Objectives SSc-interstitial lung disease (ILD) is one of the leading causes of mortality in SSc. Data from randomized controlled trials (RCTs) support rituximab and tocilizumab monotherapy but there are limited data regarding their use for those who fail standard immunomodulatory therapies.Methods SSc patients treated with rituximab or tocilizumab were retrospectively identified in a single centre cohort. Linear mixed effect models were used to analyse before and after treatment lung function trajectory, and identify patient characteristics associated with treatment response.Results A total of 127 patients were included for analysis. Fifty-one of 94 (54.2%) and 13 of 33 (39.4%) of the rituximab and tocilizumab cohorts, respectively, were receiving concurrent MMF. Pre-treatment decline in absolute change % forced vital capacity (%FVC)/year and % diffusion capacity for carbon monoxide (%DLCO)/year, respectively, was similar in both cohorts (-3.2% and -4.0% rituximab, and -3.2% and -3.6% tocilizumab). Both treatments resulted in lung function stabilization (%FVC/year and %DLCO/year: 1.2% and +0.2% rituximab cohort, 1.0% and 1.0% tocilizumab cohort). Anti-topoisomerase antibody (ATA)-positive patients had a significant response on %FVC/year to tocilizumab compared with ATA-negative patients. Gender had a significant impact on %FVC/year response to rituximab, with males responding to a greater degree than females. Age, ILD extent and skin subset had no impact on treatment response.Conclusion Combination rituximab or tocilizumab with background immunosuppressive therapy is associated with stabilization in lung function trajectory among those who remain refractory to standard immunosuppressives. Specific patient characteristics have an impact on lung function response. Improved FVC response among ATA patients receiving tocilizumab validate data from RCTs.

OBJECTIVES:To explore prognostic and predictive markers of SSc-associated interstitial lung disease (SSc-ILD) outcomes in a phase 3 trial (focuSSced) and prognostic markers in a real-world cohort (SMART). METHODS:The focuSSced SSc-ILD subgroup included 68 of 106 placebo-treated and 68 of 104 tocilizumab-treated patients. The SMART cohort included 505 patients with SSc-ILD. Linear mixed-effect models were used to identify factors associated with change in forced vital capacity (FVC). Kaplan-Meier estimation and Cox regression were used for time-to-event analyses. RESULTS:In placebo-treated focuSSced patients, sex was a significant prognostic factor for FVC decline; males had increased risk for absolute decline ≥10% in percent-predicted FVC (ppFVC) and 0.22% faster weekly FVC decline than females (P = 0.0001). FVC was 9.8% lower in patients with CRP >6 mg/ml vs those with CRP ≤6 mg/ml (P = 0.0059). Tocilizumab reduced the risk for ≥10% decline in ppFVC in patients who were male, had earlier disease (<2 years duration), had IL-6 levels <10 pg/ml, or had anti-topoisomerase antibodies (ATA). In the SMART cohort, prognostic factors for ppFVC <70% were male sex, ATA, and low baseline FVC. Males had 3.3% lower FVC 1 year after disease onset (P < 0.001) and 0.6% faster yearly decline (P = 0.03) than females. CONCLUSION:Prognostic markers in SSc-ILD were similar between focuSSced and SMART. Male sex and inflammatory markers were associated with lower FVC but IL-6 ≥10 pg/ml was not predictive of response to tocilizumab. TRIAL REGISTRATION:ClinicalTrials.gov: NCT02453256.

ObjectivePulmonary hypertension (PH) is a serious complication of systemic sclerosis (SSc). In this study, we explored the prediction of short‐term risk for PH using serial pulmonary function tests (PFTs) and other disease features.MethodsSSc patients in whom disease onset occurred ≥10 years prior to data retrieval and for whom autoantibody specificity and PFT data were available were included in this study. Mixed‐effects modeling was used to describe changes in PFTs over time. Landmarking was utilized to include serial assessments and stratified Cox proportional hazards regression analysis with landmarks as strata was used to develop the PH prediction models.ResultsWe analyzed data from 1,247 SSc patients, 16.3% of whom were male and 35.8% of whom had diffuse cutaneous SSc. Anticentromere, antitopoisomerase, and anti–RNA polymerase antibodies were observed in 29.8%, 22.0%, and 11.4% of patients, respectively, and PH developed in 13.6% of patients. Over time, diffusing capacity for carbon monoxide (DLco) and carbon monoxide transfer coefficient (Kco) declined in all SSc patients (up to 1.5% per year) but demonstrated much greater annual decline (up to 4.5% and 4.8%, respectively) in the 5–7 years preceding PH diagnosis. Comparisons between multivariable models including either DLco, Kco, or forced vital capacity (FVC)/DLco ratio, demonstrated that both absolute values and change over the preceding year in those measurements were strongly associated with the risk of PH (hazard ratio [HR] 0.93 and 0.76 for Kco and its change; HR 0.90 and 0.96 for DLco and its change; and HR 1.08 and 2.01 for FVC/DLco ratio and its change; P < 0.001 for all). The Kco‐based model had the greatest discriminating ability (Harrell's C‐statistic 0.903).ConclusionOur findings strongly support the importance of PFT trends over time in identifying patients at risk of developing PH.

