Does regression of skin thickening predict improvement of internal organ involvement and survival in patients with diffuse cutaneous systemic sclerosis? A EUSTAR analysis.

OBJECTIVE: Patients with diffuse cutaneous systemic sclerosis (dcSSc) frequently show spontaneous improvement of skin fibrosis. Our aim was to examine whether an improvement in skin fibrosis predicts lower likelihood of visceral organ progression and better survival. METHODS: Patients from the European Scleroderma Trials and Research (EUSTAR) cohort with dcSSc, baseline modified Rodnan skin score (mRSS) ≥7, and valid mRSS at 12±3 months follow up were included. Regression/progression of skin fibrosis was defined as a decrease/increase in mRSS >5 points and ≥25% from baseline to follow up. The outcomes included progression of lung, renal, cardiac and gastrointestinal manifestations using consensus derived definitions and all-cause death. Regressive, stable and progressive patients were compared by univariate, Kaplan-Meier survival curve and Cox regression analysis. RESULTS: Of 1257 included patients, 883 (70.2%) were stable, 282 (22.4%) regressive, and 92 (7.3%) progressive. Regressive patients, adjusted for baseline mRSS, baseline immunosuppression, baseline FVC, and disease duration, showed a significantly lower probability of FVC decline ≥10% than progressive patients (p=0.00003), lower probability of all-cause mortality during follow up (p=0.035) compared to progressive patients. .Improvement of skin fibrosis was not associated with progression of other organ manifestations. CONCLUSION: We found that regression of skin fibrosis is associated with a lower probability of lung progression and better survival at follow up. The link between the disease course of skin and lung fibrosis in SSc can help to better stratify patients in clinical practice and enrich for ILD progressive patients in clinical trials.

Characterization of genetic landscape and novel inflammatory biomarkers in patients with adult-onset Still's disease.

OBJECTIVES: Adult-onset Still's disease (AOSD) is systemic autoinflammatory disorder of unknown aetiology. Genetic studies have been limited. Here, we conducted detailed genetic and inflammatory biomarker analysis of a large AOSD cohort to investigate the underlying pathology and identify novel targets for potential treatment. METHODS: We investigated AOSD cases (n=60) for rare germline and somatic variants using whole exome sequencing with virtual gene panels. Transcriptome profiles were investigated by bulk RNA sequencing whole blood. Cytokine profiling was performed on an extended patient cohort (n=106), alongside measurements of NLRP3 inflammasome activation using a custom assay, and Type I Interferon (IFN) score using a novel method. RESULTS: We observed higher-than-expected frequencies of rare germline variants associated with monogenic autoinflammatory disorders in AOSD cases (AOSD 38.4% vs healthy controls 20.4%), and earlier onset of putative somatic variants associated with clonal haematopoiesis of indeterminate potential. Transcriptome profiling revealed positive correlation between Still's activity score (SAS) and gene expression associated with the innate immune system. ASC/NLRP3 specks levels and Type I IFN scores were significantly elevated in AOSD cases compared to healthy controls (p=0.0001 and 0.0015 respectively), in addition to several cytokines: IL-6 (p<0.0001), IL-10 (p<0.0075), IL-12p70 (p=0.0005), IL-18 (p<0.0001), IL-23 (p<0.0001), IFN-α2 (p=0.0009), and IFNγ (p=0.0002). CONCLUSIONS: Our study shows considerable genetic complexity within AOSD and demonstrates the potential utility of the ASC/NLRP3 specks assay for disease stratification and targeted treatment. The enriched genetic variants identified may not, by themselves, be sufficient to cause disease but may contribute to a polygenic model for AOSD.

Oral health and dental care challenges in scleroderma-perspectives of dentists, rheumatologists and patients.

