Whole exome sequencing in patients with childhood-onset systemic lupus erythematosus: Results from a Croatian national study.

The purpose of this study was to identify new and low-frequency gene variants using whole exome sequencing (WES) in patients with childhood-onset systemic lupus erythematosus (cSLE), that may be involved in the pathogenesis of SLE. We performed WES on selected 17 trios (in some cases including other informative family members) in which the proband presented with severe, atypical clinical features, resistance to conventional therapy, a family pattern of occurrence and/or syndromic characteristics. After performing WES and analysis of gene variants, 17 novel and/or low-frequency variants were identified in 7 patients. One variant was classified as pathogenic (KMT2D, NM_003482.3:c.8626delC, predicted to truncate the protein p.(Gln2876Serfs*34)) and two as likely pathogenic according to the American College of Medical Genetics and Genomics classification guidelines (ADAR, NM_001111.3:c.2815A>G, predicted to encode p.(Ile939Val); BLK, NM_001715.2:c.211G>A, predicted to encode p.(Ala71Thr)). The other variants remain of uncertain significance at this point of time. WES is an important diagnostic and research instrument, producing a growing list of likely genes and gene variants that may be of relevance in the pathogenesis of cSLE and potentially point to novel therapeutic targets.

Evaluation of thyroid dysfunction in childhood-onset systemic lupus erythematosus: Risk factors for Hashimoto's thyroiditis.

OBJECTIVE: Increased frequency of autoimmune thyroid disease, particularly Hashimoto's thyroiditis (HT) was reported several studies in the literature, in individuals with childhood-onset systemic lupus erythematosus (cSLE). Our study aimed to investigate the prevalence and contributing factors of thyroid dysfunction and HT among cSLE patients. METHODS: Thyroid function tests were obtained cross-sectionally from cSLE patients. Demographic, clinical, and laboratory characteristics and activity scores were collected from medical records. Patients diagnosed with cSLE were compared to the healthy control group for the frequency of thyroid dysfunction. The Mann-Whitney U, independent samples t test, and the Chi-square or Fisher's exact test were used to compare study groups. A p-value below 0.05 was considered statistically significant. RESULTS: Out of 73 cSLE patients, 14 (19.1%) had subclinical hypothyroidism, 9 (12.3%) had clinical hypothyroidism, 12 (16.4%) were diagnosed with HT, and 12 (16.4%) had a family history of HT. Thyroid USG was performed in 5 euthyroid patients and 1 borderline subclinical hypothyroid patient with positive thyroid autoantibody and reported as diffuse heterogeneous echogenicity enlargement in the thyroid gland. There were no significant differences in clinical and laboratory data or medication used between the groups with and without HT; however, patients with HT had a higher frequency of clinical hypothyroidism and family history of HT. Cumulative prednisolone dose was significantly lower in patients diagnosed with HT. The frequency of HT was considerably higher in patients with cSLE compared to the healthy control group. CONCLUSION: The results demonstrate an increased incidence of HT in cSLE patients, even if they are euthyroid, and recommend that cSLE patients be screened more frequently.

Active implementation of low disease activity state as a treatment endpoint in childhood-onset systemic lupus erythematosus in routine practice is both feasible and associated with better outcomes.

INTRODUCTION: Treat-to-target (T2T) strategies aim to facilitate tight disease control to improve outcomes. No previous studies evaluated prospectively the feasibility and impact of the T2T strategy in routine practice in childhood-onset SLE (cSLE). METHODS: Adolescents and young adults (AYA) with cSLE were recruited for T2T implementation from a large tertiary centre over a period of 6 months and followed up at least twice over a prospective period of 12 months. RESULTS: During Oct 2022-April 2023, 135/162 (83.3%) AYA with cSLE had disease scores evaluated at their routine appointment to enable inclusion in the study, and 122/135 (91.2%) had their disease assessed, and a suitable treatment target agreed and documented at each routine clinical appointment over the 12 months prospective follow-up. T2T strategy led to improved disease control at 12 months: more AYA with cSLE achieved clinical remission off steroids (4.1% vs. 10.7%, P = 0.048), or minimum childhood-lupus low disease activity (cLLDAS) (81.9% vs. 91.8%, P = 0.022). Achieving minimum cLLDAS for longer than 3 months was associated with reduced damage accrual (HR = 1.7; 95%CI = 1.1-2.5; P < 0.0001) at 12 months. CONCLUSION: T2T strategy implementation was achievable and associated with improved cSLE control. Spending at least 3/12 months in cLLDAS led to less damage accumulation. Key Points • This is the first large prospective study in AYA with cSLE to evaluate the impact of active T2T implementation in routine practice. • T2T strategies were feasible to implement in 122/135 (91.2%) AYA with cSLE in routine practice. • The T2T approach was associated with improved disease control and decreased damage accrual at 12 months.

