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BackgroundType I interferons (IFN-Is) play a role in a broad range of rheumatic and musculoskeletal diseases (RMDs), and compelling evidence suggests that their measurement could have clinical value, although testing has not progressed into clinical settings.ObjectiveTo develop evidence-based points to consider (PtC) for the measurement and reporting of IFN-I assays in clinical research and to determine their potential clinical utility.MethodsEULAR standardised operating procedures were followed. A task force including rheumatologists, immunologists, translational scientists and a patient partner was formed. Two systematic reviews were conducted to address methodological and clinical questions. PtC were formulated based on the retrieved evidence and expert opinion. Level of evidence and agreement was determined.ResultsTwo overarching principles and 11 PtC were defined. The first set (PtC 1–4) concerned terminology, assay characteristics and reporting practices to enable more consistent reporting and facilitate translation and collaborations. The second set (PtC 5–11) addressed clinical applications for diagnosis and outcome assessments, including disease activity, prognosis and prediction of treatment response. The mean level of agreement was generally high, mainly in the first PtC set and for clinical applications in systemic lupus erythematosus. Harmonisation of assay methodology and clinical validation were key points for the research agenda.ConclusionsIFN-I assays have a high potential for implementation in the clinical management of RMDs. Uptake of these PtC will facilitate the progress of IFN-I assays into clinical practice and may be also of interest beyond rheumatology.

Objectives To improve the definitions of inflammatory arthritis within the musculoskeletal (MSK) domain of the BILAG-2004 index by incorporating imaging findings and clinical features predictive of response to treatment. Methods The BILAG MSK Subcommittee proposed revisions to the BILAG-2004 index definitions of inflammatory arthritis, based on review of evidence in two recent studies. Data from these studies were pooled and analysed to determine the impact of the proposed changes on the severity grading of inflammatory arthritis Results The revised definition for severe inflammatory arthritis includes definition of “basic activities of daily living”. For moderate inflammatory arthritis, it now includes synovitis, defined by either observed joint swelling or MSK ultrasound evidence of inflammation in joints and surrounding structures. For mild inflammatory arthritis, the definition now includes reference to symmetrical distribution of affected joints and guidance on how ultrasound may help re-classify patients as moderate or no inflammatory arthritis. Data from two recent SLE trials were analysed (219 patients). 119 (54.3%) were graded as having mild inflammatory arthritis (BILAG-2004 C). Of these, 53 (44.5%) had evidence of joint inflammation (synovitis or tenosynovitis) on ultrasound. Applying the new definition increased the number of patients classified as moderate inflammatory arthritis from 72 (32.9%) to 125 (57.1%), while patients with normal ultrasound (n = 66/119) could be recategorised as BILAG-2004 D (inactive disease). Conclusions Proposed changes to the definitions of inflammatory arthritis in the BILAG 2004 index will result in more accurate classification of patients who are more or less likely to respond to treatment.

Background/Aims Advances in rational drug design and recent clinical trials are leading to emergence of a range of novel therapies for SLE and therapeutic options in clinical practice are expected to broaden rapidly. The optimal real-world place of emerging and established agents will be guided by understanding their differential efficacy on specific SLE manifestations as well as efficacy for more resistant disease. Anifrolumab, a type-I interferon receptor blocking monoclonal antibody, showed efficacy in SLE in phase III trials with a notable effect on mucocutaneous disease although specific lesion subtypes and chroncicity were not explored. Severe refractory mucocutaneous SLE such as scarring discoid lesions are an important and common clinical challenge in current practice. We therefore prospectively evaluated the real-world efficacy and quality of life impact of anifolumab for active mucocutaneous SLE, recalcitrant to multiple biologic and immunosuppressant therapies. Methods Seven patients commenced anifrolumab (300 mg by monthly iv infusion) following application to the manufacturer’s early access programme (NCT 04750057). Prior biologic therapies were discontinued at least 5 half-lives in advance. Mucocutaneous disease activity was captured by Cutaneous Lupus Disease Area and Severity Index (CLASI) activity score and medical photography. Patient reported health-related quality of life comprising the Dermatology Life Quality Index (DLQI); Lupus-QoL and EQ5D-5L were evaluated at baseline, three and six months. Results Seven female patients with active mucocutaneous SLE (Discoid LE n = 5, chilblain LE n = 1, subacute cutaneous LE n = 1) and median disease duration of 17 years were evaluated. Median baseline CLASI activity score was 17 (range 10-26; higher scores indicating severe disease). Median number of previously failed therapies was 7 and included rituximab in 6/7, belimumab in 2/7 and thalidomide in 4/7. Rapid resolution of scale and erythema in DLE was established within 1 month of anifrolumab treatment. Improvements to chilblain lupus were evident by three months. CLASI activity score was improved ≥75% in all patients at 3 months. Clinical responses were associated with significant improvements in DLQI (p 15 mg daily, recent COVID-19 infection and new on-treatment hypogammaglobulinaemia (IgG Conclusion We report rapid real-world efficacy and quality of life impact of anifrolumab on highly refractory mucocutaneous SLE, which exceeded that anticipated from existing clinical trial data. Findings suggest a unique role for emerging interferon targeting therapies in management of mucocutaneous SLE but emphasize need for enhanced VZV precautions among higher risk patients. Disclosure L. Carter: Consultancies; UCB. Z. Wigston: None. P. Laws: Consultancies; Amgen, Celgene, Janssen, Leo, Lilly and Sanofi. Member of speakers’ bureau; AbbVie, Actelion and BMS. Grants/research support; UCB, Almirall, and Novartis. E.M. Vital: Consultancies; Roche, GSK, AstraZeneca, Aurinia Pharmaceuticals, Lilly and Novartis. Grants/research support; Roche, AstraZeneca and Sandoz.

Although the clinical approach to the management of musculoskeletal manifestations in systemic lupus erythematosus (SLE) is often similar to that of rheumatoid arthritis (RA), there are distinct differences in immunopathogenesis, structural and imaging phenotypes and therapeutic evidence. Additionally, there are few published comparisons of these diseases. The objective of this narrative literature review is to compare the immunopathogenesis, structural features, magnetic resonance imaging (MRI) and musculoskeletal ultrasound (MSUS) studies and management of joint manifestations in RA and SLE. We highlight the key similarities and differences between the two diseases. Overall, the literature evaluated indicates that synovitis and radiographical progression are the key features in RA, while inflammation without swelling, tendinitis and tenosynovitis are more prominent features in SLE. In addition, the importance of defining patients with RA by the presence or absence of autoantibodies and categorizing patients with SLE by synovitis detected by musculoskeletal ultrasound and by structural phenotype (non-deforming, non-erosive arthritis, Jaccoud's arthropathy and 'Rhupus') with respect to joint manifestations will also be discussed. An increased understanding of the joint manifestations in RA and SLE may inform evidence-based clinical decisions for both diseases.

