultured skin biopsy fragments and generated a global single-cell map of the explanted human skin. The quality metrics of the generated scRNA-seq datasets were comparable between freshly dissociated and cultured skin. Overall, by enabling efficient cell isolation and comprehensive cell mapping, our skin dissociation-scRNA-seq workflow can greatly facilitate scRNA-seq discoveries across diverse human skin pathologies and ex vivo skin explant experimentations.

Does tenosynovitis of the hand detected by B-mode ultrasound predict loss of clinical remission in rheumatoid arthritis? Results from a real-life cohort.

Objective: The role of US-detected tenosynovitis (USTS) in the management of rheumatoid arthritis remains controversial. The aim of this study was to investigate whether tenosynovitis can predict a flare in rheumatoid arthritis patients in remission in a real-life cohort. Methods: Rheumatoid arthritis patients from the Swiss Clinical Quality Management cohort were included in this study if they were in clinical remission, defined by 28-joint disease activity score (DAS28-ESR) <2.6, and had an available B-mode tenosynovitis score. The patients were stratified according to the presence or absence of tenosynovitis (USTS+ vs. USTS-). Cox proportional hazard models were used for time-to-event analysis until the loss of remission, after adjustment for multiple confounders. The impact of baseline US performed early in remission and the advent of flares at different fixed time periods after baseline were investigated in sensitivity analysis. Results: Tenosynovitis was detected in 10% of 402 rheumatoid arthritis patients in remission. At baseline, USTS+ patients in remission had significantly higher DAS28-ESR (mean (SD): USTS- 1.8 (0.5) versus USTS+ 2.0 (0.5); p = 0.0019) and higher additional disease activity parameters, such as physician global assessment, and simplified- and clinical-disease activity index. Joint synovitis detected by B-mode US was associated with tenosynovitis (mean (SD) 7.2 (6.3) in USTS- versus 9.0 (5.4) in USTS+, respectively; p = 0.02). A disease flare was observed in 69% of remission phases, with no differences in the time to loss of remission between USTS+ and USTS- groups. Conclusion: While US-detected tenosynovitis was associated with higher disease activity parameters in rheumatoid arthritis patients in clinical remission, it was not able to predict a flare.

Current differentiation between radiographic and non-radiographic axial spondyloarthritis is of limited benefit for prediction of important clinical outcomes: data from a large, prospective, observational cohort.

OBJECTIVE: To compare disease characteristics and outcomes between patients with axial spondyloarthritis with non-radiographic disease (nr-axSpA), bilateral grade 2 sacroiliitis (r22axSpA) and unilateral/bilateral grade 3-4 sacroiliitis (r3+axSpA) according to the modified New York criteria. METHODS: We included patients with axial spondyloarthritis with available pelvic radiographs from the Swiss Clinical Quality Management Cohort. Retention of a first tumour necrosis factor inhibitor (TNFi) was investigated with multiple adjusted Cox proportional hazards models. The proportion of patients reaching 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) at 1 year was assessed with multiple adjusted logistic regression analyses. Spinal radiographic progression, defined as an increase in ≥2 mSASSS units in 2 years, was assessed in generalised estimating equation models. RESULTS: From 2080 patients, those with nr-axSpA (n=485) and r22axSpA (n=443) presented with lower C reactive protein levels and less severe clinical spinal involvement compared with patients with r3+axSpA (n=1152). While TNFi retention was similar in r22axSpA and nr-axSpA, the risk of discontinuation was significantly lower in r3+axSpA (HR 0.60, 95% CI 0.44 to 0.82 vs nr-axSpA). BASDAI50 responses at 1 year were comparable in r22axSpA and nr-axSpA, with a better response associated with r3+axSpA (OR 2.05, 95% CI 1.09 to 3.91 vs nr-axSpA). Spinal radiographic progression was similar in r22axSpA and nr-axSpA and significantly higher in r3 +axSpA. CONCLUSION: Patients with r22axSpA are comparable to nr-axSpA patients but differ from patients with more severe sacroiliac damage with regard to treatment effectiveness and spinal radiographic progression. Therefore, current differentiation between nr-axSpA and radiographic disease seems of limited use for outcome prediction.

Role of synovial fibroblast subsets across synovial pathotypes in rheumatoid arthritis: a deconvolution analysis.

