Systemic Lupus Erythematosus Damage Research Articles

Leukocyte Telomere Length and Childhood Onset of Systemic Lupus Erythematosus in the Black Women's Experiences Living with Lupus Study.

ObjectiveThe study objective was to compare leukocyte telomere length (LTL) among patients with systemic lupus erythematosus (SLE) diagnosed in childhood versus adulthood.MethodsData are from the Black Women's Experiences Living with Lupus (BeWELL) study. Multivariable linear regression analyses that examined childhood diagnosis of SLE (diagnosed before 18 years of age), age, and their interaction in relationship to LTL were conducted, adjusting for a range of demographic, socioeconomic, and health‐related covariates.ResultsThe total analytic sample size was 415. Forty participants (9.6%) were diagnosed in childhood. There was no main effect of childhood diagnosis on LTL (b = 0.007; 95% confidence interval [CI]: −0.089 to 0.103). However, the interaction between age and childhood diagnosis was significant (b = −0.008; 95% CI: −0.016 to −0.001), indicating a steeper inverse association between age and LTL among those diagnosed in childhood compared with those diagnosed in adulthood. This interaction remained statistically significant (P = 0.024) after controlling for disease duration measured dichotomously (less than 10 years vs. 10 years or more); it was marginally significant (P = 0.083) when controlling for disease duration measured continuously.ConclusionThis cross‐sectional analysis suggests that Black women with childhood‐onset SLE may undergo accelerated LTL shortening compared with their adult‐onset counterparts. This relationship persisted even after controlling for differences in SLE damage and disease duration. These findings inform research on immunosenescence mechanisms of SLE.

The role of anti-ribosomal P autoantibodies in the prediction of neuropsychiatric damage in systemic lupus erythematosus based on CSTAR cohort (XIV).

To identify the predictive value of anti-ribosomal P protein (anti-RibP) antibodies on the accrual of neuropsychiatric damage in systemic lupus erythematosus (SLE) patients in a large cohort in the Chinese SLE Treatment and Research group (CSTAR) database. This single-center prospective study was conducted based on data from the CSTAR registry. At baseline, we collected demographic characteristics, autoantibody profiles, clinical manifestations, disease activity status, and organ damage. Follow-up data were collected by reviewing clinical records and telephone interviews. Anti-RibP antibodies were identified by immunoblot containing all three native RibP (P0, P1, P2) antigenic proteins. Of 2395 SLE patients with complete follow-up data, 659 (27.5%) were anti-RibP antibody positive. At baseline, positive anti-RibP antibodies were associated with a higher proportion of neurological involvement (𝑃 < 0.05). During follow-up, patients with positive anti-RibP antibodies were more likely to accumulate neuropsychiatric damage (adjusted HR = 3.8, 95% CI 2.7-57), p < 0.001). What is more, the cumulative probability of new-onset neurological involvement increased gradually in anti-RibP antibody-positive patients. Anti-RibP antibodies can provide information about not only organ involvement at baseline, but also neuropsychiatric damage accrual and new-onset neurological involvement during follow-up. We suggested that anti-RibP antibody detection should be done in the newly diagnosed SLE patients to predict organ involvement and even the accumulation of neuropsychiatric damage. • Positive anti-RibP antibodies were associated with baseline neurological involvement. • Baseline positive anti-RibP antibodies can predict the neuropsychiatric damage accrual and new-onset neurological involvement.

An evaluation of costs associated with overall organ damage in patients with systemic lupus erythematosus in the United States.

IntroductionApproximately 33–50% of patients with systemic lupus erythematosus (SLE) develop organ damage within 5 years of diagnosis. Real-world studies that capture the healthcare resource utilization (HCRU) and costs associated with SLE-related organ damage are limited. The aim of this study was to evaluate HCRU and costs associated with organ damage in patients with SLE in the USA.MethodsThis retrospective study (GSK study 208380) used the PharMetrics Plus administrative claims database from 1 January 2008 to 30 June 2019. Patients with SLE and organ damage were identified using International Classification of Diseases (ICD)-9/10 codes derived from the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. The first observed diagnosis of organ damage was designated as the index date. Selection criteria included: ≥18 years of age; ≥1 inpatient or ≥2 outpatient claims for SLE (≥30 days apart before the index date; ICD-9: 710.0 or ICD-10: M32, excluding M32.0); ≥1 inpatient or ≥3 outpatient claims for organ damage within 6 months for the same organ system code; continuous enrollment of 12 months both pre- and post-index date. The proportion of patients with new organ damage, disease severity, SLE flares, SLE-related medication patterns, HCRU and all-cause costs (2018 US$) were assessed 12 months pre- and post-index date.ResultsOf the 360,803 patients with a diagnosis of SLE, 8952 patients met the inclusion criteria for the presence of new organ damage. Mean (standard deviation (SD)) age was 46.4 (12.2) years and 92% of patients were female. The most common sites of organ damage were neuropsychiatric (22.0%), ocular (12.9%), and cardiovascular (11.4%). Disease severity and proportion of moderate/severe flare episodes significantly increased from pre- to post-index date (p < 0.0001). Overall, SLE-related medication patterns were similar pre- versus post-index date. Inpatient, emergency department and outpatient claims increased from pre- to post-index date and mean (SD) all-cause costs were 71% higher post- versus pre-index date ($26,998 [57,982] vs $15,746 [29,637], respectively).Conclusions:The economic impact associated with organ damage in patients with SLE is profound and reducing or preventing organ damage will be pivotal in alleviating the burden for patients and healthcare providers.

