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The chikungunya virus is an arthritogenic alphavirus. Acute infection may be followed by persistent arthralgia, often causing significant functional impairment. The 2014–2015 chikungunya fever (CHIKF) epidemic resulted in a marked increase in cases presenting to rheumatology and tropical diseases services. A combined multidisciplinary rheumatology–tropical diseases service for assessment, management, and follow-up of patients with proven CHIKF and persistent (≥ 4 weeks) arthralgia was proposed and rapidly developed at The Hospital for Tropical Diseases in London. Rapid set up of a multidisciplinary clinic in response to the epidemic was achieved. Of a total of 54 patients, 21 (38.9%) patients with CHIKF developed persistent arthralgia and were reviewed by the multidisciplinary service. A combined assessment approach enabled comprehensive multidisciplinary assessment of CHIKF, assessment of joint pathology through ultrasound, and appropriate follow-up. A combined rheumatology–tropical diseases service was successfully used to identify and assess CHIKF-associated morbidity. Future outbreaks may be approached by establishing tailored multidisciplinary clinics.

Background/Aims Haemophagocytic lymphohistiocytosis (HLH) is a devastating condition caused by uncontrolled activation of the immune system. If left untreated, the condition leads to multi-organ failure and death. Even with treatment, recent UK data has shown a mortality rate of 50%. In 2019, a group of clinicians from University College London Hospital (UCLH) came together with the aim of improving outcomes for patients with HLH. The UCLH HLH multi-disciplinary meeting (MDM) has been running since that time and includes representation from rheumatology, haematology, infectious diseases, tropical medicine, virology, neurology, and critical care. Clinicians from any UK trust are invited to join and present patients. As part of a service evaluation project, we aimed to assess the scope of this meeting with regards to the number, demographics and primary diagnoses of patients discussed and the geographical location of the referring clinical team. Methods This is a retrospective descriptive analysis of all patients discussed at the UCLH HLH MDT from 2nd September 2020 to 20th July 2022. Data were obtained from electronic health records and analysed in Prism version 9.4.1. This work has been registered as a service evaluation project within the Division of Medical Specialities at UCLH. Results 93 patients were discussed. 38 were female. 55 were male. The median age was 38 years. Triggers for HLH were haematological malignancy (38.0%), infection (29.3%) rheumatological (14.1%) primary HLH (6.5%) and unknown (7.6%). In 4 patients, HLH was not felt to be the underlying diagnosis. 40 patients were managed as inpatients at UCLH, 37 of whom were transferred from other trusts. Geographical data were obtained on 81 patients. Patients were referred from all 9 regions of England: London (34), North East (1), North West (2), Yorkshire (2), East Midlands (1), West Midlands (3) South East (11), East of England (11), South West (11) as well as Wales (2), Scotland (2) and Ireland (1). Haemophagocytosis was confirmed on bone marrow biopsy in 66.7% of patients. Mortality data showed that 32 (34%) patients died following their diagnosis. Conclusion A multi-disciplinary approach is essential in the management of HLH. Our data show that patients with HLH are young, have a high mortality and broad range of pathology. The UCLH HLH MDT currently serves a wide geographical area across the UK and UCLH acts as a tertiary referral centre for patients with the condition. Disclosure N.S. Shah: None. M. Hutchinson: None. S. Clark: None. E. Sanchez: None. M. Brown: None. N. Stone: None. A.S. Carr: None. B. Carpenter: None. A. Laurence: None. S.H. Gohil: None. R.S. Tattersall: None. J.J. Manson: None. A. Jones: None.