Objectives Secondary inefficacy with infusion reactions and anti-drug antibodies (secondary non-depletion nonresponse, 2NDNR) occurs in 14% of SLE patients receiving repeated rituximab courses. We evaluated baseline clinical characteristics, efficacy and safety of obinutuzumab, a next-generation humanized type-2 anti-CD20 antibody licensed for haematological malignancies in SLE patients with 2NDNR to rituximab. Methods We collated data from SLE patients receiving obinutuzumab for secondary non-response to rituximab in BILAG centres. Disease activity was assessed using BILAG-2004, SLEDAI-2K and serology before, and 6 months after, obinutuzumab 2× 1000 mg infusions alongside methylprednisolone 100 mg. Results All nine patients included in the study received obinutuzumab with concomitant oral immunosuppression. At 6 months post-obinutuzumab, there were significant reductions in median SLEDAI-2K from 12 to 6 (P = 0.014) and total BILAG-2004 score from 21 to 2 (P = 0.009). Complement C3 and dsDNA titres improved significantly (both P = 0.04). Numerical, but not statistically significant improvements were seen in C4 levels. Of 8/9 patients receiving concomitant oral prednisolone at baseline (all >10 mg/day), 5/8 had their dose reduced at 6 months. Four of nine patients were on 5 mg/day and were in Lupus Low Disease Activity State following obinutuzumab. After obinutuzumab, 6/9 patients with peripheral B cell data achieved complete depletion, including 4/4 assessed with highly sensitive assays. Of the nine patients, one obinutuzumab non-responder required CYC therapy. One unvaccinated patient died from COVID-19. Conclusions Obinutuzumab appears to be effective and steroid-sparing in renal and non-renal SLE patients with secondary non-response to rituximab. These patients have severe disease with few treatment options but given responsiveness to B cell depletion, switching to humanized type-2 anti-CD20 therapy is a logical approach.

Background Observations with rituximab suggest B-cell independent mechanisms of cutaneous lupus (CLE) in SLE, especially discoid. Type-I interferon receptor blockade with anifrolumab shows efficacy in SLE but efficacy on cutaneous disease of specific morphologies has not been studied. Interferon has pleotropic immune effects and which of these are critical to therapeutic response is unknown. Objective We evaluated clinical efficacy and quality of life impact of type-I interferon-blockade in (i) rituximab-refractory CLE; (ii) discoid and other morphologies; (iii) transcriptomic and flow cytometric biomarkers. Methods We conducted a prospective single-centre study of anifrolumab in refractory mucocutaneous SLE. CLASI activity score, health related quality of life, 96-probe TaqMan® gene expression analysis capturing key SLE blood transcriptome signatures, and 8-colour flow cytometry were undertaken at baseline, 1, 3 and 6 months. Results 7 patients (DLE n=5, chilblain LE n=1, SCLE n=1) were evaluated. Median (range) prior therapies was 6 (3, 15), including rituximab in 6/7. Median CLASI-A showed rapid and sustained improvement from 17 at baseline to 6 (p=0.016) at 1 month and 0 (p Conclusions These data indicate rapid efficacy of anifrolumab in DLE and rituximab-resistant CLE. Response is associated with suppression of a subset of ISGs and decline in intermediate monocytes. Suppression of all ISGs or the wider SLE blood transcriptome is not required for response.

Type I interferons have been suspected for decades to have a crucial role in the pathogenesis of systemic lupus erythematosus (SLE). Evidence has now overturned several long-held assumptions about how type I interferons are regulated and cause pathological conditions, providing a new view of SLE pathogenesis that resolves longstanding clinical dilemmas. This evidence includes data on interferons in relation to genetic predisposition and epigenetic regulation. Importantly, data are now available on the role of interferons in the early phases of the disease and the importance of non-haematopoietic cellular sources of type I interferons, such as keratinocytes, renal tubular cells, glial cells and synovial stromal cells, as well as local responses to type I interferons within these tissues. These local effects are found not only in inflamed target organs in established SLE, but also in histologically normal skin during asymptomatic preclinical phases, suggesting a role in disease initiation. In terms of clinical application, evidence relating to biomarkers to characterize the type I interferon system is complex, and, notably, interferon-blocking therapies are now licensed for the treatment of SLE. Collectively, the available data enable us to propose a model of disease pathogenesis that invokes the unique value of interferon-targeted therapies. Accordingly, future approaches in SLE involving disease reclassification and preventative strategies in preclinical phases should be investigated.

Gene expression profiles are associated with the clinical heterogeneity of SLE but are not well studied as biomarkers for therapy. Many clinical and demographic features influence treatment responses. We studied gene expression and response to rituximab in a multi-ethnic UK cohort refractory to standard therapy.Baseline expression of transcripts known to associate with clinical features of SLE was evaluated in whole blood by 96-probe Taqman® array in patients (n=213) with active SLE, prospectively enrolled in British Isles Lupus Assessment Group (BILAG) Biologics Registry. Autoantibodies were measured using immunoprecipitation and ELISA. Response to first cycle rituximab (n=110) was determined by BILAG-2004 criteria at 6 months.Interferon scores were lower in European ancestry patients than all other groups. The relationship between blood interferon scores and plasmablast, neutrophil, myeloid, inflammation and erythropoiesis-annotated scores differed between patients of European and non-European ancestries. Hierarchical clustering revealed 3 distinct non-European ancestry patient subsets with stratified response to rituximab which was not explained by sociodemographic and clinical variables. Response was lowest in an interferon-low, neutrophil-high cluster and highest in a cluster with high expression across all signatures (p0.001). Clusters within European ancestry patients did not predict response to rituximab but segregated patients by global disease activity and renal involvement. In both ancestral groups, interferon-high clusters associated with U1RNP-Sm antibodies.Ancestry appears central to the immunological and clinical heterogeneity in SLE. These results suggest that ancestry, disease activity and transcriptional signatures could each assist predict the effectiveness of B-cell depletion. This article is protected by copyright. All rights reserved.

The Physician Global Assessment International Standardisation COnsensus in Systemic Lupus Erythematosus (PISCOS) study aimed to obtain an evidence-based and expert-based consensus standardisation of the Physician Global Assessment (PGA) scoring of disease activity in systemic lupus erythematosus (SLE). An international panel of 79 SLE experts participated in a three-round Delphi consensus process, in which 41 statements related to the PGA in SLE were rated, using a 0 (strongly disagree) to 10 (strongly agree) numerical rating scale. Statements with agreement of 75% or greater were selected and further validated by the expert panel. Consensus was reached on 27 statements, grouped in 14 recommendations, for the use of the PGA in SLE, design of the PGA scale, practical considerations for PGA scoring, and the relationship between PGA values and levels of disease activity. Among these recommendations, the expert panel agreed that the PGA should consist of a 0–3 visual analogue scale for measuring disease activity in patients with SLE in the preceding month. The PGA is intended to rate the overall disease activity, taking into account the severity of active manifestations and clinical laboratory results, but excluding organ damage, serology, and subjective findings unrelated to disease activity. The PGA scale ranges from “no disease activity” (0) to the “most severe disease activity” (3) and incorporates the values 1 and 2 as inner markers to categorise disease activity as mild (≥0·5 to 1), moderate (>1 and ≤2) and severe (>2 to 3). Only experienced physicians can rate the PGA, and it should be preferably scored by the same rater at each visit. The PISCOS results will allow for increased homogeneity and reliability of PGA ratings in routine clinical practice, definitions of remission and low disease activity, and future SLE trials.

