Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) represents one of the most challenging and potentially life-threatening conditions faced by rheumatologists. Part of the challenge has been the limited therapeutic options available and the substantial concern related to their toxicity, which are time dependent and dose dependent. Systemic glucocorticoids (GC) have been the cornerstone of AAV therapy since the 1950s; however, the extensive list of risks associated with its use are well described. Cyclophosphamide and rituximab have become the standard therapy for remission induction in organ or life-threatening AAV but not all patients achieve or sustain remission and many remain on long-term GC therapy. Recent attention focuses on achieving sustainable steroid-free induction and remission maintenance through transformative innovation of novel drug development or repurposing. This review sheds light on the significant advances made in similar or more effective novel innovative steroid-sparing or reduction strategies in AAV.

Objective Monogenic Behçet’s disease (BD)–like conditions are increasingly recognized and to date have been found to predominantly involve loss‐of‐function variants in TNFAIP3. This study was undertaken to identify genetic and pathobiologic mechanisms associated with a BD‐like mucocutaneous ulcerative syndrome and neuromyelitis optica (NMO) occurring in 3 generations of an Irish family (n = 5 cases and 5 familial controls). Methods Whole‐exome sequencing was used to identify potential pathogenic variants in affected family members and determine segregation between affected and unaffected individuals. Relative v‐rel reticuloendotheliosis viral oncogene homolog A (RELA) expression in peripheral blood mononuclear cells was compared by Western blotting. Human epithelial and RelA −/− mouse fibroblast experimental systems were used to determine the molecular impact of the RELA truncation in response to tumor necrosis factor (TNF). NF‐κB signaling, transcriptional activation, apoptosis, and cytokine production were compared between wild‐type and truncated RELA in experimental systems and patient samples. Results A heterozygous cytosine deletion at position c.1459 in RELA was detected in affected family members. This mutation resulted in a frameshift p.His487ThrfsTer7, producing a truncated protein disrupting 2 transactivation domains. The truncated RELA protein lacks a full transactivation domain. The RELA protein variants were expressed at equal levels in peripheral mononuclear cells. RelA −/− mouse embryonic fibroblasts (MEFs) expressing recombinant human RELAp.His487ThrfsTer7 were compared to those expressing wild‐type RELA; however, there was no difference in RELA nuclear translocation. In RelA −/− MEFs, expression of RELAp.His487ThrfsTer7 resulted in a 1.98‐fold higher ratio of cleaved caspase 3 to caspase 3 induced by TNF compared to wild‐type RELA ( P = 0.036). Conclusion Our data indicate that RELA loss‐of‐function mutations cause BD‐like autoinflammation and NMO via impaired NF‐κB signaling and increased apoptosis.

Lupus is a heterogenous multisystem autoimmune disease whereby nephritis is one of its most common cause of overall morbidity and mortality. Accurate, timely diagnosis and effective treatment in lupus nephritis (LN) remains a challenge to many clinicians including those who are directly involved in the daily care of these patients. Despite significant improvement in patients’ survival rate in recent years, in this era of precision medicine, there is pressing need to further improve our understanding and management of this disease. Our chapter would shed light on the key issues in LN including recent advances in our scientific understanding of its’ pathophysiology, major challenges and treatment strategies.