Capillaroscopy in the daily clinic of the pediatric rheumatologist.

In the last decade, nailfold capillaroscopy is finding its way to the daily clinic of (pediatric) rheumatologist. This review will provide the necessary knowledge for the clinician performing this easy and non-invasive examination in children. In the first part, background information on type of capillaroscopy device and standardized (internationally validated) interpretations for the different capillary variables compared to healthy pediatric controls will be provided. The second part focusses on capillary changes that are observed in Raynaud's phenomenon with follow-up recommendations. This part will also cover capillaroscopy findings in juvenile systemic sclerosis, childhood-onset systemic lupus erythematosus, juvenile dermatomyositis and -mixed connective tissue disease, as well as correlations with disease severity. Lastly, a research agenda shows the current gaps we have in knowledge in this niche of nailfold capillaroscopy in pediatric connective tissue diseases.

The TRUST Study-TRansition US Together: Evaluating the Impact of a Parent- and Adolescent-Centered Transition Toolkit on Transition Readiness in Patients with Juvenile Idiopathic Arthritis and Childhood-Onset Systemic Lupus Erythematosus.

OBJECTIVE: Adolescents with chronic rheumatic disease must increasingly take on more responsibility for disease management from parents as they transition from pediatric to adult care. Yet, there are limited resources to inform and support parents about transition. Here, we evaluate the impact of a Transition Toolkit, geared towards parents and adolescents, on transition readiness, and explore the potential impact of parent-adolescent communication. METHODS: A prospective cohort study of youths aged 14-18 years old and their parents was performed. Participant demographics, disease characteristics, transition readiness scores (Transition-Q, max 100), and parent-adolescent communication scores (PACS, max 100) were collected at enrollment (when the Transition Toolkit was shared with adolescents and their parents. Generalized estimating equation (GEE) analyses determined the influence of the Toolkit on transition readiness and explored the role of parent-adolescent communication quality. Subgroup analyses were conducted by sex. RESULTS: A total of 21 patients were included; 19 completed one post-intervention Transition-Q and 16 completed two. Transition-Q scores increased over time and the rate of increase doubled after the Toolkit was shared (ß = 7.8, p < 0.05, and ß = 15.5, p < 0.05, respectively). CONCLUSION: Transition readiness improved at each follow-up, the greatest increase was seen after the Toolkit was shared. Parent-adolescent communication quality did not appear to impact changes in transition readiness.

Does the esv3587290 Copy Number Variation in the VANGL1 Gene Differ as a Genetic Factor for Developing Nephritis in Mexican Childhood-Onset Systemic Lupus Erythematosus Patients?

A ~3-kb deletion-type DNA copy number variation (CNV, esv3587290) located at intron 7 of the VANGL1 gene (1p13.1, MIM*610132) has been proposed as a genetic factor in lupus nephritis (LN) development in adult systemic lupus erythematosus (SLE) patients across European-descent populations, but its replication in other ethnicities has been inconsistent and its association with LN in childhood-onset SLE (cSLE) remains unknown. Here, we performed an exploratory association study in a sample of 66 unrelated cSLE Mexican patients (11 males, 55 females; ages 7.8 to 18.6 years). Two stratified groups were compared: cSLE patients with (N = 39) or without (N = 27) LN, as diagnosed by renal biopsy (N = 17), proteinuria (N = 33), urinary protein-creatinine ratio > 0.2 (N = 34), and erythrocyturia and/or granular casts in urinary sediment (N = 16). For esv3587290 CNV genotyping, we performed an end-point PCR assay with breakpoint confirmation using Sanger sequencing. We also determined the allelic frequencies of the esv3587290 CNV in 181 deidentified ethnically matched individuals (reference group). The obtained genotypes were tested for Hardy-Weinberg equilibrium using the χ2 test. Associations between LN and esv3587290 CNV were tested by calculating the odds ratio (OR) and using Pearson's χ2 tests, with a 95% confidence interval and p ≤ 0.05. The esv3587290 CNV allele (OR 0.108, 95% CI 0.034-0.33, p = 0.0003) and the heterozygous genotype (OR 0.04, 95% CI 0.119-0.9811, p = 0.002) showed a significant protective effect against LN development. Finally, we characterized the precise breakpoint of the esv3587290 CNV to be NG_016548.1(NM_138959.3):c.1314+1339_1315-897del in our population. This report supports the notion that a broad genetic heterogeneity underlies the susceptibility for developing LN.