Objectives: The oral healthcare challenges of people living with scleroderma are poorly understood, yet frequently reported. This mixed methods study aimed to investigate oral health and dental care challenges associated with scleroderma from the perspective of dentists, rheumatologists and patients. Methods: Dentists, rheumatologists and scleroderma patients in the UK completed a survey about their experiences of oral health, dental care and quality of life. People with scleroderma were also interviewed. We conducted descriptive analysis of quantitative data and used thematic analysis to examine qualitative data. Results: A total of 95.5% of patients reported oral and dental manifestations of scleroderma (ODMS); 57.1% reported high physical impacts, 53.8% high psychological impacts and 47.7% high social impacts. Only 13% of patients were informed of ODMS at diagnosis. No dentist or rheumatologist felt fully confident in managing ODMS. The most frequent suggestion for improvement among patients and dentists was increased information for dentists. We identified three key themes: significant negative impact on quality of life, barriers to accessing dental care and characteristics of good dental care. Conclusion: ODMS are prevalent issues, constituting a significant burden on quality of life. Rheumatologists should inform scleroderma patients of ODMS and embed oral health inquiries into annual reviews. Communication between medical and dental practitioners should be encouraged to facilitate early identification and management of ODMS.

EULAR recommendations for the treatment of systemic sclerosis: 2023 update.

OBJECTIVES: To update the 2017 European Alliance of Associations for Rheumatology (EULAR) recommendations for treatment of systemic sclerosis (SSc), incorporating new evidence and therapies. METHODS: An international task force was convened in line with EULAR standard operating procedures. A nominal group technique exercise was performed in two rounds to define questions underpinning a subsequent systematic literature review. The evidence derived was discussed and overarching principles, recommendations and future research agenda were iteratively developed with voting rounds. RESULTS: The task force agreed on 22 recommendations covering 8 clinical/organ domains including Raynaud's phenomenon, digital ulcers, pulmonary arterial hypertension, scleroderma renal crisis, skin fibrosis, interstitial lung disease (ILD), gastrointestinal manifestations and arthritis. Most new recommendations are related to skin fibrosis and ILD. These included novel recommendations for the use of mycophenolate mofetil, nintedanib, rituximab and tocilizumab for the treatment of these crucial disease manifestations. The recommendations also included first-line and second-line interventions, providing increased utility for rheumatology practitioners. Important additions to the future research agenda included consideration of novel interventions for the management of vascular, musculoskeletal and gastrointestinal manifestations and calcinosis, as well as for the local management of digital ulcers. CONCLUSION: These updated recommendations include the first set of synthetic and biological targeted therapies recommended for key fibrotic manifestations of SSc as well as first-line combination treatment for newly diagnosed pulmonary artery hypertension and prioritise a new research agenda for the coming years.

Systemic Sclerosis dermal fibroblast exosomes trigger a Type 1 interferon response in keratinocytes through the TBK/JAK/STAT signalling axis.

BACKGROUND: Activation of Type I IFN response has been shown to correlates with disease activity in systemic sclerosis. It is currently unknown whether the tissue-specific Type I IFN activation is a consequence of the response observed in blood or rather its source. Exosomes from SSc fibroblasts were recently shown to activate macrophages in vitro. Here, we aimed to determine the source of Type I IFN signature in SSc skin biopsies and the potential role of exosomes from SSc dermal fibroblasts in the process. METHODS: Skin biopsies were obtained from healthy and SSc patients' forearms and processed for dermal fibroblasts and keratinocytes. Exosomes were isolated from healthy and SSc dermal fibroblast supernatants by ultracentrifugation and added to human skin keratinocytes. Keratinocyte transcriptome was analysed by RNA-seq analysis. TANK-binding kinase (TBK) and JAK were inhibited using a small molecule inhibitor (GSK8612) and Tofacitinib, respectively. RESULTS: SSc skin biopsies showed highest levels of Type I IFN response in the epidermal layer. RNA-seq analysis of keratinocytes transcriptome following exposure to dermal fibroblast exosomes showed strong upregulation of IFN signature genes induced by SSc exosomes compared to Healthy control. Inhibition of TBK or JAK activity suppressed the upregulation of the IFN signature induced by SSc exosomes. CONCLUSION: IFN activation of SSc keratinocytes is dependent on their crosstalk with dermal fibroblasts and inducible by extracellular exosomes. Our data indicates that SSc fibroblasts exosomes contributes to theType I IFN activation in SSc skin through activation of pattern recognition receptors upstream of TBK.

Systemic sclerosis and anorectal dysfunction: The Leeds experience.