Sirs, Systemic lupus erythematosus (SLE) is a heterogeneous multisystem autoimmune disease. It is widely believed that C-reactive protein (CRP) remains normal or only modestly elevated in uninfected SLE patients despite intense disease activity (1-2). However, it is often difficult to differentiate between a disease flare and infection when SLE patients have high CRP, especially when it presents with concomitant fever. Cardiac involvement in SLE is not uncommon, and most commonly manifests as pericardial effusion and/or pericarditis, which may progress into more life-threatening large effusions and tamponade (3-4). We describe three afebrile female SLE patients without palpable synovitis who developed pericardial effusion and/or pericarditis and elevated CRP. They consecutively presented between April and June 2020 at the University Hospital of Kerry, Ireland (Table I). All patients fulfilled the new European League against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for SLE (5). CRP levels were measured by immunoturbidimetric assay on a Beckman Coulter AU analyser (Beckman Coulter, CA, USA). The first patient was a 67-year-old female on maintenance hydroxychloroquine 400 mg daily and mycophenolate mofetil 500 mg twice daily, who presented to the emergency department (ED) with a 3-week history of non-specific symptoms, mainly fatigue. She denied any shortness of breath or chest pain. She was afebrile with normal vital signs and, apart from looking pale, physical examination was unremarkable, including normal heart sounds without murmur and no palpable synovitis. Blood analysis demonstrated CRP of 255mg/L, haemoglobin (Hb) of 7.8g/dL, platelet count of 631x109/L, lymphocytes of 0.39x109/L, mildly elevated transaminases (AST 64 U/L; ALT 63U/L) and normal renal function. Urine dipstick was negative for protein or blood. Initial cardiac screening (including ECG and serial troponins) was unremarkable. Septic screen was negative, including negative nasopharyngeal SARS-CoV-2 RT-PCR swab. Chest radiograph evidenced newly developed cardiomegaly without pleural effusion or infiltrate that prompted an urgent transthoracic echocardiogram (TTE). This revealed large posterolateral pericardial effusion, mildly impaired left ventricular function without tamponade or constrictive features. Computed tomography pulmonary angiogram (CTPA) revealed small left sided pleural effusion, but no evidence of pulmonary embolus (PE). She remained haemodynamically stable and was transferred to the coronary care unit for close observation. Her symptoms and CRP levels responded promptly with high-dose oral prednisolone taper and low dose colchicine, while her Hb slowly improved and serial echocardiogram demonstrated full resolution of pericardial fluid and ventricular function. The second patient was a 47-year-old female presenting with substernal pleuritic chest pain associated with positional variation and dyspnoea. She had non-specific arthralgia and no evidence of clinical synovitis. She had been previously diagnosed with SLE fulfilling the diagnostic criteria at a different rheumatology centre; however, her hydroxychloroquine was eventually stopped after she remained in remission for several years. There was no history of thromboembolic events or rheumatic fever. Blood analysis demonstrated mild but persistently elevated CRP (between 9–21mg/L within 12 months), low platelet of 101x109/L with normal liver and renal profiles. Initial cardiac screening and septic screen were negative. TTE demonstrated a small pericardial effusion and moderate aortic regurgitation. She was given a rapid tapering dose of oral steroid therapy, recommenced taking hydroxychloroquine and started on azathioprine with resolution of all symptoms, blood indices and pericardial effusion (on repeated TTE). The third patient was a 64-year-old female previously diagnosed with seronegative inflammatory arthritis after initially presenting with symmetrical polyarthritis; however, failed multiple disease-modifying anti rheumatic drugs (DMARDs) including conventional DMARDs, several anti-tumour necrosis factors (anti-TNFs) and a janus kinase (JAK) inhibitor. She then developed recurrent dyspnoea associated with pleuritic-type chest pain and presented on several different occasions to the ED with normal initial cardiac screening and CTPA. TTE demonstrated small but stable pericardial effusion (compared to previous TTE). These findings combined with 1) persistent but mildly elevated CRP (between 6-42 mg/L) within a period of 18 months; 2) development of significant lower limb rashes; 3) ultrasound demonstrating synovial thickening of multiple joints but without evidence of acute synovitis; this prompted a reassessment of her diagnosis. Antibodies were positive for ANA, anti-dsDNA, and crithidia anti-dsDNA with negative anti-histone antibody. She was started on an oral steroid taper but was never really able to be weaned off steroids completely or reduced to lower acceptable doses; she was subsequently put on rituximab with a resolution of symptoms, CRP and TTE finding. Despite no current established predictive factors to assess patients who are at greatest risk to develop pericarditis in SLE patients, our small case series highlights: 1) presence of markedly elevated CRP (>50mg/L) especially without development of fever or palpable synovitis Table I. Summary of SLE patients with elevated CRP and pericardial involvement.