IFN-I Score and Rare Genetic Variants in Children with Systemic Lupus Erythematosus.

Introduction: Interferon I (IFN I) signaling hyperactivation is considered one of the most important pathogenetic mechanisms in systemic lupus erythematosus (SLE). Early manifestation and more severe SLE courses in children suggest a stronger genetic influence in childhood-onset SLE (cSLE). Aim: To evaluate IFN-I score and SLE-associated genetic variants in cSLE. Material and Methods: 80 patients with cSLE were included in the study. IFN I-score was assessed by real-time PCR quantitation of 5 IFN I-regulated transcripts (IFI44L, IFI44, IFIT3, LY6E, MXA1) in 60 patients. Clinical exome sequencing (CES) was performed in 51 patients. Whole-exome sequencing was performed in 32 patients with negative results of CES. Results: 46/60 patients (77%) had elevated IFN-I scores. Leucopenia and skin involvement were associated with over-expression of IFI44 and IFI44L, while hypocomplementemia-with hyperactivation of IFIT3, LY6E, and MX1. No correlation of IFN-I score with disease activity was found. At least one rare genetic variant, potentially associated with SLE, was found in 29 (56.9%) patients. The frequency of any SLE-genetic variants in patients with increased IFN scores was 84%, in patients with normal IFN scores-33%, and in the group whose IFN score was not assessed was 65% (p = 0.040). The majority of genetic variants (74%) are functionally related to nucleic acid sensing and IFN-signaling. The highest frequency of genetic variants was observed in Sakha patients (9/14; 64.3%); three and two unrelated patients had identical variants in PTPN22 and TREX1 genes, respectively. Conclusions: More than half of patients with childhood-onset SLE have rare variants in SLE-associated genes. The IFN-I score could be considered a tool for the selection of patients for further genetic assessment in whom monogenic lupus is suspected.

Hospitalization and Mortality Due to Infection Among Children and Adolescents With Systemic Lupus Erythematosus in the United States.

OBJECTIVE: We aimed to determine the frequency and types of infections in hospitalized children with childhood-onset systemic lupus erythematosus (cSLE), and to identify risk factors for intensive care unit (ICU) admission and mortality. METHODS: We conducted a retrospective study of youth aged 2 to 21 years using International Classification of Diseases (ICD) codes for SLE assigned during admission to a hospital participating in the Pediatric Health Information System, a database of United States children's hospitals, from 2009 to 2021. Generalized linear mixed effects models were used to identify risk factors for ICU admission and mortality among children hospitalized with infection. RESULTS: We identified 8588 children with cSLE and ≥ 1 hospitalization. Among this cohort, there were 26,269 hospitalizations, of which 13% had codes for infections, a proportion that increased over time (P = 0.04). Bacterial pneumonia was the most common hospitalized infection. In-hospital mortality occurred in 0.4% (n = 103) of cSLE hospitalizations for any indication and 2% of hospitalizations for infection (n = 60). The highest mortality rates occurred with Pneumocystis jirovecii pneumonia (21%) and other fungal infections (21%). Lupus nephritis (LN) and endstage renal disease (ESRD) were associated with increased odds of ICU admission (odds ratio [OR] 1.47 [95% CI 1.2-1.8] and OR 2.40 [95% CI 1.7-3.4]) among children admitted for serious infection. ESRD was associated with higher mortality (OR 2.34 [95% CI 1.1-4.9]). CONCLUSION: Hospitalizations with ICD codes for infection comprised a small proportion of cSLE admissions but accounted for the majority of mortality. The proportion of hospitalizations for infection increased over time. LN and ESRD were risk factors for poor outcomes.

