Comparison of systemic lupus international collaborating clinics 2012 classification criteria and European league against rheumatism/American college of rheumatology 2019 classification criteria for early detection of childhood onset systemic lupus erythematosus (multi-center study).

OBJECTIVE: To assess the performance of the new EULAR/ACR criteria, particularly for early detection of cSLE, in comparison to the SLICC criteria among the pediatric population in multiple centers in Saudi Arabia. METHODS: We conducted a retrospective study that enrolled pediatric patients up to the age of 14 years who've been diagnosed with SLE and followed in pediatric rheumatology clinics at 9 multi-tertiary hospitals in Saudi Arabia from 2010 to 2021 as a case group and were compared to a similar group of pediatric patients who've had defined rheumatological diseases other than SLE with a positive ANA titer (≥1:80) as controls. In total, 245 patients were included and distributed as 129 cases (diagnosed by expert pediatric rheumatologists) versus 116 patients in the control group. All relevant clinical information, including history, physical examination findings, and laboratory tests, was documented at the initial presentations. Then, the two sets of SLE classification criteria were applied to both groups to define who's going to meet both or either one of them. The exclusion criteria included those who had insufficient data or had overlapping or undifferentiated diseases. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), receiver operating curve (ROC), and accuracy were calculated for SLICC 2012 and EULAR/ACR 2019 criteria (total scores≥ 10 and ≥ 13). We performed a Chi-squared test to compare sensitivity and specificity of SLICC 2012 and EULAR/ACR 2019. RESULTS: For SLICC (cut-off ≥4 criteria), the sensitivity was found to be 96.9% (95% CI 92.6%-99.4%) and the specificity was 94.8% (95% CI 89.6%-98.32%), with PPV and NPV of 95.4% and 96.5%, respectively. The ROC for it was 0.96 (95% CI 0.93-0.99), and this criterion had an accuracy of 95%. Regarding EULAR/ACR (total score ≥ 10), the performance measure showed a sensitivity of 99.2% and a specificity of 86.2%. Similarly, PPV was 88.9%; while NPV was a little higher (99.0%) than SLICC. The ROC for EULAR/ACR (total score ≥ 10) was 0.93 (95% CI 0.89-0.96), and this criterion had an accuracy of 93%. However, there was no statistically significant difference between the sensitivity and specificity of either using SLICC or EULAR/ACR (total score ≥ 10), as reflected by a p-value of 0.86 using the Chi-squared test. Although applying the EULAR/ACR with a total score of ≥ 13 revealed lower sensitivity (93.8%) than both the SLICC and the EULAR/ACR (total score ≥ 10), the specificity for it was found to increase up to 91.4% (85.7-96.2%) compared to the (86.2%) specificity of the EULAR/ACR (total score ≥ 10). CONCLUSION: In this cohort among the Saudi population with childhood-onset SLE, the new EULAR/ACR 2019 criteria efficiently enable early detection of SLE, although a more frequent rate of false positives was observed with them. Escalating the total score from ≥ 10 to ≥ 13 in the cSLE population improved the specificity close to that of SLICC 2012. Further prospective studies in pediatrics need to be done for the validation of a cut- off score of ≥ 13 in cSLE rather than the traditional score of ≥ 10 in aSLE.

Burnout syndrome among rheumatologists and rheumatology fellows in Arab countries: an ArLAR multinational study.

