Gender differences in juvenile systemic sclerosis patients: Results from the international juvenile scleroderma inception cohort.

Objective: To compare organ involvement and disease severity between male and female patients with juvenile onset systemic sclerosis. Methods: Demographics, organ involvement, laboratory evaluation, patient-reported outcomes and physician assessment variables were compared between male and female juvenile onset systemic sclerosis patients enrolled in the prospective international juvenile systemic sclerosis cohort at their baseline visit and after 12 months. Results: One hundred and seventy-five juvenile onset systemic sclerosis patients were evaluated, 142 females and 33 males. Race, age of onset, disease duration, and disease subtypes (70% diffuse cutaneous) were similar between males and females. Active digital ulceration, very low body mass index, and tendon friction rubs were significantly more frequent in males. Physician global assessment of disease severity and digital ulcer activity was significantly higher in males. Composite pulmonary involvement was also more frequent in males, though not statistically significantly. After 12 months, they are the pattern of differences changed female patients had significantly more frequent pulmonary involvement. Conclusion: In this cohort, juvenile onset systemic sclerosis had a more severe course in males at baseline and but the pattern changed after 12 months. Some differences from adult findings persisted, there is no increased signal of pulmonary arterial hypertension or heart failure in male pediatric patients. While monitoring protocols of organ involvement in juvenile onset systemic sclerosis need to be identical for males and females.

Clonally expanded PD-1-expressing T cells are enriched in synovial fluid of juvenile idiopathic arthritis patients.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic condition in childhood. The disease etiology remains largely unknown; however, a key role in JIA pathogenesis is surely mediated by T cells. T-lymphocytes activity is controlled via signals, known as immune checkpoints. Delivering an inhibitory signal or blocking a stimulatory signal to achieve immune suppression is critical in autoimmune diseases. However, the role of immune checkpoints in chronic inflammation and autoimmunity must still be deciphered. In this study, we investigated at the single-cell level the feature of T cells in JIA chronic inflammation, both at the transcriptome level via single-cell RNA sequencing and at the protein level by flow cytometry. We found that despite the heterogeneity in the composition of synovial CD4+ and CD8+ T cells, those characterized by PD-1 expression were clonally expanded tissue-resident memory (Trm)-like cells and displayed the highest proinflammatory capacity, suggesting their active contribution in sustaining chronic inflammation in situ. Our data support the concept that novel therapeutic strategies targeting PD-1 may be effective in the treatment of JIA. With this approach, it may become possible to target overactive T cells regardless of their cytokine production profile.

Semiquantitative classification (SQC) and Oxford classifications predict poor renal outcome better than The International Study of Kidney Disease in Children (ISKDC) and Haas in patients with IgAV nephritis: a multicenter study.

INTRODUCTION: Several histologic classifications are used in the evaluation of IgA vasculitis nephritis (IgAVN), however, to date, no studies have determined which one has the strongest association with the severity of IgAVN and, as a consequence, its outcomes. MATERIALS AND METHODS: Patients included in the study were diagnosed with IgAV and IgAVN in seven tertiary university medical centers in Croatia, Italy and Israel. The International Study of Kidney Disease in Children (ISKDC), Haas, Oxford, and Semiquantitative classification (SQC) classifications were used in the analysis and description of renal biopsy. Time from biopsy to outcome evaluation was a statistically significant factor in outcome prediction that was used to define the base model, and was a covariate in all the tested models. RESULTS: Sixty-seven patients were included in this study. The SQC classification proved to be the best one in outcome prediction, followed by the Oxford classification. The ISKDC and Haas classifications could not predict renal outcome. The Oxford parameters for mesangial hypercellularity and tubular atrophy, as well as the SQC parameters for cellular crescents showed an independent statistically significant contribution to outcome prediction. High level of twenty-four hour protein excretion was associated with a higher grade in the Oxford, SQC and ISKDC classifications. Endocapillary proliferation was positively associated with the Pediatric Vasculitis Activity Score (PVAS) at diagnosis, while tubular atrophy was negatively associated. CONCLUSION: The SQC, followed by the Oxford classification were found to provide the best classifications of renal biopsy analysis in patients to predict the outcome in patients with IgAVN. Cellular crescents, mesangial hypercellularity and tubular atrophy showed significant contributions, indicating that active and chronic variables should be included in the estimation.

Pediatric Recurrent Pericarditis: Appropriateness of the Standard of Care and Response to IL-1 Blockade.

