Phenotype and disease course differences in monogenic and sporadic childhood lupus.

OBJECTIVE: To report the differences in phenotypic characteristics, disease course, and outcome in monogenic and sporadic childhood lupus (SC-lupus) from a single tertiary childhood lupus clinic. METHODS: A descriptive, observational, cross-sectional study was conducted. Data were retrospectively collected at the last follow-up visit on patients with monogenic lupus proven by genetic variants and SC-lupus seen between June 1997 and July 2022. SC-lupus patients were selected by systematic sampling from lupus patients presenting to our lupus clinic; the first patient was chosen randomly, and the subsequent patients were chosen at intervals of three. Data comprised the clinical and laboratory findings, disease activity using the SLEDAI, and damage measured by the pSDI. RESULTS: A total of 54 patients with a median disease duration of 6.8 (IQR 3.5-10.5) years were included. There were 27 patients with monogenic lupus and 27 patients with SC-lupus, with a median age at disease onset of 3.5 (IQR 1.0-6.0), and 9.5 (IQR 7.0-11.8), respectively. (p < 0.05). The rate of consanguinity and family history of lupus were higher in monogenic lupus patients. The two groups were comparable. However, monogenic lupus patients showed more gastrointestinal tract symptoms, and failure to thrive (p < 0.05). They also had more infections. The frequency of the autoantibody profile was higher in monogenic lupus patients. Belimumab was more frequently used in monogenic lupus while rituximab in SC-lupus patients. Monogenic lupus patients had a higher mean SLEDAI, but statistically, it was insignificant. Patients with monogenic lupus had greater disease damage, with a higher mean pSDI and a higher mortality rate (p < 0.05). CONCLUSION: Patients with monogenic lupus are likely to have an early disease onset and a strong family history of lupus, as well as a guarded prognosis, which is likely due to the disease's severity and frequent infections. These differences may be related to the high consanguinity rate and underlying genetic variants.

New insights on genetic variants and phenotypic features of childhood large-vessel vasculopathy: a systematic review and single-centre series.

OBJECTIVES: To describe the phenotypic, genetic, and outcome characteristics of large-vessel vasculopathy (LVV) in childhood associated with genetic variants. Additionally, a systematic literature review was conducted to delineate the differences between LVV with and without genetic variants. METHODS: The medical records of all children with LVV seen between January 2000 and September 2022 at our institution were retrospectively reviewed for demographic, clinical and genetic data, and outcomes at the last follow-up visit. In addition, we systematically reviewed the literature for the clinical features and known variants of previously reported cases. RESULTS: Eleven patients with childhood LVV were identified; five (three males) of them had proven genetic variants (two DOCK8variants, one FOXP3, one DiGeorge syndrome, and one ZNF469 variant), while six patients had sporadic childhood LVV. Remarkably, patients with genetic variants were younger and had early-onset disease. However, the diagnosis of LVV was delayed compared to those without genetic variants. All patients with genetic variants were treated with corticosteroids, and three patients required sequential immunosuppressive drugs. Four patients underwent surgical intervention, and one received a haematopoietic stem-cell transplant (HSCT). Three patients achieved clinical remission, and two died. Furthermore, data from 20 previously published cases was extracted from the literature. All patients had inherited disorders. Of those, 14 patients had a genetically proven diagnosis. Most of them are treated with corticosteroids and immunosuppressive drugs, with partial responses. Two patients underwent HSCT. There were four deaths. CONCLUSIONS: This study demonstrates that a variety of inherited disorders may contribute to childhood LVV. Strong genetic evidence and the preponderance of autosomal-recessive inheritance may allow us to propose that monogenic LVV is a distinct entity.

The SLC29A3 variant, neutrophilic dermatosis, and hyperferritinemia imitate systemic juvenile idiopathic arthritis in a Saudi child: a case report.

Genetic defects of SLC29A3 result in a wide range of syndromic histiocytosis that encompasses H syndrome. Patients with SLC29A3 variants typically have hyperpigmentation, hypertrichosis, hepatosplenomegaly, sensorineural hearing loss, diabetes mellitus, and hypogonadism. Herein, we identify a novel phenotype in a girl presenting with clinical and laboratory findings similar to systemic juvenile arthritis and hyperferritinemia. Exome sequencing identified a homozygous variant in SLC29A3 (NM_018344.5: c.707C>T [p.T236M]). Our patient did not show the cardinal features of the broad spectrum of SLC29A3-related disorders. She demonstrated remarkable improvement in her clinical and laboratory manifestations after starting interleukin-1 blockade (Anakinra). Recent research suggests that SLC29A3-related disorders are accompanied with autoinflammation and autoimmunity due to an overactive inflammasome pathway, which is most likely induced by mitochondrial and lysosomal dysfunction. Hence, our findings may expand the phenotypic features of the SLC29A3 variant. Patients with the SLC29A3 variant and systemic inflammation may benefit from interleukin-1 blockade as a therapeutic option.