Background/Aims Randomised controlled trials (RCTs) of rituximab (RTX) in primary Sjogren’s syndrome (pSS) have failed to alleviate glandular symptoms and fatigue. The question remains as to whether B-cell depleting therapies have a place for the treatment of pSS. Post-hoc analyses from RCTs showed greater improvement in objective measures such as salivary flow rate, salivary gland ultrasound and histology scores in RTX-treated group vs placebo. Moreover, there are limited data on efficacy of the initial and repeat cycles of RTX on extra-glandular pSS. Here, our objectives were to assess the effectiveness of RTX on extra-glandular symptoms and identify predictors of short-term response with a view to personalised B-cell depleting therapy in pSS. Methods A retrospective longitudinal cohort study was conducted in 40 consecutive RTX-treated pSS patients in a single-centre for over 15 years. All patients fulfilled the 2002 AEG criteria and were CCP negative. Clinical response at 6 months was defined as ≥ 3 point reduction of ESSDAI from baseline. B-cell subsets were measured using highly sensitive flow cytometry. Predictors of short-term response were analysed using penalised logistic regression. Results 38/40 (95%) patients were female, mean (SD) age 54 (13.7) years, median (IQR) disease duration 5 (2-9) years, 39/40 (98%) had positive ANA and 28/40 (70%) were on concomitant immunosuppressant (IS). Mean (SD) ESSDAI at RTX initiation was 11.5 (6.7) and main domains for RTX were articular (73%), skin (23%), haematological (18%), PNS (15%) and lungs (10%). 169 RTX cycles were administered with a total follow-up of 165PY. In Cycle 1 (C1) RTX, the proportion of patient achieving ESSDAI response from baseline was 29/40 (73%; 95% CI 58-87). There were significant reductions in ESSDAI, daily prednisolone dose and IgG levels at 6 months (all p < 0.05). Of C1 responders, 23/29 received retreatment on clinical relapse; of which 8/23 (35%) lost response [secondary non-depletion non-response (2NDNR) associated with anti-RTX antibodies as we previously observed in SLE=4 (17%)]; side effects=1; ineffective=3. Of C1 non-responders, 9/11 were retreated but only 2/9 responded in C2. Overall, 13/40 (33%) discontinued RTX within two cycles. In multivariable analysis, concomitant immunosuppressant [OR 0.07 (95% CI 0.01-0.52); p = 0.010] and achieving compete B-cell depletion in C1 [0.04 (0.02-0.82); 0.036] reduced non-response to RTX. Conclusion All patients with pSS should be co-prescribed immunosuppressant with RTX and future therapeutics should aim to achieve complete depletion. About one in six pSS patients lose response in repeat cycles which is associated with 2NDNR phenomenon. The use of humanised or next-generation type 2 anti-CD20 antibodies should overcome these issues and improve the clinical response of extra-glandular pSS. Disclosure S. Pepple: None. J. Arnold: None. E. M Vital: Consultancies; Dr Vital has received consulting fees from Roche. Grants/research support; Dr Vital has received funding for research from Roche. A. C Rawstron: None. C. Pease: None. S. Dass: None. P. Emery: Consultancies; Prof Emery has received consulting fees from Roche. Grants/research support; Prof Emery has received funding for research from Roche. M. Md Yusof: None.

Background/Aims Rituximab is widely used to treat rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) but clinical response varies. Efficacy is determined by the efficiency of depletion, which may depend on a variety of Fc gamma receptor (FcγR)-dependent mechanisms. Previous research was limited by complexity of the FCGR locus, not integrating copy number variation with functional SNP, and small sample size. Here, we aimed to assess the effect of the full range of FcγRs variants on depletion, clinical response and functional effect on NK-cell-mediated killing in two rheumatic diseases with a view to personalised B-cell depleting therapies. Methods A prospective longitudinal study was conducted in 873 patients (RA = 611; SLE=262) from four cohorts (BSRBR-RA, BILAG-BR, Leeds RA and Leeds SLE Biologics). For RA, the outcome measures were 3C-DAS28CRP and 2C-DAS28CRP at 6 (+/-3) months post-rituximab (adjusted for baseline DAS28). For SLE, major clinical response (MCR) was defined as improvement of active BILAG-2004 domains to grade C/better at 6 months. B-cell depletion was evaluated by highly-sensitive flow cytometry. Qualitative and quantitative polymorphisms for five major FcγRs were measured using a commercial multiplex ligation-dependent probe amplification. Median NK cell FcγRIIIa expression (CD3-CD56+CD16+) and NK-cell degranulation (CD107a) in the presence of rituximab-coated Daudi/Raji B-cell lines were assessed using flow cytometry. Results In RA, for FCGR3A, carriage of V allele (coefficient -0.25 [SE 0.11]; p = 0.02) and increased copies of V allele (-0.20 [0.09]; p = 0.02) were associated with better 2C-DAS28 response. Irrespective of FCGR3A genotype, increased gene copies were associated with a better response. In SLE, 177/262 (67.6%) achieved BILAG response (MCR=34.4%; Partial=33.2%). MCR was associated with increased copies of FCGR3A-158V allele, OR 1.64 (95% CI 1.12-2.41) and FCGR2C-ORF allele 1.93 (1.09-3.40). Of patients with B-cells data in the combined cohort, 236/413 (57%) achieved complete depletion post-rituximab. Only homozygosity for V allele and higher copies of FCGR3A V allele were associated with increased odds of depletion. Patients with complete depletion had higher NK cell FcγRIIIa expression at rituximab initiation than those with incomplete depletion (p = 0.04) and this higher expression was associated with improved EULAR response in RA. Moreover, for FCGR3A, degranulation activity was increased in V allele carriers vs FF genotype in the combined cohort; p = 0.02. Conclusion FcγRIIIa is the major low affinity FcγR and increased copies of the FCGR3A-158V allele, encoding the allotype with a higher affinity for IgG1, was associated with clinical and biological responses to rituximab in two autoimmune diseases. This was supported by functional data on NK cell-mediated cytotoxicity. In SLE, increased copies of the FCGR2C-ORF allele was also associated with improved response. Our findings indicate that enhancing FcγR-effector functions could improve the next generation of CD20-depleting therapies and genotyping could stratify patients for optimal treatment protocols. Disclosure M. Md Yusof: None. J. Robinson: None. V. Davies: None. D. Wild: None. M. Morgan: None. J. Taylor: None. Y. El-Sherbiny: None. D. Morris: None. L. Liu: None. A. Rawstron: None. M. Buch: None. D. Plant: None. H. Cordell: None. J. Isaacs: None. I. Bruce: None. P. Emery: Grants/research support; PE has received consultancy fees and funding for research from Roche within the last 3 years. A. Barton: None. T. Vyse: None. J. Barrett: None. E. Vital: Grants/research support; EMV has received consultancy fees and funding for research from Roche within the last 3 years. A. Morgan: None.