BackgroundSecukinumab is a recombinant human monoclonal immunoglobulin IgG antibody that selectively targets IL-17A and blocks its interaction with the IL-17 receptor. Inhibition of the downstream effects of this proinflammatory cytokine thereby interferes with key psoriasis disease pathways while promoting normalization of immune function and skin histology.ObjectivesThe aim of the study was two-fold; firstly, to compare the response to Secukinumab in psoriatic arthritis (PsA) patients who were biologically naive and experienced, and secondly to compare the response between smokers and non-smokers.MethodsIn collaboration with the National Psoriatic arthritis Registry of Ireland, patients who were diagnosed and treated as PsA at University Hospital Kerry between March 2017 and October 2018 were included in this population-based cohort study.Patients demographic, clinical characteristics, treatment strategies (including response rates and adverse effects) were captured at baseline and at follow-up outpatient visits.ResultsA total of 96 patients were identified and included in the study (mean age of 56.6 years; male to female ratio of 1:1, 49 males, 47 females). Of these patients, 15 received Secukinumab (7 biologically-naive patients, 8 patients with previous treatment failure to anti-TNF agents (3 patients received one anti-TNF, 5 received two different anti-TNFs). In the biologically-naive group, 5 patients(71%) had completeresponse to Secukinumab, one patient (14.3%) had complete improvement of joint symptoms but remained fatigued (high BRAF score) while 1 patient (14.3%) had no improvement. All 7 of these patients were exposed to cigarette smoking (6 current smokers, one ex-smoker). In patients who previously failed anti-TNF, five(62.5%) remained symptomatic (tender & swollen joints, PROMs and BRAF score remained high) despite treatment with Secukinumab. Only three patients (37.5%) responded well to treatment. Two of the eight patients never smoked (both did not respond to Secukinumab) while the other 6 patients (3 responded, 3 had no response) were ex-smokers.ConclusionIn our study, Secukinumab demonstrated better response to the biologically-naive PsA patients, while smoking did not increase the risk of disease activity among PsA patients receiving Secukinumab.Disclosure of interestsNone declared

Background: Vertebral fragility fracture (VFF) is the most common osteoporotic fracture and a strong predictor for future vertebral fracture(s) and/or hip fracture. A clear reporting of VFF by radiologists offers ample opportunity for early diagnosis and appropriate management of osteoporosis among treating physicians. Objectives: The objectives of this study were two-fold; to evaluate 1) the reporting of VFF by radiologists at one of the largest acute hospitals in southern Ireland 2) the management of osteoporosis (adherence to screening for secondary causes and commencement/switching of anti-resorptive therapy accordingly) for patients with VFF. Methods: We conducted a retrospective cross sectional study involving all patients (n=199) who attended our specialist rheumatology outpatient clinics at University Hospital Kerry during the month of November 2018. Patients who previously had undergone plain radiography of the spine (PRS) in the previous 5 years were identified and reassessed for evidence of VFFs. Basic demographic, drug history, clarification of fragility fracture and previous related trauma, investigations for secondary causes of osteoporosis, and treatment received for osteoporosis were documented. Results: 73 of the 199 patients had undergone previous PRS, 9 of which had evidence for VFFs. Only two patients (22.2%) were reported as having vertebral “fractures”, while 7 others had different terms used to describe the fracture(s)-2 patients with “wedging”, 1 with “compression”, 2 with “loss of height” and 2 with “collapse”. All (2 patients; 100%) with VFF reported as “fracture” had complete clarification of VFF, secondary osteoporotic work-up and treated with anti-resorptive therapy accordingly. Among the other 7 patients with VFFs but not reported as having “fracture”, 1 patient had concomitant report of “osteoporotic” bones and had complete management for osteoporosis. 4 patients had concomitant report of “osteopenia”, 3 (75%) of which received complete management for osteoporosis; while only 50% (1 patient) of the 2 remaining patients without further description of bone density received appropriate management. Further 6 patients with non-VFF were reported to have reduced bone density (1 reported as “osteoporotic” bones; 5 as “osteopenic” bones). Only one of them (16.7%) had further work-up, evaluation and management for osteoporosis. Conclusion: Clear radiological report of PRS with VFFs using the word “fracture” is a strong predictor for appropriate management of bone health. It is essential that other terms used to describe VFFs such as “wedging”, “compression”, “loss of height” and “collapse” not to be used alone without the concomitant use of the word “fracture”. Disclosure of Interests: None declared

