The exercise-app Axia for axial spondyloarthritis enhances the home-based exercise frequency in axial spondyloarthritis patients - A cross-sectional survey.

BACKGROUND: Patients with axial spondyloarthritis (axSpA) benefit from regular home-based exercise (HbE). In spite of recommendations, a relevant proportion of German axSpA patients does not adhere to recommended HbE practices. To enhance HbE care, we developed the novel digital therapeutic (DTx) "Axia" compliant with the European medical device regulation (MDR). Axia offers a modern app-based HbE solution with patient educative content and further integrated features. OBJECTIVE: We aimed to assess Axia's efficacy, attractiveness, and functionality through a survey among axSpA-patients involved in the first user tests. METHODS: A mixed-method online questionnaire with 38 items was administered to 37 axSpA volunteers after using Axia. Numeric rating scales (NRS) and likelihood scales were primarily used. RESULTS: HbE frequency significantly increased from a median of 1 day/week to 6 days/week (p < 0.001) by using Axia. Existing HbE practitioners also increased their frequency (median of 4 days/week before, 6 days/week with Axia, p < 0.05). Axia received a median rating of 5 out of 5 stars. On NRS scales, Axia scored a median of 9 for intuitiveness and design, and a median of 8 for entertainment. 64.9% reported improved range of motion, 43.2% reported reduced pain, and 93.6% enhanced disease-specific knowledge. All users recommended Axia to other patients. CONCLUSION: Axia increases axSpA patients HbE frequency, possibly due to its good intuitiveness and design, leading to reduction in pain and subjective improvement of range of motion. This warrants further investigation in large randomized controlled interventional trials to establish its efficacy conclusively and patients adherence to HbE.

Evaluation of a hybrid telehealth care pathway for patients with axial spondyloarthritis including self-sampling at home: results of a longitudinal proof-of-concept mixed-methods study (TeleSpactive).

Patients with axial spondyloarthritis (axSpA) require close monitoring to achieve the goal of sustained disease remission. Telehealth can facilitate continuous care while relieving scarce healthcare resources. In a mixed-methods proof-of-concept study, we investigated a hybrid telehealth care axSpA pathway in patients with stable disease over 6 months. Patients used a medical app to document disease activity (BASDAI and PtGA bi-weekly, flare questionnaire weekly). To enable a remote ASDAS-CRP (TELE-ASDAS-CRP), patients used a capillary self-sampling device at home. Monitoring results were discussed and a decision was reached via shared decision-making whether a pre-planned 3-month on-site appointment (T3) was necessary. Ten patients completed the study, and eight patients also completed additional telephone interviews. Questionnaire adherence was high; BASDAI (82.3%), flares (74.8%) and all patients successfully completed the TELE-ASDAS-CRP for the T3 evaluation. At T3, 9/10 patients were in remission or low disease activity and all patients declined the offer of an optional T3 on-site appointment. Patient acceptance of all study components was high with a net promoter score (NPS) of +50% (mean NPS 8.8 ± 1.5) for self-sampling, +70% (mean NPS 9.0 ± 1.6) for the electronic questionnaires and +90% for the T3 teleconsultation (mean NPS 9.7 ± 0.6). In interviews, patients reported benefits such as a better overview of their condition, ease of use of telehealth tools, greater autonomy, and, most importantly, travel time savings. To our knowledge, this is the first study to investigate a hybrid approach to follow-up axSpA patients including self-sampling. The positive results observed in this scalable proof-of-concept study warrant a larger confirmatory study.

CD200+ fibroblasts form a pro-resolving mesenchymal network in arthritis.