Systemic sclerosis is an autoimmune disorder which frequently affects the gastrointestinal tract. Anorectal dysfunction is common in systemic sclerosis and is manifested mainly by atrophy of internal anal sphincter. Faecal incontinence is the result of internal anal sphincter atrophy secondary to systemic sclerosis. In this study, we aimed to assess the internal anal sphincter in 17 patients with faecal incontinence and systemic sclerosis using anorectal manometry and endoanal ultrasound and compare them with an age and gender-matched control group without systemic sclerosis. Most patients have limited cutaneous systemic sclerosis. Majority of the patients with systemic sclerosis and faecal incontinence presented with symptoms of faecal leakage and urgency. Systemic sclerosis patients had low basal sphincter pressures. The mean thickness of internal anal sphincter in systemic sclerosis group was significantly lower than the control group (p < 0.001). Rectal sensation is preserved in systemic sclerosis. There was no difference in the mean thickness of the external anal sphincter between the two groups. To conclude internal anal sphincter is atrophic in systemic sclerosis resulting in decreased resting sphincter pressures and passive faecal leakage. Further investigations and studies are needed to determine the natural course of faecal incontinence in systemic sclerosis, associated risk factors and efficacy of therapeutic interventions.

Self-reported skin severity and quality of life in systemic sclerosis: multicentre validation of PASTUL.

OBJECTIVES: The aim of this study was to validate the Patient self-Assessment of Skin Thickness in Upper Limb questionnaire (PASTUL) in systemic sclerosis (SSc) and assess impact of skin involvement on health-related quality of life (HRQoL). METHODS: Participants were included in four UK centres. PASTUL specifies a grading of skin at 8 sites corresponding to the modified Rodnan Skin Score (mRSS). Construct validity was assessed by comparing PASTUL scores with mRSS. HRQoL was evaluated with EQ5D5L and Leeds SSc HRQoL questionnaires. Additionally, correlation between PASTUL and Scleroderma Skin Patient reported Outcome (SSPRO) was explored. Follow-up was 12 months. RESULTS: In total, 196 participants were included, mean age was 56.4 years (SD 13.9), 80.6% female (n = 158), mean disease duration 11.9 years (SD 9.9), 110 (56.1%) had limited cutaneous (lcSSc) and 81 (41.3%) diffuse cutaneous SSc (dcSSc). PASTUL and upper limb mRSS were well correlated at baseline, 6 and 12 months (ICC = 0.67, 0.78 and 0.62, p< 0.001). Test-retest reliability was good (ICC = 0.83, p< 0.001). There was a stronger correlation between PASTUL and upper limb mRSS in dcSSc compared with lcSSc (0.69 vs 0.51, p< 0.001). In participants with early disease (< 4 years) PASTUL was moderately correlated with HRQoL (r = 0.53, p< 0.001), correlations were weaker in the whole group. Mean time to do the PASTUL self-assessment was 5.0 min (SD 3.7). CONCLUSION: PASTUL is a feasible outcome tool that adds to assessments as SSPRO. Skin thickening is correlated with HRQoL, particularly in early disease.

Sexual Dimorphism in Sex Hormone Metabolism in Human Skeletal Muscle Cells in Response to Different Testosterone Exposure.

Muscle tissue is an important target of sex steroids, and particularly, testosterone plays essential roles in muscle cell metabolism. Wide ranges of studies have reported sex differences in basal muscle steroidogenesis, and recently several genes have been identified to be regulated by androgen response elements that show innate sex differences in muscle. However, studies accounting for and demonstrating cell sexual dimorphism in vitro are still scarce and not well characterized. Here, we demonstrated the ability of 46XX and 46XY human primary skeletal muscle cells to differently activate steroidogenesis in vitro, likely related to sex-chromosome onset, and to differently induce hormone release after increasing doses of testosterone exposure. Cells were treated with testosterone at concentrations of 0.5, 2, 5, 10, 32, and 100 nmol/L for 24 h. Variations in 17ß-HSD, 5α-R2, CYP-19 expression, DHT, estradiol, and androstenedione release, as well as IL6 and IL8 release, were analyzed, respectively, by RT-PCR, ELISA, and luminex-assay. Following testosterone treatments, and potentially at any concentration level, an increase in the expression of 17ß-HSD, 5α-R2, and CYP-19 was observed in 46XY cells, accompanied by elevated levels of DHT, androstenedione, and IL6/IL8 release. Following the same treatment, 46XX cells exhibited an increase in 5α-R2 and CYP-19 expression, a conversion of androgens to estrogens, and a reduction in IL6 and IL8 release. In conclusion, this study demonstrated that sex-chromosome differences may influence in vitro muscle cell steroidogenesis and hormone homeostasis, which are pivotal for skeletal muscle metabolism.