BACKGROUND: Burnout is frequent among physicians and seems to be underestimated among rheumatologists. OBJECTIVE: To estimate the frequency of burnout in a sample of rheumatologists practising in the Arab countries and determine its associated factors. METHODS: This was a descriptive cross-sectional study conducted by the Arab League of Associations for Rheumatology (ArLAR research group) using an anonymous electronic questionnaire set up on the Google Forms platform. All Arab rheumatologists and rheumatology fellows were invited to participate in the spring of 2022 via ArLAR social media accounts, societies' WhatsApp groups, and mass emails. Burnout was defined by at least one positive domain of the Maslach Burnout Inventory (MBI) (Emotional exhaustion, Depersonalization, and Personal accomplishment). The final score was correlated to socio-demographic factors using a multivariable binary logistic regression. RESULTS: The study included 445 rheumatologists and rheumatology fellows with an average age of 45.2 years (SD 11.5); 61.8% were men. The frequency of burnout among rheumatologists was 61.3% and was driven by low personal accomplishment scores (58.1%). Younger age (OR 1.92 (95%CI 1.20-3.08)), dissatisfaction with the specialty (OR 2.036 (95% CI 1.20-3.46)), and low income (OR 2.26 (95% CI 1.01-5.10)) were associated with burnout. CONCLUSION: The frequency of burnout in a sample of rheumatologists in Arab countries is very high, driven by low personal accomplishment scores and associated with a low income, dissatisfaction with the specialty and younger age. Some associated factors might be modifiable, thus reducing the burden of burnout on rheumatologists and on the healthcare system. Key Points • The frequency of burnout in a sample of Arab rheumatologists was 61.3% according to the MBI. • The score was mainly driven by low personal accomplishment scores (58.1%). • Younger age, dissatisfaction with the specialty, and low income were associated with burnout. • Acting upon modifiable risk factors would help reducing the burden of burnout on rheumatologists and on the healthcare system.

Safety and efficacy of biologics in childhood systemic lupus erythematosus: a critical systematic review.

Biologic agents are increasingly being used to treat adult patients with systemic lupus erythematosus (SLE). However, the available data on biologic agents' use in childhood-onset SLE (cSLE) remains limited. To collate available evidence related to the efficacy and safety of using biologic agents in cSLE. The study followed the PRISMA checklist for reporting the data and conducted a thorough search using PubMed, Cochrane Library, and Scopus from January 2005 to August 2023. Only articles meeting specific criteria were included, focusing on cSLE, the use of biologic agents, and having outcome measures at six- and 12-month follow-ups for safety and efficacy. Case reports were excluded, and four independent reviewers screened the articles for accuracy, with a fifth reviewer resolving any discrepancies that arose to achieve a consensus. The final selection included 18 studies with a total of 593 patients treated with biologic agents for severe and/ or refractory cSLE. The most common indication for using biologic agents was lupus nephritis. Rituximab was used in 12 studies, while belimumab was used in six studies. The studies evaluated the efficacy of biologic agents based on SLE disease activity scores, laboratory parameter improvements, and reduced corticosteroid dosage. Positive outcomes were reported, with improvements in renal, hematologic, and immunologic parameters along with mild adverse effects, mostly related to mild infections and infusion reactions. Belimumab and rituximab have shown promise as potential treatments for severe and refractory cSLE cases, leading to decreased disease activity and complete or partial remission in many patients with an acceptable safety profile. However, further research is needed to better understand their benefits and potential risks in these patients. Key Points • This review emphasizes the lack of sufficient randomized controlled trials exploring the use of biologics in childhood systemic lupus erythematosus (cSLE). • Treatment plans for cSLE are being derived from those used for adult systemic lupus erythematosus. • According to current evidence, belimumab and rituximab can be potential treatment options for refractory and severe cases of cSLE. • Additional studies are required to reach more definitive conclusions.

Comparison of EULAR/PRINTO/PReS Ankara 2008 and 2022 ACR/EULAR Classification Criteria for Granulomatosis with Polyangiitis in Children.

