Major Organ Involvement Research Articles

Pragmatic targets for moderate/severe SLE and their implications for clinical care and trial design: sustained DORIS or LLDAS for at least 6 months is sufficient while their attainment for at least 24 months ensures high specificity for damage-free progression

ObjectivesTreatment targets in systemic lupus erythematosus (SLE) have been validated in unselected—in terms of severity—cohorts, which limits their generalisability. We assessed remission (Definition of Remission in SLE (DORIS)) and Lupus...

The effect of colchicine on mucocutaneous and joint manifestations of Behçet's disease

Mucocutaneous lesions are the most common manifestation and hallmark of Behçet’s Syndrome (BS). They show a significant impact on patients' quality of life and more importantly, may occur concurrently with major organ involvement. Colchicine is the first-line therapy for patients with mucocutaneous involvement because of its good tolerability and safety profile. The literature lacks clear data on the duration of treatment of mucocutaneous symptoms and the prognosis of patients who interrupt colchicine therapy. This study was planned to observe differences in mucocutaneous findings, joint findings and disease activity, in the colchicine-free period of the patients who were followed up with the diagnosis of BS without active major organ involvement and who were in remission and discontinued colchicine treatment. Our study demonstrated a significant increase in the rate of patients who developed aphthae after the discontinuation of colchicine treatment, which is the primary endpoint, and in the number of newly developed aphthae, which is the secondary endpoint. A significant increase was observed in the rate of patients who developed erythema nodosum in the first and second months. There was no significant difference in the development of genital ulcers after discontinuation of colchicine. The rate of nodular lesion development in female patients increased during the colchicine-free period. Due to the low number of patients who developed joint complaints, we could not demonstrate the efficacy of colchicine in our study.

The mediator role of treatment response on oral health related quality of life in Behçet's syndrome.

The aim of the study was to analyse the effects of Treatment Response with oral ulcers on oral health related quality of life in Behçet's syndrome (BS). In the cross-sectional study, 339 BS patients (F/M: 179/160, mean age: 36,13±9,81 years) were included. Data were collected by clinical examinations and patient reported outcome measures (PROMs) regarding Oral Health Impact Profile-14 (OHIP-14) questionnaire and self-reported Treatment Responses coded by a 5-point Likert-type scale (1: symptoms were cured- 5: symptoms were worsened). Moderated Mediation analysis (MA) was used to understand how oral ulcer activity (independent variable; X) influenced OHIP-14 score (outcome variables, Y) through self-reported Treatment Response (M1) and age (M2) as possible mediator variables (M) and disease course (mucocutaneous and musculuskeletal involvement vs. major organ involvement) as a possible moderator variable (W) on these relationships. In Moderated MA, OHIP-14 score (Y) was mediated by the presence of oral ulcer (X) (p=0.0000), the negative Treatment Response (M1) (p=0.0001) and being young (M2) (p=0.0053) with mucocutaneous involvement (W)(p=0.0039). Self-reported Treatment Response as an underestimated issue has a Mediator role in relation to oral ulceration on oral health related quality of life in the framework of patient empowerment strategies. Therefore, study results give clues to assist physicians and dentists for better understanding of patients' perspective.

Unravelling a Case of Coronary Vasculitis

Background Coronary vasculitis is a rare cause of myocardial infarction through varied mechanisms. We report the case of a 32-year-old female found to have diffuse coronary microaneurysms during treatment for an Inferior ST Elevation Myocardial Infarction (STEMI), with challenges in pinpointing the underlying aetiology. Results Our patient has been diagnosed with a seronegative arthritis and had been initiated on regular Golimumab 4 months prior. She presented with prolonged fever for 4 weeks and inflammatory oligoarthritis with left sacroiliac joint pain. During this admission, Antinuclear antibody was 1:2560 and anti ds DNA was 1:80. She had highly positive Rickettsia conorii IgG titres of 1:128, suggestive of acute infection with Orientia tsustsugamushi. Meropenem and doxycyclin for presumed typhus had no impact on her fever spikes. In the 10th week of the illness, she developed ischaemic chest pain with electrocardiographic changes of inferior STEMI and was thrombolysed. Invasive coronary angiography revealed numerous coronary microaneurysms affecting all major myocardial vessels, with minimal coronary artery disease. Following multidisciplinary discussion, she was treated with intravenous methylprednisolone, antiplatelets, a statin and warfarin for a diagnosis of coronary vasculitis. Repeat angiography showed complete resolution of the microaneurysms. She continues on anticoagulation and has since had no coronary events. Conclusion Typhus and medium vessel vasculitis such as Kawasaki and Polyarteritis Nodosa were potential diagnoses for this presentation. A diagnosis of SLE was established due to the highly specific immunological profile. As there are reports of high Rickettsial titres in autoimmune disease, which alongside the lack of response to doxycyclin makes Typhus unlikely. The possibility of golimumab induced SLE was briefly entertained due to similar reports, but the positivity of ds DNA and major organ involvement made this possibility unlikely. We highlight the cardiac involvement in this case due to its high morbidity on young patients, and the current paucity of knowledge on SLE-related endothelial dysfunction and immune-mediated vascular damage. The role of anticoagulation in this inflammatory milieu too, is controversial. This case highlights a rare presentation of SLE, with an emphasis on coronary vasculitis. It adds to the current knowledge on the complex cardiovascular risk in SLE and highlights ambiguous areas in current management strategies to prompt further research.