Fibroblasts are important regulators of inflammation, but whether fibroblasts change phenotype during resolution of inflammation is not clear. Here we use positron emission tomography to detect fibroblast activation protein (FAP) as a means to visualize fibroblast activation in vivo during inflammation in humans. While tracer accumulation is high in active arthritis, it decreases after tumor necrosis factor and interleukin-17A inhibition. Biopsy-based single-cell RNA-sequencing analyses in experimental arthritis show that FAP signal reduction reflects a phenotypic switch from pro-inflammatory MMP3+/IL6+ fibroblasts (high FAP internalization) to pro-resolving CD200+DKK3+ fibroblasts (low FAP internalization). Spatial transcriptomics of human joints indicates that pro-resolving niches of CD200+DKK3+ fibroblasts cluster with type 2 innate lymphoid cells, whereas MMP3+/IL6+ fibroblasts colocalize with inflammatory immune cells. CD200+DKK3+ fibroblasts stabilized the type 2 innate lymphoid cell phenotype and induced resolution of arthritis via CD200-CD200R1 signaling. Taken together, these data suggest a dynamic molecular regulation of the mesenchymal compartment during resolution of inflammation.

Pre-assessment of patients with suspected axial spondyloarthritis combining student-led clinics and telemedicine: a qualitative study.

OBJECTIVE: Patients referred to rheumatologists are currently facing months of inefficient waiting time due to the increasing demand and rising workforce shortage. We piloted a pre-assessment of patients with suspected axial spondyloarthritis (axSpA) combining student-led clinics and telemedicine (symptom assessment, symptom monitoring and at-home capillary self-sampling) to improve access to rheumatology care. The aim of this study was to explore (1) current challenges accessing axSpA care and (2) patients' first-hand experiences. METHODS: Embedded within a clinical trial, this study was based on qualitative interviews with patients with suspected axSpA (n = 20). Data was analysed via qualitative content analysis. RESULTS: Student-led clinics were perceived as high-quality care, comparable to conventional rheumatologist-led visits. Patients expressed that their interactions with the students instilled a sense of trust. History-taking and examinations were perceived as comprehensive and meticulous. Telehealth tools were seen as empowering, offering immediate and continuous access to symptom assessment at home. Patients reported a lack of specificity of the electronic questionnaires, impeding accurate responses. Patients requested a comments area to supplement questionnaire responses. Some patients reported receiving help to complete the blood collection. CONCLUSION: Patients' access to rheumatology care is becoming increasingly burdensome. Pre-assessment including student-led clinics and telemedicine was highly accepted by patients. Patient interviews provided valuable in-depth feedback to improve the piloted patient pathway.

Case Report: Effectiveness of secukinumab in systemic sclerosis with early skin progress after autologous hematopoietic stem cell transplantation and end-stage kidney disease.

Autologous hematopoietic stem cell transplantation (aHSCT) represents an effective treatment option in patients with severe forms of systemic sclerosis (SSc) by resetting the immune system. Nevertheless, secondary autoimmune disorders and progressive disease after aHSCT might necessitate renewed immunosuppressive treatments. This is particularly challenging when organ dysfunction, i.e., end-stage kidney failure, is present. In this case report, we present the unique case of a 43-year-old female patient with rapidly progressive diffuse systemic sclerosis who underwent aHSCT despite end-stage renal failure as consequence of SSc-renal crisis. Therefore, conditioning chemotherapy was performed with melphalan instead of cyclophosphamide with no occurrence of severe adverse events during the aplastic period and thereafter. After aHSCT, early disease progression of the skin occurred and was successfully treated with secukinumab. Thereby, to the best of our knowledge, we report the first case of successful aHSCT in a SSc-patient with end-stage kidney failure and also the first successful use of an IL-17 inhibitor to treat early disease progression after aHSCT.

Student-led clinics and ePROs to accelerate diagnosis and treatment of patients with axial spondyloarthritis: results from a prospective pilot study.

