OBJECTIVES:The objective of this study was to evaluate early damage, and its evolution and prognostic relevance in an inception cohort of patients with Takayasu arteritis (TAK) using the Large Vessel Vasculitis Index of Damage (LVVID). METHODS:Baseline LVVID was scored in an inception cohort of TAK who were within 3 months of cohort entry, at 1 year, and at the last follow-up at or after 1 year. Levels of associations between initial LVVID scores and demographic characteristics, disease activity, and angiographic subtypes were evaluated. Hazard ratios (HRs) for mortality per point/quartile increase in baseline LVVID scores were calculated using Cox proportional hazards regression. Damage evolution from baseline to 1 year or last follow-up was assessed using the paired Student's t test. Pre-treatment predictors of progression were assessed using logistic regression. RESULTS:Of 199 patients (141 females; 54 paediatric-onset), 192/199 (96.5%) had damage (most often cardiovascular) as indicated by the LVVID at presentation, 112/114 (98.2%) at 1 year, and 126/130 (96.9%) at last follow-up. Initial LVVID was greater with active disease, Hata's type V, or Goel's cluster 1 angiographic subtypes. Higher baseline LVVID was consistently associated with increased mortality [crude HR per point increase 1.49 (95% CI 1.24-1.81) or per quartile increase in LVVID 1.92 (1.21-3.05)], despite adjustment for disease activity or angiographic subtype. Significant progression of LVVID was observed at 1 year (3.49 ± 2.01 vs 3.27 ± 1.86, P < 0.001) or at the last follow-up (3.73 ± 2.18 vs 3.28 ± 1.88 P < 0.001), and was predicted by active disease at presentation [ odds ratio (OR) 2.89] and glucocorticoid (OR 3.53) or immunosuppressant use (OR 3.52). CONCLUSION:Most patients with TAK had recordable early damage, which was associated with future mortality.

Abstract Introduction Enthesitis related arthritis (ERA) category of juvenile arthritis is a form of juvenile spondylarthritis. In many immune-inflammatory disorders a subclinical phase precedes a clinical disease. First degree relatives either due to genetic predisposition or sharing of environment have a high recurrence risk for these diseases. No data is available in siblings of ERA patients. Methods 38 sibling-proband pairs were evaluated after consent. Clinical examination, X-ray LS-spine, MRI of SI-joints and MSUS for enthesitis were done to detect subclinical disease in siblings. Frequency of lymphocyte and monocyte subsets, IL-17 producing NK cells, NK-T cells, γδ T cells and CD4 lymphocytes, IL-6 and TNF-α producing monocytes was measured using FACS. Faecal calprotectin levels were measured using ELISA. Results 38 siblings of 36 proband (13.8±3.5 years) were included. 20 of 38 siblings were HLA-B27 positive. Among siblings, none had arthritis, 1 each had inflammatory back pain and uveitis. On radiological assessment, 5 showed evidence of sacroiliitis (Grade II-4, Grade IV-1) on X-ray while 5 siblings had bone marrow edema around SI joints (one quadrant-4, four quadrants-1) on MRI. On MSUS enthesitis was seen in 2 siblings (patellar tendon-1, Tendoachillies-1). All but one with abnormalities were HLA-B27 positive. In comparison to siblings, the probands had lower frequency of classical monocytes (p < 0.05), IL-6 producing monocytes (p < 0.01) and higher frequency of Th17 cells (p < 0.05). The faecal calprotectin levels were higher in probands (p < 0.01). Analysing only the HLA-B27 siblings since subclinical disease was seen in only HLA-B27 siblings, the frequency of IL-17 producing CD4 T cells and γδ T cells (p < 0.01) and faecal calprotectin levels (p < 0.01) were higher in probands when compared with B27 positive siblings. Conclusion Subclinical disease is seen in subset of HLA-B27 siblings of patients with ERA. Gut inflammation and a pro-inflammatory state probably results in clinical disease in probands. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)

Myositis specific antibodies are clinically useful biomarkers in inflammatory myositis. Although immunoprecipitation is regarded as the gold standard, line immune assay (LIA) is widely used in practice. However, LIA is limited by multiple MSA positivity in up to 15