Cost-of-illness changes before and after the diagnosis of systemic lupus erythematosus: a nationwide, population-based observational study in Korea

Abstract Objectives To estimate the direct healthcare cost progression from before to after systemic lupus erythematosus (SLE) diagnosis and to compare healthcare costs by disease severity. Methods Patients with incident SLE diagnosed between 2008 and 2018 were identified from the Korean National Health Insurance database. Annual direct healthcare costs for 5 years before and after SLE were estimated and compared with those of age-, sex- and calendar month-matched (1:4) controls, without SLE. Direct healthcare costs were compared by disease severity of SLE using regression analysis. Results Among 11 173 patients with SLE and 45 500 subjects without SLE, annual direct healthcare costs per person increased in the year before SLE diagnosis and peaked in the first year after diagnosis. They were 7.7-fold greater in the SLE patients than in the subjects without SLE ($5871 vs $759). Severe SLE was associated with 3.284-fold (95% CI: 3.075, 3.507) higher annual costs than mild SLE during the year after diagnosis. Older age (age 60–79 years), lupus nephritis, interstitial lung diseases, and comorbidities such as avascular necrosis and chronic kidney disease were associated with higher annual direct healthcare costs (times [95% CI]) in the first year after diagnosis: age 60–69: 1.119 (1.034, 1.211); age 70–79: 1.470 (1.342, 1.611); lupus nephritis: 1.794 (1.711, 1.881); interstitial lung diseases: 1.435 (1.258, 1.638); avascular necrosis: 6.208 (4.541, 8.487); and chronic kidney disease: 1.858 (1.673, 2.064). Conclusion Patients with SLE incurred significantly higher direct healthcare costs than subjects without SLE during the first year after diagnosis. Disease severity, older age, major organ involvements and comorbidities were associated with increased healthcare costs.

Investigation of Biopsychosocial Status, Fatigue, Sleep Quality, Alexithymia, Cognitive Functions, and Quality of Life in Behçet's Disease.

The aim of this study was to compare the effects of Behçet's disease in terms of anxiety, biopsychosocial status, fatigue, sleep quality, alexithymia, cognitive level, and quality of life according to major and minor organ involvement. The study was planned as a single-centre cohort study. Fifty patients diagnosed with Behçet's (mean age 43±11.96 years) were included in the study. The patients were divided into two groups as major organ involvement (uveitis, neuro-Behçet's, or vascular type Behçet's disease) and minor organ involvement (mucocutaneous type Behçet's disease). Biopsychosocial status was evaluated with Biopsychosocial Questionnaire (BETY-BQ), anxiety with Beck Anxiety Inventory (BAI), fatigue with Multidimensional Assessment of Fatigue (MAF) Scale, sleep quality with Pittsburgh Sleep Quality Index (PSQI), alexithymia with Toronto Alexithymia Scale-20 (TAS-20), cognition level with Mini-Mental State Examination (MMSE), and quality of life with Short Form-36 (SF-36). In the comparison according to minor and major organ involvement, there was no significant difference between the groups in BETY-BQ, BAI, MAF, PSQI, TAS-20, MMSE and SF-36 (p>0.05). Behçet's disease negatively effects in parameters such as biopsychosocial status, fatigue, sleep quality, alexithymia and quality of life. The presence of major or minor organ involvement in the patients did not change these negative effects.

