Global collaboration is the cornerstone of scientific advancement. Frontiers in Medicine has organized a series of special edition Research Topics, with the goal of highlighting the latest advancements in Rheumatology across the globe, showcasing the academic excellence and high-quality work of internationally recognized researchers. These collections aim to shed light on the recent progress made across the entire breadth of the field, and reflect on the future challenges faced by researchers across borders.

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King's College Hospital NHS Foundation Trust

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Frontiers in Medicine

Rheumatology

Global Excellence in Rheumatology: Europe

Rheumatology is a rapidly evolving specialty where major breakthroughs have been produced in recent years, from a paradigm change in clinical management of rheumatic and musculoskeletal diseases (RMDs) to the discovery of novel drugs and biological agents to manipulate the immune response in the context of autoimmunity and autoinflammation. European rheumatology is to be commended for its contribution to the global excellence in rheumatology worldwide, including the development of evidence-based consensus recommendations for clinical management (<a href="#B1">1</a>, <a href="#B2">2</a>), the development of robust methodologies to combine efforts from all stakeholders (rheumatologists, researchers, health professionals in rheumatology and people with RMDs) (<a href="#B3">3</a>), the establishment of international collaborations across European countries using registries and databases (<a href="#B4">4</a>–<a href="#B6">6</a>), and the harmonization of training programs (<a href="#B7">7</a>). Several of these achievements can be largely connected to the leadership of a common entity, the European Alliance of Rheumatology Associations (EULAR), who has served as an umbrella for clinical and research affairs in this setting. The present Research Topic provides a summary of the European excellence in rheumatology, covering the whole range from clinical science to basic and translational research, using a number of different approaches.The need for novel targets in RMDs is an area of constant research, with the aims not only of establishing personalized medicine approaches but also to expand and refine the therapeutic armamentarium. This point is addressed in the present Research Topic in a series of review articles focused on two of the most prevalent immune-mediated RMDs: systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). <a href="https://doi.org/10.3389/fmed.2022.952304">Parodis et al.</a> comprehensively summarized the potential of B-cell altering therapeutics, including B-cells, B-cell related cytokines, and plasma cells, as well as combination strategies. A special emphasis is made in the promising role of B-cells as biomarkers to guide such strategies, with the aim of maximizing clinical benefit, although the exact readouts are yet to be identified. In the case of RA, <a href="https://doi.org/10.3389/fmed.2023.956127">Gremese et al.</a> advocated for the therapeutic potential of IL-8- and IL-17-targeted approaches based on the pathogenic role of these two molecules. In fact, this may explain at least in part the inadequate response of a proportion of RA patients to biological therapies with other mechanisms of action. A series of elegant experiments in animal and in vitro models as well as evidence from synovial studies reinforced this rationale, and candidate approaches, such as bi-specific antibodies or JAK inhibitors are discussed.Basic and translational science has been also instrumental in expanding both the knowledge on RMDs pathogenesis and the therapeutic armamentarium. <a href="https://doi.org/10.3389/fmed.2023.1029021">Barker et al.</a> have reported a significant dysregulation of the mTOR pathway at synovial tissue level, also related to alterations in the Hippo-YAP pathway, leading to immunometabolism traits. The inhibitory effect of rapamycin may pave the ground for novel therapeutic strategies focused on these pathways.The present Research Topic also showcases different examples of excellence in clinical science. In benefit of solid, evidence-based and good practices in research, the registration of study protocols (beyond industry-sponsored clinical trials) has become more frequent in recent years, and it is usually mandatory for certain institution and funding agencies. Following this step, <a href="https://doi.org/10.3389/fmed.2022.871744">Rademacher et al.</a> have presented their protocol to evaluate the feasibility of rheopheresis for Raynaud's syndrome and digital ulcers in systemic sclerosis, also including a number of secondary endpoints (from imaging to patient-reported outcomes). The results of this apheresis approach are much awaited, since current evidence relies on retrospective studies or case reports, thus limiting clinical application. Another clinical study has shed new light on a highly relevant, although usually less attended, topic in RMDs care: the work participation. <a href="https://doi.org/10.3389/fmed.2022.881943">Dejaco et al.</a> demonstrated that treatment with golimumab, a biological disease-modifying antirheumatic drug that blocks TNF, led to a significant improvement in work productivity and activity in real-world patients with RA, psoriatic arthritis and axial spondyloarthritis, with no major differences across the three patient groups. Although limited in follow-up (24 months), these results warrant further research into this area, with the ultimate goal of reducing work impairment in people with RMDs. Whether work participation outcomes should be considered to guide treatment recommendations need to be considered in future guidelines.Finally, it must be recognized how much artificial intelligence and machine learning techniques are shaping our world and the way we interact with our environment, either in professional or personal domains (<a href="#B8">8</a>). The paper by <a href="https://doi.org/10.3389/fmed.2022.954056">Knitza et al.</a> introduces how machine learning approaches can be used to improve a rheumatology referral system, by including laboratory parameters and enabling individual feature adaptations. In a system of increasing clinical pressure and overloaded staff, machine learning approaches show promise to improve early referrals, a major unmet need in the clinical care of RMDs. Additionally, it may also have several benefits in the implementation of telemedicine in rheumatology, particularly in the post-COVID-19 era. However, trials addressing cost-effectiveness, clinical validation and cross-cultural adaptations are needed.In summary, even in a challenging momentum for health systems, European rheumatology continues to show its hallmarks as a pioneer specialty. Multi-level approaches, high standards and solid methodological procedures to solve complex questions and cover the whole disease process are the pillars of the excellence of European rheumatology, with the ultimate goals of improving clinical care and patients&apos; lives.JR-C edited the final version of the manuscript. All authors drafted, revised the manuscript, and approved the final version of the manuscript.JR-C is supported by European Union FEDER funds and Fondo de Investigaci&#xf3;n Sanitaria from Instituto de Salud Carlos III (ISCIII) (reference PI21/00054). MJ is funded by a National Institute for Health Research (NIHR) Advanced Fellowship (NIHR301413).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.The views expressed in this publication are those of the authors and not necessarily those of the NIHR, NHS or the UK Department of Health and Social Care.