OBJECTIVE: Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmic antibody-associated vasculitis. The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR)-endorsed classification criteria for GPA was derived using data only from adult patients. We aimed to assess the performance of the ACR/EULAR classification criteria for GPA in pediatric patients and compare it with the EULAR/Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology European Society (PReS)-endorsed Ankara 2008 criteria for GPA. METHODS: Retrospective data of pediatric patients with GPA in 20 centers from 9 countries were evaluated. The diagnosis of GPA was made according to the expert opinion. The sensitivity, specificity, positive predictive value, and negative predictive value of the criteria sets were evaluated. RESULTS: The study included 77 patients with GPA and 108 controls (immunoglobulin A vasculitis (n = 44), Takayasu's arteritis (n = 20), microscopic polyangiitis (n = 16), polyarteritis nodosa (n = 14), Behçet's disease (n = 12), eosinophilic granulomatosis with polyangiitis (n = 1), and Cogan's syndrome (n = 1)) with a median age of 17.8 and 15.2 years, respectively. Of patients with GPA, constitutional symptoms (85.7%) and ear-nose-throat involvement (79.2%) were the most common presentations. In the GPA group, 73 patients fulfilled the Ankara 2008 criteria and 69 the ACR/EULAR classification criteria. Sensitivities of the Ankara 2008 criteria and the ACR/EULAR classification criteria were 94.8% and 89.6%, while specificities were 95.3% and 96.3%, respectively. No significant difference was found between sensitivities and specificities of both classification criteria (p= 0.229 and p= 0.733, respectively). CONCLUSION: In children, both the ACR/EULAR and EULAR/PRINTO/PReS Ankara 2008 classification criteria for GPA perform well and similarly.

Validation of the PEDiatric Behçet's Disease classification criteria: an evidence-based approach.

OBJECTIVES: to validate the PEDiatric Behçet's Disease classification criteria (PEDBD) with an evidence-based approach. METHODS: 210 pediatric patients (70 Behçet's disease (BD), 40 Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis, 35 familial Mediterranean fever, 26 hyper-IgD syndrome, 22 TNF-Receptor associated Periodic fever Syndrome, 17 undefined recurrent fevers) were randomly selected from the Eurofever Registry. A set of 11 experienced clinicians/researchers blinded to the original diagnosis evaluated the patients. Using the table consensus as gold standard (agreement ≥ 80%), the PEDBD, ISG and ICBD criteria were applied to BD patients and to confounding diseases with other autoinflammatory conditions in order to define their sensitivity, specificity and accuracy. RESULTS: At the end of the third round, a consensus was reached in 139/210 patients (66.2%). The patients with a consensus ≥80% were classified as confirmed-BD (n = 24), and those with an agreement of 60-79% as probable-BD (n = 10). When comparing these patients with the confounding diseases group, an older age at disease onset, the presence of oral and genital ulcers, skin papulo-pustular lesions, a positive pathergy test and posterior uveitis were BD distinctive elements. The ISG, ICBD and PEDBD criteria were applied to confirmed-BD and to the confounding disease group, showing a sensitivity of 0.50, 0.79 and 0.58, a specificity of 1.00, 0.97, 0.99, and an accuracy of 0.91, 0.94 and 0.92, respectively. CONCLUSIONS: the PEDBD criteria were very specific, while the ICBD resulted to be more sensitive. The complexity of childhood BD suggests larger prospective international cohorts to further evaluate the performance of the criteria.

Phenotype and disease course differences in monogenic and sporadic childhood lupus.

OBJECTIVE: To report the differences in phenotypic characteristics, disease course, and outcome in monogenic and sporadic childhood lupus (SC-lupus) from a single tertiary childhood lupus clinic. METHODS: A descriptive, observational, cross-sectional study was conducted. Data were retrospectively collected at the last follow-up visit on patients with monogenic lupus proven by genetic variants and SC-lupus seen between June 1997 and July 2022. SC-lupus patients were selected by systematic sampling from lupus patients presenting to our lupus clinic; the first patient was chosen randomly, and the subsequent patients were chosen at intervals of three. Data comprised the clinical and laboratory findings, disease activity using the SLEDAI, and damage measured by the pSDI. RESULTS: A total of 54 patients with a median disease duration of 6.8 (IQR 3.5-10.5) years were included. There were 27 patients with monogenic lupus and 27 patients with SC-lupus, with a median age at disease onset of 3.5 (IQR 1.0-6.0), and 9.5 (IQR 7.0-11.8), respectively. (p < 0.05). The rate of consanguinity and family history of lupus were higher in monogenic lupus patients. The two groups were comparable. However, monogenic lupus patients showed more gastrointestinal tract symptoms, and failure to thrive (p < 0.05). They also had more infections. The frequency of the autoantibody profile was higher in monogenic lupus patients. Belimumab was more frequently used in monogenic lupus while rituximab in SC-lupus patients. Monogenic lupus patients had a higher mean SLEDAI, but statistically, it was insignificant. Patients with monogenic lupus had greater disease damage, with a higher mean pSDI and a higher mortality rate (p < 0.05). CONCLUSION: Patients with monogenic lupus are likely to have an early disease onset and a strong family history of lupus, as well as a guarded prognosis, which is likely due to the disease's severity and frequent infections. These differences may be related to the high consanguinity rate and underlying genetic variants.

