Sex differences in patient-reported outcomes and the association with clinical factors in axial spondyloarthritis patients treated with tumour necrosis factor inhibitors.

OBJECTIVES: To investigate sex differences in patient-reported outcome measures (PROMs) among axSpA patients initiating their first TNFi and identify factors contributing to these disparities over the follow-up. METHODS: Data were included from 15 EuroSpA registries and consisted of axSpA patients initiating their first TNFi, with ≥2 measurements for each analysed PROM (BASDAI and BASFI, scale 0-100) taken at any time point. Linear mixed models were employed to analyse sex differences in PROMs over 24 months and to evaluate how baseline characteristics were related to the observed sex differences. RESULTS: We analysed 13 102 (38% women) in the BASDAI analyses and 10 623 (38% women) in the BASFI analyses. At follow-up, mean sex differences in BASDAI increased from 4.3 units at baseline (95% CI, 3.5-5.1)-8.0 (7.2-8.8) at 6 months, and in BASFI from 2.2 (1.4-3.1)-4.6 (3.6-5.5), with consistently worse scores in women. Baseline characteristics could not substantially account for the observed sex differences over time; however, the magnitude of the sex differences was reduced by HLA-B27 positivity, longer disease duration, and increased CRP levels, but increased by TNFi initiation in later years and peripheral arthritis. CONCLUSION: In axSpA patients initiating their first TNFi, baseline sex differences in BASDAI and BASFI increased two-fold after 6 months of treatment and persisted thereafter, with worse scores in women. Several baseline characteristics moderated the sex differences, though none could fully account for them. These findings improve our understanding of sex differences and underscore their importance in axSpA.

Exploring TNFi drug-levels and anti-drug antibodies during tapering among patients with inflammatory arthritis: secondary analyses from the randomised BIODOPT trial.

To evaluate tumour necrosis factor inhibitor (TNFi) drug-levels and presence of anti-drug antibodies (ADAb) in patients with inflammatory arthritis who taper TNFi compared to TNFi continuation. Patients with rheumatoid arthritis, psoriatic arthritis, or axial spondyloarthritis on stable TNFi dose and in low disease activity ≥ 12 months were randomised (2:1) to disease activity-guided tapering or control. Blood samples at baseline, 12- and 18-months were evaluated for TNFi drug-levels and ADAb. In total, 129 patients were randomised to tapering (n = 88) or control (n = 41). Between baseline and month 18, a significant shift in TNFi drug-levels were observed in the tapering group resulting in fewer patients with high drug-levels (change: - 14% [95% CI - 27 to - 1%]) and more with low drug-levels (change: 18% [95% CI 5-31%]). Disease activity was equivalent between groups at 18 months, mean difference: RA - 0.06 (95% CI - 0.44 to 0.33), PsA 0.03 (95% CI - 0.36 to 0.42), and axSpA 0.16 (- 0.17 to 0.49), equivalence margins ± 0.5 disease activity points. ADAb were detected in eight patients, all from the tapering group. TNFi drug-level category or ADAb were not predictive for achieving successful tapering at 18 months. TNFi drug-levels decreased during tapering which indicate adherence to the tapering algorithm. Despite the difference in TNFi drug-levels at 18 months, disease activity remained equivalent, and only few tapering patients had detectable ADAb. These data do not support using TNFi drug-level and/or ADAb to guide the tapering decision but future research with larger trials is needed.Trial registration: EudraCT: 2017-001970-41, December 21, 2017.

Exploring complement biomarkers in suspected axial spondyloarthritis.

