Genome Sequencing in an Individual Presenting with 22q11.2 Deletion Syndrome and Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis is a heterogeneous group of diseases characterized by arthritis with poorly known causes, including monogenic disorders and multifactorial etiology. 22q11.2 proximal deletion syndrome is a multisystemic disease with over 180 manifestations already described. In this report, the authors describe a patient presenting with a short stature, neurodevelopmental delay, and dysmorphisms, who had an episode of polyarticular arthritis at the age of three years and eight months, resulting in severe joint limitations, and was later diagnosed with 22q11.2 deletion syndrome. Investigation through Whole Genome Sequencing revealed that he had no pathogenic or likely-pathogenic variants in both alleles of the MIF gene or in genes associated with monogenic arthritis (LACC1, LPIN2, MAFB, NFIL3, NOD2, PRG4, PRF1, STX11, TNFAIP3, TRHR, UNC13DI). However, the patient presented 41 risk polymorphisms for juvenile idiopathic arthritis. Thus, in the present case, arthritis seems coincidental to 22q11.2 deletion syndrome, probably caused by a multifactorial etiology. The association of the MIF gene in individuals previously described with juvenile idiopathic arthritis and 22q11.2 deletion seems unlikely since it is located in the distal and less-frequently deleted region of 22q11.2 deletion syndrome.

Ocular toxoplasmosis following anti-tumour necrosis factor-α therapy combined with oral methotrexate therapy: A case report and review of literature.

Purpose: To report a case of ocular toxoplasmosis following long-term treatment with adalimumab and review the literature on ocular toxoplasmosis following anti-Tumour necrosis factor-α therapy. Method: A retrospective chart review of A 21-year-old male who developed retinochoroiditis in his left eye following adalimumab therapy combined with oral methotrexate. Result: A known patient of juvenile idiopathic arthritis (JIA) on adalimumab and oral methotrexate for the last four years presented to us with a blurring of vision for the last 15 days. Fundus examination of the left eye revealed severe vitritis and two patches of retinochoroiditis in the inferior part of the fundus. Subsequent investigations confirmed it to be a case of toxoplasma retinochoroiditis, and he responded to anti-toxoplasma treatment. A review of literature on a similar topic revealed five such cases, and the index case was the first such report in patients with JIA. Conclusion: The index case highlights the importance of early recognition and management of opportunistic infections in patients receiving biologicals.

Pericardial effusion in children admitted with juvenile idiopathic arthritis: A multicenter retrospective cohort study from the pediatric health information system.

Objectives: This study aimed to determine if the presence of a pericardial effusion is associated with adverse outcomes among children admitted with juvenile idiopathic arthritis. Patients and methods: The multicenter, retrospective cohort study was conducted with 4,332 patients (1,554 males, 2,778 females; median age: 12 years; IQR, 7, 15 years) using the Pediatric Health Information System. Data from hospital admissions between January 1, 2004, and September 15, 2015, were obtained for patients with an International Disease Classification, Ninth Revision code for juvenile idiopathic arthritis. Pericardial effusion was the primary predictor variable; the outcomes of interest were length of stay, hospital costs, and readmission within 90 days. Multivariate models were created to evaluate associations between pericardial effusion and adverse outcomes. We also analyzed factors associated with increased odds of having pericardial effusion in juvenile idiopathic arthritis. Results: One hundred twenty (3%) patients had a code for pericardial effusion. Children with pericardial effusion had a longer median length of stay (7 days (IQR 3, 12) vs. 3 days (IQR 2,6), p<0.001), higher median costs ($17,688 (IQR 8,657, 40,623) vs. $8,456 (IQR 4,865, 16,302), p<0.001), and greater rates of readmission (22% vs. 15%, p=0.045). Multivariate analysis demonstrated no significant association between pericardial effusion and outcomes of interest. Black race and male sex were associated with increased odds of having pericardial effusion. Conclusion: Pericardial effusion is rare among children admitted with juvenile idiopathic arthritis but is associated with significant morbidity; its presence may be a marker of disease severity. Black children and males admitted with juvenile idiopathic arthritis warrant special consideration and may benefit from screening echocardiography.

What has changed in total hip arthroplasty in patients of juvenile idiopathic arthritis since 2000? A systematic review and pooled data analysis.