The 2024 British Society for Rheumatology guideline for management of systemic sclerosis-executive summary.

This guideline was developed according to the British Society for Rheumatology Guidelines Protocol by a Guideline Development Group comprising healthcare professionals with expertise in SSc and people with lived experience, as well as patient organization representatives. It is an update of the previous 2015 SSc guideline. The recommendations were developed and agreed by the group and are underpinned by published evidence, assessed by systematic literature review and reinforced by collective expert opinion of the group. It considers all aspects of SSc including general management, treatment of organ-based complications, including cardiopulmonary, renal and gastrointestinal tract manifestations, as well as broader impact of disease. Whilst it is focused on adults with SSc we expect that the guideline will be relevant to people of all ages and expert input and review by paediatric rheumatologists and other relevant specialists considered where the guideline was, or may not be, applicable to young people with SSc and juvenile-onset disease. In addition to providing guidance on disease assessment and management the full guideline also considers service organization within the National Health Service and future approaches to audit of the guideline. The lay summary that accompanies this abstract can be found in Supplemental information 1.

The 2024 British Society for Rheumatology guideline for management of systemic sclerosis.

This guideline was developed according to the British Society for Rheumatology Guidelines Protocol by a Guideline Development Group comprising healthcare professionals with expertise in SSc and people with lived experience, as well as patient organization representatives. It is an update of the previous 2015 SSc guideline. The recommendations were developed and agreed by the group and are underpinned by published evidence, assessed by systematic literature review and reinforced by collective expert opinion of the group. It considers all aspects of SSc including general management, treatment of organ-based complications, including cardiopulmonary, renal and gastrointestinal tract manifestations, as well as broader impact of disease. Whilst it is focused on adults with SSc we expect that the guideline will be relevant to people of all ages and expert input and review by paediatric rheumatologists and other relevant specialists considered where the guideline was, or may not be, applicable to young people with SSc and juvenile-onset disease. In addition to providing guidance on disease assessment and management the full guideline also considers service organization within the National Health Service and future approaches to audit of the guideline. The lay summary that accompanies this abstract can be found in Supplemental information 1.

Molecular glues that inhibit specific Zn2+-dependent DUB activity and inflammation.

Deubiquitylases (DUBs) play a pivotal role in cell signalling and are often regulated by homo- or hetero-interactions within protein complexes. The BRCC36 isopeptidase complex (BRISC) regulates inflammatory signalling by selectively cleaving K63-linked polyubiquitin chains on Type I interferon receptors (IFNAR1). BRCC36 is a Zn2+-dependent JAMM/MPN DUB, a challenging ubiquitin protease class for the design of selective inhibitors. We identified first-in-class DUB inhibitors that act as BRISC molecular glues (BLUEs). BLUEs inhibit DUB activity by stabilising a BRISC dimer consisting of 16 subunits. The BLUE-stabilised BRISC dimer is an autoinhibited conformation, whereby the active sites and interactions with the recruiting subunit SHMT2 are blocked. This unique mode of action leads to highly selective inhibitors for BRISC over related complexes with the same catalytic subunit, splice variants and other JAMM/MPN DUBs. Structure-guided inhibitor resistant mutants confirm BLUEs on-target activity in cells, and BLUE treatment results in reduced interferon-stimulated gene (ISG) expression in human peripheral blood mononuclear cells from Scleroderma patients, a disease linked with aberrant IFNAR1 activation. BLUEs represent a new class of molecules with potential utility in Type I interferon-mediated diseases and a template for designing selective inhibitors of large protein complexes by promoting protein-protein interactions instead of blocking them.

Long-term retention rate, adverse event temporal patterns and rescue treatment strategies of mycophenolate mofetil in systemic sclerosis: insights from real-life.

