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Background: Haemophagocytic lymphohistiocytosis (HLH) is a rare hyper-inflammatory condition with poor outcomes. Objectives: Few population-based estimates of the incidence and survival in adults exist. We aimed to provide these data for England. Methods: We used population-based linked data from primary care, secondary care, cancer registries and mortality databases in England to identify people diagnosed with HLH between 1 January 2000 and 31 December 2016. We calculated annual incidence rates by age and sex, modelled change in incidence over time with Poisson regression, calculated overall 1-year survival using Kaplan–Meier methods and estimated adjusted hazard ratios (HRs) of death using a Cox proportional hazards model. Results: We identified 214 patients with HLH. The reported age and sex-adjusted incidence increased twofold over the period, from around one to around two per million. Incidence was highest in those below 1 year (14.6 per million) and ≥75 years (2.2 per million), and lowest in those aged 15–44 years (0.8 per million). One-year survival varied by age and sex from 77% (95% confidence interval [CI] 63%–86%) in those

Background/Aims Haemophagocytic lymphohistiocytosis (HLH) is a syndrome characterised by the presence of severe uncontrolled systemic inflammation due the overproduction of inflammatory cytokines and macrophage activation. The majority of adult patients have secondary HLH, triggered by either infection, haematological malignancy or rheumatic disease. Early recognition and initiation of definitive treatment is of vital importance as HLH leads to multi-organ failure and death if left untreated, with mortality of up to 80% in some cohorts. Methods Under-recognition of the disease and vast differences in the management of patients with HLH between specialities have been common problems. To address this, a Rheumatology-led HLH multi-disciplinary team (MDT) meeting was established at University College London Hospital (UCLH) in 2018. The MDT includes physicians from Rheumatology, Infectious Disease, Haematology, Intensive Care, Nephrology and Neurology and feeds into the national HLH group HASC - HLH Across Specialty Collaboration. The MDT is now held bimonthly, discussing between 2 and 4 cases each meeting. The MDT functions as a decision-making tool, while providing consensus on patient management, including collaboration on how to access urgent HLH-directed treatments such as Anakinra for secondary care centres without access. It also serves as a unique learning opportunity for trainees from different disciplines. Results Since the introduction of the MDT the number of patients diagnosed with HLH at ULCH has increased from an average of 6 per year in 2014-2016 to 12 per year in 2018-2020. In the last two years we have seen improved survival from years 2017/18 to 2019/20 (Table 1); survival was approximately 30% in 2017 and 75% in 2019. P018 Table 1:Outcomes of patients diagnosed with HLH (using ICD codes D761 and D762) at University College London Hospital since 2005.YEARALIVEDECEASED200511200601201021201111201220201334201442201525201641201737201839201993202095 Conclusion We believe that the HLH MDT has directly contributed to these improvements by encouraging earlier recognition and subspeciality collaboration. We encourage other sites to adopt a multi-disciplinary approach to managing patients with HLH to promote awareness of the condition and improve patient outcomes. Disclosure D.R. Ludwig: None. J. Manson: None. A. Jones: None. S. Mackenzie: None. N. Mccann: None.

Background/Aims In rheumatoid arthritis (RA), musculoskeletal ultrasound (MSK-US) has greater sensitivity for the detection of active disease than clinical assessment using the DAS28 score, which is prone to false elevation by a spuriously high tender joint count (TJC) and/or visual analogue score (VAS) from non-RA causes. Thus, DAS28 may correlate poorly with MSK-US findings. In pregnancy, standardised disease activity of RA comprises calculation of the modified DAS28(3)CRP score, with removal of the VAS and ESR, both of which are confounded by pregnancy, and replacement with CRP; however, it is unknown whether non-specific musculoskeletal pain and/or peripheral oedema in (especially late) pregnancy might contribute to the TJC or swollen joint count (SJC) respectively and thus render this adapted score less reliable. Therefore, we conducted this study of pregnant RA patients and controls to assess the ability of the DAS28(3)CRP to detect disease activity compared with MSK-US. Methods Pregnant RA patients were recruited from the UCLH obstetric rheumatology clinic from September 2018 to March 2020. Patients underwent clinical assessment with DAS28(3)CRP and MSK-US longitudinally through pregnancy/post-partum. A control group of age-matched non-pregnant female RA patients was recruited from general rheumatology clinics and had equivalent assessments. MSK-US was undertaken using a Logiq S8. The standard protocol comprised 22-joint assessment of hands (dorsal longitudinal and transverse views of wrists, metacarpophalangeal and proximal interphalangeal joints). Quantification of Power Doppler (PD) signal was made as per the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) US definitions. PD scores were calculated as mean scores of all joints scanned. Statistical correlations were performed in SPSS using Spearman’s rank coefficient as data were non-normally distributed. Results A total of 45 MSK-US scans of pregnant/postpartum RA patients (N = 24, mean age 34.5+-3.6) were performed and compared to a control group of non-pregnant RA patients, who were scanned once each (N = 18, mean age 32.3+-5.2; p = 0.12). In the second (T2) and third trimester (T3) and the postpartum (PP), there was a significant positive correlation between DAS28(3)CRP and PD score (T2, ρ = 0.87 (p < 0.01); T3, ρ = 0.76 (p < 0.01); PP, ρ = 0.68 (p = 0.03)). Interestingly, each of these were stronger correlations than the equivalent comparison in non-pregnant RA patients (ρ = 0.51 (p = 0.03)). TJC also significantly positively correlated with PD score in each trimester of pregnancy and postpartum, but not in non-pregnant patients; difference between correlation coefficients was statistically significant for each trimester (T1, p < 0.01; T2, p = 0.05; T3, p = 0.05). Conclusion Interestingly, we found that that DAS28(3)CRP correlates better with PD signal on MSK-US in pregnancy than in non-pregnancy. Specifically, there was significantly better correlation of the TJC with PD score. It is unclear why non-inflammatory contributors to the TJC may be less prominent in pregnancy and further investigation is warranted. Disclosure C. Raine: Grants/research support; C.R. has received research funding from UCB. J. Manson: None. C. Ciurtin: None. I. Giles: Grants/research support; IG has received an unrestricted educational grant, speaker's fees and travel fees from UCB.

