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The Canadian Tofacitinib for Rheumatoid Arthritis Observational (CANTORAL) is the first Canadian prospective, observational study assessing tofacitinib. The objective was to assess effectiveness and safety for moderate to severe rheumatoid arthritis (RA). Coprimary and secondary outcomes are reported from an interim analysis.Patients initiating tofacitinib from October 2017 to July 2020 were enrolled from 45 Canadian sites. Coprimary outcomes (month 6) included the Clinical Disease Activity Index (CDAI)-defined low disease activity (LDA) and remission. Secondary outcomes (to month 18) included the CDAI and the 4-variable Disease Activity Score in 28 joints (DAS28) using the erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) level to define LDA and remission; the proportions of patients achieving mild pain (visual analog scale20 mm), and moderate (≥30%) and substantial (≥50%) pain improvements; and the proportions of patients achieving a Health Assessment Questionnaire disability index (HAQ DI) score greater or equal to normative values (≤0.25) and a HAQ DI score greater or equal to minimum clinically important difference (MCID) (≥0.22). Safety was assessed to month 36.Of 504 patients initiating tofacitinib, 44.4% received concomitant methotrexate. At month 6, 52.9% and 15.4% of patients were in CDAI-defined LDA and remission, respectively; a similar proportion of patients achieved outcomes by month 3 (first post-baseline assessment). By month 3, 27.2% and 41.7% of patients, respectively, were in DAS28-ESR-defined LDA and DAS28-CRP3.2; 14.7% and 25.8% achieved DAS28-ESR remission and DAS28-CRP2.6. By month 3, mild pain and moderate and substantial pain improvements occurred in 29.6%, 55.6%, and 42.9% of patients, respectively; 19.9% and 53.7% of patients achieved a HAQ DI score greater than or equal to normative values and a HAQ DI score greater than or equal to MCID, respectively. Outcomes were generally maintained to month 18. Incidence rates (events per 100 patient-years) for treatment-emergent adverse events (AEs), serious AEs, and discontinuations due to AEs were 126.8, 11.9, and 14.5, respectively, and AEs of special interest were infrequent.Tofacitinib was associated with early and sustained improvement in RA signs and symptoms in real-world patients. Effectiveness and safety were consistent with the established tofacitinib clinical profile.

Background Fatigue is a common symptom of systemic autoimmune rheumatic disease (SARD). Patients with SARD have a protracted pre-clinical phase during which progressive immunologic derangements occur culminating in disease. In this study, we sought to determine when fatigue develops and whether its presence correlates with inflammatory factors or predicts disease progression. Methods Anti-nuclear antibody (ANA)-negative healthy controls (HCs) and ANA-positive participants with no criteria, at least one clinical criteria (undifferentiated connective tissue disease, UCTD), or meeting SARD classification criteria were recruited. Fatigue was assessed using a modified version of the FACIT-F questionnaire and the presence of fibromyalgia determined using a questionnaire based on the modified 2010 ACR criteria. Peripheral blood expression of five IFN-induced genes was quantified by NanoString and the levels of IL-1β, IL-6, or TNF-α by ELISA. Results Fatigue was as prevalent and severe in individuals lacking SARD criteria as it was in UCTD and SARD. Overall, ~ 1/3 of ANA+ subjects met fibromyalgia criteria, with no differences between sub-groups. Although fatigue was more severe in these individuals, those lacking fibromyalgia remained significantly more fatigued than ANA− HC. However, even in these subjects, fatigue correlated with the widespread pain index and symptom severity scores on the fibromyalgia questionnaire. Fatigue was not associated with elevated cytokine levels in any of the ANA+ sub-groups and did not predict imminent disease progression. Conclusions Fatigue is common in ANA+ individuals lacking sufficient criteria for a SARD diagnosis, correlates with fibromyalgia-related symptoms, and is not associated with inflammation or predictive of disease progression.