Association of High Calcitriol Serum Levels and Its Hydroxylation Efficiency Ratio with Disease Risk in SLE Patients with Vitamin D Deficiency.

Vitamin D (calcidiol) deficiency in systemic lupus erythematosus (SLE) is more frequent than in healthy subjects (HS); it is associated with clinical activity and damage in SLE. Although calcidiol is considered the best indicator of the vitamin D serum status, its deficiency could not reflect its hydroxylation efficiency ratio and calcitriol serum status. This study was aimed at assessing the association of calcidiol and calcitriol serum levels and its hydroxylation efficiency ratio with the risk to clinical and renal disease activities in SLE patients. A cross-sectional study was conducted in 308 SLE and HS women; calcidiol and calcitriol serum levels were evaluated by immunoassays. SLE patients showed lower calcidiol serum levels vs. HS (21.2 vs. 24.2 ng/mL; p < 0.001). Active SLE patients presented higher calcidiol/calcitriol ratio scores vs. inactive SLE patients (2.78 vs. 1.92 pg/ng; p = 0.02), and SLE patients with renal disease activity showed a pattern of calcidiol-deficient levels (19.5 vs. 25.3 ng/mL; p < 0.04) with higher calcitriol levels (47 pg/mL vs. 41.5 pg/mL; p = 0.02) and calcidiol/calcitriol ratio scores (2.13 vs. 1.54 pg/ng; p < 0.02) compared to SLE patients without renal disease activity. Calcidiol levels were negatively correlated with calcitriol levels (r = −0.26; p = 0.001) and urine proteins (mg/dL) (r = −0.39; p < 0.01). Regarding calcitriol levels, it was positively correlated with the blood lymphocyte count (r = 0.30; p < 0.001) and negatively correlated with the glomerular filtration rate (r = −0.28; p = 0.001). Moreover, the calcitriol/calcidiol ratio was positively correlated with urine proteins (r = 0.38; p < 0.01). The calcidiol deficiency (OR = 2.27; 95% CI = 1.15-4.49; p < 0.01), high calcitriol levels (T3rd, OR = 4.19, 95% CI = 2.23-7.90; p < 0.001), and a high calcitriol/calcidiol ratio score (T3rd, OR = 5.93, 95% CI: 3.08-11.5; p < 0.001) were associated with the risk for SLE. In conclusion, a pattern of calcidiol deficiency with high calcitriol serum levels and a high vitamin D hydroxylation efficiency ratio was associated with disease risk in SLE patients.

Tissue resident cell processes determine organ damage in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects almost any organ. Multiple immunological abnormalities involving every domain of the immune system contribute to the expression of the disease. It is now recognized that elements of the immune system instigate processes in tissue resident cells which execute organ damage. Although correction of ongoing immune aberrations is important in the control of disease activity, targeting tissue specific injurious processes may prove desirable in limiting organ damage.

2019-EULAR/ACR classification criteria domains at diagnosis: predictive factors of long-term damage in systemic lupus erythematosus.

The objective of this study is to assess the role of the 2019-European League Against Rheumatism/American College of Rheumatology (2019-EULAR/ACR) classification criteria at diagnosis and its domains in predicting long-term damage in systemic lupus erythematosus(SLE). We performed a retrospective analysis using an electronic chart database utilized in routine clinical care of SLE patients and established in 2000 in a tertiary hospital. Two hundred and nine consecutive SLE patients with disease onset ≥18 years old and long disease duration were included. Cumulative damage at the last visit was scored using the SLICC/ACR-Damage Index (SDI). The median age at SLE diagnosis was 28 years (18-63), disease duration was 14 years (8-25), and 88% were females. Damage (SDI≥1) was observed in 116/209 (55%). Patients with (SDI≥1, n=116) and without damage (SDI=0, n=93) had similar median disease duration [14 (8-25) vs. 12 (8-25) years, p=0.090] and age at diagnosis [23 (18-55) vs. 23 (18-56) years, p=0.998]. No correlation was observed between total 2019-EULAR/ACR score at diagnosis and SDI at last visit (r=0.007, p=0.913). Presence of renal domain at diagnosis was associated with renal damage at last visit (OR=3.6, 95%CI 1.2-10.4, p=0.017) and antiphospholipid antibodies domain predicted neuropsychiatric damage (OR=3.0, 95%CI 1.2-7.6, p=0.015). A ROC analysis identified that a cut-off >24 in 2019-EULAR/ACR score could predict a trend for renal damage (p=0.077) with a lower renal survival (Kaplan-Meier curve) for patients above this limit (p=0.029). A multivariate logistic regression analysis revealed that 2019-EULAR/ACR score >24 at diagnosis (OR 4.583, 95%CI 1.052-19.962, p=0.043) was independently associated with renal damage. Specific domains in the 2019-EULAR/ACR criteria at diagnosis were associated with long-term organ-specific damage, particularly renal and neuropsychiatric harm. A 2019-EULAR/ACR score >24 predicted worse renal survival. Key Points • Presence of renal domain of the 2019-EULAR/ACR classification criteria at diagnosis was associated with long-term renal damage. • Presence of antiphospholipid antibodies domain at diagnosis was associated with long-term neuropsychiatric damage. • A 2019-EULAR/ACR overall score >24 at diagnosis was independently associated with renal damage and predicted worse renal long-term survival.