We aimed to investigate (1) student-led clinics and (2) electronic patient-reported outcomes (ePROs) to accelerate diagnosis and treatment of patients with axial spondyloarthritis (axSpA). Patients with suspected axSpA completed an initial student-led clinic visit (T-1) prior to their planned actual rheumatologist visit (T0). Acceleration of patient appointment and NSAID therapy start, availability of diagnostic findings, and treatment response at T0 were evaluated. Beginning at T-1, patients completed electronic BASDAI questionnaires every 2 weeks. Concordance of paper-based and electronic BASDAI was evaluated. Patient acceptance of ePRO reporting and student-led clinics was measured using the net promoter score (NPS). 17/36 (47.2%) included patients were diagnosed with axSpA. Student-led clinics (T-1) significantly accelerated patient appointments by more than 2 months (T0, T-1, p < 0.0001) and axSpA guideline-conform NSAID treatment (p < 0.0001). At T0, diagnostic workup was completed for all patients and 7/17 (41.2%) axSpA patients presented with a clinically important improvement or were in remission. 34/36 (94.4%) patients completed at least 80% of the ePROs between T-1 and T0. Electronic and paper-administered BASDAI correlated well (r = 0.8 p < 0.0001). Student-led clinics and ePROs were well accepted by patients with NPS scores of + 62.0% (mean ± SD 9.2/10.0 ± 0.9) and + 30.5% (mean ± SD 8.0/10.0 ± 1.7), respectively. In conclusion, student-led clinics and ePRO monitoring were well accepted, accelerated diagnostic workup and treatment in patients with axSpA.

An AI-Powered Clinical Decision Support System to Predict Flares in Rheumatoid Arthritis: A Pilot Study.

Treat-to-target (T2T) is a main therapeutic strategy in rheumatology; however, patients and rheumatologists currently have little support in making the best treatment decision. Clinical decision support systems (CDSSs) could offer this support. The aim of this study was to investigate the accuracy, effectiveness, usability, and acceptance of such a CDSS-Rheuma Care Manager (RCM)-including an artificial intelligence (AI)-powered flare risk prediction tool to support the management of rheumatoid arthritis (RA). Longitudinal clinical routine data of RA patients were used to develop and test the RCM. Based on ten real-world patient vignettes, five physicians were asked to assess patients' flare risk, provide a treatment decision, and assess their decision confidence without and with access to the RCM for predicting flare risk. RCM usability and acceptance were assessed using the system usability scale (SUS) and net promoter score (NPS). The flare prediction tool reached a sensitivity of 72%, a specificity of 76%, and an AUROC of 0.80. Perceived flare risk and treatment decisions varied largely between physicians. Having access to the flare risk prediction feature numerically increased decision confidence (3.5/5 to 3.7/5), reduced deviations between physicians and the prediction tool (20% to 12% for half dosage flare prediction), and resulted in more treatment reductions (42% to 50% vs. 20%). RCM usability (SUS) was rated as good (82/100) and was well accepted (mean NPS score 7/10). CDSS usage could support physicians by decreasing assessment deviations and increasing treatment decision confidence.

Real-world usage of digital health applications (DiGA) in rheumatology: results from a German patient survey.

Mobile health applications and digital therapeutics (DTx) aim to improve current patient care. Real-world data on DTx are, however, scarce. The aim of this study was to evaluate the adherence, acceptance, and efficacy of DTx in a clinical routine rheumatology setting. We conducted a prospective observational cohort study assessing the use, adherence, acceptance, and efficacy of the DTx DiGA (Digitale Gesundheitsanwendungen) by survey over 12 weeks. Patients included had to have a rheumatic disease and had been prescribed a DiGA. Acceptance was assessed using the Net promoter score (NPS). 48 patients were prescribed DiGA. Of these, 39/48 (81%) completed the follow-up survey. 21/39 (54%) patients downloaded the DTx and 20/39 (51%) used the DTx at least once. 9/39 (23%) of patients stopped quickly afterward and 5/39 (13%) reported having completed the whole DTx program. Lack of time and commitment were reported as the main reasons for non-use. Overall acceptance of DiGA was high (Net promoter score (NPS) mean (SD) 7.8/10 (2.3)). While the majority of patients (60%) reported no improvement, one subgroup of patients (7/20, 35%) who regularly used an exercise-based DTx for back pain reported symptom improvement. Acceptance of DTx in patients with rheumatic diseases is high, however onboarding to DTx use and adherence to DTx is still challenging in patients with rheumatic diseases. In a subgroup of patients with back pain, however, the use of an exercise-based DTx led to symptom improvement.

Digitally supported shared decision-making and treat-to-target in rheumatology: a qualitative study embedded in a multicenter randomized controlled trial.