Osteonecrosis as a rare musculoskeletal complication in Behcet’s disease- the largest case series with literature review

BackgroundBehcet disease (BD) as a variable vessel vasculitis is mainly characterized by ocular involvement, genital and oral aphthosis, and erythema nodosum. However, major organ involvements including gastrointestinal involvement, nervous system, and vascular involvement are among the severe complications. Osteonecrosis is a rare complication of patients with BD. We aim to report the largest series of BD patients suffering from osteonecrosis.MethodsWe have retrospectively reviewed all patients in Iran Behcet’s Disease Registry and reported those with osteonecrosis. Patients’ medication and clinical features, symptoms, and details of osteonecrosis will also be presented. Furthermore, previously reported cases will also be reviewed.ResultsSeven thousand eight hundred thirty-one patients were diagnosed with BD and registered. 18 patients developed ON with an incidence of 0.22%. The most common involvement during the disease progression was oral aphthosis which appeared in 100% of patients followed by ocular involvement in 85.7% and skin involvement in 71.4%. Vascular, ocular, and nervous system involvements are significantly higher in BD patients with osteonecrosis than the other BD patients. For the management of acute episode of uveitis, deep vein thrombosis, severe gastrointestinal involvement, arterial involvement, nervous system Involvement, and joint involvement high dose of glucocorticoids is indicated.ConclusionsON tends to appear as a multifocal involvement in BD patients, hence, after diagnosis of ON in one joint other possible sites of ON should be investigated.

Factors Underlying Impaired Organ Recovery Despite a Deep Hematologic Response in Patients with Systemic AL Amyloidosis

Background: Amyloid-mediated organ dysfunction is the main determinant of survival for patients with light chain (AL) amyloidosis. Reducing the production of amyloidogenic light chains with plasma cell-directed therapy is a prerequisite for organ response. Despite achieving a hematologic complete response (hemCR), some patients have enduring organ dysfunction. A better grasp of the mechanisms underlying organ recovery is needed, especially as attention moves to novel therapeutics that trigger removal of existing amyloid deposits, and as graded organ response criteria to gauge improvement more precisely than traditional binary systems are adopted. Aims: We designed this study to identify the (1) rates of organ non-response and (2) possible reasons for impaired organ recovery in patients with AL amyloidosis with hemCR after treatment. Methods: Patients with biopsy confirmed AL amyloidosis who presented to our center for post-treatment assessment between February 2019 and June 2023 were included if they had major organ involvement (heart, kidney and/or liver) and were evaluable for organ response (Palladini, 2012). Graded cardiac response was assessed by validated criteria (Muchtar, 2022). We excluded patients who received amyloid fibril-targeted antibody therapies. To eliminate the possibility of insufficient hematologic response as a confounder for organ non-response, we focused only on patients with hemCR. Organ response was measured as best response >3 months from hemCR achievement. Reasons for organ non-response were postulated by our multidisciplinary team after extensive workup and review of clinical data. Results: Among 143 patients with hemCR, the median age at diagnosis was 58 years (range 30-78); 94 (66%) were male; and 24 (17%) identified as non-white race. Kidney, heart and liver involvement was present in 117 (82%), 68 (48%) and 17 (12%) patients, respectively; 54 (38%) had ≥2 major organs affected. Final treatment granting hemCR was high-dose melphalan and stem cell transplantation for 49 (34%); bortezomib-based for 37 (26%); daratumumab monotherapy for 31 (22%); daratumumab-CyBorD for 18 (13%); and an immunomodulatory drug for 8 (6%) patients; 58 (41%) required ≥2 lines of therapy to achieve hemCR. Failure to attain organ response was observed in 40/117 (34%), 19/68 (28%) and 3/17 (18%) of patients with kidney, heart and liver involvement, respectively. Of 42 patients with both kidney and heart involvement, 21 (50%) had concordant responses of both organs; 6 (14%) had concordant non-responses; and 15 (36%) had discordant responses. Among 49 heart responders, 14 (29%) attained CarCR (nadir BNP ≤80 pg/mL); 16 (33%) CarVGPR (>60% reduction); and 19 (39%) CarPR (31-60% reduction); 40/77 (52%) kidney responders attained proteinuria <500 mg/24h. Clinical features of organ non-responders in relation to responders are reported in Table 1. Notably, kidney non-responders had more advanced disease at baseline, whereas heart non-responders more often had lambda-typic amyloidogenic light chains. Among kidney non-responders, 2 had stable and another 2 had rising proteinuria level; the remaining 36 had improved proteinuria but were categorized as non-response due to >25% worsening of eGFR. Among heart non-responders, 5 had stable elevation of BNP and 14 experienced organ progression (BNP increase >30% and >50 pg/mL); 2 required heart transplantation. The two most common factors believed to underlie kidney non-response were permanent kidney damage at diagnosis needing dialysis and treatment-related toxicity (Table 2). For 10 (25%) kidney non-responders, there was no apparent explanation, 7 of whom had detectable measurable residual disease (MRD) by multiparametric flow cytometry. Most cases of heart non-response had no apparent explanation; 6 of these 8 patients had detectable MRD. Conclusions: Despite effective treatment of the plasma cell clone, a considerable number of patients with AL amyloidosis in hemCR have enduring organ dysfunction. We found that the reasons for organ non-response differed across organ systems. Response was not always concordant for all involved organs, suggesting heterogeneity in organ biology in terms of mechanisms for amyloid-mediated injury and intrinsic ability to repair. Careful scrutiny of reasons for organ non-response is warranted before providing further hematologic treatments, which may be ineffective for organ recovery.

