Rhupus syndrome in children: A multi-center retrospective cohort study and literature review.

OBJECTIVE: In this study, we aimed to evaluate the characteristics of pediatric rhupus patients including all the related series in the literature. METHODS: Thirty pediatric patients with rhupus syndrome from 12 different centers in Turkey were included in this study. The literature was also reviewed for pediatric patients with rhupus syndrome. RESULTS: The most prominent phenotype of these 30 patients was juvenile idiopathic arthritis (JIA) (60%) at the disease onset and SLE (73.3%) at the last visit. Major SLE-related organ involvements were skin (80%), hematological system (53.3%), and kidney (23.3%). Arthritis was polyarticular (73.3%), asymmetric (66.7%), and erosive (53.3%) in most patients. Hydroxychloroquine (100%), glucocorticoids (86.7%), and mycophenolate mofetil (46.7%) were mostly used for SLE, while glucocorticoids (76.6%), methotrexate (73.3%), and nonsteroidal anti-inflammatory drugs (NSAIDs) (57.6%) were mainly preferred for JIA. Our literature search revealed 20 pediatric patients with rhupus syndrome (75% were RF positive). The most prominent phenotype was JIA (91.7%) at the disease onset and SLE (63.6%) at the last visit. Major SLE-related organ involvements were skin (66.7%), hematological system (58.3%), and kidney (58.3%). Arthritis was polyarticular (77.8%), asymmetric (63.6%), and erosive (83.3%) in most patients. Glucocorticoid (100%), hydroxychloroquine (76.9%), and azathioprine (46.2%) were mostly used for SLE, while methotrexate (76.9%) and NSAIDs (46.2%) were mainly preferred for the JIA phenotype. CONCLUSION: Our study is the largest cohort in the literature evaluating pediatric rhupus cases. Most of the pediatric patients had polyarticular, asymmetric, and erosive arthritis, as well as organ involvements associated with SLE, including the skin, hematological system, and kidney.

Towards a standardized program of transitional care for adolescents with juvenile idiopathic arthritis for Turkey: a national survey study.

BACKGROUND: Juvenile idiopathic arthritis (JIA) is a prevalent childhood chronic arthritis, often persisting into adulthood. Effective transitional care becomes crucial as these patients transition from pediatric to adult healthcare systems. Despite the concept of transitional care being recognized, its real-world implementation remains inadequately explored. This study aims to evaluate the thoughts and practices of healthcare providers regarding transitional care for JIA patients. METHODS: A cross-sectional survey was conducted among pediatric and adult rheumatologists in Turkey. Based on the American Academy of Pediatrics' six core elements of transitional care, the survey included 86 questions. The respondents' demographic data, attitudes towards transitional care, and practical implementation were assessed. RESULTS: The survey included 48 rheumatologists, with 43.7% having a transition clinic. The main barriers to establishing transition programs were the absence of adult rheumatologists, lack of time, and financial constraints. Only 23.8% had a multidisciplinary team for transition care. Participants agreed on the importance of coordination and cooperation between pediatric and adult healthcare services. The timing of the transition process varied, with no consensus on when to initiate or complete it. Participants advocated for validated questionnaires adapted to local conditions to assess transition readiness. CONCLUSIONS: The study sheds light on the challenges and perspectives surrounding transitional care for JIA patients in Turkey. Despite recognized needs and intentions, practical implementation remains limited due to various barriers. Cultural factors and resource constraints affect the transition process. While acknowledging the existing shortcomings, the research serves as a ground for further efforts to improve transitional care and ensure better outcomes for JIA patients transitioning into adulthood.

Impact of serological activity on flare following clinically inactive disease and remission in childhood-onset systemic lupus erythematosus.