The SLC29A3 variant, neutrophilic dermatosis, and hyperferritinemia imitate systemic juvenile idiopathic arthritis in a Saudi child: a case report.

Genetic defects of SLC29A3 result in a wide range of syndromic histiocytosis that encompasses H syndrome. Patients with SLC29A3 variants typically have hyperpigmentation, hypertrichosis, hepatosplenomegaly, sensorineural hearing loss, diabetes mellitus, and hypogonadism. Herein, we identify a novel phenotype in a girl presenting with clinical and laboratory findings similar to systemic juvenile arthritis and hyperferritinemia. Exome sequencing identified a homozygous variant in SLC29A3 (NM_018344.5: c.707C>T [p.T236M]). Our patient did not show the cardinal features of the broad spectrum of SLC29A3-related disorders. She demonstrated remarkable improvement in her clinical and laboratory manifestations after starting interleukin-1 blockade (Anakinra). Recent research suggests that SLC29A3-related disorders are accompanied with autoinflammation and autoimmunity due to an overactive inflammasome pathway, which is most likely induced by mitochondrial and lysosomal dysfunction. Hence, our findings may expand the phenotypic features of the SLC29A3 variant. Patients with the SLC29A3 variant and systemic inflammation may benefit from interleukin-1 blockade as a therapeutic option.

New insights on genetic variants and phenotypic features of childhood large-vessel vasculopathy: a systematic review and single-centre series.

OBJECTIVES: To describe the phenotypic, genetic, and outcome characteristics of large-vessel vasculopathy (LVV) in childhood associated with genetic variants. Additionally, a systematic literature review was conducted to delineate the differences between LVV with and without genetic variants. METHODS: The medical records of all children with LVV seen between January 2000 and September 2022 at our institution were retrospectively reviewed for demographic, clinical and genetic data, and outcomes at the last follow-up visit. In addition, we systematically reviewed the literature for the clinical features and known variants of previously reported cases. RESULTS: Eleven patients with childhood LVV were identified; five (three males) of them had proven genetic variants (two DOCK8variants, one FOXP3, one DiGeorge syndrome, and one ZNF469 variant), while six patients had sporadic childhood LVV. Remarkably, patients with genetic variants were younger and had early-onset disease. However, the diagnosis of LVV was delayed compared to those without genetic variants. All patients with genetic variants were treated with corticosteroids, and three patients required sequential immunosuppressive drugs. Four patients underwent surgical intervention, and one received a haematopoietic stem-cell transplant (HSCT). Three patients achieved clinical remission, and two died. Furthermore, data from 20 previously published cases was extracted from the literature. All patients had inherited disorders. Of those, 14 patients had a genetically proven diagnosis. Most of them are treated with corticosteroids and immunosuppressive drugs, with partial responses. Two patients underwent HSCT. There were four deaths. CONCLUSIONS: This study demonstrates that a variety of inherited disorders may contribute to childhood LVV. Strong genetic evidence and the preponderance of autosomal-recessive inheritance may allow us to propose that monogenic LVV is a distinct entity.

A homozygous truncating mutation of FGL2 is associated with immune dysregulation.

