M.Y. Md Yusof

Brief Report: Responses to Rituximab Suggest B Cell–Independent Inflammation in Cutaneous Systemic Lupus Erythematosus

The immunopathogenesis of systemic lupus erythematosus (SLE) is heterogeneous, and responses of skin to rituximab are variable. This study was undertaken to determine the phenotype of rituximab‐responsive disease.

The role of ultrasound in assessing musculoskeletal symptoms of systemic lupus erythematosus: a systematic literature review

OBJECTIVES Musculoskeletal symptoms are common in SLE and are associated with significant morbidity. However, assessing their nature can be challenging, with implications for treatment decisions and measuring response. US has been shown to be valid and reliable for the assessment of other inflammatory arthritides, but data in SLE are more limited. The objectives of this systematic literature review were to determine the characteristics of musculoskeletal US abnormalities in SLE and to evaluate the metric properties of US in the detection and quantification of musculoskeletal symptoms. METHODS We systematically searched the literature using the PubMed, Embase and Cochrane Library databases for studies using musculoskeletal US for assessing SLE. Studies were assessed for quality using the Quality Assessment of Diagnostic Accuracy Studies tool and for their metric qualities, including reliability and validity. RESULTS Nine studies were identified. Most studies investigated construct validity. Rates of abnormality were highly variable: synovitis and tenosynovitis were reported in 25-94% and 28-65% of patients, respectively; power Doppler and erosions were reported in 10-82% and 2-41% of patients, respectively. There was poor to moderate association between US abnormalities and disease activity indices and immunological findings. There was moderate to high risk of bias and there were concerns about applicability in most studies. CONCLUSION US has potential value in the assessment of musculoskeletal symptoms in SLE. However, there is methodological variation between studies that may account for lack of consensus on US abnormalities. Studies that address these problems are required before US can used as an outcome measure in SLE.

Certolizumab pegol in rheumatoid arthritis: current update

Introduction: The development of TNF-α inhibitors (TNF-is) represents a major advancement in the treatment of rheumatoid arthritis (RA). Currently, there are five agents licensed for moderate–to-severely active RA. Certolizumab pegol (CZP) is a novel PEGylated, constant fragment-free TNF-i therapy, which is the focus of this review. Areas covered: Data from Phase III randomised controlled trials in terms of clinical efficacy, radiographic progression, patient-reported outcomes and safety profile are reviewed. These include long-term data from open-label extension studies. Expert opinion: The advantages of CZP include rapid reduction of disease activity, low rates of injection-site reaction and may be safe for use in pregnancy. The long-term data strengthen the position of CZP for use either as monotherapy or preferably in combination with disease modifying anti-rheumatic drugs (DMARDs), in moderate-to-severely active RA, comparable to other TNF-is. Notably, prolonged CZP exposure is not associated with increased risk of severe infection compared to general population, contrasting with preliminary analysis of short-term data. Over the next few years, evidence will be available on the use of CZP in combination with methotrexate for remission induction in DMARD-naïve patients, biomarkers and the development and licensing of TNF-i biosimilars.

Repeat cycles of rituximab on clinical relapse in ANCA-associated vasculitis: identifying B cell biomarkers for relapse to guide retreatment decisions

Objective To assess clinical and B cell biomarkers to predict relapse after rituximab in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) using retreatment on clinical relapse strategy. Methods 35 patients with AAV received treatment with 2×1000 mg rituximab, repeated on clinical relapse (up to 5 cycles). Disease activity was assessed by Birmingham Vasculitis Activity Score (BVAS) and peripheral B cell subsets using highly sensitive flow cytometry (HSFC) as previously described; both performed at baseline and every 3 months. Results Response rates were high: >83%, with median time-to-relapse of 82 weeks for cycle 1 (C1) and >54 weeks for all cycles. Prior to rituximab, AAV was characterised by naïve B-lymphopenia compared to healthy controls. This dysregulation was more marked in patients with raised C-reactive protein (CRP) (p<0.05). In C1, no clinical feature predicted relapse. However, repopulation of naïve B cell at 6 months was associated with a reduced risk of relapse (HR: 0.326, 95% 0.114 to 0.930, p=0.036). Relapse rates at 12 and 18 months were 0% and 14% with naïve repopulation at 6 months, and 31% and 54% without naïve repopulation. Conclusions Responses to B cell depletion therapy are long-lasting and relapse post-treatment may be predicted by absence of naïve B cell repopulation at 6 months. Naïve B-lymphopenia may be a biomarker of disease activity in AAV.

