Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis.

Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov (NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.

The deficiency of DNASE1L3 does not affect systemic sclerosis pathogenesis in two inducible murine models of the disease.

We induced systemic sclerosis (SSc)-like disease in both wild-type and Dnase1l3-deficient mice using two distinct approaches involving bleomycin and hypochlorous acid injections. Our observations revealed that the deficiency in DNASE1L3 did not affect tissue fibrosis or inflammation caused by these treatments. Despite the association of single nucleotide polymorphisms in humans with SSc pathogenesis, our study demonstrates that DNASE1L3 is dispensable in two inducible murine models of SSc-like pathogenesis.

Racial variability in immune responses only partially explains differential systemic sclerosis disease severity.

OBJECTIVE: To understand if autoantibodies account for racial variation in disease severity, we compared autoantibody distribution and associated phenotype between self-identified black and white systemic sclerosis (SSc) patients. METHODS: 803 black and 2178 white SSc patients had systematic testing for autoantibodies using Euroimmun (centromere (ACA), RNA-polymerase III (POLR3), Scl70, PM/Scl, NOR90, Th/To, Ku, U3RNP and Ro52) and commercial ELISA (U1RNP). In this observational study, logistic regression was performed to assess the association between self-identified race and outcomes, adjusting for autoantibodies. To estimate whether the effect of race was mediated by autoantibody status, race coefficients from multivariate models including and excluding autoantibodies were compared. RESULTS: Anti-Scl70, anti-U1RNP, anti-U3RNP, anti-Th/To, anti-Ku and anti-NOR90 were more common in the black cohort than in the white cohort, which was enriched for ACA, anti-POLR3 and anti-PM/Scl. Black individuals had a higher prevalence of severe Raynaud's, skin, lung, gastrointestinal and renal disease whereas white individuals had a higher prevalence of severe heart and muscle disease. Adjusting for autoantibodies decreased the effect of race on outcome for telangiectasias, forced vital capacity <70%, pulmonary hypertension and severe lung, heart, muscle and gastrointestinal disease by 11%-44% and increased the association between race and renal crisis and severe kidney disease by 37%-52%. CONCLUSIONS: This study is the largest systematic analysis of autoantibody responses in a geographically diverse population of black SSc patients. Black and white individuals with SSc have distinct autoantibody profiles. Autoantibodies explain only a fraction of the effect of race on clinical outcomes, suggesting other factors contribute to disparate outcomes between these groups.

Inflammatory tissue priming: novel insights and therapeutic opportunities for inflammatory rheumatic diseases.

Due to optimised treatment strategies and the availability of new therapies during the last decades, formerly devastating chronic inflammatory diseases such as rheumatoid arthritis or systemic sclerosis (SSc) have become less menacing. However, in many patients, even state-of-the-art treatment cannot induce remission. Moreover, the risk for flares strongly increases once anti-inflammatory therapy is tapered or withdrawn, suggesting that underlying pathological processes remain active even in the absence of overt inflammation. It has become evident that tissues have the ability to remember past encounters with pathogens, wounds and other irritants, and to react more strongly and/or persistently to the next occurrence. This priming of the tissue bears a paramount role in defence from microbes, but on the other hand drives inflammatory pathologies (the Dr Jekyll and Mr Hyde aspect of tissue adaptation). Emerging evidence suggests that long-lived tissue-resident cells, such as fibroblasts, macrophages, long-lived plasma cells and tissue-resident memory T cells, determine inflammatory tissue priming in an interplay with infiltrating immune cells of lymphoid and myeloid origin, and with systemically acting factors such as cytokines, extracellular vesicles and antibodies. Here, we review the current state of science on inflammatory tissue priming, focusing on tissue-resident and tissue-occupying cells in arthritis and SSc, and reflect on the most promising treatment options targeting the maladapted tissue response during these diseases.

Identification and validation of anti-protein arginine methyltransferase 5 (PRMT5) antibody as a novel biomarker for systemic sclerosis (SSc).

