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The Turkish Journal of Pediatrics May 2024Given the strong genetic background of familial Mediterranean fever (FMF), the frequently reported co-existing diseases in children with FMF should also be investigated...
BACKGROUND
Given the strong genetic background of familial Mediterranean fever (FMF), the frequently reported co-existing diseases in children with FMF should also be investigated in other family members. Therefore, we aimed to examine the medical conditions of first-degree relatives (FDRs) of our pediatric patients with FMF in the present study.
METHODS
Chronic diseases of FDRs of pediatric 449 FMF, 147 juvenile idiopathic arthritis (JIA) patients and 93 healthy controls (HC) were questioned during their routine clinical visits for 9 consecutive months.
RESULTS
A total of 1975 FDRs of 449 FMF, 690 FDRs of 147 JIA patients, and 406 FDRs of 93 HC were included into the study. The most common medical conditions were non-atopic asthma (n=71, 3.6%), type 2 DM (n=14, 2%), and tonsillectomy history (n=12, 2.95%) in the FMF, JIA, and HC groups, respectively. Atopic diseases (FMF vs. JIA: p=0.013; FMF vs. HC: p=0.014), rheumatic diseases (FMF vs. JIA: p=0.030; FMF vs. HC: p=0.017), and surgical histories (FMF vs. JIA: p<0.01; FMF vs. HC: p=0.026), including adenoidectomy, tonsillectomy, and appendectomy, were significantly more common in the FMF group than in other groups.
CONCLUSIONS
Our novel findings may contribute to understanding the hereditary burden of co-existing diseases in children with FMF and encourage further studies involving genetic screenings.
Topics: Humans; Familial Mediterranean Fever; Female; Male; Child; Child, Preschool; Arthritis, Juvenile; Adolescent; Turkey; Case-Control Studies; Family; Adult; Asthma
PubMed: 38814299
DOI: 10.24953/turkjpediatr.2024.4589 -
Cureus Apr 2024The aim of this study was to explore the patterns of pediatric uveitis and the types of ocular complications of uveitis and to determine the possible risk factors...
AIM
The aim of this study was to explore the patterns of pediatric uveitis and the types of ocular complications of uveitis and to determine the possible risk factors associated with visual impairment.
METHOD
This was a cross-sectional study conducted at Queen Rania Children's Hospital between June 2020 and June 2023. All children diagnosed with uveitis were enrolled in the study. After collecting data from the patients and reviewing their medical records regarding age, gender, and past ocular and medical history, the patients were subjected to a detailed ophthalmic exam including best-corrected visual acuity (BCVA). Anterior segment exam using the slit lamp, intraocular pressure exam using Goldmann applanation tonometry, and posterior segment exam using 78 and 90 diopter Volk lenses were performed. Patients with other ocular diseases that affected visions not related to uveitis were excluded from the study.
RESULTS
A total of 82 children, accounting for 130 eyes, were enrolled in this study, with ages ranging from 2 to 16 years (mean age 10.5±4.3 years). Among them, 27 were males, constituting 32.9% of the participants. Unilateral uveitis was observed in 34 eyes, representing 26.2% of cases. The mean age of uveitis onset was 6.9±1.9 years, and the mean disease duration was 4.8±0.4 years. The majority of cases i.e. 90.8% (n = 74) were non-infectious, with 92.3% (n = 76) classified as non-granulomatous and 79.2% (n = 65) categorized as chronic. Anterior uveitis was the most prevalent site of inflammation in 70.8% of cases (n = 58), followed by panuveitis in 20.0% of cases (n = 16), intermediate uveitis in 6.2% of cases (n = 5), and posterior uveitis in 3.0% of cases (n = 2). The cause of uveitis could not be identified in 40.0% (n = 33) of cases. Juvenile idiopathic uveitis emerged as the most commonly known disorder associated with uveitis in 40.0% (n = 33) of cases. Complications were identified in 52.3% (n = 43) of cases, with posterior synechiae being the most prevalent; 26.9% (n = 22) demonstrated an improvement in BCVA, while 21.5% (n = 18) experienced a decline in BCVA relative to the initial assessment Conclusion: Pediatric uveitis tends to manifest as anterior, chronic, bilateral, and non-granulomatous. Higher frequencies of severe visual impairment are linked to panuveitis, infectious and granulomatous uveitis, early-onset, long-duration cases, and male gender. The use of biologics has a positive effect, significantly improving or preserving visual acuity.