Editorial: Global excellence in rheumatology: Europe

Despite the relevant advances in our understanding of the pathogenetic mechanisms regulating inflammation in rheumatoid arthritis (RA) and the development of effective therapeutics, to date, there is still a proportion of patients with RA who do not respond to treatment and end up progressing toward the development of joint damage, extra-articular complications, and disability. This is mainly due to the inter-individual heterogeneity of the molecular and cellular taxonomy of the synovial membrane, which represents the target tissue of RA inflammation. Tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) are crucial key players in RA pathogenesis fueling the inflammatory cascade, as supported by experimental evidence derived from in vivo animal models and the effectiveness of biologic-Disease Modifying Anti-Rheumatic Drugs (b-DMARDs) in patients with RA. However, additional inflammatory soluble mediators such as IL-8 and IL-17 exert their pathogenetic actions promoting the detrimental activation of immune and stromal cells in RA synovial membrane, tendons, and extra-articular sites, as well as blood vessels and lungs, causing extra-articular complications, which might be excluded by the action of anti-TNFα and anti-IL6R targeted therapies. In this narrative review, we will discuss the role of IL-8 and IL-17 in promoting inflammation in multiple biological compartments (i.e., synovial membrane, blood vessels, and lung, respectively) in animal models of arthritis and patients with RA and how their selective targeting could improve the management of treatment resistance in patients.

Despite the relevant advances in our understanding of the pathogenetic mechanisms regulating inflammation in rheumatoid arthritis (RA) and the development of effective therapeutics, to date, there is still a proportion of patients with RA who do not respond to treatment and end up progressing toward the development of joint damage, extra-articular complications, and disability. This is mainly due to the inter-individual heterogeneity of the molecular and cellular taxonomy of the synovial membrane, which represents the target tissue of RA inflammation. Tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) are crucial key players in RA pathogenesis fueling the inflammatory cascade, as supported by experimental evidence derived from in vivo animal models and the effectiveness of biologic-Disease Modifying Anti-Rheumatic Drugs (b-DMARDs) in patients with RA. However, additional inflammatory soluble mediators such as IL-8 and IL-17 exert their pathogenetic actions promoting the detrimental activation of immune and stromal cells in RA synovial membrane, tendons, and extra-articular sites, as well as blood vessels and lungs, causing extra-articular complications, which might be excluded by the action of anti-TNFα and anti-IL6R targeted therapies. In this narrative review, we will discuss the role of IL-8 and IL-17 in promoting inflammation in multiple biological compartments (i.e., synovial membrane, blood vessels, and lung, respectively) in animal models of arthritis and patients with RA and how their selective targeting could improve the management of treatment resistance in patients.