OBJECTIVES: In the complex panorama of autoimmune diseases, the characterisation of pivotal contributing autoantibodies that are involved in disease progression remains challenging. This study aimed to employ a global antibody profiling strategy to identify novel antibodies and investigate their association with systemic sclerosis (SSc). METHODS: We implemented this strategy by conducting immunoprecipitation (IP) following on-bead digestion with the sera of patients with SSc or healthy donors, using antigen pools derived from cell lysates. The enriched antigen-antibody complex was proceeded with mass spectrometry (MS)-based quantitative proteomics and over-represented by bioinformatics analysis. The candidate antibodies were then orthogonally validated in two independent groups of patients with SSc. Mice were immunised with the target antigen, which was subsequently evaluated by histological examination and RNA sequencing. RESULTS: The IP-MS analysis, followed by validation in patients with SSc, revealed a significant elevation in anti-PRMT5 antibodies among patients with SSc. These antibodies exhibited robust diagnostic accuracy in distinguishing SSc from healthy controls and other autoimmune conditions, including systemic lupus erythematosus and Sjögren's syndrome, with an area under the curve ranging from 0.900 to 0.988. The elevation of anti-PRMT5 antibodies was verified in a subsequent independent group with SSc using an additional method, microarray. Notably, 31.11% of patients with SSc exhibited seropositivity for anti-PRMT5 antibodies. Furthermore, the titres of anti-PRMT5 antibodies demonstrated a correlation with the progression or regression trajectory in SSc. PRMT5 immunisation displayed significant inflammation and fibrosis in both the skin and lungs of mice. This was concomitant with the upregulation of multiple proinflammatory and profibrotic pathways, thereby underscoring a potentially pivotal role of anti-PRMT5 antibodies in SSc. CONCLUSIONS: This study has identified anti-PRMT5 antibodies as a novel biomarker for SSc.

Combined inhibition of IL-1, IL-33 and IL-36 signalling by targeting IL1RAP ameliorates skin and lung fibrosis in preclinical models of systemic sclerosis.

BACKGROUND: The interleukin (IL)-1 receptor accessory protein (IL1RAP) is an essential coreceptor required for signalling through the IL-1, IL-33 and IL-36 receptors. Here, we investigate the antifibrotic potential of the combined inhibition of these cytokines by an anti-IL1RAP antibody to provide a scientific background for clinical development in systemic sclerosis (SSc). METHODS: The expression of IL1RAP-associated signalling molecules was determined by data mining of publicly available RNA sequencing (RNAseq) data as well as by imaging mass cytometry. The efficacy of therapeutic dosing of anti-IL1RAP antibodies was determined in three complementary mouse models: sclerodermatous chronic graft-versus-host disease (cGvHD), bleomycin-induced dermal fibrosis model and topoisomerase-I (topo)-induced fibrosis. RESULTS: SSc skin showed upregulation of IL1RAP and IL1RAP-related signalling molecules on mRNA and protein level compared with normal skin. IL-1, IL-33 and IL-36 all regulate distinct gene sets related to different pathophysiological processes in SSc. The responses of human fibroblasts and endothelial cells to IL-1, IL-33 and IL-36 were completely blocked by treatment with an anti-IL1RAP antibody in vitro. Moreover, anti-IL1RAP antibody treatment reduced dermal and pulmonary fibrosis in cGvHD-induced, bleomycin-induced and topoisomerase-induced fibrosis. Importantly, RNAseq analyses revealed effects of IL1RAP inhibition on multiple processes related to inflammation and fibrosis that are also deregulated in human SSc skin. CONCLUSION: This study provides the first evidence for the therapeutic benefits of targeting IL1RAP in SSc. Our findings have high translational potential as the anti-IL1RAP antibody CAN10 has recently entered a phase one clinical trial.

Successful long-term systemic sclerosis treatment by high-frequent low-dose B cell-depleting therapy.