PubMed: 38803751
DOI: 10.7759/cureus.59136 -
Cureus Apr 2024Pediatric uveitis is a rare but sight-threatening condition. Prompt and adequate treatment is crucial to preserve vision and avoid long-term complications. In cases...
OBJECTIVES
Pediatric uveitis is a rare but sight-threatening condition. Prompt and adequate treatment is crucial to preserve vision and avoid long-term complications. In cases that are resistant to corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs), anti-tumor necrosis (anti-TNF) biologic agents are usually added. In this study, we report our experience with adalimumab (ADA) anti-TNF use in this group of patients.
METHODS
This is a retrospective observational study conducted in a tertiary pediatric uveitis clinic, in Manchester Royal Eye Hospital. All patients were pediatric patients (aged 2-18 years old) under follow-up during the period of six months. The patients' data were analyzed according to the diagnosis, age of onset of uveitis, systemic medications used before and concomitantly with ADA, duration of uveitis before starting ADA, its effect, and time to notice the therapeutic effect in controlling inflammation. Finally, cases were reviewed for the development of anti-drug antibodies.
RESULTS
Forty-two patients were included in the study. Idiopathic uveitis was diagnosed in 47.6% of patients and 40.5% of patients were associated with juvenile idiopathic arthritis (JIA). Most (97.6%) of patients were using topical steroids before starting ADA and 95.2% continued using steroids after established ADA use, but systemic steroid use was reduced from 33.3% to 14.3%. The most common non-biologic DMARD used before ADA was methotrexate (MTX) (90.5%). One-third of the patients started ADA between 6 and 12 months after the diagnosis of uveitis, while this percentage dropped to 9.5% the year after diagnosis. Seventy-eight percent of patients acquired complete clinical control of inflammation on ADA use. Almost 78.6% of patients showed a full response in less than six months. In eight patients who were not controlled or were transiently controlled on ADA, three patients had positive anti-drug antibodies. In one patient, antidrug antibodies were identified after 12 years of ADA use, and in another, after 4 years.
CONCLUSION
Adalimumab is an effective, well-tolerated drug in children with uveitis refractory to non-biologic DMARD therapy. DMARDs were usually used alongside ADA in this cohort and few patients had confirmed ADA antibodies.
PubMed: 38800327
DOI: 10.7759/cureus.59019 -
Journal of Autoimmunity May 2024- Janus Kinase inhibitors (JAKi) are a new class of drugs available for pediatric rheumatic diseases. This study aimed to describe the safety and effectiveness of JAKi...
OBJECTIVES
- Janus Kinase inhibitors (JAKi) are a new class of drugs available for pediatric rheumatic diseases. This study aimed to describe the safety and effectiveness of JAKi in these diseases, with a focus on longitudinal interferon-stimulated genes (ISG) assessment.
METHODS
- We present a single-center retrospective study of children with refractory pediatric rheumatic diseases including connective tissue diseases, monogenic type I interferonopathies or juvenile idiopathic arthritis, receiving JAKi. According to physicians' assessment, treatment effectiveness was classified at 12 months as a complete response in the total absence of disease activity, partial response in case of significant (>50%) but incomplete improvement or no response in the case of non-response or improvement of less than 50% of the clinical and biological parameters. ISG were monitored longitudinally using Nanostring technology.
RESULTS
- 22 children were retrospectively included in this study, treated either by baricitinib or ruxolitinib. Complete response was achieved at 12 months in 9/22 (41%) patients. 6/22 (27%) patients were non-responders and treatment had been discontinued in five of them. Within the interferon (IFN)-related diseases group, ISG-score was significantly reduced 12 months after JAKi onset (p = 0.0068). At 12 months, daily glucocorticoid doses had been reduced with a median dose of 0.16 mg/kg/day (IQR 0.11; 0.33) (p = 0.0425). 7/22 (32%) patients had experienced side effects, infections being the most common. Increase of the body mass index was also recorded in children in the first 6 months of treatment.