Background/Aims The BILAG-2004 index grades musculoskeletal (MSK) inflammation as mild (C), moderate (B) and severe (A), based on clinical features. In a recent study, 27% of SLE patients with MSK pain have ultrasound (US) synovitis without swelling, and respond better to therapy than those with normal ultrasound. We aimed to revise the MSK domain of the BILAG-2004 index to improve its utility in modern practice. Methods An MSK sub-committee reviewed the existing BILAG-2004 MSK definitions and glossary, then re-analysed data from recent studies to propose revised definitions. Results The new definitions/changes are: (i) BILAG-C arthralgia (if US is not performed) is defined as a classical inflammatory symmetrical small-joint distribution of symptomatic joints on clinical assessment, based on the features most associated with US inflammation in a previous study. If US is performed, all previous BILAG-C patients are reclassified: (ii) BILAG-B now includes patients without swelling if they have significant synovitis/tenosynovitis on US in symptomatic joints/tendons; (iii) patients with arthralgia without swelling are scored as BILAG-D instead of C, if US of the symptomatic joints has been performed and is normal; (iv) a more detailed definition of functional impairment is provided for BILAG-A. Data from 221 symptomatic SLE patients (BILAG-A-C) in two recent studies were re-analysed in the light of the above changes. 121/221 (54.8%) were graded clinically as having arthralgia / myalgia (BILAG-C) on BILAG-2004 . Of these, 53/121 (43.8%) had evidence of synovitis (GS > 1 or PD > 0) or tenosynovitis (GS > 0 or PD > 0) on US. The effect on grading if US were performed on all BILAG C cases is shown in table 1. Conclusion Future versions of the BILAG index will allow the use of US to classify patients who are graded as mild inflammatory arthritis (BILAG-C) to moderate (BILAG-B) or non-inflammatory pain (BILAG-D/E). Although US is not required for all assessments it may be used when there is diagnostic uncertainty. This is in keeping with clinical practice in inflammatory arthritis care, and similar to use of other investigations (e.g. renal biopsy) that contribute to BILAG assessments of other systems. Disclosure R.D. Sandler: None. E.M. Vital: None. A. Prabu: None. C. Riddell: None. K.I. Mahmoud: None. L. Teh: None. C.J. Edwards: None. C. Yee: None.

Objective In light of reports of de novo LN during belimumab (BLM) treatment, we sought to determine its frequency and contributing or protective factors in a real-life setting. Methods Patients with SLE who received BLM between 2011 and 2017 at five European academic practices were enrolled (n = 95) and followed longitudinally for a median time of 13.1 months [interquartile range (IQR): 6.0–34.7]; 52.6% were anti-dsDNA positive, 60.0% had low complement levels, and 69.5% had no renal involvement prior to/at BLM initiation [mean disease duration at baseline: 11.4 (9.3) years]. Age- and sex-matched patients with non-renal SLE who had similar serological profiles, but were not exposed to BLM, served as controls (median follow-up: 132.0 months; IQR: 98.3–151.2). Results We observed 6/66 cases (9.1%) of biopsy-proven de novo LN (4/6 proliferative) among the non-renal BLM-treated SLE cases after a follow-up of 7.4 months (IQR: 2.7–22.2). Among controls, 2/66 cases (3.0%) of de novo LN (both proliferative) were observed after 21 and 50 months. BLM treatment was associated with an increased frequency and/or shorter time to de novo LN [hazard ratio (HR): 10.7; 95% CI: 1.7, 67.9; P = 0.012], while concomitant use of antimalarial agents along with BLM showed an opposing association (HR: 0.2; 95% CI: 0.03, 0.97; P = 0.046). Conclusion Addition of BLM to standard-of-care did not prevent LN in patients with active non-renal SLE, but a favourable effect of concomitant use of antimalarials was implicated. Studies of whether effects of B-cell activating factor inhibition on lymphocyte subsets contribute to LN susceptibility are warranted.

Summary B-cell depletion therapy is an effective option for the treatment of rheumatoid arthritis but often does not result in complete B-cell depletion. Complete B-cell depletion after rituximab treatment is associated with clinical response, and this outcome leads to long-term maintenance of therapy. Low pretreatment plasmablast counts, concomitant treatment with disease-modifying antirheumatic drugs, no smoking exposure, the presence of anticitrullinated protein antibodies or rheumatoid factor, and a low interferon signature are all predictive of complete B-cell depletion and clinical response. Half of patients who initially show complete B-cell depletion and clinical response after rituximab treatment eventually lose responsiveness with further infusions. However three-quarters of these patients regain this outcome in their following treatment cycle, suggesting that loss of response is reversible and that patients can still benefit from rituximab retreatment. The efficacy of reduced doses of rituximab is being investigated, but preliminary results suggest that these strategies are best used for maintenance therapy, particularly in patients who suffer adverse events or who are at a high risk of infection. Infusion-related reactions are the most common adverse events associated with rituximab treatment, and monitoring of IgG concentrations is crucial, as low concentrations are correlated with an increased risk of infection.

Objectives To determine whether SLE patients with inflammatory joint symptoms and US synovitis/tenosyovitis achieve better clinical responses to glucocorticoids compared with patients with normal scans. Secondary objectives included identification of clinical features predicting US synovitis/tenosynovitis. Methods In a longitudinal multicentre study, SLE patients with physician-diagnosed inflammatory joint pain received intramuscular methylprednisolone 120 mg once. Clinical assessments, patient-reported outcomes and bilateral hand/wrist USs were collected at 0, 2 and 6 weeks. The primary outcome (determined via internal pilot) was the early morning stiffness visual analogue scale (EMS-VAS) at 2 weeks, adjusted for baseline, comparing patients with positive (greyscale ≥2 and/or power Doppler ≥1) and negative US. Post hoc analyses excluded FM. Results Of 133 patients, 78 had a positive US. Only 53 (68%) of these had one or more swollen joint. Of 66 patients with one or more swollen joint, 20% had a negative US. A positive US was associated with joint swelling, symmetrical small joint distribution and serology. The primary endpoint was not met: in the full analysis set (N = 133) there was no difference in baseline-adjusted EMS-VAS at week 2 [−7.7 mm (95% CI −19.0, 3.5); P = 0.178]. After excluding 32 patients with FM, response was significantly better in patients with a positive US at baseline [baseline-adjusted EMS-VAS at 2 weeks −12.1 mm (95% CI −22.2, −0.1); P = 0.049]. This difference was greater when adjusted for treatment [−12.8 mm (95% CI −22, −3); P = 0.007]. BILAG and SLEDAI responses were higher in US-positive patients. Conclusion In SLE patients without FM, those with a positive US had a better clinical response to therapy. Imaging-detected synovitis/tenosynovitis may be considered to decide on therapy and enrich clinical trials.