Background Haemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening syndrome characterised by hyperinflammation and macrophage activation. Viral infections such as Epstein-Barr virus (EBV) are a well-recognised trigger of HLH but the treatment of such cases is not well-defined. We present a case of primary EBV driven HLH that was successfully treated with the interleukin-1 inhibitor anakinra in addition to rituximab and high-dose steroids. Case A 22-year-old female with no past medical history developed a mononucleosis-like illness lasting five days characterised by fevers, sore throat and neck swelling. Two weeks following this she presented with fevers, night sweats, fatigue and right upper quadrant pain. She was diagnosed with HLH based on high fevers with hyperferritaemia, hypertriglyceridaemia, pancytopaenia, abnormal liver function tests and hepatosplenomegaly. Extensive investigation revealed an EBV viral load of 23,000,000 copies/ml with nil other obvious triggers. A diagnosis of primary-driven EBV HLH was made. She was treated with the interleukin-1 inhibitor anakinra, methylprednisolone and IVIG and a single dose of rituximab. Following the commencement of treatment, the patient made a dramatic improvement. Her EBV viral load reduced to 660 within nine days and her blood counts and liver function returned to normal. She was discharged from hospital on day sixteen. She continued the anakinra for 5 weeks at a weaning dose and completed a 12-week weaning dose of steroids. She has returned to her studies and has no lasting complications from her illness. Discussion This case highlights the potential of primary EBV infection to cause fulminant HLH. The prompt diagnosis and treatment of HLH using anakinra and rituximab in addition to conventional HLH treatment was safe, and associated with a dramatic clinical improvement. The use of anakinra has been documented in other cases of HLH but none, to our knowledge, of primary EBV-driven HLH with no underlying haematological or rheumatological condition.

Summary Background A subset of patients with severe COVID-19 develop a hyperinflammatory syndrome, which might contribute to morbidity and mortality. This study explores a specific phenotype of COVID-19-associated hyperinflammation (COV-HI), and its associations with escalation of respiratory support and survival. Methods In this retrospective cohort study, we enrolled consecutive inpatients (aged ≥18 years) admitted to University College London Hospitals and Newcastle upon Tyne Hospitals in the UK with PCR-confirmed COVID-19 during the first wave of community-acquired infection. Demographic data, laboratory tests, and clinical status were recorded from the day of admission until death or discharge, with a minimum follow-up time of 28 days. We defined COV-HI as a C-reactive protein concentration greater than 150 mg/L or doubling within 24 h from greater than 50 mg/L, or a ferritin concentration greater than 1500 μg/L. Respiratory support was categorised as oxygen only, non-invasive ventilation, and intubation. Initial and repeated measures of hyperinflammation were evaluated in relation to the next-day risk of death or need for escalation of respiratory support (as a combined endpoint), using a multi-level logistic regression model. Findings We included 269 patients admitted to one of the study hospitals between March 1 and March 31, 2020, among whom 178 (66%) were eligible for escalation of respiratory support and 91 (34%) patients were not eligible. Of the whole cohort, 90 (33%) patients met the COV-HI criteria at admission. Despite having a younger median age and lower median Charlson Comorbidity Index scores, a higher proportion of patients with COV-HI on admission died during follow-up (36 [40%] of 90 patients) compared with the patients without COV-HI on admission (46 [26%] of 179). Among the 178 patients who were eligible for full respiratory support, 65 (37%) met the definition for COV-HI at admission, and 67 (74%) of the 90 patients whose respiratory care was escalated met the criteria by the day of escalation. Meeting the COV-HI criteria was significantly associated with the risk of next-day escalation of respiratory support or death (hazard ratio 2·24 [95% CI 1·62–2·87]) after adjustment for age, sex, and comorbidity. Interpretation Associations between elevated inflammatory markers, escalation of respiratory support, and survival in people with COVID-19 indicate the existence of a high-risk inflammatory phenotype. COV-HI might be useful to stratify patient groups in trial design. Funding None.

Summary The term cytokine storm syndromes describes conditions characterised by a life-threatening, fulminant hypercytokinaemia with high mortality. Cytokine storm syndromes can be genetic or a secondary complication of autoimmune or autoinflammatory disorders, infections, and haematological malignancies. These syndromes represent a key area of interface between rheumatology and general medicine. Rheumatologists often lead in management, in view of their experience using intensive immunosuppressive regimens and managing cytokine storm syndromes in the context of rheumatic disorders or infection (known as secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome [sHLH/MAS]). Interleukin (IL)-1 is pivotal in hyperinflammation. Anakinra, a recombinant humanised IL-1 receptor antagonist, is licenced at a dose of 100 mg once daily by subcutaneous injection for rheumatoid arthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, and cryopyrin-associated periodic syndromes. In cytokine storm syndromes, the subcutaneous route is often problematic, as absorption can be unreliable in patients with critical illness, and multiple injections are needed to achieve the high doses required. As a result, intravenous anakinra is used in clinical practice for sHLH/MAS, despite this being an off-licence indication and route of administration. Among 46 patients admitted to our three international, tertiary centres for sHLH/MAS and treated with anakinra over 12 months, the intravenous route of delivery was used in 18 (39%) patients. In this Viewpoint, we describe current challenges in the management of cytokine storm syndromes and review the pharmacokinetic and safety profile of intravenous anakinra. There is accumulating evidence to support the rationale for, and safety of, intravenous anakinra as a first-line treatment in patients with sHLH/MAS. Intravenous anakinra has important clinical relevance when high doses of drug are required or if patients have subcutaneous oedema, severe thrombocytopenia, or neurological involvement. Cross-speciality management and collaboration, with the generation of international, multi-centre registries and biobanks, are needed to better understand the aetiopathogenesis and improve the poor prognosis of cytokine storm syndromes.