BACKGROUND:SLE has increased risk of invasive pneumococcal disease due to immune dysregulation and immunosuppression. European Alliance of Associations for Rheumatology recommendations suggest sequential vaccination with conjugate vaccine, followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23). However, data on immunogenicity of sequential vaccination in SLE are limited. METHODS:Adult patients with SLE (American College of Rheumatology 2019 criteria) with inactive disease, stable immunosuppression for 3 months and prednisolone ≤10 mg/day were included. Sequential arm received 10-valent pneumococcal conjugate vaccine, followed by PPSV23. The second arm received only PPSV23. The two cohorts were recruited independently without randomisation. Antibodies at baseline and 12-14 weeks to pneumococci (serotypes 1, 5, 6B, 14 and 19F) were measured by ELISA and opsonophagocytic assay for functional antibodies. The primary outcome was a twofold increase in 3/5 serotypes. 40 subjects were enrolled in each arm and 15 healthy adults for response to PPSV23. RESULTS:35 completed the study in the PPSV23 arm and 34 in the sequential arm. Baseline parameters were comparable.Response to PPSV23 was poorer in SLE (74.28%) compared with healthy controls (100%). There was no difference in the primary outcome between sequential vaccination (82.35%, 95% CI 68% to 94%) and PPSV23 (74.28%, 95% CI 60% to 89%). All 15 non-responders were on prednisolone. Among responders, only 41/54 (76%) were on prednisolone. There was no difference in other immunosuppressive drugs. Increasing age predicted poor response on multivariable analysis in all serotypes.Major adverse events included one event of Miller Fisher variant of Guillain-Barré syndrome in the sequential arm. Minor adverse events included one each with injection-site pain, migraine, fever and fatigue after conjugate vaccine, and one with fever after PPSV23. Three minor adverse events in the PPSV23 group included one each with injection-site pain, herpes zoster, headache and fever. In the PPSV23 arm, three minor flares were seen, while in the sequential arm, one major flare and one minor flare occurred. INTERPRETATION:Both vaccination strategies are safe with adequate antibody response. In low- and middle-income countries, a single-dose PPSV23 may be adequate if cost negates sequential vaccination.

Objective: To describe the clinical profile and outcome of patients with catastrophic antiphospholipid syndrome (CAPS) from a tertiary care Rheumatology centre in North India. Methods: A retrospective analysis of data of patients between 1990 and March 2024 was done. Those with rapid involvement of three or more organ systems with moderate to high titres of antiphospholipid antibodies (aPL) at least once were considered physician-diagnosed CAPS. Results: Fourteen patients were considered as cases of CAPS. The majority were females, with a median age of 28 years (26.25–37.25). Two-thirds of the patients had systemic lupus erythematosus (SLE) as the background illness. Thrombocytopenia was present in all cases, and CAPS was the presenting manifestation in half of them. An identifiable trigger was found in only nine cases predominantly infection. Triple therapy with intravenous immunoglobulin (IVIG), pulse steroids, and heparin was received by six patients, resulting in clinical recovery in five of them. Nine patients received anticoagulation and the rest received glucocorticoids, other immunosuppressive agents and antibiotics for underlying sepsis. Among the five patients who did not receive heparin, three died of multiorgan dysfunction. Two patients died despite anticoagulation owing to late presentation and delay in initiation of heparin. Conclusion: A high index of suspicion should be kept for CAPS, especially in a young female with rapidly progressive multiorgan dysfunction in the background of autoimmune features or pregnancy morbidity. Triple therapy using heparin, IVIG and high-dose steroids should be considered in patients with suspected CAPS.