OBJECTIVES: To investigate lectin pathway proteins (LPPs) as biomarkers for axial spondyloarthritis (axSpA) in a cross-sectional cohort with a suspicion of axSpA, comprising newly diagnosed axSpA and chronic low back pain (cLBP) individuals. METHODS: Serum samples from 515 participants within the OptiRef cohort, including 151 axSpA patients and 364 cLBP patients, were measured using immunoassays for LPPs (mannan-binding lectin (MBL), collectin liver-1 (CL-L1), M-ficolin, H-ficolin and L-ficolin, MBL-associated serine proteases (MASP)-1, -2 and -3, MBL-associated proteins (MAp19 and MAp44) and the complement activation product C3dg). RESULTS: Serum levels of L-ficolin, MASP-2 and C3dg were elevated in axSpA patients, whereas levels of MASP-3 and CL-L1 were decreased, and this remained significant for C3dg and MASP-3 after adjustment for C reactive protein (CRP). A univariate regression analysis showed serum levels of CL-L1, MASP-2, MASP-3 and C3dg to predict the diagnosis of axSpA, and MASP-3 and C3dg remained significant in a multivariate logistic regression analysis. Assessment of the diagnostic potential showed that a combination of human leukocyte antigen B27 (HLA-B27) and measurements of L-ficolin, MASP-3 and C3dg increased the diagnostic specificity for axSpA, however, with a concomitant loss of sensitivity. CONCLUSIONS: Serum levels of complement activation, that is, C3dg, and MASP-3 differed significantly between axSpA and cLBP patients after adjustment for CRP. Although combining HLA-B27 with measurements of L-ficolin, MASP-3 and C3dg increased the diagnostic specificity for axSpA, this seems unjustified due to the concomitant loss of sensitivity. However, both C3dg and MASP-3 were associated with axSpA diagnosis in multivariate logistic regression, suggesting an involvement of complement in the inflammatory processes and possibly pathogenesis in axSpA.

Drug effectiveness of 2nd and 3rd TNF inhibitors in psoriatic arthritis - relationship with the reason for withdrawal from the previous treatment.

OBJECTIVE: To investigate real-world retention and remission rates in PsA patients initiating a 2nd or 3rd TNFi and the association with reason for discontinuation from the previous TNFi-treatment. METHODS: Prospectively collected routine care data from 12 European registries were pooled. Retention rates (Kaplan-Meier estimation) and crude/LUNDEX-adjusted rates of Disease Activity Score 28 and Disease Activity index for PSoriatic Arthritis (DAS28 and DAPSA28) remission were calculated and compared with adjusted Cox regression analyses and Chi-squared test, respectively). RESULTS: We included 5233 (2nd TNFi) and 1906 (3rd TNFi) patients. Twelve-month retention rates for the 2nd and 3rd TNFi were 68% (95%CI: 67-70%) and 66% (64-68%), respectively. Patients who stopped the previous TNFi due to AE/LOE had 12-month retention rates of 66%/65% (2nd TNFi), and 65%/63% (3rd TNFi), respectively. Patients who stopped the previous TNFi due to LOE after less vs more than 24 weeks had 12-month retention rates of 54%/69% (2nd TNFi), and 58%/65% (3rd TNFi). Six-month crude/LUNDEX-adjusted DAS28 remission rates were 48%/35% and 38%/27%, and DAPSA28 remission rates were 19%/14% and 14%/10%, for the 2nd and 3rd TNFi. CONCLUSION: Two-thirds of patients remained on TNFi at 12months for both the 2nd and 3rd TNFi, while one-third and one-quarter of patients were in DAS28 remission after 6months on the 2nd and 3rd TNFi. While drug effectiveness was similar in patients who stopped the previous TNFi due to AE compared to overall LOE, drug effectiveness was better in patients who had stopped the previous TNF due to secondary LOE compared to primary LOE.

Patient-reported outcomes in axial spondyloarthritis and psoriatic arthritis patients treated with secukinumab for 24 months in daily clinical practice.

OBJECTIVES: In patients with axial spondyloarthritis (axSpA) or psoriatic arthritis (PsA) initiating secukinumab, we aimed to assess and compare the proportion of patients achieving 6-, 12- and 24-month patient-reported outcomes (PRO) remission and the 24-month retention rates. PATIENTS AND METHODS: Patients with axSpA or PsA from 16 European registries, who initiated secukinumab in routine care were included. PRO remission rates were defined as pain, fatigue, Patient Global Assessment (PGA) ≤2 (Numeric Rating Scale (NRS) 0-10) and Health Assessment Questionnaire (HAQ) ≤0.5, for both axSpA and PsA, and were calculated as crude values and adjusted for drug adherence (LUNDEX). Comparisons of axSpA and PsA remission rates were performed using logistic regression analyses (unadjusted and adjusted for multiple confounders). Kaplan-Meier plots with log-rank test and Cox regression analyses were conducted to assess and compare secukinumab retention rates. RESULTS: We included 3087 axSpA and 3246 PsA patients initiating secukinumab. Crude pain, fatigue, PGA and HAQ remission rates were higher in axSpA than in PsA patients, whereas LUNDEX-adjusted remission rates were similar. No differences were found between the patient groups after adjustment for confounders. The 24-month retention rates were similar in axSpA vs. PsA in fully adjusted analyses (HR [95 %CI] = 0.92 [0.84-1.02]). CONCLUSION: In this large European real-world study of axSpA and PsA patients treated with secukinumab, we demonstrate for the first time a comparable effectiveness in PRO remission and treatment retention rates between these two conditions when adjusted for confounders.