Do we really need cyclophosphamide for lupus nephritis?

A 14-year-old patient presents with hematuria and proteinuria. Clinical evaluation reveals a positive anti-nuclear antibody titer, positive anti-double stranded DNA antibody and hypocomplementemia. Systemic lupus erythematosus (SLE) is diagnosed based on the 2019 EULAR/ACR (European League Against Rheumatism/American College of Rheumatology) classification criteria (Aringer et al. Arthritis Rheumatol 71:1400-1412, 2019). A kidney biopsy is performed that confirms the presence of immune complex glomerulonephritis, ISN-RPS (International Society of Nephrology/Renal Pathology Society) class IV (Bajema et al. Kidney Int 93:789-796, 2018). According to the latest clinical practice guidelines (Rovin et al. Kidney Int 100:753-779, 2021; Fanouriakis et al. Ann Rheum Dis 83:15-29, 2023), there are alternatives to treating this patient with cyclophosphamide. But what if this patient also presented with oliguria and volume overload requiring intensive care and dialysis? What if this patient also presented with altered mental status and seizures, and was diagnosed with neuropsychiatric lupus? What if this patient was also diagnosed with a pulmonary hemorrhage and respiratory failure? The clinical practice guidelines do not address these scenarios that are not uncommon in patients with SLE. Moreover, in some countries worldwide, patients do not have the privilege of access to biologics or more expensive alternatives. The purpose of this review is to evaluate the contemporary options for initial treatment of nephritis in patients with SLE.

Comparison of systemic lupus international collaborating clinics 2012 classification criteria and European league against rheumatism/American college of rheumatology 2019 classification criteria for early detection of childhood onset systemic lupus erythematosus (multi-center study).

OBJECTIVE: To assess the performance of the new EULAR/ACR criteria, particularly for early detection of cSLE, in comparison to the SLICC criteria among the pediatric population in multiple centers in Saudi Arabia. METHODS: We conducted a retrospective study that enrolled pediatric patients up to the age of 14 years who've been diagnosed with SLE and followed in pediatric rheumatology clinics at 9 multi-tertiary hospitals in Saudi Arabia from 2010 to 2021 as a case group and were compared to a similar group of pediatric patients who've had defined rheumatological diseases other than SLE with a positive ANA titer (≥1:80) as controls. In total, 245 patients were included and distributed as 129 cases (diagnosed by expert pediatric rheumatologists) versus 116 patients in the control group. All relevant clinical information, including history, physical examination findings, and laboratory tests, was documented at the initial presentations. Then, the two sets of SLE classification criteria were applied to both groups to define who's going to meet both or either one of them. The exclusion criteria included those who had insufficient data or had overlapping or undifferentiated diseases. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), receiver operating curve (ROC), and accuracy were calculated for SLICC 2012 and EULAR/ACR 2019 criteria (total scores≥ 10 and ≥ 13). We performed a Chi-squared test to compare sensitivity and specificity of SLICC 2012 and EULAR/ACR 2019. RESULTS: For SLICC (cut-off ≥4 criteria), the sensitivity was found to be 96.9% (95% CI 92.6%-99.4%) and the specificity was 94.8% (95% CI 89.6%-98.32%), with PPV and NPV of 95.4% and 96.5%, respectively. The ROC for it was 0.96 (95% CI 0.93-0.99), and this criterion had an accuracy of 95%. Regarding EULAR/ACR (total score ≥ 10), the performance measure showed a sensitivity of 99.2% and a specificity of 86.2%. Similarly, PPV was 88.9%; while NPV was a little higher (99.0%) than SLICC. The ROC for EULAR/ACR (total score ≥ 10) was 0.93 (95% CI 0.89-0.96), and this criterion had an accuracy of 93%. However, there was no statistically significant difference between the sensitivity and specificity of either using SLICC or EULAR/ACR (total score ≥ 10), as reflected by a p-value of 0.86 using the Chi-squared test. Although applying the EULAR/ACR with a total score of ≥ 13 revealed lower sensitivity (93.8%) than both the SLICC and the EULAR/ACR (total score ≥ 10), the specificity for it was found to increase up to 91.4% (85.7-96.2%) compared to the (86.2%) specificity of the EULAR/ACR (total score ≥ 10). CONCLUSION: In this cohort among the Saudi population with childhood-onset SLE, the new EULAR/ACR 2019 criteria efficiently enable early detection of SLE, although a more frequent rate of false positives was observed with them. Escalating the total score from ≥ 10 to ≥ 13 in the cSLE population improved the specificity close to that of SLICC 2012. Further prospective studies in pediatrics need to be done for the validation of a cut- off score of ≥ 13 in cSLE rather than the traditional score of ≥ 10 in aSLE.