CONCLUSION
- JAKi represent a promising treatment of immune-mediated pediatric diseases, enabling to decrease type-I IFN transcriptomic signature in responding patients, especially in the context of juvenile dermatomyositis. JAKi represent steroid-sparing drugs but they induce metabolic changes linked to weight gain, posing a concern in the treatment of young patients and teenagers. More data are required to define the efficacy and safety of JAKi in the management of refractory pediatric rheumatic diseases.
PubMed: 38797048
DOI: 10.1016/j.jaut.2024.103248 -
Children (Basel, Switzerland) May 2024The diagnosis of juvenile idiopathic arthritis (JIA) is often entrusted to the pediatric rheumatologist specialist. Timely referral to a specialized center is crucial....
The diagnosis of juvenile idiopathic arthritis (JIA) is often entrusted to the pediatric rheumatologist specialist. Timely referral to a specialized center is crucial. This study aims to assess the consultation and investigation patterns of patients with joint complaints before rheumatology referral. This longitudinal cohort study included patients with joint complaints who were referred to the Pediatric Rheumatology Unit. The cohort included 301 patients (58% female), 50 of them (17%) diagnosed with JIA. Compared to patients with orthopedic conditions or functional diseases, JIA patients had seen more specialists ( < 0.01) and received a quicker diagnosis ( < 0.01). Patients with early JIA diagnosis (within 3 months from symptoms onset) were younger (8.46 vs. 11.5 years old; = 0.04), more frequently female (78% vs. 47%, = 0.03), and with higher erythrocyte sedimentation rate (ESR) values (37 vs. 9 mm/h; = 0.02) than those diagnosed later. Patients with a late diagnosis of JIA had a significantly longer median time between the first healthcare visit and the PR referral (25 vs. 101 days; < 0.01). The main contributor to diagnostic delay in JIA was the time required for PR referral after the first healthcare consult. Younger age, female sex, and higher ESR values were associated with earlier diagnosis of JIA.
PubMed: 38790595
DOI: 10.3390/children11050600 -
Pediatric Rheumatology Online Journal May 2024Macrophage activation syndrome (MAS), an example of secondary hemophagocytic lymphohistiocytosis, is a potentially fatal complication of rheumatic diseases. We aimed to...
BACKGROUND
Macrophage activation syndrome (MAS), an example of secondary hemophagocytic lymphohistiocytosis, is a potentially fatal complication of rheumatic diseases. We aimed to study the clinical and laboratory characteristics, treatment schemes, and outcomes of different rheumatic disorders associated with MAS in children. Early warning indicators of MAS have also been investigated to enable clinicians to make a prompt and accurate diagnosis.
METHODS
Fifty-five patients with rheumatic diseases complicated by MAS were enrolled between January 2017 and December 2022. Clinical and laboratory data were collected before disease onset, at diagnosis, and after treatment with MAS, and data were compared between patients with systemic juvenile idiopathic arthritis (sJIA), Kawasaki disease (KD), and systemic lupus erythematosus (SLE). A random forest model was established to show the importance score of each variable with a significant difference.
RESULTS
Most (81.8%) instances of MAS occurred during the initial diagnosis of the underlying disease. Compared to the active stage of sJIA, the platelet count, erythrocyte sedimentation rate, and fibrinogen level in sJIA-MAS were significantly decreased, whereas ferritin, ferritin/erythrocyte sedimentation rate, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and D-dimer levels were significantly increased. Ferritin level, ferritin/erythrocyte sedimentation rate, and platelet count had the greatest predictive value for sJIA-MAS. The level of IL-18 in the sJIA-MAS group was significantly higher than in the active sJIA group, whereas IL-6 levels were significantly lower. Most patients with MAS were treated with methylprednisolone pulse combined with cyclosporine, and no deaths occurred.
