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IntroductionWe previously reported a specific defect of rheumatoid arthritis (RA) monocyte polarization to anti-inflammatory M2-like macrophages related to increased miR-155 expression in all RA patients except those receiving adalimumab (ADA). In this longitudinal study, we examined whether different tumor necrosis factor inhibitors were able to restore monocyte polarization to M2-like macrophages and their effect on the transcriptomic signature.MethodsM2-like polarization induced by human serum AB was studied in 7 healthy donors and 20 RA patients included in the ABIRA cohort before and 3 months after starting ADA or etanercept (ETA). The differential gene expression of M2- and M1-related transcripts was studied in macrophage-derived monocytes after differentiation.ResultsAt baseline, RA monocytes showed a defect of polarization to M2-like macrophages as compared with healthy donor monocytes, which was negatively correlated with disease activity. M2-like polarization from circulating monocytes was restored only with ADA and not ETA treatment. The transcriptomic signature demonstrated downregulation of M2-related transcripts and upregulation of M1-related transcripts in active RA. In patients receiving ADA, the transcriptomic signature of M2-related transcripts was restored.ConclusionThis longitudinal study demonstrates that ADA but not ETA is able to restore the M2-like polarization of monocytes that is defective in RA.

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 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.

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.

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.

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.

The advent of sophisticated diagnostics has enabled the discovery of previously unknown arthropod-borne viruses like Chikungunya. This infection has become increasingly prevalent in the last 10 years across the Indian Ocean and has been brought to media attention by a recent outbreak in the Caribbean. The outbreak has been aided by a drastic rise in air travel, allowing infected individuals to transport the virus to previously unaffected regions. In addition, a recently documented viral mutation has allowed its transmission by the Aedes albopictus mosquito, therefore facilitating outbreaks in Southern Europe and the USA. The duration and extent of the arthritis seen peri- and post infection has become a topic of academic interest. Although published data are largely observational, there has been a definite increase in original research focusing on this. Symptoms can persist for years, particularly in older patients with pre-existing medical conditions. The etiology is still not fully understood, but viral persistence and immune activation within synovial fluid have been shown in mouse models. There have been no prospective clinical trials of treatment in humans; however, animal trials are in process. The mainstay of treatment remains anti-inflammatories and steroids where necessary. The clinical presentation seems to mimic common rheumatological conditions like rheumatoid arthritis; therefore recent recommendations suggest the use disease-modifying agents as a common practice for the specific syndrome. This review uses recent published data and draws on our own clinical experience to provide an overview of joint complications of Chikungunya infection.

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.

Objective Autoantibody production in patients with systemic lupus erythematosus (SLE) is associated with abnormalities of B cell function and phenotype. Clinical responses to B cell depletion therapy (BCDT), based on rituximab, are encouraging. Therefore, we undertook this study to investigate the effect of BCDT on antibody profiles. Methods Serial sera from 16 patients with active, refractory SLE were assayed for antinucleosome antibodies, anti–double-stranded DNA (anti-dsDNA), anti–extractable nuclear antigen, anti–tetanus toxoid, and antibodies to pneumococcal capsular polysaccharide for at least 1 year following BCDT. Anti-dsDNA antibodies derived from the VH4.34 immunoglobulin germ line gene (9G4+) were also measured. Results All patients achieved peripheral B cell depletion and improved clinically for at least 3 months. Antinucleosome and anti-dsDNA antibodies decreased to a mean ± SD of 64 ± 37% and 38 ± 33% of baseline values, respectively, by 6–8 months post-BCDT. Levels of other autoantibodies and antimicrobial antibodies were generally unchanged. In the 9 of 16 patients who were still well at 1 year, anti-dsDNA antibodies fell to 42 ± 36% of baseline values at 6–8 months and to 37 ± 33% at 10–14 months. In patients who had disease flares within 1 year of BCDT, levels of these antibodies decreased to 60 ± 40% and 83 ± 93% of baseline values at 6–8 months and at 10–14 months, respectively. Circulating anti-dsDNA antibodies were positive for 9G4 expression in 4 of 6 patients tested, and flares in 2 of these patients were accompanied by rises in 9G4+ anti-dsDNA antibodies. Conclusion These observations suggest that B cell clones committed to producing antinucleosome and anti-dsDNA antibodies, including the VH4.34 subpopulation of anti-dsDNA antibodies, have a relatively rapid turnover compared with B cell clones producing other antibodies. There was also a trend toward a greater and more sustained decrease in anti-dsDNA antibodies in patients with clinical benefit lasting >1 year.