Does decision tree analysis predict oral ulcer activity-related factors in patients with Behçet's syndrome?

The study aimed to identify the interactions among treatment protocols and oral ulcer activity related factors in patients with Behçet's syndrome (BS) using the Classification and Regression Tree (CART) algorithm. In this cross-sectional study, 979 patients with BS were included from16 centres in Turkey, Jordan, Brazil and the United Kingdom. In the CART algorithm, activities of oral ulcer (active vs. inactive), genital ulcer (active vs. inactive), cutaneous involvement (active vs. inactive), musculoskeletal involvement (active vs. inactive), gender (male vs. female), disease severity (mucocutaneous and musculoskeletal involvement vs. major organ involvement), smoking habits (current smoker vs. non-smoker), tooth brushing habits (irregular vs. regular), were input variables. The treatment protocols regarding immunosuppressive (IS) or non-IS medications were the target variable used to split from parent nodes to purer child nodes in the study. In mucocutaneous and musculoskeletal involvement (n=538), the ratio of IS use was higher in patients with irregular toothbrushing (ITB) habits (27.1%) than in patients with regular toothbrushing (RTB) habits (14.2%) in oral ulcer activity. In major organ involvement (n=441), male patients with ITB habits were more likely treated with IS medications compared to those with RTB habits (91.6% vs. 77.6%, respectively). Male BS patients on IS who have major organ involvement and oral ulcer activity with mucocutaneous and musculoskeletal involvement have irregular toothbrushing habits. Improved oral hygiene practices should be considered to be an integral part for implementing patient empowerment strategies for BS.

A Comparison of Adult and Juvenile Behcet Patients and a Look at Clinical Trends: Retrospective Data from a Turkish Follow-Up Cohort Study

Background: Previous reports indicate that juvenile Behçet’s disease (BD) may have a different course than adult BD. However, as a direct comparison with adult Behçet patients has only been made in a limited number of studies, the issue is still controversial. Objectives: The primary aim of our study was to compare clinical manifestations in a large cohort of juvenile and adult Behçet patients registered in a single centre. The secondary aim of our study was to compare the data of newly diagnosed patients registered between 1998 and 2020 with the data of those registered between 1976 and 1997. Methods: Data were collected retrospectively from medical records of patients registered between 1998 and 2020. Juvenile BD was defined as fulfilment of International Criteria for Behçet’s Disease at or before 16 years of age. Results: A similar course of disease was noted in juvenile and adult Behçet patients with no significant difference in the frequency of mucocutaneous findings, major organ involvement, and positivity of the pathergy test. A comparison of the periods, 1976–1997 and 1998–2020, revealed no significant difference in the prevalence of mucocutaneous lesions and major organ involvement. Conclusions: Our results indicate that juvenile and adult Behçet patients have a similar course with a similar frequency of clinical manifestations. Contrary to reports suggesting an overall tendency to milder disease over time, no decrease in the risk of major organ involvements was observed. A significant trend towards a decline in pathergy test positivity was noted.

Comparative Effectiveness of Rituximab- Versus Cyclophosphamide-Based Remission Induction Strategies in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis for the Risk of Kidney Failure and Mortality.