CONCLUSIONS
Thrombocytopenia, ferritin levels, the ferritin/erythrocyte sedimentation rate, and elevated aspartate aminotransferase levels can predict the occurrence of MAS in patients with sJIA. Additionally, our analysis indicates that IL-18 plays an important role in the pathogenesis of MAS in sJIA-MAS.
Topics: Humans; Macrophage Activation Syndrome; Male; Female; Child; Arthritis, Juvenile; Child, Preschool; Adolescent; Ferritins; Lupus Erythematosus, Systemic; Blood Sedimentation; Retrospective Studies; Platelet Count; Mucocutaneous Lymph Node Syndrome
PubMed: 38783316
DOI: 10.1186/s12969-024-00991-3 -
The Journal of Experimental Medicine Aug 2024Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or...
Nucleic acid-sensing Toll-like receptors (TLR) 3, 7/8, and 9 are key innate immune sensors whose activities must be tightly regulated to prevent systemic autoimmune or autoinflammatory disease or virus-associated immunopathology. Here, we report a systematic scanning-alanine mutagenesis screen of all cytosolic and luminal residues of the TLR chaperone protein UNC93B1, which identified both negative and positive regulatory regions affecting TLR3, TLR7, and TLR9 responses. We subsequently identified two families harboring heterozygous coding mutations in UNC93B1, UNC93B1+/T93I and UNC93B1+/R336C, both in key negative regulatory regions identified in our screen. These patients presented with cutaneous tumid lupus and juvenile idiopathic arthritis plus neuroinflammatory disease, respectively. Disruption of UNC93B1-mediated regulation by these mutations led to enhanced TLR7/8 responses, and both variants resulted in systemic autoimmune or inflammatory disease when introduced into mice via genome editing. Altogether, our results implicate the UNC93B1-TLR7/8 axis in human monogenic autoimmune diseases and provide a functional resource to assess the impact of yet-to-be-reported UNC93B1 mutations.
Topics: Animals; Humans; Mice; Autoimmunity; Membrane Transport Proteins; DNA Mutational Analysis; Toll-Like Receptors; Mutation; Female; Male; Mice, Inbred C57BL; HEK293 Cells; Toll-Like Receptor 7; Autoimmune Diseases
PubMed: 38780621
DOI: 10.1084/jem.20232005 -
Pediatric Rheumatology Online Journal May 2024Juvenile Dermatomyositis (JDM) is the leading cause of non-infectious inflammatory myopathy in children. It is a heterogeneous group of autoimmune diseases characterized...
BACKGROUND
Juvenile Dermatomyositis (JDM) is the leading cause of non-infectious inflammatory myopathy in children. It is a heterogeneous group of autoimmune diseases characterized by a variable combination of muscular, dermatological, and visceral involvement. Myositis-specific autoantibodies help define homogeneous subgroups with common clinical characteristics and prognoses. Anti-SAE (small ubiquitin-like modifier 1 (SUMO-1) activating enzyme) antibodies are among the most recently discovered specific autoantibodies. The presence of these antibodies is very rare, making it challenging to define clinical features and prognosis in the juvenile form. We report the first case of an African patient with juvenile dermatomyositis and positive anti-SAE antibodies.
CASE REPORT
A 5-year-3-month-old Moroccan boy presented to the pediatric emergency department with dysphagia that had been evolving for two days, preceded two months earlier by facial erythema associated with fatigue, lower limb pain, difficulty walking, and progressive inflammatory polyarthralgia. On admission, the child had a heliotrope rash with predominant pseudo-angioedema on the lips, periungual telangiectasia, and Gottron's papules over the bilateral interphalangeal and metatarsophalangeal joints. The patient had a more pronounced proximal muscle weakness in the lower limbs. He had no urticaria, fever, arthritis, calcinosis, cutaneous ulcers, or lipodystrophy. The Joint examination was normal, as was the pleuropulmonary examination. The electroneuromyography showed myogenic changes in all four limbs. Laboratory findings showed elevated levels of creatine phosphokinase and lactate dehydrogenase and a mild inflammatory syndrome. The electrocardiogram was normal. The anti-SAE antibodies were positive. The boy was diagnosed with juvenile dermatomyositis. He received methylprednisolone bolus therapy followed by oral prednisone. The latter was gradually tapered in combination with weekly intramuscular methotrexate. As a result, dysphagia disappeared within 48 h. After two weeks, there was an improvement in the muscular score and a significant regression of facial pseudo-angioedema.