OBJECTIVES: To assess the association between serological activity (SA) and clinical inactivity in SLE and to investigate whether SA predicts flare after clinically inactive disease (CID) and remission. METHODS: Longitudinal data of children from 3 paediatric rheumatology referral centres were retrospectively reviewed. CID was defined as clinical SLEDAI = 0 in patients with a prednisolone dose < 15 mg/day. A modified DORIS remission on treatment criteria was used to determine remission. RESULTS: Of the 124 patients included, 89.5% displayed SA at onset. Through follow-up, the rate of SA decreased to 43.3% at first CID and 12.1% at remission. Among patients with CID, 24 (20.7%) experienced a moderate to severe flare before the attainment ofremission. While previous proliferative lupus nephritis (OR : 10.2, p: 0.01) and autoimmune haemolytic anaemia (OR : 6.4, p: 0.02) were significantly associated with an increased odds of flare after CID, SA at CID was not associated with flare. In contrast, 21 (19.6%) patients experienced a flare in a median of 18 months after remission. Hypocomplementemia (OR : 9.8, p: 0.02) and a daily hydroxychloroquine dose < 5 mg/kg (OR : 5.8, p: 0.02) at remission significantly increased the odds of flare. CONCLUSION: SA increases the odds of flare at remission but not at CID. Suboptimal dosing of hydroxychloroquine should be avoided, especially in children with SA in remission to lower the risk of flares.

Letrozole-induced inflammatory arthritis and tendinopathy in pediatric rheumatology setting.

Musculoskeletal symptoms associated with the use of aromatase inhibitors are a well-known side effect of these drugs and are more prevalent in postmenopausal women. Aromatase inhibitor-associated symptoms are not overt inflammatory processes so are described as arthralgia syndrome. In contrast, aromatase inhibitor-associated inflammatory conditions such as myopathies, vasculitis, and rheumatoid arthritis were also reported. To our knowledge, inflammatory arthritis or tendinopathy associated with aromatase inhibitors were not reported in children despite their increased off-label use in the pediatric setting. Herein, we report a girl with inflammatory arthritis and tendinopathy associated with letrozole treatment.

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.

Significance of the immunofluorescence staining patterns and titres of the antinuclear antibody test in paediatric rheumatology setting.

BACKGROUND: Antinuclear antibody (ANA) is among the most frequently ordered tests in paediatric rheumatology setting. Diseases like systemic lupus erythematosus and Sjögren syndrome is closely related with a positive ANA and classified as ANA associated diseases. Besides, ANA test is ordered in patients with juvenile idiopathic arthritis (JIA) to assess the risk for uveitis and a positive ANA could be detected in children with nonrheumaticrheumatic conditions. In this study, we aimed to investigate frequency of positive ANA in paediatric rheumatology setting and the association of immunofluorescence staining patterns and titres of ANA with rheumatic diseases. METHODS: : Immunofluorescence staining patterns, and titres of the ANA and diagnoses of children who tested for ANA between January 2016 and December 2021 were retrospectively analysed. RESULTS: Among 2477 patients with ANA tested, 28.1% had a positive ANA result. Among them, 39.2% had a diagnosis of a rheumatic disease. Most common rheumatic diagnosis was JIA (43.8%) and ANA associated diseases were observed in 24.5% of the patients with a rheumatic diagnosis. While ANA associated diseases had significantly more frequent homogenous staining, dense fine speckled pattern was significantly more common in children with nonrheumatic diagnoses. Despite ANA associated diseases was found to be significantly associated with higher titres, no difference was observed between patients with JIA and nonrheumatic conditions. DISCUSSION: Our study showed that the majority of children with a positive ANA test were not diagnosed with a rheumatic disease. While titres and patterns of ANA were found to be important in diagnosis of rheumatic diseases, ordering ANA test with solid indications might give improved probability of rheumatic diagnoses in children with a positive test.

Mercury exposure mimicking systemic lupus erythematosus in a thirteen-year-old girl.