Background There is a breadth of evidence supporting a key role for abnormal B-cell function in the pathogenesis of systemic sclerosis and associated interstitial lung disease (SSc-ILD) [1,2]. A previous pilot study investigated the efficacy of belimumab, a recombinant human immunoglobulin G1 lambda (IgG1λ) monoclonal antibody that binds to and neutralises B-lymphocyte stimulator (BLyS) subsequently inhibiting the survival of B cells [3], in reducing modified Rodnan skin score (mRSS) in 20 patients with SSc [4]. Belimumab is well tolerated and is approved for the treatment of patients with active systemic lupus erythematosus and active lupus nephritis receiving standard therapy [5].We hypothesise that by reducing the number of B cells and dampening B-cell effector functions in the circulation and tissue, belimumab will reduce inflammation and fibrosis across multiple organ systems in patients with SSc. This will result in the stabilisation of, and/or reduction in, lung function decline and skin thickening in SSc, and improvements in patients' quality of life. Objectives To present the design of a randomised controlled trial that will evaluate the efficacy and safety of subcutaneous (SC) belimumab versus placebo in adult patients with SSc-ILD. Methods In this global, parallel-group, Phase 2/3, randomised, double-blind, placebo-controlled, two-arm, 52-week study (GSK Study 218224), eligible adults with a documented diagnosis of SSc and ILD (as confirmed by high-resolution computed tomography) will be randomised 1:1 to receive either belimumab 200 mg SC weekly (Arm 1), or matching SC placebo weekly (Arm 2), for 52 weeks (Figure 1). Participants will be permitted to continue their stable doses of standard therapy throughout the study. The primary endpoint of the study is absolute change from baseline in forced vital capacity (ml) at Week 52. Key secondary endpoints, analysed at Week 52, include: absolute change from baseline in mRSS, absolute change from baseline in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, and SSc progression or death. Patient-reported outcomes (listed in the Figure 1) will also be assessed. A comprehensive biomarker approach will be implemented to evaluate the belimumab modulating effects on key biological processes involved in SSc pathogenesis (fibrosis and inflammation) in circulation and in skin biopsies. Safety will be monitored throughout the study. Results Target sample size is planned to be approximately 300 patients, with 150 patients per arm. Conclusion We present the design of a global Phase 2/3 study that will test the efficacy and safety of SC belimumab in patients with SSc-ILD. Together, the study endpoints enable the assessment of the efficacy of belimumab on a broad range of disease manifestations, disease progression, and impact on patient burden and survival. References [1]Thoreau B et al. Front Immunol 2022;13:933468[2]Ebata S et al. J Dermatol 2022;49:179–83[3]Huang W et al. JCI Insight 2018;3:e122525[4]Gordon JK et al. Arthritis Rheumatol 2018;70:308–16[5]GSK. Benlysta US prescribing information. 2022[6]van den Hoogen F et al. Ann Rheum Dis 2013;72:1747–55 Acknowledgements Study funded by GSK (GSK Study 218224). Medical writing support was provided by Olivia Hill, MPharmacol, Fishawack Indicia Ltd, UK, part of Fishawack Health, and was funded by GSK. Disclosure of Interests Christopher P Denton Speakers bureau: Janssen; Boehringer Ingelheim, Consultant of: GSK, CSL Behring, Boehringer Ingelheim, Merck, Roche, Sanofi, Grant/research support from: GSK, CSL Behring, Inventiva, Horizon, Robert Spiera Consultant of: GSK, Regeneron, Abbvie, Sanofi, Chemocentryx, Novartis, Galderma, Vera, Chemomab, Boehringer Ingelheim, BMS, Grant/research support from: Roche-Genentech, AstraZeneca, GSK, Kadmon, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Novartis, Inflarx, Principia, Distler Jörg Speakers bureau: AbbVie, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Janssen and UCB, Consultant of: AbbVie, Active Biotech, Anamar, ARXX, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Celgene, Galapagos, GSK, Inventiva, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: Anamar, ARXX, BMS, Bayer Pharma, Boehringer Ingelheim, Cantargia, Celgene, CSL Behring, Galapagos, GSK, Inventiva, Kiniksa, Sanofi-Aventis, Tanabe-Mitsubishi RedX, UCB, Employee of: JHWD is stock owner of 4D Science and Scientific Lead of FibroCure, Dinesh Khanna Speakers bureau: Janssen, Consultant of: Actelion, Amgen, Boehringer Ingelheim, GSK, Horizon, Janssen, Prometheus, Talaris, Grant/research support from: BMS, Pfizer, Boehringer Ingelheim, Michael Kreuter Speakers bureau: Boehringer Ingelheim, Roche, Consultant of: Boehringer Ingelheim, Roche, GSK, Grant/research support from: Boehringer Ingelheim, Roche, Masataka Kuwana Speakers bureau: Abbvie, Asahi-Kasei, Astellas, Boehringer Ingelheim, Chugai, Eisai, MBL, Mochida, Nippon Shinyaku, Ono Pharmaceuticals, Tanabe-Mitsubishi, Consultant of: AstraZeneca, Boehringer Ingelheim, Chugai, Corbus, GSK, Horizon, Tanabe-Mitsubishi, Grant/research support from: Boehringer-Ingelheim, Elizabeth Volkmann Speakers bureau: Former member of speakers bureau for Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Roche, GSK, Galderma, CLS Behring, Grant/research support from: Boehringer Ingelheim, Kadmon, Horizon, Prometheus, Jasna Cotic Employee of: GSK, Olaide Raji Employee of: GSK, Anne Hammer Shareholder of: GSK, Employee of: GSK, Chiara Zeccin Shareholder of: GSK, Employee of: GSK, Andre van Maurik Shareholder of: GSK, Employee of: GSK, Jose Miyar Olaiz Shareholder of: GSK, Employee of: GSK, William Fahy Employee of: GSK, Ryan Tomlinson Shareholder of: GSK, Employee of: GSK, Daniela Dastros-Pitei Shareholder of: GSK, Employee of: GSK, Svetlana Nihtyanova Shareholder of: GSK, Consultant of: Roche, Employee of: GSK, Elaine Irving Employee of: GSK, Toby Maher Speakers bureau: BI, Roche/Genentech,United Therapeutics, Consultant of: BI, Roche, AZ, BMS, GSK, Pfizer, Sanofi, United Therapeutics, Grant/research support from: AZ, GSK.Figure 1Study design*An open-label extension will be performed.FVC, forced vital capacity; R, randomisation