BACKGROUND: Mycophenolate mofetil (MMF) is a mainstay for the treatment of systemic sclerosis (SSc). The occurrence and implications of MMF-related adverse events on drug retention rates in real life remain poorly defined. We aimed to determine the MMF retention rate and to investigate the causes and patterns of discontinuation, adverse events (AEs) and treatment options used after discontinuation. METHODS: SSc patients who started MMF treatment underwent a retrospective longitudinal assessment for up to 5 years. We documented the incidence, predictors, and impacts of MMF treatment on gastrointestinal intolerance, infections, laboratory abnormalities, and cancer. Rescue strategies implemented after MMF discontinuation were recorded. RESULTS: The 5-year MMF retention rate of 554 patients stood at 70.7% and 19.6% of them stopped MMF due to AEs. One out of every four patients experienced a dose reduction or discontinuation of MMF due to AEs, with gastrointestinal intolerance being the predominant cause. The 5-year cumulative incidence rates for gastrointestinal intolerance, cancer, severe infections, and laboratory toxicity leading to MMF discontinuation were 6.4%, 4.1%, 3.1%, and 2.1%, respectively. Lower respiratory tract was the most affected, with bacteria being the predominant causative agent. Intestinal and pulmonary circulation involvement were tied to elevated AE rates and MMF discontinuation. The most common approaches post-MMF cessation were "watch and wait" and switch to rituximab. CONCLUSIONS: MMF use in SSc appears to be limited by the occurrence of AEs, both in terms of persistence and dosing of the drug. Rescue options after MMF discontinuation are limited and many patients remain without immunosuppressant.

The Potential Role of Butyrate in the Pathogenesis and Treatment of Autoimmune Rheumatic Diseases.

The gut microbiota is a complex ecosystem of microorganisms residing in the human gastrointestinal tract, playing a crucial role in various biological processes and overall health maintenance. Dysbiosis, an imbalance in the composition and function of the gut microbiota, is linked to systemic autoimmune diseases (SAD). Short-chain fatty acids (SCFAs), especially butyrate, produced by the gut microbiota through the fermentation of dietary fibers, play a significant role in immunomodulation and maintaining intestinal homeostasis. Butyrate is essential for colonocyte energy, anti-inflammatory responses, and maintaining intestinal barrier integrity. Studies show reduced butyrate-producing bacteria in SAD patients, suggesting that increasing butyrate levels could have therapeutic benefits. Butyrate's anti-inflammatory effects and its potential therapeutic role have been studied in rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus, systemic sclerosis, and Behçet's disease. Despite promising in vitro and animal model results, human studies are limited, and the optimal strategies for modulating dysbiosis in SADs remain elusive. This review explores the current evidence on the immunoregulatory role of butyrate and its potential therapeutic effects in SAD.

Clinically relevant differences between primary Raynaud's phenomenon and secondary to connective tissue disease.

OBJECTIVES: Raynaud's phenomenon (RP) is a symptom complex associated with digital vascular compromise. Our aim was to examine for clinically relevant differences between primary RP (PRP) and secondary RP (SRP) to connective tissue disease. METHODS: We report cross-sectional results from the Patient Survey of experiences of Raynaud's Phenomenon (PASRAP), which aimed to explore the broad-ranging impact of RP. The survey was widely distributed online including via social medial. Participation was voluntary and responses were anonymous. RESULTS: 1229 respondents completed PASRAP with self-reported RP: PRP 218 (17.7 %) and SRP 1011 (82.3 %) of which 903 (92.9 %) Systemic Sclerosis. The mean (SD) age was significantly lower in respondents with PRP (41.7 [11.8] vs 54.2 [12.4] years, P<0.0001). During attacks, more subjects with SRP reported cyanotic colour changes (92.2 % vs 86.5 %, P=0.0089). Patients with PRP experienced more pain (72.1 % vs 55.9 %, P<0.0001), numbness (80.3 % vs 69.4 %, P=0.0016), stinging/throbbing (93.4 % vs 80.8 %, P<0.0001), and tingling (84.0 % vs 77.5 %, P=0.0345). Only half of respondents' symptoms were adequately controlled by their current medication(s), more commonly in SRP (55.2 % vs 45.2 %, P=0.0084). There were important differences in the triggers, number, and seasonal variation of RP attacks. CONCLUSION: There are clinically relevant differences between PRP and SRP concerning the multifaceted lived patient experience of RP. Neurosensory symptoms are more common in PRP. Patients with SRP are older and present with more colour changes, overrepresented by cyanosis, and with less complete resolution of symptoms between attacks. These data provide novel insights for future RP clinical trial design.

Advances in the diagnosis of multiorgan involvement in systemic sclerosis: a focus on MRI.