OBJECTIVES: Systemic sclerosis (SSc) is a multiorgan disease with a 10-year mortality rate of up to 50 %. B cell-depleting therapy with rituximab (RTX) appears effective in SSc treatment, but data from randomized controlled trials (RCTs) are lacking, and the frequency and dosage of RTX in SSc have no consensus. We aimed to evaluate the long-term efficacy and safety of quarterly RTX administration in SSc. METHODS: This study retrospectively analyzed 40 patients with SSC treated with RTX twice within 14 days every 3 months from 2010 to 2020. The patients fulfilled the LeRoy and the American College of Rheumatology/European League Against Rheumatism Criteria for SSc. Modified Rodnan skin score (mRSS), lung function test results, and serum immunoglobulin (IgG, IgA, and IgM) concentrations were analyzed. RESULTS: A total of 40 patients with SSc received RTX over a median time of 3.9 years (range: 1-10 years). The median mRSS (baseline: 19, 24 months: 16, p < 0.001) demonstrated a significant improvement, and the predicted forced vital capacity was stable. No new or unexpected safety signals, especially regarding treatment-related infectious adverse events, were observed. Immunoglobulin concentrations were within normal range, and specific antibodies to pneumococcal polysaccharides were preserved despite long-term B cell-depleting therapy. None of the patients died during the observation period of up to 10 years. CONCLUSION: SSc was effectively and safely treated with low-dose RTX quarterly. RCTs are warranted to validate the advantage of continuous B cell depletion by quarterly low-dose RTX administration compared to other treatment intervals.

Anti-U1RNP antibodies are associated with a distinct clinical phenotype and a worse survival in patients with systemic sclerosis.

OBJECTIVES: To clarify the impact of anti-U1RNP antibodies on the clinical features and prognosis of patients with SSc. METHODS: We conducted a monocentric case-control, retrospective, longitudinal study. For each patient with SSc and anti-U1RNP antibodies (SSc-RNP+), one patient with mixed connective tissue disease (MCTD) and 2 SSc patients without anti-U1RNP antibodies (SSc-RNP-) were matched for age, sex, and date of inclusion. RESULTS: Sixty-four SSc-RNP+ patients were compared to 128 SSc-RNP- and 64 MCTD patients. Compared to SSc-RNP-, SSc-RNP+ patients were more often of Afro-Caribbean origin (31.3% vs. 11%, p < 0.01), and more often had an overlap syndrome than SSc-RNP- patients (53.1 % vs. 22.7%, p < 0.0001), overlapping with Sjögren's syndrome (n = 23, 35.9%) and/or systemic lupus erythematosus (n = 19, 29.7%). SSc-RNP+ patients were distinctly different from MCTD patients but less often had joint involvement (p < 0.01). SSc-RNP+ patients more frequently developed interstitial lung disease (ILD) (73.4% vs. 55.5% vs. 31.3%, p < 0.05), pulmonary fibrosis (PF) (60.9% vs. 37.5% vs. 10.9%, p < 0.0001), SSc associated myopathy (29.7% vs. 6.3% vs. 7.8%, p < 0.0001), and kidney involvement (10.9% vs. 2.3% vs. 1.6%, p < 0.05). Over a 200-month follow-up period, SSc-RNP+ patients had worse overall survival (p < 0.05), worse survival without PF occurrence (p < 0.01), ILD or PF progression (p < 0.01 and p < 0.0001). CONCLUSIONS: In SSc patients, anti-U1RNP antibodies are associated with a higher incidence of overlap syndrome, a distinct clinical phenotype, and poorer survival compared to SSc-RNP- and MCTD patients. Our study suggests that SSc-RNP+ patients should be separated from MCTD patients and may constitute an enriched population for progressive lung disease.

Impaired LAIR-1-mediated immune control due to collagen degradation in fibrosis.