Background Long-term registries are essential to evaluate new therapies in a patient population that differs from clinical trials and usually varies over time. Objectives To describe the profile of rheumatoid arthritis (RA) patients treated with infliximab (IFX), golimumab subcutaneous (GLM) or intravenous (GLM-IV) in Canadian routine care, along with its effectiveness and safety. Methods 1577 RA patients treated with IFX, GLM or GLM-IV were enrolled into the Biologic Treatment Registry Across Canada (BioTRAC) between 2006-2015, 2010-2017 and 2014-2017, respectively. Study visits occurred at baseline and every 6 months thereafter. Effectiveness was assessed with changes in TJC28, SJC28, MDGA, PtGA, pain, HAQ, and acute phase reactants. Safety was evaluated with the incidence of adverse events (AEs) and drug survival. Results Of the 890 IFX-, 530 GLM- and 157 GLM-IV-treated patients, the proportion of females were 75.7%- 77.1%, the mean age were 55.8-57.7 and the mean disease duration were 6.5-8.6 years. Most patients were bio-naive (> 80%). A significant decrease in disease duration and disease activity scores (DAS, TJC, SJC, HAQ, AM stiffness, MDGA, PtGA, CRP, ESR) were observed in the IFX cohort over time (p Treatment with IFX, GLM and GLM-IV significantly improved all disease parameters over time (P AEs were reported for 61.5%, 67.4% and 59.2% (105, 113 and 82.6 events/100 PYs) and SAEs for 21.2%, 15.5% and 3.8% (11.7, 34.4 and 9.0 events/100 PYs) covering 2714, 1077 and 257 years of exposure for IFX, GLM and GLM-IV-treated patients, respectively. The most frequently occurring AEs were arthralgia and upper respiratory tract infection (>5%). Eighteen, 7 and 1 deaths occurred among IFX-, GLM- and GLM-IV-treated patients, respectively. The proportion of patients who discontinued treatment were 74.0% over a mean 3.0 years of exposure to IFX-, 52.8% over 2.0 years of exposure to GLM and 45.2% over 1.6 year of exposure to GLM-IV. Conclusion In this real-world study of Canadian patients with RA, differences in baseline characteristics between patients treated with an anti-TNF over time and between agents shows potential selection biases when selecting a given therapy and may impact the proportion of patients achieving a target-specific outcome. Treatment significantly reduced disease activity and improved functionality in a similar fashion and were also safe and well tolerated. Disclosure of Interests: Proton Rahman: None declared, Philip Baer Grant/research support from: Janssen sponsored study, Consultant for: Eli Lilly, Pfizer, Abbvie, Amgen, Merck, Novartis, Sanofi Genzyme, Paladin, Janssen, Johnson & Johnson, Speakers bureau: Eli Lilly, Pfizer, Abbvie, Amgen, Janssen, Denis Choquette Grant/research support from: Abbvie, Amgen, Eli Lilly, Novartis, Pfizer, Sandoz, Consultant for: Abbvie, Amgen, Eli Lilly, Novartis, Pfizer, Sandoz, Speakers bureau: Abbvie, Amgen, Eli Lilly, Novartis, Pfizer, Sandoz, Rafat Faraawi: None declared, Louis Bessette Grant/research support from: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Sanofi, Lilly, Novartis, Consultant for: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Celgene, Lilly, Novartis, Speakers bureau: Amgen, BMS, Janssen, Roche, UCB, AbbVie, Pfizer, Merck, Celgene, Lilly, Novartis, Milton Baker Grant/research support from: Janssen Sponsored Study, Raman Rai Consultant for: Janssen, Amgen, BMS, Roche, Abbvie, Pfizer, Merck, Novartis, Speakers bureau: Janssen, Amgen, Roche, BMS, Abbvie, John Kelsall Grant/research support from: Janssen Sponsored Study, Larissa Lisnevskaia Grant/research support from: Janssen Sponsored Study, Jodie Reis Grant/research support from: Janssen Sponsored Study, Keltie Anderson Grant/research support from: Janssen Sponsored Study, Wojciech Olszynski Grant/research support from: Janssen sponsored study, Emmanouil Rampakakis : None declared, Odalis Asin MIilan Employee of: Employee of Janssen, Allen Lehman Employee of: Employee of Janssen, Meagan Rachich Shareholder of: Janssen, Employee of: Employee of Janssen, Francois Nantel Shareholder of: Janssen, Employee of: Employee of Janssen