PURPOSE OF REVIEW: Systemic sclerosis (SSc) is a rare chronic multisystem autoimmune disease characterized by endothelial dysfunction, tissue hypoxia, and diffuse organ fibrosis. MRI provides a radiation free approach to noninvasively assess the key manifestations of SSc in multiple organs. The purpose of this review is to summarize recent advances in MRI techniques to provide diagnostic and prognostic information in patients with SSc. RECENT FINDINGS: MRI can probe processes that play a key role in the development of SSc-related complications, including neointima proliferation, fibrosis, and hypoxia. Feature tracking and parametric mapping MRI can detect cardiac involvement at the subclinical level. Contrast-free MRI angiography with Digital Artery Volume Index (DAVIX) assessment allow comprehensive assessment of hand involvement. T1 mapping and BOLD imaging can assess SSc effects on skeletal muscle, and lung MRI is becoming a key method for imaging of interstitial lung disease. As a new exciting application, the sodium content of the skin can be quantified by 23Na MRI reflective of glycosaminoglycan content. SUMMARY: Recent advances in MRI provide a unique opportunity to study the key pathophysiologic processes and clinical manifestations of SSc in multiple organs noninvasively, which can pave the way for the development of effective therapies.

Gastrointestinal disease in systemic sclerosis: the neglected organ system?

PURPOSE OF REVIEW: Identifying outcomes and clinical trial endpoints enabled the discovery of new inflammatory bowel disease (IBD) treatments. Herein, we describe efforts to advance the study of gastrointestinal (GI) manifestations in systemic sclerosis (SSc). RECENT FINDINGS: Insights into the scope of the problem, as well as advancements in the measurement and treatment of SSc-GI, are underway. Proposed SSc esophageal endophenotypes are now defined, risk stratification methods are growing, and imaging and functional studies are now employed to guide therapeutic interventions. Additional progress is being made in characterizing the gut microbiome in patients with SSc. Research into the role of the immune response in the pathogenesis of SSc-GI disease is also ongoing, evolving simultaneously with the development of methods to facilitate data collection with real-time capture of diet, exercise, and medication data. SUMMARY: Multidisciplinary teams are working to deepen our understanding of SSc-GI disease pathogenesis, to identify biomarkers for risk stratification and the assessment of disease activity, and to develop and validate outcomes and clinical trial endpoints to pave the way toward effective therapy for SSc-GI disease.

A randomised, parallel-group, double-blind, placebo-controlled phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis: DAISY study design and rationale.

OBJECTIVES: The type I interferon pathway is a promising target for treatment of patients with systemic sclerosis (SSc). Here, we describe the design of a multinational, randomised phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis (DAISY). METHODS: DAISY includes a 52-week double-blind, placebo-controlled treatment period, a 52-week open-label active treatment period, and a 12-week safety follow-up period. The patient population includes a planned 306 adults with limited or diffuse cutaneous active SSc who satisfied American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria. Use of standard immunosuppressants, including mycophenolate mofetil, at a stable dose prior to randomisation is permitted in addition to weekly subcutaneous anifrolumab or placebo. Efficacy will be assessed at Week 52 via Revised-Composite Response Index in SSc (CRISS)-25 response (primary endpoint). Lung function and skin thickness will be assessed via change from baseline in forced vital capacity in patients with SSc-associated interstitial lung disease and modified Rodnan Skin Score, respectively (key secondary endpoints). CONCLUSIONS: The DAISY trial will evaluate the efficacy and safety of anifrolumab as a first-in-class treatment option for patients with both limited and diffuse cutaneous SSc and will provide insight into the contributions of type I interferon to SSc pathogenesis. Revised-CRISS-25 can account for improvement and worsening in a broad set of validated clinical measures beyond lung function and skin thickness, including clinician- and patient-reported outcomes, capturing the heterogeneity of SSc.