Tissue repair is disturbed in fibrotic diseases like systemic sclerosis (SSc), where the deposition of large amounts of extracellular matrix components such as collagen interferes with organ function. LAIR-1 is an inhibitory collagen receptor highly expressed on tissue immune cells. We questioned whether in SSc, impaired LAIR-1-collagen interaction is contributing to the ongoing inflammation and fibrosis. We found that SSc patients do not have an intrinsic defect in LAIR-1 expression or function. Instead, fibroblasts from healthy controls and SSc patients stimulated by soluble factors that drive inflammation and fibrosis in SSc deposit disorganized collagen products in vitro, which are dysfunctional LAIR-1 ligands. This is dependent of matrix metalloproteinases and platelet-derived growth factor receptor signaling. In support of a non-redundant role of LAIR-1 in the control of fibrosis, we found that LAIR-1-deficient mice have increased skin fibrosis in response to repeated injury and in the bleomycin mouse model for SSc. Thus, LAIR-1 represents an essential control mechanism for tissue repair. In fibrotic disease, excessive collagen degradation may lead to a disturbed feedback loop. The presence of functional LAIR-1 in patients provides a therapeutic opportunity to reactivate this intrinsic negative feedback mechanism in fibrotic diseases.

Increased CD8+ tissue resident memory T cells, regulatory T cells and activated natural killer cells in systemic sclerosis lungs.

OBJECTIVE: Multiple observations indicate a role for lymphocytes in driving autoimmunity in SSc. While T and NK cells have been studied in SSc whole blood and bronchoalveolar lavage fluid, their role remains unclear, partly because no studies have analysed these cell types in SSc-interstitial lung disease (ILD) lung tissue. This research aimed to identify and analyse the lymphoid subpopulations in SSc-ILD lung explants. METHODS: Lymphoid populations from 13 SSc-ILD and 6 healthy control (HC) lung explants were analysed using Seurat following single-cell RNA sequencing. Lymphoid clusters were identified by their differential gene expression. Absolute cell numbers and cell proportions in each cluster were compared between cohorts. Additional analyses were performed using pathway analysis, pseudotime and cell ligand-receptor interactions. RESULTS: Activated CD16+ NK cells, CD8+ tissue resident memory T cells and Treg cells were proportionately higher in SSc-ILD compared with HC lungs. Activated CD16+ NK cells in SSc-ILD showed upregulated granzyme B, IFN-γ and CD226. Amphiregulin, highly upregulated by NK cells, was predicted to interact with epidermal growth factor receptor on several bronchial epithelial cell populations. Shifts in CD8+ T cell populations indicated a transition from resting to effector to tissue resident phenotypes in SSc-ILD. CONCLUSIONS: SSc-ILD lungs show activated lymphoid populations. Activated cytotoxic NK cells suggest they may kill alveolar epithelial cells, while their expression of amphiregulin suggests they may also induce bronchial epithelial cell hyperplasia. CD8+ T cells in SSc-ILD appear to transition from resting to the tissue resident memory phenotype.

Systemic sclerosis-associated pulmonary arterial hypertension is characterized by a distinct peripheral T helper cell profile.

OBJECTIVES: Systemic sclerosis (SSc) is characterized by multiple clinical manifestations. Vasculopathy is a main disease hallmark and ranges in severity from an exacerbated Raynaud phenomenon to pulmonary arterial hypertension (PAH). The potential involvement of the immune system in SSc-associated vascular abnormalities is not clear. Here, we set out to study SSc-related immune parameters and determine whether and which peripheral T cell subsets associate with vascular severity in SSc patients. METHODS: Peripheral blood and clinical data were collected from 30 SSc patients, 5 patients with idiopathic PAH and 15 age and sex-matched healthy donors (HD). In this cross-sectional cohort, SSc patients with PAH (n = 15) were matched for their age, sex and medication with SSc patients with no signs of PAH (n = 15). Lymphocyte subsets were quantified by multi-colour flow cytometry. RESULTS: SSc patients exhibited elevated percentages of T peripheral helper cells (Tph), CD4+GZMB+ T cells and decreased levels of Th1 cells compared with HD. Increased presence of both CD4+ and CD8+ exhausted-like (CD28-) T cells, characterized by raised cytokine and cytotoxic signature, was also observed in SSc compared with HD blood. Furthermore, IL-4 expressing CD4+CD8+ T cells were significantly increased in SSc peripheral blood. Interestingly, the presence of PAH in SSc was accompanied by a distinct T helper profile, characterized by raised percentages of Th17 and Tph cells. CONCLUSION: SSc patients with severe vasculopathy (presence of PAH) exhibited a distinct T cell profile, suggesting a potential role of auto-immune inflammation in SSc vascular complications.