B cell depletion using rituximab is widely used to treat autoimmune diseases, but patient response varies. The efficacy of rituximab is limited by the efficiency of depletion. Strategies to improve response include altering rituximab dosing, switching anti-CD20-mAb, alternative B cell targets, or non-B cell targeted therapies. Implementing an appropriate strategy requires understanding of the mechanism(s) of resistance to depletion and, if this varies between individuals, a means to test for it. Rituximab kills B cells via a variety of Fcγ receptor (FcγR)-dependent mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), as well as non-FcγR mechanisms. We conducted a longitudinal cohort study in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) using two national registries. Qualitative and quantitative FCGR functional variants were measured using multiplexed ligation-dependent probe amplification, supplemented by novel FCGR2C assays.We provide consistent evidence that FCGR3A, specifically increased number of copies of the FCGR3A-158V allele, was the major FcγR gene associated with rituximab response, including clinical response in RA and SLE and depth of B cell depletion in the combined cohort. In SLE, we provide preliminary data suggesting increased FCGR2C ORF copies were also associated with improved clinical response. Furthermore, we demonstrated the impact of disease status and concomitant therapies on both natural killer cell FcγRIIIa expression and rituximab-induced ADCC; demonstrating increased FcγRIIIa expression and FCGR3A genotype were independently associated with clinical response and B cell depletion. Our findings highlight the importance of enhancing FcγR-effector functions, may help stratify patients, and support ongoing development of next-generation CD20 depleting therapeutics.One Sentence SummaryThe high affinity FcγRIIIa allotype on NK cells explains depth of B cell depletion and clinical response in rituximab therapy for autoimmune disease

ObjectivesTo characterise the efficacy and safety of anifrolumab in patients with systemic lupus erythematosus (SLE) according to interferon gene signature (IFNGS), demographic and clinical subgroups.MethodsWe performed post hoc analyses of pooled data from the 52-week phase III TULIP-1/TULIP-2 placebo-controlled trials of intravenous anifrolumab in moderate-to-severe SLE. Outcomes were assessed in predefined subgroups: IFNGS (high/low), age, sex, body mass index, race, geographic region, age of onset, glucocorticoid use, disease activity and serological markers.ResultsIn pooled data, patients received anifrolumab 300 mg (360/726) or placebo (366/726); 82.6% were IFNGS-high. IFNGS-high patients had greater baseline disease activity and were more likely to have abnormal serological markers versus IFNGS-low patients. In the total population, a greater proportion of patients treated with anifrolumab versus placebo achieved British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) response at week 52 (difference 16.6%; nominal pConclusionsOverall, this study supports the consistent efficacy and safety of anifrolumab across a range of patients with moderate-to-severe SLE. In a few subgroups, small sample sizes limited conclusions from being drawn regarding the treatment benefit with anifrolumab.Trial registration numberNCT02446912,NCT02446899.

Objective BILAG-2004 index is a comprehensive disease activity instrument for SLE but administrative burden and potential frequency of errors limits its use in routine practice. We aimed to develop a tool for more accurate, time-efficient scoring of BILAG-2004 index with full fidelity to the existing instrument. Methods Frequency of BILAG-2004 items was collated from a BILAG-biologics registry (BILAG-BR) dataset. Easy-BILAG prototypes were developed to address known issues affecting speed and accuracy. After expert verification, accuracy and usability of the finalized Easy-BILAG was validated against standard format BILAG-2004 in a workbook exercise of 10 case vignettes. Thirty-three professionals ranging in expertise from 14 UK centres completed the validation exercise. Results Easy-BILAG incorporates all items present in ≥5% BILAG-BR records, plus full constitutional and renal domains into a rapid single page assessment. An embedded glossary and colour-coding assists domain scoring. A second page captures rarer manifestations when needed. In the validation exercise, Easy-BILAG yielded higher median scoring accuracy (96.7%) than standard BILAG-2004 documentation (87.8%, P = 0.001), with better inter-rater agreement. Easy-BILAG was completed faster (59.5 min) than the standard format (80.0 min, P = 0.04) for 10 cases. An advantage in accuracy was observed with Easy-BILAG use among general hospital rheumatologists (91.3 vs 75.0, P = 0.02), leading to equivalent accuracy as tertiary centre rheumatologists. Clinicians rated Easy-BILAG as intuitive, convenient, and well adapted for routine practice. Conclusion Easy-BILAG facilitates more rapid and accurate scoring of BILAG-2004 across all clinical settings, which could improve patient care and biologics prescribing. Easy-BILAG should be adopted wherever BILAG-2004 assessment is required.

We thank Dr Karim, MY for his interest in and kind comments on our study (1), in which we reported a low rate (i.e. 7 out of 700; 1%) of patients who required immunoglobulin replacement therapy (IGRT) for recurrent infections despite treatment with prophylactic antibiotics and/or hypogammaglobulinemia during rituximab (RTX) therapy in our cohort. This rate was the lowest compared to other published cohorts, which predominantly comprised patients with ANCA‐associated vasculitis (AAV), ranging from 4–21% (2‐4).