PURPOSE: The prevalence of juvenile idiopathic arthritis (JIA) is estimated to be 16-150 per 100,000 children worldwide. The hip joint may be involved in over 50% of children leading to significant morbidity which may require surgical intervention in the form of arthroplasty. The literature lacks a concise overview of the outcomes, including complication and implant survival of total hip arthroplasty (THA) in juvenile idiopathic arthritis (JIA). The aim of this study is to systematically analyze the literature and report the outcomes of THA in JIA. METHODS: Search was conducted in the online databases PubMed, Embase and Cochrane database. It included all original studies which evaluated clinical and/or radiological outcomes of THA in JIA with a minimum sample size of 5 patients and published in English. The level of evidence of the included studies was graded according to the Oxford Centre for Evidence Based Medicine. The Institute of Health Economics checklist was used to assess the quality of the studies included. RESULTS: The nine studies included were retrospective in nature with all being Level IV according to Oxford Centre for Evidence Based Medicine. 475 hips in 304 patients with majority of them being females (241/304, 79.2%) were included in this review. All the studies reported the outcome objectively using various scores. The proportion of revision surgeries (92/378), either femoral or acetabular, noted was 22% (95% CI 10-33%). The proportion of acetabular revisions (72/378) was 16% (95% CI 8-25%) as compared to 4% (95% CI 1-6%) for femoral revisions (20/378). There was no difference in survivorship when cemented and uncemented implants were compared. CONCLUSION: JIA patients with advanced hip disease represent a unique population with need for extra-long implant longevity. THA in patients of JIA leads to improved pain relief as well as mobility but the conversion of the same outcomes to functional activity is not proportionally improved. The current trend is the use of uncemented and ceramic-on-ceramic implants. Acetabular implants require earlier revision as compared to femoral implants. Age at surgery can be delayed by early institution of methotrexate which indirectly improves implant survival. LEVEL OF EVIDENCE: IV.

Clinician's dilemma: Naproxen-induced liver injury.

Naproxen is a widely used nonsteroidal anti-inflammatory drug (NSAID) in pediatric population, used for mild-to-moderate pains, arthritis, and other immune-mediated disorders. It rarely causes clinically apparent liver injury in the adult population taking high doses of the drug over a prolonged period and is reported even rarer in pediatric population. We present a case of drug-induced liver injury (DILI) in a 13-year-old girl taking naproxen in therapeutic doses for juvenile rheumatoid arthritis. There was a complete recovery of liver function following discontinuation of naproxen therapy.

Effectiveness of Early Physical Therapy Rehabilitation in Patient With Juvenile Rheumatoid Arthritis.

A diverse group of idiopathic inflammatory arthritis that affects children under the age of 16 and lasts six weeks or longer is known as juvenile idiopathic arthritis (JIA) or juvenile rheumatoid arthritis (JRA). It causes joint pain and morning stiffness, and the affected joints swell and become difficult to move. During flares, patients may experience flu-like symptoms such as muscle aches and fatigue. Disease-modifying antirheumatic drugs (DMARDs) are the mainstay of rheumatoid arthritis (RA) treatment. If necessary, immunosuppressive medications can be administered in stages. Nonsteroidal anti-inflammatory drugs (NSAIDs) are pain relievers for joints. Physical therapy treatment aims to reduce pain, improve joint range, correct movement patterns, strengthen weak structures, improve cardiovascular endurance, and improve patients' quality of life. We present a case of a 12-year-old boy who presented to the hospital with knee pain and an inability to walk without assistance after falling on the ground one month prior. Medical history revealed that the patient had juvenile rheumatoid arthritis, which was confirmed on investigations. The consultant physician referred the patient for pre-rehabilitation physiotherapy before corrective surgery.

A Rare Occurrence of Scleromalacia Perforans With Juvenile Rheumatoid Arthritis: A Case Report.

Here, we report a case of a nine-year-old boy with chronic juvenile rheumatoid arthritis (JRA) leading to scleromalacia perforans (SP). We rarely see SP with fixed deformities of rheumatoid arthritis in the hands, but not as a starting point of the disease. He reported eye manifestations associated with JRA on further investigation and inquiry. The right globe was preserved on presentation, and the left was perforated. He lost sight in his left eye when he was treated with antibiotics and visited various physicians in his native region.

Horse-Specific Cryptosporidium Genotype in Human with Crohn's Disease and Arthritis.

We identified an unusual subtype of a Cryptosporidium sp. horse genotype as the cause of cryptosporidiosis in a 13-year-old girl in Poland who was undergoing immunosuppressive treatment for juvenile rheumatoid arthritis and Crohn's disease. The same subtype was identified in a horse the girl had ridden.

Multicentric Carpotarsal Osteolysis Syndrome in a Mother and Daughter with a MAFB Missense Variant and Natural History of the Disease.