A novel two-score system for interferon status segregates autoimmune diseases and correlates with clinical features

Measurement of type I interferon (IFN-I) has potential to diagnose and stratify autoimmune diseases, but existing results have been inconsistent. Interferon-stimulated-gene (ISG) based methods may be affected by the modularity of the ISG transcriptome, cell-specific expression, response to IFN-subtypes and bimodality of expression. We developed and clinically validated a 2-score system (IFN-Score-A and -B) using Factor Analysis of 31 ISGs measured by TaqMan selected from 3-IFN-annotated modules. We evaluated these scores using in-vitro IFN stimulation as well as in sorted cells then clinically validated in a cohort of 328 autoimmune disease patients and healthy controls. ISGs varied in response to IFN-subtypes and both scores varied between cell subsets. IFN-Score-A differentiated Systemic Lupus Erythematosus (SLE) from both Rheumatoid Arthritis (RA) and Healthy Controls (HC) (both p < 0.001), while IFN-Score-B differentiated SLE and RA from HC (both p < 0.001). In SLE, both scores were associated with cutaneous and hematological (all p < 0.05) but not musculoskeletal disease activity. Comparing with bimodal (IFN-high/low) classification, significant differences in IFN-scores were found between diagnostic groups within the IFN-high group. Our continuous 2-score system is more clinically relevant than a simple bimodal classification of IFN status. This system should allow improvement in diagnosis, stratification, and therapy in IFN-mediated autoimmunity.

Response to: ‘Which B-cell subset should we target in lupus?’ by Ferraccioli and Houssiau

We read with interest the editorial by Ferraccioli and Houssiau proposing the specific targeting of long-lived plasma cells (PCs) in human lupus nephritis (LN).1 The authors present a cogent summary of experiments showing that long-lived PCs alone are sufficient to induce murine LN, and that targeting of PCs in these models is successful. However, we believe that clinical experience with the treatment of human SLE indicates that plasmablasts and short-lived PCs, recently derived from autoreactive B cells, are more important in the …

A9.06 Analysis of cell-specific interferon response in systemic lupus erythematosus using a novel flow cytometric assay

Background and objectives Type I interferons (IFN-I) have diverse effects on immune cell populations in SLE, Measuring IFN-I using whole blood interferon-stimulated gene (ISG) expression does not completely explain clinical features of SLE. Objective: develop a cell-specific assay using a surface protein encoded by an ISG (BST2). This would allow convenient analysis of IFN response in individual populations to improve immunophenotyping of SLE patients. Materials and methods PBMCs from 133 SLE patientsand 19 healthy controls (HC) were analysed by flow cytometry for cell surface BST2 protein on each immune cell subset. Cells were FACS-sorted into naïve and memory B-cells, plasmablasts, CD3+ T-cells, NK-cells and monocytes in 12 SLE patients and 16 healthy controls. Expression of BST2, as well as 32 other ISGs, were measured using qPCR. Results Analysis of sorted cells confirmed that surface BST2 is a valid cell-specific IFN assay. BST2 expression correlated with BST2 surface protein within each immune subset: naïve B-cells (r = 0.63, p = 0.009); memory B-cells (r = 0.78, p < 0.001); plasmablasts (r = 0.58, p = 0.018);NK cells (0.63, p = 0.008);T-cells (r = 0.61, p = 0.012); monocytes (r = 0.47, p = 0.064). We next used surface BST2 to compare IFN activity of each subset with clinical features in 133 patients. A significant correlation between the PBMC 33-gene IFN score and surface BST2 for each cell subset (all p < 0.001) confirmed validity of BST2 biomarker in this larger population as a measure of overall IFN status. BST2 was significantly higher in SLE than HC on naïve and memory B-cells (p = 0.004, p = 0.003), plasmablasts (p = 0.047), T cells (p = 0.043), but not different on monocytes (p = 0.406). Association of disease activity (total BILAG) with BST2 on naïve and memory B-cells (Tau-a = 0.23 and 0.22 respectively) was substantive and approximately twice as strong as monocytes and T-cells (Tau-a = 0.12 and 0.14). A similar pattern was seen for anti-dsDNA titre, with no association with monocyte BST-2 (Tau-a = 0.07) but a substantive association for memory B cell BST-2 (Tau-a = 0.18). Conclusion IFN-I response differs in cell subsets. This can be measured in a fast, cost-effective, convenient assay using flow cytometric analysis of surface BST2. Our results show that IFN activity measured on B cells is more clinically relevant than on other cell populations.