Immunogenicity and safety of BNT162b2 vaccination in adolescents with systemic lupus erythematosus.

OBJECTIVES: We evaluated the immunogenicity and safety of BNT162b2 vaccination in adolescents with systemic lupus erythematosus (adoSLE) receiving either high- or low-dose immunosuppressant (High-IS and Low-IS). METHODS: Patients aged 12-18 years diagnosed with SLE were enrolled. High-IS was defined as >7.5 mg/day prednisolone or with other immunosuppressant, while Low-IS was defined as only ≤7.5 mg/day of prednisolone and no immunosuppressant. Two doses of BNT162b2 vaccination were given 4 weeks apart, followed by a booster (third) dose at 4-6 months later. Anti-spike receptor binding domain (anti-RBD) IgG against Wuhan, neutralising antibody (NT) against Wuhan and Omicron variants, and cellular immune response by IFN-γ-ELISpot assay were evaluated following vaccination. Adverse events (AEs) and SLE flare were monitored. RESULTS: A total of 73 participants were enrolled, 40 and 33 in the High-IS and Low-IS group, respectively. At 4 weeks following the 2nd dose, overall anti-RBD IgG seropositivity was 97.3%, with no difference between the groups (p = .498). AdoSLE on High-IS had lower anti-RBD IgG (p < .001), Wuhan NT (p < .001), and IFN-γ-ELISpot (p = .022) than those on Low-IS. A 3rd dose induced significantly higher antibody responses than after the 2nd dose (p < .001) in both groups and established seroconversion against Omicron variants, with persistent lower antibody levels in High-IS group. SELENA-SLEDAI scores within 12 weeks after 2-dose vaccination was higher than before vaccination (3.1 vs 2.5; p < .036); however, the occurrence of disease flare by SELENA-SLEDAI flare index was not different after vaccination compared to before vaccination, consistent across groups. Non-severe AEs occurred similarly in both groups. CONCLUSION: AdoSLE on High-IS induced lower SARS-CoV-2 vaccine immune responses than Low-IS. Vaccination can increase disease activity and requires close monitoring for disease flare.

Bibliometric analysis of childhood-onset systemic lupus erythematosus from 2000 to 2022.

BACKGROUND: Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disorder. When SLE occurs in individuals under the age of 18, it is referred to as childhood-onset SLE (cSLE). Currently, there is a dearth of bibliometric research pertaining to cSLE. METHOD: Relevant studies in the field of cSLE from 2000 to 2022 were screened from the Web of Science Core Collection (WoSCC). CiteSpace and VOSviewer software were used to visualize the annual publications, countries, institutions, authors, journals, keywords, and references, after which the authors conducted the scientific analysis. RESULTS: A total of 2857 articles were included in this study, and the number of articles published in the past 20 years showed an overall upwards trend. The most prolific countries are the United States, China, and Brazil; however, the United States, Canada, and the United Kingdom are clearly superior in terms of literary influence, and there is more cooperation between them and their institutions. LUPUS (n = 389) contributed the most to the variance. Brunner, HI's contribution in the field of cSLE is outstanding. The words related to 'lupus nephritis' and 'antibodies' are important words reflected in the keyword network diagram. The keywords included 'evidence-based recommendation', 'validation', 'diagnosis' and 'adult' from 2019, and 'continuous bursts' to the present. CONCLUSION: This study examined the research status of cSLE patients, discussed and analysed the research hotspots and trends in this field, and provided a reference for further research in this field to promote the development of cSLE research.

Clinical characteristics and prognosis of childhood-onset lupus mesenteric vasculitis as the initial presentation-a case-control study.