Background/Aims Haemophagocytic lymphocytosis (HLH) is a multi-system hyperinflammatory syndrome with high mortality. Early treatment and multi-disciplinary team (MDT) management improves outcomes. In 2021, NHS England released guidelines for HLH treatment with anakinra; these mandate MDT discussion prior to treatment. HLH is rare and expertise varies throughout the UK, causing potential inequality in access to care. This scoping study aimed to assess HLH service provision across the UK. Methods An online survey was designed and disseminated via professional networks, including Hyperinflammation and HLH across specialty collaboration (HiHASC) members (www.hihasc.org) and contacts at individual hospitals. Quantitative data were analysed using SurveyMonkeyTM analysis. The survey was created to inform national service development, response was voluntary and data have been anonymized. Results 93 survey responses were obtained from 80 healthcare trusts, including three in Scotland and two in Wales. Responses covered 39/42 integrated care boards (ICBs) in England, representing all 7 clinical commissioning regions. Respondent’s specialties included Rheumatology, Haematology, Paediatrics, and Intensive Care. In 33% (13/39) of ICBs, Scotland and Wales no formal HLH provision existed; management relied on individual practice or informal discussions. 36% (14/39) of ICBs utilised ad hoc MDTs to manage HLH. Formal provision of HLH MDTs existed in 31% (12/39) of ICBs although these did not cover all trusts in the ICB. Only one MDT had a paid administrator.20% (n = 16) of trusts had an agreed HLH guideline; 7 were developed locally and 9 utilised external guidelines. Anakinra had been prescribed for HLH in 31% of trusts since 2021. Prescribing requirements were satisfied via ad hoc discussions in 33% of trusts, local Haematology or Rheumatology MDTs in 24% of trusts, and involvement of tertiary centres in 7% of trusts. A further 25% of trusts used a single HLH MDT for anakinra discussions. Only 10% (n = 8) of consultants had HLH included in job plans. A further 36% (n = 29) wanted this. 96% (n = 69) of respondents would value a national or regional HLH MDT. 20% (n = 14) of respondents offered to lead an MDT, with a further 53% (n = 37) willing to offer expertise. The most frequently proposed model for this MDT was a regular, online meeting with advance referrals. The largest barrier to MDT participation was lack of time. Other barriers included limited exposure to HLH and lack of funding or paid administrative support. Conclusion Specialist HLH services are inconsistently provided throughout the UK, suggesting inequitable access to care. Many ICBs rely on ad hoc HLH provision or have no formal HLH service. In areas providing HLH MDT services, these are often outside of job plans and lack administrative support. There is unsustainable reliance on a single centre. Strong support exists for national or regional HLH MDTs, which will require funding. Disclosure M.F. Cox: None. J.J. Manson: None. R.S. Tattersall: None.

Background/Aims To assess the potential for whole-body MRI (WBMRI) to modify rheumatologists’ impression of disease activity and treatment management in adolescent patients with JIA. Methods Two rheumatology consultants experienced in managing people with JIA reviewed anonymised clinical data from an opportunistic sample of 30 patients with JIA (aged 15-24), not under their care. The cohort were clinically assessed by a senior rheumatology fellow before undergoing a research WBMRI scan, reported for musculoskeletal inflammation by a radiologist blinded to clinical information. The clinical findings and patient-reported outcomes recorded on that visit, alongside the patients’ present and past treatments, imaging and laboratory results were included in the clinical summaries examined by each rheumatologist. They then independently rated their impression of disease activity (See Table 1) and documented their resulting treatment recommendations per patient, in a two-stage approach. The first stage data analysis did not include the WBMRI reports. In stage two, the rheumatologists re-rated disease activity and treatment suggestions in light of WBMRI findings. The responses without and with the WBMRI findings were compared for each consultant and between them. Results Disease activity ratings were changed after reviewing the WBMRI reports in 16/30 and 17/30 patients by the rheumatologist A and B respectively. The activity category (‘active’ to ‘inactive’ or vice versa) changed in 7/16 and 4/17 cases, respectively. The certainty in the activity status increased for both rating clinicians (from ‘likely’ to ‘definitely’ in the same category or from ‘not sure’ to any other category) in 7/16 and 11/17 cases, respectively, whilst decreased for both in two cases. Disease activity assessments and treatment recommendations with and without WBMRI, are summarised in Table 1. Inter-rater agreement without and with WBMRI regarding disease activity (active/inactive) was 84.00% and 82.1% respectively, and regarding the intention to change treatment (yes/no) was 63.3% and 83.3%, respectively. Conclusion WBMRI scan findings changed the rheumatologists’ impression or level of certainty regarding disease activity in about half the patients and treatment plan in about one-third. Therefore, a larger study involving a greater number of rheumatologists across the country, should be considered to validate these results. Disclosure V. Choida: None. R.S. Tattersall: None. J.J. Manson: None. D. Sen: None. C. Ciurtin: None. M.A. Hall-Craggs: None.

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

Haemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune dysregulation, characterised by extreme inflammation, fever, cytopaenias and organ dysfunction. HLH can be triggered by conditions such as infection, autoimmune disease and malignancy, among others. Both a familial and a secondary form have been described, the latter being increasingly recognised in adult patients with critical illness. HLH is difficult to diagnose, often under-recognised and carries a high mortality. Patients can present in a very similar fashion to sepsis and the two syndromes can co-exist and overlap, yet HLH requires specific immunosuppressive therapy. HLH should be actively excluded in patients with presumed sepsis who either lack a clear focus of infection or who are not responding to energetic infection management. Elevated serum ferritin is a key biomarker that may indicate the need for further investigations for HLH and can guide treatment. Early diagnosis and a multidisciplinary approach to HLH management may save lives.

