British Society for Rheumatology Annual Conference 2023 Abstracts

The proceedings contain 343 papers. The topics discussed include: implementation of a disease modifying anti-rheumatic drug blood monitoring software: 8 years of experience in a single center;effectiveness of colchicine among patients with COVID-19 infection: a randomized, open labelled, clinical trial;rheumatic autoimmune diseases following COVID-19 infection: an observational study in Iraqi Kurdistan region;COVID-19 in male elite Irish-based athletes at a national sports institute;the effects of a pain management program for patients with an inflammatory arthritis;a retrospective analysis of the effectiveness safety of platelet rich plasma injections in primary osteoarthritis in knee joint, in patients attending a tertiary care hospital, Sri Lanka;a cohort study;do proformas used in fracture liaison service appointments reflect national osteoporosis clinical standards? a content analysis;calcium pyrophosphate dihydrate crystal in operated rheumatoid arthritis of the knee;cardiac amyloidosis: a case series of 31 patients with a comprehensive literature review;scoping review for the application of center of pressure for patient or intervention assessment in rheumatoid conditions;and four SNPs associated with monocyte/macrophage cell lineage uniquely associated with CRPS-1 in discovery and replication cohorts and suggest predisposition to regional osteopenia and digit misperception.

Severe Autoimmune Hemolytic Anemia in a Young Child with Active Covid-19 Infection

INTRODUCTION: Autoimmune hematological complications related to COVID-19 are rare. There are only 5 pediatric case reports of autoimmune hemolytic anemia (AIHA) among 14 million pediatric COVID-19 cases in USA. Four were older (13-17 years), two had underlying autoimmune/hematologic conditions. Immunologic analysis varied, with cold, warm & mixed hemolytic anemias described. We present a previously healthy child with COVID-19 associated severe AIHA with peripheral reticulocytopenia. DESCRIPTION: A 3-year-old male presented with lethargy, fever, tachycardia and jaundice 10 days after COVID-19 diagnosis. Pertinent labs include hemoglobin (Hgb) 3.8 g/dL, Hct 9.9%, bilirubin 3.6 mg/dL, platelets 321,000/muL, RBC count 1.2 M/muL, WBC 35,600/muL, MCV 82.5fL. Reticulocyte count (RC) was only 2.8%. Peripheral blood smear showed anisocytosis, poikilocytosis, nucleated RBCs and left shifted granulocytosis. Bone marrow biopsy revealed erythroid hyperplasia without underlying malignancy;myeloid:erythroid ratio of 0.3:1. The outside hospital reported cold C3 agglutination following 4degreeC incubation, while our laboratory identified spontaneous agglutination at room temperature (warm agglutination). IV fluids, O2, and methylprednisolone (4 mg/kg/day) were started and two packed RBC transfusions (total 30 ml/kg) given for symptomatic anemia with Hgb < 4 g/dL. LDH peaked at 2255 U/L on Day 3. Reticulocyte count was low (2.8%-3.8%) Days 1-3, increased to 6.5% on Day 4 and peaked at >30.0% on Day 7. He was changed to oral prednisone 2 mg/kg/day on Day 12 and discharged on Day 13 with Hgb 7.0 g/dL and RC 29.9%. Most recent Hgb is 13.0 g/dL and RC 2.6%. DISCUSSION: COVID-19 associated AIHA is rare, and previously reported mostly in older children. Our patient was previously healthy, and demonstrated a strong bone marrow response with erythroid hyperplasia. Peripheral reticulocytosis was delayed, and correlated with initiation of systemic steroid therapy. Our patient had both cold and warm agglutination supporting extensive autoimmune destruction of early red cell lineage. These findings support immune activation during acute COVID-19 infection and COVID-19 as a trigger for AIHA. Patients developing AIHA may need to be tested for COVID-19 and carefully monitored for complications.

Regulatory Immune Mechanisms and Gastrointestinal Co-morbidity in ASD

Nearly half of all children with autism spectrum disorders (ASD) also have co morbid gastrointestinal (GI) symptoms that can affect behavior through a brain-immune gut feedback loop. The primary GI condition is due to uncontrolled inflammation. The main objectives of this project are (1) to characterize defects in Tregs function and ability to suppress responses;(2) to identify epigenetic mechanisms that control Tregs lineage commitment;and (3) to determine the stability of Tregs under inflammatory conditions and the Tregs- T helper (TH)17 balance, in children with ASD and GI symptoms. Our main hypothesis is that Tregs dysfunction causes a lack of immune control in children with ASD who experience GI co-morbidities.