BACKGROUND: Lupus mesenteric vasculitis (LMV) as initial presentation is rare, especially in childhood-onset systemic lupus erythematosus (cSLE). It is a critical complication of lupus. At present, the research on cSLE with LMV as the initial presentation is few. The aim of this study was to analyze the clinical characteristics and prognosis of cSLE with LMV in the Chinese population, compared with non-LMV cSLE. METHODS: A retrospective case-controlled study was conducted on 55 cSLE patients between July 2018 and July 2021. The clinical data, laboratory findings, imaging, treatment, and follow-up data were collected and compared between the two groups of cSLE with LMV and non-LMV. Non-LMV cSLE patients were matched according to the age and sex of LMV patients. RESULTS: A total of 11 cSLE patients with LMV as the LMV group and 44 cSLE patients without LMV as the non-LMV group were included. The average age of onset was 12.55 ± 1.57 years old, the male-to-female ratio was 2:9, and high disease activity was observed in the LMV group. Abdominal pain was most common in LMV. Compared with the non-LMV, the percentage of abdominal pain, vomiting, abdominal distension, and diarrhea was higher, and gastrointestinal tract, serous cavity, kidney, and lung damage were higher in the LMV group (P < 0.05). In abdominal-enhanced CT, the percentage of intestinal wall thickening, peritoneal effusion, mesenteric vascular enhancement, hydronephrosis with ureteral dilatation, intestinal congestion, and gastric mucosa thickening in the LMV group were higher than those in the non-LMV group (P < 0.05). The percentage of receiving methylprednisolone pulse combined with cyclophosphamide pulse therapy in LMV was higher than in non-LMV. The clinical symptoms disappeared quickly, and there were no deaths in the LMV group. Compared with the non-LMV group, the 24-h urinary protein was higher, the complement C3 was lower, and the disease activity was higher in the LMV group (P < 0.05). CONCLUSIONS: LMV often occurs in 12 ~ 13-year-old girls with high disease activity of cSLE. Abdominal pain is the most common and more susceptible to damage to the kidney, serous cavity, and lung in cSLE with LMV. Methylprednisolone pulse combined with CTX pulse therapy is effective. After the treatment above, cSLE with LMV has a good prognosis, but the overall recovery is worse than non-LMV patients.

Childhood-onset systemic lupus erythematosus: characteristics and the prospect of glucocorticoid pulse therapy.

Childhood-onset systemic lupus erythematosus (cSLE) is an autoimmune disease that results in significant damage and often needs more aggressive treatment. Compared to adult-onset SLE, cSLE has a stronger genetic background and more prevalent elevated type I Interferon expression. The management of cSLE is more challenging because the disease itself and treatment can affect physical, psychological and emotional growth and development. High dose oral glucocorticoid (GC) has become the rule for treating moderate to severe cSLE activity. However, GC-related side effects and potential toxicities are problems that cannot be ignored. Recent studies have suggested that GC pulse therapy can achieve disease remission rapidly and reduce GC-related side effects with a reduction in oral prednisone doses. This article reviews characteristics, including pathogenesis and manifestations of cSLE, and summarized the existing evidence on GC therapy, especially on GC pulse therapy in cSLE, followed by our proposal for GC therapy according to the clinical effects and pathogenesis.

The Role of Genetic Risk Factors in Pathogenesis of Childhood-Onset Systemic Lupus Erythematosus.

The pathogenesis of childhood-onset systemic lupus erythematosus (cSLE) is complex and not fully understood. It involves three key factors: genetic risk factors, epigenetic mechanisms, and environmental triggers. Genetic factors play a significant role in the development of the disease, particularly in younger individuals. While cSLE has traditionally been considered a polygenic disease, it is now recognized that in rare cases, a single gene mutation can lead to the disease. Although these cases are uncommon, they provide valuable insights into the disease mechanism, enhance our understanding of pathogenesis and immune tolerance, and facilitate the development of targeted treatment strategies. This review aims to provide a comprehensive overview of both monogenic and polygenic SLE, emphasizing the implications of specific genes in disease pathogenesis. By conducting a thorough analysis of the genetic factors involved in SLE, we can improve our understanding of the underlying mechanisms of the disease. Furthermore, this knowledge may contribute to the identification of effective biomarkers and the selection of appropriate therapies for individuals with SLE.

A multi-site pilot randomized clinical trial of the Treatment and Education Approach for Childhood-onset Lupus (TEACH) program: study design and COVID-19 adaptations.