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 The COVID-19 pandemic has had a significant impact on the management of outpatients. During the first wave of the pandemic, and in common with other departments, almost all our patient consultations happened over the phone. As the rate of infection fell, we felt it was crucial that the patient voice was heard as we re-organised clinical areas and re-opened services. In view of this, we conducted an online survey to better understand patient concerns around visiting our hospital for appointments and how we can adapt the way we work to ensure patient safety and satisfaction. Methods Using our electronic patient record, we identified patients from the clinic lists of 2 adult rheumatology consultants over a 6-week period between June and August 2020. This timeframe was selected as it was towards the end of the UK nationwide shielding period and our department was returning to deliver an increasing proportion of outpatient care face-to-face. Included patients had to have been treated with an immunosuppressive drug and only those on monotherapy hydroxychloroquine, sulfasalazine or prednisolone under 5mg were excluded. We consented each patient via telephone before sending them an email link to an online anonymised survey. This included a combination of 9 multiple choice and white space questions. Results 65 patients were identified of which 16 were excluded as we were unable to contact them or they declined consent. 49 patients were sent the survey of which 31 responses were received. 21/31 (67%) of patients had been shielding. The survey revealed six themes of concern. These include: lack of social distancing in common hospital areas, lack of personal protective equipment compliance amongst staff, prolonged time spent in waiting rooms, lack of knowledge on new hospital policies, logistics of using public transport to come to the hospital, and the importance of retaining virtual consultations going forward. 55% of patients stated they would feel safe in returning to the hospital for face-to-face appointments over the next few months. Conclusion Important themes have emerged from this project that we have presented to our rheumatology multi-disciplinary team, Director of Innovation and Head of Patient Experience. This has reinforced adaptations in our hospital environment such as installing safe distance seating in waiting rooms and scheduled phlebotomy slots. Further, where possible we call patients before face-to-face appointments to inform them of our safety measures and try to schedule these patients for outside peak travel hours. We acknowledge that using an online survey may limit responses from older individuals or those with English as a second language. Despite this, our project has shown the importance of recognising the unique concerns of rheumatology patients and the value in using their opinions to create a “new normal” for our outpatient environment. Disclosure R. Amarnani: None. B. Goulden: None. J. Manson: None. V. Morris: 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.

Background Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. Methods and findings The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn’s disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253–0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437–0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616–4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319–3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923–5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139–6.764], p < 1 × 10−5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106–4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. Conclusion In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies., In a multicohort prospective study of patients from 12 countries, Signe Hässler and colleagues investigate clinical and genetic factors associated with development of anti-biopharmaceutical drug antibodies in patients with autoimmune diseases., Author summary Why was this study done? Biopharmaceutical products such as monoclonal antibodies are widely used to treat autoimmune diseases. Biopharmaceutical products may induce the development of antidrug antibodies, which often lead to therapy failure. Patient-related factors that influence the development of antidrug antibodies need to be characterized. What did the researchers do and find? We set up a European multicohort prospective study on 4 autoimmune diseases (multiple sclerosis, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis) treated with 8 different biopharmaceutical products. We collected demographic and clinical data and tested antidrug antibodies in longitudinal serum samples from 560 patients. For 457 patients who gave consent, we also collected genetic data. We identified antibiotics and immunosuppressants as negatively associated risk factors and heavy smoking, infections during the study, the HLA-DQA1*05 allele and a minor variant in the CXCL12 chemokine gene associated with increased protein expression as risk factors of antidrug antibody development. What do these findings mean? Our findings suggest that the combination of immunosuppressant and biopharmaceutical therapy could be associated with decreased risk of antidrug antibody occurrence, which has implications for rheumatoid arthritis and inflammatory bowel diseases, for which immunosuppressants are often, but not always, given together with biopharmaceuticals. Patients heterozygotes or homozygotes for the HLA-DQA1*05 allele may have an increased risk of antidrug antibody occurrence associated with biopharmaceutical therapy. The small study size warrants a validation through independent studies, in particular for the genetic findings.

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.