BACKGROUND: The clinical presentation of mercury (Hg) intoxication may mimic rheumatic diseases. Hg exposure is associated with systemic lupus erythematosus (SLE)-like disease in genetically susceptible rodents and Hg is among the environmental factors in the development of SLE in humans. Herein, we presented a case with clinical and immunological features suggestive of SLE but diagnosed with Hg intoxication. CASE: A thirteen-year-old female with myalgia, weight loss, hypertension and proteinuria was referred to our clinic for the evaluation of possible SLE. Physical examination of the patient was unremarkable except for a cachectic appearance and hypertension, laboratory investigation revealed positive anti-nuclear antibody, dsDNA antibody and hypocomplementemia with nephrotic range proteinuria. Inquiry for toxic exposures revealed a continuous exposure to an unknown silverly shiny liquid for a month which was thought to be Hg. Due to the fulfillment of Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE, a percutaneous kidney biopsy was performed whether proteinuria resulted because of the Hg exposure or flare of lupus nephritis. Blood and 24-hour urine Hg levels were high, and no findings associated with SLE were observed in the examination of the kidney biopsy. The patient was diagnosed with Hg intoxication and, clinical and laboratory findings, including hypocomplementemia, positive ANA and anti-dsDNA antibody, improved with chelation therapy. Also, no findings associated with SLE were observed in the follow-up of the patient. CONCLUSIONS: In addition to the toxic effects, Hg exposure may cause autoimmune features. As far as we know, this is the first-time Hg exposure was associated with hypocomplementemia and anti-dsDNA antibody in a patient. Also, this case highlights the inconvenience of the use of classification criteria for diagnostic purposes.

Neuropsychiatric involvement in juvenile-onset systemic lupus erythematosus: A multicenter study.

INTRODUCTION: Neuropsychiatric (NP) involvement is a restricted area in juvenile-onset systemic lupus erythematosus (jSLE). AIM: To investigate the prevalence, demographic and clinical features, and outcomes of the neurological involvement in the Turkish jSLE population. METHODS: This study was based upon 24 referral centers' SLE cohorts, multicenter and multidisciplinary network in Turkey. Patient data were collected by a case report form which was standardized for NP definitions according to American Collage of Rheumatology (ACR). Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) neuropsychiatric part was used to determine NP damage. Variables were evaluated Ward's hierarchical clustering analyses, univariate, and multivariate logistic regression analyses. RESULTS: A hundred forty-nine of 1107 jSLE patients had NP involvement (13.5%). The most common NPSLE findings were headache (50.3%), seizure (38.3%), and acute confusional state (33.6%). Five clusters were identified with all clinical and laboratory findings. The first two clusters involved neuropathies, demyelinating diseases, aseptic meningitis, and movement disorder. Cluster 3 involved headache, activity markers and other SLE involvements. Idiopathic intracranial hypertension, cerebrovascular disease, cognitive dysfunction, psychiatric disorders and SLE antibodies were in the fourth, and acute confusional state was in the fifth cluster. In multivariate analysis, APA positivity; OR: 2.820, (%95CI: 1.002-7.939), P: 0,050, plasmapheresis; OR: 13.804 (%95CI: 2.785-68.432), P: 0,001, SLEDAI scores; OR: 1.115 (%95CI: (1.049-1.186), P: 0,001 were associated with increased risk for neurologic sequelae. CONCLUSION: We detected the prevalence of juvenile NPSLE manifestations in Turkey. We have identified five clusters that may shed light pathogenesis, treatment and prognosis of NP involvements. We also determined risk factors of neurological sequelae. Our study showed that new definitions NP involvements and sequelae for childhood period are needed.

Genotype-Phenotype Associations of Children With Familial Mediterranean Fever in a Cohort Consisting of M694V Mutation and Implications for Colchicine-Resistant Disease.