Background The utility of musculoskeletal ultrasound (MSK-US) in the measurement of disease activity of rheumatoid arthritis (RA) is well established. However, it has not been formally studied in pregnancy, with the literature limited to a single case report. Standard disease activity assessment in RA pregnancy comprises measurement of the DAS28(3) CRP score, which removes the visual analogue score (VAS) and replaces ESR with CRP, as both of these components may be confounded by pregnancy. Use of this modified score remains problematic as the tender joint count may be affected by non-specific musculoskeletal pain in pregnancy, and the swollen joint count may be obscured by peripheral oedema, especially late in pregnancy. No study of RA in pregnancy has used MSK-US to measure disease activity. Our objective was to conduct a pilot study of MSK-US in RA pregnancy, and compare findings with clinical assessment using the DAS28(3)CRP score. Methods We offered MSK-US to pregnant RA patients attending the UCLH obstetric rheumatology clinic from September 2018 to September 2019. Patients were assessed longitudinally through pregnancy/post-partum where possible. Examination was undertaken using a Logiq S8 US machine. The standard protocol comprised 22-joint assessment of hands (dorsal longitudinal and transverse views of wrists, metacarpophalangeal and proximal interphalangeal joints). In the feet, bilateral MTP joints were scanned with longitudinal views. Quantification of Power Doppler (PD) signal and grey scale (GS) synovitis was made as per the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) US definitions. PD and GS scores were calculated as mean scores of all joints scanned. Results To date, 17 pregnant RA patients have undergone a total of 35 MSK-US studies. Disease activity assessments showed 10/17 patients with persistent low activity through pregnancy, 5/17 with moderate or good response, 1/17 with no response and 1/17 with a moderate flare. Overall, PD scores correlated well with DAS28(3) CRP assessment (R2 = 0.68). All patients at moderate or high disease activity by DAS28(3) CRP had ≥1 joint with detectable PD signal, but 2/21 patients clinically in ‘remission’ and 3/7 patients in ‘low disease activity’ had detectable PD. One patient with only 2 tender and 1 swollen joints (and normal CRP; DAS28 3.17) had very extensive PD signal and contributed to the decision to recommence anti-TNF treatment in the 3rd trimester. It was noted that increased vascularity in pregnancy can complicate the assessment of synovial PD signal. MSK-US was particularly helpful in distinguishing true joint synovitis from subcutaneous oedema in the feet. Conclusion This is the first series of MSK-US in pregnant RA patients. The detection of active joint synovitis (by PD signal) in clinical remission/low disease activity states suggests a potential role for MSK-US in confirming apparent low disease activity in pregnancy, and thus guiding stratification of treatment. Disclosures C. Raine None. J. Manson None. C. Ciurtin None. I. Giles None.

Tumor necrosis factor-α inhibitors (TNFis) have revolutionized the management of rheumatoid arthritis (RA), however despite considerable progress, only a small proportion of patients maintain long-term clinical response. Selection of, and switching between, biologics is mainly empirical, experiential, and not evidence-based. Most biopharmaceutical proteins (BP) can induce an immune response against the foreign protein component. Immunogenicity and the development of anti-drug antibodies (ADAs) is considered one of the main reasons for loss of therapeutic efficacy (secondary failure). ADAs may neutralize and/or promote clearance of circulating BP with resultant low serum drug levels, loss of clinical response, poor drug survival and adverse events, such as infusion reactions. ADA identification is technically difficult and not standardized, making interpretation of immunogenicity data from published clinical studies challenging. Trough TNFi drug levels correlate with clinical outcomes, exhibiting a “concentration-response” relationship. Measurement of ADA and drug levels may improve patient care and improve cost-effectiveness of BP use. However, in the absence of clinically-validated, reliable assays and consensus guidelines, therapeutic drug monitoring (TDM) and immunogenicity testing have not been widely adopted in routine clinical practice in Rheumatology. Here we discuss the utility and relevance of TDM and immunogenicity testing of TNFis in RA (focusing on the most widely used TNFis globally, with the most available data, i.e., infliximab, adalimumab, and etanercept), the limitations of currently available assays and potential future immunopharmacological strategies to personalize disease management.

Rheumatology is a multisystem discipline that requires a multisystem approach to history-taking. The symptoms can be wide-ranging, and the novice is best served by following a thorough and systematic approach to history-taking. The more experienced physician with rheumatological expertise will swiftly identify an emerging pattern of symptoms and build a picture of a likely diagnosis, using more selective questioning to illustrate associated features and exclude important differential diagnoses.

Objective A subset of patients with seropositive rheumatoid arthritis (RA) do not mount a C‐reactive protein (CRP) response during flares. We hypothesize that these patients are more likely to experience poor clinical care and less likely to respond to traditional therapy. This study questioned whether this presentation was associated with worse disease outcome and distinct immunological features. Methods Using Power Doppler ultrasound, 48 RA patients with active synovitis were recruited; 30 had normal (n)CRP (5 mg/L or less) and 18 had high (h)CRP (more than 5 mg/L) levels. All had equivalent disease burden assessed by other clinical and laboratory parameters. Results Time to diagnosis and time to first disease‐modifying antirheumatic drug were significantly longer in nCRP compared with hCRP patients (P < 0.05). Significantly more nCRP patients needed escalation to biologics after 2‐year follow‐up (P = 0.01). The inflammatory milieu was also different between the two subgroups. Synergy between inflammatory cytokines observed in hCRP patients was lost in nCRP patients, and nCRP patients had significantly increased regulatory T‐cell (Treg) frequencies that correlated positively with predictors of poor disease outcome. Conversely, hCRP but not nCRP patients demonstrated a significant upregulation of alternative complement pathway factors that correlated negatively with Treg frequency. Conclusion Patients with nCRP during flares of RA had an altered immunological profile compared with hCRP patients and experienced diagnostic delays and responded less favorably to conventional treatment.