Case report - Introduction A small sub-group of COVID-19 patients develop secondary haemophagocytic lymphohistiocytosis (sHLH), a multisystem progressive hyperinflammatory syndrome characterised by fever, hepatosplenomegaly, hyperferritinaemia, cytopenia, and multiple-organ failure, which if not identified and promptly treated may be fatal. There have been isolated reports of adults developing PIMS-TS, a rare inflammatory multisystem syndrome seen in children with COVID-19 which shares common features with Kawasaki disease, toxic shock syndrome and macrophage activation syndrome / sHLH. Here we present a case of COVID-19-associated PIMS-TS in an adult complicated by frank sHLH (COV-HLH) which, after a protracted course, responded to combination immunotherapy including the IL-1 antagonist anakinra. Case report - Case description A 22-year-old female of Nigerian-descent with sickle cell trait presented with fever, headache, sore throat, arthralgia, abdominal pain, diarrhoea/vomiting, swollen feet/legs, and macular rash on hands/forearms. A 3-day flu-like illness occurred 8 weeks earlier. Persistent pyrexia, tachycardia and hypotension required ICU admission for inotropic support. Although she briefly required oxygen, hypoxaemia was not a prominent feature. Bloods revealed CRP>200mg/L, ferritin>14,000ng/mL, raised D-Dimer, procalcitonin, Troponin-T and ALT, anaemia, lymphopenia, and neutrophilia. Computed-tomography showed mild bibasilar subpleural ground-glass changes, pelvic free fluid, and peritoneal enhancement. As treatment for suspected COV-HLH, or connective tissue disorder, intra-venous hydrocortisone 100mg QDS was given; fever resolved and blood parameters transiently improved. Second nasopharyngeal SARS-CoV-2 RT-PCR was positive and screen for other infection and autoimmune disease negative. Echocardiography and CTA excluded coronary aneurysms although Troponin-T peak was 330ng/L. Rapidly rising ferritin and triglycerides, falling cell counts and fibrinogen, led to a diagnosis of COV-HLH. Intra-venous anakinra 70mg (1mg/kg) BD was initiated. When pyrexia remained >40 °C, inotrope requirement persisted, cell counts fell and ferritin rose to 45,861ng/ml, anakinra was increased over 48h to 200mg BD with intra-venous methylprednisolone 1g OD x2. After 7 days anakinra was weaned to 100mg subcutaneous BD enabling discharge. Outpatient bone marrow aspirate/trephine showed reactive hyperplasia, no leukaemia or haemophagocytosis. Genomic testing showed no primary genetic cause. A week later she was readmitted with fatigue, arthralgia, pyrexia, tachycardia, haematuria, and ferritin of 23,000ng/mL (nadir 4,000ng/mL). FDG-PET showed hepatosplenomegaly with no lymphoma. Anakinra was increased to 200mg IV BD with IVIG 1mg/kg OD x2 and methylprednisolone 1g IV OD x3, then cyclosporine 1mg/kg IV BD. Fevers and haemoproteinuria resolved within 1 week and inflammatory markers fell allowing discharge on a reducing regime of subcutaneous anakinra, oral prednisolone and cyclosporine. She remained well; ferritin and FBC finally normalised >2 months after presentation. Case report - Discussion Through the UK HLH across speciality collaboration (HASC) we are aware of only a handful of UK cases of adult presentation PIMS-TS and even fewer with frank sHLH. Our patient’s ethnic background and presentation were typical for paediatric PIMS-TS. Hence, we actively excluded coronary artery aneurysms, a key feature of the Kawasaki-type variant of PIMS-TS. Initial COVID-19 swabs were negative as was extensive investigation for other sepsis triggers. A high clinical suspicion of COVID-19 led to the second positive swab and early recognition of sHLH. Diagnosis of HLH can be challenging due to its non-specific features and was even more difficult in critically ill patients during the peak of the pandemic, where bone marrow biopsy and cross-sectional imaging (key components of diagnostic scoring systems such as the HScore) were difficult to obtain. Persistent pyrexia, hyperferritinaemia and recognition of worsening trends in all relevant domains raised suspicion of sHLH. On initiation of anakinra, her HScore was only 118, although her illness peak was 162, well above the HASC agreed threshold of 132 for HLH diagnosis during the pandemic. She subsequently had a negative bone marrow biopsy in line with >50% of critical care patients with sHLH; a demonstration that biopsy proven haemophagocytosis is not necessary for a clinical diagnosis of sHLH. No other sHLH trigger was found. Early recognition and intensive treatment may have contributed to the positive outcome; sHLH mortality in ICU patients can reach nearly 70%. These decisions were facilitated by early discussion with MDT members of HASC. The initial dose of 70mg IV BD and speed of wean after an effective dose was achieved were insufficient. A longer period on 400mg anakinra daily, a slower wean, plus addition of methylprednisolone, IVIG and cyclosporin appeared to aid the resolution of her relapse. Case report - Key learning points COVID-19 infection is complicated by hyperinflammatory syndromes (cytokine storm, PIMS-TS, sHLH) in a significant minority of patients. In the absence of a treatment for COVID-19, early recognition of treatable complications should be a clinical priority.Adult clinicians should be aware of PIMS-TS which may rarely occur in young adults, especially those of African descent. The CDC definition extends to those aged up to 21. Cardiac aneurysms should be actively excluded in this group.The challenges associated with sHLH diagnosis became more apparent during the peak of the COVID-19 pandemic where key tests were difficult to obtain. Current scoring systems are insensitive for evolving sHLH. A high index of clinical suspicion and a multidisciplinary team approach, in which rheumatologists are key, is important for early recognition and treatment. Although no other sHLH trigger was found in this case, we have seen COV-HLH patients with underlying connective tissue disorder, haematological malignancy or a primary genetic defect, which should be considered if COV-HLH patients do not respond to treatment.Optimal treatment for sHLH and the hyperinflammatory syndromes associated with COVID-19 is not supported by randomised controlled trials but there is accumulating evidence for anakinra. Whilst its use in sHLH remains off-license, UK guidelines have been developed, with an emphasis on early and high dose treatment. Careful anakinra weaning regimens should be considered and patient progress regularly reviewed to avoid relapse of sHLH and subsequent readmission. Our patient also appeared to have a favourable response to corticosteroid and other combined immunosuppressive treatments including IVIG and cyclosporine. It remains to be seen if the incidence of adult-onset PIMS-TS and COV-HLH will reduce now that Dexamethasone is standard of care in adult patients with COVID-19.

