Search

Objective: To assess the usefulness of serum ferritin and soluble interleukin-2 receptor (sIL-2r) levels as markers of disease activity in childhood systemic lupus erythematosus (cSLE) and their role in screen for subclinical macrophage activation syndrome (MAS). Patients and methods: This is a cross-sectional analysis of prospectively collected data. Consecutive children who met the Systemic Lupus International Collaborating Clinics (SLICC) criteria were enrolled between June 2015 and June 2017. All patients interviewed and assessed for disease activity using SLE disease activity index (SLEDAI). Biochemical and serological tests including markers of disease activity and MAS were measured by standard laboratory procedure. Results: A total of 31 (25 female; 6 male) consecutive cSLE patients with a mean age of 10.6 (±3.2) years were included. The most frequent manifestations were mucocutaneous and musculoskeletal (84%) followed by hematological (64.5%) then renal involvement (58%). Twenty-two patients had active disease (SLEDAI ≥ 4), with a mean of 9.8. Mean serum ferritin and sIL-2r were 555 (±1860) and 2789 (±1299) respectively. Both correlated significantly with leucocyte, platelet count, transferrin, C3 and SLEDAI (p

Background and objectives: To examine the frequency of endocrinopathies in children with systemic lupus erythematosus (SLE) and juvenile idiopathic arthritis (JIA). Design and setting: A cross-sectional study. Patients and methods: A study was conducted in Saudi children with SLE and JIA who were seen at King Faisal Specialist Hospital and Research Centre, Riyadh, between September 2013 and April 2015. All enrolled patients completed the clinical evaluation, which included information about family history of autoimmune disease, growth parameters and tanner stage, as well as the following assessments: vitamin D profile (parathyroid hormone and 25-OH vitamin D levels), TSH, FT4 and total T3, thyroglobulin antibodies, thyroperoxidase antibodies, random blood sugar, HbA1C, IGF1, IGFBP-3, LH, and FSH. Results: A total of 42 patients, 22 with JIA and 20 with SLE, were included in the study. The mean participant age was 12.2 ± 5.3 years with a mean disease duration of 3.2 ± 3.4 years. Female gender was predominant (17 SLE, 13 JIA) in the patient population. Fifteen patients (35.7%) presented with a family history of autoimmune disease. The most frequently detected endocrinopathies were vitamin D insufficiency (35%) and thyroid disease (31%). Eight JIA patients and 7 SLE patients exhibited low vitamin D levels; 10 patients presented with hyperparathyroidism. Thyroid dysfunction was observed in 13 patients (8 SLE, 5 JIA), and 2 patients were found to be euthyroid (normal TSH, FT4) with positive thyroid autoantibodies. Furthermore, 7 patients presented with subclinical hypothyroidism (high TSH, normal FT4), and 4 patients presented with overt hypothyroidism (high TSH, low FT4). Seven patients (4 SLE and 3 JIA) presented with short stature due to growth hormone insufficiency (low IGF1, IGFBP-3). Two patients exhibited delayed puberty accompanied by low LH levels. Diabetes mellitus was more frequently observed in patients with JIA (4 patients) than in patients with SLE (1 patient). Conclusion: Our findings demonstrated that coexistence of endocrinopathies is not uncommon in children diagnosed with JIA and SLE. Abnormal thyroid function occurs frequently and at a similar rate in children diagnosed with SLE and JIA. Thus, screening for endocrinopathies, namely thyroid disease, during the assessment of childhood SLE and JIA is worth consideration.

Background and objectives To evaluate the frequency of antiphospholipid antibodies (APLa) among patients with childhood lupus nephritis (cLN) and to assess their impact on long-term renal outcomes. Design and setting This is an observational hospital based study. Patients and methods Patients with cLN diagnosed by renal biopsy seen between January 2002 and June 2014 were included. APLa positivity was defined if detection was positive on 2 occasions 6–12 weeks apart during their follow up. Demographic features, age at disease onset, disease duration, follow-up duration and clinical and laboratory variables at the time of renal biopsy were collected. The renal biopsy was reviewed for the nephritis class, microthrombi, activity and chronicity indices. Renal outcome measures included the serum creatinine levels, protein/creatinine ratio and end stage renal disease (ESRD). Results Fifty-nine, (49 female) patients with a mean age of 19.8 years and mean disease duration of 6.8 years were involved. APLa were detected in 46 (78%) patients. Twenty-two patients had class IV nephritis, which was more prevalent in APLa positive patients. The frequencies of class III and V nephritis was similar in 10 patients in each class (7 patients in each class with APLa). The presence of APLa did not correlate with nephritis activity or the chronicity indices. Microthrombosis was found in 10 patients, and 8 of them had APLa. Patients with APLa had a higher frequency of elevated serum creatinine and hypertension, 9 developed ESRD, and 7 had APLa. There was no statistically significant association between the presence of APLa and the accrual damage index and clinical manifestations. Furthermore, there was no association between APLa and other autoantibodies. Conclusion The frequency of APLa in cLN was high. While the association is not statistically significant, APLa positive patients tend to develop renal microthrombi and are probably at higher risk of ESRD.