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

Introduction Glomerulonephritis is a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE). Deposition of autoantibodies in the glomeruli plays a key role in the development of lupus nephritis (LN). Different groups have proposed that either anti-nucleosome antibodies or antibodies that bind the intrinsic renal antigen, α-actinin, are central to the pathogenesis of LN. These theories have been based mainly on cross-sectional studies in patients and on experiments in animal models. No previous longitudinal studies have compared the relationships between levels of these antibodies and markers of renal function. We assessed how well anti-α-actinin, anti-nucleosome and anti-double-stranded DNA (anti-dsDNA) antibodies reflected renal outcome measures in patients with new-onset LN followed for up to 2 years. Methods Renal disease activity was monitored by measuring urine protein/creatinine ratio (PCR), serum albumin and a composite outcome of renal remission. At each time point, anti-nucleosome and anti-α-actinin antibodies were measured by enzyme-linked immunosorbent assay. High-avidity anti-dsDNA antibodies were measured using the Farrzyme assay. We analysed relationships between levels of the three antibodies and between antibody levels and renal outcome measures over time. Results Levels of anti-nucleosome and anti-dsDNA were positively correlated with each other (r = 0.6, P = 0.0001) but neither correlated with anti-α-actinin level. At baseline, mean anti-nucleosome levels were higher in patients with LN than in healthy controls (0.32 versus 0.01, P < 0.001). The same was true for anti-dsDNA antibodies (0.50 versus 0.07, P < 0.001) but not for anti-α-actinin (0.33 versus 0.29). Over the follow-up period, anti-nucleosome and anti-dsDNA levels associated positively with urine PCR (P = 0.041 and 0.051, respectively) and negatively with serum albumin (P = 0.027 and 0.032, respectively). Both anti-nucleosome and anti-dsDNA levels were significantly lower during renal remission than when renal disease was active (P = 0.002 and 0.003, respectively). However, there was no relationship between anti-α-actinin levels and urine PCR, serum albumin or remission status. Conclusions This prospective longitudinal clinical study is the first to compare levels of anti-nucleosome, anti-dsDNA and anti-α-actinin antibodies in the same patients with SLE. Our results support the concept that, in the majority of patients, anti-nucleosome antibodies play a major role in pathogenesis of LN, in contrast to anti-α-actinin antibodies.

Previous studies have shown the importance of somatic mutations and arginine residues in the complementarity-determining regions (CDRs) of pathogenic anti-double-stranded DNA (anti-dsDNA) antibodies in human and murine lupus, and in studies of murine antibodies, a role of mutations at position 53 in V(H) CDR2 has been demonstrated. We previously demonstrated in vitro expression and mutagenesis of the human IgG1 monoclonal antibody B3. The present study was undertaken to investigate, using this expression system, the importance of the arginine residue at position 53 (R53) in B3 V(H).R53 was altered, by site-directed mutagenesis, to serine, asparagine, or lysine, to create 3 expressed variants of V(H). In addition, the germline sequence of the V(H)3-23 gene (from which B3 V(H) is derived) was expressed either with or without arginine at position 53. These 5 new heavy chains, as well as wild-type B3 V(H), were expressed with 4 different light chains, and the resulting antibodies were assessed for their ability to bind to nucleosomes, alpha-actinin, cardiolipin, ovalbumin, beta(2)-glycoprotein I (beta(2)GPI), and the N-terminal domain of beta(2)GPI (domain I), using direct binding assays.The presence of R53 was essential but not sufficient for binding to dsDNA and nucleosomes. Conversely, the presence of R53 reduced binding to alpha-actinin, ovalbumin, beta(2)GPI, and domain I of beta(2)GPI. The combination B3 (R53S) V(H)/B3 V(L) bound human, but not bovine, beta(2)GPI.The fact that the R53S substitution significantly alters binding of B3 to different clinically relevant antigens, but that the alteration is in opposite directions depending on the antigen, implies that this arginine residue plays a critical role in the affinity maturation of antibody B3.