Background EULAR Sjögren’s syndrome disease activity index (ESSDAI) assesses systemic disease activity in patients (pts) with primary Sjögren’s syndrome (pSS); however, weaknesses include exclusion of patient-reported symptoms, tear and salivary gland function, and a marked placebo (PBO) response. Composite of Relevant Endpoints for Sjögren’s Syndrome (CRESS) is a recently developed composite outcome measure validated using data from three Phase 3 randomised controlled trials of pts with pSS. 1 Concise CRESS (cCRESS) is used when ocular staining score and salivary gland ultrasonography are unavailable. ESSDAI was an endpoint in a Phase 2, PBO-controlled study, evaluating the safety and efficacy of belimumab (BEL) and rituximab (RTX) sequential administration (BEL/RTX), and BEL and RTX monotherapies in pts with pSS. Although the results numerically favoured BEL/RTX over PBO, this was not statistically significant. Objectives To evaluate the efficacy of BEL/RTX and monotherapies using cCRESS overall responses at Weeks (Wks) 24, 52, and 68, and individual item responses at Wk 24 in pts with pSS who completed the Phase 2 study. Methods In the Phase 2, double-blind, 68-Wk study ( NCT02631538 ) adults were randomised (2:2:2:1) into 4 treatment arms: BEL/RTX (n=24; weekly BEL 200 mg subcutaneous [SC] to Wk 24 followed by weekly PBO SC to Wk 52 + RTX 1000 mg intravenous [IV], Wk 8 + 10), BEL monotherapy (n=24; weekly BEL 200 mg SC to Wk 52), RTX monotherapy (n=25; RTX 1000 mg IV, Wk 8 + 10), or PBO (n=13). Pts were classified post hoc as cCRESS responders when ≥3 of the following 5 items were met: 1) Clinical (Clin)ESSDAI score <5 (low disease state); 2) decrease of ≥1 point or ≥15% from baseline (BL) in EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI); 3) increase of ≥5 mm from BL in abnormal Schirmer’s test, or no change to abnormal if normal at BL; 4) unstimulated whole saliva (UWS) increase of ≥25% from BL, or any increase from BL if score was 0 at BL; 5) decrease of ≥25% in the rheumatoid factor (RF) titre from BL, or decrease of ≥10% in IgG from BL. 1 Results Of 86 randomised pts, 60 completed follow-up to Wk 68 (completer population) and were included in the analysis. Most pts were female (95%, n=57); mean (SD) age was 49.6 (13.0) years. BL disease characteristics are presented in the Table 1. Table 1. Clinical, functional, and laboratory parameters at BL and cCRESS responders at Wks 24, 52, and 68 (completer population) PBO (n=8) BEL/RTX (n=17) BEL (n=19) RTX (n=16) Pt parameters at BL, mean (SD ) ClinESSDAI 11.1 (3.76) 11.7 (5.47) 9.2 (3.77) 11.7 (4.76) ESSPRI 6.4 (2.05) 6.0 (1.97) 6.5 (1.68) 5.9 (2.20) Schirmer, mm/5 min 2.7 (3.25) 5.3 (6.44) 3.3 (3.16) 2.8 (3.15) UWS, ml/min 0.1 (0.11) 0.1 (0.12) 0.1 (0.09) 0.1 (0.14) RF, KU/l 60.8 (42.24) 30.9 (38.20) 37.0 (34.98) 105.0 (200.97) IgG, g/l 20.4 (6.65) 16.7 (5.00) 18.1 (7.19) 16.5 (6.09) cCRESS responders, n (% ) Wk 24 4 (50.0) 9 (52.9) 7 (36.8) 5 (31.3) Wk 52 4 (50.0) 10 (58.8) 8 (42.1) 4 (25.0) Wk 68 1 (12.5) 6 (35.3) 7 (36.8) 3 (18.8) At Wks 24 and 52, the proportion of cCRESS responders was numerically higher with BEL/RTX than with either BEL, RTX, or PBO, but the difference was not significant (Table 1). At Wk 68, the proportion of cCRESS responders was numerically higher with BEL/RTX than with RTX or PBO (Table 1). The 5 cCRESS items contributed relatively equally to total cCRESS response, with the highest response observed in the RF/IgG item and the lowest in the tear gland item (Schirmer’s test; Figure 1). Figure 1. cCRESS and individual item responders at Wk 24 (completer population ) Conclusion At Wks 24, 52, and 68, BEL/RTX was generally associated with a numerically higher cCRESS response rate compared with the monotherapies or PBO. The PBO response for cCRESS was notable and similar to the PBO response for ClinESSDAI. The PBO response in the tear and salivary gland items was greater than in the other treatment arms, perhaps due to the use of cCRESS instead of CRESS. Due to the small sample size, the results should be interpreted with caution. References [1]Arends S, et al. Lancet Rheumatol 2021;3:553–62 Acknowledgements This post hoc analysis of the GSK Study 201842 was funded by GlaxoSmithKline (GSK). Medical writing support was provided by Casmira Brazaitis, PhD, Fishawack Indicia Ltd, UK, part of Fishawack Health, and was funded by GSK. Disclosure of Interests Hendrika Bootsma Consultant of: BSM, Roche, Novartis, Medimmune and Union Chimique Belge, Grant/research support from: BSM and Roche, Suzanne Arends: None declared, Liseth de Wolff: None declared, Kenneth L Clark Shareholder of: GSK, Employee of: GSK, Andre van Maurik Shareholder of: GSK, Employee of: GSK, Prafull Mistry Shareholder of: GSK, Employee of: GSK, Pragya Shukla Shareholder of: GSK, Employee of: GSK, Svetlana Nihtyanova Shareholder of: GSK, Consultant of: Roche, Employee of: GSK, Norma Lynn Fox Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK

OBJECTIVES:The aim of this study was to explore outcomes in a cohort of dcSSc patients fulfilling eligibility criteria for stem cell transplantation (SCT) studies but receiving standard immunosuppression. METHODS:From a large single-centre dcSSc cohort (n = 636), patients were identified using the published SCT trials' inclusion criteria. Patients meeting the trials' exclusion criteria were excluded. RESULTS:Of the 227 eligible patients, 214 met the inclusion criteria for ASTIS (Autologous Stem Cell Transplantation International Scleroderma), 82 for SCOT (Scleroderma: Cyclophosphamide Or Transplantation) and 185 for the UPSIDE (UPfront autologous haematopoietic Stem cell transplantation vs Immunosuppressive medication in early DiffusE cutaneous systemic sclerosis) trial, and 66 were excluded based on age >65 years, low diffusing capacity of the lungs for carbon monoxide (DLco), pulmonary hypertension or creatinine clearance <40 ml/min. The mean follow-up time was 12 years (s.d. 7). Among the eligible patients, 103 (45.4%) died. Survival was 96% at 2 years, 88% at 5 years, 73% at 10 years and 43% at 20 years. Compared with this 'SCT-eligible' cohort, those patients who would have been excluded from SCT trials had a worse long-term survival (97% at 2 years, 77% at 5 years, 52% at 10 years and 15% at 20 years, log rank P < 0.001). Excluded patients also had a significantly worse long-term event-free survival. Hazard of death was higher in patients with higher age at onset [hazard ratio (HR) 1.05, P < 0.001], higher ESR at baseline (HR 1.01, P = 0.025) and males (HR 2.12, P = 0.008). CONCLUSION:SCT inclusion criteria identify patients with poor outcome despite current best practice treatment. Patients meeting the inclusion criteria for SCT but who would have been excluded from the trials because of age, pulmonary hypertension, poor kidney function or DLco <40% had worse outcomes.