Summary Background Type I interferons are involved in systemic lupus erythematosus (SLE) pathogenesis. In a phase 2 trial, anifrolumab, a human monoclonal antibody to type I interferon receptor subunit 1, suppressed interferon gene signatures and substantially reduced SLE disease activity. Here, we sought to confirm the efficacy of anifrolumab versus placebo in a phase 3 trial of adult patients with SLE and moderate-to-severe disease activity despite standard-of-care treatment. Methods TULIP-1 was a double-blind, randomised, controlled, phase 3 trial done at 123 sites in 18 countries. Included patients were aged 18–70 years, with moderate-to-severe SLE, and ongoing stable treatment with either prednisone or equivalent, an antimalarial, azathioprine, mizoribine, mycophenolate mofetil or mycophenolic acid, or methotrexate. Patients were randomly assigned (2:1:2) to receive placebo, anifrolumab 150 mg, or anifrolumab 300 mg intravenously every 4 weeks for 48 weeks. Stable standard-of-care treatment continued except for mandatory attempts at oral corticosteroid tapering for patients receiving prednisone or equivalent of 10 mg/day or more at baseline. The primary outcome was the difference between the proportion of patients who achieved an SLE responder index-4 (SRI-4) response at week 52 with anifrolumab 300 mg versus with placebo. Key secondary outcomes were the difference between the anifrolumab 300 mg group and the placebo group in: proportion of patients in the interferon gene signature test—high subgroup who achieved SRI-4 at week 52; proportion of patients on 10 mg/day or more corticosteroids at baseline who achieved a sustained dose reduction to 7·5 mg/day or less from week 40 to 52; proportion of patients with a cutaneous lupus erythematosus disease area and severity index (CLASI) activity score of 10 or higher at baseline who achieved a 50% or more reduction in CLASI score by week 12; proportion of patients who achieved SRI-4 at week 24; and annualised flare rate through week 52. Other measures of disease activity were also assessed at week 52, including the British Isles Lupus Assessment Group-based composite lupus assessment (BICLA). Safety was also assessed. Efficacy and safety analyses were done in the population of patients who received at least one dose of study drug. This trial was registered at ClinicalTrials.gov (NCT02446912). Findings Between June 9, 2015, and June 16, 2017, 457 patients were randomly assigned to the anifrolumab 300 mg group (n=180), the anifrolumab 150 mg group (n=93), or the placebo group (n=184). The proportion of patients at week 52 with an SRI-4 response was similar between anifrolumab 300 mg (65 [36%] of 180) and placebo (74 [40%] of 184; difference −4·2 [95% CI −14·2 to 5·8], p=0·41). Similarly, proportions of patients with an SRI-4 response at week 24, and at week 52 in patients in the interferon gene signature test—high subgroup, did not differ between the anifrolumab and placebo groups. In patients with baseline oral corticosteroids of at least 10 mg/day, sustained dose reduction to 7·5 mg/day or less was achieved by 42 (41%) of 103 patients in the anifrolumab 300 mg group and 33 (32%) of 102 patients in the placebo group (difference 8·9 [95% CI −4·1 to 21·9]). In patients with CLASI activity score of at least 10 at baseline, at least 50% reduction by week 12 was achieved by 24 (42%) of 58 patients in the anifrolumab 300 mg group and 14 (25%) of 54 in the placebo group (difference 17·0 [95% CI −0·3 to 34·3]). Annualised flare rates were 0·60 for anifrolumab and 0·72 for placebo (rate ratio 0·83 [95% CI 0·60 to 1·14]). BICLA response was achieved by 67 (37%) of 180 patients receiving anifrolumab 300 mg versus 49 (27%) of 184 receiving placebo (difference 10·1 [95% CI 0·6 to 19·7]). Anifrolumab's safety profile was similar to that observed in phase 2, with similar proportions of patients having a serious adverse event between groups (25 [14%] of 180 for anifrolumab 300 mg, ten [11%] of 93 for anifrolumab 150 mg, and 30 [16%] of 184 for placebo). Interpretation The primary endpoint was not reached. However, several secondary endpoints, including reduction in oral corticosteroid dose, CLASI responses, and BICLA responses, suggest clinical benefit of anifrolumab compared with placebo. Conclusive evidence for the efficacy of anifrolumab awaits further phase 3 trial data. Despite the inherent limitations of a 1-year phase 3 study, such as incomplete knowledge of applicability to the general population and scarce detection of rare safety signals, in addition to complications from prespecified restricted medication rules, our results suggest that anifrolumab might have the potential to provide a treatment option for patients who have active SLE while receiving standard therapy. Funding AstraZeneca.

ObjectivesThe objectives of this study were to assess the reliability of a novel objective outcome measure, laser Doppler imaging (LDI), its validity against skin biopsy histology and other clinical instruments, including localized cutaneous lupus disease area and severity index (L-CLASI) and visual analogue scale (VAS) score of photographs, and its responsiveness to clinical change with therapy.MethodsA prospective observational cohort study was conducted in 30 patients with active cutaneous lupus erythematosus (CLE). At baseline and 3 months, disease activity was assessed using L-CLASI and a high resolution LDI system by two assessors. Skin biopsy was scored as 0 = non-active, 1 = mild activity and 2 = active. Photographs were assessed by two clinicians using 100 mm VAS. Inter-rater reliability was analyzed using Bland–Altman limits of agreement. Correlation between histology and LDI, L-CLASI and VAS and sensitivity to change of LDI with physician subjective assessment of change (PSAC) at 3 months were analyzed using Kendall’s tau-a.ResultsOf 30 patients with CLE, 28 (93%) were female, mean (SD) age 48.4 (11.5) y, 25 (83%) were Caucasians, 25 (83%) had concurrent systemic lupus erythematosus and 16 (53%) were smokers. CLE subtypes were acute = 9, subacute = 8 and chronic = 13. Inter-rater agreement for LDI was fair but for VAS score of photographs was poor. In 20 patients with biopsy, correlation with histology was better for LDI (tau-a = 0.53) than L-CLASI (tau-a = 0.26) (difference = 0.27; 90% CI 0.05–0.49) or VAS score of photographs (tau-a = 0.17) (difference = 0.36; 90% CI 0.04–0.68). There was a moderate correlation between PSAC score and change in LDI (tau-a = 0.56; 90% CI 0.38–0.74; p ConclusionLDI provides a reliable, valid and responsive quantitative measure of inflammation in CLE. It has a better correlation with histology compared to clinical instruments. LDI provides an objective outcome measure for clinical trials.

Objective To assess the responsiveness of clinical outcome measures in musculoskeletal SLE compared with US. Methods A prospective pilot study was conducted in consecutive SLE patients with inflammatory musculoskeletal symptoms. Clinical assessments including SLEDAI, BILAG, 28 tender and swollen joint counts, physician and patient visual analogue scales (VAS), and US were performed at 0, 2 and 4 weeks following 120 mg i.m. methylprednisolone acetate. Responsiveness was analysed using changes and effect sizes using Cohen’s criteria. Results Twenty patients were recruited. Fifteen out of 20 had clinical swelling at baseline. All clinical and US parameters were significantly improved at week 4 (all P ⩽ 0.01). Musculoskeletal-BILAG score improved in 16/20. Musculoskeletal-SLEDAI improved in 7/20. SLE responder index 4 criteria were assessed in 19 patients with SLEDAI ⩾4 at baseline and were met in 9/19 at 4 weeks. Effect sizes at 4 weeks were large (>0.5) for US, physician VAS and BILAG, and medium (>0.3) for joint counts and SLEDAI. Large effect sizes for improvement in US grey-scale and power Doppler were observed in both SLE responder index 4 responders (r = −0.51 and −0.56, respectively) and non-responders (r = −0.62 and −0.59, respectively) at 4 weeks. Conclusion This is the first study to measure the responsiveness of clinical outcome measures in musculoskeletal SLE against an objective inflammation measure. BILAG and physician VAS were the most responsive clinical instruments. US was highly responsive in musculoskeletal SLE, while SLEDAI and joint counts appeared suboptimal for detection of improvement. These results suggest that clinical trials based on the SLEDAI and SLE responder index 4 may underestimate the efficacy of therapy in SLE.