BACKGROUND: The type II transmembrane protein fibrinogen-like protein 2 (FGL2) plays critical roles in hemostasis and immune regulation. The C-terminal immunoregulatory domain of FGL2 can be secreted and is a mediator of regulatory T (Treg) cell suppression. Fgl2-/- mice develop autoantibodies and glomerulonephritis and have impaired Treg cell function. OBJECTIVE: Our aim was to identify the genetic underpinning and immune function in a patient with childhood onset of leukocytoclastic vasculitis, systemic inflammation, and autoantibodies. METHODS: Whole-exome sequencing was performed on patient genomic DNA. FGL2 protein expression was examined in HEK293 transfected cells by immunoblotting and in PBMCs by flow cytometry. T follicular helper cells and Treg cells were examined by flow cytometry. Treg cell suppression of T-cell proliferation was assessed in vitro. RESULTS: The patient had a homozygous mutation in FGL2 (c.614_617del:p.V205fs), which led to the expression of a truncated FGL2 protein that preserves the N-terminal domain but lacks the C-terminal immunoregulatory domain. The patient had an increased percentage of circulating T follicular helper and Treg cells. The patient's Treg cells had impaired in vitro suppressive ability that was rescued by the addition of full-length FGL2. Unlike full-length FGL2, the truncated FGL2V205fs mutant failed to suppress T-cell proliferation. CONCLUSIONS: We identified a homozygous mutation in FGL2 in a patient with immune dysregulation and impaired Treg cell function. Soluble FGL2 rescued the Treg cell defect, suggesting that it may provide a useful therapy for the patient.

Practice Patterns and Approach to Childhood Lupus Nephritis in Saudi Arabia.

Renal involvement of systemic lupus erythematosus needs aggressive treatment. Despite the development of multiple international guidelines, differences in practices exist. This study aimed to explore the current practices of pediatric rheumatologists and nephrologists for the diagnosis, management, and monitoring of lupus nephritis (LN) in Saudi Arabia through a survey. Among the 61 respondents, 54.1% were pediatric nephrologists and 49.9% were pediatric rheumatologists. Predominantly, the participating physicians received training either nationally (57%) or in North America (45%). Most of the respondents (77%) did not have a combined rheumatology-nephrology clinic, primarily because of space or time limitations (75%), or a lack of the other specialty (13%). In terms of the decision to request a renal biopsy, the most common factors were nephrotic-range proteinuria (85%) and a lower level of proteinuria associated with hypocomplementemia or elevated anti-double-stranded (ds) DNA (73%). There was marginal agreement over monitoring the disease's activity and treatment response; Complements 3 and 4, anti-dsDNA, protein-creatinine ratio, and estimated glomerular filtration rate were the most popular parameters. The main reason for repeating a renal biopsy was a new renal manifestation that was inconsistent with the previous biopsy. There was considerable variability in the induction therapies used to initiate and taper corticosteroids and conventional immunosuppressive drugs. Most respondents (91%) used angiotensin-converting enzyme agents to control proteinuria. Considerable agreement exists among Saudi physicians managing children with LN but significant variations exist regarding the therapeutic strategies. Additional endeavors are needed to establish a unified national clinical approach for managing LN in children.

Development and Implementation of the AIDA International Registry for Patients With Undifferentiated Systemic AutoInflammatory Diseases.

Objective: This paper points out the design, development and deployment of the AutoInflammatory Disease Alliance (AIDA) International Registry dedicated to pediatric and adult patients affected by Undifferentiated Systemic AutoInflammatory Diseases (USAIDs). Methods: This is an electronic registry employed for real-world data collection about demographics, clinical, laboratory, instrumental and socioeconomic data of USAIDs patients. Data recruitment, based on the Research Electronic Data Capture (REDCap) tool, is designed to obtain standardized information for real-life research. The instrument is endowed with flexibility, and it could change over time according to the scientific acquisitions and potentially communicate with other similar tools; this platform ensures security, data quality and data governance. Results: The focus of the AIDA project is connecting physicians and researchers from all over the world to shed a new light on heterogeneous rare diseases. Since its birth, 110 centers from 23 countries and 4 continents have joined the AIDA project. Fifty-four centers have already obtained the approval from their local Ethics Committees. Currently, the platform counts 290 users (111 Principal Investigators, 179 Site Investigators, 2 Lead Investigators, and 2 data managers). The Registry is collecting baseline and follow-up data using 3,769 fields organized into 23 instruments, which include demographics, history, symptoms, trigger/risk factors, therapies, and healthcare information access for USAIDs patients. Conclusions: The development of the AIDA International Registry for USAIDs patients will facilitate the online collection of real standardized data, connecting a worldwide group of researchers: the Registry constitutes an international multicentre observational groundwork aimed at increasing the patient cohort of USAIDs in order to improve our knowledge of this peculiar cluster of autoinflammatory diseases. NCT05200715 available at https://clinicaltrials.gov/.