To compare rituximab- versus cyclophosphamide-based remission induction strategies for the long-term risks of kidney failure and death in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a real-world cohort. We performed a cohort study using the Mass General Brigham AAV Cohort, which includes proteinase 3-ANCA+ and myeloperoxidase (MPO)-ANCA+ AAV patients diagnosed from January 1, 2002 to December 31, 2019. We included cases in which the initial remission induction strategy was based either on rituximab or cyclophosphamide. The primary outcome was the composite outcome of kidney failure or death. We used multivariable Cox proportional hazards models and propensity score-matched analyses to assess the association of rituximab- versus cyclophosphamide-based treatment strategies with the composite outcome of kidney failure or death. Of 595 included patients, 352 patients (~60%) received rituximab-based and 243 patients (~40%) received cyclophosphamide-based regimens. The mean age was 61 years, 58% of patients were female, 70% of patients were MPO-ANCA+, and 69% of patients had renal involvement (median estimated glomerular filtration rate 37.3 ml/minute/1.73 m2 ). There were 133 events at 5 years, and the incidence rates in rituximab- and cyclophosphamide-based regimens were 6.8 and 6.1 per 100 person-years, respectively. The risk of kidney failure or death was similar in both groups in multivariable-adjusted analyses (hazard ratio [HR] 1.03 [95% confidence interval (95% CI) 0.55-1.93]) and in propensity score-matched analyses (HR 1.05 [95% CI 0.55-1.99]) at 5 years. Our findings were similar when outcomes were assessed at 1 and 2 years as well as in subgroups stratified according to renal involvement and severity as well as major organ involvement. Rituximab- and cyclophosphamide-based remission induction strategies for AAV are associated with similar risks of kidney failure and death.

A patient-driven registry on Behçet's disease: the AIDA for patients pilot project.

This paper describes the creation and preliminary results of a patient-driven registry for the collection of patient-reported outcomes (PROs) and patient-reported experiences (PREs) in Behçet's disease (BD). The project was coordinated by the University of Siena and the Italian patient advocacy organization SIMBA (Associazione Italiana Sindrome e Malattia di Behçet), in the context of the AIDA (AutoInflammatory Diseases Alliance) Network programme. Quality of life, fatigue, socioeconomic impact of the disease and therapeutic adherence were selected as core domains to include in the registry. Respondents were reached via SIMBA communication channels in 167 cases (83.5%) and the AIDA Network affiliated clinical centers in 33 cases (16.5%). The median value of the Behçet's Disease Quality of Life (BDQoL) score was 14 (IQR 11, range 0-30), indicating a medium quality of life, and the median Global Fatigue Index (GFI) was 38.7 (IQR 10.9, range 1-50), expressing a significant level of fatigue. The mean Beliefs about Medicines Questionnaire (BMQ) necessity-concern differential was 0.9 ± 1.1 (range - 1.8-4), showing that the registry participants prioritized necessity belief over concerns to a limited extent. As for the socioeconomic impact of BD, in 104 out of 187 cases (55.6%), patients had to pay from their own pocket for medical exams required to reach the diagnosis. The low family socioeconomic status (p < 0.001), the presence of any major organ involvement (p < 0.031), the presence of gastro-intestinal (p < 0.001), neurological (p = 0.012) and musculoskeletal (p = 0.022) symptoms, recurrent fever (p = 0.002), and headache (p < 0.001) were associated to a higher number of accesses to the healthcare system. Multiple linear regression showed that the BDQoL score could significantly predict the global socioeconomic impact of BD (F = 14.519, OR 1.162 [CI 0.557-1.766], p < 0.001). Preliminary results from the AIDA for Patients BD registry were consistent with data available in the literature, confirming that PROs and PREs could be easily provided by the patient remotely to integrate physician-driven registries with complementary and reliable information.

Risk and Factors associated with disease manifestations in systemic lupus erythematosus - lupus nephritis (RIFLE-LN): a ten-year risk prediction strategy derived from a cohort of 1652 patients.

Lupus nephritis (LN) remains one of the most severe manifestations in patients with systemic lupus erythematosus (SLE). Onset and overall LN risk among SLE patients remains considerably difficult to predict. Utilizing a territory-wide longitudinal cohort of over 10 years serial follow-up data, we developed and validated a risk stratification strategy to predict LN risk among Chinese SLE patients - Risk and Factors associated with disease manifestations in systemic Lupus Erythematosus - Lupus Nephritis (RIFLE-LN). Demographic and longitudinal data including autoantibody profiles, clinical manifestations, major organ involvement, LN biopsy results and outcomes were documented. Association analysis was performed to identify factors associated with LN. Regression modelling was used to develop a prediction model for 10-year risk of LN and thereafter validated. A total of 1652 patients were recruited: 1382 patients were assigned for training and validation of the RIFLE-LN model; while 270 were assigned for testing. The median follow-up duration was 21 years. In the training and validation cohort, 845 (61%) of SLE patients developed LN. Cox regression and log rank test showed significant positive association between male sex, age of SLE onset and anti-dsDNA positivity. These factors were thereafter used to develop RIFLE-LN. The algorithm was tested in 270 independent patients and showed good performance (AUC = 0·70). By using male sex, anti-dsDNA positivity, age of SLE onset and SLE duration; RIFLE-LN can predict LN among Chinese SLE patients with good performance. We advocate its potential utility in guiding clinical management and disease monitoring. Further validation studies in independent cohorts are required.