BackgroundSystemic lupus erythematosus (SLE) management objectives include preventing disease flares while minimizing glucocorticoid exposure. Pooled data from the phase 3 TULIP-1 and TULIP-2 trials in patients with moderate to severe SLE were analyzed to determine anifrolumab’s effect on flares, including those arising with glucocorticoid taper.MethodsTULIP-1 and TULIP-2 were randomized, placebo-controlled, 52-week trials of intravenous anifrolumab (300 mg every 4 weeks for 48 weeks). For patients receiving baseline glucocorticoid ≥10 mg/day, attempted taper to ≤7.5 mg/day prednisone or equivalent from Weeks 8–40 was required and defined as sustained reduction when maintained through Week 52. Flares were defined as ≥1 new BILAG-2004 A or ≥2 new BILAG-2004 B scores versus the previous visit. Flare assessments were compared for patients receiving anifrolumab versus placebo.ResultsCompared with placebo (n = 366), anifrolumab (n = 360) was associated with lower annualized flare rates (rate ratio 0.75, 95% confidence interval [CI] 0.60–0.95), prolonged time to first flare (hazard ratio 0.70, 95% CI 0.55–0.89), and fewer patients with ≥1 flare (difference −9.3%, 95% CI −16.3 to −2.3), as well as flares in organ domains commonly active at baseline (musculoskeletal, mucocutaneous). Fewer BILAG-based Composite Lupus Assessment responders had ≥1 flare with anifrolumab (21.1%, 36/171) versus placebo (30.4%, 34/112). Of patients who achieved sustained glucocorticoid reductions from ≥10 mg/day at baseline, more remained flare free with anifrolumab (40.0%, 76/190) versus placebo (17.3%, 32/185).ConclusionsAnalyses of pooled TULIP-1 and TULIP-2 data support that anifrolumab reduces flares while permitting glucocorticoid taper in patients with SLE. ClinicalTrials.gov identifiers TULIP-1 NCT02446912 (clinicaltrials.gov/ct2/show/NCT02446912); TULIP-2 NCT02446899 (clinicaltrials.gov/ct2/show/NCT02446899).

Background: Infectious diseases and vaccines can occasionally cause new-onset or flare of immune-mediated diseases (IMDs). The adjuvanticity of the available SARS-CoV-2 vaccines is based on either TLR-7/8 or TLR-9 agonism, which is distinct from previous vaccines and is a common pathogenic mechanism in IMDs. Methods: We evaluated IMD flares or new disease onset within 28-days of SARS-CoV-2 vaccination at five large tertiary centres in countries with early vaccination adoption, three in Israel, one in UK, and one in USA. We assessed the pattern of disease expression in terms of autoimmune, autoinflammatory, or mixed disease phenotype and organ system affected. We also evaluated outcomes. Findings: 27 cases included 17 flares and 10 new onset IMDs. 23/27 received the BNT - 162b2 vaccine, 2/27 the MRNA-1273 and 2/27 the ChAdOx1 vaccines. The mean age was 54.4 ± 19.2 years and 55% of cases were female. Among the 27 cases, 21 (78%) had at least one underlying autoimmune/rheumatic disease prior the vaccination. Among those patients with a flare or activation, four episodes occurred after receiving the second-dose and in one patient they occurred both after the first and the second-dose. In those patients with a new onset disease, two occurred after the second-dose and in one patient occurred both after the first (new onset) and second-dose (flare). For either dose, IMDs occurred on average 4 days later. Of the cases, 20/27 (75%) were mild to moderate in severity. Over 80% of cases had excellent resolution of inflammatory features, mostly with the use of corticosteroid therapy. Atypical rheumatic manifestations included idiopathic pericarditis (n = 2), neurosarcoidosis with small fiber neuropathy (n = 1), demyelination (n = 1), and myasthenia gravis (n = 2). In 22 cases (81.5%), the insurgence of Adverse event following immunization (AEFI)/IMD could not be explained based on the drug received by the patient. In 23 cases (85.2%), AEFI development could not be explained based on the underlying disease/co-morbidities. Only in one case (3.7%), the timing window of the insurgence of the side effect was considered not compatible with the time from vaccine to flare. Interpretation: Despite the high population exposure in the regions served by these centers, IMDs flares or onset temporally-associated with SARS-CoV-2 vaccination appear rare. Most are moderate in severity and responsive to therapy although some severe flares occurred. Funding: none.

Background/Aims SLE is heterogeneous in clinical presentation, underlying immunology, and response to therapy. Patients with severe or resistant disease receive cyclophosphamide or rituximab. Although effective, late use of these therapies entails cumulative damage. Emerging predictors of response to rituximab include demographics, IFN-Scores and autoantibodies. For such predictors to change treatment strategy we need to understand their association with the effectiveness of other therapeutic options at earlier decision points. Prospective studies of treatment pathways are difficult to perform, requiring large populations followed for many years. We therefore investigated this question by analysing retrospective treatment pathways since diagnosis in patients whose biomarker status is subsequently known. Methods In patients with established SLE, attending Leeds SLE clinic, we collected demographics, clinical characteristics and blood at a single timepoint. Two previously validated IFN-Scores (IFN-Score A and IFN-Score B) were measured using Taqman. Autoantibodies were measured using immunoprecipitation. Treatment history covering all antimalarials, oral and intravenous immunosuppressants (agent, start and stop dates and reasons) since diagnosis was collected. Univariable and multivariable Cox proportional hazards models were used to test variables as predictors of the primary endpoint: time to cyclophosphamide/rituximab. Results 124 patients were included. Follow up since diagnosis was Median (IQR) 37.5 (27.4-52.3) years, total therapies per patient was 3 (1-4), therapies per year was 0.2 (0.1-0.3). 54/124 (44%) patients required cyclophosphamide/rituximab. Results of Cox regression are shown in the table. There was a significant association between high expression of IFN-Score B and requirement for cyclophosphamide/rituximab as well as trends for age in the first quartile ( Conclusion Patients developing SLE before age 28 with raised interferon scores may be forecast to develop severe disease, fail oral therapies, and require rituximab. While this retrospective analysis may be confounded by a survivorship bias, our findings are consistent with other literature on these variables as predictors of severe disease. Future work will analyse more biomarkers in a larger and more varied patient population. P163 Table 1:CharacteristicCYC/RTX=Yes n(%)CYC/RTX =No n(%)Univariable Hazard ratio (95% CI)Univariable p valueMultivariable Hazard Ratio (95% CI)Multivariable p valueAgeQ1: under 2822 (71%)9 (29%)2.25 (0.99,5.12)0.0541.74 (0.95,3.18)0.074Q2: 28-3812 (39%)19 (61%)1.03 (0.41,2.56)0.949Not includedNot includedQ3: 38-5212 (39%)19 (61%)1.52 (0.62,3.72)0.360Not includedNot includedQ4: over 528 (26%)23 (74%)referencereferenceNot includedNot includedEthnicityCaucasian42 (48%)46 (52%)1.17 (0.58,2.35)0.660Not includedNot includedAfroCaribbean, South Asian, East Asian, Other10 (36%)18 (64%)referencereferenceNot includedNot includedIFN Score A, mean (SD)–2.59 (–2.67)–3.84 (–2.71)1.10 (0.98,1.24)0.113Not includedNot includedIFN Score B, mean (SD)–2.61 (–1.16)–3.53 (–1.76)1.31 (1.05,1.64)0.0171.23 (0.98,1.55)0.079Anti-Sm/U1RNP Ab positive17 (61%)11 (39%)1.50 (0.84,2.67)0.171Not includedNot includedAnti-Ro(60) Ab positive14 (45%)17 (55%)0.88 (0.47,1.65)0.686Not includedNot included Disclosure S. Hassan: Grants/research support; S.U.H. is funded as NIHR Leeds Biomedical Research Centre Research Fellow. K. Mahmoud: None. L. Carter: None. K. Dutton: None. D. Li: None. I.N. Bruce: None. N. McHugh: None. T. Consortium: None. Z. Wigston: None. P. Emery: Consultancies; P.E. has received consultant fees from BMS, Abbott, Pfizer, MSD, Novartis, Roche and UCB. Grants/research support; P.E. has received research grants paid to his employer from Abbott, BMS, Pfizer, MSD and Roche. A. Psarras: None. M. Md Yusof: Grants/research support; M.Y.M.Y. is funded as a Wellcome fellow. E. Vital: Honoraria; E.M.V. has homoraria from Roche, GSK and AstraZenica. Grants/research support; E.M.V. has research grant support from Roche, GSK and AstraZenica.

