Sinisa Savic

University of Leeds · Leeds Institute of Rheumatic and Musculoskeletal Medicine

Somatic mutations in UBA1 cause VEXAS (Vacuoles, E1 ubiquitin activating enzyme, X-linked, Autoinflammatory Somatic) syndrome, an adult-onset inflammatory disease with an overlap of hematologic manifestations. VEXAS syndrome is characterized by a high mortality rate and significant clinical heterogeneity. We sought to determine independent predicto...

Background COVID-19 is associated with acute respiratory distress and cytokine release syndrome. The Janus kinase (JAK)1/JAK2 inhibitor ruxolitinib reduces inflammatory cytokine concentrations in disorders characterised by cytokine dysregulation, including graft-versus-host disease, myelofibrosis, and secondary hemophagocytic lymphohistiocytosis. W...

CRAC channel regulator 2 A (CRACR2A) is a large Rab GTPase that is expressed abundantly in T cells and acts as a signal transmitter between T cell receptor stimulation and activation of the Ca ²⁺ -NFAT and JNK-AP1 pathways. CRACR2A has been linked to human diseases in numerous genome-wide association studies, however, to date no patient with damagi...

The family of autoinflammatory diseases (AIDs) continues to expand and now includes over 40 genetically defined disorders. Their defining feature is a dysregulated inflammatory innate immune response. Many AIDs have overlapping clinical characteristics, and dermatological manifestations are common. Autoinflammatory features have also been recognize...

Objectives Adult‐onset Still's disease (AOSD) is systemic autoinflammatory disorder of unknown aetiology. Genetic studies have been limited. Here, we conducted detailed genetic and inflammatory biomarker analysis of a large AOSD cohort to investigate the underlying pathology and identify novel targets for potential treatment. Methods We investigat...

Background Use of electronic health records (EHR) to provide real-world data for research is established, but using EHR to deliver randomised controlled trials (RCTs) more efficiently is less developed. The Allergy AntiBiotics And Microbial resistAnce (ALABAMA) RCT evaluated a penicillin allergy assessment pathway versus usual clinical care in a UK...

The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is crucial for inflammasome assembly and activation of several inflammasomes, including NLRP3. ASC aggregates are detected in human sera post pyroptotic cell death, but their inflammasome origin remains unclear. This study aimed to develop a method to detect A...

Background Adult-onset Still’s disease (AOSD) is a systemic autoinflammatory condition of unknown aetiology. AOSD is presumed to have a polygenic basis but there is genetic and clinical overlap with monogenic autoinflammatory disorders[1]. Genetic studies thus far have been limited and although a role for NLRP3 inflammasome in disease pathogenesis...

A história das doenças autoinflamatórias remonta a séculos, com as primeiras observações e descrições encontradas em textos médicos antigos e registos históricos. Embora as descrições pormenorizadas das síndromes de febre periódica familiar só tenham surgido na segunda metade do século XX, as febres periódicas têm sido documentadas desde a antiguid...

La historia de las enfermedades autoinflamatorias se remonta a siglos atrás, con observaciones y descripciones tempranas encontradas en textos médicos antiguos y registros históricos. Aunque las descripciones detalladas de los síndromes de fiebre periódica familiar no aparecieron hasta la segunda mitad del siglo XX, las fiebres periódicas se han do...

Inflammation is a key driver in the pathogenesis of cystic fibrosis (CF). We assessed the effectiveness of elexacaftor/tezacaftor/ivacaftor (ETI) therapy on downregulating systemic and immune cell-derived inflammatory cytokines. We also monitored the impact of ETI therapy on clinical outcome. Adults with CF, heterozygous for F508del (n = 19), were...

The precise link between inflammation and pathogenesis of myelodysplastic syndrome (MDS) is yet to be fully established. We developed a novel method to measure ASC/NLRP3 protein specks which are specific for the NLRP3 inflammasome only. We combined this with cytokine profiling to characterise various inflammatory markers in a large cohort of patien...