Interleukin-23 serum level in systemic lupus erythematosus patients: Relation to disease activity and different disease parameters

Aim of the workTo assess serum level of interleukin 23 (IL-23) in systemic lupus erythematosus (SLE) patients and to evaluate its association with disease parameters and activity. Patients and methodsThe study involved 40 SLE patients and 40 controls. The SLE disease activity index (SLEDAI) and damage index (SDI) were assessed. Serum level of IL-23 was measured byenzyme linked immunosorbant assay (ELISA). ResultsPatients were 38 females and 2 males (F:M 19:1),with a mean age of 31.3 ± 7.5 years (17–50 years) and disease duration 4.8 ± 2.9 years (1–13 years). Their mean SLEDAI was 14.3 ± 6.8 (3–32) and SDI 0.4 ± 0.5 (0–2). 85% of patients had photosensitivity, alopecia in 60%, malar rash in 57.5%, oral ulcers 52.5%, arthralgia/arthritis 47.5%, serositis and lupus nephritis in 27.5%, discoid rash in 22.5% and neuropsychiatric in 2.5%. Mean serum level of IL-23 was significantly elevated in patients (107.9 ± 17.3 ng/L; 72.7–165.5 ng/mL) compared to controls (91.6 ± 19.1 ng/L;57.6–140.3 ng/mL; p < 0.001). IL-23 was significantly elevated in patients with oral ulcers (p = 0.03), arthritis (p < 0.001), lupus nephritis (p = 0.01), alopecia (p = 0.02) and positive anti-dsDNA (p < 0.001). IL-23 significantly correlated with SLEDAI(r = 0.89, p < 0.001), complement C3 (r = -0.55, p < 0.001) and C4 (r = -0.5, p = 0.001). IL-23 could significantly predict SLE at a cut-off 93.1 ng/L (sensitivity 80% and specificity 55%). ConclusionIL-23 may be involved in the pathogenesis of SLE; especially in renal, mucocutaneous and musculoskeletal manifestations and it can be used as a disease activity biomarker. These findings support the possibility of its use as a therapeutic target in SLE.

Systemic lupus erythematosus children in Egypt: Homeland spectrum amid the global situation.

This study aims to present the manifestations of juvenile systemic lupus erythematosus (JSLE) across Egypt, to focus on age at onset and gender-driven influence on disease characteristics, and to compare findings to other countries. The study included 404 Egyptian children with systemic lupus erythematosus (SLE) presenting to one of the specialized rheumatology centers corresponding to 13 major governorates. Juvenile cases age was ≤ 16°years at the time of recruitment. The SLE Disease Activity Index (SLEDAI) and damage index (DI) were assessed. The mean age was 13.2 ± 2.4°years; 355 females and 49 males (7.2:1), and the disease duration was 2.3 ± 1.6years, while age at disease onset was 11.1 ± 2.5°years. Their SLEDAI was 13.5 ± 12.3, and DI, 0.36 ± 0.78. The overall estimated prevalence of childhood-SLE patients in the recruited cohort in Egypt was 1/100,000 population (0.24/100000 males and 1.8/100000 females). 7.4% developed pre-pubertal SLE (≤ 7years); 73.3%, peri-pubertal; and 19.3% during early adolescence. The differences according to age group were equal for gender and clinical manifestations except skin lesions present in 59.3% of pre-pubertal onset, 74.6% of peri-pubertal, and 84.2% of adolescents (p = 0.029), and renal involvement in 73.8% of peripubertal, 62.1% of pre-pubertal and 58.9% of adolescents (p = 0.03). Laboratory investigations, SLEDAI, and DI were similar among age categories. Lupus nephritis was more common in Egypt compared to JSLE from other countries. Our large multicenter study identified that female gender influenced disease characteristics with more frequent skin involvement. Skin lesions were significantly higher in adolescents, while renal involvement in peri-pubertal children.