Development and Implementation of the AIDA International Registry for Patients With Undifferentiated Systemic AutoInflammatory Diseases.

Objective: This paper points out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to pediatric and adult patients affected by Undifferentiated Systemic AutoInflammatory Diseases (USAIDs). Methods: This is an electronic registry employed for real-world data collection about demographics, clinical, laboratory, instrumental and socioeconomic data of USAIDs patients. Data recruitment, based on the Research Electronic Data Capture (REDCap) tool, is designed to obtain standardized information for real-life research. The instrument is endowed with flexibility, and it could change over time according to the scientific acquisitions and potentially communicate with other similar tools; this platform ensures security, data quality and data governance. Results: The focus of the AIDA project is connecting physicians and researchers from all over the world to shed a new light on heterogeneous rare diseases. Since its birth, 110 centers from 23 countries and 4 continents have joined the AIDA project. Fifty-four centers have already obtained the approval from their local Ethics Committees. Currently, the platform counts 290 users (111 Principal Investigators, 179 Site Investigators, 2 Lead Investigators, and 2 data managers). The Registry is collecting baseline and follow-up data using 3,769 fields organized into 23 instruments, which include demographics, history, symptoms, trigger/risk factors, therapies, and healthcare information access for USAIDs patients. Conclusions: The development of the AIDA International Registry for USAIDs patients will facilitate the online collection of real standardized data, connecting a worldwide group of researchers: the Registry constitutes an international multicentre observational groundwork aimed at increasing the patient cohort of USAIDs in order to improve our knowledge of this peculiar cluster of autoinflammatory diseases. NCT05200715 available at https://clinicaltrials.gov/.

Performance of the EULAR/ACR 2019 classification criteria for systemic lupus erythematous in monogenic lupus.

OBJECTIVE: To evaluate the application of the EULAR/ACR-2019 criteria to monogenic lupus patients and compare its performance against the SLICC-2012 criteria. METHODS: In a multicenter retrospective cohort study, consecutive patients with monogenic lupus from three tertiary lupus clinics were enrolled. The diagnosis of monogenic lupus was based on the expert physician's opinion or fulfilling the SLICC-2012 criteria. All enrolled patients had genetic variants. A control group of sporadic childhood SLE (cSLE) and non-SLE patients, were included. A descriptive data analysis was conducted, and the EULAR/ACR-2019 and SLICC-2012 criteria were applied to both groups. RESULTS: Forty-nine patients with monogenic lupus with a median age at diagnosis of 6.0 (IQR 3.0-10.8) years and 104 controls (55 patients with cSLE and 49 non-lupus patients with a median age at diagnosis of 10.0 and 5.0 respectively) were included. Forty-four (89.8%) patients with monogenic lupus fulfilled the EULAR/ACR-2019 with a mean score of 22.3±8.9. The most frequent domains were immunologic (93.9%), musculoskeletal and renal (each 57.1%), and mucocutaneous (55.1%). Fifty-four (98.2%) cSLE patients and six (12.2%) non-lupus patients met the EULAR/ACR-2019 criteria with a mean score of 22.5±9.2 and 8.5±5.2, respectively. The sensitivity of the EULAR/ACR-2019 criteria in monogenic lupus was 89.9% (95% CI: 78.3-90.2), while the specificity was 87.6% (95% CI: 75.2-88.7). CONCLUSION: This is the first and largest cohort of monogenic lupus patients testing the performance of the 2019-EULAR/ACR criteria. It efficiently classifies monogenic lupus patients, irrespective of the underlying genetic variants. Further studies are needed before these criteria are adopted worldwide. Key Points • Typically, patients with monogenic lupus have early onset severe disease, especially with mucocutaneous manifestations and a strong family history of SLE. • Monogenic lupus is a distinctive entity and might differ from the sporadic childhood SLE. • Our study includes a large multinational cohort of monogenic lupus with heterogeneous phenotypic features and underlying genetic variants. • Our study demonstrates that the EULAR/ACR-2019 criteria efficiently classified monogenic lupus patients, irrespective of the diversity of the underlying genetic variants.