P457 ISCHEMIC STROKE AS A FIRST PRESENTATION OF ATYPICAL ENDOCARDITIS AFTER SINGLE CORONARY ARTERY BYPASS GRAFTING (CABG) AND MITRAL VALVE REPLACEMENT

Abstract A 71–year–old patient with a history of prostatic cancer, recently underwent CABG and mitral valve replacement and during cardiac rehabilitation (CR) was diagnosed with a cryptogenic stroke while on treatment with oral anticoagulant and antiaggregants. It is worth mentioning that during hospitalization he suffered several feverish episodes without major organ involvement with the only exception of the one related to the chest scar infection. He was admitted to CR department with high fever (38.5 C) and hemocultures were positive for Staphylococcus epidermidis which was also isolated from the chest scar. The transthoracic echocardiogram executed at the admission did not show any pathological alteration. After 5 days of antibiotic therapy and optimized medical therapy, he had an ischemic stroke. NIHSS score was initially 10. Acute presentation of ischemic stroke was peculiar: he had left hemiparesis with Babinski sign, but a concomitant Broca‘s aphasia, thus suggesting multiple areas of cerebral ischemia. He was evaluated with a basal computerized tomography (CT) scan which didn’t show any sign of ischemic stroke and NIHSS score completely reversed after 30 minutes to 0: this was more suggestive for a transient ischemic attack rather than ischemic stroke but despite the negative CT scan, the subsequent cerebral magnetic resonance imaging showed ischemic signs localized in different vascular territories. Supra–aortic vessels were normal. Therefore, we performed a transesophageal echocardiography (TEE) which showed a peculiar vegetation over the mitral valve, presenting more as a filament rather than typical vegetation. Despite the absence of fever, negative PCR, negative procalcitonine and white blood cells within the normal limits, we performed hemocultures and Staphylococcus haemolyticus was isolated. Antibiotic therapy was immediately started; however, after three weeks of appropriate therapy the TEE exam showed an evolution of the valve’s lesion which required surgical revision. Conclusion This case highlights how ischemic stroke related to multiple ischemic foci may be the only sign of an underlying endocarditis that caused septic embolization. Indeed, the patient was completely asymptomatic, did not have fever, inflammatory markers were negative and only clinical investigations to understand the nature of his stroke allowed us to make the diagnosis of endocarditis.

OA12 Comparing disease manifestations and outcomes in juvenile-onset SLE and adult-onset SLE patients: a nested case-control study within a Singapore cohort

Abstract Background/Aims To compare disease manifestations and outcomes of juvenile-onset SLE (jSLE) and adult-onset SLE (aSLE) patients using a nested case-control study of patients in a Singapore cohort. Methods A prospective cohort of SLE patients was established at Tan Tock Seng Hospital from 1 January 2002 to 31 December 2017. Sociodemographic, clinical, laboratory and treatment data were collected according to a standardised protocol. jSLE patients (≤18 years old) were selected from this cohort and matched for gender and disease duration in a 1:1 ratio with aSLE patients. Data from the enrolment visit (V0) and last visit (VL) were analysed in this study. Results There were 148 jSLE patients with sufficient information for analysis who were matched with 148 aSLE patients. Fever and lymphadenopathy (p &amp;lt; 0.001) and hypocomplementemia (p = 0.002 at V0) were significantly more common in jSLE, while cardiovascular manifestations were significantly more common in aSLE patients (p = 0.008 at VL). Disease activity measured by the SLE Disease Activity Index (SLEDAI) was higher in the jSLE group at V0 (median SLEDAI 4 vs 2, p=0.05) and at VL (median SLEDAI 2.5 vs 0, p = 0.007). A significantly higher proportion of jSLE patients received immunosuppressants (intravenous cyclophosphamide, mycophenolate mofetil, azathioprine and ciclosporin) (p = 0.003 at V0, p &amp;lt; 0.001 at VL) and intravenous methylprednisolone (p &amp;lt; 0.001 at V0 and VL) compared to aSLE patients. Conclusion A higher proportion of jSLE patients have fever, lymphadenopathy, hypocomplementemia, or more active disease requiring greater use of immunosuppressants compared to aSLE patients. Early diagnosis and treatment of jSLE may prevent development of major organ involvement, in particular renal and neuropsychiatric. Disclosure B.Y. Thong: None. Y. Khong: None. X. Lim: None. H. Howe: None.