Люпус-нефрит: сучасна парадигма лікування

Вовчаковий нефрит є найпоширенішим та життєзагрозливим проявом системного червоного вовчака і продовжує зумовлювати високий відсоток термінальної ниркової недостатності. У даному огляді описуються сучасне лікування вовчакового нефриту, а також нові терапевтичні стратегії. Діагностика ураження нирок при системному червоному вовчаку (люпус-нефрит), згідно з рекомендаціями ACR, базується на таких критеріях: клінічні та лабораторні прояви у вигляді протеїнурії &gt; 0,5 г на добу (або більше 3 «+» при визначенні тест-смужкою) і/або наявність клітинних скупчень, включаючи скупчення еритроцитів і циліндрів (гемоглобінових, зернистих, тубулярних або змішаних). Додатковим критерієм є результати гістологічного дослідження біоптату нирки з підтвердженням наявності характерного для люпус-нефриту імунокомплексного ураження нирок. Тактика ведення пацієнтів із вовчаковим нефритом складається з двох послідовних фаз: початкової (індукційної) і підтримуючої, коли використовуються поєднання глюкокортикоїдів і імуносупресорів. Під час індукційної фази проводиться інтенсивне лікування глюкокортикоїдами в комбінації з іншими імунодепресантами для швидкого пригнічення імунокомплексного запалення нирок і припинення розвитку їх пошкодження. Метою даного підходу і головним завданням індукційної терапії є відновлення ниркової функції і індукція ремісії шляхом контролю імунологічної активності процесу. Підтримуюча терапія застосовується для закріплення ремісії і запобігання загостренням шляхом використання препаратів або режимів лікування з меншим ризиком ускладнень. Незважаючи на невтішні результати декількох недавніх досліджень, нові методи лікування, спрямовані на різні імунологічні шляхи, активно вивчаються при вовчаковому нефриті. Найбільш перспективним напрямком є терапія, спрямована на В-клітини. Поглиблення розуміння патогенезу вовчакового нефриту, розробка нових методів лікування та оптимізація дизайну клінічних випробувань забезпечать успішний розвиток і впровадження нових ліків при вовчаку.

Abstract MP24: Selective Activation Of DMV Neurons Improves Renal Injury In Systemic Lupus Erythematosus

The cholinergic anti-inflammatory pathway is a vagally-mediated mechanism that controls inflammation. Our published data suggest that an impaired cholinergic anti-inflammatory pathway contributes to hypertension and renal disease in female mice with systemic lupus erythematosus (SLE), since pharmacological potentiation of the efferent vagus via administration of galantamine reduces renal inflammation, mean arterial pressure (MAP) and glomerulosclerosis. The aim of the current study is to selectively target neurons within the dorsal motor nucleus of the vagus (DMV) to stimulate the efferent vagus and the cholinergic anti-inflammatory pathway using designer receptors exclusively activated by designer drugs (DREADDs). We hypothesized that selective activation of DMV neurons would reduce inflammation, eliminating the associated end organ damage in SLE. To study this, female SLE ( NZBWF1 ) and parental control ( NZW ) mice received bilateral microinjections of pAAV-hSyn-hM3D(Gq)-mCherry or pAAV-hSyn-mCherry (control virus) into the DMV at 31 weeks of age using the following coordinates with calamus as reference: 0 mm caudal, 0.25 mm lateral and 0.48 mm ventral. Two weeks post-microinjection, DREADD agonist CNO (3mg/kg) was administered subcutaneously for 2 weeks starting at 33 weeks. At 35 weeks, mice were housed in metabolic cages for urine collection and catheters were implanted in the carotid artery for MAP measurement. Mice were subsequently euthanized and the brain collected to confirm the site of virus microinjection. Selective activation of DMV neurons decreased the incidence of albuminuria [&gt; 300 mg/dL; 66% (4 out of 6) vs. 0% (0 out of 7)], urinary leukocytes [62.5% (5 out of 8) vs. 50% (3 out of 6)] and blood in the urine [50% (4 out of 8) vs. 16% (1 out of 6)] in SLE mice. MAP did not significantly change with the chemogenetic activation of DMV neurons in SLE mice or parental controls (SLE/control virus: 146 ± 6, n=7; SLE/Gq DREADD: 142 ± 3, n=6; NZW/control virus: 126 ± 4, n=4; NZW/Gq DREADD: 132 ± 2, n=5). These results suggests that this timeline of selective activation of DMV neurons in SLE mice reduces renal injury without altering blood pressure, but future studies will confirm the effect on hypertension and renal inflammation in SLE mice

Accelerated Atherosclerosis in Systemic Lupus Erythematosus: Role of Fibroblast Growth Factor 23- Phosphate Axis.