Autoantibodies to nuclear valosin-containing protein-like protein: systemic sclerosis-specific antibodies revealed by in vitro human proteome.

OBJECTIVES: To identify and characterize undescribed systemic sclerosis (SSc)-specific autoantibodies targeting nucleolar antigens and to assess their clinical significance. METHODS: We conducted proteome-wide autoantibody screening (PWAS) against serum samples from SSc patients with nucleolar patterned anti-nuclear antibodies (NUC-ANAs) of specific antibodies (Abs) unknown, utilizing wet protein arrays fabricated from in vitro human proteome. Controls included SSc patients with already-known SSc-specific autoantibodies, patients with other connective tissue diseases and healthy subjects. The selection of nucleolar antigens was performed by database search in the Human Protein Atlas. The presence of autoantibodies was certified by immunoblots and immunoprecipitations. Indirect immunofluorescence assays on HEp-2 cells were also conducted. Clinical assessment was conducted by retrospective review of electronic medical records. RESULTS: PWAS identified three candidate autoantibodies, including anti-nuclear valosin-containing protein-like (NVL) Ab. Additional measurements in disease controls revealed that only anti-NVL Abs are exclusively detected in SSc. Detection of anti-NVL Abs was reproduced by conventional assays such as immunoblotting and immunoprecipitation. Indirect immunofluorescence assays demonstrated homogeneous nucleolar patterns. Anti-NVL Ab-positive cases were characterized by significantly low prevalence of diffuse skin sclerosis and interstitial lung disease, compared with SSc cases with NUC-ANAs other than anti-NVL Abs, such as anti-U3-RNP and anti-Th/To Abs. CONCLUSION: Anti-NVL Ab is an SSc-specific autoantibody associated with a unique combination of clinical features, including limited skin sclerosis and lack of lung involvement.

Pyroptosis and its role in autoimmune skin disease.

Autoimmune skin disease is a kind of heterogeneous disease with complicated pathogenesis. Many factors such as genetic, infectious, environmental and even psychological factors may interact together to trigger a synergistic effect for the development of abnormal innate and adaptive immune responses. Although the exact mechanisms remain unclear, recent evidence suggests that pyroptosis plays a pivotal role in the development of autoimmune skin disease. The feature of pyroptosis is the first formation of pores in cellular membranes, then cell rupture and the release of intracellular substances and pro-inflammatory cytokines, such as interleukin-1 beta (IL-1ß) and IL-18. This hyperactive inflammatory programmed cell death damages the homeostasis of the immune system and advances autoimmunity. This review briefly summarises the molecular regulatory mechanisms of pyrin domain-containing protein 3 (NLRP3) inflammasome and gasdermin family, as well as the molecular mechanisms of pyroptosis, highlights the latest progress of pyroptosis in autoimmune skin disease, including systemic lupus erythematosus, psoriasis, atopic dermatitis and systemic scleroderma and attempts to identify its potential advantages as a therapeutic target or prognostic biomarker for these diseases.

Insight into the role of IRF7 in skin and connective tissue diseases.