OBJECTIVES: The aim of this study was to investigate the clinical associations of the second allele mutations and the effect of genotype and presenting features on colchicine resistance in children with familial Mediterranean fever (FMF), carrying at least one M694V variant. METHODS: The medical records of the patients diagnosed with FMF, in whom at least one allele M694V mutation was detected, were reviewed. Patients were grouped according to the genotype as M694V homozygotes, compound heterozygote M694V with an exon 10 mutation, compound heterozygote M694V with a variant of unknown significance (VUS), and M694V heterozygotes. Disease severity was assessed with the International Severity Scoring System for FMF. RESULTS: Among the 141 patients included, homozygote M694V (43.3%) was the most frequent MEFV genotype. Clinical manifestations of FMF at diagnosis were not significantly different according to genotypic alterations except homozygote M694V. Besides, homozygous M694V was associated with a more severe disease, with more frequent comorbidities and colchicine-resistant disease. A lower disease severity score was observed in compound heterozygotes with VUS than in M694V heterozygotes (median 1 vs 2, p = 0.006). Regression analysis revealed that homozygous M694V, arthritis, and frequency of attacks were associated with an increased risk of colchicine-resistant disease. CONCLUSIONS: Clinical manifestations of FMF at diagnosis with a M694V allele were predominantly influenced by the M694V rather than the second allele mutations. Although homozygous M694V was associated with the most severe form, the presence of compound heterozygosity with a VUS did not affect disease severity or clinical features. Homozygous M694V confers the highest risk of colchicine-resistant disease.

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.

Depression, anxiety, and sleep quality in childhood onset systemic lupus erythematosus and relationship with brain-derived neurotrophic factor.

BACKGROUND: The association between brain-derived neurotrophic factor (BDNF) and systemic lupus erythematosus (SLE) is controversial, and no study investigated the clinical associations of BDNF in patients with childhood onset systemic lupus erythematosus (cSLE). In this study, we aimed to investigate the serum levels of BDNF in patients with cSLE and examine whether a relationship of BDNF exists among depression, anxiety, and sleep quality. METHODS: Thirty patients and age-sex matched healthy controls were included. Depression, anxiety, sleep quality and quality of life were assessed by relevant questionnaires. Disease activity was assessed according to the SLE disease activity index (SLEDAI) and serum BDNF level was measured by the enzyme-linked immunosorbent assay method. RESULTS: Serum BDNF level was significantly lower in cSLE patients than healthy controls (21981 vs 29905 pg/mL, p = 0.001) and significantly decreased level was observed in active cSLE (SLEDAI >0), then those with SLEDAI = 0 (17110 vs 26852 pg/mL, p = 0.005). Although the scores of the depression, anxiety, sleep quality and quality of life questionnaires were strongly correlated with each other, no correlation was observed with serum BDNF levels. CONCLUSIONS: In patients with cSLE, serum level of BDNF was significantly decreased compared to healthy controls. Our results suggest that serum BDNF levels were not associated with the presence of anxiety, depression and poor sleep quality and might be dictated by the pathophysiological process of SLE rather than mood disorders.

Hematologic manifestations of juvenile systemic lupus erythematosus: An emphasis on anemia.

OBJECTIVE: Anemia is common in patients with juvenile systemic lupus erythematosus (jSLE). While autoimmune hemolytic anemia (AIHA) is the only etiology included in the classification criteria, the etiology of anemia in jSLE may be diverse. We aimed to investigate the etiology of anemia in jSLE and the relationship between anemia and disease characteristics at onset and during the follow-up period. METHODS: Patients diagnosed with jSLE who met the Systemic Lupus Erythematosus International Collaborating Clinics classification criteria between January 2012 and December 2020 were retrospectively analyzed. RESULTS: Hematologic involvement was observed in 70% of the patients. Anemia was the most common cytopenia among patients (60%). Anemia of chronic disease (ACD) and AIHA were the most common etiological factors, both observed in 23% of patients. Patients with anemia had a significantly higher rate of positive ds-DNA antibody and higher erythrocyte sedimentation rate (ESH) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores. ESH, serum ferritin, and SLEDAI scores negatively correlated with hemoglobin levels in patients with anemia. Iron deficiency was the sole etiology of new-onset anemia. Patients with new-onset anemia during the follow-up period had significantly lower hemoglobin values at onset and a higher rate of renal involvement. CONCLUSION: Anemia in jSLE is mostly AIHA and ACD, but iron deficiency is not rare. The severity of inflammation is associated with the severity of anemia. During the follow-up period, iron deficiency was the predominant cause of anemia, especially in patients with lower hemoglobin concentrations at onset and renal involvement.