PurposeDespite management advances, accelerated atherosclerotic cardiovascular disease (ACVD) remains a major cause of morbimortality in systemic lupus erythematosus (SLE) patients; that is not fully explained by traditional risk factors. Fibroblast growth factor-23 (FGF23) is a bone-derived phosphaturic hormone with multiple klotho-dependent and independent effects, including promotion of atherosclerosis and vascular calcification, particularly in the context of chronic kidney disease. Increased circulating FGF23 was reported in SLE patients, particularly with lupus nephritis (LN); but its atherogenic role in these disorders was not explored.Subjects and MethodsThree study groups of predominantly middle-aged females were categorized by the 2012 SLE International Collaborating Clinics (SLICC) criteria as SLE (without LN), LN, or controls matching for traditional CVD risk profile. Measures of SLE activity, damage, steroid therapy, and glomerular filtration rate were calculated. Fasting blood samples were checked for serum lipid profile, anti-DNA, urea, creatinine, uric acid, proteins, albumin, calcium, phosphorus, C3, C4, CRP, vitamin-D3, intact parathyroid hormone and FGF23 (iFGF23). By carotid ultrasonography, mean common carotid artery intima-media thickness (CC-IMT), plaque score (PS) and internal carotid resistive index (ICRI) were recorded.ResultsCC-IMT, ICRI and serum iFGF23 differed along the study groups (LN>SLE>controls). In both SLE and LN patients, serum iFGF23 had a significant positive correlation with serum phosphorus, CC-IMT and PS. On multivariate analysis, the strongest predictor of increased CC-IMT was cumulative steroid dose in SLE and serum iFGF23 in LN patients. Most significant independent predictors of increased serum iFGF23 were hyperphosphatemia in SLE and proteinuria in LN patients.ConclusionFGF23-phosphate axis has a key role in accelerated ACVD in SLE patients. Serum phosphorus and iFGF23 should be included in ACVD risk profile assessment of these patients. Prospective studies shall define the role of dietary and/or pharmacologic control of hyperphosphatemia and proteinuria in reducing circulating iFGF23 and ACVD in them.

POS0697 SAFETY OF BELIMUMAB IN ADULT PATIENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS: A LARGE INTEGRATED SAFETY ANALYSIS OF CONTROLLED CLINICAL TRIAL DATA

Background:Belimumab (BEL), a monoclonal antibody that antagonizes B-lymphocyte stimulator, was first approved in 2011 for active, autoantibody-positive systemic lupus erythematosus (SLE). BEL has been studied for over 10 years; and while safety data from individual trials have been informative, a large integrated safety analysis has not yet been conducted.Objectives:Perform pooled analyses to evaluate the safety of BEL in adult patients with SLE.Methods:Aggregate analyses were performed using safety data for patients ≥18 years of age pooled from six randomised, placebo (PBO)-controlled BEL clinical trials (GSK studies: LBSL02, 110752, 110751, 112341, 113750, and 115471). Patients from GSK studies LBSL02, 110752, and 110751 received intravenous (IV) BEL 1, 4 (LBSL02 only), or 10 mg/kg, or PBO on Days 1, 14, 28, and every 28 days thereafter. Patients from GSK studies 113750 and 115471 received IV BEL 10 mg/kg or PBO on Days 1, 14, 28, and every 28 days thereafter. Patients from GSK study 112341 received subcutaneous (SC) BEL 200 mg, or PBO weekly. Safety analyses included the incidence of adverse events (AEs), serious AEs (SAEs), severe AEs, AEs of special interest (AESI), and mortality of BEL (all doses and formulations combined) vs PBO at Week 52.Results:The pooled analysis included 4170 patients. Overall, 81.0% (n=2280/2815) of patients receiving BEL and 76.6% (n=1038/1355) of patients receiving PBO completed their respectively enrolled study; the most common reason for withdrawal was occurrence of an AE in both groups. The majority of patients were female (BEL: 94.5%; PBO: 93.6%), the mean age in both groups was 38 years, and baseline characteristics (race, SLE duration, disease activity, SLE damage, complement levels, anti-dsDNA binding, SLE medication usage) were similar between treatments.The incidence of patients experiencing ≥1 AE, ≥1 SAE, and mortality was similar across treatments (Table 1); the most commonly reported SAEs in both groups were infections and infestations (BEL: 5.4% [n=151/2815]; PBO: 5.9% [n=80/1355]). The mean duration of treatment exposure was similar between groups (BEL: 334.1 days; PBO: 325.3 days).A greater proportion of patients experienced AESI with BEL vs PBO for post-infusion/injection systemic reactions (from IV or SC administration) and depression/suicide/self-injury (Table 1). The proportion of patients experiencing an AESI of infections and malignancies was similar between groups.Conclusion:Consistent with individual studies, BEL demonstrated a similar safety profile to PBO in this large integrated safety analysis of six trials. These results support a positive benefit–risk profile of BEL in the treatment of adult SLE.Funding:GSKTable 1.Pooled AE dataN (%)PBO (IV + SC)N=1355BEL (IV + SC)N=2815AE1184 (87.4)2440 (86.7)SAE230 (17.0)421 (15.0)Severe AE (severe or life threatening)209 (15.4)377 (13.4)AE resulting in study drug discontinuation109 (8.0)184 (6.5)Death6 (0.4)16 (0.6)AESIPost-infusion/injection systemic reactions*110 (8.1)286 (10.2)Serious2 (0.1)13 (0.5)All infections of special interest (OIs, HZ, TB, sepsis)97 (7.2)173 (6.1)Serious17 (1.3)40 (1.4)All OIs92 (6.8)157 (5.6)Active TB5 (0.4)4 (0.1)All HZ59 (4.4)106 (3.8)All sepsis10 (0.7)20 (0.7)Malignancies excluding NMSC2 (0.1)8 (0.3)Including NMSC3 (0.2)12 (0.4)Depression (inc. mood disorders and anxiety)/suicide/self-injury92 (6.8)210 (7.5)Serious5 (0.4)9 (0.3)*Occurring on or within 3 days of infusion/injection date.HZ, herpes zoster; NMSC, non-melanoma skin cancer; OIs, opportunistic infections; TB, tuberculosisAcknowledgements:Medical writing assistance was provided by Helen Taylor, Fishawack Indicia Ltd., UK, part of Fishawack Health, and was funded by GSK.Disclosure of Interests:Daniel J. Wallace Speakers bureau: GSK, Consultant of: GSK, Tatsuya Atsumi Speakers bureau: GSK, Consultant of: GSK, Grant/research support from: GSK, Mark Daniels Shareholder of: GSK, Employee of: GSK, Anne Hammer Shareholder of: GSK, Employee of: GSK, Paige Meizlik Shareholder of: GSK, Employee of: GSK, Holly Quasny Shareholder of: GSK, Employee of: GSK, Andreas Schwarting Speakers bureau: Novartis, Roche, GSK, Pfizer, Amgen, Consultant of: GSK, Grant/research support from: AbbVie, Pfizer, Novartis, GSK, Actelion, Fengchun Zhang: None declared, David Roth Shareholder of: GSK, Employee of: GSK