Patient-Reported Outcomes (PROs) and PRO Remission Rates in 12,262 Biologic-Naïve Patients With Psoriatic Arthritis Treated With Tumor Necrosis Factor Inhibitors in Routine Care.

OBJECTIVE: To evaluate patient-reported outcomes (PROs) after initiation of tumor necrosis factor inhibitor (TNFi) treatment in European real-world patients with psoriatic arthritis (PsA). Further, to investigate PRO remission rates across treatment courses, registries, disease duration, sex, and age at disease onset. METHODS: Visual analog scale or numerical rating scale scores for pain, fatigue, patient global assessment (PtGA), and the Health Assessment Questionnaire-Disability Index (HAQ-DI) from 12,262 patients with PsA initiating a TNFi in 13 registries were pooled. PRO remission rates (pain ≤ 1, fatigue ≤ 2, PtGA ≤ 2, and HAQ-DI ≤ 0.5) were calculated for patients still on the treatment. RESULTS: For the first TNFi, median pain score was reduced by approximately 50%, from 6 to 3, 3, and 2; as were fatigue scores, from 6 to 4, 4, and 3; PtGA scores, from 6 to 3, 3, and 2; and HAQ-DI scores, from 0.9 to 0.5, 0.5, and 0.4 at baseline, 6, 12, and 24 months, respectively. Six-month Lund Efficacy Index (LUNDEX)-adjusted remission rates for pain, fatigue, PtGA, and HAQ-DI scores were 24%, 31%, 36%, and 43% (first TNFi); 14%, 19%, 23%, and 29% (second TNFi); and 9%, 14%, 17%, and 20% (third TNFi), respectively. For biologic-naïve patients with disease duration < 5 years, 6-month LUNDEX-adjusted remission rates for pain, fatigue, PtGA, and HAQ-DI scores were 22%, 28%, 33%, and 42%, respectively. Corresponding rates for patients with disease duration > 10 years were 27%, 32%, 41%, and 43%, respectively. Remission rates were 33%, 40%, 45%, and 56% for men and 17%, 23%, 24%, and 32% for women, respectively. For patients aged < 45 years at diagnosis, 6-month LUNDEX-adjusted remission rate for pain was 29% vs 18% for patients ≥ 45 years. CONCLUSION: In 12,262 biologic-naïve patients with PsA, 6 months of treatment with a TNFi reduced pain by approximately 50%. Marked differences in PRO remission rates across treatment courses, registries, disease duration, sex, and age at onset of disease were observed, emphasizing the potential influence of factors other than disease activity on PROs.

Identification of patient endotypes and adalimumab treatment responders in axial spondyloarthritis using blood-derived extracellular matrix biomarkers.