Background Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5⁺-DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 is an RNA sensor and a key pattern recognition receptor for the SARS-CoV-2 virus. Methods This is a retrospective observational study of a surge in...

Common Variable Immunodeficiency (CVID) is a heterogeneous primary immunodeficiency disorder characterised by impaired antibody production, leading to recurrent infections and an increased susceptibility to viral pathogens. This literature review aims to provide a comprehensive overview of CVID’s relationship with viral infections, encompassing dis...

Background: Infectious diseases are a major cause of mortality in spite of existing public health, anti-microbial and vaccine interventions. We aimed to define plasma proteomic associates of infection mortality and then apply Mendelian randomisation (MR) to yield biomarkers that may be causally associated. Methods: We used UK Biobank plasma proteom...

Mast cells are infamous for mediating allergic and inflammatory diseases due to their capacity of rapidly releasing a wide range of inflammatory mediators stored in cytoplasmic granules. However, mast cells also have several important physiological roles that involves selective and agonist-specific release of these active mediators. Whilst a filter...

VEXAS is a new entity encompassing a variety of clinical manifestations spanning from autoimmune/auto-inflammatory to hematologic conditions including MDS, plasma cell dyscrasias, and recurrent thrombosis. Somatic mutations of the X-linked UBA1 gene in hematopoietic stem and progenitor cells constitute the molecular underpinnings of VEXAS, typicall...

Background: Hereditary angioedema (HAE) is characterized by recurrent and unpredictable episodes of subcutaneous and/ or submucosal swelling.Objective: To characterize the real-world treatment burden associated with existing on-demand therapies, we analyzedadministration-site adverse drug reactions (ADR) associated with approved on-demand HAE thera...

Introduction: Incorrect penicillin allergy records are recognised as an important barrier to the safe treatment of infection and affect an estimated 2.7 million people in England. Penicillin allergy records are associated with worse health outcome and antimicrobial resistance. The ALlergy AntiBiotics And Microbial resistAnce (ALABAMA) trial aims t...

Background: Activated phosphoinositide-3-kinase (PI3K) δ Syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking. Objectives: Report the extended spectrum of dise...

The transcription factor STAT6 (Signal Transducer and Activator of Transcription 6) is a key regulator of Th2 (T-helper 2) mediated allergic inflammation via the IL-4 (interleukin-4) JAK (Janus kinase)/STAT signalling pathway. We identified a novel heterozygous germline mutation STAT6 c.1255G > C, p.D419H leading to overactivity of IL-4 JAK/STAT si...

Background The NLRP3 inflammasome is a critical multi-molecular platform involved in mediating innate immune responses, and could play a role in Adult onset Still’s disease (AOSD). Upon NLRP3 inflammasome activation, a large protein complex assembles, resulting in the re-localisation of apoptosis-associated speck-like protein containing a caspase r...

Background: The human CD19 antigen is expressed throughout B cell ontogeny with the exception of neoplastic plasma cells and a subset of normal plasma cells. CD19 plays a role in propagating signals from the B cell receptor and other receptors such as CXCR4 in mature B cells. Studies of CD19-deficient patients have confirmed its function during th...

Mast cells are infamous for mediating allergic and inflammatory diseases due to their capacity of rapidly releasing a wide range of inflammatory mediators stored in cytoplasmic granules. However, mast cells also have several important physiological roles that involves selective and agonist-specific release of these active mediators. Whilst a filter...

Background: Cystic fibrosis (CF) is one of the most common life-limiting autosomal-recessive disorders and is caused by genetic defects in the CF transmembrane conductance regulator (CFTR) gene. Some of the features of this multisystem disease can be present in primary immunodeficiency (PID). Objective: We hypothesized that a carrier CFTR status...

Background Concerns have been raised regarding the reduced immunogenicity of vaccines against COVID-19 in patients with autoimmune diseases treated with rituximab. However, the incidence and severity of breakthrough infections in unbiased samples of patients with specific rheumatic and musculoskeletal diseases are largely unknown. We aimed to asses...