Assessment of longitudinal serum neutrophil extracellular trap–inducing activity in anti-neutrophil cytoplasmic antibody–associated vasculitis and glomerulonephritis in a prospective cohort using a novel bio-impedance technique

Neutrophil extracellular traps (NET) have been implicated in the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Here, we developed a novel, label-free, high-throughput bio-impedance technique to effectively measure serum NET-inducing activity. Using this technique, NET-inducing activity of serum derived from patients with AAV was assessed in a prospective cohort of 62 patients presenting with active AAV with major organ involvement. Thirty-five patients presented with new and 27 patients presented with relapsing AAV, of whom 38 had kidney and/or 31 had lung involvement. NET-inducing activity was assessed at diagnosis of active AAV (time zero), during the first 6 weeks of treatment, and after 6 months of treatment. Forty-seven patients revealed elevated NET-inducing activity at time zero. After initiation of immunosuppressive treatment, NET-inducing activity was reduced at six weeks. A subsequent increase at six months could potentially identify patients with relapsing disease (hazard ratio, 11.45 [interquartile range 1.36-96.74]). NET-inducing activity at time zero correlated with kidney function and proteinuria. Importantly, in kidney tissue, NETs co-localized with lesions typical of ANCA-associated glomerulonephritis and even correlated with systemic serum NET-inducing activity. Thus, our prospective data corroborate the importance of NET formation in AAV and ANCA-associated glomerulonephritis and the potential of longitudinal evaluation, as monitored by our novel bio-impedance assay and detailed histological evaluation.

Clinical phenotype in scleroderma patients based on autoantibodies.

We aimed to characterize the clinical phenotype of patients with SSc based on autoantibodies (topoisomerase antibody (Scl-70), ACA and ANA). We included patients with SSc who fulfilled the 2013 ACR/EULAR criteria, with disease duration ≤15 years. Six groups of patients were defined: ACA-lcSSC, Scl-70-lcSSc, ANA-lcSSc, Scl-70-dcSSc, ANA-dcSSc and ACA-dcSSc patients. We compared the different groups of patients. In the ANA subgroup, we included patients negative for SSc-specific antibodies (Scl-70 and ACA). We assessed the following: risk of interstitial lung disease (ILD), myositis, scleroderma renal crisis, cardiac involvement, gastrointestinal involvement, pulmonary hypertension, treatment, cancer and all-cause mortality. One hundred and thirteen SSc patients were included: 72 (64%) females, 82 (73%) lcSSc and 31 (27%) dcSSc. Among patients with lcSSc, 43 (52%) were ACA+, 16 (19%) Scl-70+ and 23 (28%) ANA+, and among patients with dcSSc, 13 (42%) patients were Scl-70+, 11 (35%) ANA+ and 7 (23%) ACA+. Scl-70-lcSSc patients had a significantly shorter time from RP to SSc diagnosis (P = 0.04), higher CRP (P = 0.04), renal scleroderma crisis (P = 0.02), ILD (P = 0.03) and diastolic dysfunction (P = 0.04) than ANA-lcSSc patients. Scl-70-dcSSc patients had a higher rate of myositis (P = 0.04), renal crisis (P = 0.03), CRP elevation (P = 0.002), ILD (P = 0.04), pericardial effusion (P = 0.03) and cancer (P = 0.04) than ANA-dcSSc patients. The risk of ILD was higher in Scl-70 patients during the first 10 years than in ACA+ and ANA+ patients (P = 0.03 and P = 0.02, respectively). The risk of major organ involvement was higher in Scl-70+ patients, followed by ANA+ and ACA+ patients, throughout 15 years of follow-up. All-cause mortality was higher in dcSSc patients than in lcSSc patients, but no differences were found regarding antibody positivity. We have characterized the clinical phenotype of patients based on autoantibodies: Scl-70 patients show the greatest risk of major organ involvement, followed by ANA+ patients and ACA+ patients. The risk of ILD in Scl-70+ patients suggests that these patients should be monitored closely, irrespective of skin involvement. These results might provide new ways to help with the early diagnosis and management and in assessment of the prognosis of the disease.