Effects of melatonin supplementation on serum oxidative stress markers and disease activity in systemic lupus erythematosus patients: A randomised, double-blind, placebo-controlled trial.

Considering pathological significance of oxidative stress in systemic lupus erythematosus (SLE), current research aimed to evaluate the effects of melatonin supplementation on oxidative stress markers and disease activity in SLE. In this randomised double-blind, placebo-controlled trial, 32 SLE females were selected and randomly assigned into two groups to take 10mg/day melatonin or placebo for 12weeks. Before and after trial, serum malondialdehyde (MDA) and total antioxidant capacity (TAC) were measured and disease activity was determined by Systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K). Twenty-five patients (13 in the melatonin and 12 in the placebo groups) completed the trial. Melatonin supplementation caused significant reduction in serum MDA compared with baseline (P=.003) and placebo group (P=.004). Serum TAC level did not change significantly in the melatonin group compared with baseline and placebo group (P>.05). Furthermore, melatonin supplementation did not cause significant change in disease activity compared to baseline and placebo group (P>.05). This study demonstrated affirmative effects of melatonin in decreasing oxidative stress in SLE patients without any effect on disease activity. Further investigations are required to affirm these primitive findings and to achieve concise conclusions.What's known Free radical damage and oxidative stress has a remarkable function in systemic lupus erythematosus (SLE) pathogenesis. Products derived from oxidative modification cascades are found in biological fluids and their redundancy has a correlation with disease activity and organ damage in SLE. Dietary supplements, which decrease oxidative stress, would be useful in managing SLE. Melatonin is a potent antioxidant and has anti-inflammatory and immunomodulatory characteristics. Limited in vitro and animal studies are available indicating desirable effects of melatonin in preventing from SLE organ damage, thereby opening a new area of investigation that can contribute to using melatonin as a therapy or co-therapy for SLE. What's new Melatonin supplementation caused significant reduction in serum MDA compared with baseline and placebo group. Serum TAC level did not change significantly in the melatonin group compared with baseline and placebo group. Furthermore, melatonin supplementation did not cause significant change in disease activity compared to baseline and placebo group.

Therapeutic Potential and Immunomodulatory Role of Coenzyme Q10 and Its Analogues in Systemic Autoimmune Diseases.

Coenzyme Q10 (CoQ10) is a mitochondrial electron carrier and a powerful lipophilic antioxidant located in membranes and plasma lipoproteins. CoQ10 is endogenously synthesized and obtained from the diet, which has raised interest in its therapeutic potential against pathologies related to mitochondrial dysfunction and enhanced oxidative stress. Novel formulations of solubilized CoQ10 and the stabilization of reduced CoQ10 (ubiquinol) have improved its bioavailability and efficacy. Synthetic analogues with increased solubility, such as idebenone, or accumulated selectively in mitochondria, such as MitoQ, have also demonstrated promising properties. CoQ10 has shown beneficial effects in autoimmune diseases. Leukocytes from antiphospholipid syndrome (APS) patients exhibit an oxidative perturbation closely related to the prothrombotic status. In vivo ubiquinol supplementation in APS modulated the overexpression of inflammatory and thrombotic risk-markers. Mitochondrial abnormalities also contribute to immune dysregulation and organ damage in systemic lupus erythematosus (SLE). Idebenone and MitoQ improved clinical and immunological features of lupus-like disease in mice. Clinical trials and experimental models have further demonstrated a therapeutic role for CoQ10 in Rheumatoid Arthritis, multiple sclerosis and type 1 diabetes. This review summarizes the effects of CoQ10 and its analogs in modulating processes involved in autoimmune disorders, highlighting the potential of these therapeutic approaches for patients with immune-mediated diseases.