Introduction: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described, late-onset, acquired autoinflammatory disorder caused by mutations in the UBA1 gene. The various clinical manifestations of VEXAS broadly divided into inflammatory or haematological. VEXAS defines a new disease category - the hematoinfl...

Introduction The objective of the current study is to describe treatment burden associated with FDA-approved on-demand therapies for hereditary angioedema (HAE) attacks using the real-world frequency of administration site reactions reported in the FDA's Adverse Event Reporting System (FAERS). Method : We searched FAERS data from 10/01/2009 to 3/3...

Broadly neutralizing antibodies (bNAbs) have huge potential as novel anti-viral therapeutics due to their ability to recognize highly conserved epitopes that are seldom mutated in viral variants. A sub-set of bovine antibodies possess an ultralong complementarity-determining region (CDR)H3 that is highly adept at recognizing such conserved epitopes...

Background Individuals with primary and secondary immunodeficiency (PID/SID) were shown to be at risk of poor outcomes during the early stages of the SARS-CoV-2 pandemic. SARS-CoV-2 vaccines demonstrate reduced immunogenicity in these patients. Objectives To understand whether the risk of severe COVID-19 in individuals with PID or SID has changed...

The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact of RAG1/RAG2 on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation repres...

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5–2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillb...

The licensed dose for omalizumab within Europe for chronic spontaneous urticaria (CSU) is 300mg 4‐weekly and is based on the most effective dose in clinical trials. Many patients require longer term treatment with omalizumab and there is limited guidance on how to manage these patients. We report on a large cohort of 357 patients with CSU who have...

Background Patients with primary and secondary antibody deficiency are vulnerable to COVID-19 and demonstrate diminished responses following two-dose SARS-CoV-2 vaccine schedules. Third primary vaccinations have been deployed to enhance their humoral and cellular immunity. Objectives To determine the immunogenicity of the third primary SARS-CoV-2...

Objectives About 6% of the UK general practice population has a record of a penicillin allergy but fewer than 10% of these are likely to be truly allergic. In the ALABAMA (Allergy Antibiotics and Microbial resistance) feasibility trial, primary care patients with penicillin allergy were randomised to penicillin allergy assessment pathway or usual c...

jats:sec> Background As rituximab (RTX) is a B-cell depleting agent, there are concerns regarding its safety during the COVID pandemic. Data from registries during pre-vaccination period reported increased risk of poor outcomes in RTX-treated patients vs TNFi. However, registry data could be limited by reporting bias in determining true incidence....

Background As rituximab (RTX) is a B-cell depleting agent, there are concerns regarding its safety during the COVID pandemic. Data from registries during pre-vaccination period reported increased risk of poor outcomes in RTX-treated patients vs TNFi. However, registry data could be limited by reporting bias in determining true incidence. There are...

Background In COVACTA, a randomised, placebo-controlled trial in patients hospitalised with coronavirus disease-19 (COVID-19), tocilizumab did not improve 28-day mortality, but shortened hospital and intensive care unit stay. Longer-term effects of tocilizumab in patients with COVID-19 are unknown. Therefore, the efficacy and safety of tocilizumab...

Background/Aims We report a patient presenting with an inflammatory illness consistent with relapsing polychondritis (RP) and a pancytopaenia. Testing of his bone marrow revealed confirmation of the somatic mutation for the newly recognised condition VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. VEXAS is an acquired, ad...

Background Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood.ObjectivesCOVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune response...

Background Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood. Objectives COVID-19 in patients with antibody deficiency (COV-AD) is a multi-site UK study that aims to determine the immune respons...

Autoinflammatory diseases were first recognized as distinct rheumatological conditions caused by antigen-independent activation of the innate immune system's cells nearly 20 years ago. Initially, studies in families with the prototype periodic fever syndromes led to the identification of genes highly expressed in myeloid cells that regulate the pro...

Background Terminal complement pathway deficiencies often present with severe and recurrent infections. There is a lack of good-quality data on these rare conditions. This study investigated the clinical outcome and genetic variation in a large UK multi-center cohort with primary and secondary terminal complement deficiencies. Methods Clinicians f...

