Childhood-onset systemic lupus erythematosus (cSLE) and malignancy: a nationwide multicentre series review.

BACKGROUND: Increased malignancy frequency is well documented in adult-systemic lupus erythematosus (SLE), but with limited reports in childhood-onset SLE (cSLE) series. We explored the frequency of malignancy associated with cSLE, describing clinical and demographic characteristics, disease activity and cumulative damage, by the time of malignancy diagnosis. METHOD: A retrospective case-notes review, in a nationwide cohort from 27 Pediatric Rheumatology centres, with descriptive biopsy-proven malignancy, disease activity/damage accrual, and immunosuppressive treatment were compiled in each participating centre, using a standard protocol. RESULTS: Of the 1757 cSLE cases in the updated cohort, 12 (0.7%) developed malignancy with median time 10 years after cSLE diagnosis. There were 91% females, median age at cSLE diagnosis 12 years, median age at malignancy diagnosis 23 years. Of all diagnosed malignancies, 11 were single-site, and a single case with concomitant multiple sites; four had haematological (0.22%) and 8 solid malignancy (0.45%). Median (min-max) SLEDAI-2 K scores were 9 (0-38), median (min-max) SLICC/ACR-DI (SDI) score were 1 (1-5) Histopathology defined 1 Hodgkin's lymphoma, 2 non-Hodgkin's lymphoma, 1 acute lymphoblastic leukaemia; 4 gastrointestinal carcinoma, 1 squamous cell carcinoma of the tongue and 1 anal carcinoma; 1 had sigmoid adenocarcinoma and 1 stomach carcinoid; 3 had genital malignancy, being 1 vulvae, 1 cervix and 1 vulvae and cervix carcinomas; 1 had central nervous system oligodendroglioma; and 1 testicle germ cell teratoma. CONCLUSION: Estimated malignancy frequency of 0.7% was reported during cSLE follow up in a multicentric series. Median disease activity and cumulative damage scores, by the time of malignancy diagnoses, were high; considering that reported in adult series.

Chronic neutropenia in childhood: experience of a tertiary center.

OBJECTIVE: To assess the prevalence of chronic neutropenia (CN) and the clinical profile of patients with CN aged up to 18 years, followed in the pediatric hematology, rheumatology, or immunology outpatient clinic of a tertiary medical center from May 1, 2018, to 30 April 2019. METHODS: Retrospective observational study carried out by collecting data from the patient's medical charts. CN was defined as absolute neutrophil count (ANC) below 1.5 × 109/L lasting over three months. Autoimmune neutropenia (AIN) was defined by clinical criteria and an over twofold increase in ANC after glucocorticoid stimulation. AIN was considered secondary when associated with autoimmune or immunoregulatory disorders. Wilcoxon and Fisher's exact tests were used to compare variables; the significance level was 5 %. RESULTS: A total of 1,039 patients were evaluated; 217 (20 %) presented CN. Twenty-one (2 %) had AIN, classified as primary in 57 % of the cases. The average age at the onset of symptoms was 38.6 months. During follow-up, patients had 4.2 infections on average; frequency was higher among patients with secondary AIN (p = 003). Isolated neutropenia occurred in 43 % of the patients with AIN. Neutropenia resolved in eight (38 %) of the 21 patients with AIN within 19.6 months on average. Eight patients with secondary AIN met the criteria for Inborn Errors of Immunity. CONCLUSION: AIN prevalence was 2 %. Most cases were first evaluated by a pediatric immunologist or rheumatologist rather than a pediatric hematologist. This study highlights the need for a multidisciplinary approach involving a pediatric immunologist, rheumatologist, and hematologist.

A brazilian nationwide multicenter study on deficiency of deaminase-2 (DADA2).

INTRODUCTION: The deficiency of ADA2 (DADA2) is a rare autoinflammatory disease provoked by mutations in the ADA2 gene inherited in a recessive fashion. Up to this moment there is no consensus for the treatment of DADA2 and anti-TNF is the therapy of choice for chronic management whereas bone marrow transplantation is considered for refractory or severe phenotypes. Data from Brazil is scarce and this multicentric study reports 18 patients with DADA2 from Brazil. PATIENTS AND METHODS: This is a multicentric study proposed by the Center for Rare and Immunological Disorders of the Hospital 9 de Julho - DASA, São Paulo - Brazil. Patients of any age with a confirmed diagnosis of DADA2 were eligible for this project and data on clinical, laboratory, genetics and treatment were collected. RESULTS: Eighteen patients from 10 different centers are reported here. All patients had disease onset at the pediatric age (median of 5 years) and most of them from the state of São Paulo. Vasculopathy with recurrent stroke was the most common phenotype but atypical phenotypes compatible with ALPS-like and Common Variable Immunodeficiency (CVID) was also found. All patients carried pathogenic mutations in the ADA2 gene. Acute management of vasculitis was not satisfactory with steroids in many patients and all those who used anti-TNF had favorable responses. CONCLUSION: The low number of patients diagnosed with DADA2 in Brazil reinforces the need for disease awareness for this condition. Moreover, the absence of guidelines for diagnosis and management is also necessary (t).