The forgotten key players in rheumatoid arthritis: IL-8 and IL-17 – Unmet needs and therapeutic perspectives

ObjectivesThe mammalian target of Rapamycin (mTOR) is a metabolic master regulator of both innate and adaptive immunity; however, its exact role in stromal cell biology is unknown. In this study we explored the role of the mTOR pathway on Rheumatoid Arthritis synovial fibroblast (RASF) metabolism and activation and determined if crosstalk with the Hippo-YAP pathway mediates their effects.</sec>MethodsPrimary RA synovial fibroblasts (RASF) were cultured with TNFα alone or in combination with the mTOR inhibitor Rapamycin or YAP inhibitor Verteporfin. Chemokine production, matrix metalloproteinase (MMP) production, and adhesion marker expression were quantified by real-time PCR, ELISA, and/or Flow Cytometry. Invasion assays were performed using Transwell invasion chambers, while wound repair assays were used to assess RASF migration. Cellular bioenergetics was assessed using the Seahorse XFe96 Analyzer. Key metabolic genes (GLUT-1, HK2, G6PD) were measured using real-time PCR. Reanalysis of RNA-Seq analysis was performed on RA (n = 151) and healthy control (HC) (n = 28) synovial tissue biopsies to detect differential gene and pathway expression. The expression of YAP was measured by Western Blot.</sec>ResultsTranscriptomic analysis of healthy donor and RA synovial tissue revealed dysregulated expression of several key components of the mTOR pathway in RA. Moreover, the expression of phospho-ribosomal protein S6 (pS6), the major downstream target of mTOR is specifically increased in RA synovial fibroblasts compared to healthy tissue. In the presence of TNFα, RASF display heightened phosphorylation of S6 and are responsive to mTOR inhibition via Rapamycin. Rapamycin effectively alters RASF cellular bioenergetics by inhibiting glycolysis and the expression of rate limiting glycolytic enzymes. Furthermore, we demonstrate a key role for mTOR signaling in uniquely mediating RASF migratory and invasive mechanisms, which are significantly abrogated in the presence of Rapamycin. Finally, we report a significant upregulation in several genes involved in the Hippo-YAP pathway in RA synovial tissue, which are predicted to converge with the mTOR pathway. We demonstrate crosstalk between the mTOR and YAP pathways in mediating RASF invasive mechanism whereby Rapamycin significantly abrogates YAP expression and YAP inhibition significantly inhibits RASF invasiveness.</sec>ConclusionmTOR drives pathogenic mechanisms in RASF an effect which is in part mediated via crosstalk with the Hippo-YAP pathway.</sec>

