Significance of the weighted complement domain of the EULAR/ACR classification criteria in juvenile onset systemic lupus erythematosus.

OBJECTIVE: We aimed to compare the clinical and laboratory characteristics of patients with SLE according to the weighted complement status of the EULAR/ACR criteria and investigate whether different weighting of the complement status at disease onset is associated with outcomes. METHODS: Patients diagnosed with juvenile onset SLE who fulfilled the 2019 EULAR/ACR classification criteria were retrospectively analyzed. RESULTS: Among 43 patients included, hypocomplementemia was observed in 37 (86%), mostly with a low level of both complement C3 (C3) and complement C4 (C4) (53.5%). In patients with low levels of both C3 and C4, more common cutaneous (65.2% vs 28.6%, p: 0.045), musculoskeletal involvement (78.3% vs 42.9%, p: 0.039), autoimmune hemolytic anemia (52.2% vs 14.3%, p: 0.035), positive anti-dsDNA (65.2% vs 21.4%, p: 0.017) and anti-Sm antibodies (60.9% vs 21.4%, p: 0.04) were observed. In addition these patients had higher scores from the 2019 EULAR/ACR classification criteria (26 vs 15.5, p: < 0.0001). Remission and flare rates, and SLE associated damage were not differed according to the complement status in patients with hypocomplementemia. CONCLUSION: Observation of more frequent clinical and serological activity with higher total scores from the EULAR/ACR classification criteria supported the higher scoring of patients with low C3 and C4 in the weighted criteria. However, since significant number of patients did not exhibit low complement C4, and the frequency of kidney involvement did not differ according to the weighted complement status, complement C3 might be suggested as a more important diagnostic tool in patients with juvenile onset SLE. Also, weighted complement status at onset did not seem to affect the disease outcomes.

Lupus low disease activity state as a treatment target for pediatric patients with lupus nephritis.

BACKGROUND: Lupus low disease activity state (LLDAS) is a treatment target for patients with SLE and is associated with decreased risk for severe flare and new damage. We investigated the utility of the achievement of LLDAS in children with lupus nephritis and whether attainment of LLDAS is associated with more favorable outcomes. METHODS: Data of children, diagnosed with biopsy-proven lupus nephritis between January 2012 and December 2020, were retrospectively analyzed. RESULTS: For patients who did not achieve LLDAS after initial treatment (first 6 months), presence of autoimmune hemolytic anemia (62% vs. 18%, p = 0.047), anti-Sm (85% vs. 18%, p = 0.003) and anti-dsDNA (77% vs. 27%, p = 0.038) antibodies, proliferative lupus nephritis (77% vs. 27%, p = 0.038), and hypertension (69% vs. 9%, p = 0.005) at onset were more frequently encountered. Also, a lower rate of complete kidney response (43% vs. 100%, p = 0.005) and a higher rate of hypertension (86% vs. 13%, p = 0.002) were observed in patients who did not achieve LLDAS-50, defined as being in LLDAS at least 50% of the observation time. Attainment of both LLDAS after initial treatment and LLDAS-50 were associated with lower rates of kidney flare (p = 0.001 and p = 0.002, respectively) and damage accrual (p = 0.007 and p = 0.02, respectively) through the observation period. CONCLUSIONS: LLDAS is an attainable treatment target for children with lupus nephritis and associated with lower rates of kidney flare and damage. Presence of hematologic involvement, hypertension, and proliferative lupus nephritis at onset adversely influenced the early achievement of LLDAS. A higher resolution version of the Graphical abstract is available as Supplementary information.

Early onset left ventricular remodeling in juvenile systemic lupus erythematosus; Insight from 3-dimensional speckle tracking echocardiography.