Interferons (IFNs) are signalling proteins primarily involved in initiating innate immune responses against pathogens and promoting the maturation of immune cells. Interferon Regulatory Factor 7 (IRF7) plays a pivotal role in the IFNs signalling pathway. The activation process of IRF7 is incited by exogenous or abnormal nucleic acids, which is followed by the identification via pattern recognition receptors (PRRs) and the ensuing signalling cascades. Upon activation, IRF7 modulates the expression of both IFNs and inflammatory gene regulation. As a multifunctional transcription factor, IRF7 is mainly expressed in immune cells, yet its presence is also detected in keratinocytes, fibroblasts, and various dermal cell types. In these cells, IRF7 is critical for skin immunity, inflammation, and fibrosis. IRF7 dysregulation may lead to autoimmune and inflammatory skin conditions, including systemic scleroderma (SSc), systemic lupus erythematosus (SLE), Atopic dermatitis (AD) and Psoriasis. This comprehensive review aims to extensively elucidate the role of IRF7 and its signalling pathways in immune cells and keratinocytes, highlighting its significance in skin-related and connective tissue diseases.

Bicaudal D2 autoantibodies are highly specific for systemic sclerosis.

OBJECTIVE: Autoantibodies directed against the intracellular protein bicaudal D2 (BICD2) have been identified as a specific marker of systemic sclerosis (SSc). Since autoantibodies are of value in predicting disease onset and identifying meaningful clinical subsets, as well as having prognostic value, this study aimed to establish the prevalence of BICD2 autoantibodies (anti-BICD2) in a cohort of patients with connective tissue disease and healthy controls. METHOD: In this cross-sectional study, 363 patients with connective tissue disease (121 SSc, 141 systemic lupus erythematosus, 101 myositis, and 100 blood donors) were tested for the presence of anti-BICD2. All SSc patients were tested for specific anti-nuclear antibodies (ANAs), and clinical and laboratory associations were evaluated in the SSc patients, stratified by anti-BICD2 status. RESULTS: In the SSc cohort, 35 patients had autoantibodies directed against BICD2. The specificity of anti-BICD2 in SSc patients was 96.5%; however, the sensitivity was only 28.9%. Anti-BICD2 and centromere autoantibodies were present together in 91% of the anti-BICD2-positive SSc patients, and in none of the cases was anti-BICD2 the only antibody present. Anti-BICD2-positive patients had lower forced expiratory volume in 1 s (FEV1) (p = 0.01) and lower carbon monoxide transfer coefficient (KCO) (p = 0.01) than anti-BICD2-negative SSc patients, but they had higher forced vital capacity (p = 0.03). CONCLUSION: Autoantibodies against BICD2 were highly specific for SSc patients. Reduced FEV1 and KCO in anti-BICD2-positive patients may indicate that the presence of anti-BICD2 is associated with altered lung function in an unknown pathophysiological manner, which awaits further elucidation.

Systemic sclerosis: one year in review 2024.

Systemic sclerosis (SSc) is a rare and chronic connective tissue disease of unknown aetiology and characterised by three main pathogenetic events represented by endothelial damage, inflammation with activation of the immune system leading to production of specific autoantibodies and finally fibrosis. SSc is a heterogeneous disease and the classification in two subsets, the limited cutaneous (lcSSc) subset and the diffuse cutaneous one (dcSSc), is not capable of capturing the broad and different phenotypic expression of the disease. In the last years progress has been made in the knowledge of SSc pathogenesis, in its early diagnosis and new therapeutic strategies have been proposed, however, the management of SSc still represents a challenge for the clinician. For this reason, every year several studies investigate new insights of disease pathogenesis, internal organ involvement and therapeutic approaches. The purpose of this review is to provide an overview of the literature published in 2023.

Systemic sclerosis and environment: an intriguing and still debated association.

Systemic sclerosis (SSc) is characterised by a heterogeneous clinical expression probably reflecting the different genetic background of each patient. Progress has been made in the definition of the principal pathogenetic events of the disease that can be summarised in endothelial damage and dysfunction, inflammation with activation of immune system and fibrosis. The aetiology of the disease still remains to be clarified and probably the first events are attributable to the repeated action of environmental stimuli in genetically predisposed subjects.The aim of the present manuscript is to review the most recent and relevant data regarding the association of SSc with environmental factors.