Objectives To assess the prevalence and burden of SSc-related gastrointestinal dysfunction (SSc-GI) and to evaluate associations with demographic, clinical and serological characteristics. Methods Patients completed the UCLA SCTC GIT 2.0 questionnaire for SSc-GI disease to assess the burden of GI disease across multiple functional and psychological domains. Questionnaire scores were assessed using non-parametric and quantile regression analyses. Results Our cohort included 526 patients with SSc, with a typical distribution of disease-associated autoantibodies (ACA, ARA, ATA, PM-Scl, U1RNP, U3RNP). We demonstrated associations between hallmark antibodies and the domain-specific burden of GI disease. In particular, ACA, ARA and ENA-negative demonstrated increased SSc-GI disease burden, while PM-Scl conferred relative protection. In a distributional analysis, associations with autoantibodies were particularly marked in those with the highest burden of GI disease. Conclusion There is a significant burden of SSc-GI disease in patients with SSc; reflux and bloating symptoms are most prominent. SSc hallmark antibodies may predict increased risk of SSc-GI disease, in particular ACA and ARA, while PM-Scl may be protective.

Background: Linear morphoea is a severe morphoea subtype associated with extracutaneous manifestations, potentially permanent disfigurement and functional impairment. Linear morphoea is more prevalent in paediatric patients, and knowledge of disease in adults is limited. The objective of this study was to compare paediatric- and adult-onset linear morphoea, in an exclusively adult population. Methodology: This was a retrospective cohort study of adult patients with linear morphoea seen over a 3-year period at a single-site adult tertiary-referral Connective Tissue Disease centre. Clinical markers of disease severity and course, including anatomical distribution, extracutaneous manifestations, cutaneous symptoms, associated autoimmunity, inflammatory blood parameters, Dermatology Life Quality Index scores, treatment requirements and modified Localised Scleroderma Activity Tool were assessed and compared in paediatric- and adult-onset linear morphoea. Results: Of 298 patients with morphoea seen during the study period, 135 had linear morphoea and 133 were included in the study. Most were female (78.9%), the mean age was 36.5 years and almost half (43.6%) had adult-onset disease. Disease was similarly severe between groups with regard to anatomical distribution, cutaneous symptoms (n = 89, 66.9%), extracutaneous manifestations (n = 76, 57.1%), antinuclear antibody-positivity (n = 40, 40.4%), raised erythrocyte sedimentation rate (n = 27, 25.0%) and associated autoimmune diagnoses (n = 15, 11.3%). Prescribed treatments were similar between groups; 73.7% receiving methotrexate and almost one-third (32.3%) requiring more than one steroid-sparing agent. Those with paediatric-onset had more disease-related damage, with a mean modified Localised Scleroderma Skin Damage Index score of 19.5 (95% confidence interval: 17.0-22.0) versus 8.1 (95% confidence interval: 4.4-11.8; p < 0.001). Significantly more patients with adult-onset linear morphoea had quiescent disease (p = 0.0332), and even after correcting for disease duration, paediatric-onset patients still had 2.6 times greater odds of active disease (odds ratio = 2.59, 95% confidence interval: 0.9-7.6; p = 0.083). Conclusion: Linear morphoea in adults can be a severe disease with extracutaneous, autoimmune and systemic features. Adults with paediatric-onset disease appear to have more severe cumulative damage, greater functional impairment and ongoing disease activity. This patient subgroup may require particularly close monitoring and more aggressive therapy.

Abstract Background Skin thickness improves over time in most diffuse cutaneous systemic sclerosis (dcSSc) patients and the use of group level skin score (mRss) as an endpoint is clinical trials can be challenging. We explore the association between individual mRss trajectories and outcome in early dcSSc patients. Methods Subjects with at least one mRss assessment within the first 5 years from onset were included. Random effects models were fitted to evaluate changes in mRss over time and model-predicted individual patient intercepts and slopes were included in Cox regression to assess associations with outcome. Results Of the 467 patients, 22.7% were male and mean age of disease onset was 45.5 years. Most frequent autoantibodies were anti-Scl70 in 30.2% and anti-RNA polymerase (ARA) in 30.0% of subjects. Average mRss at 12 months from onset was 25 and this declined over time, slowing down with longer disease duration (3.4, 2.7, 1.9 and 1.2 units at years 2, 3, 4 and 5). Higher initial mRss associated with greater subsequent decline (correlation coefficient -0.3). Both higher baseline mRSS (intercept) and slower decline (higher slope) predicted increased risk of death with 8% increase in hazard for every unit higher baseline mRss and 4% increase for every unit higher slope (Table 1). Adjusting for autoantibodies did not change the estimates. ANA+ENA- subjects had the highest risk of death, followed by ATA + (HR 0.91, p = 0.677 v ANA+ENA-), while risk was lowest among ARA+ subjects (HR 0.47, p = 0.002 v ANA+ENA-). Risk of pulmonary complications was associated with rate of change in mRss but not with baseline absolute value. A unit slower yearly decline in mRss increased the hazard of pulmonary fibrosis (PF) by 3.5% and pulmonary hypertension (PH) by 7% (Table 1). The association between mRss and PF disappeared after adjusting for antibody specificities, while the association between skin and PH did not change. Autoantibodies did not show significant association with PH development within this dcSSc cohort. Conclusion Although at a group level there is an improvement in skin over the initial 5 years, for individual patients, poor outcome for skin predicts increased risk of pulmonary complications and higher mortality. Disclosures S.I. Nihtyanova None. E.C. Derrett-Smith None. C. Fonseca None. V.H. Ong None. C.P. Denton None.