OBJECTIVE: To explore the potential of a panel of ECM remodelling markers as endotyping tools for axial spondyloarthritis (axSpA) by separating patients into subtypes and investigate how they differ among each other in disease activity scores and response to treatment with adalimumab. METHODS: In three axSpA studies, a panel of 14 blood-based ECM biomarkers related to formation of collagen (PRO-C2, PRO-C3, PRO-C6), degradation of collagen by metalloproteinases (C1M, C2M, T2CM, C3M, C4M, C6M, C10C), matrix metalloproteinase (MMP)-degraded prolargin (PROM), MMP-degraded and citrullinated vimentin (VICM), basement membrane turnover (PRO-C4) and neutrophil activity (CPa9-HNE) were assessed to enable patient clustering (endotyping). MASH (n=41) was a cross-sectional study, while Adalimumab in Axial Spondyloarthritis study (ASIM,n=45) and Danish Multicenter Study of Adalimumab in Spondyloarthritis (DANISH, n=49) were randomised, double-blind placebo-controlled trials of adalimumab versus placebo every other week for 6 or 12 weeks, respectively, followed by active treatment. Biomarker data were log-transformed, standardised by mean centering and scaled by the SD prior to principal component analysis and K-means clustering. RESULTS: Based on all three studies, we identified two orthogonal dimensions reflecting: (1) inflammation and neutrophil activity (driven by C1M and CPa9-HNE) and (2) collagen turnover (driven by PRO-C2). Three endotypes were identified: high inflammation endotype (Endotype1), low inflammation endotype (Endotype 2) and high collagen turnover endotype (Endotype3). Endotype1 showed higher disease activity (Ankylosing Spondylitis Disease Activity Score (ASDAS)) at baseline compared with Endotype2 and Endotype3 and higher percentage of patients responding to adalimumab based on ASDAS clinical improvement at week 24. Endotype3 showed higher percentage of patients with 50% improvement in Bath Ankylosing Spondylitis Disease Activity Index response at week 24 compared with Endotype2. CONCLUSION: These endotypes differ in their tissue remodelling profile and may in the future have utility for patient stratification and treatment tailoring.

Predictors of DAPSA28 remission in patients with psoriatic arthritis initiating a first TNF inhibitor: results from 13 European registries.

OBJECTIVES: In bio-naïve patients with PsA initiating a TNF inhibitor (TNFi), we aimed to identify baseline predictors of Disease Activity index for PsA in 28 joints (DAPSA28) remission (primary objective) and DAPSA28 moderate response at 6 months, as well as drug retention at 12 months across 13 European registries. METHODS: Baseline demographic and clinical characteristics were retrieved and the three outcomes investigated per registry and in pooled data, using logistic regression analyses on multiply imputed data. In the pooled cohort, selected predictors that were either consistently positive or negative across all three outcomes were defined as common predictors. RESULTS: In the pooled cohort (n = 13 369), 6-month proportions of remission, moderate response and 12-month drug retention were 25%, 34% and 63% in patients with available data (n = 6954, n = 5275 and n = 13 369, respectively). Five common baseline predictors of remission, moderate response and 12-month drug retention were identified across all three outcomes. The odds ratios (95% CIs) for DAPSA28 remission were: age, per year: 0.97 (0.96-0.98); disease duration, years (<2 years as reference): 2-3 years: 1.20 (0.89-1.60), 4-9 years: 1.42 (1.09-1.84), ≥10 years: 1.66 (1.26-2.20); men vs women: 1.85 (1.54-2.23); CRP of >10 vs ≤10 mg/l: 1.52 (1.22-1.89) and 1 mm increase in patient fatigue score: 0.99 (0.98-0.99). CONCLUSION: Baseline predictors of remission, response and adherence to TNFi therapy were identified, of which five were common for all three outcomes, indicating that the predictors emerging from our pooled cohort may be considered generalizable from country level to disease level.

Sex Differences in the Effectiveness of First-Line Tumor Necrosis Factor Inhibitors in Psoriatic Arthritis: Results From the European Spondyloarthritis Research Collaboration Network.

OBJECTIVE: Women with psoriatic arthritis (PsA) may have reduced tumor necrosis factor inhibitor (TNFi) effectiveness compared to men. We examined sex differences in treatment response and retention rates during 24 months of follow-up among patients with PsA initiating their first TNFi. METHODS: Data from patients with PsA across 13 European Spondyloarthritis Research Collaboration Network registries starting their first TNFi were pooled. Logistic regression was used to analyze the association between sex and treatment response using low disease activity (LDA) according to the Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) (<3.2) at six months as the primary outcome. Analyses were adjusted for age, country, conventional synthetic disease-modifying antirheumatic drug treatment, and TNFi start year. Retention rates were explored using the Kaplan-Meier estimator. RESULTS: We analyzed the treatment response of 7,679 patients with PsA (50% women) with available data on LDA at six months. At baseline, women and men had similar characteristics, including mean DAS28-CRP (women vs men, 4.4 [SD 1.2] vs 4.2 [SD 1.2]), though patient-reported outcome measures were worse in women. At six months, 64% of women and 78% of men had LDA (relative risk [RR] 0.82; 95% confidence interval [CI] 0.80-0.84). This difference was similar after adjustment (RR 0.83; 95% CI 0.81-0.85). TNFi retention rates were evaluated in 17,842 patients with PsA. Women had significantly lower retention rates than men at all time points (women 79%, 64%, and 50% vs men 88%, 77%, and 64% at 6, 12, and 24 months, respectively). CONCLUSION: Despite comparable disease characteristics at baseline, women with PsA have reduced treatment response and retention rates to their first TNFi, highlighting the need to consider sex differences in PsA research and management.