Chronic arthritis related to SARS-CoV-2 infection in a pediatric patient: A case report.

Although the pattern of proinflammatory cytokines induced in COVID-2019 is similar to that of rheumatoid arthritis, the association of arthritis with SARS-CoV-2 infection is extremely rare and the symptoms are generally acute and self-limited. Herein we present the clinical case of a child who developed chronic arthritis after SARS-CoV-2 infection. An 11-year-old girl started with symptoms of multisystem inflammatory syndrome temporally associated with COVID-19 infection and subsequently developed chronic arthritis. After six weeks of arthritis, corticosteroids were started which resulted in clinical improvement after two weeks of use. Serology for SARS-CoV-2 was positive in the fifth week after symptom onset. Currently, the patient has no clinical complaints but continues to experience morning stiffness, high erythrocyte sedimentation rate, and synovial hypertrophy with no power Doppler signal on ultrasound. We alert to the possibility that SARS-CoV-2 may be a trigger of chronic arthritis.

Chronic arthritis related to SARS-CoV-2 infection in a pediatric patient: A case report

ABSTRACT Although the pattern of proinflammatory cytokines induced in COVID-2019 is similar to that of rheumatoid arthritis, the association of arthritis with SARS-CoV-2 infection is extremely rare and the symptoms are generally acute and self-limited. Herein we present the clinical case of a child who developed chronic arthritis after SARS-CoV-2 infection. An 11-year-old girl started with symptoms of multisystem inflammatory syndrome temporally associated with COVID-19 infection and subsequently developed chronic arthritis. After six weeks of arthritis, corticosteroids were started which resulted in clinical improvement after two weeks of use. Serology for SARS-CoV-2 was positive in the fifth week after symptom onset. Currently, the patient has no clinical complaints but continues to experience morning stiffness, high erythrocyte sedimentation rate, and synovial hypertrophy with no power Doppler signal on ultrasound. We alert to the possibility that SARS-CoV-2 may be a trigger of chronic arthritis.

Higher interferon score and normal complement levels may identify a distinct clinical subset in children with systemic lupus erythematosus.

BACKGROUND: Systemic lupus erythematosus (SLE) is a complex multi-system disease, characterized by both autoimmune and autoinflammatory clinical and laboratory features. The role of type I interferon (IFN) in SLE has been demonstrated from the 2000s, by gene expression analyses showing significant over-expression of genes related to type I IFN signalling pathway (IFN signature). However, several studies questioned the role of measuring the intensity of IFN signature (IFN score) to chase SLE activity. We would assess if the IFN signature can help the clinical and therapeutic stratification of patients with pediatric SLE. METHODS: We measured the IFN score in peripheral whole blood from a series of subjects with childhood-onset SLE and correlated the results with clinical and laboratory parameters. RESULTS: Thirty-one subjects were included in the study, among which the 87% displayed a positive IFN score. The only significant relation was found for high IFN score in subjects with normocomplementemia. No correlation was observed between IFN score and SLEDAI-2K, BILAG-2004 and SLICC. Patients with high IFN score and normal complement levels also presented lower anti-dsDNA antibodies. CONCLUSIONS: The integration between IFN signature analysis and complement levels may easily distinguish two groups of subjects, in which the autoimmune or autoinflammatory component of the disease seems to be prevalent.

Homocysteine, folate, hs-C-reactive protein, tumor necrosis factor alpha and inflammatory proteins: are these biomarkers related to nutritional status and cardiovascular risk in childhood-onset systemic lupus erythematosus?