BACKGROUND: Early diagnosis and treatment of myocardial affection in patients with systemic lupus erythematosus (SLE) are crucial. OBJECTIVES: To evaluate the ventricular systolic function in juvenile-onset systemic lupus erythematosus (j-SLE) patients by 3-D speckle tracking echocardiography (3D-STE) and to determine the predictors of left ventricular (LV) dysfunction if present. METHODS: Twenty-six SLE patients without heart failure and 21 healthy controls were studied by standard echocardiogram and 3D-STE. Conventional parameters included LV ejection fraction (EF), fractional shortening (FS), and mitral annular plane systolic excursion (MAPSE). Global LV strain (GLS) and global area strain (GAS) were obtained by 3D-STE. Medical records, including diagnosis criteria, duration of disease, and SLE disease activity index (SLEDAI) were evaluated. RESULTS: The mean age was similar in patients and controls 11.42 vs 11.48 years p = 0.93. The mean duration of the disease was 1.87 ± 1.02 years and SLEDAI ranged from 0 to 9. By conventional and tissue Doppler imaging echocardiography, only MAPSE was significantly lower in SLE patients compared to controls (14.56 vs 18.46 mm, p < 0.001). By 3D speckle tracking echocardiography, GLS and GAS were significantly reduced in SLE patients compared to controls (-15.07 vs -19.9.4%, -34.6% vs -39.7%, respectively, p < 0.001). Multiple linear regression and ROC analyses indicated that the SLEDAI score was the only predictive factor for the left ventricular remodeling. CONCLUSIONS: These results indicate that early subclinical LV dysfunction occur in jSLE patients even with normal EF and SLE disease activity might be a potential driver for LV deformation.

Evaluation of Choroidal Thickness, Choroidal Vascularity Index and Peripapillary Retinal Nerve Fiber Layer in Patients with Juvenile Systemic Lupus Erythematosus.

OBJECTIVE: The aim of this study was to conduct a detailed ophthalmological examination in children with systemic lupus erythematosus (jSLE), including choroidal thickness (ChT), choroidal vascularity index (CVI) and peripapillary retinal nerve fiber layer (RNFL). METHODS: The study included all jSLE patients ( n = 21) diagnosed according to the Systemic Lupus International Collaborating Clinics classification criteria between January 2017 and April 2017, and an age- and gender-matched control group ( n = 21). The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) was used to assess disease activity. After routine eye examinations, ChT at five points (750 µ and 1500 µ from the center of the fovea both in the temporal and nasal quadrants and under the fovea), total subfoveal choroidal area (TCA), luminal area (LA), stromal area (SA), CVI and RNFL thickness at the optic disc were evaluated. RESULTS: One patient had active ocular involvement in the form of episcleritis. Another patient had corticosteroid-induced cataract. The median age of the patients was 16 years (6-19 years). ChT at five points, TCA, LA and SA were found to be higher in patients with jSLE, whereas RNFL thickness and CVI were similar to those of the healthy control individuals. No correlation was determined between optical coherence tomography findings, SLEDAI and the immunological parameters (antinuclear antibodies, anti-double-stranded DNA, complements 3 and 4, extracted nuclear antigen antibody, antiphospholipid antibody). Intraretinal and subretinal fluid was not present in any of the patients. CONCLUSION: The choroid was thicker in patients with jSLE than in the control group. The study results suggest that jSLE may affect the choroid. Ophthalmological evaluation is important in SLE patients, even in the absence of relevant complaints.

Low C4, C4A and C4B gene copy numbers are stronger risk factors for juvenile-onset than for adult-onset systemic lupus erythematosus.

OBJECTIVE: Complete deficiency of Complement C4 component is a strong genetic risk factor for SLE. C4 is encoded by two different genes, C4A and C4B, which show considerable gene copy number (GCN) variation. This study investigates the association of total C4, C4A and C4B GCN with JSLE. METHODS: Ninety JSLE patients, 170 adult-onset SLE (aSLE) patients and 200 healthy individuals were evaluated for C4A and C4B GCN by quantitative real-time PCR. RESULTS: JSLE patients had lower GCN for C4A (mean = 1.7; 95% CI: 1.5, 1.9) and C4B (mean = 1.5; 95% CI: 1.3, 1.6) compared with healthy individuals (mean C4A = 2.3; 95% CI: 2.2, 2.5, P < 0.001; C4B = 2.0; 95% CI: 1.8, 2.1; P < 0.001) or with aSLE patients (mean C4A = 1.9; 95% CI: 1.8, 2.1, P = 0.006; mean C4B = 1.8; 95% CI: 1.7, 1.9, P < 0.001). Low total C4 GCN (<4 copies) was more frequent in JSLE than in healthy individuals (59% vs 28%; P < 0.001). The same was observed for low C4A (⩽1 copy) (52% vs 18%; P < 0.001) and for low C4B (60% vs 31%; P < 0.001). JSLE had a stronger association with low total C4 (OR = 3.68, 95% CI: 2.19, 6.20), C4A (OR = 4.98, 95% CI: 2.88, 8.62) and C4B (OR = 3.26; 95% CI: 1.95, 5.47) than aSLE (C4 OR = 2.03; 95% CI: 1.32, 3.13; C4A OR = 2.36; 95% CI: 1.46, 3.81; C4B OR = 1.13; 95% CI: 0.73, 1.74). In addition, pericarditis in JSLE patients was associated with low C4 (OR = 4.13; 95% CI: 1.02, 16.68; P = 0.047) and low C4A (OR = 5.54; 95% CI: 1.37, 22.32; P = 0.016). CONCLUSION: Low total C4, C4A and C4B GCN were associated with a stronger risk for developing JSLE than aSLE. Additionally, low total C4 and C4A GCN are risk factors for pericarditis in JSLE.