Objectives: The mammalian target of Rapamycin (mTOR) is a metabolic master regulator of both innate and adaptive immunity; however, its exact role in stromal cell biology is unknown. In this study we explored the role of the mTOR pathway on Rheumatoid Arthritis synovial fibroblast (RASF) metabolism and activation and determined if crosstalk with the Hippo-YAP pathway mediates their effects.Methods: Primary RA synovial fibroblasts (RASF) were cultured with TNFα alone or in combination with the mTOR inhibitor Rapamycin or YAP inhibitor Verteporfin. Chemokine production, matrix metalloproteinase (MMP) production, and adhesion marker expression were quantified by real-time PCR, ELISA, and/or Flow Cytometry. Invasion assays were performed using Transwell invasion chambers, while wound repair assays were used to assess RASF migration. Cellular bioenergetics was assessed using the Seahorse XFe96 Analyzer. Key metabolic genes (GLUT-1, HK2, G6PD) were measured using real-time PCR. Reanalysis of RNA-Seq analysis was performed on RA (n = 151) and healthy control (HC) (n = 28) synovial tissue biopsies to detect differential gene and pathway expression. The expression of YAP was measured by Western Blot.Results: Transcriptomic analysis of healthy donor and RA synovial tissue revealed dysregulated expression of several key components of the mTOR pathway in RA. Moreover, the expression of phospho-ribosomal protein S6 (pS6), the major downstream target of mTOR is specifically increased in RA synovial fibroblasts compared to healthy tissue. In the presence of TNFα, RASF display heightened phosphorylation of S6 and are responsive to mTOR inhibition via Rapamycin. Rapamycin effectively alters RASF cellular bioenergetics by inhibiting glycolysis and the expression of rate limiting glycolytic enzymes. Furthermore, we demonstrate a key role for mTOR signaling in uniquely mediating RASF migratory and invasive mechanisms, which are significantly abrogated in the presence of Rapamycin. Finally, we report a significant upregulation in several genes involved in the Hippo-YAP pathway in RA synovial tissue, which are predicted to converge with the mTOR pathway. We demonstrate crosstalk between the mTOR and YAP pathways in mediating RASF invasive mechanism whereby Rapamycin significantly abrogates YAP expression and YAP inhibition significantly inhibits RASF invasiveness.Conclusion: mTOR drives pathogenic mechanisms in RASF an effect which is in part mediated via crosstalk with the Hippo-YAP pathway.

The mammalian target of rapamycin contributes to synovial fibroblast pathogenicity in rheumatoid arthritis

B cell hyperactivity is a hallmark of the complex autoimmune disease systemic lupus erythematosus (SLE), which has justified drug development focusing on B cell altering agents during the last decades, as well as the off-label use of B cell targeting biologics. About a decade ago, the anti-B cell activating factor (BAFF) belimumab was the first biological agent to be licensed for the treatment of adult patients with active yet non-renal and non-neuropsychiatric SLE, to later be expanded to include treatment of pediatric SLE and, recently, lupus nephritis. B cell depletion is recommended as an off-label option in refractory cases, with the anti-CD20 rituximab having been the most used B cell depleting agent to date while agents with a slightly different binding specificity to CD20 such as obinutuzumab have also shown promise, forming a part of the current pipeline. In addition, terminally differentiated B cells have also been the targets of experimental therapies, with the proteasome inhibitor bortezomib being one example. Apart from being promising drug targets, B and plasma cells have also shown promise in the surveillance of patients with SLE, especially for monitoring B cell depleting or B cell altering therapies. Inadequate B cell depletion may signify poor expected clinical response to rituximab, for example, while prominent reductions in certain B cell subsets may signify a protection against flare development in patients treated with belimumab. Toward an era with a richer therapeutic armamentarium in SLE, including to a large extent B cell altering treatments, the challenge that emerges is to determine diagnostic means for evidence-based therapeutic decision-making, that uses clinical information, serological markers, and gene expression patterns to guide individualized precision strategies.

B cell hyperactivity is a hallmark of the complex autoimmune disease systemic lupus erythematosus (SLE), which has justified drug development focusing on B cell altering agents during the last decades, as well as the off-label use of B cell targeting biologics. About a decade ago, the anti-B cell activating factor (BAFF) belimumab was the first biological agent to be licensed for the treatment of adult patients with active yet non-renal and non-neuropsychiatric SLE, to later be expanded to include treatment of pediatric SLE and, recently, lupus nephritis. B cell depletion is recommended as an off-label option in refractory cases, with the anti-CD20 rituximab having been the most used B cell depleting agent to date while agents with a slightly different binding specificity to CD20 such as obinutuzumab have also shown promise, forming a part of the current pipeline. In addition, terminally differentiated B cells have also been the targets of experimental therapies, with the proteasome inhibitor bortezomib being one example. Apart from being promising drug targets, B and plasma cells have also shown promise in the surveillance of patients with SLE, especially for monitoring B cell depleting or B cell altering therapies. Inadequate B cell depletion may signify poor expected clinical response to rituximab, for example, while prominent reductions in certain B cell subsets may signify a protection against flare development in patients treated with belimumab. Toward an era with a richer therapeutic armamentarium in SLE, including to a large extent B cell altering treatments, the challenge that emerges is to determine diagnostic means for evidence-based therapeutic decision-making, that uses clinical information, serological markers, and gene expression patterns to guide individualized precision strategies.