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.

Detection of IgE-autoantibodies to nuclear antigens in patients with systemic sclerosis and analysis of their clinical relevance.

OBJECTIVES: Antinuclear antibodies (ANA) of the IgE-type have been described in several connective tissue disorders (CTD) but not yet in systemic sclerosis (SSc). Aim of the study was, therefore, to establish an ELISA for the demonstration of IgE-autoantibodies to topoisomerase-I (topo-I) and the centromeric proteins A and B (CENP-A/B), to assess their prevalence and reactivity in SSc and to analyse their clinical relevance. METHODS: One hundred fifty-one patients with SSc and 88 with CREST-syndrome, 291 patients with other CTD, and 23 patients with fibromyalgia syndrome (FM) as a control collective were included into the study. Patients' sera were analysed by an in-house-ELISA for IgE autoantibodies against topo-I and CENP-A/B using recombinant antigens. Patients were assessed for median Rodnan skin score(mRSS), different organ and cutaneous manifestations. RESULTS: Of the patients with CREST syndrome, 67% had IgE-anti-CENP-A- and 77% IgE-anti-CENP-B-antibodies. IgE-anti-topo-I antibodies were found in 56% of patients with SSc. Prevalence and reactivity were significantly higher in CREST and SSc, respectively, than in other CTD or FM. IgE-reactivity strongly correlated with IgG-antibody reactivity. In CRESTsyndrome, IgE-anti-CENP-A (but not CENP-B)-antibodies were significantly higher and more prevalent in patients with skin ulcers, high mRSS, and more than four organ manifestations. They did not correlate with blood eosinophil counts. In contrast, for IgE-anti-topo-I antibodies no correlation with clinical manifestations was observed. CONCLUSIONS: IgE-autoantibodies against CENP-A/B and topo-I occur in SSc underlining the concept that SSc may be a T helper cell type 2 mediated disease. IgE-anti-CENP-A-antibodies correlated with disease activity, but this has to be confirmed in larger studies.

Potential efficacy of T and B lymphocyte-targeted therapies on articular involvement of patients with rheumatoid arthritis and systemic sclerosis overlap syndrome. Results from a 2-centre series of 19 cases.

OBJECTIVES: To analyse in routine practice the efficacy of targeted therapies on joint involvement of patients with rheumatoid arthritis/systemic sclerosis (RA/SSc) overlap syndrome. METHODS: This was a retrospective analysis of medical records of two academic centres over a 10-year period. Joint response to targeted therapies was measured according to EULAR criteria based on Disease Activity Score (DAS)-28. In addition, changes in CRP level and glucocorticoid consumption were recorded. RESULTS: Nineteen patients were included. Methotrexate (n=11) and hydroxychloroquine (n=4) were the most used first-line treatments. Targeted therapies were frequently used (n=14). Tocilizumab was the most selected therapy (n=8), then rituximab (n=5), abatacept and anti-tumour necrosis factor (n=4). Twenty-one treatment sequences were assessed, including 18 with EULAR response criteria. Responses were "good" or "moderate" in 100% (4/4) of patients treated with abatacept, 80% (4/5) with rituximab, 40% (2/5) with tocilizumab, and 25% (1/4) with anti-TNF. T and B lymphocyte-targeted therapies (abatacept, rituximab) resulted more frequently in a "good" or "moderate" response compared to cytokine inhibitors (tocilizumab, etanercept, infliximab) with a significant decrease in DAS-28 at 6 months (-1.75; p=0.016) and a trend to a lower consumption of glucocorticoids. CONCLUSIONS: In patients with RA/SSc overlap syndrome refractory to conventional synthetic-DMARDs, T and B lymphocyte-targeted therapies seem to be a promising therapeutic option to control joint activity.