Background: Autoinflammatory diseases manifest as recurrent fever and sterile inflammation impacting multiple organs. In rheumatology clinics, polygenic conditions like Systemic onset JIA, Adult-onset Still's disease and Behcet's disease prevail, whereas monogenic variants are rare, often leading to diagnostic delays. Early recognition of phenotypic traits and genetic testing are pivotal in guiding treatment, utilizing biologics, small molecules, or allogenic stem cell transplant. Objectives: To describe the clinical spectrum, genetic etiology and outcomes of patients with autoinflammatory diseases. Methods: A retrospective analysis encompassing patients from our clinic from 2013-2023 was undertaken. We scrutinized patients clinically diagnosed with autoinflammatory syndromes. Clinical profiles and available genetic test results were collated from case records and electronic databases. Results: Among the 47 suspected cases of autoinflammatory diseases, 27 underwent genetic testing, confirming diagnosis in 21 instances. Notably one suspected Blau syndrome case tested negative for NOD2 mutation. For the 26 cases displaying the characteristic clinical phenotype, the median age of presentation was 168 months (72-213), with onset typically occurring around a median age of 39 months (6-174). The male to female ratio was 1.36:1. There was median delay in diagnosis of 48 months (24-115) and patients had a median follow up duration of 16.5 (5.5-46.5) months. Predominant manifestations included fever (n=15, 57.6%), mucocutaneous symptoms (n=15, 57.6%), musculoskeletal symptoms (n=10, 38.4%), cytopenia (n=6,23.07%), vasculitis (n=5,19.2%) and hearing loss (n=3, 11.5%), alongside diverse systemic manifestations. A history of infections was present in 5 patients (19.2%). Family history of consanguinity was present in 1 patient (3.8%) while similar diseases or unexplained early deaths in relatives was there in 7 patients (26.9%). Diagnoses spanned various conditions like Hyper IgD syndrome, Muckle Wells syndrome, Neonatal onset multisystem inflammatory disease (NOMID), Histiocytosis-Lymphadenopathy plus syndrome (H syndrome) and deficiency of adenosine deaminase 2 (DADA2) among others, highlighting the spectrum of disorders encountered (Table 1). Regarding treatment response, 18 patients (69.2%) had good or partial response to therapy while 6 patients (23.07%) were lost to follow up. Majority of patients (n=22, 84.61%) had received some form of immunosuppression. One patient with STING associated vasculopathy of infancy (SAVI) who had excellent initial treatment response to Tofacitinib had weaning of the effect later, while another patient with DADA2 and severe cytopenia succumbed to her illness. Conclusion: The spectrum of monogenic autoinflammatory syndromes continues to broaden. Early identification, facilitated by vigilant observation and interdepartmental collaboration, can significantly enhance treatment efficacy and enable informed genetic counselling. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared.

Background: Primary immune regulatory disorders (PIRDs) are inborn errors of immunity resulting in severe and recurrent infections as well as traits like autoinflammation, autoimmunity, lymphoproliferation, and susceptibility to malignancies. Due to diverse clinical presentations, they present to multiple specialities, often leading to delayed diagnoses and morbidity. Early detection and initiating targeted therapies are crucial. The spectrum of these disorders is expanding and data from North India is sparse. This study is aimed to describe the clinical spectrum and outcomes of immune regulatory defects from North India. Objectives: To describe the clinical spectrum, genetic etiology and outcomes of patients with primary immune regulatory defects. Methods: A retrospective analysis of patients suspected of having immune regulatory defects at our hospital between 2013 and 2023 was conducted. Patient data, including clinical profiles and genetic test results were compiled from case records and electronic databases. Results: Of the 25 suspected cases, 12 had a confirmed genetic diagnosis. 