FRI0335 An Evaluation of Clinical Outcome Measures for Musculoskeletal Lupus Using Ultrasound as A Gold Standard: Table 1

Background Musculoskeletal symptoms in SLE patients are common, but difficult to assess clinically. Ultrasound (US) is an objective measure of synovitis. Objectives To test clinical tools currently used for musculoskeletal lupus against US as a gold standard. Methods A multicentre cross-sectional study recruited 107 patients in Leeds and Southampton fulfilling ACR/SLICC criteria for SLE, all had history of musculoskeletal symptoms and 79% had pain at the time of evaluation. Patients with positive CCP or RF were excluded. Patients were clinically assessed using BILAG, SLEDAI, tender joint count (TJC), swollen joint count (SJC), physician and patient VAS (both 0–100, for MSK symptoms). US hand was used to examine joints and tendon sheaths. Results There was disagreement between US and clinical joint swelling in 26% of patients. In the 40% with clinical joint swelling, US confirmed this in 83%. 20% of all patients had US synovitis that was not detected clinically. Overall, objective synovitis was found in 40% of patients using clinical swelling and 53% using US. US was correlated with SJC (R=0.389, P≤0.001), MSK-BILAG numeric score (R=0.503, P≤0.001), and physician VAS (R=0.5, P≤0.001), but not with TJC, SLEDAI, or patient VAS. We then looked for clinical appearance of patients with US-proven synovitis: see table 1. We identified significant associations in the whole cohort. In multivariate analysis only physician-VAS was significant (p=0.018). However, in 50 patients with no joint swelling, 15 had US synovitis, but no clinical variable could identify this.Table 1 US+ve, median (IQR) US−ve, median (IQR) p MSK- BILAG 2 (2) 3 (1) <0.001 SLEDAI 4 (6) 2 (4) 0.006 Physician VAS 41 (50) 8 (20) <0.001 Patient VAS 55 (33) 45 (70) 0.085 ESR 21 (45) 12.5 (24) 0.086 TJC 6.5 (10) 3 (9) 0.034 SJC 1.5 (4) 0 (0) <0.001 Conclusions Swollen Joint Count, Physician VAS, and MSK-BILAG all correlate with true synovitis as defined by US. However, these variables are all based on the clinical detection of joint swelling and 50% of this cohort did not have joint swelling. In the latter group, no clinical variable was helpful in identifying the 30% of patients with US-proven synovitis. US should be used to evaluate MSK-SLE patients who do not have clinical synovitis. Disclosure of Interest None declared

FRI0315 A Prospective Study To Assess Responsiveness of Clinical and Ultrasound Outcome Measures for Musculoskeletal Sle: Table 1

Background Musculoskeletal manifestations affect up to 95% of SLE patients. Assessment can be problematic as not all patients have swelling. There is a clinical need to better select SLE patients with musculoskeletal symptoms who may respond to therapy and assess their response. We previously analysed 100 patients with MSK symptoms and showed that ultrasound (US) detects synovitis in patients with no clinical swelling. Objectives To assess the responsiveness of clinical assessment tools and US in musculoskeletal SLE. Methods 107 patients fulfilling ACR/SLICC criteria for SLE with musculoskeletal involvement were analysed in a cross-sectional study. 16 of these with current inflammatory symptoms entered a pilot study of US before and after intramuscular injection of depomedrone 120mg. These 16 patients were followed up and assessed clinically using BILAG, SLEDAI, patient VAS, physician VAS, tender joint count, swollen joint count) and US of hand (joints and tendon sheath) at 0, 2 and 4 weeks. Results Of 107 patients only 35 (32.7%) had swelling clinically at baseline but 53 (49.5%) had US synovitis. Response in US and clinical parameters for the 16 longitudinal patients is shown in Table1.Table 1 Week 0 Week 2 P* Week 4 P BILAG-MSK n (%)  A 6/16 (37.5) 3/16 (18.7) 1/16 (0.06)  B 6/16 (37.5) 3/16 (18.7 2/16 (12.5)  C 4/16 (25) 5/16 (31.2) 6/16 (37.5)  D 0/16 (0) 5/16 (31.2) 6/16 (37.5) BILAG improved, n (%) N/A 10/16 (62.5) 13/16 (81) SLEDAI MSK Criterion = 4 points,  n (%) 14/16 (87.5) 10 /16 (62.5) 9 /16 (56) SLEDAI improved, n (%) 4/14 (28.5) 5/14 (36) TJC (0–28), median (IQR) 8 (4.3–12.3) 4 (1.0 −13.5) 0.228 4 (1–14.8) 0.197 SJC (0–28), median (IQR) 3 (0.3–5) 0 (0–1) 0.059 0 (0–0) 0.003 Symptomatic joints, median (IQR) 15 (5.8–21.5) 2 (0–13) 0.047 3.5 (1–14.8) 0.066 Patient VAS (0–100), median (IQR) 55 (30–78.5) 30 (8.8–40) 0.016 35 (10–48.8) 0.059 Physician VAS (0–100), median (IQR) 31 (13–65.5) 23 (5–50) 0.001 21 (3.8–43.5) 0.001 US- total PD, median (IQR) 8.5 (4.8–34.8) 1 (0–6.3) 0.002 1 (0–1) 0.001 US-total GS, median (IQR) 24 (17–46) 12.5 (5.3–23.8) 0.002 10.5 (7–13.8) 0.001 No. joints with synovitis, median (IQR) 8 (5–19.3) 3 (0.8–7.5) 0.004 2 (1–4) 0.001 P values compare 2 and 4 weeks with baseline. Value under 0.05 considered as trend, values under 0.025 considered significant. Conclusions Although swollen joint count was responsive to change with therapy, US was more sensitive in detecting active joints disease at baseline and showed greater and more significant change with therapy. The responsiveness of swollen joints likely explains the responsiveness in BILAG musculoskeletal system index and physician VAS. However, tender and symptomatic joint counts, as well as SLEDAI, were poorly responsive to therapy. Overall, US is the tool most responsive to change for monitoring musculoskeletal disease activity in SLE. Disclosure of Interest None declared