Multicentric carpotarsal osteolysis syndrome (MCTO; MIM #166300) is a rare skeletal disorder characterized by osteolysis affecting particularly the carpal, metacarpal, and tarsal bones, although other bones might be involved. MCTO is an autosomal dominant disease caused by heterozygous variants in the MAFB gene, frequently misdiagnosed as juvenile rheumatoid arthritis due to similar clinical manifestations. This study reports the first Brazilian family diagnosed with MCTO with progressive osteolysis of the carpal and tarsal bones, presenting a c.161C>T (p.Ser54Leu) heterozygous variant in the MAFB gene, describing the clinical, radiological, and molecular findings, compared with literature data, and discussing the different clinical and molecular diagnosis, as well as the natural history of the disease. Since MCTO is a disorder with progressive symptoms, an early diagnosis is important to avoid unnecessary investigations and treatments and to provide the proper follow-up.

Clinical efficacy of intra-articular injection with Triamcinolone acetonide in patients with juvenile idiopathic arthritis / 中华实用儿科临床杂志

Objective:To observe the clinical efficacy of intra-articular injection with Triamcinolone acetonide on the treatment of juvenile idiopathic arthritis (JIA).Methods:The clinical data of 26 children diagnosed with JIA undergoing the intra-articular injection of Triamcinolone acetonide for the joints with obvious swelling and pain at the Children′s Hospital Affiliated to Capital Institute of Pediatrics from October 2018 to December 2019 who were retrospectively analyzed.Erythrocyte sedimentation rate (ESR) and C-reactive protein(CRP) were tested before and after the application of Triamcinolone acetonide.Detailed clinical manifestations were recorded.The nonparametric Kruskal- Wallis test was used to compare the differences in clinical evaluation indicators and changes in laboratory tests at diffe-rent treatment times. Results:Among the 26 children, 8 were boys and 18 were girls.After the intra-articular injection of Triamcinolone acetonide, 9 cases (34.62%) achieved complete remission, 15 cases(57.69%) achieved partial remission, and 2 cases (7.69%) were not responsive to the intra-articular injection.The overall therapeutic efficacy was 92.31%.Compared with pre-treatment period, from 4 weeks after treatment, assessment of disease activity by the physicians and parents of the children was significantly improved after 4-week treatment, and the number of active joints, ESR and CRP and the Juvenile Arthritis Disease Activity Score with 27 joints (JADAS 27) gradually decreased, and the differences were statistically significant (all P<0.05). No adverse drug reactions were seen during the treatment and follow-up period. Conclusions:Intra-articular injection of Triamcinolone acetonide is effective in contro-lling joint symptoms of JIA with less adverse events.

C1-2 rotatory subluxation as a presenting sign in juvenile rheumatoid arthritis.

STUDY DESIGN: Case report. INTRODUCTION: Juvenile rheumatoid arthritis (JRA) typically presents with fever, rash, anterior uveitis, and/or joint pain. We present three cases with initial torticollis due to rotatory subluxation of C1-C2 as an initial sign of JRA. CASE REPORTS: Three girls, ages 5-9, presented with C1-2 rotatory subluxation. Traction was able to reduce the atlanto-axial joint in all cases. Based on imaging, history, exam, and laboratory results, they were diagnosed with JRA. After reduction of the atlantoaxial joint, they were transitioned to a halo vest and disease-modifying antirheumatic drugs (DMARDs). The older 2 children underwent C1-2 fusion. The younger child has minimal symptoms and has not undergone surgical intervention 4 years from initial presentation. CONCLUSION: Rotatory subluxation can be the first presenting sign of JRA. Younger children may be able to be treated conservatively with traction and medication, while older children may require occiput to C2 fusion due to bony destruction and basilar invagination. LEVEL OF EVIDENCE: IV.

The utility of therapeutic plasma exchange in Hyperviscosity syndrome associated with juvenile rheumatoid arthritis: A case report.

Hyperviscosity syndrome (HVS) is a life-threatening syndrome caused by high concentrations of large plasma proteins like IgM, rheumatoid factor, and other immune complexes, leading to increased blood viscosity and symptoms such as visual abnormalities, neurological impairment, bleeding diathesis, and thrombosis. While Waldenström's macroglobulinemia accounts for 80% to 90% of cases, HVS may develop in other clinical settings characterized by elevations in plasma proteins. Limited evidence currently exists describing the safety and efficacy of therapeutic plasma exchange (TPE) for the management of HVS secondary to non-neoplastic conditions. We report a case of recurrent HVS associated with juvenile rheumatoid arthritis and Felty syndrome that demonstrated improvement in clinical symptoms following initiation of TPE. These findings suggest that TPE may be utilized as an adjunct treatment option in patients with HVS secondary to autoimmune disorders.

Juvenile idiopathic arthritis, gait characteristics and relation to function.