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.

The COVID-19 pandemic is a global public health crisis, with considerable mortality and morbidity exerting pressure on health-care resources, including critical care. An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. Here, we consider the scientific rationale for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation. Since GM-CSF also has a key role in homoeostasis and host defence, we discuss potential risks associated with inhibition of GM-CSF in the context of viral infection and the challenges of doing clinical trials in this setting, highlighting in particular the need for a patient risk-stratification algorithm.

Background Secondary HLH (sHLH) in adults is a paradigm of a disorder with multiple challenges. It is rare and under-recognised, clinical features are non-specific and heterogeneous, it may present to a broad range of specialties and there is no single test which can unambiguously diagnose the condition. The investigation of such patients often occurs in a piecemeal fashion, which causes delays in establishing diagnosis leading to missed opportunities to start treatment early. Treatment protocols are extrapolated from mostly paediatric data from the primary, genetic form of HLH with insufficient clinical trials in adults to provide robust evidence-based management approaches. There is a resultant wide range in clinical practice and sHLH has a high mortality rate. Addressing these issues and improving knowledge about the disorder therefore requires cross-speciality, multi-centre working. Within the UK, these challenges have begun to be addressed over the past 24 months, resulting in the creation of local and regional HLH MDTs, the formation of a national network of interested specialists (HASC: the HLH across-specialty collaboration) as well as the creation of a national HLH registry as part of the UK Histiocytosis Registry (UKHR). Methods The aim of this project was to create a national guideline for the diagnosis and investigation of adult patients with suspected sHLH in order to start to standardise practice across the UK. Over 30 clinicians from a broad range of specialties, from both paediatric and adult practice, were consulted. These included sub-specialist input from rheumatology, haematology, infectious diseases, virology, nephrology, intensive care and immunology with collaborations from 15 centres around the UK. The HASC meetings were used as a forum to collaborate and develop the guidance. Results We created an investigation algorithm dividing tests for work-up into 3 sections: 1. Routine initial work 2. HLH-specific testing, comprehensive infection work-up, guidance on tissue biopsy 3. Identification and work-up of suspected adult cases of familial/genetic HLH (fHLH). The guidance also uses HASC multi-professional expertise to provide approaches to controversial areas including ferritin and sCD25 thresholds in adults, deep skin biopsies for suspected intravascular lymphoma and specific scenarios such as neurological presentations and CAR-T therapy. Clinicians from different specialties across the UK and specialist laboratories with an interest in HLH have been identified in order to make the HLH network more accessible. The aim is to have the guideline hosted by Histio UK, and freely available on their website. Conclusion This guideline is based on cross-specialty consensus expert opinion with reference to published literature in order to develop best practice. The coordinated investigation of patients with sHLH is key to improving early diagnosis and treatment and is just one part of the collaborative multi-faceted approach that is required to improve overall outcomes for patients with sHLH. Disclosures S. Mackenzie None. R. Low None. M. Brown None. E. Sanchez None. K. Gilmour None. T. Youngstein None. R. Tatersall None. B. Carpenter None. A. Patel None. C. Mcnamara None. J. Manson None.