FRI0569 The Role of Musculoskeletal Ultrasound in the Stratification of SLE; A Multicenter Cross-Sectional Study

Background Musculoskeletal symptoms in systemic lupus erythematosus (SLE) are common and cause substantial morbidity. However, assessing the nature of these symptoms can be challenging. Multiple recent studies have reported positive musculoskeletal ultrasound (US) findings in SLE patients with joints symptoms. However, the severity of such abnormalities and their relationship to the clinical condition are poorly understood. Objectives The objectives of this study were to determine the characteristics and severity of musculoskeletal US abnormalities in SLE and to correlate these abnormalities with the clinical condition and BILAG classification. Methods Patients fulfilling the ACR diagnostic criteria for SLE were included in Leeds and Southampton. Patients had hand US examination (including joints and tendon sheaths) and clinical assessment including BILAG, SLEDAI, tender joint count (TJC) and swollen joint count (SJC). Patients had hematology and immunology assessment. Any patient who had Rhupus (RF or CCP positive) was excluded. Results A total of 55 patients were recruited. Among them, 18%, 18%, 55% and 9% of patients were BILAG A, B, C and D respectively. In those with inflammatory joint symptoms (BILAG A-C), 58.3% had significant US finding (GS ≥2 and/or PD≥1). All BILAG A had moderate-severe PD (i.e.PD≥2). However, a substantial number of patients who had BILAG B (i.e. clinical synovitis) were judged not to have significant US findings. In contrast, many patients with BILAG C did have significant US abnormality (Table). Erosions were found in about one third of BILAG A patients. Tenosynovitis was also found in a significant number of BILAG A-C patients (Table). 16% of patients had synovitis on US but no swollen joints. There was a moderate positive correlation between presence of PD and presence of erosions (Correlation Coefficient (CC)=0.44 (p<0.001)). There was a strong positive correlation between US synovitis and SJC (CC=0.72 and 0.82 (p<0.001) for GS and PD respectively). However, there was a weak positive correlation between US synovitis and TJC (CC=0.031 and 0.23 (p=0.85 and 0.168) for GS and PD respectively). There was moderate correlation between US synovitis and SLEDAI (CC=0.29 and 0.42 (p=0.002 and 0.033) for GS and PD respectively). Neither inflammatory markers nor SLE immunological markers (i.e ANA, ENA, complements and immunoglobulins)appeared to be associated with joint inflammation. Table 1. Frequencies of different ultrasound abnormalities in Different BILAG groups Ultrasound abnormality A (n=10) B (n=10) C (n=30) D (n=5) GS ≥2 and/or PD≥1 100% 80% 38% 0% PD ≥1 100% 80% 20% 0% PD ≥2 100% 40% 7% 0% Erosions 33% 20% 7% 0% Tenosynovitis 45% 30% 11% 0% Conclusions US appears to have value in the assessment and stratification of musculoskeletal symptoms in SLE. Ultrasound was able to detect clinically significant synovitis in patients who had BILAG C or had no swollen joints. In addition, a substantial number of patients with clinical synovitis were judged not to have significant US findings. There was a moderate positive association between PD and joints erosions. Ultrasound may be more sensitive than clinical examination and BILAG in classifying joint pathology in SLE. Disclosure of Interest None declared