Background Long-term registries are essential to evaluate new therapies in a patient population that differs from clinical trials and usually varies over time. Objectives To describe the profile of psoriatic arthritis (PsA) patients selected for treatment with infliximab (IFX), golimumab (GLM) or ustekinumab (UST) treatment in Canadian routine care and to describe the long-term real-world effectiveness and safety of these agents. Methods 462 PsA patients treated with IFX, GLM or UST were enrolled into the Biologic Treatment Registry Across Canada (BioTRAC) registry between 2006-2015, 2010-2017 and 2014-2017, respectively. Study visits occurred at baseline and every 6 months thereafter. Effectiveness was assessed with changes in TJC28, SJC28, skin, enthesitis, dactylitis, pain, HAQ, acute phase reactants. Safety was evaluated with the incidence of adverse events (AEs) and drug survival rates. Results Of the 111 IFX-, 281 GLM- and 70 UST-treated patients, the proportion of males were 52.3%, 46.3% and 37.1%, the mean age was 48.4, 52.8 and 53.1 years and the mean disease duration was 5.8, 6.1 and 5.7 years, respectively. Most patients were bio-naive (85.6%, 77.9% and 55.7% for IFX, GLM and UST, respectively (p Treatment with IFX, GLM and UST was associated with significant improvements in all disease parameters over time (P AEs were reported for 74.8%, 69.8% and 52.9% (138, 114 and 115 events/100 PYs) and SAEs for 19.8%, 8.5% and 5.7% (8.8, 19.6 and 28.6 events/100 PYs) covering 325, 567 and 87 years of exposure for IFX-, GLM- and UST-treated patients, respectively. One, one and no death occurred IFX-, GLM- and UST-treated patients, respectively. The proportion of patients who discontinued treatment were 63.1%, 50.9% and 50.0% over a mean exposure of 2.9, 1.9 and 1.2 years to IFX, GLM and UST, respectively. Conclusion Differences in baseline characteristics between patients treated with an anti-TNF over an anti-IL12/23 agent suggest that the level of joint to skin involvement might be driving physician choice when the time comes to choose a biologic agent. IFX, GLM and UST treatment significantly reduced disease activity and improved functionality in a similar fashion and were well tolerated in patients with PsA. Disclosure of Interests Proton Rahman: None declared, Regan Arendse Grant/research support from: Janssen Sponsored Study, Isabelle Fortin Grant/research support from: ABBVIE, AMGEN, ASTRAZENECA, BMS, CELGENE, GSK, JANSSEN, PFIZER, SANOFI, UCB, Consultant for: LILLY, NOVARTIS, SANOFI, Speakers bureau: NOVARTIS, PFIZER, Andrew Chow Grant/research support from: Abbvie, Celgene, EliLilly, GSK, Janssen, Novartis, Pfizer, UCB, Consultant for: Abbvie, BMS, Celgene, EliLilly, GSK, Janssen, Novartis, Pfizer, Roche,UCB, Speakers bureau: Abbvie, BMS, EliLilly, Janssen, Novartis, Pfizer, Majed Khraishi Grant/research support from: Novartis, Consultant for: Amgen, Celgene, Gebro, Janssen, Novartis, Pfizer, Lilly, Merck, Suneil Kapur Grant/research support from: Abbvie, Merck, Janssen, Novartis, Eli Lilly, Amgen, Michel Zummer: None declared, Jon Chan Grant/research support from: Janssen, UCB, Novartis, Pfizer, Celgene, Consultant for: Amgen, Celgene, Eli Lilly, Janssen, Amgen, Abbvie, Novartis, Pfizer, UCB, Sandoz, Merck, Larissa Lisnevskaia Grant/research support from: Janssen Sponsored Study, Raheem Kherani Grant/research support from: Janssen, BMS, Abbvie, Consultant for: Abbvie, Amgen, BMS, Janssen, Lilly, Merck, Pfizer, Roche, Speakers bureau: Jannsen, BMS, Emmanouil Rampakakis : None declared, Odalis Asin MIilan Employee of: Employee of Janssen, Allen Lehman Employee of: Employee of Janssen, Meagan Rachich Shareholder of: Janssen, Employee of: Employee of Janssen, Francois Nantel Shareholder of: Janssen, Employee of: Employee of Janssen