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.

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.

Poster presentation Tuesday 8 October Background Haemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) is a hyperinflammatory syndrome which can complicate sepsis, malignancy or autoimmune/autoinflammatory disease, potentially leading to critical illness and death at all ages. A previous service evaluation of children with ferritin > 10,000 μg/L, which is highly specific for HLH/MAS, reported mortality of 33% and in 44% there was no documented evidence that HLH had been considered by clinicians. The condition may present to generalists, specialists and intensivists and prompt recognition and treatment can be life-saving. A consensus for the management of HLH in older children and adults has not been defined. The aim of this ongoing project is to identify current practice and improve the evidence-base for diagnosis and treatment of HLH. Methods A national cross-specialty group was established in June 2018 including paediatric and adult specialists in rheumatology, haematology, oncology, immunology, infectious diseases, virology, nephrology and intensive care. Clinicians, scientists, pharmacists and data management experts have been incorporated. The group, which numbers over 50 professionals, has met on three occasions to set clinical and research priorities and is supported by Histiocytosis UK, a charity representing patients with HLH. Results The group agreed these priorities: To complete a retrospective service evaluation of adult patients with ferritin > 10,000 μg/L identified over a 3-year period using a standardised proforma established in the previous paediatric cohort [provisionally, this has identified over 200 adults with a mortality rate of 39%]To provide education to clinicians across the UK to improve recognition of HLH [in progress]To develop guidance for investigation of suspected HLH [in progress]To link local multi-specialty teams experienced in managing HLH to create a national network [in progress]To conduct a retrospective, observational study of the use and outcomes of anakinra treatment in HLHTo establish a national registry for HLH as part of the UK Histiocytosis Registry (UKHR) using the REDCap online portal for data collection. Patients with definite and probable HLH, including those with MAS secondary to rheumatological conditions, will be eligible for recruitment. Baseline demographic and clinical data, investigations which contribute to the HLH 2004 criteria and H score, and underlying diagnoses will constitute a minimal dataset. Treatments, and responses, and long-term follow-up data will be recorded. In addition to data collection, with the appropriate consents, biological samples will be available for genetic and histopathological analysis and cellular samples for in vitro studies. Conclusion HLH/MAS is an under-recognised condition with high mortality. A national cross-specialty, all-age collaboration has established priorities to improve clinical care and advance research. Development of a registry, with collection of biological samples, will facilitate investigation of disease pathogenesis and help to stratify patients with a view to future clinical trials. Conflicts of Interest The authors declare no conflicts of interest.

ObjectiveThe inflammatory idiopathic myopathies (IIM) are a group of rare autoimmune diseases defined by muscle weakness and characterized by pro-inflammatory infiltrates in muscle. Little is known about the immunological profile in peripheral blood of these patients and how this relates to IIM subtypes. This study aimed to stratify adult and juvenile-onset IIM patients according to immune cell profile.MethodsPeripheral blood mononuclear cells from 44 patients with adult myositis (AM), 15 adolescent-onset juvenile dermatomyositis (a-JDM), and 40 age-matched healthy controls were analysed by flow cytometry to quantify 33 immune cell subsets. Adult myositis patients were grouped according to myositis subtype; DM and polymyositis; and also autoantibody specificity. Disease activity was determined by the myositis disease activity assessment tool and clinicians’ decision on treatment.ResultsUnique immune signatures were identified for DM, polymyositis and a-JDM compared with healthy controls. DM patients had a T-cell signature comprising increased CD4+ and TH17 cell frequencies and increased immune cell expression of IL-6. Polymyositis patients had a B-cell signature with reduced memory B cells. A-JDM had decreased naïve B cells and increased CD4+T cells. All patient groups had decreased CD8+central memory T-cell frequencies. The distinct immune signatures were also seen when adult myositis patients were stratified according to auto-antibody expression; patients with anti-synthetase-antibodies had reduced memory B cells and patients with autoimmune rheumatic disease overlap had an elevated Th17 profile.ConclusionUnique immune signatures were associated with adult vs juvenile disease. The Th17 signature in DM patients supports the potential use of IL-17 inhibitors in treatment of IIMs.

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.