Endometrial preparation protocols prior to frozen embryo transfer - convenience or safety?

The number of frozen embryo transfer (FET) cycles is increasing rapidly worldwide. Different endometrial preparations for FET result in comparable live birth rates. However, several recent publications have reported higher maternal risks for hypertensive disorders of pregnancy (HDP), pre-eclampsia and postpartum haemorrhage (PPH) in programmed cycles (PC-FET) compared with natural cycles and modified natural cycles with an intact corpus luteum. Nevertheless, PC-FET is frequently used in ovulatory women despite the increased risks for HDP, pre-eclampsia and PPH. Although randomized controlled studies have been suggested, PC-FET raises several methodological problems. Large study populations would be required to investigate the outcomes in question, and the inclusion of ovulatory women, where the intervention may increase the risk of a negative outcome, is ethically troublesome. In the authors' opinion, the existing evidence from large observational studies and systematic reviews is sufficiently strong to recommend an endometrial preparation strategy that aims to maintain or stimulate the corpus luteum to minimize the risk of HDP and pre-eclampsia after FET cycles.

Commonalities and differences in set-up and data collection across European spondyloarthritis registries - results from the EuroSpA collaboration.

BACKGROUND: In European axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) clinical registries, we aimed to investigate commonalities and differences in (1) set-up, clinical data collection; (2) data availability and completeness; and (3) wording, recall period, and scale used for selected patient-reported outcome measures (PROMs). METHODS: Data was obtained as part of the EuroSpA Research Collaboration Network and consisted of (1) an online survey and follow-up interview, (2) upload of real-world data, and (3) selected PROMs included in the online survey. RESULTS: Fifteen registries participated, contributing 33,948 patients (axSpA: 21,330 (63%), PsA: 12,618 (37%)). The reported coverage of eligible patients ranged from 0.5 to 100%. Information on age, sex, biological/targeted synthetic disease-modifying anti-rheumatic drug treatment, disease duration, and C-reactive protein was available in all registries with data completeness between 85% and 100%. All PROMs (Bath Ankylosing Spondylitis Disease Activity and Functional Indices, Health Assessment Questionnaire, and patient global, pain and fatigue assessments) were more complete after 2015 (68-86%) compared to prior (50-79%). Patient global, pain and fatigue assessments showed heterogeneity between registries in terms of wording, recall periods, and scale. CONCLUSION: Important heterogeneity in registry design and data collection across fifteen European axSpA and PsA registries was observed. Several core measures were widely available, and an increase in data completeness of PROMs in recent years was identified. This study might serve as a basis for examining how differences in data collection across registries may impact the results of collaborative research in the future.

Complement Proteins L-Ficolin and M-Ficolin Are Increased in Patients With Axial Spondyloarthritis and Decrease After Tumor Necrosis Factor Inhibitor Treatment.