Objective Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc) strongly associated with anti-RNA polymerase III antibody (ARA) autoantibodies. We investigated genetic susceptibility and altered protein expression in renal biopsy specimens in ARA-positive patients with SRC. Methods ARA-positive patients (n = 99) with at least 5 years’ follow-up (49% with a history of SRC) were selected from a well characterized SSc cohort (n = 2254). Cases were genotyped using the Illumina Human Omni-express chip. Based on initial regression analysis, 9 single-nucleotide polymorphisms (SNP) were chosen for validation in a separate cohort of 256 ARA-positive patients (40 with SRC). Immunostaining of tissue sections from SRC or control kidney was used to quantify expression of candidate proteins based upon genetic analysis of the discovery cohort. Results Analysis of 641,489 SNP suggested association of POU2F1 (rs2093658; P = 1.98 × 10−5), CTNND2 (rs1859082; P = 5.58 × 10−5), HECW2 (rs16849716; P = 1.2 × 10−4), and GPATCH2L (rs935332; P = 4.92 × 10−5) with SRC. Further, the validation cohort showed an association between rs935332 within the GPATCH2L region, with SRC (P = 0.025). Immunostaining of renal biopsy sections showed increased tubular expression of GPATCH2L (P = 0.026) and glomerular expression of CTNND2 (P = 0.026) in SRC samples (n = 8) compared with normal human kidney controls (n = 8), despite absence of any genetic replication for the associated SNP. Conclusion Increased expression of 2 candidate proteins, GPATCH2L and CTNND2, in SRC compared with control kidney suggests a potential role in pathogenesis of SRC. For GPATCH2L, this may reflect genetic susceptibility in ARA-positive patients with SSc based upon 2 independent cohorts.

Objective. To investigate the association between proton pump inhibitor (PPI) use and the presence and severity of calcinosis in SSc.Methods. We analysed data from two SSc cohorts from a single centre. Cohort 1 included 199 patients reviewed over 10 years, for whom retrospective data on PPI use and calcinosis were available. Cohort 2 was recruited prospectively and included 215 consecutive patients, who underwent clinical assessment. Outcomes of interest were presence of current calcinosis (CC) or calcinosis at any time (CAT).Results. The cohort 1 data analysis showed that among patients on standard dose PPI 20% had calcinosis, while in those on high doses of PPI calcinosis was present in 39% (P = 0 .003) . Analysis of the data from cohort 2 confirmed these findings, demonstrating that the odds of CAT increased significantly with longer PPI exposure [odds ratio (OR) 1.04, 95% CI: 1.02, 1.06; P < 0.001], longer disease duration (OR 1.08, 95% CI: 1.05, 1.12; P < 0.001) and greater age (OR 1.03, CI: 1.01, 1.05; P = 0 .010) . Multivariable logistic regression showed that higher exposure to PPI remained a significant predictor of calcinosis, with PPI exposure >10years increasing the risk of CAT >6-fold, compared with no PPI (OR 6.37, 95% CI: 1.92, 21.17; P = 0 .003) after adjusting for disease duration and antibodies.Conclusion. We confirm a significant association between high PPI exposure with severity of calcinosis in SSc. Given the clinical impact of calcinosis and reflux in SSc, PPI exposure as a potentially modifiable risk factor for calcinosis requires further evaluation.

Systemic sclerosis is an autoimmune disease leading to vasculopathy and fibrosis of skin and internal organs. Despite likely shared pathogenic mechanisms, the patterns of skin and lung fibrosis differ. Pathogenesis of interstitial lung disease, a major cause of death in systemic sclerosis, reflects the intrinsic disease pathobiology and is associated with distinct clinical phenotypes and laboratory characteristics. The commonest histological pattern of systemic sclerosis-interstitial lung disease is non-specific interstitial pneumonia. Systemic sclerosis-interstitial lung disease pathogenesis involves multiple components, including susceptibility and triggering factors, which could be genetic or environmental. The process is amplified likely through ongoing inflammation and the link between inflammatory activity and fibrosis with IL6 emerging as a key mediator. The disease is driven by epithelial injury, reflected by markers in the serum, such as surfactant proteins and KL-6. In addition, mediators that are produced by epithelial cells and that regulate inflammatory cell trafficking may be important, especially CCL2. Other factors, such as CXCL4 and CCL18, point towards immune-mediated damage or injury response. Monocytes and alternatively activated macrophages appear to be important. Transforming growth factor beta appears central to pathogenesis and regulates epithelial repair and fibroblast activation. Understanding pathogenesis may help to unravel the stages of systemic sclerosis-interstitial lung disease, risks of progression and determinants of outcome. With this article, we set out to review the multiple factors, including genetic, environmental, cellular and molecular, that may be involved in the pathogenesis of systemic sclerosis-interstitial lung disease and the mechanisms leading to sustained fibrosis. We propose a model for the pathogenesis of systemic sclerosis-interstitial lung disease, based on the available literature.