Establishing core domain sets for Chronic Nonbacterial Osteomyelitis (CNO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO): A report from the OMERACT 2020 special interest group.

OBJECTIVE: A working group was established to develop a core domain set (CDS) for Chronic Nonbacterial Osteomyelitis (CNO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO) following the OMERACT filter 2.1. METHODS: A scoping review to identify disease-related manifestations was performed, followed by a special interest group (SIG) session at OMERACT2020 to begin the CNO/SAPHO CDS framework. RESULTS: Candidate items were identified from the scoping review and most fell under Life Impact and Pathophysiology Manifestation core areas. A SIG agreed on the need to develop a CDS for CNO and SAPHO (100%) and for children and adults (91%). CONCLUSION: Based on candidate items identified, qualitative research and Delphi surveys will be performed as next steps.

Hallmark trials in ANCA-associated vasculitis (AAV) for the pediatric rheumatologist.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) refers to a complex group of systemic vasculitides that are characterized by primary small-to-medium sized blood vessel inflammation with the presence of autoantibodies known as ANCA. AAV diseases include Granulomatosis with Polyangiitis (GPA), Eosinophilic Granulomatosis with Polyangiitis (EGPA), and Microscopic Polyangiitis (MPA). AAVs are challenging conditions associated with high cumulative disease and treatment related morbidity and mortality. Given its rarity and the resulting paucity of pediatric-specific clinical trial evidence, pediatric rheumatologists have had to often extrapolate from adult literature for management and therapeutic decisions. The aim of this review is to provide a comprehensive overview of the important findings and overall conclusions of critical landmark clinical trials in the induction and maintenance treatments in adult AAV for the pediatric rheumatologist. This review also highlights the outcomes of recent pediatric AAV observational studies and discusses the future research priorities in pediatric AAV management.

Validation of the Cutaneous Lupus Erythematosus Disease Area and Severity Index and pSkindex27 for use in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To determine the measurement properties of the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) and the paediatric adaptation of the Skindex29 (pSkindex27) when used in childhood-onset SLE (cSLE). METHODS: Patients with mucocutaneous involvement of cSLE were evaluated at the study entry and 6 months later. Besides the CLASI and pSkindex27, the Pediatric Quality of Life Inventory Generic Core scale (PedsQL-GC), its Rheumatology Module (PedsQL-RM), the SLE Disease Activity Index (SLEDAI) and the SLE Damage Index (SDI) were completed. RESULTS: The CLASI and pSkindex27 had high internal consistency (both Cronbach α >0.82). Children were able to complete the pSkindex27, with self-report and caregiver proxy-reports showing excellent agreement (intraclass correlation coefficient=0.97). The CLASI Activity Score (CLASI-A) was strongly correlated with the mucocutaneous domain score of the SLEDAI as was the CLASI Damage Score (CLASI-D) with that of the SDI (both: Spearman correlation coefficients (rs) >0.68). pSkindex27 summary scores were moderately correlated with those of the PedsQL-GC and PedsQL-RM (all: rs >|0.51|), the CLASI-A and CLASI-D (both: rs > 0.64), respectively. Patients who experienced a >50% improvement of the CLASI-A between study visits had significantly higher PedsQL-GC and pSkindex27 scores than those without improvement of mucocutaneous features. CONCLUSION: Both CLASI and pSkindex27 are useful assessment tools in cSLE, active and chronic mucocutaneous lesions and their changes over time can be measured using the CLASI and the pSkindex27 can capture the impact of mucocutaneous involvement on patient health-related quality of life.

Monogenic interferonopathies: Phenotypic and genotypic findings of CANDLE syndrome and its overlap with C1q deficient SLE.