Background: The human CD19 antigen is expressed throughout B cell ontogeny with the exception of neoplastic plasma cells and a subset of normal plasma cells. CD19 plays a role in propagating signals from the B cell receptor and other receptors such as CXCR4 in mature B cells. Studies of CD19-deficient patients have confirmed its function during the...

Background Patients with primary and secondary antibody deficiency are vulnerable to COVID-19 and demonstrate diminished responses following two-dose SARS-CoV-2 vaccine schedules. Third primary vaccinations have been deployed to enhance their humoral and cellular immunity. Objectives To determine the immunogenicity of the third primary SARS-CoV-2...

XMEN (X-linked immunodeficiency with magnesium defect) is caused by loss-of-function mutations in MAGT1 which is encoded on the X chromosome. The disorder is characterised by CD4 lymphopenia, severe chronic viral infections and defective T-lymphocyte activation. XMEN patients are susceptible to Epstein-Barr virus infections and persistently low lev...

Objectives To assess antibody and T cell responses to SARS-CoV-2 vaccination in patients with rheumatoid arthritis (RA) on disease-modifying antirheumatic drugs (DMARDs). Methods This prospective study recruited 100 patients with RA on a variety of DMARDs for antibody and T cell analysis, pre-vaccination and 4 weeks post-vaccination. Positive anti...

Despite the clear benefits of vaccination against COVID-19, there was significant unease relating to the government policy of mandatory vaccination of health and care staff in England and the potential inequities this may lead to. Healthcare staff, and in particular doctors, speaking out on this issue may have inadvertently provided a narrative, wh...

In March 2020, the United Kingdom Primary Immunodeficiency Network (UKPIN) established a registry of cases to collate the outcomes of individuals with PID and SID following SARS-CoV-2 infection and treatment. A total of 310 cases of SARS-CoV-2 infection in individuals with PID or SID have now been reported in the UK. The overall mortality within th...

Background Time to relapse after rituximab for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is variable, and optimal retreatment strategy has remained unclear. In AAV following rituximab induction, the study objective was to evaluate clinical and B-cell predictors of relapse in order to develop a retreatme...

Systemic autoinflammatory diseases (SAID) are conditions caused by dysregulation or disturbance of the innate immune system, with neutrophils and macrophages the main effector cells. Although there are now more than 40 distinct, genetically defined SAIDs, the genetic/molecular diagnosis remains unknown for a significant proportion of patients with...

Background Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood. Objectives COVID in patients with antibody deficiency (COV-AD) is a multi-site United Kingdom study that aims to determine the immu...

Somatic mutations in the gene encoding the major E1 ubiquitin ligase, UBA1, were recently identified as a cause of VEXAS, a late-onset acquired auto-inflammatory syndrome. Differential diagnoses for patients subsequently found to have VEXAS include relapsing polychondritis, Sweet’s syndrome, myelodysplastic syndrome (MDS), giant cell arteritis (GCA...

Background Ligelizumab, a next‐generation, humanized anti‐immunoglobulin E (IgE) monoclonal antibody is in development as a treatment for patients with chronic spontaneous urticaria, whose symptoms are inadequately controlled with standard‐of‐care therapy. Objective To evaluate the long‐term safety and re‐treatment efficacy of ligelizumab 240 mg i...

Background Patients with some types of immunodeficiency can suffer chronic or relapsing infection with SARS-CoV-2. This leads to morbidity and mortality, infection control challenges and the risk of evolution of novel viral variants. Optimal treatment for chronic COVID-19 is unknown. Objective To characterise a cohort of patients with chronic or r...

The NLRP3 inflammasome is a vital mediator of innate immune responses. There are numerous NLRP3 mutations that cause NLRP3-associated autoinflammatory diseases (NLRP3-AIDs), mostly in or around the NACHT domain. Here, we present a patient with a rare leucine-rich repeat (LRR) domain mutation, p.Arg920Gln (p.R920Q), associated with an atypical NLRP3...