CONCLUSION
We report the first African patient with anti-SAE autoantibody-positive JDM. He had a typical dermatological manifestation of JDM associated with pseudo-angioedema predominant on the lips; a rarely reported sign in DM and JDM patients. The patient responded well to corticosteroid therapy and methotrexate.
Topics: Humans; Male; Dermatomyositis; Autoantibodies; Child, Preschool; Ubiquitin-Activating Enzymes; Morocco
PubMed: 38773611
DOI: 10.1186/s12969-023-00921-9 -
Mediterranean Journal of Rheumatology Mar 2024We have summarised the existing evidence supporting the concept that systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) are part of the... (Review)
Review
AIM
We have summarised the existing evidence supporting the concept that systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease (AOSD) are part of the same Still's disease spectrum.
METHODS
A PubMed/Embase database search was conducted using specific search strings and free text words to screen for relevant articles. The search was limited to studies in humans, published up to June 2023, in English-language.
SUMMARY
sJIA and AOSD are rare autoinflammatory disorders that have similar pathophysiological and clinical features. The clinical presentations of sJIA and AOSD are highly variable, with differential diagnoses that include a broad range of malignancies, infectious diseases, and autoimmune disorders, which contribute to delays in diagnosis. Several sets of classification exist to help diagnose patients in clinical practice; the International League of Associations for Rheumatology criteria for sJIA and the Yamaguchi and Fautrel criteria for AOSD are the most-used criteria. The therapeutic strategy for Still's disease aims to relieve signs and symptoms, prevent irreversible joint damage and potentially life-threatening complications, and avoid deleterious side effects of treatment. Recently, targeted therapies such as interleukin (IL)-1 and IL-6 inhibitors have become available for the treatment of sJIA and AOSD. While these biologics were originally largely reserved for patients in whom non-steroidal anti-inflammatory drugs, corticosteroids and conventional synthetic disease-modifying anti-rheumatic drugs had failed, they are increasingly used earlier in the treatment paradigm. Among IL-1 inhibitors, canakinumab is the only biologic approved in the US for the treatment of both sJIA and AOSD.
PubMed: 38756937
DOI: 10.31138/mjr.290323.dat -
Nature Communications May 2024The transition from natal downs for heat conservation to juvenile feathers for simple flight is a remarkable environmental adaptation process in avian evolution....
The transition from natal downs for heat conservation to juvenile feathers for simple flight is a remarkable environmental adaptation process in avian evolution. However, the underlying epigenetic mechanism for this primary feather transition is mostly unknown. Here we conducted time-ordered gene co-expression network construction, epigenetic analysis, and functional perturbations in developing feather follicles to elucidate four downy-juvenile feather transition events. We report that extracellular matrix reorganization leads to peripheral pulp formation, which mediates epithelial-mesenchymal interactions for branching morphogenesis. α-SMA (ACTA2) compartmentalizes dermal papilla stem cells for feather renewal cycling. LEF1 works as a key hub of Wnt signaling to build rachis and converts radial downy to bilateral symmetry. Novel usage of scale keratins strengthens feather sheath with SOX14 as the epigenetic regulator. We show that this primary feather transition is largely conserved in chicken (precocial) and zebra finch (altricial) and discuss the possibility that this evolutionary adaptation process started in feathered dinosaurs.
Topics: Animals; Feathers; Chickens; Finches; Gene Expression Regulation, Developmental; Extracellular Matrix; Epigenesis, Genetic; Gene Regulatory Networks; Wnt Signaling Pathway; Keratins; Biological Evolution; Morphogenesis
PubMed: 38755126
DOI: 10.1038/s41467-024-48303-3