Background Bechet’s disease (BD) is a heterogeneous multifactorial auto-inflammatory condition characterised by recurrent episodes of oral and genital ulceration, uveitis and skin lesions, with less frequent involvement of the gastrointestinal tract, large blood vessels and central nervous system. The NF-κB pathway is a ‘master-regulator’ of immune and inflammatory signaling, with the ability to control the expression of key inflammatory genes and genes associated with apoptosis and proliferation. Objectives To identify the pathobiology associated with a novel genetic mutation identified in a 3-generation family with Behçet’s-like mucocutaneous ulceration syndrome, primarily involving childhood-onset chronic oral and genital ulcers. Methods The novel RELA mutation was identified using whole exome sequencing. Immunoblot of peripheral blood mononuclear cell (PBMCs) lysates from affected family members was used to determine if the predicted truncated protein was expressed. PBMCs were stimulated with TNF; NFkB phosphorylation was measured relative to unstimulated cells form affected and unaffected family members. HEK293T cells transfected with plasmids encoding either wild-type or the novel RELA-mutant and overexpression confirmed via immunoblot. An in vitro model of the RELA truncation was used to observe the effect of the RELA truncation on response to TNF stimulation. Apoptosis protein arrays, western blots, and ELISA assays were used to investigate the effect of TNF on wild-type RELA compared to the mutant protein. Mouse Embryonic Fibroblasts (MEFs) isolated from RELA-/- mice, which do not express endogenous RELA, were transfected with plasmids encoding either wild-type or the novel RELA-mutant. Wild Type MEF cells (with endogenous RELA) were used as a control. Cells were stimulated with LPS (2.5ug/ml) or no treatment control for 12 hours. Results A heterozygous cysteine deletion at position 1459 in RELA was detected in all affected individuals as previously reported. This mutation results in a frameshift His487ThrfsTer7, producing a truncated protein of 492 amino acids. RELAHis487ThrfsTer7 heterozygotes have different phosphorylation kinetics of key NFkB pathway proteins in response to TNF compared to wild-type controls. Cells overexpressing RELAHis487ThrfsTer7, had increased pro-apoptotic proteins (BAD, cleaved caspase 3 and SMAC) whereas anti-apoptotic proteins (BCL2, CLASPIN) were decreased compared to cells transfected with wildtype RELA. Cells transfected with RELAHis487ThrfsTer7 were less sensitive to TNF stimulation compared to wild-type controls, as measured by induction of TNF-sensitive proteins. Conclusion This study gives novel information on both the genetic basis and biological mechanisms of BD in individual families. Familial mutations that induce haploinsufficiency of RELA have recently been associated with BD. However, the His487ThrfsTer7 results in protein truncation rather than haploinsufficiency. Our study supports several recently published studies that loss-of-function mutations in the NF-κB pathway are linked with the development of familial early-onset BD-like syndromes. We propose that RELAHis487ThrfsTer7 causes altered NFκB signaling resulting in reduced mucosal cell recovery and the observed Behçet’s-like mucocutaneous ulceration syndrome. Disclosure of Interests: Emma Dorris: None declared, fahd adeeb: None declared, Dylan Lawless: None declared, Wan Lin Ng: None declared, Aqeel Anjum: None declared, Niamh Morgan: None declared, Eoin Cummins: None declared, Sinisa Savic Grant/research support from: Novartis and Sobi, Alexander Fraser: None declared, Gerry Wilson: None declared

Background Behçet’s disease (BD) has a complex multifactorial pathogenesis and presents with phenotypic heterogeneity predominantly mucocutaneous ulcerations, ocular lesions and skin manifestations. More recently, there have been reported cases of monogenic spectrum defects presented with BD-like similarities or phenotype. Objectives We investigated an Irish Caucasian family of eleven that included two half-sisters with early-onset BD, and another sister with neuromyelitis optica, all who were born to asymptomatic non-consanguines parents. More recently, one of the sisters’ daughter developed recurrent oral aphthosis at the age of 10 years old. Methods Peripheral blood mononuclear cells were extracted from patients and non-affected donor blood using standard fractionation methods. Following quality assessment and quantification whole exome sequencing was performed on all participants. Results Whole exome sequencing data identified segregation of a novel pathogenic stop codon mutation in the nuclear factor NF-κB p65 subunit (RelA) resulting in a non-functional protein. The mutation involves cytosine deletion and results in a His487ThrfsTer7 frameshift (His487ThrfsTer7) RelA resulting in loss of transcription activation-1 (TA1) and a portion of TA2 from RelA. The mutation was seen within the three generations, including the three half-sisters, their father as well as one of the proband’s daughter, potentially describing a new syndrome. Conclusions Our study suggests that loss-of-function mutations in the NF-κB pathway, a pivotal mediator of inflammation and apoptosis, are linked with the development of familial early-onset BD-like syndromes. Better insights and further understanding of this ”orphan” immunogenetic syndrome carries high clinical impact to assist early disease recognition and potential discoveries of novel targeted therapies. Disclosure of Interest None declared