BACKGROUND: Juvenile Idiopathic Arthritis (JIA) is a chronic inflammatory arthritis that impacts biomechanical features of gait. This systematic review describes the effects of JIA on gait motion parameters and walking performance. METHODS: Six databases were searched (PubMed/Medline, Cochrane, the EBSCOHost database SPORTDiscus, Web of Science, and Embase). Studies were restricted to children with any subtype of JIA who were assessed for gait motion features (kinematic, kinetic, temporalspatial) or walking performance (velocity or distance covered); could include intervention or treatment exposure with measures of gait and gait speed; could involve comparison of gait in JIA to healthy controls. Quality of evidence was assessed using the GRADE system. This systematic review was registered at PROSPERO (CRD42018109582) RESULTS: The search yielded 625 papers, 23 of which described biomechanical features of gait and/or assessed walking performance. Twenty studies measured walking velocity and walking ability using simple field tests or laboratory methods. Eleven studies measured temporalspatial parameters such as cadence, step length, stride length, step width, single and double support time. Nine studies evaluated kinetic measurements including joint power, flexion and extension and joint moments. Nine studies evaluated kinematic parameters including range of motion, pelvic tilt, center of motion and trunk sway. CONCLUSIONS: Key features of gait in children with JIA include slower gait velocity, shortened step length, decreased range of motion at the hip, knee and ankle with trend towards flexion, decreased joint power, anteriorly tilted pelvis and trunk with shifted center of motion. There is a potential to ameliorate JIA-related gait changes with exercise and/or pharmaceutical interventions.

A novel loss-of-function mutation in LACC1 underlies hereditary juvenile arthritis with extended intra-familial phenotypic heterogeneity.

OBJECTIVE: To investigate phenotypic and molecular characteristics of a consanguineous family with autosomal-recessive, polyarticular, juvenile isiopathic arthriris (JIA) with extra-articular manifestations, including renal amyloidosis and Crohn's disease, associated with a novel homozygous truncating variant in LACC1. METHODS: Whole exome sequencing (WES) or targeted Sanger verification were performed in 15 participants. LACC1 expression and cytokine array were analysed in patient-derived and CRISPR/Cas9-generated LACC1-knockout macrophages (Mϕ). RESULTS: A homozygous truncating variant (p.Glu348Ter) in LACC1 was identified in three affected and one asymptomatic family member, and predicted harmful by causing premature stop of the LACC1 protein sequences, and by absence from ethnically-matched controls and public variation databases. Expression studies in patient-derived macrophages (Mϕ) showed no endogenous p.Glu348Ter-LACC1 RNA transcription or protein expression, compatible with nonsense-mediated mRNA decay. WES analysis in the asymptomatic homozygous subject for p. Glu348Ter-LACC1 detected an exclusive heterozygous variant (p.Arg928Gln) in complement component C5. Further complement activity analysis suggested a protective role for the p.Arg928Gln-C5 variant as a phenotypic modifier of LACC1-associated disease. Finally, cytokine profile analysis indicated increased levels of pro-inflammatory cytokines in LACC1-disrupted as compared with wild-type Mϕ. CONCLUSIONS: Our findings reinforce the role of LACC1 disruption in autosomal-recessive JIA, extend the clinical spectrum and intra-familial heterogeneity of the disease-associated phenotype, indicate a modulatory effect of complement factor C5 on phenotypic severity, and suggest an inhibitory role for wild-type LACC1 on pro-inflammatory pathways.

Recommendations for the management of childhood juvenile idiopathic arthritis-type chronic anterior uveitis.

IMPORTANCE: Australian- and New Zealand-based, uveitis-specialized ophthalmologists have produced recommendations for the management of juvenile idiopathic arthritis (JIA)-type chronic anterior uveitis. BACKGROUND: Historically, the visual prognosis of JIA-type chronic anterior uveitis has been poor. New medical advances are likely to improve outcomes, but recently published guidelines are tailored for ophthalmic care in Europe and the United States. DESIGN: This work involved a consensus survey and a panel meeting. PARTICIPANTS: The Australian and New Zealand JIA-Uveitis Working Group (29 ophthalmologists) participated in the work. METHODS: The Delphi technique was used to achieve consensus. MAIN OUTCOME MEASURES: This work yielded consensus statements. RESULTS: The Working Group achieved consensus around 18 statements related to clinical evaluation, use of topical and regional corticosteroids, use of systemic corticosteroid and non-corticosteroid immunomodulatory drugs, and management of secondary cataract and glaucoma in childhood JIA-type uveitis. CONCLUSIONS AND RELEVANCE: Recommendations of the Australian and New Zealand JIA-Uveitis Working Group provide current and regionally applicable advice for managing chronic anterior uveitis in children with JIA.