Abstract Background Pulmonary fibrosis (PF) is common in systemic sclerosis (SSc) and serial pulmonary function tests (PFTs) are used for routine PF monitoring. Forced vital capacity (FVC) decline reflects progression in PF and FVC is frequently used as an endpoint in clinical trials. We explore the changes in FVC over time in patients with SSc-PF, receiving standard management, including immunosuppression. Methods Only SSc patients with CT-confirmed PF were included. FVC changes over the first 10 years from onset and their associations were assessed using linear mixed effects models. Predictors of time from first PFT to development of threshold FVC (FVC<70% and FVC<50%) were analysed using Cox regression. Results We identified 505 SSc-PF subjects, 21.6% were male, average age at onset was 47 years and 49.3% had diffuse cutaneous subset (dcSSc). The most common autoantibody was anti-Scl70 in 40.4%, followed by anti-RNA polymerase (ARA) in 11.7% and anti-centromere (ACA) in 7.1%. In 16.4% of the patients, ANA was positive, but no ENAs were identified (ANA+ENA-). Average FVC at 12 months from onset was 80.1% (SD 19.3) and this declined by 0.32% per year (p = 0.007) at a group level. There was no significant correlation between baseline FVC and subsequent change (correlation coefficient -0.13; 95%CI -0.26, 0.01). For every year older age at onset, average FVC increased by 0.32%, p < 0.001. Males had 3.3% lower FVC at 1 year from onset (p < 0.001) and 0.6% faster decline per year (p = 0.034) compared to females. DcSSc subjects had 5.6% lower FVC compared to limited disease (p = 0.003). Average FVC at 1 year from onset in ARA+ subjects were higher than any other antibody (15.1% v. ANA+ENA-, p < 0.001; 14.6% v. ATA, p < 0.001 and 12.5% v. ACA, p = 0.010). Nevertheless, ARA+ subjects had FVC decline rates similar to ATA+ and ANA+ENA- subjects, while ACA+ patients had a small but significant increase in FVC over time. Factors that increased the risk for FVC drop below the thresholds were male sex, ATA and low baseline FVC (Table 1). Conclusion This study provides insight into long-term patterns of FVC change and develops a model that may help predict those most at risk of significant decline. Disclosures S.I. Nihtyanova None. E.C. Derrett-Smith None. C. Fonseca None. V.H. Ong None. C.P. Denton None.

Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5 , and one in each of STAT4 , CD226 and IRAK1 , selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population ( n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10–1.54), p corr = 0.015) and rs10488631 (OR 1.48 (1.14–1.92), p corr = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18–1.73), p corr = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5 , rs10488631 (OR 1.72 (1.24–2.39), p corr = 0.0098), and rs2004640 (OR 1.39 (1.11–1.75), p corr = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45–2.38), p corr = 6.6 × 10 −6 ). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51–0.85), p corr = 0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD. Key points • We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole. • None of the tested SNPs were risk factors for SSc-ILD specifically. • The STAT4 rs7574865 T allele was protective against the development of lung fibrosis in SSc patients. • Further work is required to understand the genetic basis of lung fibrosis in association with scleroderma.