OBJECTIVE: To report the clinical and genetic features of the first cases of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome in an Arab population and to compare them with patients of C1q deficient systemic lupus erythematosus (SLE). MATERIALS AND METHODS: This is a retrospective case series of patients with CANDLE syndrome and C1q deficient SLE seen at a single tertiary hospital. Medical records were reviewed for demographic data, clinical and laboratory features, histopathology and imaging findings, and response to therapeutic intervention. Descriptive data were summarized. RESULTS: Three patients from unrelated families fulfilled the clinical manifestations of CANDLE syndrome. The disease onset was within the first 4 months of age. Two patients had uncommon features including uveitis, pulmonary involvement, aseptic meningitis and global delay. Skin biopsy showed heterogeneous findings. Genomic DNA screening was homozygous for mutation in PSMB8, (NM_004159.4:c.212C>T, p.T71M) in one patient and inconclusive for the other two patients. The comparison group was three patients with familial C1q deficient SLE from three unrelated families, who were born to consanguineous parents with at least one affected sibling. They presented with extensive mucocutaneous lesions, discoid rash and scarring alopecia. They required frequent admissions due to infections. CONCLUSION: This is the first report of CANDLE syndrome in an Arab population; our patients had heterogeneous phenotypic and genetic features with overlap manifestations with C1q deficient SLE. Both are monogenic interferonopathies. However, C1q deficient SLE had more systemic inflammatory disease.

Vitamin D status in children with systemic lupus erythematosus and its association with clinical and laboratory parameters.

To assess serum 25-hydroxyvitamin D (25-OH vitamin D) status in Saudi children with systemic lupus erythematosus (SLE) and determined its association with clinical, laboratory variables and disease activity. This cross-sectional study comprised children with SLE who are followed at Pediatric Lupus Clinic. All patients reviewed for demographic data, age of first disease manifestations, and disease duration. All included patients evaluated for disease activity, which is completed by using the SLE Disease Activity Index (SLEDAI) and laboratory parameters included a vitamin D profile, bone markers at enrollment and 3 months later. All patients treated with Cholecalciferol (vitamin D3 2000 IU daily) and calcium supplement (Caltrate 600 mg twice daily). Twenty-eight patients (26 female) with mean age of 9.7 years completed the evaluation. Fifteen patients had more than one major organ involvement. Most of the patients are on daily vitamin D3 supplement (800 IU) prior enrollment. The baseline assessment revealed 24 patients had low levels of serum 25-OH vitamin D levels, with a mean of 51.1 ± 33.6 nmol/L; 25 patients had high autoantibodies; and 18 patients had high protein/creatinine ratio, with a mean of 0.9 ± 1.7. Bone density was subnormal with a mean of 0.9 ± 1. The mean disease activity was 6 ± 5.6. Levels of 25-OH vitamin D correlated inversely with autoantibodies and SLEDAI and positively with bone density but not statistically significant. After 3 months, treatment of vitamin D3 (2000 IU daily) and Caltrate (600 mg twice daily), 17 patients had improvement in SLEDAI score and autoimmune markers. Disease activity of childhood SLE is probably linked with low serum 25-OH vitamin D levels. Accordingly, high daily vitamin D3 supplement could potentially impact disease activity of childhood SLE. Further follow up and more patients needed to confirm this finding.

The impact of antiphospholipid antibodies in children with lupus nephritis.

BACKGROUND AND OBJECTIVES: To evaluate the frequency of antiphospholipid antibodies (APLa) among patients with childhood lupus nephritis (cLN) and to assess their impact on long-term renal outcomes. DESIGN AND SETTING: This is an observational hospital based study. PATIENTS AND METHODS: Patients with cLN diagnosed by renal biopsy seen between January 2002 and June 2014 were included. APLa positivity was defined if detection was positive on 2 occasions 6-12 weeks apart during their follow up. Demographic features, age at disease onset, disease duration, follow-up duration and clinical and laboratory variables at the time of renal biopsy were collected. The renal biopsy was reviewed for the nephritis class, microthrombi, activity and chronicity indices. Renal outcome measures included the serum creatinine levels, protein/creatinine ratio and end stage renal disease (ESRD). RESULTS: Fifty-nine, (49 female) patients with a mean age of 19.8 years and mean disease duration of 6.8 years were involved. APLa were detected in 46 (78%) patients. Twenty-two patients had class IV nephritis, which was more prevalent in APLa positive patients. The frequencies of class III and V nephritis was similar in 10 patients in each class (7 patients in each class with APLa). The presence of APLa did not correlate with nephritis activity or the chronicity indices. Microthrombosis was found in 10 patients, and 8 of them had APLa. Patients with APLa had a higher frequency of elevated serum creatinine and hypertension, 9 developed ESRD, and 7 had APLa. There was no statistically significant association between the presence of APLa and the accrual damage index and clinical manifestations. Furthermore, there was no association between APLa and other autoantibodies. CONCLUSION: The frequency of APLa in cLN was high. While the association is not statistically significant, APLa positive patients tend to develop renal microthrombi and are probably at higher risk of ESRD.