OBJECTIVE: To analyze, in a cohort of pediatric patients with recurrent pericarditis undergoing anti-interleukin (IL)-1 treatment: the agent and dosing used as first-line treatment, the long-term efficacy of IL-1 blockers, the percentage of patients achieving a drug-free remission, and the presence of variables associated with drug-free remission. STUDY DESIGN: Data were collected from patients' charts. The annualized relapse rate (ARR) was used for evaluation of treatment efficacy, and bivariate logistic regression analysis was used for variables associated with drug-free remission. RESULTS: Fifty-eight patients, treated between 2008 and 2018, were included in the study (mean follow-up. 2.6 years). Of the 56 patients treated with first-line drugs, 14 not responsive patients were underdosed. Fifty-seven patients were treated with anakinra: the ARR before and during daily treatment was 3.05 and 0.28, respectively (P < .0001); an increase to 0.83 was observed after the reduction/withdrawal of treatment (P < .0001). The switch from anakinra to canakinumab (5 patients) was associated to an increase of the ARR (0.49 vs 1.46), but without statistical significance (P = .215). At last follow-up, only 9 of the 58 patients had withdrawn all treatments. With the limits of a retrospective study and the heterogeneity between the patients enrolled in the study, a shorter duration of treatment with anakinra was the only variable associated with drug-free remission. CONCLUSIONS: This study shows that most pediatric patients with recurrent pericarditis needing IL-1 blockade received an inadequate treatment with first-line agents. The effectiveness of anakinra is supported by this study, but few patients achieved drug-free remission. The different rate of response to anakinra and canakinumab may suggest a possible role of IL-1α in the pathogenesis of recurrent pericarditis.

Anti-SSA/Ro positivity and congenital heart block: obstetric and foetal outcome in a cohort of anti-SSA/Ro positive pregnant patients with and without autoimmune diseases.

OBJECTIVES: Neonatal lupus (NL) is an acquired disease caused by the transplacental passage of anti-SSA/Ro antibodies. The rate of congenital heart block (CHB), its most serious manifestation, ranges from 1 to 5%. The aim of this study was to retrospectively assess the prevalence of CHB in anti-SSA/Ro positive pregnant women with or without systemic autoimmune diseases from 2010 to 2020. METHODS: Patients underwent monthly visit and a shared follow-up programme of weekly (16th-24th week) foetal heart rate assessment by obstetric ultrasound. RESULTS: 322 pregnancies in 258 anti-SSA/Ro patients were included; 314 were followed from the beginning of pregnancy because of the known presence of anti-SSA/Ro autoantibodies and 1 case of CHB occurred in an anti-SSA/Ro+ asymptomatic subject (0.3%). In the same period, 8 additional patients were referred to our clinics after in utero CHB diagnosis and subsequent discovery of anti-SSA/Ro without a disease diagnosis. Globally, 9 cases of congenital CHB (2.8%) occurred: 7 complete, 1 II-III degree and 1 rst degree CHB. Anti-SSB/La positivity was associated with a higher risk of CHB (7.8% vs. 1.2%; p=0.0071). No differences in maternal or foetal outcomes were found in comparison with a large cohort of unselected pregnancies except for caesarian section. Hydroxychloroquine (HCQ) was used in 58.3% pregnancies, with a different prevalence according with maternal diagnosis. CONCLUSIONS: Our data suggest that anti-SSA/Ro positive patents with a de ned systemic autoimmune disease undergoing a strict follow-up since positive pregnancy test display a low risk of pregnancy complications, including but not limited to NL.

Standardized nailfold capillaroscopy in children with rheumatic diseases: a worldwide study.

OBJECTIVES: To standardly assess and describe nailfold videocapillaroscopy (NVC) assessment in children and adolescents with juvenile rheumatic and musculoskeletal diseases (jRMD) vs healthy controls (HCs). MATERIAL AND METHODS: In consecutive jRMD children and matched HCs from 13 centres worldwide, 16 NVC images per patient were acquired locally and read centrally per international consensus standard evaluation of the EULAR Study Group on Microcirculation in Rheumatic Diseases. A total of 95 patients with JIA, 22 with JDM, 20 with childhood-onset SLE (cSLE), 13 with juvenile SSc (jSSc), 21 with localized scleroderma (lSc), 18 with MCTD and 20 with primary RP (PRP) were included. NVC differences between juvenile subgroups and HCs were calculated through multivariable regression analysis. RESULTS: A total of 6474 images were assessed from 413 subjects (mean age 12.1 years, 70.9% female). The quantitative NVC characteristics were significantly lower or higher in the following subgroups compared with HCs: for density: lower in jSSc, JDM, MCTD, cSLE and lSc; for dilations: higher in jSSc, MCTD and JDM; for abnormal shapes: higher in JDM and MCTD; for haemorrhages: higher in jSSc, MCTD, JDM and cSLE. The qualitative NVC assessment of JIA, lSc and PRP did not differ from HCs, whereas the cSLE and jSSc, MCTD, JDM and cSLE subgroups showed more non-specific and scleroderma patterns, respectively. CONCLUSIONS: This analysis resulted from a pioneering registry of NVC in jRMD. The NVC assessment in jRMD differed significantly from HCs. Future prospective follow-up will further elucidate the role of NVC in jRMD.