Summary Background Evidence suggests an important role for gut-microbiota dysbiosis in the development of rheumatoid arthritis (RA). The link between changes in gut bacteria and the development of joint inflammation is missing. Here, we address whether there are changes to the gut environment and how they contribute to arthritis pathogenesis. Methods We analyzed changes in markers of gut permeability, damage, and inflammation in peripheral blood and serum of RA patients. Serum, intestines, and lymphoid organs isolated from K/BxN mice with spontaneous arthritis or from wild-type, genetically modified interleukin (IL)-10R−/−or claudin-8−/−mice with induced arthritis were analyzed by immunofluorescence/histology, ELISA, and flow cytometry. Findings RA patients display increased levels of serum markers of gut permeability and damage and cellular gut-homing markers, both parameters positively correlating with disease severity. Arthritic mice display increased gut permeability from early stages of disease, as well as bacterial translocation, inflammatory gut damage, increases in interferon γ (IFNγ)+and decreases in IL-10+intestinal-infiltrating leukocyte frequency, and reduced intestinal epithelial IL-10R expression. Mechanistically, both arthritogenic bacteria and leukocytes are required to disrupt gut-barrier integrity. We show that exposing intestinal organoids to IFNγ reduces IL-10R expression by epithelial cells and that mice lacking epithelial IL-10R display increased intestinal permeability and exacerbated arthritis. Claudin-8−/−mice with constitutively increased gut permeability also develop worse joint disease. Treatment of mice with AT-1001, a molecule that prevents development of gut permeability, ameliorates arthritis. Conclusions We suggest that breakdown of gut-barrier integrity contributes to arthritis development and propose restoration of gut-barrier homeostasis as a new therapeutic approach for RA. Funding Funded by Versus Arthritis (21140 and 21257) and UKRI/MRC (MR/T000910/1)., Graphical abstract, Highlights Serum gut-permeability markers LPB, LPS, and I-FABP are increased in RA Mice with arthritis have increased gut permeability and intestinal inflammation Both bacteria and leukocytes are needed to disrupt gut-barrier integrity Prevention of gut-barrier dysfunction in arthritis ameliorates joint inflammation, Context and significance Rheumatoid arthritis is an autoimmune disorder characterized by chronic joint inflammation. Accumulating evidence suggests that changes in the composition of the bacteria residing in the gut could be responsible for joint inflammation. Currently, it is unclear how bacteria or their products instruct cells of the immune system to become harmful and induce arthritis. Researchers at University College London have shown that, in arthritis, there is profound damage to the gut lining, which fails to work properly as a barrier, as well as an accumulation in the gut of white blood cells that cause inflammation. The authors show that, in arthritis, bacteria cross the prohibited border of the intestinal lining and that repairing gut permeability defects with specific drugs inhibits joint inflammation., Changes to the gut bacteria have been associated with the development of arthritis; however, the mechanistic connection with disease remains unknown. Matei et al. identify pathological changes to the gut tissue in arthritis, including loss of gut-barrier integrity and inflammatory-cell infiltration, and show that restoration of gut homeostasis ameliorates disease.