Limited data are available about the ultrasound (US)-detected inflammatory features in patients with suspicion of inflammatory arthritis (S-IA) vs. established rheumatoid arthritis (RA). Our study aimed to assess if the presence of power Doppler (PD) can be predicted by a combination of clinical, laboratory and US parameters. We conducted a real-life, retrospective cohort study comparing clinical, laboratory and US parameters of 108 patients with established RA and 93 patients with S-IA. We propose a PD signal prediction model based on a beta-binomial distribution for PD variable using a mix of outcome measures. Patients with RA in clinical remission had significantly more active inflammation and erosions on US when compared with patients with S-IA with similar disease scores (p = 0.03 and p = 0.01, respectively); however, RA patients with different disease activity score (DAS-28) scores had similar PD scores (p = 0.058). The PD scores did not correlate with erosions (p = 0.38) or DAS-28 scores (p = 0.28) in RA patients, but they correlated with high disease activity in S-IA patients (p = 0.048). Subclinical inflammation is more common in patients with RA in clinical remission or with low disease activity than in patients with S-IA; therefore, US was more useful in assessing for true remission in RA rather than diagnosing IA in patients with low disease activity scores. This is the first study to propose a PD prediction model integrating several outcome measures in the two different groups of patients. Further research into validating this model can minimise the risk of underdiagnosing subclinical inflammation.

The coronavirus disease 2019 (COVID-19) has resulted in a global pandemic with multiple casualties. Within the UK, specific groups of patients including those with rheumatic diseases requiring significant immunosuppression were advised to shield from the public to protect themselves from COVID-19 during the heart of the pandemic.1 In their important paper, Gianfrancesco et al found lower rates of hospitalisation in patients with rheumatic diseases with COVID-19 who were taking traditional synthetic and biological disease modifying antirheumatic drugs (DMARDs).2 With regard to biologic DMARDs, most of their registry patients were taking tumour necrosis factor inhibitors but did also include other therapies including interleukin-6 (IL-6) antagonists. They also provide an interesting suggestion of the potential benefit of biologic DMARD therapy in COVID-19 patients particularly in cases associated with a hyperinflammatory response. Indeed, it has been recognised that subsets of COVID-19 patients can develop a cytokine storm involving the uncontrolled production of cytokines such as IL-6.3 4 Moreover, observational studies suggest the potential benefit of IL-6-antagonism using tocilizumab (TOC).5–7 Internationally, TOC has been used in Italy, China and Ireland.8–10 Early during the UK pandemic, there was no access to clinical trials. Moreover, our Trust faced the second highest pressure index in the UK in relation to the number of admissions of COVID-19 patients.11 Our intensive care unit and …

Objectives Optimal management of rheumatoid arthritis (RA) depends on accurate evaluation of disease activity. Foot synovitis is not included in the most used RA outcome measure (DAS-28 score). The aim of this study was to investigate how musculoskeletal ultrasound (MSK-US) examination of hand and feet correlate with the disease activity score (DAS-28 score). We also explored whether performing MSK-US assessments of hands alone compared with hands and feet underestimates the disease activity in RA. Methods This is a real-life cross-sectional study of 101 patients (51 with RA and 50 with other musculoskeletal conditions) with inflammatory small joint pain, who underwent MSK-US examination of hands and feet. Results MSK-US-detected hand synovitis was found in 18/51 (35.3%) RA patients and 16/50 (32%) of those with other musculoskeletal conditions (p = 0.96), while foot synovitis was detected in 18/51 (35.3%) and 12/50 (24%) patients, respectively (p = 0.78). DAS-28 did not correlate with any of the US outcome measures in patients with RA. Six out of 13 (46.1%) RA patients in remission, 7/14 (50%) with low disease activity and 18/32 (56.2%) with moderate disease activity (according to DAS-28 definition) had active synovitis as assessed by the MSK-US examination of their hands and feet. MSK-US-detected synovitis led to treatment escalation in 26/51 (51%) RA patients. Conclusion This study emphasises that MSK-US examination of hands and feet has led to optimised management of the majority of RA patients, which would have not been possible otherwise, because of the lack of correlation between DAS-28 assessment and MSK-US outcomes. Key Points • The most used disease activity score in rheumatoid arthritis (DAS-28) did not correlate with US outcome measures derived from hands and feet examination. • DAS-28 did not differentiate between RA patients with subclinical active synovitis versus well-controlled disease on US. • As a result of US examination of the hands and feet, 51% RA patients had their immunosuppressive treatment optimised. Electronic supplementary material The online version of this article (10.1007/s00330-019-06187-8) contains supplementary material, which is available to authorized users.

Objective Inflammatory disease activity in patients with systemic lupus erythematosus (SLE) may affect the development of atherosclerosis, contributing to their increased risk of cardiovascular disease (CVD). This process may be mediated by anti–apolipoprotein A-I (anti–Apo A-I), anti–high-density lipoprotein (anti-HDL), and anti–C-reactive protein (anti-CRP) autoantibodies. We undertook this study to examine whether levels of these antibodies rise in association with increased SLE disease activity. Methods IgG anti–Apo A-I, anti-HDL, and anti-CRP levels were measured in serum from the following groups: 39 patients with persistently high disease activity (British Isles Lupus Assessment Group [BILAG] A or B score) over the previous 2 years, 42 patients with persistently low disease activity (no BILAG A or B scores) over the previous 2 years, 34 healthy controls, 25 individual patients from whom paired samples (at time of disease flare and quiescence) were obtained and compared, 16 patients with newly diagnosed lupus nephritis from whom multiple samples were obtained and who were followed up prospectively for up to 2 years, and 24 patients with SLE who had experienced CVD events. Results Serum levels of IgG anti–Apo A-I, anti-HDL, and anti-CRP were higher in patients with SLE than in controls. Anti–Apo A-I and anti-HDL levels, but not anti-CRP levels, were higher in patients with persistently high disease activity than in those with low disease activity. Mean levels of the 3 autoantibodies in patients who had experienced CVD events lay between the mean levels in the high and low disease activity groups. Only levels of anti–Apo A-I were significantly higher in samples obtained from individual patients during disease flares than in samples obtained during disease quiescence. In the lupus nephritis patients, anti–Apo A-I and anti-HDL levels correlated with serum levels of high avidity IgG anti–double-stranded DNA. Conclusion Persistent disease activity is associated with a significant increase in IgG anti–Apo A-I and anti-HDL in patients with SLE.