Off-label use of canakinumab in pediatric rheumatology and rare diseases.

Since the first success of interleukin-1 blockade in cryopyrin-associated periodic syndrome, the use of interleukin-1 inhibitors has expanded to other disorders, including off-label indications. In particular, canakinumab has been employed in an off-label fashion in several diseases such as rare monogenic autoinflammatory diseases and multifactorial autoinflammatory diseases, disclosing an excellent efficacy and good safety profile in pediatric patients unresponsive to standards of care. In addition, hyperferritinemic syndromes and complex disorders, as well as Kawasaki disease, uveitis, and other pediatric rare disorders, represent additional areas where canakinumab efficacy is worth exploring. Altogether, the results summarized below are of paramount importance in pediatric patients where a considerable proportion of treatments are prescribed off-label. This review focuses on the off-label use of canakinumab in pediatric patients affected by systemic immune-mediated diseases.

Increased Immunity against the Oral Germs Porphyromonas gingivalis and Prevotella intermedia in Different Categories of Juvenile Idiopathic Arthritis.

(1) Background: The link between periodontal disease and rheumatoid arthritis (RA) is now widely reported. Several studies suggest the role of Porphyromonas gingivalis (P. gingivalis) in the pathophysiology of RA and some observations highlight the improvement of the disease activity induced by therapies against P. gingivalis. We have very little data on the prevalence of P. gingivalis carriage in patients with juvenile idiopathic arthritis (JIA) and its possible involvement in the pathophysiology of inflammatory joint diseases in children. (2) Methods: The specific IgG responses against P. gingivalis and Prevotella intermedia (P. intermedia) were determined in a cohort of 101 patients with JIA and 19 patients with other autoimmune diseases (inflammatory bowel disease and type 1 diabetes). (3) Results: Specific anti-P. gingivalis and anti-P. intermedia IgG titers were higher in JIA group than in control groups. These differences were mainly observed in the oligoarthritis group. The same pattern was observed in enthesitis-related arthritis (ERA). (4) Conclusions: Children with oligoarticular and ERA subsets had higher IgG titers to P. gingivalis and P. intermedia. These results suggest involvement of an oral dysbiosis in the occurrence of JIA in these subgroups.

Canakinumab treatment in a young girl with refractory chronic recurrent multifocal osteomyelitis associated with pyoderma gangrenosum.

BACKGROUND: Chronic recurrent multifocal osteomyelitis (CRMO) is a bone inflammatory disorder characterized by osteolytic, usually multiple, symmetric lesions. Diagnosis is one of exclusion, and no standardized therapies are available. Presumed deregulation of the interleukin (IL)-1ß axis, as observed in 2 monogenic autoinflammatory conditions such as Majeed syndrome (LPIN2 mutations) and deficiency of IL-1 receptor antagonist (IL1RN mutations) with CRMO-like bone involvement, suggests the blockade of IL-1 as potentially useful also in this condition, even if scarce data are available. CASE PRESENTATION: We report the case of a 13-year-old girl affected by a multidrug-resistant and pyoderma gangrenosum-complicated CRMO treated with canakinumab, a human monoclonal antibody targeting IL-1ß. CONCLUSION: In this young patient pyoderma gangrenosum and CRMO showed a rapid and satisfactory response to canakinumab, although over time a decreased efficacy in controlling bone disease was observed.

Development of a score for early identification of children with Kawasaki disease requiring second-line treatment in multi-ethnic populations in Europe: A multicentre retrospective cohort study.