B cells in systemic lupus erythematosus: Targets of new therapies and surveillance tools

IntroductionRheport is an online rheumatology referral system allowing automatic appointment triaging of new rheumatology patient referrals according to the respective probability of an inflammatory rheumatic disease (IRD). Previous research reported that Rheport was well accepted among IRD patients. Its accuracy was, however, limited, currently being based on an expert-based weighted sum score. This study aimed to evaluate whether machine learning (ML) models could improve this limited accuracy.</sec>Materials and methodsData from a national rheumatology registry (RHADAR) was used to train and test nine different ML models to correctly classify IRD patients. Diagnostic performance was compared of ML models and the current algorithm was compared using the area under the receiver operating curve (AUROC). Feature importance was investigated using shapley additive explanation (SHAP).</sec>ResultsA complete data set of 2265 patients was used to train and test ML models. 30.5% of patients were diagnosed with an IRD, 69.3% were female. The diagnostic accuracy of the current Rheport algorithm (AUROC of 0.534) could be improved with all ML models, (AUROC ranging between 0.630 and 0.737). Targeting a sensitivity of 90%, the logistic regression model could double current specificity (17% vs. 33%). Finger joint pain, inflammatory marker levels, psoriasis, symptom duration and female sex were the five most important features of the best performing logistic regression model for IRD classification.</sec>ConclusionIn summary, ML could improve the accuracy of a currently used rheumatology online referral system. Including further laboratory parameters and enabling individual feature importance adaption could increase accuracy and lead to broader usage.</sec>

Introduction: Rheport is an online rheumatology referral system allowing automatic appointment triaging of new rheumatology patient referrals according to the respective probability of an inflammatory rheumatic disease (IRD). Previous research reported that Rheport was well accepted among IRD patients. Its accuracy was, however, limited, currently being based on an expert-based weighted sum score. This study aimed to evaluate whether machine learning (ML) models could improve this limited accuracy.Materials and methods: Data from a national rheumatology registry (RHADAR) was used to train and test nine different ML models to correctly classify IRD patients. Diagnostic performance was compared of ML models and the current algorithm was compared using the area under the receiver operating curve (AUROC). Feature importance was investigated using shapley additive explanation (SHAP).Results: A complete data set of 2265 patients was used to train and test ML models. 30.5% of patients were diagnosed with an IRD, 69.3% were female. The diagnostic accuracy of the current Rheport algorithm (AUROC of 0.534) could be improved with all ML models, (AUROC ranging between 0.630 and 0.737). Targeting a sensitivity of 90%, the logistic regression model could double current specificity (17% vs. 33%). Finger joint pain, inflammatory marker levels, psoriasis, symptom duration and female sex were the five most important features of the best performing logistic regression model for IRD classification.Conclusion: In summary, ML could improve the accuracy of a currently used rheumatology online referral system. Including further laboratory parameters and enabling individual feature importance adaption could increase accuracy and lead to broader usage.

Machine learning-based improvement of an online rheumatology referral and triage system