OBJECTIVES: To integrate published single-cell RNA sequencing (scRNA-seq) data and assess the contribution of synovial fibroblast (SF) subsets to synovial pathotypes and respective clinical characteristics in treatment-naïve early arthritis. METHODS: In this in silico study, we integrated scRNA-seq data from published studies with additional unpublished in-house data. Standard Seurat, Harmony and Liger workflow was performed for integration and differential gene expression analysis. We estimated single cell type proportions in bulk RNA-seq data (deconvolution) from synovial tissue from 87 treatment-naïve early arthritis patients in the Pathobiology of Early Arthritis Cohort using MuSiC. SF proportions across synovial pathotypes (fibroid, lymphoid and myeloid) and relationship of disease activity measurements across different synovial pathotypes were assessed. RESULTS: We identified four SF clusters with respective marker genes: PRG4+ SF (CD55, MMP3, PRG4, THY1neg ); CXCL12+ SF (CXCL12, CCL2, ADAMTS1, THY1low ); POSTN+ SF (POSTN, collagen genes, THY1); CXCL14+ SF (CXCL14, C3, CD34, ASPN, THY1) that correspond to lining (PRG4+ SF) and sublining (CXCL12+ SF, POSTN+ + and CXCL14+ SF) SF subsets. CXCL12+ SF and POSTN+ + were most prominent in the fibroid while PRG4+ SF appeared highest in the myeloid pathotype. Corresponding, lining assessed by histology (assessed by Krenn-Score) was thicker in the myeloid, but also in the lymphoid pathotype + the fibroid pathotype. PRG4+ SF correlated positively with disease severity parameters in the fibroid, POSTN+ SF in the lymphoid pathotype whereas CXCL14+ SF showed negative association with disease severity in all pathotypes. CONCLUSION: This study shows a so far unexplored association between distinct synovial pathologies and SF subtypes defined by scRNA-seq. The knowledge of the diverse interplay of SF with immune cells will advance opportunities for tailored targeted treatments.

Impact of the COVID-19 pandemic on the disease course of patients with inflammatory rheumatic diseases: results from the Swiss Clinical Quality Management cohort.

OBJECTIVES: To investigate whether the transient reduction in rheumatology services imposed by virus containment measures during the COVID-19 pandemic was associated with disease worsening in axial spondyloarthritis (axSpA), rheumatoid arthritis (RA) or psoriatic arthritis (PsA). METHODS: Patient-reported disease activity assessed during face-to-face visits and/or via a smartphone application were compared between three periods of each 2 months duration (before, during and after the COVID-19-wave) from January to June 2020 in 666 patients with axSpA, RA and PsA in the Swiss Clinical Quality Management cohort. RESULTS: The number of consultations dropped by 52%, whereas the number of remote assessments increased by 129%. The proportion of patients with drug non-compliance slightly increased during the pandemic, the difference reaching statistical significance in axSpA (19.9% vs 13.2% before the pandemic, p=0.003). The proportion of patients with disease flares remained stable (<15%). There was no increase in mean values of the Bath Ankylosing Disease Activity Index, the Rheumatoid Arthritis Disease Activity Index-5 and the Patient Global Assessment in patients with axSpA, RA and PsA, respectively. CONCLUSION: A short interruption of in-person patient-rheumatologist interactions had no major detrimental impact on the disease course of axSpA, RA and PsA as assessed by patient-reported outcomes.

Differences between men and women with nonradiographic axial spondyloarthritis: clinical characteristics and treatment effectiveness in a real-life prospective cohort.

BACKGROUND: Sex differences with regard to clinical manifestations and response to tumor necrosis factor inhibitors (TNFi) have been delineated for the radiographic form of axial spondyloarthritis (axSpA). More limited evidence for a differential effectiveness of treatment in genders exists for the nonradiographic disease state (nr-axSpA). The aim of the study was to compare demographics, clinical parameters, and response to TNFi in women versus men with nr-axSpA. METHODS: We compared disease characteristics of 264 women and 231 men with nr-axSpA at inclusion in the prospective Swiss Clinical Quality Management Cohort. Response to a first TNFi was assessed in 85 women and 78 men without diagnosed co-morbid fibromyalgia. The primary outcome was the proportion of patients achieving the 40% improvement in the Assessment of SpondyloArthritis international Society criteria (ASAS40) at 1 year. Additional response outcomes were evaluated as secondary outcomes. Patients having discontinued TNFi were considered non-responders. Logistic regression analyses were adjusted for baseline differences, which might potentially mediate the effect of sex on treatment response. RESULTS: Compared to men, women had a longer diagnostic delay, a higher level of perceived disease activity, and more enthesitis and were in a lower percentage HLA-B27 positive. An ASAS40 response was achieved by 17% of women and 38% of men (OR 0.34; 95% CI 0.12, 0.93; p = 0.02). A significantly lower response rate in women was confirmed in the adjusted analysis (OR 0.19; 95% CI 0.05, 0.62; p = 0.009) as well as for the other outcomes assessed. CONCLUSION: Despite only few sex differences in patient characteristics in nr-axSpA, response rates to TNFi are significantly lower in women than in men.