Background Using musculoskeletal ultrasound (US) to assess joint erosions and disease activity in patients with rheumatoid arthritis (RA) an atypical subgroup was identified with active disease demonstrated by significant Power Doppler, but normal C-reactive protein (CRP) levels. We questioned whether this presentation was associated with delayed diagnosis or relative under treatment, risking worse disease outcome and/or disability. We hypothesized that understanding the underlying immune pathology in this atypical subset of patients could directly influence therapeutic targeting in patients whose needs are not currently met. Objectives Define the immunological and clinical phenotype of RA patients with active disease and either normal or high CRP levels. Investigate whether lack of CRP response is associated with altered inflammatory cytokine signaling and exploit the immunological and clinical phenotype of this patient subgroup to propose a more appropriate treatment algorithm. Methods 44 RA patients with active synovitis were recruited, defined by ≥1 joint with Power Doppler detected by US, 29 had normal (n)CRP (≤5mg/L) and 15 had high (h)CRP (>5mg/L) levels. Peripheral blood mononuclear cells (PBMCs) and serum as well as detailed clinical and disease activity scores were collected. Blood from 18 age and sex matched healthy donors was obtained. Multicolour flow cytometry was used to perform in depth PBMC immunophenotyping and serum cytokines were assessed using a Cytometric Bead Array. Results The erosion accrual rate was elevated in patients with nCRP compared to hCRP suggesting more disease-associated joint damage, while no significant differences were detected between patient groups in terms of autoantibody levels, ESR and disease activity scores. Inflammatory cytokine levels were elevated in both the nCRP and hCRP patients including IL1β ( p =0.0364; 0.0233) and IL6 ( p =0.0009; 0.0007) which are known to trigger CRP production. This suggested that nCRP patients could have defects in downstream IL6 signaling, or alternatively, the disease mechanism may not be IL6-dependent in the nCRP group. Since IL6 is known to support T-cell and T-follicular helper-cell (Tfh) activation and differentiation we compared the T-cell phenotype in the two patient groups. As expected, CD4 + T-cells from hCRP patients with RA were activated compared to healthy donors ( p =0.0054) and had increased central memory (p=0.0380, T-CM) and Th17 populations. Similarly, only Tfh-cells in hCRP patients were activated compared to nCRP ( p =0.0026). In contrast, nCRP patients had a less inflammatory phenotype characterized by the highest level of regulatory T-cells (T-reg) compared to healthy donors ( p =0.0036) and hCRP ( p =0.0303) and raised serum IL10 suggesting increased immune modulation in these patients. This was supported by a significant correlation between Treg and TCM populations in the nCRP ( p =0.05) but not the hCRP patients. Conclusions Overall, this supports altered immunological mechanisms in nCRP compared to hCRP patients which could have therapeutic implications. Disclosure of Interest None declared

Background Assessment of active synovitis in rheumatoid arthritis (RA) is complex but essential for diagnosis and ongoing management. Clinical assessment is supported by serum laboratory analysis of inflammatory markers, high sensitivity C-reactive protein (hsCRP) and erythrocyte sedimentation rate (ESR). Musculoskeletal power Doppler ultrasonography (PDUS) has recently demonstrated greater sensitivity over clinical assessment and serum inflammatory markers in detecting active synovitis. Objectives To investigate the association between findings on PDUS, clinical assessment, serum hsCRP and ESR in the assessment of active synovitis in RA. Methods This cross-sectional study evaluated 218 consecutive RA patients (82% female) referred to ultrasound (US) clinic. Two assessors performed US examination using a 22 hand joint protocol, assessing wrists, metacarpophalangeal and proximal interphalangeal joints bilaterally (OMERACT scoring system). HsCRP and ESR were measured within 1 month of US scan. Patients with ≥3 swollen (SJ) and ≥3 tender joints (TJ) in hands were considered to have significant clinical synovitis (active or chronic). Results Of 218 patients with RA, 100 (46%) had positive PDUS signal in at least one joint. Raised hsCRP was found in 25% and raised ESR in 45%. Seventy-two of 202 patients (36%) had ≥3 TJ and ≥3SJ (clinically active synovitis). Whilst tender joint count was not correlated with positive PDUS (OR 1.01, p=0.334), swollen joint count (SJC) demonstrated strong association, with >30% increase in odds for positive PDUS for increase in SJC by one (OR 1.3, p Of 196 patients with ESR and PDUS data available, 44 (47%) of PDUS positive and 45 (44%) of PDUS negative patients had raised ESR, showing no significant association (p=0.667). There was no difference in proportion of patients with raised CRP (25%) in PDUS positive vs. negative groups (p=0.748). ESR and SJC were only very weakly correlated (Spearman9s rho =0.16, p=0.03). Of 138 patients with either clinical or serological evidence of disease activity, 73 (53%) had positive PDUS. Among asymptomatic patients with normal hsCRP and ESR, 21 (38%) were PDUS positive (p=0.058). Conclusions Both hsCRP and ESR correlated poorly with clinical examination and PDUS detection of active synovitis. This should raise awareness among clinicians that hsCRP, ESR and clinical examination are misleading in appreciating the risk of ongoing inflammation in some patients with RA, as 38% of active RA patients in our study fell into this category. Further research into establishing the appropriate hsCRP cut-off value to distinguish between a subclinical inflammatory state and disease remission might yield better understanding of the role of hsCRP in monitoring disease activity in RA. Disclosure of Interest None declared