OBJECTIVE: We have previously reported elevated levels of the complement lectin pathway proteins L-ficolin and H-ficolin in patients with axial spondyloarthritis (axSpA) compared with healthy controls. The aim of the present study was to investigate these biomarkers in a cross-sectional cohort of patients suffering from low back pain (LBP). Further, we aimed to investigate changes in lectin pathway protein levels after initiation of adalimumab (ADA; a tumor necrosis factor inhibitor) in a longitudinal cohort of patients with axSpA. METHODS: Lectin pathway protein levels (mannan-binding lectin [MBL], collectin liver 1, H-ficolin, L-ficolin, M-ficolin, MBL-associated serine protease [MASP]-1, MASP-2, MASP-3, MBL-associated protein 19 [MAp19], and MAp44) in EDTA plasma were determined in 2 well-characterized cohorts: (1) a clinical cross-sectional cohort of patients with LBP, including patients with axSpA (n = 23), patients with unspecific LBP (uLBP) with ≥ 1 SpA features (n = 55), and patients with uLBP without SpA features or magnetic resonance imaging findings suggestive of axSpA (n = 64); and (2) a randomized double-blinded, placebo-controlled trial cohort of patients with axSpA (n = 49) initiating ADA therapy. Lectin pathway protein levels were determined using immunoassays. RESULTS: Plasma levels of L-ficolin and M-ficolin were significantly increased in the cross-sectional cohort of newly diagnosed patients with axSpA compared with clinically relevant controls with uLBP (all P < 0.05). Both L-ficolin and M-ficolin decreased significantly after ADA therapy (P < 0.05). CONCLUSION: L-ficolin and M-ficolin levels are elevated in newly diagnosed patients with axSpA compared with clinically relevant controls. Both L-ficolin and M-ficolin levels decrease significantly after initiating ADA therapy. These findings provide new insights into the inflammatory processes in axSpA and support the involvement of complement in axSpA pathogenesis.

Extracellular matrix turnover biomarkers reflect pharmacodynamic effects and treatment response of adalimumab in patients with axial spondyloarthritis-results from two randomized controlled trials.

OBJECTIVE: To investigate if extracellular matrix (ECM) blood-based biomarkers reflect the pharmacodynamic effect and response to TNF-α inhibitor therapy (adalimumab, ADA), in patients with axial spondyloarthritis (axSpA). METHODS: We investigated ECM biomarkers in two randomized, double-blind, placebo-controlled trials of axSpA patients (DANISH and ASIM, n = 52 and n = 49, respectively) receiving ADA 40 mg or placebo every other week for 12 and 6 weeks, respectively, and thereafter ADA to week 48. Serum concentrations of degraded type I (C1M), II (C2M, T2CM), III (C3M), IV (C4M), VI (C6M), type X (C10C) collagen; metabolite of C-reactive protein (CRPM), prolargin (PROM), citrullinated vimentin (VICM), calprotectin (CPa9-HNE); and formation of type II (PRO­C2), III (PRO­C3), and VI (PRO­C6) turnover of type IV collagen (PRO-C4) were measured at baseline and weeks 6 or 12, 24, and 48. The pharmacodynamic effect and treatment response to ADA was evaluated by linear mixed models, and correlations between biomarkers and clinical scores were assessed by Spearman's correlation. RESULTS: C1M, C3M, C4M, C6M, CRP, PRO-C4, and CPa9-HNE levels declined after 6 or 12 weeks in patients receiving ADA compared to placebo (all p < 0.05). Patients with AS Disease Activity Score C-reactive protein (ASDAS CRP) major improvement and/or clinically important improvement had significantly higher C1M, C3M, C4M, C6M, and PRO-C4 levels than patients with no/low improvement at baseline (all p < 0.05). Baseline levels of biomarkers showed weak to moderate correlations with ASDAS and structural damage scores. CONCLUSION: ECM metabolites showed a pharmacodynamic effect and were associated with ASDAS response during TNF-α inhibitor treatment in patients with axSpA.

Differences and similarities between the EULAR/ASAS-EULAR and national recommendations for treatment of patients with psoriatic arthritis and axial spondyloarthritis across Europe.

This is the first report comparing EULAR and national treatment recommendations for PsA patients across Europe, and the first this decade to compare ASAS-EULAR and national treatment recommendations in axSpA patients. An electronic survey was completed from October 2021-April 2022 by rheumatologists in 15 European countries. One and four countries followed all EULAR and ASAS-EULAR recommendations, respectively. Five countries had no national treatment recommendations for PsA and/or axSpA, but followed other regulations. In several countries, national treatment recommendations predated the most recent EULAR/ASAS-EULAR recommendations. Entry criteria for starting biologic/targeted synthetic disease-modifying anti-rheumatic drugs varied considerably. In several countries, for PsA patients with significant skin involvement, interleukin-17 inhibitors were not given preference. The positioning of Janus Kinase inhibitors differed and Phosphodiesterase-4 inhibitors were not in use/reimbursed in most countries. This study may motivate European countries to update their national treatment recommendations, to align them better with the latest international recommendations.

Fasting-sensitive SUMO-switch on Prox1 controls hepatic cholesterol metabolism.