Abstract Background The FaSScinate and FocuSSced trials of tocilizumab versus placebo in early diffuse systemic sclerosis (SSc) highlighted the potential impact of tocilizumab on lung function with preservation of lung function in those treated with tocilizumab versus placebo, despite only a trend of benefit for skin fibrosis. Our centre have been using tocilizumab to treat SSc patients and overlap inflammatory arthritis, in line with NICE guidance treatment for inflammatory arthritis. We report here our experience of tocilizumab in SSc and the impact on lung function. Methods A retrospective medical chart review of patients attending our centre with SSc and having ever been on tocilizumab were identified, mostly with overlap inflammatory arthritis. Patients included in the FaSScinate trial were excluded, however patients receiving compassionate use of tocilizumab following the phase 3 FocuSSced trial were included. Mann-Whitney-U test was used for statistical analysis. Results In total 32 patients were identified. 68.8% (n = 22) of patients had a diagnosis of dcSSc. 75% (n = 24) patients were female. The most common autoantibodies were ATA (anti-topoisomerase antibody) (34.3%) and ARA (anti-RNA polymerase-III antibody) (18.8%). 46.9% (n = 17) patients had known interstitial lung disease. 6 patients received tocilizumab on a compassionate basis following completion of the open label phase of the focuSSced clinical trial, the remainder had overlap inflammatory arthritis. Mean age of disease onset was 38.6 years, and the median disease duration to tocilizumab initiation was 7.9 years. 11 patients discontinued tocilizumab: 6 due to cessation of the compassionate use access, 2 due to side effects, 3 due to lack of benefit. 75% (n = 24) patients had serial lung function data to compare FVC and DLCO before and after initiation of treatment. Baseline FVC prior to tocilizumab was 3.09L (sd = 0.98). To standardise results, the yearly change rate in FVC and DLCO was calculated. Median change in % predicted FVC was -1.5% (IQR=0.107) and median change in % predicted DLCO was -0.5% (IQR=0.061). Subgroup analysis revealed a significant difference between autoantibody groups and change in FVC while on tocilizumab. It was notable that there was an increase in median change in FVC in patients with ATA antibody (3.27%, IQR=0.1355) whereas there was a decrease in median change in FVC in all other autoantibody groups (-4.7%, IQR=0.111, p = 0.0019). There was a near significant difference in change in DLCO between these antibodies at 12 months (p = 0.056) in favour of improvement in ATA subgroup. Conclusion We report our experience of the impact of tocilizumab on lung function in SSc. Consistent with trial results, there is a signal of potential benefit for lung function among those with ATA autoantibody irrespective of disease subset. As this autoantibody confers high risk of extensive lung fibrosis in SSc it may help in future case selection. Disclosures K.E.N. Clark None. Y. Suleman None. S.I. Nihtyanova None. V.H. Ong None. C.P. Denton Grants/research support; Actelion, GlaxoSmithKline, Bayer, Sanofi, lnventiva, Boehringer Ingelheim, Roche, Bristol Myers Squibb, CSL Behring, UCB, Leadiant Biosciences.

Background: Systemic sclerosis (SSc) is typically manifests with distinct SSc-specific antibodies (SSc-Abs): anti-topoisomerase I (ATA), anti-centromere (ACA), anti-RNA polymerase III (ARA), anti-U3RNP (u3RNP), anti-U1RNP (U1RNP), anti-PmScl (PmScl), anti-Ku (Ku) and anti-Th/T0 (Th/T0), each being characterised by different clinical features and prognosis. The presence of >1 SSc-Abs is rare with minimum data about these patients’ clinical phenotype. Objectives: To describe and compare the clinical features of SSc patients with >1 SSc-Ab Methods: The autoantibody profiles of 2799 SSc patients from February 2001 to June 2017 were retrospectively reviewed. Patients with >1 SSc-Abs were identified. Clinical features were collected and compared to historical cohorts of SSc patients with single SSc-Ab positivity. Patients were excluded if treated prior to their immunology test with rituximab, iv immunoglobulins or stem cell transplantation. Statistical analysis was performed using Fisher exact test. Results: 72 patients (2.6%) with >1 SSc-Ab were identified. Full clinical data were available for 63 patients. 60 patients (2.1%) had double Ab positivity and 3 patients had triple Ab positivity (0.1%). 13 Ab combinations were present. U1RNP and ATA was the most frequent combination (35%), patients were significantly younger (51.38 years) than both U1RNP (58.64 years, p=0.050) and ATA (62.03 years, p=0.002) patients and more commonly of diffuse subset (dcSSc) (p=0.001 and p=0.041 respectively). Compared to ATA patients overlap features were more frequent (43% vs 15%, p=0.004) including inflammatory arthritis (p=0.025) and myositis (p=0.013) (Table 1). U1RNP and ACA had a significantly higher prevalence of pulmonary arterial hypertension compared to U1RNP (p=0.039) and ACA (p=0.022) patients, and compared to ACA patients they were younger (57.88 vs 68.75, p=0.015) with a higher incidence of myositis (p=0.001). U1RNP and ARA patients were more frequently dcSSc subtype compared to U1RNP patients (75% vs 21%, p=0.040). U1RNP and PmScl patients had a higher prevalence of myositis compared to U1RNP patients (p=0.006). ATA and ACA patients behaved similarly to ATA patients with a significantly higher prevalence of lung fibrosis (p=0.006) and myositis (p=0.041) compared to ACA. ACA and PmScl (7%) had higher prevalence of myositis compared to ACA patients (p=0.04). Table 1. Frequency of clinical features in some of the double antibody group combinations, compared to our cohort of patients with only one of the SSc specific antibody. Significant p values (<0.05) highlighted in bold. ILD (interstitial lung disease), PAH (pulmonary arterial hypertension), SRC (scleroderma renal crisis). Conclusion: Coexistence of hallmark autoantibodies is exceedingly rare in SSc patients. When combined, both SSc-Abs have the potential to synergistically interact and modify the clinical phenotype. Disclosure of Interests: Corrado Campochiaro Speakers bureau: Novartis, Pfizer, Roche, GSK, SOBI, Kristina Clark: None declared, Lauren Host: None declared, Alper Sari: None declared, Svetlana Nihtyanova: None declared, Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Voon Ong: None declared