Performance of the EULAR/ACR 2019 classification criteria for systemic lupus erythematous in monogenic lupus.

OBJECTIVE: To evaluate the application of the EULAR/ACR-2019 criteria to monogenic lupus patients and compare its performance against the SLICC-2012 criteria. METHODS: In a multicenter retrospective cohort study, consecutive patients with monogenic lupus from three tertiary lupus clinics were enrolled. The diagnosis of monogenic lupus was based on the expert physician's opinion or fulfilling the SLICC-2012 criteria. All enrolled patients had genetic variants. A control group of sporadic childhood SLE (cSLE) and non-SLE patients, were included. A descriptive data analysis was conducted, and the EULAR/ACR-2019 and SLICC-2012 criteria were applied to both groups. RESULTS: Forty-nine patients with monogenic lupus with a median age at diagnosis of 6.0 (IQR 3.0-10.8) years and 104 controls (55 patients with cSLE and 49 non-lupus patients with a median age at diagnosis of 10.0 and 5.0 respectively) were included. Forty-four (89.8%) patients with monogenic lupus fulfilled the EULAR/ACR-2019 with a mean score of 22.3±8.9. The most frequent domains were immunologic (93.9%), musculoskeletal and renal (each 57.1%), and mucocutaneous (55.1%). Fifty-four (98.2%) cSLE patients and six (12.2%) non-lupus patients met the EULAR/ACR-2019 criteria with a mean score of 22.5±9.2 and 8.5±5.2, respectively. The sensitivity of the EULAR/ACR-2019 criteria in monogenic lupus was 89.9% (95% CI: 78.3-90.2), while the specificity was 87.6% (95% CI: 75.2-88.7). CONCLUSION: This is the first and largest cohort of monogenic lupus patients testing the performance of the 2019-EULAR/ACR criteria. It efficiently classifies monogenic lupus patients, irrespective of the underlying genetic variants. Further studies are needed before these criteria are adopted worldwide. Key Points • Typically, patients with monogenic lupus have early onset severe disease, especially with mucocutaneous manifestations and a strong family history of SLE. • Monogenic lupus is a distinctive entity and might differ from the sporadic childhood SLE. • Our study includes a large multinational cohort of monogenic lupus with heterogeneous phenotypic features and underlying genetic variants. • Our study demonstrates that the EULAR/ACR-2019 criteria efficiently classified monogenic lupus patients, irrespective of the diversity of the underlying genetic variants.

International Consensus for the Dosing of Corticosteroids in Childhood-Onset Systemic Lupus Erythematosus With Proliferative Lupus Nephritis.