Effectiveness of secukinumab versus an alternative TNF inhibitor in patients with axial spondyloarthritis previously exposed to TNF inhibitors in the Swiss Clinical Quality Management cohort.

OBJECTIVE: To compare effectiveness of treatment with secukinumab (SEC) with that of alternative tumour necrosis factor inhibitors (TNFis) in patients with axial spondyloarthritis (axSpA) after withdrawal from one or more TNFis. METHODS: Patients diagnosed as having axSpA in the Swiss Clinical Quality Management cohort were included if they had initiated SEC (n=106) or an alternative TNFi (n=284) after experiencing TNFi failure. Drug retention was investigated with matching weights propensity score (PS) analyses and multiple adjusted Cox proportional hazards models. Matching weights PS-based analyses and multiple-adjusted logistic regression analyses were used to assess the proportion of patients reaching 50% reduction in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) at 1 year. RESULTS: SEC was more often used as third-line or later-line biological drug (76% vs 40% for TNFi). Patients starting SEC had higher BASDAI, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index and C reactive protein levels. A comparable risk of drug discontinuation was found for SEC versus TNFi (HR 1.14, 95% CI 0.78 to 1.68 in the PS-based analysis and HR 1.16, 95% CI 0.79 to 1.71 in the multiple-adjusted analysis). No significant difference in BASDAI50 responses at 1 year was demonstrated between the two modes of biological drug action, with CI of estimates being, however, wide (OR for SEC vs TNFi 0.76, 95% CI 0.26 to 2.18 and 0.78, 95% CI 0.24 to 2.48 in the PS-based and the covariate-adjusted model, respectively). CONCLUSION: Our data suggest a comparable effectiveness of SEC versus an alternative TNFi after prior TNFi exposure.

Spinal radiographic progression in axial spondyloarthritis and the impact of classification as nonradiographic versus radiographic disease: Data from the Swiss Clinical Quality Management cohort.

OBJECTIVE: To investigate whether spinal radiographic progression relates to structural damage at the sacroiliac level in axial spondyloarthritis (axSpA). METHODS: Patients classified as nonradiographic (nr-) and radiographic (r-) axSpA in the Swiss Clinical Quality Management cohort with radiographs performed every 2 years, scored according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), were included. The relationship between classification status and spinal progression during 2 years was investigated using binomial generalized estimating equations models with adjustment for sex, ankylosing spondylitis disease activity score (ASDAS) and tumour necrosis factor inhibitor treatment. Baseline spinal damage was considered an intermediate variable and included in sensitivity analyses. RESULTS: In total, 88 nr-axSpA and 418 r-axSpA patients contributed to data for 725 radiographic intervals. R-axSpA patients were more frequently male, had a longer disease duration and higher structural damage at baseline. Mean (SD) mSASSS change over 2 years was 0.16 (0.62) units in nr-axSpA and 0.92 (2.78) units in r-axSpA, p = 0.01. Nr-axSpA was associated with a significantly lower progression in 2 years (defined as an increase in ≥2 mSASSS units) in adjusted analyses (OR 0.33, 95%CI 0.13; 0.83), confirmed with progression defined as the formation of ≥1 syndesmophyte. Mediation analyses revealed that sacroiliitis exerted its effect on spinal progression indirectly by being associated with the appearance of a first syndesmophyte (OR 0.09, 95%CI 0.02; 0.36 for nr-axSpA vs r-axSpA). Baseline syndesmophytes were predictors of further progression. CONCLUSION: Spinal structural damage is mainly restricted to patients with r-axSpA, leading to relevant prognostic and therapeutic implications.