The year 2007 marks the 50th anniversary of the identification of antibodies to double-stranded (ds) DNA. Whilst widely regarded as synonymous with patients who have systemic lupus erythematosus (SLE), doubts have been raised about their significance and the extent to which they are genuinely part of the pathogenesis of the disease rather than being mere bystanders. Problems with assays used to detect them are still evident but they remain widely utilized both to help establish the diagnosis of SLE and to monitor the progress of the disease. This review explores each of these aspects and concludes that whilst some way short of ideal, their measurement remains a useful criterion for the disease and some of these antibodies do appear to be genuinely pathogenic. However, further research is needed to establish beyond ‘reasonable doubt’ whether they are merely part of the spectrum of anti-nucleosome antibodies, the precise mechanisms by which they ‘exert’ their pathogenic effects and to what extent blocking them would be a useful therapeutic goal.

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.

Systemic lupus erythematosus (SLE) is a clinically heterogeneous disease, which is autoimmune in origin and is characterized by the presence of autoantibodies directed against nuclear antigens. It is a multi-system disease, and patients can present in vastly different ways. Prevalence varies with ethnicity, but is estimated to be about 1 per 1000 overall with a female to male ratio of 10:1. The clinical heterogeneity of this disease mirrors its complex aetiopathogenesis, which highlights the importance of genetic factors and individual susceptibility to environmental factors. SLE can affect every organ in the body. The most common manifestations include rash, arthritis and fatigue. At the more severe end of the spectrum, SLE can cause nephritis, neurological problems, anaemia and thrombocytopaenia. Over 90% of patients with SLE have positive anti-nuclear antibodies (ANA). Significant titres are accepted to be of 1:80 or greater. SLE is a relapsing and remitting disease, and treatment aims are threefold: managing acute periods of potentially life-threatening ill health, minimizing the risk of flares during periods of relative stability, and controlling the less life-threatening, but often incapacitating day to day symptoms. Hydroxychloroquine and non-steroidal anti-inflammatory drugs are used for milder disease; corticosteroids and immunosuppressive therapies are generally reserved for major organ involvement; anti-CD20 monoclonal antibody is now used in patients with severe disease who has not responded to conventional treatments. Despite enormous improvements in prognosis since the introduction of corticosteroids and immunosuppressive drugs, SLE continues to have a significant impact on the mortality and morbidity of those affected.

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

When purified under rigorous conditions, some murine anti-double-stranded-DNA (anti-dsDNA) antibodies actually bind chromatin rather than dsDNA. This suggests that they may actually be antinucleosome antibodies that only appear to bind dsDNA when they are incompletely dissociated from nucleosomes. Experiments in murine models suggest that antibody–nucleosome complexes may play a crucial role in the pathogenesis of glomerulonephritis in systemic lupus erythematosus. Some human monoclonal anti-DNA antibodies are pathogenic when administered to mice with severe combined immunodeficiency (SCID). Our objective was to achieve stable expression of sequence-altered variants of one such antibody, B3, in Chinese hamster ovary (CHO) cells. Purified antibodies secreted by these cells were tested to investigate whether B3 is actually an antinucleosome antibody. The pathogenic effects of the antibodies were tested by implanting CHO cells secreting them into SCID mice. Purified B3 does not bind to dsDNA unless supernatant from cultured cells is added, but does bind to nucleosomes. The strength of binding to dsDNA and nucleosomes is dependent on the sequence of the light chain. Mice that received CHO cells secreting wild-type B3 developed more proteinuria and died earlier than control mice that received nonsecreting CHO cells or mice that received B3 with a single light chain mutation. However, none of the mice had histological changes or deposition of human immunoglobulin G in the kidneys. Sequence changes may alter the pathogenicity of B3, but further studies using different techniques are needed to investigate this possibility.