Neutrophils in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus: Same Foe Different M.O.

Dysregulated neutrophil activation contributes to the pathogenesis of autoimmune diseases including rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Neutrophil-derived reactive oxygen species (ROS) and granule proteases are implicated in damage to and destruction of host tissues in both conditions (cartilage in RA, vascular tissue in SLE) and also in the pathogenic post-translational modification of DNA and proteins. Neutrophil-derived cytokines and chemokines regulate both the innate and adaptive immune responses in RA and SLE, and neutrophil extracellular traps (NETs) expose nuclear neoepitopes (citrullinated proteins in RA, double-stranded DNA and nuclear proteins in SLE) to the immune system, initiating the production of auto-antibodies (ACPA in RA, anti-dsDNA and anti-acetylated/methylated histones in SLE). Neutrophil apoptosis is dysregulated in both conditions: in RA, delayed apoptosis within synovial joints contributes to chronic inflammation, immune cell recruitment and prolonged release of proteolytic enzymes, whereas in SLE enhanced apoptosis leads to increased apoptotic burden associated with development of anti-nuclear auto-antibodies. An unbalanced energy metabolism in SLE and RA neutrophils contributes to the pathology of both diseases; increased hypoxia and glycolysis in RA drives neutrophil activation and NET production, whereas decreased redox capacity increases ROS-mediated damage in SLE. Neutrophil low-density granulocytes (LDGs), present in high numbers in the blood of both RA and SLE patients, have opposing phenotypes contributing to clinical manifestations of each disease. In this review we will describe the complex and contrasting phenotype of neutrophils and LDGs in RA and SLE and discuss their discrete roles in the pathogenesis of each condition. We will also review our current understanding of transcriptomic and metabolomic regulation of neutrophil phenotype in RA and SLE and discuss opportunities for therapeutic targeting of neutrophil activation in inflammatory auto-immune disease.

Smoking exposure in pack-years predicts cutaneous manifestations and damage in systemic lupus erythematosus.

To examine the impact of cumulative smoking in pack-years on systemic lupus erythematosus (SLE) cutaneous manifestations and damage. Our cohort study included 632 adult SLE patients at an academic center, meeting 1997 ACR or 2012 SLICC classification criteria. Outcomes were: (1) cutaneous SLICC Damage Index (SDI), (2) ACR and SLICC criteria. Smoking exposure was defined as low (<5 pack-years), medium (5-10), and high (>10), compared to non-smokers. Analysis used multivariable logistic regression to calculate odds ratios and confidence intervals (OR, (95% CI)). Among 632 SLE patients, mean age 42 ± 14, 91% were female, 82% White, and 40% were ever smokers. Black patients were more likely to have smoked (51% vs. 41% White, 11% Other). Chronic SLICC and SDI cutaneous criteria showed linear pack-year trends, meeting significance with high smoking exposure (OR 2.2, (1.2, 4.2); OR 4.2, (1.9, 9.2)). Those with medium exposure were more likely to meet acute SLICC cutaneous criteria (OR 2.3, (1.1, 5.1)). Low exposure predicted any cutaneous SLICC and ACR criteria (OR 3.7, (1.3, 10.6); OR 2.0 (1.03, 3.8)). Patients of color had more chronic SLICC cutaneous criteria (Other Race OR 3.6 (1.6, 8.1)) and SDI skin damage (Black OR 2.6 (1.1, 5.9)) even controlling for smoking exposure. Smoking was an independent risk factor for cutaneous SLE. High pack-year exposure and non-White race increased chronic skin manifestations and SDI damage. Findings suggested a dose relationship between smoking and cutaneous SLE damage, making cessation messaging important to potentially improve outcomes and reduce some disparities.

Impact and associations of lymphopenia in a cohort of Egyptian systemic lupus erythematosus patients: Potential link to complement (C3) and corticosteroids

Aim of the workTo investigate the relation between lymphopenia and clinical disease activity, disease associated end organ damage, laboratory markers and medications received in systemic lupus erythematosus (SLE) patients. Another objective was to investigate the prognostic value of lymphopenia. Patients and methodsThe medical records of 698 SLE patients under follow-up at the Rheumatology clinics of Cairo and KafrElsheikh University hospitals were revised. Demograghic and laboratory data, SLE disease activity index (SLEDAI), damage index and drug history were assessed. ResultsMean age of 28.4 ± 8.8 years (12–60 years), they were 640 females and 58 males (F:M 11:1) and a disease duration of 6.2 ± 4.7 (0.1–31 years). The study included 674 adults and 24 juvenile cases. 280 (40%) had lymphopenia. Patients with lymphopenia had significantly consumed complement 3 (C3) (p < 0.001), C4 (p = 0.002) and anticardiolipin IgG (p = 0.05). Patients with lymphopenia had a significantly higher incidence of infections (p < 0.001), antiphospholipid antibodies (p = 0.014), frequent intake of cyclophosphamide (p = 0.001), pulse steroid therapy (p < 0.001) and other drugs (p = 0.009) including IVIG and plasmapheresis. Univariate regression model revealed the predictive potential of consumed C3, anticardiolipin IgG, cyclophosphamide, pulse steroid therapy, steroids > 40 mg/day, infections, antiphospholipids for associated lymphopenia. On multivariate analysis only consumed C3 (p = 0.008) and pulse steroid therapy (p = 0.036) remained as independent risk factors for lymphopenia. ConclusionLymphopenia may be more than a hematological finding in SLE patients that was found to be associated with complement consumption, high steroid doses and cyclophosphamide administration, infections and antiphospholipids. The key independent risk factors for lymphopenia are pulse steroid and C3.