BACKGROUND: Childhood-onset Systemic Lupus Erythematosus (cSLE) is an autoimmune disease associated with fatigue, mood symptoms, and pain. Fortunately, these symptoms are potentially modifiable with psychological intervention such as cognitive-behavioral therapy (CBT). The Treatment and Education Approach for Childhood-onset Lupus (TEACH) program is a CBT intervention developed to target these symptoms for adolescents and young adults with cSLE. This pilot randomized controlled trial (RCT) aims to determine the feasibility and effect of TEACH for youth with cSLE. Adjustments to the study protocol following the COVID-19 pandemic are also described. METHODS: This two-arm multisite RCT will explore the feasibility (primary outcome) and effect (secondary outcome) of a remotely delivered TEACH protocol. Participants will be randomized to a six-week remotely delivered TEACH program plus medical treatment as usual (TAU) or TAU alone. We will include patients ages 12-22 years presenting to rheumatology clinics from six sites. Validated measures of fatigue, depressive symptoms, and pain will be obtained at baseline and approximately eight and 20 weeks later. Protocol adjustments were also made due to the COVID-19 pandemic, in collaboration with the investigative team, which included patients and caregivers. CONCLUSIONS: Findings from this multi-site RCT aim to document the feasibility of TEACH and provide an estimate of effect of a remotely delivered TEACH protocol on fatigue, depression, and pain symptoms in youth with cSLE as compared to standard medical treatment alone. This findings may positively impact clinical care for patients with cSLE. CLINICAL TRIALS: gov registration: NCT04335643.

Risk factors for mortality in 1528 Brazilian childhood-onset systemic lupus erythematosus patients.

OBJECTIVES: To identify associations between mortality in cSLE patients and their characteristics: clinical and laboratory features, disease activity and damage scores, and treatment; to evaluate risk factors associated with mortality in cSLE; and to determine the most frequent causes of death in this group of patients. METHODS: We performed a multicenter retrospective cohort using data from 1,528 cSLE patients followed in 27 pediatric rheumatology tertiary centers in Brazil. Patients' medical records were reviewed according to a standardized protocol, in which information regarding demographic and clinical features, disease activity and damage scores, and treatment were collected and compared between deceased cSLE patients and survivors. Univariate and multivariate analyses by Cox regression model were used to calculate risk factors for mortality, whereas survival rates were analyzed by Kaplan-Meier plots. RESULTS: A total of 63/1,528 (4.1%) patients deceased, 53/63 were female (84.1%), median age at death was 11.9 (9.4-13.1) years and median time interval between cSLE diagnosis and death was 3.2 (0.5-5.3) years. Sepsis was the main cause of death in 27/63 (42.8%) patients, followed by opportunistic infections in 7/63 (11.1%), and alveolar hemorrhage in 6/63 (9.5%) patients. The regression models resulted in neuropsychiatric lupus (NP-SLE) (HR = 2.56, 95% CI = 1.48-4.42) and chronic kidney disease (CKD) (HR = 4.33, 95% CI = 2.33-4.72), as risk factors significantly associated with mortality. Overall patient survival after cSLE diagnosis at 5, 10, and 15 years were 97%, 95.4%, and 93.8%, respectively. CONCLUSIONS: This study confirmed that the recent mortality rate in cSLE in Brazil is low, but still of concern. NP-SLE and CKD were the main risk factors for mortality, indicating that the magnitude of these manifestations was significantly high.

Outcomes of achieving lupus low disease activity state and damage accrual in childhood-onset systemic lupus erythematosus.