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 …

Background:Anti-Drug Antibodies (ADA) to adalimumab increase drug clearance in rheumatoid arthritis (RA).Objectives:To study the ability of drug concentration or estimating clearance to identify ADA to adalimumab.Methods:Adalimumab concentration was measured with a validated ELISA. ADA was measured using a capture ELISA (Theradiag®) and the Meso scale discovery (MSD) platform. Using a bayesian PK model, adalimumab clearance was estimated at 1, 3, 6 and 12 months. Predictions for ADA presence were calculated, and the correlation between ADA and adalimumab clearance was analysed.Results:We analyzed 108 samples from 53 RA patients. Serum concentrations and clearance estimates showed good prediction performance for ADA presence (Table 1). There was a correlation between adalimumab clearance and ADA (Figure 1).Table 1.Immunogenicity prediction of adalimumab, using trough concentration or estimated clearanceTime of visitADA methodAdalimumab trough concentrationAdalimumab estimated clearanceAUC ROCp-valueAUC ROCp-valueMonth 1THER.55.6411.52.8358MSD.65.0821.61.1872Month 3THER.89.0006.91.0003MSD.73.0096.72.0131Month 6THER.95.0035.95.0035MSD.85.0004.84.0006Month 12THER.87.0045.86.0057MSD.88.0002.88.0002Figure 1.correlation between adalimumab estimated clearance and ADA as provided by the Meso scale discovery (MSD) plateformConclusion:Adalimumab concentration and clearance should be considered as reliable predictors for ADA presence in RA patients.Acknowledgments:Measurement of adalimumab serum concentrations was performed within the ‘Centre pilote de suivi biologique des anticorps thérapeutiques’ (CePiBAc)– Pilot centre for therapeutic antibodies monitoring platform of Tours University Hospital, which was cofinanced by the European Regional Development Fund (ERDF). We thank Oscar Knight, Delphine Delord and Fabien Giannoni (ABIRISK lab technician), Caroline Brochon and Anne Claire Duveau (CePIBAc), Aliette Decock-Giraudaud (Centre de ressource-Biobank), Sophie Tourdot (ABRISIK Project manager), Aline Doublet (Assistance Publique Hopitaux de Paris, Agnès Hincelin-Méry (Sanofi, Chilly-Mazarin, France). This work has received support from the Innovative Medicines Initiative Joint Undertaking (IMI JU) under grant agreement no. 115303, the resources of which are composed of financial contributions from the European Union’s Seventh Framework Programme (FP7/2007-2013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies’ in-kind contributions.Disclosure of Interests:David Ternant Consultant of: Sanofi and Amgen., Jamal Elhasnaoui: None declared, Natacha Szely: None declared, Salima Hacein-Bey: None declared, Aude Gleizes: None declared, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Jessica Manson: None declared, Martin SOUBRIER: None declared, Olilvier Brocq: None declared, Jérôme Avouac: None declared, Anna Fogdell-Hahn Grant/research support from: Biogen Idec and Pfizer., Consultant of: Pfizer, Biogen, Merck-Serono, and Sanofi-Genzyme., Pierre Dönnes: None declared, Gilles Paintaud Grant/research support from: Amgen, Genzyme (Sanofi), Lilly, Merck, Novartis, and Roche Pharma., Consultant of: Chugai, Novartis and Shire (Takeda), with remunerations received by his institution., Céline Desvignes: None declared, Florian Deisenhammer: None declared, Sebastian Spindeldreher Employee of: Novartis, Marc Pallardy: None declared, Xavier Mariette Consultant of: BMS, Gilead, Medimmune, Novartis, Pfizer, Servier, UCB, Denis Mulleman Grant/research support from: Non-governmental organisation Lions Club Tours Val de France, French Society for Rheumatology., Consultant of: Pfizer, Novartis.

Haemophagocytic lymphohisticytosis (HLH) is a syndrome of uncontrolled, severe systemic inflammation (hyperinflammation) arising either from a genetic immune system defect [primary (pHLH)] or triggered as a complication of malignancy, infection, or rheumatologic disease [secondary (sHLH)]. Patients with HLH often have non-specific symptoms and become progressively and critically unwell, with fever, cytopenia and multi-organ failure. Untreated, HLH is almost universally fatal, but even when treated, mortality is high, particularly when HLH complicates malignancy. HLH is managed with immunosuppression, and this can seem difficult to justify in such unwell patients. This review aims to examine the diagnostic and treatment challenges posed by sHLH and to improve recognition among rheumatologists who, being expert in the management of multisystem diseases and in the use of immunosuppression, are ideally placed to deliver care and build an evidence base for better disease characterization and treatment.

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.

Summary The differentiation of IL-10-producing regulatory B cells (Bregs) in response to gut-microbiota-derived signals supports the maintenance of tolerance. However, whether microbiota-derived metabolites can modulate Breg suppressive function remains unknown. Here, we demonstrate that rheumatoid arthritis (RA) patients and arthritic mice have a reduction in microbial-derived short-chain fatty acids (SCFAs) compared to healthy controls and that in mice, supplementation with the SCFA butyrate reduces arthritis severity. Butyrate supplementation suppresses arthritis in a Breg-dependent manner by increasing the level of the serotonin-derived metabolite 5-Hydroxyindole-3-acetic acid (5-HIAA), which activates the aryl-hydrocarbon receptor (AhR), a newly discovered transcriptional marker for Breg function. Thus, butyrate supplementation via AhR activation controls a molecular program that supports Breg function while inhibiting germinal center (GC) B cell and plasmablast differentiation. Our study demonstrates that butyrate supplementation may serve as a viable therapy for the amelioration of systemic autoimmune disorders., Graphical Abstract, Highlights • Stool butyrate levels are reduced in patients with RA compared to healthy controls • Supplementation with butyrate suppresses arthritis severity in a mouse model • Suppression of arthritis by butyrate supplementation depends upon AhR+Bregs • Butyrate increases serotonin-derived 5-HIAA, which directly activates AhR+Bregs, The environmental signals that influence Breg function are not yet fully defined. Here, Rosser et al. demonstrate that the short-chain fatty acid butyrate supports Breg function by increasing the level of the serotonin-derived metabolite 5-Hydroxyindole-3-acetic acid (5-HIAA). 5-HIAA, in turn, activates the aryl-hydrocarbon receptor, a newly discovered transcriptional regulator for Bregs.