Systemic sclerosis is a chronic autoimmune disease that leads to inflammation and scarring of the skin and internal organs, especially the lungs. Systemic sclerosis and lupus are both associated with increased interferon signalling, which is usually triggered by viral infections, but is related to damaging inflammation in these diseases. Anifrolumab, a drug that blocks interferon signalling, is already used to treat patients with lupus (also known as SLE), so it could potentially be used to treat patients with systemic sclerosis. This publication details the DAISY study design and explains why it is needed. This study will follow 2 groups of 153 patients with systemic sclerosis over 2 years. During the first year, in addition to any standard immunosuppressant therapy, the groups will receive weekly injections of either anifrolumab or "dummy drug" (placebo). In the second year, all patients will receive anifrolumab with their standard immunosuppressant therapy. Multiple factors will be considered to evaluate the efficacy of anifrolumab treatment, including clinical measurements of skin thickness and lung function, and questionnaires completed by clinicians and patients to report on patient health and their everyday function during treatment. The DAISY study will investigate the efficacy and safety of anifrolumab treatment in a diverse group of patients with systemic sclerosis who currently have limited options for effective treatment. The study will evaluate the impact of anifrolumab treatment on multiple aspects of the disease, and how patients feel about their overall health-related quality of life.

Tailoring the treatment of inflammatory rheumatic diseases by a better stratification and characterization of the clinical patient heterogeneity. Findings from a systematic literature review and experts' consensus.

Inflammatory rheumatic diseases are different pathologic conditions associated with a deregulated immune response, codified along a spectrum of disorders, with autoinflammatory and autoimmune diseases as two-end phenotypes of this continuum. Despite pathogenic differences, inflammatory rheumatic diseases are commonly managed with a limited number of immunosuppressive drugs, sometimes with partial evidence or transferring physicians' knowledge in different patients. In addition, several randomized clinical trials, enrolling these patients, did not meet the primary pre-established outcomes and these findings could be linked to the underlying molecular diversities along the spectrum of inflammatory rheumatic disorders. In fact, the resulting patient heterogeneity may be driven by differences in underlying molecular pathology also resulting in variable responses to immunosuppressive drugs. Thus, the identification of different clinical subsets may possibly overcome the major obstacles that limit the development more effective therapeutic strategies for these patients with inflammatory rheumatic diseases. This clinical heterogeneity could require a diverse therapeutic management to improve patient outcomes and increase the frequency of clinical remission. Therefore, the importance of better patient stratification and characterization is increasingly pointed out according to the precision medicine principles, also suggesting a new approach for disease treatment. In fact, based on a better proposed patient profiling, clinicians could more appropriately balance the therapeutic management. On these bases, we synthetized and discussed the available literature about the patient profiling in regard to therapy in the context of inflammatory rheumatic diseases, mainly focusing on randomized clinical trials. We provided an overview of the importance of a better stratification and characterization of the clinical heterogeneity of patients with inflammatory rheumatic diseases identifying this point as crucial in improving the management of these patients.

Concordance and Prognostic Relevance of Different Definitions of Systemic Sclerosis Interstitial Lung Disease Progression.

RATIONALE: Interstitial lung disease (ILD) in systemic sclerosis (SSc) is a common complication that has varied progression rate and prognosis. Different progression definitions are available: include minimal clinically important worsening of forced vital capacity (FVC MCIW), EUSTAR (EUropean Scleroderma Trials and Research group) progression, OMERACT (Outcome Measures in Rheumatology Clinical Trials) progression, and Erice ILD working group progression. Pulmonary function and symptoms changes may act as specific confounding factors applying these definitions in SSc. OBJECTIVE: To assess the concordance and prognostic value of four different definitions in SSc-ILD patients overall and specific clinical groups. METHODS: Progression status in consecutive SSc-ILD patients was assessed over 24 months, 60-month disease-related mortality risk was compared between progressors and non-progressors using the four definitions. RESULTS: Among 245 patients, 26 SSc-related deaths were reported. Mortality was linked to progression for FVC MCIW (HR 2.27, 95% CI 1.03-4.97), OMERACT (HR 2.90, 95% CI 1.28-6.57), and Erice definitions (HR 11.02, 95% CI 2.38-51.08). The association between progression and mortality was poor in patients with disease duration ≥3 years, mild functional impairment, and pulmonary artery systolic pressure (PASP)≥40 mmHg. Erice criteria appeared superior in patients with duration ≥3 years, limited cutaneous variant, and PASP<40 mmHg. OMERACT criteria performed better in diffuse cutaneous variant patients with severe functional impairment. CONCLUSIONS: The four evaluated definitions of progression in SSc-ILD are not interchangeable, resulting in up to a third of cases being classified differently based on the adopted criteria, and presenting different prognostic values, particularly within specific clinical groups.