OBJECTIVE: To develop a standardized steroid dosing regimen (SSR) for physicians treating childhood-onset systemic lupus erythematosus (SLE) complicated by lupus nephritis (LN), using consensus formation methodology. METHODS: Parameters influencing corticosteroid (CS) dosing were identified (step 1). Data from children with proliferative LN were used to generate patient profiles (step 2). Physicians rated changes in renal and extrarenal childhood-onset SLE activity between 2 consecutive visits and proposed CS dosing (step 3). The SSR was developed using patient profile ratings (step 4), with refinements achieved in a physician focus group (step 5). A second type of patient profile describing the course of childhood-onset SLE for ≥4 months since kidney biopsy was rated to validate the SSR-recommended oral and intravenous (IV) CS dosages (step 6). Patient profile adjudication was based on majority ratings for both renal and extrarenal disease courses, and consensus level was set at 80%. RESULTS: Degree of proteinuria, estimated glomerular filtration rate, changes in renal and extrarenal disease activity, and time since kidney biopsy influenced CS dosing (steps 1 and 2). Considering these parameters in 5,056 patient profile ratings from 103 raters, and renal and extrarenal course definitions, CS dosing rules of the SSR were developed (steps 3-5). Validation of the SSR for up to 6 months post-kidney biopsy was achieved with 1,838 patient profile ratings from 60 raters who achieved consensus for oral and IV CS dosage in accordance with the SSR (step 6). CONCLUSION: The SSR represents an international consensus on CS dosing for use in patients with childhood-onset SLE and proliferative LN. The SSR is anticipated to be used for clinical care and to standardize CS dosage during clinical trials.

Epidemiology and demographics of juvenile idiopathic arthritis in Africa and Middle East.

Juvenile Idiopathic Arthritis (JIA) is a group of chronic heterogenous disorders that manifests as joint inflammation in patients aged <16 years. Globally, approximately 3 million children and young adults are suffering from JIA with prevalence rates consistently higher in girls. The region of Africa and Middle East constitute a diverse group of ethnicities, socioeconomic conditions, and climates which influence the prevalence of JIA. There are only a few studies published on epidemiology of JIA in the region. There is an evident paucity of adequate and latest data from the region. This review summarizes the available data on the prevalence of JIA and its subtypes in Africa and Middle East and discusses unmet needs for patients in this region. A total of 8 journal publications were identified concerning epidemiology and 42 articles describing JIA subtypes from Africa and Middle East were included. The prevalence of JIA in Africa and Middle East was observed to be towards the lower range of the global estimate. We observed that the most prevalent subtype in the region was oligoarticular arthritis. The incidence of uveitis and anti-nuclear antibody (ANA) positivity were found to be lower as compared to the incidence from other regions. There is a huge unmet medical need in the region for reliable epidemiological data, disease awareness, having regional and local treatment guidelines and timely diagnosis. Paucity of the pediatric rheumatologists and economic disparities also contribute to the challenges regarding the management of JIA.

Consensus clinical approach for a newly diagnosed systemic juvenile idiopathic arthritis among members of the pediatric rheumatology Arab group.

BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) is a diagnosis of exclusion. The complex nature and clinical variety of the disease, as well as the vast clinical variation of disease presentation, may lead to difficulties in disease detection and subsequent delays in treatment. AIM: To provide a consensus guidance on the management of newly diagnosed sJIA patients among pediatric rheumatologists in Arab countries. METHODS: This work was conducted in two phases. The first phase utilized an electronic survey sent through an email invitation to all pediatric rheumatologists in Arab countries. In the second phase, a Task Force of ten expert pediatric rheumatologists from Arab countries met through a series of virtual meetings. Results obtained in phase one were prioritized using a nominal group and Delphi-like techniques in phase two. RESULTS: Seven overarching principles and a set of recommendations were approved by the Task Force to form the final consensus. CONCLUSION: This is the first consensus on a clinical approach for pediatric rheumatic diseases among Arab pediatric rheumatologists. It is presented as a guidance on the clinical approach to sJIA that requires further evidence, and future updates are anticipated.

Familial Clustering of Juvenile Psoriatic Arthritis Associated with a Hemizygous FOXP3 Mutation.

PURPOSE OF REVIEW: We describe the clinical and genetic findings in four patients from a single family who presented with refractory psoriatic arthritis and were hemizygous in the forkhead box protein 3 (FOXP3) gene (c.1222G>A). RECENT FINDINGS: We report four siblings with hemizygous mutation in the FOXP3 gene (c.1222G>A) who presented with type 1 diabetes mellitus and psoriatic arthritis poorly responsive to treatment. Our findings expand the phenotype spectrum of FOXP3 mutations. Immune dysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) syndrome is a rare disorder caused by mutations in FOXP3 gene, which lead to early onset of constellation of autoimmune manifestations. This report highlights the influence of immune dysregulation in juvenile arthritis.