Background Despite the interest in validating ultrasound (US) as an outcome measure in rheumatology, progress has been achieved only in defining the pathological US abnormalities associated with rheumatoid arthritis (RA). A recent review of US studies in osteoarthritis (OA) showed very limited data about hand OA (1). Patients with OA have been previously described as having synovial thickening (SH), erosions, osteophytes and rarely positive Power Doppler (PD) signal on US examination (2). These findings suggest a possible overlap between US features of hand OA and RA. Objectives This study aimed to investigate the usefulness of a standardised US examination protocol for hand joints in differentiating subclinical RA from OA, in patients with equivocal clinical examination. In addition, we explored which simplified hand US scores perform better for every disease taken separately. Methods A retrospective, observational study was conducted in patients with inflammatory hand joint pains referred to the US clinic with suspected subclinical inflammation. We compared patients with established RA (n=224) and hand OA (n=73), with respect of several demographic, clinical, laboratory and US parameters. We used a 22 hand joint US examination protocol (wrists, metacarpophalangeal and proximal interphalangeal joints bilaterally - OMERACT scoring system) for all patients, and compared it with a range of smaller, pre-defined US joint scores. Results Significant statistical differences were found for age at the time of scan, US parameters and clinical examination between the two groups. Subclinical joint inflammation in the context of equivocal clinical examination was found in 9.6% OA patients compared to 46.4% in RA (p Conclusions Our study findings reflected differences between the incidence and characteristics of subclinical inflammation in patients with RA and OA. The attractiveness of using US scores assessing a smaller number of joints may pose limitations, despite being of benefit in a time-constrained clinical setting. Our study assessed comparatively the utility of several US hand scores, however, further research is need to validate their use in practice. References Keen HI, Wakefield RJ, Conaghan PG. A systematic review of ultrasonography in osteoarthritis. Annals of the rheumatic diseases. 2009;68(5):611–9. Vlychou M, Koutroumpas A, Malizos K, Sakkas LI. Ultrasonographic evidence of inflammation is frequent in hands of patients with erosive osteoarthritis. Osteoarthritis and cartilage/OARS, Osteoarthritis Research Society. 2009;17(10):1283–7. Disclosure of Interest None declared

Background Ultrasound (US) assessment of small joints is essential for the diagnosis of polyarticular inflammatory arthritis (IA) and guidance of the therapeutic decisions in patients with established rheumatoid arthritis (RA). The access to US varies among hospitals and rheumatology services. Even if a considerable proportion of patients with hand joint pain or established RA might have subclinical inflammation, it is not cost-effective to screen them all. Objectives The objective of our study was to build a statistical model to assess the influence of several outcome measures (such as number of tender joints (TJC) and swollen joints (SJC) out of 28, GVAS, CRP, ESR, presence of RF and anti CCP antibodies, disease duration and medication) on the presence of Power Doppler (PD) signal at the US examination of hand joints. Methods We proposed a regression model to assess the contribution of every outcome measure to the risk of having active joint inflammation as well as predict PD signal. We excluded patients with PD signal present in more than 10/22 joints to ensure homogeneity in the data. We conducted a real life study including 276 patients referred for the suspicion of active joint inflammation (new referrals for the suspicion of IA, RA patients and patients with other inflammatory rheumatic conditions). We assessed 22 hand joints in every patient, irrespective of their hand symptoms, using the Omeract scoring system for PD signal. All patients had clinical assessments and lab tests within 2 weeks from the US scan. The proposed regression model was based on a beta-binomial distribution (1 = disease present, 0 = disease absent) for the PD score variable and a mix of main interaction effects for the outcome measures stated above. Negative interaction effects showed that the respective outcome was associated with a lower number of joints with PD signal. Results The marginal effects of different variables on the number of joints with PD signal at the US examination in newly referred patients for the suspicion of IA, previous diagnosis of RA, and patients with other inflammatory conditions were examined. Our statistical model suggested that patients with RA diagnosis treated with Tocilizumab tend to have a lower PD score than patients treated with other biologics or DMARDs, despite similar clinical and laboratory findings. The presence of RF increased the PD score only in patients with clinical suspicion of IA. CRP and ESR had almost no effect on predicting PD. Out of all three clinical outcomes, TJC, SJC and GVAS, only the SJC correlated with an increased PD score and only in patients with RA. Conclusions This prediction model has potential to be useful in identifying what patients will benefit from having an US scan and improve our referral criteria to the US clinics, aiming also to minimise the risk of underdiagnosing active IA. Disclosure of Interest None declared