Clinical disease activity and flare in SLE: Current concepts and novel biomarkers.

Systemic lupus erythematosus (SLE) is a complex and heterogeneous systemic autoimmune disease associated with innate and adaptive immune dysregulation. SLE occurs primarily in females of childbearing age, with increased prevalence and severity in minority populations. Despite improvements in treatment modalities, SLE patients frequently experience periods of heightened disease activity and flare that can lead to permanent organ damage, increased morbidity, and early mortality. Such outcomes impair quality of life and inflict a significant socioeconomic burden. Predicting changes in SLE disease activity could allow for closer monitoring and preemptive treatment, but existing clinical, demographic and serologic markers have been only modestly predictive. Novel, proactive approaches to clinical disease management are thus critically needed. Panels of blood biomarkers can detect a breadth of immune pathway dysregulation that captures SLE heterogeneity and disease activity. Alterations in the balance of pro-inflammatory and regulatory soluble mediators have been associated with changes in clinical disease activity and are detectable several weeks prior to clinical flare occurrence. A soluble mediator score has been highly predictive of impending flare in both European American and African American SLE patients, and this score does not require a priori knowledge of specific pathway activation in the patient. We review current concepts of disease activity and flare in SLE, focusing on the potential of novel blood biomarkers to characterize and predict changes in disease activity. Measuring the disordered immune response in SLE in this way promises to improve disease management and prevent organ damage in SLE.

Expanding the Role of Complement Therapies: The Case for Lupus Nephritis

The complement system is an innate immune surveillance network that provides defense against microorganisms and clearance of immune complexes and cellular debris and bridges innate and adaptive immunity. In the context of autoimmune disease, activation and dysregulation of complement can lead to uncontrolled inflammation and organ damage, especially to the kidney. Systemic lupus erythematosus (SLE) is characterized by loss of tolerance, autoantibody production, and immune complex deposition in tissues including the kidney, with inflammatory consequences. Effective clearance of immune complexes and cellular waste by early complement components protects against the development of lupus nephritis, while uncontrolled activation of complement, especially the alternative pathway, promotes kidney damage in SLE. Therefore, complement plays a dual role in the pathogenesis of lupus nephritis. Improved understanding of the contribution of the various complement pathways to the development of kidney disease in SLE has created an opportunity to target the complement system with novel therapies to improve outcomes in lupus nephritis. In this review, we explore the interactions between complement and the kidney in SLE and their implications for the treatment of lupus nephritis.

Infection in systemic lupus erythematosus patients

BackgroundInfection is a leading cause of morbidity, mortality and hospital admission in systemic lupus erythematosus (SLE) patients. Aim of the workTo study infection in SLE patients regarding site of infection, pathogenic organism, hospitalization and/or intensive care unit (ICU) admission. Patients and methodsThis study included 79 patients. SLE disease activity index (SLEDAI-2K) and damage index were evaluated. Detailed information about the site of infection and pathogens were reported. Results71 females and 8 male patients (F:M 8.9:1), with a mean age of 29 ± 9.6 years (17–55 years) and disease duration of 5.9 ± 5.7 years, 55 (69.6%) patients had infection at time of study while 24 (30.4%) did not. The SLEDAI-2 k and damage index were significantly higher in SLE patients with infection (14.2 ± 11.8 and 3.7 ± 3.7) compared to those without infection (5.9 ± 5.03 and 1.8 ± 1.3) (p = 0.03 and p = 0.045 respectively). Those with infection had a shorter disease duration (4.9 ± 5.2 vs 8.3 ± 6.2; p = 0.005), received more cyclophosphamide (56.4% vs 16.7%; p = 0.001), higher erythrocyte sedimentation rate (ESR) (75.5 ± 27.1 vs 35.8 ± 24.7 mm/1sthr) (p < 0.0001) and consumed complement (C3) (71.1 ± 28.4 vs 97.2 ± 28.2; p < 0.0001). 17/55 (30.9%) had more than one site of infection and 46/55 (83.6%) required hospital admission. 17 (30.9%) of hospitalized patients were transferred to the ICU. The main pathogenic organisms were bacterial (40%), fungal (27.3%), viral (10.9%) and unconfirmed in 21.8%. Chest was the commonest site (40%) followed by the skin (34.4%), oropharynx (25.5%) and urinary tract (20%). ConclusionInfection is an important cause of hospital and ICU admission in SLE patients. Early disease, disease activity and damage, cyclophosphamide, ESR and consumed C3 were associated with infection in SLE.