Background Diagnosis of systemic autoimmune rheumatic diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA+ individuals to determine whether they share any of the cellular immunologic features seen in SARD. Methods Healthy ANA− controls and ANA+ (ANA ≥1:160 by immunofluorescence) participants with no SARD criteria, with at least one criterion (undifferentiated connective tissue disease (UCTD)), or meeting SARD classification criteria were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry and transcript levels of BAFF, interferon (IFN)-induced and plasma cell-expressed genes were quantified by NanoString. Results A number of the immunologic abnormalities seen in SARD, including changes in peripheral B (switched memory) and T (iNKT, T regulatory, activated memory T follicular helper) subsets and B cell activation, were also seen in asymptomatic ANA+ subjects and those with UCTD. The extent of these immunologic changes correlated with ANA titer or the number of different specific ANAs produced. Principal component analysis of the cellular data indicated that a significant proportion of asymptomatic ANA+ subjects and subjects with UCTD clustered with patients with early SARD, rather than ANA− healthy controls. Conclusions ANA production is associated with altered T and B cell activation even in asymptomatic individuals. Some of the currently accepted cellular features of SARD may be associated with ANA production rather than the immunologic events that cause symptoms in SARD. Electronic supplementary material The online version of this article (10.1186/s13075-018-1752-3) contains supplementary material, which is available to authorized users.

Background The diagnosis of Systemic Autoimmune Rheumatic Diseases (SARD), including Systemic Lupus Erythematosus (SLE), relies on the presence of ANAs, many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals most of whom will not develop SARD. A number of cellular immune changes are seen in SARD, and thus could constitute potential biomarkers/treatment targets for SARD, however it is not known at what point in disease progression these develop. Methods Healthy ANA- controls (n=32) and ANA+ (≥1:160 by immunofluorescence) participants with no (asymptomatic ANA+, n=61), at least one (UCTD, n=35), or meeting SARD classification criteria (n=59) were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry. Results Consistent with previous reports, SARD patients had increased proportions of activated B cells (CD86+ or CD95+) and in the SLE patient subset there were increased proportions of plasma cells/plasmablasts, as compared to ANA- controls. SARD patients also had reduced proportions of iNKT and IFN-γ producing cells, as well as, increased proportions of memory Tfh (CD4+CXCR5hiPD1hi) and T regulatory (Treg, CD4+FOXP3+HELIOS+) cells, especially in the SLE and Sjogren’s Disease patient subsets. In asymptomatic ANA+ individuals and UCTD patients, similar increases in the proportion of activated B cells, Tfh, and Treg cells, and decreases in the proportion of iNKT and IFN-γ producing cells were seen to those in SARD. In asymptomatic ANA+ individuals and SARD patients, the extent of serologic changes (number of specific ANAs detected by Bioplex® 2200 ANA screening system) positively correlated with activation in the switched memory B cell compartment and the proportion of Tfh cells, with the later being an independent predictor of serologic status in a multivariate analysis. However, significantly elevated levels of Tfh cells could still be seen in asymptomatic ANA+ individuals who lacked specific ANAs. Consistent with a role for Tfh cell in ANA production there was a strong correlation between the proportion of Tfh and plasma cells in asymptomatic ANA+ individuals. In preliminary studies, the majority of Tfh cells in asymptomatic ANA+ and UCTD patients were Tfh2 cells, with a trend to increased proportions of Tfh2 cells and decreased proportions Tfh17 cells as compared to active SLE patients. Conclusions Tfh cells appear to play an important role in the development of a positive ANA and in the epitope spreading that may accompany disease progression, and therefore constitute a promising target for treatment of early disease.