Vancomycin Induced Maturation Arrest with Reactive Promyelocyte Proliferation: A Diagnosticand Therapeutic Challenge

Introduction: Drug induced leucopenia complicates any clinicalsituation especially when it's associated with COVID-19 infection.Here we report a case of vancomycin induced myeloid maturationarrest in a patient with COVID-19 infection where his conditionreverted to normal after stopping the drug.Aims &Objectives: It highlights the adverse effects of Vancomycinleading to promyelocyte proliferation posing a diagnostic challenge todifferentiate it from neoplastic promyelocyte proliferation.Materials &Methods: Case report: A 47 year old male presentedwith fever, dry cough and difficulty in breathing for 12 days. He wasCOVID-19 positive with CT lung showing bilateral pneumonic consolidations for which Vancomycin was started. Hemogram showedhemoglobin-6.8 gm/dl, total leucocyte count-3200/cumm with a differential count revealing: Neutrophil-28% (with left shift and featuresof dyspoiesis), Lymphocyte-66%, Monocyte-4%, Eosinophil-2%(Fig. 1a), and platelets-90,000/cumm. Bone marrow aspiration(BMA) and biopsy was advised. BMA was hypercellular for age withmarked promyelocyte proliferation &maturation arrest with strongMPO positivity (1b, c d). Bone marrow biopsy also reflected similarfindings (Fig-1e). FISH for PML-RARA translocation turned out to benegative, differentiating it from Acute promyeloytic Leukemia(Fig. 1f). A diagnosis of drug induced leucopenia with reactivepromyelocyte proliferation was made. Considering worsening of thesehematological findings, Vancomycin was stopped and patient'shematological findings improved drastically with stabilization ofhematological parameters.Result: Discussion: Drug induced leukopenia occurs in a dosedependent or dose-independent (idiosyncratic) reaction. Vancomycindependent antibodies against neutrophils lead to an autoimmunereaction directly affecting progenitor cell growth especially of myeloid cell lineage leading to maturation arrest. Secondly cytotoxicT-cell mediated response also has damaging effects on hematopoieticcells. Infections like COVID-19 can also lead to suppression ofnormal myeloid maturation due to release of interleukins.Conclusions: Myeloid maturation arrest with marked promyelocyteproliferation poses a diagnostic dilemma especially in patients presenting with cytopenia as they are confused with Acute promyelocytic Leukemia. This case highlights the importance of detailed knowledgerelated to drug induced myeloid maturation arrest which is reversibleafter stoppage of the offending drug.

COVID19 Illness in Acute Myeloid Leukemia-An Interesting Contrast from the Expected

Introduction: COVID19 can be considered as one of the worstpandemics humans have faced. There haven't been many casesreported, specifically looking at its severity and outcome in patientswith hematological malignancies.Aims &Objectives: Presenting a diagnosed case of AML, on Azacytidine therapy, manifesting with COVID19 disease.Materials &Methods: On 13th July 2021, a 43 year old female,diagnosed with AML came to the OPD with history of cough, feverand running nose from last 7 days. She was receiving antimicrobialprophylaxis with levofloxacin and fluconazole. Her temperature was38 °C, BP 110/60 mm Hg, heart rate 88 bpm, and SpO2 was 97% inroom air. She tested positive for COVID19 the same day. She wasstarted on Azithromycin, Ivermectin and vitamin supplements. Herstay in COVID ward was uneventful, except for the significantchanges in her laboratory data [Table 1].Result: The patient's cell lineages went down after the chemotherapy.During COVID19 infection, she developed leukocytosis with 60%blast cells while still having neutropenia. Despite persistent neutropenia, she didn't develop any major respiratory symptoms orcomplications. Chest X-ray was normal. Her KFT, RBS, electrolytes,LFT and PT-INR were in normal range. CRP and D-Dimer wereraised. On day 10, after testing negative for COVID 19, third cycle ofchemotherapy was started, and she was discharged on day 17.Conclusions: Typical Covid19 presentation is neutrophilia and lymphopenia, which is in contrast to our result depicting increased totalleucocyte count (lymphocytosis and blasts), with consistent neutropenia. This difference could be attributed to underlying AML andtreatment received. Although there are few published reports indicating patients with myeloid malignancies and COVID19 havinghigher mortality, our patient with active AML and no other comorbidities, made a full recovery without any antiviral therapy, and hadmild respiratory symptoms only. This also calls for the need ofadditional studies to further delineate risk factors contributing tomortality in this subgroup of patients.