Background/Aims Time-to-relapse after rituximab for ANCA vasculitis is variable and optimal retreatment strategy is unclear. We previously showed that repopulation of naïve B-cells at 6 months predicts sustained response. Our objective was to evaluate clinical and B-cell predictors for relapse in multivariable analysis to develop a retreatment algorithm. Methods An observational study was conducted in 60 rituximab-treated AAV patients over 10-years. Complete response was defined as a Birmingham Vasculitis Activity Score (BVAS) v3.0=0. Repeat rituximab cycles were given on clinical relapse. Naïve, memory B-cells and plasmablasts were measured using highly sensitive flow cytometry. Clinical and B cell predictors were analysed in multivariable analysis (MVA) to develop a retreatment algorithm. Results Patients were: 33/60 (55%) male, mean(SD) age 51(19), 39/60 (65%) received concomitant immunosuppressants and 54/60 (90%) had prior therapy with cyclophosphamide. Median times to retreatment for cycles 1-5 were 87, 71, 65, 59 and 86 weeks. Over 417 patient-years follow up, 137 relapses occurred in 50 patients; 16 (in 14 patients) were major (renal=7, neurological=4, ENT=3 and lungs=2). The major-relapse rate was 3.8/100 patient-years. Results of MVA are shown in the table. With naïve B-cell repopulation at 6 months, relapse rates at 12 and 18 months were 5% and 16%, versus 45% and 59% without naïve repopulation (p < 0.001). Relapse rates at 18 and 24 months were 17% and 54% with naïve repopulation at 12 months versus and 29% and 71% without (p = 0.045). AUROC for time-to-relapse was greater if retreatment was guided by naïve B-cell repopulation than if ANCA and/or CD19+ return was used at 6 months, 0.82 and 0.52 respectively. Conclusion These results suggest the following: (i) all patients should receive an oral immunosuppressant; (ii) patients with incomplete remission should be retreated at 6 months; (iii) patients with complete remission but absent naïve B cells at 6 months should be retreated at 6 months; (iv) patients with complete remission and naïve B-cell return may not be appropriate for fixed retreatment. For this last group monitoring of clinical symptoms and B-cells may be effective and future work will address this further. This algorithm could avoid hypogammaglobulinaemia due to unnecessary retreatment. P207 Table 1:Factors associated with time-to-relapse to first cycle rituximabRisk FactorsUnivariable analysisHR (95% CI); p-values(with multiple imputation)Multivariable analysis (MVA)HR (95% CI); p-values(with multiple imputation)Age, per 10 years (BL)1.01 (0.86 – 1.17); p = 0.954Not included in MVAFemale (BL)1.15 (0.65 – 2.02); p = 0.629Not included in MVADisease duration, years (BL)1.06 (0.98 – 1.15); p = 0.160Included in MVA but removed from final model as p < 0.20Concomitant immunosuppressant (BL)0.69 (0.39 – 1.22); p = 0.2050.48 (0.24 – 0.94); p = 0.034Positive ANCA immunofluorescence (BL)0.89 (0.46 – 1.71); p = 0.725Not included in MVAPositive anti-PR3/anti-MPO (BL)0.57 (0.31 – 1.06); p = 0.077Included in MVA but removed from final model as p < 0.20CRP, mg/L (BL)1.00 (0.99 – 1.01); p = 0.456Not included in MVABVAS 3.0 per point score (BL)0.99 (0.94 – 1.05); p = 0.763Included in MVA but removed from final model as p < 0.20VDI per point score (BL)1.14 (0.87 – 1.50); p = 0.353Not included in MVANaïve B-cells, x 10 9/L* (BL)1.00 (1.00 – 1.01); p = 0.797Not included in MVAMemory B-cells, x 10 9/L* (BL)1.01 (1.00 – 1.02); p = 0.0401.01 (1.00 – 1.02); p = 0.045Plasmablasts, x 10 9/L* (BL)1.04 (0.94 – 1.16); p = 0.459Not included in MVAComplete depletion at 6 Weeks post-RTX0.90 (0.50 – 1.61); p = 0.721Not included in MVAComplete Response (26Wk)0.34 (0.19 – 0.61); p < 0.0010.24 (0.12 – 0.50); p < 0.001Positive ANCA immunofluorescence (26Wk)0.99 (0.56 – 1.75); p = 0.962Not included in MVAPositive anti-PR3/anti-MPO (26Wk)0.79 (0.44 – 1.42); p = 0.426Not included in MVACRP, mg/L (26Wk)0.99 (0.97 – 1.02); p = 0.618Not included in MVANaïve B-cell repopulation (26Wk)0.38 (0.19 – 0.76); p = 0.0060.43 (0.22 – 0.84); p = 0.013Memory B-cell repopulation (26Wk)0.45 (0.20 – 0.99); p = 0.046Included in MVA but removed from final model as p < 0.20Plasmablast cell repopulation (26Wk)1.14 (0.61 – 2.13); p = 0.675Not included in MVABL = baseline, 26Wk = 26 weeks. Disclosure J.E. Arnold: None. E.M.J. Vital: Honoraria; Roche, GSK, AstraZeneca. S. Dass: Honoraria; Roche, GSK. A. Aslam: None. A.C. Rawstron: None. S. Savic: Honoraria; Novartis, Swedish Orphan Biovitrum, Sire. Grants/research support; Novartis, Swedish Orphan Biovitrum, Octapharma, CSL Behring. P. Emery: Consultancies; BMS, Abbott, Pfizer, MSD, Novartis, Roche, UCB. Grants/research support; Abbott, BMS, Pfizer, MSD, Roche. M. Md Yusof: None.