Correcting the expression of miRNA-155 represses PP2Ac and enhances the release of IL-2 in PBMCs of juvenile SLE patients.

MicroRNA-155 is involved in immune cell, differentiation, maturation and function. MiR-155 showed variable dysregulated expression in autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) patients. MiR-155 was previously confirmed to directly target CAMP response element binding protein (CREB), which was previously identified as a positive regulator of protein phosphatase 2A (PP2A). PP2A is a key negative regulator of interleukin-2, which is an important immune modulator and was previously shown to be decreased in SLE. In this study we aimed at investigating the regulation of PP2A by miR-155 and hence its role in juvenile SLE disease pathogenesis. MiR-155 showed significant downregulation in PBMCs from juvenile SLE and juvenile familial Mediterranean fever (FMF) and significant upregulation in PBMCs from juvenile idiopathic arthritis (JIA) patients. In SLE, miR-155 expression was negatively correlated with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score and proteinuria and was positively correlated with white blood cell (WBC) count. The mRNA of the catalytic subunit of PP2A (PP2Ac) showed significant upregulation in PBMCs from SLE and FMF but not in JIA patients. Additionally, the relative expression of PP2Ac mRNA was positively correlated with SLEDAI score. Forced expression of miR-155 led to decreased relative expression of PP2Ac mRNA and increased IL-2 release in cultured-stimulated PBMCs. This study suggests for the first time the possible role of an miR-155-PP2Ac loop in regulating IL-2 release and identifies miR-155 as a potential therapeutic target in juvenile SLE disease through relieving IL-2 from the inhibitory role of PP2A.

Oral Lesion Management in Juvenile SLE with Hepatosplenomegaly.

Background: Systemic Lupus Erythematosus (SLE) is an autoimmune disease with unknown etiology resulting in chronic multi-organ inflammation. Juvenile Systemic Lupus Erythematosus (JSLE) is a specific diagnosis of SLE in juvenile, characterized by oral ulceration. Purpose: This case report attempts to provide information for oral medicine specialists in managing JSLE patients with hepatosplenomegaly. Case Presentation: A 17-year-old female patient was referred from the Pediatrics Department with mouth ulcers accompanied by dry lips and a tendency to bleed. The most concerning lesion was located on the left buccal mucosa, a single ulceration measuring 5x6mm. Multiple ulcerations spread over the upper and lower labial mucosa, with haemorrhagic crusts on the lips. Painful ulceration can lead to difficulties in mouth opening and impaired function in eating and drinking. Central erythema was seen on the palate. Pseudomembranous candidiasis was also seen on the patient's tongue. The hepatosplenomegaly was confirmed by CT scan, with enzyme values of SGPT (386 U/L) and SGOT (504 U/L). Case Management: Administration of 0.9% NaCl was instructed to the patient to maintain oral hygiene and help moisturize lips in order to remove haemorrhagic crusts. Administration of 0.025% hyaluronic acid mouthwash and topical steroid ointment mixture for ulcerated and inflammatory conditions. Drug adjustments were made based on laboratory tests and the patient's clinical condition was improving. Conclusion: Managing oral symptoms helps reduce morbidity in JSLE patients. Topical corticosteroids are considered the first line in controlling oral inflammation. Dentists play a role in improving patients' oral hygiene with the aim of reducing the risk of other opportunistic infections.

Oral lesions in adult- and juvenile-onset systemic lupus erythematosus patients: A case series report.