Systemic lupus erythematosus is a remarkable and challenging disorder. Its diversity of clinical features is matched by the complexity of the factors (genetic, hormonal, and environmental) that cause it, and the array of autoantibodies with which it is associated. In this Seminar we reflect on changes in its classification criteria; consider aspects of its more serious clinical expression; and provide a brief review of its aetiopathogenesis, major complications, coping strategies, and conventional treatment. Increased understanding of the cells and molecules involved in the development of the diseases has encouraged the identification of new, better targeted biological approaches to its treatment. The precise role of these newer therapies remains to be established.

Increased understanding of the molecular mechanisms underlying the pathogenenesis of autoimmune rheumatic diseases has led to targeted biological treatments that modulate various aspects of the immune response. These new treatments, together with more judicious use of other immunosuppressive drugs, have resulted in marked improvements in morbidity and mortality. Although belimumab, an agent that inhibits B-cell survival, is the first drug to be approved by the US Food and Drug Administration for the treatment of systemic lupus erythematosus in 50 years, many other immunological targets are under investigation. We discuss the recent advances in the biological treatment of autoimmune rheumatic diseases, with a particular focus on systemic lupus erythematosus.

Background Patients with systemic autoimmune rheumatic diseases (SARD) often have a prolonged pre-clinical phase during which they are anti-nuclear antibody (ANA)+ but lack clinical symptoms. It has been proposed that progression from asymptomatic autoimmunity to clinical disease is accompanied by immunologic changes that could be used as predictors of disease development. Previous studies indicate that a number of B cell phenotypic changes are seen in SARD patients including changes in the proportions of various naive and memory B cell subsets, increased B cell activation and elevated levels of plasmablasts/plasma cells. Objectives To determine whether ANA+ individuals who lack sufficient symptoms for a SARD diagnosis have B cell phenotypic changes similar to those seen in SARD. Methods Healthy controls (HC) and ANA+ individuals who: 1) lacked clinical symptoms of SARD (ANS); 2) had at least one clinical symptom of SARD (UCTD); or 3) had a recently diagnosed steroid and immunosuppressive naive SARD (SLE, SS, SSc, MCTD, DM) were recruited. PBMCs were isolated over a Ficoll gradient, stained with various combinations of fluorescently labeled antibodies and analyzed by flow cytometry. Anti-nuclear antibodies were measured through the hospital laboratory. Whole blood IFN signature and BAFF RNA levels were measured by NanoString. Results B cell phenotypes were examined for 32 HC, 38 ANS, 28 UCTD, and 59 early SARD (24 SS, 26 SSc, 6 SLE, 2 MCTD, 1 DM) patients. Patients with early SARD had a number of changes in their naive and memory B cell subsets, as previously reported for patients with established disease, including: increased proportions of mature naive B cells (SSc); increased proportions of T1T2 cells (SLE and SS); and trends to decreased proportions of switched memory B cells (CD27+IgD–) in all SARD. Similar decreases in the proportion of switched memory B cells were seen in ANS and UCTD patients, and as seen for the SARD patients, these cells were activated with elevated levels of CD86 as compared to HC. Significantly increased activation of the CD27–IgD– memory compartment was also seen in ANS, UCTD, SLE and SjD patients. Although significantly increased proportions of plasmablasts and/or CD138+ plasma cells were seen in all SARD patients (except those with SSc), these were not seen in ANS and UCTD patients. Nevertheless, in pre-SARD individuals (ANS + UCTD) there was a significant