Real-World Study In Ankylosing Spondylitis And Metabolomics Analysis Of Exercise Intervention

Background:Ankylosing spondylitis(AS)is a rheumatic disease characterized by chronic inflammation and progressive structural damage of the spinal and sacroiliac joints.Structural damage of AS has great heterogeneity among different populations.There is an urgent need for a relatively well-developed population-based cohort to explore the progression of structural damage in the spine and its influencing factors in Chinese patients with AS.The important role of weight management and exercise in the treatment of AS patients has been proposed,which may be related to the fact that obesity itself is a low inflammatory state has aggravated the inflammatory burden of AS.Besides,the effect of underweight on AS patients is always ignored.Pharmacotherapy combined with exercise is the best intervention strategy for AS patients,but given the complexity of AS itself and exercise-related mechanisms,it is unclear whether beneficial metabolic changes occur in AS patients through exercise intervention and the underlying metabolic mechanisms.Objective:1)Aim to explore spinal radiographic progression of patients with AS and its influencing factors based on the 6-year follow-up of the Chinese Ankylosing Spondylitis Imaging Cohort(CASPIC).2)To further examine the impact of underweight,overweight and obesity on clinical outcomes and treatment responses to biologics in Chinese patients with AS,based on the results of the first part.3)Aim to explore the regulatory effect of exercise on plasma metabolism in patients with AS based on metabolomics,and to provide theoretical and practical basis for exercise intervention on the metabolic mechanism of patients with AS.Methods:1)Two trained physicians in rheumatology independently scored the radiographs using the modified stoke ankylosing spondylitis spine score(mSASSS).Trajectories of mSASSS progression were estimated by group-based trajectory modelling,and predisposing baseline factors for such trajectories were identified by logit regression.COX regression analysis was performed to identify predictors associated with development of new syndesmophytes within 6 years.2)BMI was available in 1074 patients from the Smart-phone SpondyloArthritis Management System.Patients were categorized into four groups based on BMI:underweight,normal weight,overweight and obesity.Multivariable median regression analysis examined the effect of underweight and obesity on clinical outcomes and treatment response to biologics.3)We employed an untargeted technique to analyze the plasma metabolomics from healthy individuals,patients with AS before and after 16-week exercise,and explored the metabolic status of AS patients and the effect of exercise on the metabolism of AS patients.Results:1)A total of 177 patients with 365 radiographs were analyzed.The optimum number of mSASSS trajectory groups identified was three group:stable group(128 patients),rapid progression group(34 patients),and early progression group(15 patients).Baseline predictors associated with rapid progression group included:older age,longer duration,higher BMI,no history of TNF-α inhibitor use,existence of syndesmophyte or bone bridges at baseline,higher CRP and ASDAS at baseline.At least a new syndesmophyte developed in 50.3%patients during the entire follow-up,and the development of new syndesmophyte was significantly associated with higher BMI,higher ASDAS,and the existence of syndesmophyte or bone bridges at baseline.2)Among 1074 patients with AS,compared to patients with normal weight,patients with underweight,overweight and obesity had an increased disease activity,while patients with underweight and obesity had a significantly poor physical function and health index.The patients using TNF-α inhibitor in the overweight or obesity categories were much less likely to achieve a significant reduction on disease activity during follow-up period in the multivariate regression model(all P<0.05),taking these with normal-weight patients as a reference.3)Through untargeted plasma metabolomics of from healthy individuals,patients with AS before and after 16-week exercise,the results showed a significant difference between the metabolic profiles of patients with AS and healthy individuals.A total of 200 differential metabolites were screened,involving 48 metabolic pathways,among which the representative pathways closely associated with AS included:AminoacyltRNA biosynthesis,Arginine and proline metabolism D-Glutamine and D-glutamate metabolism,valine leucine and isoleucine biosynthesis.In addition,exercise interventions have shown significant improvement in the metabolism caused by AS,especially in Taurine and hypotaurine metabolism,Arginine and proline metabolism,and Linoleic acid metabolism.Conclusions:Patients with AS had a high heterogeneity of radiographic progression,and clinical factors associated with rapid radiographic progression included older age,longer duration,higher BMI,no history of TNF-α inhibitor use,higher CRP,higher ASDAS,and existence of syndesmophyte or bone bridges at baseline.Patients with higher BMI,higher ASDAS and those with existing syndesmophytes or bone bridges at baseline were more likely to develop new syndesmophytes over time.Both underweight and obesity except for overweight were associated independently with worse disease activity,physical function and health index.Overweight and obesity might impact on treatment responses to biologics in patients with AS.A significant change in plasma metabolism occurred in patients with AS.After 16-week exercise intervention,the plasma metabolic profile of patients with AS deviated from the patients before exercise,and tended to approach that of the healthy individuals,suggesting a positive effect of exercise intervention on the metabolic profile of patients with AS.