INTRODUCTION: At present, the treat-to-target approach has been proposed with the lupus low disease activity state (LLDAS) as an achievable target. OBJECTIVES: To determine damage accrual and baseline clinical characteristics associated with achieving LLDAS within 12 months of treatment in patients with childhood-onset systemic lupus erythematosus (c-SLE). METHODS: This retrospective cohort study was conducted at the largest university-based tertiary referral center in Thailand. Data of c-SLE patients (≤ 18 years) at diagnosis who were followed ≥ 12 months during January 2009 to December 2019 were collected. SLE disease status was categorized into LLDAS and non-optimally controlled state. SLEDAI-2K score was used to assess disease activity. Damage accrual was assessed by a pediatric version of the SLICC/ACR damage index. RESULTS: A total of 232 c-SLE patients (85.8% female) were included. At 12 months of treatment, 109 (47%) patients achieved LLDAS. Damage accrual was observed in 93 (40.1%) patients at the mean follow-up time of 6.2 ± 3.7 years. Damage accrual was significantly lower in patients who achieved LLDAS within 12 months than in those non-optimally controlled (p = 0.002). The median time to achieving LLDAS was 12.6 months (95%CI: 11.19-13.97). The median time to achieving LLDAS was significantly shorter in those without renal involvement (10.8 months, 95%CI: 9.62-12.00 vs. 15.6 months, 95%CI: 13.76-17.52, respectively; p = 0.044). Multivariable logistic regression analysis revealed absence of renal involvement as the predictor of achieving LLDAS within 12 months of treatment (aOR: 2.430, 95%CI: 1.420-4.158; p = 0.001). CONCLUSIONS: Achieving LLDAS within 12 months of treatment was associated with lower damage accrual. Absence of renal involvement was the predictor of achieving LLDAS within 12 months of treatment. Key Points • LLDAS is a promising and achievable treatment target in c-SLE. • Achieving LLDAS within 12 months of treatment is associated with lower damage accrual. • Absence of renal involvement is the predictor of achieving LLDAS within 12 months of treatment.

Gastrointestinal Involvement in Children with Systemic Lupus Erythematosus.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder. When it presents before the age of 18 years (childhood-onset systemic lupus erythematosus, cSLE), the disease course tends to be more severe with a higher rate of organ involvement and requires an early diagnosis. Gastrointestinal involvement in cSLE is rare and scarcely reported in the literature. Any organ of the gastrointestinal system may be affected, either as a direct consequence of the disease, as a subsequent complication, or as an adverse drug event. Abdominal pain is the most common GI symptom, it can be diffuse or well localized, and can underline different conditions such as hepatitis, pancreatitis, appendicitis, peritonitis, or enteritis. cSLE may have an alteration of the intestinal barrier with features of protein-losing enteropathy or, in genetically predisposed patients, may develop associated autoimmune disorders such as Coeliac Disease or Autoimmune Hepatitis. The aim of this manuscript is to provide a narrative review of gastrointestinal manifestations in cSLE focused on hepatic, pancreatic, and intestinal involvement. A comprehensive literature search based on the PubMed database was performed.

Chronic kidney disease in patients with childhood-onset systemic lupus erythematosus.

BACKGROUND: Lupus nephritis (LN) is a frequent manifestation of childhood-onset systemic lupus erythematosus (cSLE) with a potential risk for kidney failure and poor outcomes. This study aimed to evaluate stages III, IV, and V of chronic kidney disease (CKD) and investigate risk factors for CKD in cSLE patients. METHODS: We performed a nationwide observational cohort study in 27 pediatric rheumatology centers, including medical charts of 1528 cSLE patients. Data were collected at cSLE diagnosis, during follow-up, and at last visit or death, between September 2016 and May 2019. RESULTS: Of 1077 patients with LN, 59 (5.4%) presented with CKD, 36/59 (61%) needed dialysis, and 7/59 (11.8%) were submitted for kidney transplantation. After Bonferroni's correction for multiple comparisons (p < 0.0013), determinants associated with CKD were higher age at last visit, urinary biomarker abnormalities, neuropsychiatric involvement, higher scores of disease activity at last visit and damage index, and more frequent use of methylprednisolone, cyclosporine, cyclophosphamide, and rituximab. In the regression model analysis, arterial hypertension (HR = 15.42, 95% CI = 6.12-38.83, p ≤ 0.001) and biopsy-proven proliferative nephritis (HR = 2.83, 95%CI = 1.70-4.72, p ≤ 0.001) increased the risk of CKD, while children using antimalarials had 71.0% lower CKD risk ((1.00-0.29) × 100%) than children not using them. The Kaplan-Meier comparison showed lower survival in cSLE patients with biopsy-proven proliferative nephritis (p = 0.02) and CKD (p ≤ 0.001). CONCLUSIONS: A small number of patients manifested CKD; however, frequencies of dialysis and kidney transplantation were relevant. This study reveals that patients with cSLE with hypertension, proliferative nephritis, and absence of use of antimalarials exhibited higher hazard rates of progression to CKD. A higher resolution version of the Graphical abstract is available as Supplementary information.