Systemic lupus erythematosus (SLE) is an autoimmune disease with various oral manifestations, including ulceration, white keratotic plaques, oral discoid lupus erythematosus, oral lichen planus (OLP)-like lesions, non-specific erythema, purpura, petechiae, and cheilitis, which resemble lesions of other systemic diseases. Recognizing the oral manifestation of SLE is essential for comprehensive patient management. This study reports 4 cases of SLE with various oral lesions, underlying conditions and diagnostic methods.In September 2019, 2 adult SLE patients and 2 juvenile SLE patients were consulted at the Oral Medicine Clinic. The assessment of systemic diseases was conducted by the Internal Medicine and Pediatrics resident, whereas the Oral Medicine resident performed the intraoral examinations. The medical history, clinical findings and laboratory results were analyzed to establish the diagnosis.The first patient was a 38-year-old female presenting with multiple white keratotic plaques throughout the mucosa, an OLP-like lesion on the right buccal mucosa, petechiae on the hard palate, and petechiae and purpura on the upper and lower extremities. The second case was a 24-year-old female with a malar rash and multiple ulcerations on the vermilion zone, an OLP-like lesion on the left buccal mucosa, and a palatal ulcer. The third and fourth cases were 16-year-old females with a prominent butterfly rash. The patients presented with acute pseudomembranous candidiasis, an aphthous-like ulcer and keratotic plaques. They received antimicrobial therapy for the intraoral lesions and showed promising results.The oral lesions in adultand juvenile-onset SLE patients varied depending on the disease severity and treatment received.

Reduced expressions of apoptosis-related proteins TRAIL, Bcl-2, and TNFR1 in NK cells of juvenile-onset systemic lupus erythematosus patients: relations with disease activity, nephritis, and neuropsychiatric involvement.

Background: Lupus pathogenesis is mainly ascribed to increased production and/or impaired clearance of dead cell debris. Although self-reactive T and B lymphocytes are critically linked to lupus development, neutrophils, monocytes, and natural killer (NK) cells have also been implicated. This study assessed apoptosis-related protein expressions in NK cells of patients with juvenile-onset systemic lupus erythematosus (jSLE) and relations to disease activity parameters, nephritis, and neuropsychiatric involvement. Methods: Thirty-six patients with jSLE, 13 juvenile dermatomyositis (JDM) inflammatory controls, and nine healthy controls had Fas, FasL, TRAIL, TNFR1, Bcl-2, Bax, Bim, and caspase-3 expressions in NK cells (CD3-CD16+CD56+) simultaneously determined by flow cytometry. Disease activity parameters included Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, erythrocyte sedimentation rate, C-reactive protein level, anti-double strain DNA antibody level, complement fractions C3 and C4 levels. Results: Patients with jSLE had a profile of significantly reduced expression of TRAIL, Bcl-2, and TNFR1 proteins in NK cells when compared to healthy controls. Similar profile was observed in patients with jSLE with active disease, positive anti-dsDNA, nephritis, and without neuropsychiatric involvement. Patients with jSLE with positive anti-dsDNA also had reduced expression of Bax in NK cells when compared healthy controls and to those with negative anti-dsDNA. Yet, patients with jSLE with negative anti-dsDNA had reduced mean fluorescence intensity (MFI) of Bim in NK cells compared to healthy controls. Patients with jSLE with nephritis also had reduced MFI of Fas in NK cells when compared to those without nephritis. In addition, in patients with jSLE, the proportion of FasL-expressing NK cells directly correlated with the SLEDAI-2K score (rs = 0.6, p = 0.002) and inversely correlated with the C3 levels (rs = -0.5, p = 0.007). Moreover, patients with jSLE had increased NK cell percentage and caspase-3 protein expression in NK cells when compared to JDM controls. Conclusion: This study extends to NK cells an altered profile of TRAIL, Bcl-2, TNFR1, Fas, FasL, Bax, Bim, and caspase-3 proteins in patients with jSLE, particularly in those with active disease, positive anti-dsDNA, nephritis, and without neuropsychiatric involvement. This change in apoptosis-related protein expressions may contribute to the defective functions of NK cells and, consequently, to lupus development. The full clarification of the role of NK cells in jSLE pathogenesis may pave the way for new therapies like those of NK cell-based.