ObjectiveTo analyze real-world evidence on work productivity and daily activity impairment (WPAI) and health-related quality of life (HRQoL) in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) patients treated with golimumab in Austria.</sec>MethodsThis was a prospective, non-interventional, multi-center study conducted in RA, PsA and axSpA patients initiating golimumab between April 2016 and May 2020 in 40 centers in Austria. WPAI, HRQoL (RAQoL, ankylosing spondylitis (AS)QoL and PsAQoL) questionnaires and disease activity (Clinical Disease Activity Index, CDAI, in RA and PsA; Bath Ankylosing Spondylitis Disease Activity Index, BASDAI, in axSpA) were assessed at baseline and months 3, 6, 12, 18, and 24. Association between WPAI and disease activity was tested using linear regression.</sec>ResultsWe enrolled 233 patients (RA, n = 95; axSpA, n = 69; PsA, n = 69), 110 patients were followed up to month 24. Mean age was 50.2 ± 14.2 years; 64% were female. Disease activity decreased from baseline to month 24 (RA: CDAI −24.3 ± 13.5; axSpA: BASDAI −4.4 ± 2.1, and PsA: CDAI −21.7 ± 8.5, p < 0.0001, each). Total work productivity impairment (TWPI), activity impairment and presenteeism subscores continuously decreased throughout month 24 in all indications: RA (−58.3 ± 23%, −62.6 ± 23.8% and −61.7 ± 23.3%, respectively as compared to baseline; p < 0.0001, each), axSpA (−34.4 ± 38.3%, p = 0.0117; −60.9 ± 25.9%, and −43.8 ± 26.6%, respectively, p ≤ 0.0001 both) and PsA (−35.8 ± 43.7%, p = 0.0186; −52.3 ± 25.4%, p < 0.0001; and −43.3 ± 33.5%, p = 0.0007, respectively). Absenteeism scores decreased only in RA patients (−9.2 ± 24.9%, p = 0.0234). HRQoL improved between baseline and month 24 (RAQoL: −12.6 ± 7.5; ASQoL: −8.0 ± 4.3; PsAQoL; −8.3 ± 6.4, p < 0.0001, each). TWPI, presenteeism and activity impairment strongly associated with disease activity throughout the study.</sec>ConclusionsThis real-world study confirms the benefit of golimumab on work productivity/daily activity impairment in Austrian RA, PsA, and axSpA patients.</sec>

Objective: To analyze real-world evidence on work productivity and daily activity impairment (WPAI) and health-related quality of life (HRQoL) in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA) patients treated with golimumab in Austria.Methods: This was a prospective, non-interventional, multi-center study conducted in RA, PsA and axSpA patients initiating golimumab between April 2016 and May 2020 in 40 centers in Austria. WPAI, HRQoL (RAQoL, ankylosing spondylitis (AS)QoL and PsAQoL) questionnaires and disease activity (Clinical Disease Activity Index, CDAI, in RA and PsA; Bath Ankylosing Spondylitis Disease Activity Index, BASDAI, in axSpA) were assessed at baseline and months 3, 6, 12, 18, and 24. Association between WPAI and disease activity was tested using linear regression.Results: We enrolled 233 patients (RA, n = 95; axSpA, n = 69; PsA, n = 69), 110 patients were followed up to month 24. Mean age was 50.2 ± 14.2 years; 64% were female. Disease activity decreased from baseline to month 24 (RA: CDAI −24.3 ± 13.5; axSpA: BASDAI −4.4 ± 2.1, and PsA: CDAI −21.7 ± 8.5, p &lt; 0.0001, each). Total work productivity impairment (TWPI), activity impairment and presenteeism subscores continuously decreased throughout month 24 in all indications: RA (−58.3 ± 23%, −62.6 ± 23.8% and −61.7 ± 23.3%, respectively as compared to baseline; p &lt; 0.0001, each), axSpA (−34.4 ± 38.3%, p = 0.0117; −60.9 ± 25.9%, and −43.8 ± 26.6%, respectively, p ≤ 0.0001 both) and PsA (−35.8 ± 43.7%, p = 0.0186; −52.3 ± 25.4%, p &lt; 0.0001; and −43.3 ± 33.5%, p = 0.0007, respectively). Absenteeism scores decreased only in RA patients (−9.2 ± 24.9%, p = 0.0234). HRQoL improved between baseline and month 24 (RAQoL: −12.6 ± 7.5; ASQoL: −8.0 ± 4.3; PsAQoL; −8.3 ± 6.4, p &lt; 0.0001, each). TWPI, presenteeism and activity impairment strongly associated with disease activity throughout the study.Conclusions: This real-world study confirms the benefit of golimumab on work productivity/daily activity impairment in Austrian RA, PsA, and axSpA patients.