Adoptive Immune Responses to Sars-Cov2 Vaccination in CART19 Treated Patients

Background: The two FDA approved mRNA-based SARS-CoV2 vaccines have shown >90% efficacy at preventing COVID and eliciting protective immunity in nearly all healthy individuals. However, the extent of vaccine induced antibody and T cell immunity in immunocompromised patients is not well known. Our study objective is to determine if patients with hematologic malignancies treated with B-cell targeting chimeric antigen receptor (CAR) T cell therapies can mount antibody and T cell immune responses to SARS-CoV2 vaccines. A prospective single-center study to evaluate the SARS-CoV2 immune responses in immunocompromised individuals (COVAX Study) was initiated at University of Pennsylvania following the IRB guidelines. The study enrolled 8 healthy adults,12 patients are in remission after treatment (average of 40.6 months) with CART cells targeting either CD19 or CD19+CD22 and received both doses of SARS-CoV2 vaccine. Methods and Results: Serology to SARS-CoV2 spike-receptor binding domain (RBD) IgG, RBD-IgA, RBD-IgM and spike-specific T cell responses were measured prior to vaccination and serially up to 28 days after booster vaccination. RBD-IgG and RBD-IgA were detected in 8/8 and 7/8 healthy subjects compared to 5/12 and 2/12 CART patients, respectively (Figure A). In the CART cohort, several patients who demonstrated an induction of RBD-IgG (57.2/uL +/- 20.2) compared to those who were RBD-IgG-negative (9/uL +/- 10.1, ANOVA with multiple comparisons test p=0.017) have higher level of circulating B cells. No association was found with time since CART infusion, age, disease type, or vaccine manufacturer. All 8 healthy subjects demonstrated induction of SARS-Cov2 spike-specific CD4 + T cell immunity compared to 7 out of 11 CART patients (Figure B). RBD-IgG responses were not correlated with CD4 + T cell activation (Pearson correlation, R=0.21, p=0.53). Indeed, 3 CART patients demonstrated robust CD4 + T cell activation despite absence of antibody induction. Overall, 8/12 CART patients demonstrated induction of either or both humoral and T cell immune responses. Conclusions: We show that immune responses to SARS-CoV2 mRNA vaccines are induced in majority of patients who have been treated with CART therapies targeting B-cell lineage antigens. Induction of vaccine-specific antibody was strongly associated with the level of circulating B cells. However, in CART cohort patients despite severe humoral immune deficiency, strong CD4 + T cell responses were observed suggestive of a sufficient protective immunity. [Formula presented] Disclosures: Frey: Novartis: Research Funding;Sana Biotechnology: Consultancy;Kite Pharma: Consultancy;Syndax Pharmaceuticals: Consultancy. Garfall: Amgen: Honoraria;CRISPR Therapeutics: Research Funding;GlaxoSmithKline: Honoraria;Janssen: Honoraria, Research Funding;Novartis: Research Funding;Tmunity: Research Funding. Porter: American Society for Transplantation and Cellular Therapy: Honoraria;Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months;ASH: Membership on an entity's Board of Directors or advisory committees;DeCart: Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees;Janssen: Membership on an entity's Board of Directors or advisory committees;Kite/Gilead: Membership on an entity's Board of Directors or advisory committees;National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees;Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding;Tmunity: Patents & Royalties;Wiley and Sons Publishing: Honoraria. June: AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy;Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company;Novartis: Patents & Royalties.

Therapeutic mTOR blockade in systemic autoimmunity: Implications for antiviral immunity and extension of lifespan.

The mechanistic target of rapamycin (mTOR) pathway integrates metabolic cues into cell fate decisions. A particularly fateful event during the adaptive immune response is the engagement of a T cell receptor by its cognate antigen presented by an antigen-presenting cell (APC). Here, the induction of adequate T cell activation and lineage specification is critical to mount protective immunity; at the same time, inadequate activation, which could lead to autoimmunity, must be avoided. mTOR forms highly conserved protein complexes 1 and 2 that shape lineage specification by integrating signals originating from TCR engagement, co-stimulatory or co-inhibitory receptors and cytokines and availability of nutrients. If one considers autoimmunity as the result of aberrant lineage specification in response to such signals, the importance of this pathway becomes evident; this provides the conceptual basis for mTOR inhibition in the treatment of systemic autoimmunity, such as systemic lupus erythematosus (SLE). Clinical trials in SLE patients have provided preliminary evidence that mTOR blockade by sirolimus (rapamycin) can reverse pro-inflammatory lineage skewing, including the expansion of Th17 and double-negative T cells and plasma cells and the contraction of regulatory T cells. Moreover, sirolimus has shown promising efficacy in the treatment of refractory idiopathic multicentric Castleman disease, newly characterized by systemic autoimmunity due to mTOR overactivation. Alternatively, mTOR blockade enhances responsiveness to vaccination and reduces infections by influenza virus in healthy elderly subjects. Such seemingly contradictory findings highlight the importance to further evaluate the clinical effects of mTOR manipulation, including its potential role in treatment of COVID-19 infection. mTOR blockade may extend healthy lifespan by abrogating inflammation induced by viral infections and autoimmunity. This review provides a mechanistic assessment of mTOR pathway activation in lineage specification within the adaptive and innate immune systems and its role in health and autoimmunity. We then discuss some of the recent experimental and clinical discoveries implicating mTOR in viral pathogensis and aging.

Case Report: B Lymphocyte Disorders Under COVID-19 Inflammatory Pressure.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infects humans through the angiotensin converting enzyme-2 (ACE-2) receptor expressed on many cells, including lymphocytes. In Covid-19 patients IL-6 is overexpressed, and hyperactivated plasmacytoid lymphocytes are detected in peripheral blood film. We hypothesize that, due to the unpredictable interaction between the new virus and the B cell lineage of infected patients, a cascade of out of control events can ensue, capable of determining unexpected pathologic disorders involving such lineage. Here we report two cases of autoimmune hemolytic anemia (AIHA) and two cases of B-cell hematological malignancies developed or reactivated during acute SARS-CoV-2 infection. The temporal relationship of the events may suggest a potential causal relationship between SARS-CoV-2 infection and the hematopoietic disorders. We suggest that special attention should be paid to COVID-19 patients with underlining B cell lineage disorders.