19 patients had the characteristic phenotype (Male: Female= 2.1:1) presenting at a median age of 12 months (3-54). The median age of onset was 36 months (50-120), with a median delay in diagnosis of 6 (1.75- 24) months. A history of consanguinity and sibling deaths due to similar illnesses was reported in 6 cases each (31.5%). Among the 14 individuals who underwent whole exome sequencing, the diagnosis was confirmed in 12 cases. One patient was admitted for evaluation with suspected congenital hemophagocytic lymphohistiocytosis (HLH) due to death of 3 siblings with history of fever, rash and cytopenia, whose genetic analysis report is awaited. Another patient with Very Early Onset Inflammatory Bowel Disease (VEOIBD) exhibited a NOD2 heterozygous mutation categorized as a Variant of Uncertain Significance (VUS) (Table 1). Primary manifestations included fever (12,63.1%), hepatosplenomegaly (9,47.3%), lymphadenopathy (5,26.3%), and inflammatory Bowel Disease (IBD) (6,31.5%). Notably, 8 patients (42.1%) each experienced infections and had cytopenia, 12 (63.1%) exhibited failure to thrive, while 5 (26.3%) had HLH and 2 (10.5%) had interstitial lung disease. 2 patients (10.5%) each had recurrent pneumonia, septicaemia and infective diarrhoea while subcutaneous abscess and urinary tract infection were seen in 1 patient (5.2%) each. Diagnoses varied from Autoimmune Lymphoproliferative Syndrome (ALPS), Immune Dysregulation, Polyendocrinopathy, Enteropathy, X-linked (IPEX) syndrome, SOCS1 haploinsufficiency, to familial Macrophage Activation Syndrome (MAS) (Refer to Table 1). Regarding treatment response, 10 patients (52.6%) received immunosuppression, 3 (15.7%) received chemotherapy according to HLH protocol and 1 patient (5.2%) underwent HSCT. 7 patients (36.8%) positively responded, while 7 (36.8%) succumbed to the illness, and 5 (26.3%) were lost to follow-up. (Table 1). Survival at 1 year and 5 years was 71.2% (52.5%-96.6%) and 56.9% (36.9%-87.9%) respectively. Patients with any episode of HLH had worse survival, however no significant association of increased mortality was seen with infections. Conclusion: The spectrum of immune regulatory defects is rapidly expanding. Maintaining a heightened clinical suspicion and a low threshold for genetic testing is crucial for early identification. This early recognition is pivotal for initiating targeted treatment strategies and facilitating genetic counselling. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests: None declared.

Background: Infections are a major cause of morbidity and mortality in juvenile systemic lupus erythematosus (SLE). We assessed the incidence and risk factors for major infections in juvenile SLE. Methods: A retrospective review of 225 patients of juvenile SLE (ACR 1997 criteria) with age <18 years visiting the rheumatology clinic at a single centre between 2000 to 2020 was done from case records and the hospital electronic health records. Serious infection was defined as the need for hospitalization, or infection resulting in disability or death. Cox regression was used to determine factors associated with a serious infection and the effect of serious infection on overall survival. Results: We reviewed 225 children (197 girls, mean age 13.89 +/- 3.42 years) with a cumulative follow up of 1153.45 person-years. Eighty serious infections occurred in 63 (28% of the cohort) children at a rate of 69.35 serious infections per 1000 person-years. A second serious infection occurred in 12 children and 5 of them developed three infections. Among the cases with known etiology (78.75% of cases), bacterial infections were most common (N = 33) including S. Aureus (11), E. Coli (7), K. Pneumoniae (3), E. Fecalis (3), S. Pneumoniae (2), Acinetobacter spp. (2), Citrobacter (2), Salmonella (2) and P. Aeruginosa (1). Twenty six (32.5%) opportunistic infections occurred: Mycobacterium tuberculosis (18), Cytomegalovirus (3), disseminated Herpes zoster (4) and invasive candidiasis (1) with 15 (83.3%) of the tuberculosis cases being extrapulmonary. On multivariate analysis, fever (HR 8.51, 1.17-61.44), gastrointestinal involvement (HR 4.73, 1.13-19.94), current steroid dose (HR 1.36,1.14-1.62), average cumulative steroid dose per year (HR 1.004, 1.002-1.005) and cyclophosphamide (HR 2.22, 1.11-4.46) were associated with serious infection. Hospitalization rates were significantly higher in those with any serious infection (Rate-ratio 2.79, 1.81-3.77) as was damage accrual (SLICC damage index 1.04 vs 0.22). Serious infection-free survival at 1 year and 5 years was 84% (79.1-89.2) and 72% (65.4-79.2). There were 19 deaths with infection attributable mortality in 10 (52.6%). Serious infection predisposed to higher overall mortality with recurrent infections conferring a hazard ratio of 36.02 (8.07-160.62). Conclusion: Serious infections are a major cause of mortality and damage in SLE. Constitutional symptoms, gastrointestinal involvement, current and cumulative steroid dose and cyclophosphamide predict serious infections. TB prophylaxis in patients with SLE should be considered in endemic areas, especially when using high-dose steroid therapy.