Patient-reported outcomes (PRO) represent a cornerstone in the management of patients with rheumatoid arthritis (RA). However, PRO are currently recorded mainly on paper and only during on-site appointments. Electronic PRO (ePRO) enable continuous remote monitoring and could improve shared decision-making (SDM) and implementation of a treat-to-target (T2T) approach. This study aims to investigate patient and physician experiences, perceived drawbacks and benefits of using an ePRO web-app (ABATON RA) to digitally support SDM and T2T. A qualitative study embedded in a multicenter randomized controlled trial (RCT) consisting of interviews with RA patients and physicians that were subsequently analyzed using deductive-inductive qualitative content analysis. Between August 2021 and May 2022, interviews with ten RA patients and five physicians were completed. Three key themes emerged in the analysis: (i) App user experiences; (ii) perceived drawbacks of app-supported rheumatology care; and (iii) perceived benefits of app-supported rheumatology care. Continuous ePRO collection and a high level of standardization strained some RA patients. Certain ePRO seemed outdated and were hard to understand. Patients and physicians appreciated having an improved overview of disease activity, capturing disease flares and continuous remote monitoring. Paper- and time-saving were associated with using ePRO. Physicians feared to become too focused on ePRO data, stressed the lack of ePRO monitoring reimbursement and app interoperability. For RA patients and physicians, benefits seemed to outweigh observed drawbacks of the digitally supported SDM using ePRO. The software was easy to use and could lead to a better understanding of the individual disease course, resource allocation and treatment of rheumatoid arthritis.

At-home blood self-sampling in rheumatology: a qualitative study with patients and health care professionals.

BACKGROUND: The goal of the study was to investigate patients' with systemic rheumatic diseases and healthcare professionals' experiences and preferences regarding self-sampling of capillary blood in rheumatology care. METHODS: Patients performed a supervised and consecutive unsupervised capillary blood self-collection using an upper arm based device. Subsequently, patients (n = 15) and their attending health care professionals (n = 5) participated in an explorative, qualitative study using problem-centered, telephone interviews. Interview data were analyzed using structured qualitative content analysis. RESULTS: Interviewed patients reported easy application and high usability. Patients and health care professionals alike reported time and cost savings, increased independence and flexibility, improved monitoring and reduction of risk of infection during Covid-19 as benefits. Reported drawbacks include limited blood volume, limited usability in case of functional restrictions, and environmental concerns. Older, immobile patients with long journeys to traditional blood collection sites and young patients with little time to spare for traditional blood collection appointments could be user groups, likely to benefit from self-sampling services. CONCLUSIONS: At-home blood self-sampling could effectively complement current rheumatology telehealth care. Appropriateness and value of this service needs to be carefully discussed with patients on an individual basis. TRIAL REGISTRATION: WHO International Clinical Trials Registry: DRKS00024925. Registered on 15/04/2021.

Digitally-supported patient-centered asynchronous outpatient follow-up in rheumatoid arthritis - an explorative qualitative study.

OBJECTIVE: A steadily increasing demand and decreasing number of rheumatologists push current rheumatology care to its limits. Long travel times and poor accessibility of rheumatologists present particular challenges for patients. Need-adapted, digitally supported, patient-centered and flexible models of care could contribute to maintaining high-quality patient care. This qualitative study was embedded in a randomized controlled trial (TELERA) investigating a new model of care consisting of the use of a medical app for ePRO (electronic patient-reported outcomes), a self-administered CRP (C-reactive protein) test, and joint self-examination in rheumatoid arthritis (RA) patients. The qualitative study aimed to explore experiences of RA patients and rheumatology staff regarding (1) current care and (2) the new care model. METHODS: The study included qualitative interviews with RA patients (n = 15), a focus group with patient representatives (n = 1), rheumatology nurses (n = 2), ambulatory rheumatologists (n = 2) and hospital-based rheumatologists (n = 3). Data was analyzed by qualitative content analysis. RESULTS: Participants described current follow-up care as burdensome. Patients in remission have to travel long distances. Despite pre-scheduled visits physicians lack questionnaire results and laboratory results to make informed shared decisions during face-to-face visits. Patients reported that using all study components (medical app for ePRO, self-performed CRP test and joint self-examination) was easy and helped them to better assess their disease condition. Parts of the validated questionnaire used in the trial (routine assessment of patient index data 3; RAPID3) seemed outdated or not clear enough for many patients. Patients wanted to be automatically contacted in case of abnormalities or at least have an app feature to request a call-back or chat. Financial and psychological barriers were identified among rheumatologists preventing them to stop automatically scheduling new appointments for patients in remission. Rheumatology nurses pointed to the potential lack of personal contact, which may limit the holistic care of RA-patients. CONCLUSION: The new care model enables more patient autonomy, allowing patients more control and flexibility at the same time. All components were well accepted and easy to carry out for patients. To ensure success, the model needs to be more responsive and allow seamless integration of education material. TRIAL REGISTRATION: The study was prospectively registered on 2021/04/09 at the German Registry for Clinical Trials (DRKS00024928).