Accumulation of excess nutrients hampers proper liver function and is linked to nonalcoholic fatty liver disease (NAFLD) in obesity. However, the signals responsible for an impaired adaptation of hepatocytes to obesogenic dietary cues remain still largely unknown. Post-translational modification by the small ubiquitin-like modifier (SUMO) allows for a dynamic regulation of numerous processes including transcriptional reprogramming. We demonstrate that specific SUMOylation of transcription factor Prox1 represents a nutrient-sensitive determinant of hepatic fasting metabolism. Prox1 is highly SUMOylated on lysine 556 in the liver of ad libitum and refed mice, while this modification is abolished upon fasting. In the context of diet-induced obesity, Prox1 SUMOylation becomes less sensitive to fasting cues. The hepatocyte-selective knock-in of a SUMOylation-deficient Prox1 mutant into mice fed a high-fat/high-fructose diet leads to a reduction of systemic cholesterol levels, associated with the induction of liver bile acid detoxifying pathways during fasting. The generation of tools to maintain the nutrient-sensitive SUMO-switch on Prox1 may thus contribute to the development of "fasting-based" approaches for the preservation of metabolic health.

Evolution of Magnetic Resonance Imaging Lesions at the Sacroiliac Joints During and After Pregnancy by Serial Magnetic Resonance Imaging From Gestational Week Twenty to Twelve Months Postpartum.

OBJECTIVE: Sacroiliac (SI) joint magnetic resonance imaging (MRI) findings simulating sacroiliitis related to axial spondyloarthritis (SpA) may occur in women before and after birth. This study was undertaken to explore the prevalence, evolution, and topography of SI joint MRI lesions in pregnant and postpartum women. METHODS: A prospective cohort study included 103 first-time mothers who underwent up to 5 serial SI joint MRI between gestational week 20 and 12 months postpartum. After calibration, 3 assessors independently evaluated bone marrow edema (BME), including sacroiliitis according to the Assessment of SpondyloArthritis international Society (ASAS), as well as structural lesions, using the Spondyloarthritis Research Consortium of Canada (SPARCC) and a novel 2-plane assessment method. RESULTS: BME was frequent both during pregnancy and the postpartum period, peaking at 3 months postpartum with a prevalence of 69% (SPARCC) and 80% (2-plane method), but still present in 54% (SPARCC) and 58% (2-plane method) of subjects at 12 months postpartum. At 12 months postpartum, sacroiliitis according to the current ASAS definition was met in 41%, while 21% and 14% of women fulfilled the newly proposed ASAS MRI thresholds for active and structural SI joint lesions, respectively. BME clustered in the anterior middle joint portions at all time points, and ligamentous BME was rare. At 12 months postpartum, SPARCC erosion scores ≥3 (ASAS threshold) were observed in only 2.8% of women. CONCLUSION: At 12 months postpartum, 41% of women met the current ASAS sacroiliitis definition, which may result in false-positive assignments of axial SpA diagnosis in postpartum women with back pain. The topographical BME distribution and virtually absent erosions (ASAS threshold) at 12 months postpartum may help discriminate postpartum strain-related conditions from axial SpA-related sacroiliitis.

One-Third of European Patients With Axial Spondyloarthritis Reach Pain Remission With Routine Care Tumor Necrosis Factor Inhibitor Treatment.