Background Chikungunya is an arthritogenic mosquito-borne virus causing an epidemic in the Caribbean and Central America. Fever, rash and diffuse, incapacitating polyarthralgia characterise acute infection, which may be followed by persistent arthralgia, often causing significant impairment. Most rheumatologists will have seen very few, if any cases. The extent of joint pathology has not been well defined and there are little data to guide treatment. Objectives To describe the cohort of patients with chikungunya infection at University College London Hospital (UCLH), to use ultrasound to define the joint abnormalities and to assess a systematic treatment approach. Methods Records of patients seen at UCLH with proven chikungunya infection between August 2014 and January 2015 were reviewed. A tropical diseases-rheumatology clinic was set up to assess patients with persistent arthralgia, using clinical examination, DAS-28, targeted MSK ultrasound and investigation for alternative diagnoses. Treatment was commensurate with symptoms, ultrasound findings and prior therapy. Follow-up assessed clinical progress and the need for treatment escalation. Results Between August 2014 and January 2015, 54 patients with proven chikungunya infection were seen, compared to 5 patients had in the same period 12-months previously. 21 patients were seen in the tropical diseases–rheumatology clinic. 65% of patients were female, mean age was 50.5 years. 50 (93%) had travelled to the Caribbean. The median time between symptom onset and first review was 25 days (range 1-261 days), with initial illness manifest by diffuse arthralgia (93%), fever (72%), rash (52%), fatigue (20%), and headache (19%). At presentation mean CRP was 7.1mg/L (range In the cohort with persistent arthrlagia, joints affected included knees (71%), feet (62%), ankles (57%), hands (57%), wrists (48%) and elbows (14%), with a mean DAS of 2.9 (range 0.42-5.0). 9 patients (43%) reported symptoms consistent with carpal tunnel syndrome. MSK ultrasound demonstrated effusions (90%), synovial hypertrophy (85%) and osteophytes (45%). Three patients had a grade 1 power Doppler. Bone erosion was not seen in any patient. 32 patients (59%) received NSAIDs and 5 (9%) steroids. One patient received chloroquine and sulphasalazine. Wrist splints were used for carpal tunnel syndrome. 83% of the total cohort and every patient in the specialist clinic had follow-up, at a median of 6.3 weeks (range 1-22 weeks), at which point 7% had improved, 83% were improving and 7% were unchanged. No patients deteriorated. Conclusions Clinical manifestations in the current chikungunya outbreak are similar to those described previously, with arthralgia sometimes persisting for some months. Clinicians should enquire about symptoms of carpal tunnel syndrome. Ultrasound frequently demonstrated effusions and synovial hypertrophy, no patients had evidence of bone erosion. Most patients had persistent symptoms at follow-up, but only a minority with recalcitrant symptoms required systemic steroids or sulphasalazine. These findings should be used to reassure patients. Disease modifying agents should be considered in patients with ongoing symptoms despite NSAIDs and steroids. Acknowledgements Mike Brown & Robin Bailey, Hospital for Tropical Diseases Jane Osborne, Rare and Imported Pathogens Laboratory Disclosure of Interest None declared

Objective To identify the prevalence of serologically active clinically quiescent (SACQ) patients in a cohort of 290 patients with systemic lupus erythematosus (SLE). We investigated if the presence of anti–double-stranded DNA (anti-dsDNA) or antinucleosome (anti-NCS) antibodies during the SACQ period was associated with future flares. Methods SACQ patients defined as clinically inactive for 6 months (global British Isles Lupus Activity Group index [BILAG] scores 50 units/ml on at least 2 occasions by enzyme-linked immunosorbent assay [ELISA]) were identified. Patient sera collected during the defined SACQ period were also tested for anti-NCS antibodies (ELISA). We retrospectively reviewed patient clinical details and episodes of flare using the BILAG activity index. Results Twenty-seven (9%) patients were SACQ. Seventeen (81%) patients experienced a flare (total of 91 flares, up to 12 flares per person) in the next 5 years. Median duration to first flare was 15 months (range 2–46). Time to first flare after SACQ period was significantly correlated with the presence of anti-NCS (P = 0.0012), high anti-NCS antibody titers (P = 0.0006), and anti-dsDNA titers 5 times above the normal limit (P = 0.02). Patients with higher absolute anti-NCS antibody titers showed a significant correlation with the number of flares (r = 0.57, P = 0.007). Conclusion A minority of patients with SLE are SACQ. The majority of these patients experience a flare in the next 5 years and close followup is recommended. Anti-NCS antibodies may be a better predictor than anti-dsDNA antibodies for future flares.

sound, randomized, placebo-controlled double-blind studies. Ineach case, the group of patien ts treated with glucosamine showed reduced narrowing of the tibiofemoral joint space at 3 yr compared with the placebo group. This supports the hypothesis that glucosamine acts as a disease-modifying drug in osteoarthritis of the knee. Pavelka’s group also reported that fewer patients in the glucosamine group reached a cut-off value of 0.5 mm joint space narrowing during the period of the study. This level was considered to represent severe narrowing of the tibiofemoral joint space. Furthermore, the glucosamine-treated group in each study had significantly better functional outcomes than the placebo group, as measured onthe WesternOntario and McMaster Universities (WOMAC) index. Although mild adverse effects such as abdominal pain and dyspepsia were reported, these tended to be transient. There was no convincing evidence that glucosamine causes severe adverse effects such as diabetes mellitus. In conclusion, glucosamine is a safe drug for which a body of evidence suggests effectiveness in relieving symptoms, increasing function and modifying disease progressioninosteoarthritis of the kn ee. We should recommend it to our patients.

A 28 year old Afro-Caribbean woman presented to our hospital with a three day history of an acute, diffuse, urticarial, papular rash on her trunk, limbs, and face. She also had facial swelling and fever. The mucosa and conjunctiva were not affected. Her medical history was unremarkable until a recent diagnosis of seronegative inflammatory arthritis during her second trimester of pregnancy, for which she was initially treated with corticosteroids and hydroxychloroquine. After a miscarriage at 30 weeks, this was switched to sulfasalazine for the three weeks before this admission. On examination she had a fever (38.5°C), tachycardia, bilateral cervical and groin lymphadenopathy, generalised facial swelling (fig 1⇓), and a diffuse erythrodermic rash covering her trunk, face, and limbs (fig 2⇓). A full blood count showed haemoglobin 120 g/L (reference range 115-165), white cell count 5.4×109/L (4.5-11), neutrophils 3.48×109/L (2-7.5), lymphocytes 3.26×109/L (1.3-4), eosinophils 0.16×109/L (0-0.45), and platelets 150×109/L (150-440). A blood film showed a few atypical lymphocytes and reactive lymphocytosis. Liver function tests showed bilirubin 9 mmol/L (5-17), alanine transaminase 415 IU/L (10-35), alkaline phosphatase 145 IU/L (35-104). Her previous liver function test results had been within the reference range. C reactive protein was 32 mg/L (0-5); a viral screen was negative; and an immunology screen showed that antinuclear antibodies, immunoglobulins, and complement were all within the normal range. A microbiology screen showed that urine and blood cultures were negative A chest radiograph was clear. Skin biopsy showed leucocytosis and early vasculitis. ### 1. What are the important differential diagnoses in patients admitted to hospital with acute rash after drug exposure? #### Short answer Toxic epidermal necrolysis, Stevens-Johnson syndrome, drug …