Objective. The epidemiology of Behcet's disease (BD) remains poorly understood with limited international data on disease burden, progression and treatment outcomes. The aims of this study were to determine the natural history of BD in the Midwest region of Ireland and compare our findings with those from other European and Mediterranean studies. Methods. We established a cohort of patients with BD in the Midwest Region of Ireland based on ISGBD and/ or ICBD criteria. Longitudinal data were captured on demographic and clinical characteristics, disease activity and clinical outcomes. Results. The cohort included 24 Caucasian patients (16 women, 8 men) and one male patient with Middle Eastern ancestry, who satisfied the diagnostic criteria for BD. Based on the ISGBD criteria, the point prevalence of BD was 6.2 per 100,000 population. The most common clinical manifestation was oral aphthosis (100%) followed by genital aphthosis (92%) and skin lesions (92%), arthralgia/ arthriti(s4 0%), ocular involvement (32%), vascular thrombosis (12%) and pathergy phenomenon (8%). Only 1 patient was HLA-B* 51 positive. A long-term multidisciplinary approach that included physician specialists, nurse specialists, and general practitioners was adopted for ongoing patient care. Conclusion. The prevalence of BD in Ireland is higher than previously reported with a significant proportion experiencing laryngeal destruction. There are many similarities as well as several differences in the epidemiology of BD by country and indeed within countries. We fully advocate the need for national and international collaborative efforts in order to further understand the complex aetiology and immunopathology of BD in order to improve the clinical, physical, psychological wellbeing of patients.

BACKGROUND:Elevated serum uric acid (sUA) concentrations are common in the general population and are associated with chronic metabolic conditions and adverse clinical outcomes. We evaluated secular trends in the burden of hyperuricaemia from 2006-2014 within the Irish health system.METHODS:Data from the National Kidney Disease Surveillance Programme was used to determine the prevalence of elevated sUA in adults, age > 18 years, within the Irish health system. Hyperuricaemia was defined as sUA > 416.4 μmol/L in men and > 339.06 μmol/L in women, and prevalence was calculated as the proportion of patients per year with mean sUA levels above sex-specific thresholds. Temporal trends in prevalence were compared from 2006 to 2014 while general estimating equations (GEE) explored variation across calendar years expressed as odds ratios (OR) and 95% Confidence intervals (CI).RESULTS:From 2006 to 2014, prevalence of hyperuricaemia increased from 19.7% to 25.0% in men and from 20.5% to 24.1% in women, P<0.001. The corresponding sUA concentrations increased significantly from 314.6 (93.9) in 2006 to 325.6 (96.2) in 2014, P<0.001. Age-specific prevalence increased in all groups from 2006 to 2014, and the magnitude of increase was similar for each age category. Adjusting for baseline demographic characteristics and illness indicators, the likelihood of hyperuricemia was greatest for patients in 2014; OR 1.45 (1.26-1.65) for men and OR 1.47 (1.29-1.67) in women vs 2006 (referent). Factors associated with hyperuricaemia included: worsening kidney function, elevated white cell count, raised serum phosphate and calcium levels, elevated total protein and higher haemoglobin concentrations, all P<0.001.CONCLUSIONS:The burden of hyperuricaemia is substantial in the Irish health system and has increased in frequency over the past decade. Advancing age, poorer kidney function, measures of nutrition and inflammation, and regional variation all contribute to increasing prevalence, but these do not fully explain emerging trends.