positive correlation between the size of these cell subsets, as well as the proportion of T1T2 cells, and ANA titer and the number of different anti-nuclear antibodies specificities. As observed for early SARD patients, there was a trend to increased BAFF levels as compared to HC in pre-SARD individuals, which achieved statistical significance in UCTD patients. However, there was no association between the levels of BAFF and any of the B cell phenotypes, whereas the IFN signature was positively associated with the proportion of T1T2 cells. Conclusions B cell phenotypic abnormalities precede the onset of clinical disease in ANA+ individuals and have a pattern suggesting ongoing activation through T-B collaboration. Disclosure of Interest None declared

Background The systemic autoimmune rheumatic diseases (SARD; Systemic Lupus Erythematosus, Rheumatoid Arthritis, Sjogren9s Disease, Systemic Sclerosis) are proposed to have a prolonged period of pre-clinical autoimmunity culminating in clinical disease. Evidence from disease-specific studies (e.g., SLE, RA) suggests that the pre-clinical phase is marked by the accrual of immunological abnormalities such as pathogenic auto-antibodies (auto-Ab). Little is known about the cellular derangements that accompany the transition from benign to pathological autoimmunity. Abnormalities in T cell subsets including invariant NKT (iNKT) and T follicular helper (T FH ) cells are implicated in the development of systemic autoimmunity. Both a decrease in iNKT cells and an increase in T FH cells are found in patients with established SARD. Objectives To determine if T cell abnormalities associated with SARD are present in pre-clinical autoimmunity. Methods Patients (n=87) who were ANA + (titer ≥1:160) and healthy controls (HC, n=37) were recruited. Patients were stratified into clinical subsets: (1) no defining SARD symptoms (n=24); (2) undifferentiated connective tissue disease (UCTD, n=17), one or more SARD defining symptom; and (3) early SARD (n=46), fulfilling ACR criteria for a SARD diagnosis. Patients were immunosuppressive and steroid naive. PBMCs were isolated over a Ficoll gradient, stained with combinations of fluorescently labeled antibodies and analyzed by flow cytometry. ANA titer and auto-Ab profile were determined. Results A statistically significant decrease in the proportion of iNKT cells (CD3 + Vα24Jα18 TCR + ) was found for all ANA + patients relative to HC (p=0.0001). Similar results were found for each patient subset when compared to HC; ANA + asymptomatic (p=0.001), UCTD (p=0.02) and SARD (p=0.001), with no differences amongst groups. The proportion of T FH (CD4 + CXCR5 high PD-1 high ) cells was significantly elevated (p=0.01) in patients versus HC. While the proportion of T FH cells was similar between asymptomatic ANA + patients and HC, there was a significant expansion of T FH in UCTD as compared to both groups (p=0.02 and p=0.04, respectively). SARD patients had a non-significant trend to increased proportions of T FH as compared to UCTD. Patients (n=50) with higher ANA titers (≥1:640) had a significant increase (p=001) in T FH when compared to individuals (n=13) with lower ANA levels (1:160). A positive correlation (p FH and the number of auto-Abs within the patient population was found. No significant differences were noted in the iNKT or T FH cell proportions between SARD patients stratified by specific disease diagnosis. Conclusions A decrease in the iNKT cell subset is present at the earliest phase of pre-clinical autoimmunity (asymptomatic ANA + ) suggesting that loss of this T cell subset contributes to a breach of tolerance to nuclear antigens. In contrast, increases in the T FH compartment appear to parallel the onset of clinical symptoms and accrual of auto-Abs. These results suggest that an incremental development of T cell abnormalities marks the progression towards clinically significant autoimmunity. Disclosure of Interest None declared