Successful use of ofatumumab in two cases of early-onset juvenile SLE with thrombocytopenia caused by a mutation in protein kinase C δ.

BACKGROUND: We previously described an endogamous Pakistani kindred in whom we identified a novel homozygous missense mutation in the PRKCD gene encoding for protein kinase C δ (PKCδ) as a cause of monogenic systemic lupus erythematosus (SLE). PKCδ has a role in the negative regulation of B cells. Given the nature of the disease, a logical targeted therapeutic approach in these patients is B cell depletion. Indeed, the 3 siblings all had a marked clinical response and resolution of symptoms with rituximab, although 2 of the siblings had severe reactions to rituximab thus precluding further treatment with this. We therefore describe the first successful use of ofatumumab for this rare form of monogenic SLE. CASE PRESENTATION: All three affected siblings presented with SLE before the age of 3-years with lethargy, intermittent fever, thrombocytopenia, cutaneous involvement, alopecia, and hepatosplenomegaly. Tubulointerstitial nephritis was also present in 1 of the siblings. Homozygosity mapping followed by whole exome sequencing identified a homozygous missense mutation in PRKCD (p.Gly432Trp), subsequently confirmed by Sanger sequencing to be present in all 3 siblings. All 3 patients were initially treated with rituximab, however 2 of the siblings developed severe infusion-related reactions. For subsequent disease flare in these individuals we therefore used an alternative B cell depleting agent, ofatumumab (300 mg/1.73m2 on day 1; 700 mg/1.73m2 on day 15). This resulted in marked clinical improvement in both patients. To the best of our knowledge, this is the first report describing the successful use of ofatumumab for PKCδ deficiency. CONCLUSIONS: PKCδ deficiency causes a monogenic form of SLE which responds well to B cell depletion. Ofatumumab is also likely to have a therapeutic role for sporadic juvenile SLE (jSLE) patients intolerant of rituximab.

Evaluation of magnetic resonance imaging abnormalities in juvenile onset neuropsychiatric systemic lupus erythematosus.

The aim of this study was to describe the abnormalities identified with conventional MRI in children with neuropsychiatric systemic lupus erythematosus (NPSLE). This was single-centre (Great Ormond Street Hospital, London) retrospective case series of patients with juvenile NPSLE seen in 2003-2013. Brain MR images of the first episode of active NPSLE were reviewed. All patients fulfilled the 1999 ACR case definitions for NPSLE syndromes. Presenting neuropsychiatric manifestations, immunological findings and treatment are reported. Results are expressed as median and ranges or percentages. Fisher's exact test was used to identify clinical predictors of abnormal MRI. A total of 27 patients (22 females), median age 11 years (4-15), were identified. Presenting clinical symptoms included the following: headaches (85.1 %), mood disorder/depression (62.9 %), seizures (22.2 %), acute psychosis (18.5 %), cognitive dysfunction (14.8 %), movement disorder (14.8 %), acute confusional state (14.8 %), aseptic meningitis (7.4 %), demyelinating syndrome (3.7 %), myelopathy (3.7 %), dysautonomia (3.7 %) and cranial neuropathy (3.7 %). The principal MR findings were as follows: (1) absence of MRI abnormalities despite signs and symptoms of active NPSLE (59 %); (2) basilar artery territory infarction (3 %); (3) focal white matter hyperintensities on T2-weighted imaging (33 %); (4) cortical grey matter lesions (3 %); and (5) brain atrophy (18.5 %). The presence of an anxiety disorder strongly associated with abnormal MRI findings (p = 0.008). In over half the children with NPSLE, no conventional MRI abnormalities were observed; white matter hyperintensities were the most commonly described abnormalities. Improved MR techniques coupled with other alternative diagnostic imaging modalities may improve the detection rate of brain involvement in juvenile NPSLE.

Paediatric-onset systemic lupus erythematosus.

Paediatric-onset systemic lupus erythematosus (SLE) is usually more severe than its adult counterpart. In particular, there is a higher incidence of renal and central nervous system involvement. Specific measures to assess disease activity and damage have been implemented. The disease is very rare before the fifth birthday and therefore the onset of an SLE picture in the first years of life should lead to the suspicion of the presence of one of the rare monogenic diseases that causes SLE or of one of those congenital diseases that has been showed to be closely associated with the SLE.