Background The menstrual cycle is regulated by the rise and fall of sex hormones in the body. Literature has demonstrated anti-inflammatory properties in both progesterone and oestrogen hormones.1 There has been recent interest to determine the association between Behçet’s Disease (BD), a poorly understood autoinflammatory disorder and menstruation. Objectives The objective of this study was to evaluate the effect of menstruation in triggering exacerbations of Behçet’s disease in a Northern European cohort. Methods 18 female patients from our rheumatology department satisfying the International Study Group for Behçet’s Disease (ISGBD) criteria were recruited. A questionnaire was conducted via telephone to determine whether their exacerbations of BD were correlated to their menstrual cycle. Results All 18 patients responded to the questionnaire, with the mean age of 38.8 years and mean age of menarche of 13 years. Four (22.22%) patients were in menopausal state. Half (nine) of the patients reported that their BD flare ups were correlated to their menstrual cycle. Exacerbations experienced include oral aphthosis (88.9%), arthralgia (55.6%), genital ulcerations (44.4%), lethargy (44.4%), skin lesions (11.1%) and headaches (11.1%). Six of the seven patients (86%) who were on contraception were on a progesterone containing contraception. Four out of nine (44%) who did not notice any exacerbations during menstruation stated that they were on progesterone containing contraceptives. It is noteworthy that 10 patients (55.56%) had previous pregnancies while three patients experienced an episode of miscarriage and 1 had a stillbirth. Conclusions Our results demonstrated that the disease activity in BD is related to the menstrual cycle, which is contributed by the female sex hormones. The study supports previous hypothesis that the abrupt decline in progesterone during onset of menstruation is associated to disease flare in BD.2 Studies comprising larger cohorts should be conducted to further support and strengthen this evidence. References [1] Szekeres-Bartho J, Barakonyi A, Par G, et al. Progesterone as an immunomodulatory molecule. Int J Immunopharmacol. 2001; 1: 1037–48. [2] Bang D, Chun YS, Haam IB, et al. The influence of pregnancy on Behçet’s disease. Yonsei Med J. 1997; 38: 437–43 Disclosure of Interest None declared

Background Vitamin D has been shown to be directly or indirectly involved in the regulation of proliferation, differentiation, and function of immune cells. Many studies have revealed higher levels of Vitamin D deficiency among patients with autoimmune diseases compared to controls. Aim Aim of the study was to evaluate the serum 25-hydroxyvitamin D (25(OH)D) levels in Behçet’s disease (BD) patients in the midwest region of Ireland, and to correlate with its disease activity. Methods All BD patients attending our rheumatology service and satisfying the ISGBD/ICBD criteria were included in the study and compared in a 1:5 ratio with samples taken from controls matched for age, gender- and the month of the year. Exclusion criteria included other rheumatological or bone/skeletal diseases, a history of chronic kidney disease or other chronic systemic diseases, malignancies, limited physical activity, and if on vitamin D supplementation or medications that could have affected vitamin D metabolism including calcium supplements, cytotoxic drugs, anticonvulsants, bisphosphonates and thyroxine but not glucocorticoids and disease-modifying anti-rheumatic drugs. The total serum 25(OH)D was measured by using competitive chemiluminescence immunoassays (DiaSorin, Dietzenbach, Germany). Levels<20 ng/ml were defined as deficient, between 20–40 ng/ml as insufficient. Results 19 Caucasian BD patients were included in the study (5 male, 14 female, median age of 37.5 years (interquartile range (IQR), 24.3–51.2 years). The median 25(OH)D of BD patients and controls were 45 ng/ml (IQR,33–65 ng/ml) and 22 ng/ml (IQR, 15–31 ng/ml) respectively. The median 25(OH)D was relatively lower in active BD patients in comparison to inactive patients: 35 ng/ml (IQR, 22.75–47.25 ng/ml) compared to 50 ng/ml (IQR, 35–67 ng/ml). Overall, none of the patients had Vit D deficiency, however 6 patients had Vit D insufficiency. Conclusion In contrast to many previous studies in other BD cohorts and other autoimmune diseases our study suggests the mean 25(OH)D levels was significantly higher in this BD group. In patients with active disease however serum levels were relatively low compared to the inactive group which is in concordance with the literature. Our findings suggest vitamin D may be a potential suppressor of inflammation in BD, however larger studies are needed to support this thesis and to conclusively understand its role in the inflammatory pathway.