Juvenile Idiopathic Arthritis (JIA) causes caregiver burden on families with children affected with it. Our study aimed to explore this multifaceted burden in the Indian context. In this cross-sectional study, we administered the Hindi translated CAREGIVER questionnaire to adult caregivers in the families of JIA patients ≤ 18 years. The responses to the 28 items were used to calculate the burden scores in various dimensions. The relationship of the global burden scores with demographic and socioeconomic factors were analysed. Non parametric tests were used. Two hundred twenty-one caregivers participated with a median age of 39 years (IQR 32–45). This included 116 fathers, 50 mothers, 32 brothers, 18 uncles, three grandfathers, one sister, and one grandmother. The JIA patients had a median age of 15 (12–17) years, and the male-to-female ratio was 3.2:1. Enthesitis-related arthritis was the predominant subtype (72.4

Background: Deficiency of Adenosine deaminase enzyme 2 (DADA-2) is a rare autoinflammatory disease. It results from autosomal recessive mutations in the ADA2 gene on chromosome 22q11.1. It was initially described in patients of medium vessel vasculitis with recurrent strokes. With widely available genetic testing the spectrum has expanded considerably in recent years. Objectives: To describe the clinical profile, genetic etiology and outcomes of DADA-2. Methods: We retrospectively reviewed 9 genetically proven DADA-2 patients from our institute from 2015 to 2023. Patient demographics, clinical manifestations and genetic test reports were collated from case records and electronic databases. Results: Among the 9 patients 4 patients were males. Median age of onset of disease, age of diagnosis and delay in diagnosis were 18 years (13-19.5), 23 years (17-46), and 5 years (2-25) respectively. Our patients can be divided into two distinct phenotypes, one group with predominantly vasculitis (n=7, 77 %) and another with predominantly hematological (n=6, 66%) manifestations. Most common vasculitic manifestation were fever (n=4, 44%) followed by cutaneous ulcers (n=3, 33%), mononeuritis multiplex (N=3, 33%) followed by central retinal artery occlusion (n=2, 22%) while only a single patient had the classically described recurrent strokes. Most common hematological manifestation were pancytopenia (n=3, 33%),) followed by neutropenia (n=2, 22 %) and thrombocytopenia (n=1, 11%) and. One patient who presented with severe anemia was found to have pure red cell aplasia associated with low immunoglobulin M levels and a Giardia lamblia infection. A family history of their sibling death due to medium vessel vasculitis was present in 2 (28%) patients. In a single family both parents and youngest child were carriers. Among the two elder siblings, one had very early onset inflammatory bowel disease (VEOIBD) with neutropenia and other had young onset hypertension. On genetic analysis 4 patients were homozygous and 5 were compound heterozygous for the pathogenic mutation in ADA-2 gene. All patient had a mutation in exon 2 resulting in a protein change due to amino acid substitution from Glycine to Arginine or Tryptophan at position 47. Four out of the 9 patients had mutation in exon 4 resulting in protein change due to amino acid substitution from Leucine to Valine at position 188.(Table 1) We had 29.45 admission per 100-person year follow up. One patient with recurrent fever and neutropenia who was awaiting allogenic stem cell transplant succumbed due to sepsis. Seven out of the 9 patients received multiple immunosuppression including Cyclophosphamide, Azathioprine, Mycophenolate mofetil, Cyclosporine. Patient with VEOIBD was managed with Azathioprine and Mesalamine. Anaemia and cytopenia responded to immunosuppression in all. Even though only one patient received anti TNF therapy, there were no incident strokes in the cohort till date. Conclusion: In our cohort, patient phenotypes are delineated similar to the existing literature as predominantly vasculitis or hematological. Exon 2 of the ADA2 gene is a mutational hotspot in India. REFERENCES: [1] Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014 Mar 6;370(10):911-20. doi: 10.1056/NEJMoa1307361. [2] Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2). J Allergy Clin Immunol. 2020 Jun;145(6):1664-1672.e10. doi: 10.1016/j.jaci.2019.12.908. [3] Hematopoietic Cell Transplantation Cures Adenosine Deaminase 2 Deficiency: Report on 30 Patients. J Clin Immu nol. 2021 Oct;41(7):1633-1647. doi: 10.1007/s10875-021-01098-0. Acknowledgements: NIL. Disclosure of Interests: None declared.