Background Patients with systemic autoimmune rheumatic diseases (SARD) often have a prolonged pre-clinical phase during which they are anti-nuclear antibody (ANA)+ but lack clinical symptoms. It has been proposed that progression from asymptomatic autoimmunity to clinical disease is accompanied by immunologic changes that could be used as predictors of disease development. Elevated levels of interferon (IFN)-induced gene expression, termed the IFN signature, are found in several SARD conditions, and IFNs appear to play an important role in disease pathogenesis. Objectives To determine whether ANA+ individuals who lack sufficient symptoms for a SARD diagnosis share the IFN-signature. Methods ANA+ individuals who: 1) lacked clinical symptoms of SARD (ANS); 2) had a least one clinical symptom of SARD (Undifferentiated Connective Tissue Disease, UCTD); or 3) had a recently diagnosed SARD (Systemic Lupus Erythematosus, SLE; Sjogren9s Disease, SjD; Scleroderma, SSc; Mixed Connective Tissue Disease, MCTD; Dermatomyositis, DM) were recruited from clinics at UHN/MSH hospitals. None of the patients were on corticosteroids or DMARDs with the exception of hydroxychloroquine. Healthy controls (HC) were also recruited. RNA was prepared from blood archived in Tempus tubes. Expression of 5 IFN-induced genes was quantified by Nanostring, normalized to expression of housekeeping genes, and summed to generate an IFN5 score. ANAs and levels of specific autoantibodies were measured by the hospital laboratory. Results To date we have measured the IFN signature on 95 individuals (21 HC, 21 ANS, 16 UCTD, 22 SjD, 7 SSc, 6 SLE, 1 MCTD, 1 DM). There was a trend to higher mean IFN score in all groups as compared to HC (mean ± SD: HC 7,071±6,321; ANS 27,245±36,037; UCTD 27,624±24,827; SSc 34,940±40,940; SjD 61,877±33,404; SLE 62,769±50,233; MCTD/DM 97,716±24,973), which achieved statistical significance for ANS, UCTD, SjD, and SLE (corrected p=0.044, 0.003, Conclusions An IFN signature is seen in a subset of ANA+ individuals prior to a confirmed diagnosis of SARD and appears to correlate with the type and number of specific ANAs rather than onset of clinical disease. Disclosure of Interest None declared

Background Elevated levels of type I interferons (IFNs) are a characteristic feature of the systemic autoimmune rheumatic diseases (SARDs) and are thought to play an important pathogenic role. However, it is unknown whether these elevations are seen in anti-nuclear antibody–positive (ANA+) individuals who lack sufficient criteria for a SARD diagnosis. We examined IFN-induced gene expression in asymptomatic ANA+ individuals and patients with undifferentiated connective tissue disease (UCTD) to address this question. Methods Healthy ANA− control subjects and ANA+ titre (≥1:160 by immunofluorescence) participants meeting no criteria, meeting at least one criterion (UCTD) or meeting SARD classification criteria were recruited. Whole peripheral blood IFN-induced and BAFF gene expression were quantified using NanoString technology. The normalized levels of five IFN-induced genes were summed to produce an IFN5 score. Results The mean IFN5 scores were increased in all ANA+ participant subsets as compared with healthy control subjects. We found that 36.8% of asymptomatic ANA+ and 50% of UCTD participants had IFN5 scores >2 SD above the mean for healthy control subjects. In all ANA+ subsets, the IFN5 score correlated with the presence of anti-Ro/La antibodies. In the asymptomatic ANA+ subset, this score also correlated with the ANA titre, whereas in the other ANA+ subsets, it correlated with the number of different ANA specificities. Development of new SARD criteria was seen in individuals with normal and high IFN5 scores. Conclusions An IFN signature is seen in a significant proportion of ANA+ individuals and appears to be associated with ANA titre and type of autoantibodies, rather than with the presence or development of clinical SARD symptoms.