Familial aggregation of juvenile idiopathic arthritis with other autoimmune diseases: Impact on clinical characteristics, disease activity status and disease damage.

OBJECTIVES: To evaluate the impact of family history of autoimmune diseases (FHADs) on the clinical characteristics and outcome of juvenile idiopathic arthritis (JIA). METHODS: We retrospectively reviewed children with JIA seen in 7 pediatric rheumatology clinics from 6 Arab countries. All included patients met the International League of Associations for Rheumatology classification criteria for JIA and had a disease duration greater than 1 year. Data were collected at the last follow-up visit and comprised clinical findings, including FHADs. Disease activity and disease damage were assessed by Juvenile Arthritis Multidimensional Assessment Report, and juvenile arthritis damage index (JADI) respectively. Disease activity was categorized as remission off treatment, remission on treatment, or active disease. RESULTS: A total of 349 (224 females) JIA patients with a disease duration of 5 (interquartile range 2.9-7.5) years were included. The most frequent JIA categories were polyarticular JIA and oligoarticular JIA, followed by systemic JIA. There were 189 patients with FHADs and 160 patients without FHADs. The most frequent FHADs were diabetes mellitus (21.2%), JIA (18.5%), rheumatoid arthritis (12.7%). Among patients with FHADs, 140/189 (74.1%) achieved clinical remission, while 131/160 (81.9%) patients without FHDs had clinical remission (odds ratio [OR] = 1.2, 95% CI 0.97-1.5). Rate of consanguinity, enthesitis-related arthritis (ERA) and psoriatic arthritis were higher in patients with FHADs (OR = 0.6, 95% CI 0.4-0.9 and OR = 1.2, 95% CI 1.1-1.4). Also, articular JADI correlated significantly with presence of FHADs (OR = 1.1, 95% CI 1.0-1.1). CONCLUSION: This study shows that autoimmune diseases cluster within families of patients with JIA with a high proportion of ERA and psoriatic arthritis. JIA patients with FHADs are likely to have more disease damage.

New or vanishing frontiers: LACC1-associated juvenile arthritis.

BACKGROUND: The classification and pathogenic basis of juvenile idiopathic arthritis (JIA) are a subject of some controversy. Essentially, JIA is an exclusion diagnosis that represents a phenotypically heterogeneous group of arthritis of unknown origin. Familial aggregation of JIA supports the concept of genetic influence in the pathogenesis of JIA. OBJECTIVE: To present the spectrum of laccase domain-containing 1 (LACC1)-associated juvenile arthritis with clinical, biochemical, and molecular genetic data of a cohort of 43 patients, including 11 previously unpublished cases. METHODS: We studied 11 patients with different categories of juvenile idiopathic arthritis from 5 consanguineous families, all from Saudi Arabia, except 2 patients who were of Jordanian ethnicity. Whole-exome sequencing was used to identify the disease-causing variant of LACC1. We also reviewed the clinical spectrum and molecular genetic data of previously published cases of LACC1-associated juvenile arthritis. RESULTS: This study describes 43 (29 females, 14 males) patients from consanguineous multiplex families. Most of the included patients were of Arab origin with 86% having early onset disease. The most frequent categories were systemic (19 patients) and rheumatoid factor-negative polyarticular (19 patients). Thirty-seven (86%) had progressive erosive arthritis and 10 (23.3%) had persistent limb lymphedema. None of the patients had features of macrophage activation syndrome. Genetic analysis confirmed LACC1 variant in all patients; 22 patients had common founder mutation (LACC1: c.850T > C,p.C284R), while the others showed different LACC1 variants. All patients were treated aggressively with methotrexate and sequential biologic agents. Most of them showed a poor response to treatment. CONCLUSION: This report expands the pathogenic variants of LACC1 and the clinical spectrum associated with this genetic subset of juvenile arthritis. The predominance of autosomal-recessive inheritance and strong genetic evidence allowed us to propose LACC1-associated juvenile arthritis as a distinct disorder.