Background: The characteristics and burden of childhood arthritis have never been studied on a worldwide basis. We aimed to investigate prevalence of disease categories, treatment modalities and disease status across different geographic areas. Methods: International paediatric rheumatologists were asked to enrol a consecutive sample of children with juvenile idiopathic arthritis. Each patient underwent retrospective and cross-sectional assessments, including parent-reported outcomes. Level of disease activity and damage were correlated with wealth of the country, expressed as gross domestic product per capita. Findings: Between 2011 and 2016, 9,081 patients were enrolled at 130 centres in 49 countries, grouped in 8 geographic areas. A wide difference in the prevalence of disease categories across areas was seen, with systemic arthritis and oligoarthritis being relatively more common in Southeast Asia (33%) and Southern Europe (56·7%), respectively, and rheumatoid-factor negative polyarthritis and enthesitis related arthritis being relatively more frequent in North America (31·5%) and Southeast Asia (29·8%), respectively. Prevalence of uveitis was highest in Northern Europe and Southern Europe (19·2% and 19%, respectively) and lowest in Latin America (6·5%), Africa & Middle East (6·1%), and Southeast Asia (5·1%). Median age at disease onset was lower in Southern Europe (3·5 years) than in other regions (4·7-7·4 years). Biologic disease-modifying anti-rheumatic drugs (DMARDs) were prescribed more frequently in Western countries (30·5-46%) than in other geographic settings (21·1- 25·1%). Patients living in lower-income countries had greater disease activity and damage than patients cared for in wealthier countries. Damage was associated with referral delay. Interpretation: Our study documents a variability in prevalence of disease phenotypes and disparities in therapeutic choices and outcomes across geographic areas. The greater disease burden in lower-resource settings highlights the need for public health efforts aimed to improve equity in access to effective treatments and structure and process of care. Funding Statement: IRCCS Istituto Giannina Gaslini, Genoa, Italy. Declaration of Interests: Dr. Bovis reports personal fees from Biogen, Novartis, outside the submitted work. Dr. Foell reports grants from Novartis, Pfizer; personal fees from Novartis, Pfizer, Sobi, Chugai-Roche, during the conduct of the study. Dr. Shafaie reports grants from IRCCS Istituto Giannina Gaslini, during the conduct of the study. Dr. Lazar reports grants from IRCCS Istituto Giannina Gaslini, during the conduct of the study; non- financial support from Abbvie; personal fees from ROCHE, outside the submitted work. Dr. Lovell reports other funding from Astra-Zeneca Pharm, Wyeth Pharm, Amgen, Abbott, Pfizer, Hoffman-La Roche, Novartis, UBC, Takeda, Janssen, GSK, Boehringer Ingelheim, Celgene, Novartis, Roche, Bristol Myers Squibb, Abbvie, Pfizer, Roche, Forest Research, outside the submitted work. Dr. Martini reports grants from Abbvie, Boehringer, Novartis, R-Pharm, BMS, Hoffman-La Roche, Janssen, Novartis, Pfizer, Sobi, outside the submitted work; personal fees from Abbvie, Astrazeneca, Novartis, Pfizer, Roche, R-Pharm, Sanofi, UCB, outside the submitted work. Dr. Ravelli reports personal fees from AbbVie, BMS, Pfizer, Hoffman LaRoche, Novartis, Centocor, "Francesco Angelini" and Reckitt Benckiser, outside the submitted work. Dr. Ruperto reports personal fees from Abbott, AbbVie, Amgen, Biogenidec, Astellas, Alter, AstraZeneca, Baxalta Biosimilars, Boehringer, BMS, CD-Pharma,Celgene, CrescendoBio, EMD Serono, Hoffman-La Roche, Italfarmaco, Janssen, MedImmune, Medac, Novartis, Novo Nordisk, Pfizer, Rewind Arms, R-Pharma, Sanofi Aventis, Servier, Sinergie, Takeda, Vertex, UCB Biosciences GmbH, outside the submitted work; grants from Abbott, BMS, "Francesco Angelini", GlaxoSmithKline (GSK), Hoffman-La Roche, Italfarmaco, Janssen, Novartis, Pfizer, Sanofi Aventis, Schwarz Biosciences, Sobi, Xoma, Wyeth, outside the submitted work. Dr. Trachana reports personal fees from IRCCS Istituto Giannina Gaslini, during the conduct of the study; personal fees from Novartis, Pfizer, IRCCS Istituto Giannina Gaslini, outside the submitted work. Dr. Aggarwal, Dr. Al-Mayouf, Dr. Alongi, Dr. Consolaro, Dr. de Inocencio, Dr. Demirkaya, Dr. Flato, Dr. Garay, Dr. Giancane, Dr. Miettunen, Dr. Mihaylova, Dr. Montobbio, Dr. Nielsen, Dr. Orban, Dr. Pistorio, Dr. Rumba-Rozenfelde, Dr. Saad-Magalhaes, Dr. Susic, Dr. van Dijkhuizen and Dr. Wulffraat have nothing to disclose. Ethics Approval Statement: All participating centres obtained the approval of the study protocol by their local Ethics Committee, according to national laws. The parents or guardians of all patients and healthy children provided written informed consent to participation in the study.