Background: Early identification of high-risk patients is essential to stratify treatment algorithms of Kawasaki disease (KD) and to appropriately select patients at risk for complicated disease who would benefit from intensified first-line treatment. Several scores have been developed and validated in Asian populations but have shown low sensitivity in predicting intravenous immunoglobulin (IVIG) resistance in non-Asian populations. We sought methods to predict the need for secondary treatment after initial IVIG in non-Asian populations. Methods: We conducted a retrospective, multicenter study including consecutive patients with KD admitted to two tertiary pediatric hospitals in France and Italy from 2005 to 2019. We evaluated the performance of the Kawanet-score and compared it with the performances of initial echocardiography findings, and of a newly proposed score combining the Kawanet-score and initial echocardiography findings. For each score, we assessed the AUC, sensitivity and specificity for predicting the need for second-line treatment. Findings: We included 363 children with KD, 186 from France and 177 from Italy, of whom 57 (16%) required second-line therapy after the first IVIG dose. The Kawanet score, coronary artery dilation or aneurysm with maximal Z-score ≥2.0 at baseline, and abnormal initial echocardiography had a sensitivity of 43%, 55% and 65% and a specificity of 73%, 78%, 73%, respectively, for predicting the need for second-line treatment. The Kawanet-score was significantly improved by combining it with initial echocardiography findings. The best predictive performance (Sensitivity 76%, Specificity 54%) was obtained by combining the Kawanet-score with abnormal initial echocardiography, defined by the presence of either coronary artery maximal Z-score ≥2.0, pericarditis, myocarditis and/or ventricular dysfunction. This score predicted the need for second-line treatment in European, African/Afro-Caribbean and Asian ethnicity with a sensitivity of 80%, 65% and 100%, respectively, and a specificity of 56%, 51% and 61%, respectively. Interpretation: Our study proposes a score that we named the Kawanet-echo score, which allows early identification of children with KD who require a second-line treatment in multi-ethnic populations in Europe. Funding: None.

DNASE1L3 deficiency, new phenotypes, and evidence for a transient type I IFN signaling.

BACKGROUND: Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated with a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans. OBJECTIVES: To explore interferon signaling in DNASE1L3 deficient patients. To depict the characteristic features of DNASE1L3 deficiencies in human. METHODS: We identified, characterized, and analyzed five new patients carrying biallelic DNASE1L3 variations. Whole or targeted exome and/or Sanger sequencing was performed to detect pathogenic variations in five juvenile systemic erythematosus lupus (jSLE) patients. We measured interferon-stimulated gene (ISG) expression in all patients. We performed a systematic review of all published cases available from its first description in 2011 to March 24th 2022. RESULTS: We identified five new patients carrying biallelic DNASE1L3 pathogenic variations, including three previously unreported mutations. Contrary to canonical type I interferonopathies, we noticed a transient increase of ISGs in blood, which returned to normal with disease remission. Disease in one patient was characterized by lupus nephritis and skin lesions, while four others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented also with early-onset inflammatory bowel disease. Reviewing previous reports, we identified 35 additional patients with DNASE1L3 deficiency which was associated with a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Lung lesions were reported in 6/35 patients. CONCLUSIONS: DNASE1L3 deficiencies are associated with a broad phenotype including frequently lupus nephritis and hypocomplementemic urticarial vasculitis with positive ANCA and rarely, alveolar hemorrhages and inflammatory bowel disease. This report shows that interferon production is transient contrary to anomalies of intracellular DNA sensing and signaling observed in Aicardi-Goutières syndrome or STING-associated vasculitis in infancy (SAVI).

Septic Arthritis and Related Conditions.

Arthritis is a common condition that any pediatrician may have to deal with [...].

New Insights and Challenges Associated With IgA Vasculitis and IgA Vasculitis With Nephritis-Is It Time to Change the Paradigm of the Most Common Systemic Vasculitis in Childhood?

What are the challenges ahead and how have we responded so far when it comes to the non-granulomatous systemic vasculitis, characterized mainly by deposits of IgA immune complexes in the endothelium of small blood vessels-IgA vasculitis (IgAV)? That is the question to which we tried to answer. We summarized existing knowledge about epidemiology, pathogenesis, genetics, diagnostic tests and therapy in this somewhat neglected entity in pediatric rheumatology. Since etiopathogenesis of IgA vasculitis is complex, with factors other than galactose-deficient IgA1-containing immune complexes also being important, and may involve numerous interactions between environmental and genetic factors, genomics alone cannot explain the entirety of the risk for the disease. The incidence of IgAV and nephritis varies worldwide and may be a consequence of overlapping genetic and environmental factors. In addition to the role of the HLA class II genes, some studies have pointed to the importance of non-HLA genes, and modern geostatistical research has also indicated a geospatial risk distribution, which may suggest the strong influence of different environmental factors such as climate, pathogen load, and dietary factors. The application of modern geostatistical methods until recently was completely unknown in the study of this disease, but thanks to the latest results it has been shown that they can help us a lot in understanding epidemiology and serve as a guide in generating new hypotheses considering possible environmental risk factors and identification of potential genetic or epigenetic diversity. There is increasing evidence that an integrative approach should be included in the understanding of IgA vasculitis, in terms of the integration of genomics, proteomics, transcriptomics, and epigenetics. This approach could result in the discovery of new pathways important for finding biomarkers that could stratify patients according to the risk of complications, without an invasive kidney biopsy which is still the gold standard to confirm a diagnosis of nephritis, even if biopsy findings interpretation is not uniform in clinical practice. Ultimately, this will allow the development of new therapeutic approaches, especially important in the treatment of nephritis, for which there is still no standardized treatment.