Concise report: a minimal-invasive method to retrieve and identify entheseal tissue from psoriatic arthritis patients.

OBJECTIVES: To establish a minimally invasive biopsy technique for the analysis of entheseal tissue in patients with psoriatic arthritis (PsA). METHODS: Human cadavers were used for establishing the technique to retrieve tissue from the lateral humeral epicondyle enthesis (cadaveric biopsies). After biopsy, the entire enthesis was surgically resected (cadaveric resections). Biopsies and resections were assessed by label-free second harmonic generation (SHG) microscopy. The same technique was then applied in patients with PsA with definition of entheseal tissue by SHG, staining of CD45+immune cells and RNA extraction. RESULTS: Entheseal biopsies from five cadavers allowed the retrieval of entheseal tissue as validated by the analysis of resection material. Microscopy of biopsy and resection sections allowed differentiation of entheseal, tendon and muscle tissue by SHG and definition of specific intensity thresholds for entheseal tissue. In subsequent entheseal biopsies of 10 PsA patients: the fraction of entheseal tissue was high (65%) and comparable to cadaveric biopsies (68%) as assessed by SHG microscopy. Furthermore, PsA biopsies showed immune cell infiltration and sufficient retrieval of RNA for further molecular analysis. CONCLUSION: Entheseal biopsy of the lateral epicondyle is feasible in patients with PsA allowing reliable retrieval of entheseal tissue and its identification by SHG microscopy.

Patient's Perception of Digital Symptom Assessment Technologies in Rheumatology: Results From a Multicentre Study.

Introduction: An increasing number of digital tools, including dedicated diagnostic decision support systems (DDSS) exist to better assess new symptoms and understand when and where to seek medical care. The aim of this study was to evaluate patient's previous online assessment experiences and to compare the acceptability, usability, usefulness and potential impact of artificial intelligence (AI)-based symptom checker (Ada) and an online questionnaire-based self-referral tool (Rheport). Materials and Methods: Patients newly presenting to three German secondary rheumatology outpatient clinics were randomly assigned in a 1:1 ratio to complete consecutively Ada or Rheport in a prospective non-blinded multicentre controlled crossover randomized trial. DDSS completion time was recorded by local study personnel and perceptions on DDSS and previous online assessment were collected through a self-completed study questionnaire, including usability measured with the validated System Usability Scale (SUS). Results: 600 patients (median age 52 years, 418 women) were included. 277/600 (46.2%) of patients used an online search engine prior to the appointment. The median time patients spent assessing symptoms was 180, 7, and 8 min, respectively using online using search engines, Ada and Rheport. 111/275 (40.4%), 266/600 (44.3%) and 395/600 (65.8%) of patients rated the respective symptom assessment as very helpful or helpful, using online search engines, Ada and Rheport, respectively. Usability of both diagnostic decision support systems (DDSS) was "good" with a significantly higher mean SUS score (SD) of Rheport 77.1/100 (16.0) compared to Ada 74.4/100 (16.8), (p < 0.0001). In male patients, usability of Rheport was rated higher than Ada (p = 0.02) and the usability rating of older (52 years ≥) patients of both DDSS was lower than in younger participants (p = 0.005). Both effects were independent of each other. 440/600 (73.3%) and 475/600 (79.2%) of the patients would recommend Ada and Rheport to friends and other patients, respectively. Conclusion: In summary, patients increasingly assess their symptoms independently online, however only a minority used dedicated symptom assessment websites or DDSS. DDSS, such as Ada an Rheport are easy to use, well accepted among patients with musculoskeletal complaints and could replace online search engines for patient symptom assessment, potentially saving time and increasing helpfulness.