Necrotizing sarcoid-like granulomatous disease is a disorder of unknown etiology that is rarely described in childhood; it affects various organs and has a diverse clinical course. Here, we report the case of a girl with multisystem recalcitrant necrotizing sarcoid-like granulomatous disease. The diagnosis is based on histopathology and the exclusion of other disease entities known to cause granulomatous disease.

We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort’s genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.

Background Camptodactyly-arthropathy-coxavara-pericarditis (CACP) syndrome is a rare autosomal recessive disorder caused by mutations in the gene proteoglycan 4 (PRG4), affecting lubricin production, which is an essential protein for joint function. Manifestations vary between affected individuals with camptodactyly, early-onsetnon-inflammatory arthropathy, coxa vara deformity and non-inflammatory pericarditis. Objective To describe the clinical, laboratory, radiological and genetic findings of CACP syndrome in children from Saudi Arabia. Methods Medical records of all the children with CACP syndrome seen between June 1990 and June 2012 at King Faisal Specialist Hospital and Research Center, Riyadh were reviewed. The data include gender , age of first disease manifestations , referral diagnosis, clinical and radiological features, and molecular genetic studies as well as functional status at the last follow-upvisit. Results Twenty-two patients (15 boys), (clinical and genetic data of 15 patients were previously published) with mean age at diagnosis 3.7 (1–14) years, were included in this cohort study. The referral diagnosis was inaccurate in all patients; juvenile idiopathic arthritis (JIA) was the referral diagnosis in majority of the patients. Six families had more than one affected child. Camptodactyly and large joints arthropathy were present in all the cases. Camptodactyly was observed in the neonatal period in all the patients, while other joint involvement was observed through the 1st year of life. All patients had a normal cardiac evaluation but two children had evidence of pericarditis. All patients had normal inflammatory markers and the result for rheumatoid factor test was negative. Radiological findings included coxa vara with a short femoral neck and flat, irregular femoral heads and intra-osseous cysts, increased joint space, and abnormal modeling of the acetabulum with small iliac wings. Other joints (knees, ankle, elbow and wrist) showed soft-tissue swelling consistent with thick cartilage and abnormal modeling with evidence of intra-articular fluid in majority of the patients. Synovial biopsy from three patients revealed proliferating synovial epithelium with moderate fibro-collagenous densities and multinucleated giant cells, occasional lymphocytes or neutrophils were identified. Previously, a locus responsible for causing CACP syndrome has been reported in eight patients of our cohort; it has been assigned to 1q25-q31. Furthermore, in seven newly diagnosed patients from four unrelated families, five novel mutations were found. All patients were referred to us while they were on NSAIDs, 10 patients used antirheumatic drugs (prednisone and methotrexate) and two patients were treated with etanercept. In all patients, treatment was ineffective apart from mild pain relief. Conclusion CACP syndrome is an autosomal recessive disorder occurring due to mutations in the gene PRG4 encoding lubricin; it is not an uncommon disorder in Saudi Arabia. Pericarditis is rarely seen in our patients. Our data suggest that CACP syndrome may be easily confused with JIA, causing a delay in diagnosis and probably unnecessary treatment with antirheumatic drugs including biologic agents.

Lubricin, a protein product of the gene PRG4, is a secreted mucin-like proteoglycan that is a major lubricant in articulating joints. Mutations in PRG4 cause the autosomal recessive, human disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome. We developed rabbit polyclonal antibodies against human lubricin to determine the consequence of disease-causing mutations at the protein level and to study the protein's normal post-translational processing. Antiserum generated against an epitope in the amino-terminal portion of lubricin detected protein in wild-type synovial fluid and in conditioned media from wild-type cultured synoviocytes. However, the antiserum did not detect lubricin in synovial fluid or cultured synoviocytes from several patients with frameshift or nonsense mutations in PRG4. Antiserum generated against an epitope in the protein's carboxyl-terminal, hemopexin-like domain identified a post-translational cleavage event in wild-type lubricin, mediated by a subtilisin-like proprotein convertase (SPC). Interestingly, in contrast to wild-type lubricin, one disease-causing mutation that removes the last 8 amino acids of the protein, including a conserved cysteine residue, was not cleaved within the hemopexin-like domain when expressed in COS-7 cells. This suggests that formation of an intrachain disulfide bond is required for SPC-mediated cleavage and that SPC-mediated cleavage is essential to protein function.