BACKGROUND: Childhood-onset systemic lupus erythematosus (c-SLE) is a chronic autoimmune disease which increases cardiovascular risk factors (CRF) such as elevated homocysteine, TNF-α, and hs-C reactive protein. METHODS: We evaluated BMI, waist circumference (WC), 24-h recalls, SLEDAI-2 K, SLICC/ACR-DI, serum levels of homocysteine, folate, TNF-α, hs-C reactive protein, lipid profile, proteomic data, and duration of corticosteroid therapy in 19 c-SLE and 38 healthy volunteers. Physiological and anthropometric variables of c-SLE and healthy controls were compared by ANCOVA. k-cluster was used to separate c-SLE into two different groups with the best and the worst metabolic profile according to previous analysis showing some metabolites that were statistically different from controls, such as homocysteine, TNF-α, hs-CRP and folate levels. These two clusters were again compared with the control group regarding nutritional parameters, lipid profile and also proteomic data. RESULTS: Individuals with c-SLE presented higher BMI, WC, homocysteine, triglycerides, TNF-α, hs-CRP and lower folate levels when compared to controls. We found 10 proteins whose relative abundances were statistically different between control group and lupus clusters with the best (LCBMP) and the worst metabolic profile (LCWMP). A significant positive correlation was found between TNF-α and triglycerides and between hs-CRP and duration of corticosteroid therapy. CONCLUSION: Cardiovascular disease (CVD) risk parameters were worse in c-SLE. A less protective CVD proteomic profile was found in LCWMP.

Musculoskeletal Disease in MDA5-Related Type I Interferonopathy: A Mendelian Mimic of Jaccoud's Arthropathy.

OBJECTIVE: To define the molecular basis of a multisystem phenotype with progressive musculoskeletal disease of the hands and feet, including camptodactyly, subluxation, and tendon rupture, reminiscent of Jaccoud's arthropathy. METHODS: We identified 2 families segregating an autosomal-dominant phenotype encompassing musculoskeletal disease and variable additional features, including psoriasis, dental abnormalities, cardiac valve involvement, glaucoma, and basal ganglia calcification. We measured the expression of interferon (IFN)-stimulated genes in the peripheral blood and skin, and undertook targeted Sanger sequencing of the IFIH1 gene encoding the cytosolic double-stranded RNA (dsRNA) sensor melanoma differentiation-associated protein 5 (MDA-5). We also assessed the functional consequences of IFIH1 gene variants using an in vitro IFNß reporter assay in HEK 293T cells. RESULTS: We recorded an up-regulation of type I IFN-induced gene transcripts in all 5 patients tested and identified a heterozygous gain-of-function mutation in IFIH1 in each family, resulting in different substitutions of the threonine residue at position 331 of MDA-5. Both of these variants were associated with increased IFNß expression in the absence of exogenous dsRNA ligand, consistent with constitutive activation of MDA-5. CONCLUSION: These cases highlight the significant musculoskeletal involvement that can be associated with mutations in MDA-5, and emphasize the value of testing for up-regulation of IFN signaling as a marker of the underlying molecular lesion. Our data indicate that both Singleton-Merten syndrome and neuroinflammation described in the context of MDA-5 gain-of-function constitute part of the same type I interferonopathy disease spectrum, and provide possible novel insight into the pathology of Jaccoud's arthropathy.

Uveitis in childhood-onset systemic lupus erythematosus patients: a multicenter survey.

The aim of this study is to assess uveitis prevalence in a large cohort of childhood-onset systemic lupus erythematosus (cSLE) patients. A retrospective multicenter cohort study including 852 cSLE patients was performed in ten pediatric rheumatology centers (Brazilian cSLE group). An investigator meeting was held and all participants received database training. Uveitis was diagnosed through clinical assessment by the uveitis expert ophthalmologist of each center. Patients with and without uveitis were assessed for lupus clinical/laboratory features and treatments. Uveitis was observed in 7/852 cSLE patients (0.8%). Two of them had ocular complications: cataract and irreversible blindness in one patient and retinal ischemia with subsequent neovascularization and unilateral blindness in another. Uveitis was identified within the first 6 months of cSLE diagnosis in 6/7 patients (86%). Comparison of a subgroup of cSLE patients with (n = 7) and without uveitis (n = 73) and similar length of disease duration showed that patients with uveitis had increased SLEDAI-2K score (19 vs. 6; p < 0.01). In addition, fever (71 vs. 12%; p < 0.01), lymphadenopathy (29 vs. 1.4%; p = 0.02), arthritis (43 vs. 7%; p = 0.02), and use of intravenous methylprednisolone (71 vs. 22%; p = 0.01) were higher in cSLE patients with uveitis, as compared to those without this manifestation, respectively. Presence of fever was significantly associated with uveitis, independently of SLEDAI scores or use of intravenous methylprednisolone pulses, as shown by adjusted regression analysis (adjusted prevalence ratio 35.7, 95% CI 2.4-519.6; p < 0.01). Uveitis was a rare and initial manifestation of active cSLE patients. Early recognition is essential due to the possibility of irreversible blindness.