Background Ultrasound (US) assessment of small joints is a well-established method of investigation in inflammatory arthritis. Previous data suggest that there is a poor correlation with clinical examination, and has proved that US is useful in detecting subclinical inflammation (1). Objectives Our aim was to establish the proportion of inflammatory arthritis (IA) patients (newly diagnosed or established) with active synovitis detected by US in the context of normal CRP. Methods We conducted a real life study in patients with IA using a standardised US examination of 22 hand joints. We received 276 referrals between February and August 2013 and we assessed these patients for evidence of active synovitis based on the presence of Doppler signal. There were 108 patients with established rheumatoid arthritis (RA), 93 were referred for the clinical suspicion of inflammatory arthritis (IA), and the rest had other diagnoses. All the patients reported inflammatory symptoms in their hands and their clinical examination was equivocal. We report data on the two largest groups, the RA and IA groups, using descriptive statistics (Origin 6.0). P Results We found positive Doppler signal in 143 patients, and 76 (53.14%) of these have normal CRP level, as measured 2.8±1.6 weeks prior or post US examination. There were 41 RA in this group (from a total of 83 found with positive Doppler signal) and their disease duration was 12±10.2 years. Of these, 66% had positive rheumatoid factor (RF) and 63% had positive anti citrullinated peptide antibodies (ACPA). There were 23 patients referred for the suspicion of IA with positive Doppler signal and normal CRP out of 52 found with active synovitis, having a median duration of symptoms of 6.8 months ±1.9. However, the proportion of seropositive patients – 21.7% for RF and 17.3% for ACPA - was significantly decreased compared to the RA group (p=0.001). The median number of joints with Doppler signal was 3±0.54 in the RA group and 3±0.31 in the IA group (p=0.12). The number of tender joints (out of 28) was 10.6±8.6 and 9.2±7.5 in the RA and IA groups respectively (p=0.07). RA patients had significantly increased number of swollen joints (5.21±3.01 vs. 3.95±3.2, p=0.03), but the IA group of patients reported a significantly lower global health state than the RA patients (66.25±22 vs. 50.5±33.2, p=0.02). The number of clinically assessed swollen joints correlated poorly with the presence of Doppler signal in RA and IA patients (r=0.27 and r=0.42, respectively). Conclusions Normal CRP levels could be found in patients with active joint inflammation in similar proportions in patients with established RA (49.3%) and newly diagnosed with IA (44.2%). However, in the RA group there were more swollen joints that did not correlate with the presence of Doppler signal. The newly diagnosed patients with IA reported a lower health state, despite objective evidence of similar numbers of inflamed joints as the RA patients. US examination of hands is a suitable tool for active synovitis detection in symptomatic patients with normal CRP levels and equivocal clinical evidence of joint swellings. References Saleem, B et al., Arthritis Rheum. 2009 Jul;60(7):1915-22. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.4440

Background The diagnosis of an inflammatory arthropathy (IA) in the early stage of disease can be challenging. While serological markers such as Rheumatoid Factor (RF) and anti-cyclic citrullinated peptide (CCP) can be helpful, they do not have sufficient predictive ability to confirm or out rule a diagnosis of IA. Objectives We sought to describe the findings on High Resolution ultrasonography (HRUS) of the hands and wrists in a cohort of patients with recent onset suspected IA and no definite clinical synovitis. Methods All patients with suspected IA and symptoms Results 40 relevant patients were identified. 87.5% were female and the average age was 45.5 years. 25% were seropositive for RF, 25% for anti-CCP, 5% for ANA and 7.5% had concomitant psoriasis. 50% were ultimately diagnosed with an IA (75% rheumatoid arthritis, 15% undifferentiated IA and 10% psoriatic arthritis). The median CRP (4.7 v 1.15mg/dl, p=0.049) and ESR(18.5 v 7.5mm/h, p=0.006) was significantly higher in those with IA. The median number of joints with mild synovial hypertrophy was higher in those with IA (6 vs. 0, p=0.0001) with a trend towards greater moderate (median 3 vs. 0, p=0.07) and severe synovial hypertrophy (median 2 vs.0, p=0.055) in the inflammatory group. The median number of joints with PD activity (1.0 vs. 0, p=0.01) was significantly higher in those with IA as was the number of joints with erosions (4 vs. 0, p=0.0001) and grade 2 effusions (1.5 vs. 0, p=0.013). PD activity was present in at least one joint of 60% of patients with IA and in no patient with a non-IA. There was no significant difference in the median number of osteophytes. Conclusions It is noteworthy that 50% of patients referred with a suspected IA ultimately were diagnosed with an IA, with the majority of the remainder diagnosed with osteoarthritis, both groups having no obvious clinical synovitis. This highlights the difficulty in deciphering true IA by clinical findings alone and the recognised role of HRUS in detecting subtle inflammatory changes (1). The presence on US of PD activity and erosive change was found to be significantly greater in the IA cohort, thus we support the more widespread availability and use of HRUS in routine clinical practice for patients with early inflammatory symptoms, even in the absence of definite clinical synovitis, in order to facilitate earlier diagnosis and timely treatment. References D.F. Ten Cate et al., Role of ultrasonography in diagnosing early rheumatoid arthritis and remission of rheumatoid arthritis - a systematic review of the literature. Arthritis Res Ther. 2013 Jan 8;15(1): Disclosure of Interest None Declared