A Prospective Study to Evaluate the Impact of Golimumab Therapy on Work Productivity and Activity, and Quality of Life in Patients With Rheumatoid Arthritis, Psoriasis Arthritis and Axial Spondyloarthritis in a Real Life Setting in AUSTRIA. The GO-ACTIVE Study

IntroductionRaynaud’s phenomenon (RP) and digital ulcers (DU) are frequent manifestations of Systemic Sclerosis (SSc). Despite being very common in SSc patients, both conditions have proven to be notoriously difficult to study. There are very few available approved drugs with varying efficacy. It has been shown that the presence of DU is associated with increased whole blood viscosity (WBV). Rheopheresis (RheoP) is an extracorporeal apheresis technique used to treat microcirculatory disorders by improving blood viscosity. Improved blood flow and wound healing after RheoP treatments have been reported in single case reports.</sec>Methods and AnalysisWe report the clinical trial protocol of “A randomized controlled prospective single-center feasibility study of Rheopheresis for Raynaud’s syndrome and Digital Ulcers in Systemic Sclerosis (RHEACT).” RHEACT aims to investigate the efficacy of RheoP on the Raynaud Condition Score (RCS) as the primary efficacy outcome measure after 16 weeks from baseline. Thirty patients will be randomized in a 1:1:1 ratio to one of two RheoP treatment groups or assigned to the standard of care (SoC) control group (intravenous iloprost). Secondary endpoints include changes in DU, changes in nailfold video capillaroscopy and patient-reported-outcomes (Scleroderma Health Assessment Questionnaire, FACIT-Fatigue, and the Disability of Arm, Shoulder, and Hand, quick version).</sec>DiscussionApheresis techniques have been investigated in SSc but mainly in observational, retrospective studies, or single case reports. RheoP is a pathophysiologically driven potential new therapy for heavily burdened patients with SSc-associated secondary RP with or without DU.</sec>Ethics and DisseminationThe study was registered at <ext-link ext-link-type="uri" xlink:href="http://clinicaltrials.gov" xmlns:xlink="http://www.w3.org/1999/xlink">clinicaltrials.gov</ext-link> (Identifier: NCT05204784). Furthermore, the study is made publicly available on the website of the German network of Systemic Sclerosis “Deutsches Netzwerk Systemische Sklerodermie (DNSS).”</sec>

Introduction: Raynaud’s phenomenon (RP) and digital ulcers (DU) are frequent manifestations of Systemic Sclerosis (SSc). Despite being very common in SSc patients, both conditions have proven to be notoriously difficult to study. There are very few available approved drugs with varying efficacy. It has been shown that the presence of DU is associated with increased whole blood viscosity (WBV). Rheopheresis (RheoP) is an extracorporeal apheresis technique used to treat microcirculatory disorders by improving blood viscosity. Improved blood flow and wound healing after RheoP treatments have been reported in single case reports.Methods and Analysis: We report the clinical trial protocol of “A randomized controlled prospective single-center feasibility study of Rheopheresis for Raynaud’s syndrome and Digital Ulcers in Systemic Sclerosis (RHEACT).” RHEACT aims to investigate the efficacy of RheoP on the Raynaud Condition Score (RCS) as the primary efficacy outcome measure after 16 weeks from baseline. Thirty patients will be randomized in a 1:1:1 ratio to one of two RheoP treatment groups or assigned to the standard of care (SoC) control group (intravenous iloprost). Secondary endpoints include changes in DU, changes in nailfold video capillaroscopy and patient-reported-outcomes (Scleroderma Health Assessment Questionnaire, FACIT-Fatigue, and the Disability of Arm, Shoulder, and Hand, quick version).Discussion: Apheresis techniques have been investigated in SSc but mainly in observational, retrospective studies, or single case reports. RheoP is a pathophysiologically driven potential new therapy for heavily burdened patients with SSc-associated secondary RP with or without DU.Ethics and Dissemination: The study was registered at <a href="http://clinicaltrials.gov">clinicaltrials.gov</a> (Identifier: NCT05204784). Furthermore, the study is made publicly available on the website of the German network of Systemic Sclerosis “Deutsches Netzwerk Systemische Sklerodermie (DNSS).”

Study Protocol: A Randomized Controlled Prospective Single-Center Feasibility Study of Rheopheresis for Raynaud’s Syndrome and Digital Ulcers in Systemic Sclerosis (RHEACT Study)