OBJECTIVE: To investigate the distribution of patient-reported outcomes (PROs) in patients with axial spondyloarthritis (axSpA) initiating a tumor necrosis factor inhibitor (TNFi), to assess the proportion reaching PRO "remission" across registries and treatment series, and to compare patients registered to fulfill the modified New York (mNY) criteria for ankylosing spondylitis (AS) vs patients with nonradiographic axSpA (nr-axSpA). METHODS: Fifteen European registries contributed PRO scores for pain, fatigue, patient global assessment (PtGA), Bath Ankylosing Spondylitis (AS) Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), and Health Assessment Questionnaire (HAQ) from 19,498 patients with axSpA. Changes in PROs and PRO remission rates (definitions: ≤ 20 mm for pain, fatigue, PtGA, BASDAI, and BASFI; ≤ 0.5 for HAQ) were calculated at 6, 12, and 24 months of treatment. RESULTS: Heterogeneity in baseline characteristics and outcomes between registries were observed. In pooled data, 6 months after the start of a first TNFi, pain score was reduced by approximately 60% (median at baseline/6/12/24 months: 65/25/20/20 mm) in patients on treatment. Similar patterns were observed for fatigue (68/32/30/25 mm), PtGA (66/29/21/20 mm), BASDAI (58/26/21/19 mm), BASFI (46/20/16/16 mm), and HAQ (0.8/0.4/0.2/0.2). Patients with AS (n = 3281) had a slightly better response than patients with nr-axSpA (n = 993). The Lund Efficacy Index (LUNDEX)-adjusted remission rates at 6 months for pain/fatigue/PtGA/BASDAI/BASFI/HAQ were 39%/30%/38%/34%/35%/48% for the AS cohort and 30%/21%/26%/24%/33%/47% for the nr-axSpA cohort. Better PRO responses were seen with a first TNFi compared to a second and third TNFi. CONCLUSION: Patients with axSpA starting a TNFi achieved high PRO remission rates, most pronounced in those fulfilling the mNY criteria and for the first TNFi.

Levels of extracellular matrix metabolites are associated with changes in Ankylosing Spondylitis Disease Activity Score and MRI inflammation scores in patients with axial spondyloarthritis during TNF inhibitor therapy.

BACKGROUND/PURPOSE: In axial spondyloarthritis (axSpA) inflammation of the sacroiliac joints and spine is associated with local extracellular matrix (ECM) remodeling of affected tissues. We aimed to investigate the association of ECM metabolites with treatment response in axSpA patients treated with TNF-α inhibitory therapy for 46 weeks. METHODS: In a prospective clinical study of axSpA patients (n=55) initiating a TNF inhibitor (infliximab, etanercept, or adalimumab), serum concentrations of formation of type I (PRO-C1), type III (PRO-C3), and type VI (PRO-C6) collagen; turnover of type IV collagen (PRO-C4), and matrix-metalloproteinase (MMP)-degraded type III (C3M) collagen, MMP-degraded type IV (C4M), type VI (C6M), and type VII (C7M) collagen, and cathepsin-degraded type X collagen (C10C), MMP-mediated metabolite of C-reactive protein (CRPM), citrullinated vimentin (VICM), and neutrophil elastase-degraded elastin (EL-NE) were measured at baseline, week 2, week 22, and week 46. RESULTS: Patients were mostly males (82%), HLA-B27 positive (84%), with a median age of 40 years (IQR: 32-48), disease duration of 5.5 years (IQR: 2-10), and a baseline Ankylosing Spondylitis Disease Activity Score (ASDAS) of 3.9 (IQR: 3.0-4.5). Compared to baseline, PRO-C1 levels were significantly increased after two weeks of treatment, C6M levels were significantly decreased after two and 22 weeks (repeated measures ANOVA, p=0.0014 and p=0.0015, respectively), EL-NE levels were significantly decreased after 2 weeks (p=0.0008), VICM levels were significantly decreased after two and 22 weeks (p=0.0163 and p=0.0374, respectively), and CRP were significantly decreased after two and 22 weeks (both p=0.0001). Baseline levels of PRO-C1, PRO-C3, C6M, VICM, and CRP were all associated with ASDAS clinically important and major improvement after 22 weeks (ΔASDAS ≥1.1) (Mann-Whitney test, p=0.006, p=0.008, p<0.001, <0.001, <0.001, respectively), while C6M, VICM and CRP levels were associated with ASDAS clinically important and major improvement after 46 weeks (ΔASDAS ≥2.0) (p=0.002, p=0.044, and p<0.001, respectively). PRO-C1 and C6M levels were associated with a Bath AS Disease Activity Score (BASDAI) response to TNF-inhibitory therapy after 22 weeks (Mann-Whitney test, p=0.020 and p=0.049, respectively). Baseline levels of PRO-C4 and C6M were correlated with the total SPARCC MRI Spine and Sacroiliac Joint Inflammation score (Spearman's Rho ρ=0.279, p=0.043 and ρ=0.496, p=0.0002, respectively). CONCLUSIONS: Extracellular matrix metabolites were associated with ASDAS response, MRI inflammation, and clinical treatment response during TNF-inhibitory treatment in patients with axSpA.