Pregnancy in juvenile idiopathic arthritis: maternal and foetal outcome, and impact on disease activity.

Objective: This retrospective cohort study describes the modulation of disease activity during gestation and in the year following delivery as well as maternal and neonatal outcomes in a monocentric cohort of women with juvenile idiopathic arthritis (JIA). Methods: Disease activity was assessed using DAS28-CRP before conception and every 3 months during pregnancy and in the first year postpartum. The risk of complicated pregnancies was measured applying a generalized estimating equation model. Changes in disease activity during gestation and in the first year postpartum were assessed in a linear mixed model for repeated measures. Results: Thirty-one women (49 pregnancies) with persisting JIA and at least one conception were enrolled. Adjusted DAS28-CRP levels remained stable from preconception through the first trimester, but increased significantly in the second and decreased not significantly in the third. In the postpartum, adjusted disease activity peaked at 3 months after delivery, stabilized at 6 months to decrease at 1 year, although not significantly. Preconceptional DAS28-CRP and number of biological drugs predicted disease activity fluctuation during gestation. The number of biological drugs and the length of gestational exposure to biologics significantly predicted pregnancy morbidity. In particular, JIA women had a higher probability of preterm delivery compared with healthy and disease controls. Adjusted for breastfeeding and DAS28-CRP score in the third trimester, postconceptional exposure to biologics was inversely related with disease activity in the postpartum: the longer the patient continued treatment, the lower the probability of experiencing an adverse pregnancy outcome. Conclusion: These data offer novel insights on how treatment affects disease activity during pregnancy and postpartum as well as obstetric outcomes in women with JIA.

Beyond Systemic Lupus Erythematosus and Anti-Phospholipid Syndrome: The Relevance of Complement From Pathogenesis to Pregnancy Outcome in Other Systemic Rheumatologic Diseases.

Evidence about the relevance of the complement system, a highly conserved constituent of the innate immunity response that orchestrates the elimination of pathogens and the inflammatory processes, has been recently accumulated in many different rheumatologic conditions. In rheumatoid arthritis, complement, mainly the classical pathway, contributes to tissue damage especially in seropositive subjects, with complement activation occurring in the joint. Data about complement pathways in psoriatic arthritis are dated and poorly consistent; among patients with Sjögren syndrome, hypocomplementemia exerts a prognostic role, identifying patients at risk of extra-glandular manifestations. Hints about complement involvement in systemic sclerosis have been recently raised, following the evidence of complement deposition in affected skin and in renal samples from patients with scleroderma renal crisis. In vasculitides, complement plays a dual role: on one hand, stimulation of neutrophils with anti-neutrophil cytoplasmic antibodies (ANCA) results in the activation of the alternative pathway, on the other, C5a induces translocation of ANCA antigens, favouring the detrimental role of antibodies. Complement deposition in the kidneys identifies patients with more aggressive renal disease; patients with active disease display low serum levels of C3 and C4. Even though in dermatomyositis sC5b-9 deposits are invariably present in affected muscles, data on C3 and C4 fluctuation during disease course are scarce. C3 and C1q serum levels have been explored as potential markers of disease activity in Takayasu arteritis, whereas data in Behçet disease are limited to in vitro observations. Pregnancies in women with rheumatologic conditions are still burdened by a higher rate of pregnancy complications, thus the early identification of women at risk would be invaluable. A fine-tuning of complement activation is required from a physiological progression of pregnancy, from pre-implantation stages, through placentation to labour. Complement deregulation has been implicated in several pregnancy complications, such as recurrent abortion, eclampsia and premature birth; low complement levels have been shown to reliably identify women at risk of complications. Given its physiologic role in orchestrating pregnancy progression and its involvement as pathogenic effector in several rheumatologic conditions, complement system is an attractive candidate biomarker to stratify the obstetric risk among women with rheumatologic conditions.