Treat to target and tight control: Could be a new approach in the treatment of sarcoidosis?

Sarcoidosis is a chronic granulomatous disease with multisystemic involvement. Although it is accepted as a benign disease, it can sometimes cause life-threatening organ (heart, brain) involvement that determines the prognosis of the disease. There are conflicting opinions about the treatment of the disease. In the generally accepted treatment approach the "step-by-step" model has gained weight. According to this approach, corticosteroids (CS) drugs alone are preferred in the first step in patients who require treatment. In the second step, immunosuppressive drugs (IS) are used in patients who do not respond to CS and/or have contraindications to CS use, and biologics (TNF-alpha inhibitors) are used in the third step. This treatment approach may be valid in cases with mild sarcoidosis. However, although sarcoidosis is considered a benign and self-limiting disease in some major organ involvement, the "step-by-step" approach may be a treatment option that puts the patient's life in danger. In such selected patients, much more rigorous, early and combined treatment approaches that definitely include CS, IS or biologic drugs may be required. In selected sarcoidosis patients with high risk, early diagnosis, "treat-to-target" (T2T) and "tight control" follow-up of patients seems to be a rational approach. This article reviews the "step-down" treatment regimens in light of recent literature data and hypothesizes that the T2T model may be a probable new treatment approach in patients with sarcoidosis.

Earlier and more aggressive treatment with biologics may prevent relapses and further new organ involvement in Behçet's disease

ObjectiveImmunosuppressives (IS) are the choice of treatment for major organ involvement in Behçet's disease (BD). In this study, we aimed to investigate the relapse rate and new major organ development in BD under ISs during long-term follow-up. MethodsThe files of 1114 BD patients followed in Marmara University Behçet's Clinic were analyzed retrospectively. Patients with a follow-up less than 6 months were excluded. Conventional IS and biologic treatment courses were compared. ‘Events under IS’ were defined as a relapse of the same organ and/or new major organ development in patients receiving ISs. ResultsAmong 806 patients included in the final analysis (male: 56%, age at diagnosis: 29 (23–35) years, median follow-up time: 68 (33–106) months). Major organ involvement was present in 232 (50.5%) patients at diagnosis, and 227 (49.5%) developed new major organ involvement during follow-up. Major organ involvement developed earlier in males (p = 0.012) and in patients with a first-degree relative history of BD (p = 0.066). ISs were given mostly for major organ involvement (86.8%, n = 440). Overall, 36% of the patients had a relapse or new major organ involvement under ISs (relapse: 30.9%, new major organ involvement: 11.6%.) ‘Events under IS’ (35.5% vs 20.8%, p = 0.004), and relapses (29.3% vs 13.9%, p = 0.001) were more common with conventional ISs compared to biologics. ConclusionAny major event under ISs was less common with biologics compared to conventional ISs in patients with BD. These results suggest that earlier and more aggressive treatment may be an option in BD patients who had the highest risk for severe disease course.

Anti-dsDNA B-Cell ELISpot as a Monitoring and Flare Prediction Tool in SLE Patients.

Anti-dsDNA autoantibodies quantification and complement levels are widely used to monitor disease activity in systemic lupus erythematosus (SLE). However, better biomarkers are still needed. We hypothesised whether the dsDNA antibody-secreting B-cells could be a complementary biomarker in disease activity and prognosis of SLE patients. Fifty-two SLE patients were enrolled and followed for up to 12 months. Additionally, 39 controls were included. An activity cut-off (comparing active and non-active patients according to clinical SLEDAI-2K) was established for SLE-ELISpot, chemiluminescence and Crithidia luciliae indirect immunofluorescence tests (≥11.24, ≥374.1 and ≥1, respectively). Assays performances together with complement status were compared regarding major organ involvement at the inclusion and flare-up risk prediction after follow-up. SLE-ELISpot showed the best performance in identifying active patients. High SLE-ELISpot results were associated with haematological involvement and, after follow-up, with an increased hazard ratio for disease flare-up (3.4) and especially renal flare (6.5). Additionally, the combination of hypocomplementemia and high SLE-ELISpot results increased those risks up to 5.2 and 32.9, respectively. SLE-ELISpot offers complementary information to anti-dsDNA autoantibodies to evaluate the risk of a flare-up in the following year. In some cases, adding SLE-ELISpot to the current follow-up protocol for SLE patients can improve clinicians' personalised care decisions.