Altered molecular pathways and prognostic markers in active systemic juvenile idiopathic arthritis: integrated bioinformatic analysis.

Systemic juvenile idiopathic arthritis (SJIA) is a severe childhood-onset inflammatory disease characterized by arthritis accompanied by systemic auto-inflammation and extra-articular symptoms. While recent advances have unraveled a range of risk factors, the pathomechanisms involved in SJIA and potential prognostic markers for treatment success remain partly unknown. In this study, we included 70 active SJIA and 55 healthy control patients from the National Center for Biotechnology Information to analyze for differentially expressed genes (DEGs) using R. Functional enrichment analysis, protein-protein interaction (PPI), and gene module construction were performed for DEGs and hub gene set. We additionally examined immune system cell composition with CIBERSORT and predicted prognostic markers and potential treatment drugs for SJIA. In total, 94 upregulated and 24 downregulated DEGs were identified. Two specific modules of interest and eight hub genes (ARG1, DEFA4, HP, MMP8, MMP9, MPO, OLFM4, PGLYRP1) were screened out. Functional enrichment analysis suggested that complex neutrophil-related functions play a decisive role in the disease pathogenesis. CIBERSORT indicated neutrophils, M0 macrophages, CD8+ T cells, and naïve B cells to be relevant drivers of disease progression. Additionally, we identified TPM2 and GZMB as potential prognostic markers for treatment response to canakinumab. Moreover, sulindac sulfide, (-)-catechin, and phenanthridinone were identified as promising treatment agents. This study provides a new insight into molecular and cellular pathogenesis of active SJIA and highlights potential targets for further research.

Multiparameter Analysis Identifies Heterogeneity in Knee Osteoarthritis Synovial Responses.

OBJECTIVE: Synovial membrane inflammation is common in osteoarthritis (OA) and increases cartilage injury. However, synovial fluid and histology studies suggest that OA inflammatory responses are not homogeneous. Greater understanding of these responses may provide new insights into OA disease mechanisms. We undertook this study to develop a novel multiparameter approach to phenotype synovial responses in knee OA. METHODS: Cell composition and soluble protein production were measured by flow cytometry and multiplex enzyme-linked immunosorbent assay in synovium collected from OA patients undergoing knee replacement surgery (n = 35). RESULTS: Testing disaggregation conditions showed that aggressive digestion improved synovial cell yield and mesenchymal staining by flow cytometry, but it negatively impacted CD4+ T cell and CD56+ natural killer cell staining. Less aggressive digestion preserved these markers and showed highly variable T cell infiltration (range 0-43%; n = 32). Correlation analysis identified mesenchymal subpopulations associated with different nonmesenchymal populations, including macrophages and T cells (CD45+CD11b+HLA-DR+ myeloid cells with PDPN+CD73+CD90-CD34- mesenchymal cells [r = 0.65, P < 0.0001]; and CD45+CD3+ T cells with PDPN+CD73+CD90+CD34+ mesenchymal cells [r = 0.50, P = 0.003]). Interleukin-6 (IL-6) measured by flow cytometry strongly correlated with IL-6 released by ex vivo culture of synovial tissue (r = 0.59, P = 0.0012) and was highest in mesenchymal cells coexpressing CD90 and CD34. IL-6, IL-8, complement factor D, and IL-10 release correlated positively with tissue cellularity (P = 0.0042, P = 0.018, P = 0.0012, and P = 0.038, respectively). Additionally, increased CD8+ T cell numbers correlated with retinol binding protein 4 (P = 0.033). Finally, combining flow cytometry and multiplex data identified patient clusters with different types of inflammatory responses. CONCLUSION: We used a novel approach to analyze OA synovium, identifying patient-specific inflammatory clusters. Our findings indicate that phenotyping synovial inflammation may provide new insights into OA patient heterogeneity and biomarker development.