Background Infections are a major cause of morbidity and mortality in juvenile systemic lupus erythematosus (SLE). Objectives We assessed the incidence and risk factors for major infections in juvenile SLE. Methods A retrospective review of 225 patients of juvenile SLE (ACR 1997 criteria) with age <18 years visiting the rheumatology clinic at a single centre between 2000 to 2020 was done from clinical case records and data from the hospital electronic health records. Serious infection was defined as the need for hospitalization, or infection resulting in disability or death. Cox regression was used to determine factors associated with a serious infection and the effect of serious infection on overall survival. Results Among the 225 children (197 girls) with a mean age of 13.89 ±3.42 years and a cumulative follow up of 1153.45 person-years. A total of 80 serious infections occurred in 63 (28% of the cohort) individuals at a rate of 69.35 serious infections per 1000 person-years of follow-up. A second serious infection occurred in 12 children and 5 of them developed a third serious infection. Among the microbiologically confirmed cases (78.75% of cases) Bacterial infections were most common (N=33) and included S. Aureus (11), E. Coli (7), K. Pneumoniae (3), E. Fecalis (3), S. Pneumoniae (2), Acinetobacter spp. (2), Citrobacter (2), Salmonella (2) and P. Aeruginosa [1]. Twenty six (32.5%) opportunistic infections occurred: Mycobacterium tuberculosis (18), Cytomegalovirus (3), disseminated Herpes zoster (4) and invasive candidiasis (1) with 15 (83.3%) of the tuberculosis cases being extrapulmonary. On multivariate analysis fever at baseline(HR 8.51, 1.17-61.44), gastrointestinal involvement (HR 4.73, 1.13-19.94), current steroid dose (HR 1.36,1.14-1.62), average cumulative steroid dose per year (HR 1.004, 1.002-1.005) and cyclophosphamide use (HR 2.22, 1.11-4.46) were associated with serious infection (Table 1). Hospitalization rates were significantly higher in those with any serious infection (Rate ratio 2.79, 1.81-3.77). Serious infection led to more damage accrual (SLICC damage index 1.04 vs 0.22). Serious infection-free survival at 1 year, 5 years and 10 years was 84% (79.1-89.2) and 72% (65.4-79.2). There were 19 deaths with infection attributable mortality in 10 (52.6%). Serious infection predisposed to higher overall mortality (Figure 1). Conclusion Serious infections are a major cause of mortality and damage accrual in SLE. Constitutional symptoms, gastrointestinal involvement, current and cumulative steroid dose and cyclophosphamide use predict serious infections. TB prophylaxis in patients with SLE should be considered in endemic areas, especially when using high-dose steroid therapy. REFERENCES: NIL. Acknowledgements: NIL. Disclosure of Interests None Declared.Table 1Cox proportional hazard models for predictors of infectionCovariatesHazard ratio95% CIFever*8.511.17-61.45Serositis0.810.41-1.59Gastrointestinal involvement*4.761.94-19.94Major organ manifestation1.070.49-2.31SLEDAI-2K0.990.95-1.05Daily steroid dose (/10mg)*1.361.14-1.62Mean cumulative steroid dose*1.0041.002-1.005Albumin1.010.66-1.55Absolute lymphocyte count0.990.99-1Cyclophosphamide use*2.221.11-4.46*-significant baseline predictors of serious infection on follow up. Major organ manifestation referes to presence of nephritis or neuropsychiatric lupus.Figure 1A. The Kaplan meier survival curve depicts time to first serious infection. B. The Kaplan meier survival curve shows the overall survival difference between those with any serious infection ever compared to those with no serious infection in the disease course.