Iris cysts: Varied presentations and review of literature.

An iris cyst is a nonkeratinized squamous epithelial-lined space involving a layer of iris. The presentation of iris cyst can be variable-innocuous or presenting with secondary complications. The identification of whether the cyst is primary or secondary is important. The prognosis of primary iris cysts is good, as the majority does not require treatment and that of secondary iris cysts is much more capricious depending on their presentation. Their optimal management often poses a challenge for ophthalmologists. Here, we will present two cases of iris cysts with diverse presentation along with a review of the literature of this rare clinical entity.

Dental age estimation in children affected by juvenile rheumatoid arthritis.

Dental root calcification has proven to be a reliable biological evidence to estimate chronological age of children. The development of structures usually examined in the age estimation forensic practice (e.g. skeleton, teeth) is supposed to be influenced by diseases and nutritional, environmental, ethnic, and ultimately even socioeconomic factors. This research aims to study the age estimation in children affected by juvenile rheumatoid arthritis (JRA) with and without steroids treatment and compared with healthy subjects. MATERIAL AND METHODS: Dental age estimations based on 752 OPGs, 420 girls and 332 boys, aged from 3.3 to 15.99 years, were provided by applying Demirjian and Willems' original methods. Of the whole sample, 103 individuals were affected by JRA and 40 received a continuous corticosteroid therapy, over 1 year long. CONCLUSIONS: Willems' and Demirjian's original methods, as methods commonly applied to estimate age for sub-adults with unremarkable medical history, can be used for medico-legal purposes to children affected by JRA. Willems' method tended to underestimate age while Demirjian's method resulted to be prone to overestimation for both healthy and JRA-affected children. JRA showed to have no influence on root calcification process even in children that received steroid treatment for 1 year or longer.

Type 1 interferonopathy presenting as juvenile idiopathic arthritis with interstitial lung disease: report of a new phenotype.

BACKGROUND: STING-associated vasculopathy with onset in infancy (SAVI) is a type 1 interferonopathy manifesting as a pulmonary and vascular syndrome resulting from gain-of-function mutations in TMEM173, the gene encoding STING. Familial reports in the literature are sparse. CASE PRESENTATION: We report a case series of SAVI in a three generation kindred, with a phenotype of interstitial lung disease (ILD) and rheumatoid factor positive polyarticular juvenile idiopathic arthritis (JIA). Current and historical medical records were reviewed for clinical and laboratory information. Whole blood from cases 1 and 2, plus stored appendicectomy tissue from case 3, underwent DNA sequencing of the TMEM173 gene. Peripheral blood RNA was obtained from cases 1 and 2 for functional assessment of the TMEM173 mutation. DNA sequencing identified the same heterozygous TMEM173 mutation (c.463G > A; p.Val155Met) in all three cases, consistent with a diagnosis of the autosomal dominant condition SAVI. Functional assessment of this mutation identified a prominent interferon signature which was confirmed on repeat testing. CONCLUSIONS: SAVI presented in this family as ILD with early onset juvenile rheumatoid arthritis. This condition should be considered in all rheumatoid arthritis patients with early-onset ILD and in all JIA patients with ILD.

Condylar alterations and facial growth in children with juvenile idiopathic arthritis.

PURPOSE: The aim of this retrospective study was to evaluate facial growth in children with juvenile idiopathic arthritis (JIA) by means of lateral head cephalometric radiographs and relate the findings to temporomandibular joint (TMJ) condylar changes on panoramic radiographs. METHODS: Radiographic and medical records were evaluated in 65 children with JIA. Cephalometric and panoramic analyses were performed for the impact of condylar changes on facial growth. We compared children with condylar alterations, minor or major, with those without condylar alterations. RESULTS: Based on panoramic radiographs, no condylar alterations were seen in 27 of the 65 children and condylar alterations were seen in 38 children (i.e., 23 had minor and 15 major condylar alterations). The cephalometric analyses of the children with condylar changes showed significant growth disturbances with a more retrognathic mandible (SNB; p = 0.03), retruded chin position (SNPog; p = 0.02), larger mandibular angulation (ML/NSL; p = 0.009) and maxillary angulation (NL/NSL; p = 0.03) compared with children without condylar alterations. Children with minor condylar alterations had a significantly more retruded chin position (SNPog) than those with no condylar changes (p = 0.04). CONCLUSIONS: Condylar changes in the TMJ, judged on panoramic radiography, in children with JIA, have impact on craniofacial growth. Even minor alterations seem to have an impact.