Lupus manifestations in children with primary immunodeficiency diseases: Comprehensive phenotypic and genetic features and outcome.

OBJECTIVES: To report the phenotypic, genetic findings and outcome of children with lupus manifestations associated with primary immunodeficiency diseases (PIDs). METHODS: Data are retrospectively collected on patients with lupus manifestations and PIDs seen between 1998 and 2019. Data comprised the clinical findings and genetic testing, the response to treatment and the accrual damage related to SLE. RESULTS: A total of 39 patients (22 female) were reviewed. Thirty-four patients had lupus manifestations and six patients with SLE-like manifestations. Genetic analysis was performed in 25 patients. Complement deficiency was the most frequent PIDs; 26 patients were C1q deficient, three patients had C3 deficiency, two patients had C4 deficiency and one patient with heterozygous C8b variant. The other seven patients had different PIDs genetic defects that include SCID caused by PNP deficiency, CGD, CVID (PIK3CD), IL-2RB mutation, DNase II deficiency, STAT1 mutation, ISG15 mutation and Griscelli syndrome type 3. Mucocutaneous lesions, arthritis and lung involvement were the main clinical features. 84.1% experienced recurrent infections. The mean accrual damage was 2.7 ± 2.2. There were five deaths because of infection. CONCLUSION: This study suggests that patients with lupus manifestations and early onset disease, family history of SLE or recurrent infections should undergo immunological work-up and genetic testing to rule out PIDs.

Pattern and diagnostic evaluation of systemic autoinflammatory diseases other than familial Mediterranean fever among Arab children: a multicenter study from the Pediatric Rheumatology Arab Group (PRAG).

To define the spectrum and phenotypic characteristics of systemic autoinflammatory diseases (SAIDs) other than familial Mediterranean fever (FMF) in Arab children and to delineate diagnostic evaluation. Data retrospectively collected on patients with clinical and/or genetically proven SAIDs other than FMF at 10 tertiary Arab pediatric rheumatology clinics from 1990 to 2018. The collected data comprised the clinical findings and diagnostic evaluation including genetic testing, the provided treatment and the accrual damage related to SAIDs. A total of 144 patients (93 female) with a median age at onset of 2.5 (range 0.1-12) years were enrolled. The initial diagnosis was inaccurate in 49.3%. Consanguinity rate among parents was 74.6%. The median time-to-diagnosis for all SAIDs was 2.5 (range 0.1-10) years. There were 104 patients (72.2%) with a confirmed diagnosis and 40 patients with suspected SAIDs. Seventy-two had monogenic and 66 patients with multifactorial SAIDs while six patients had undifferentiated SAIDs. The most frequent monogenic SAIDs were LACC1 mediated monogenic disorders (n = 23) followed by CAPS (12), TRAPS (12), HIDS (12), and Majeed's syndrome (6). The most frequent multifactorial SAIDs was CRMO (34), followed by PFAPA (18), and early onset sarcoidosis (EOS) (14). Genetic analysis was performed in 69 patients; 50 patients had genetically confirmed disease. Corticosteroid used for 93 patients while biologic agents for 96 patients. Overall, growth failure was the most frequent accrual damage (36%), followed by cognitive impairment (13%). There were three deaths because of infection. This study shows a heterogenous spectrum of SAIDs with a high number of genetically confirmed monogenic diseases; notably, LACC1 associated diseases. Hopefully, this work will be the first step for a prospective registry for SAIDs in Arab countries.

Outcome of children with systemic rheumatic diseases admitted to pediatric intensive care unit: An experience of a tertiary hospital.

OBJECTIVE: To report the outcome of children with rheumatic diseases admitted to pediatric intensive care unit (PICU) in a tertiary hospital. METHODS: Database from PICU and pediatric rheumatology section used to retrieve all candidate patients admitted to PICU from June 2000 to December 2017. Medical records of all enrolled patients reviewed for diagnosis, organ involvement, reason of PICU admission, the length of stay, and outcome. RESULTS: Twenty-five patients (17 female, 8 male) with total of 41 admissions identified. The median PICU stay was 13.5 days (range, 3-24). The most frequent diagnoses were systemic lupus erythematosus (SLE) (48%), followed by systemic vasculitis (16%). Most admissions were from the medical ward (68.3%), while 24.4% from the emergency room. The main reason of PICU admission was a disease flare or related complications (48.8%), followed by infection (34.2%). Fifty one percent of the admissions were due to respiratory dysfunction, 46% required non-invasive respiratory support while 38% was in need for mechanical ventilation. During PICU stay, anti-microbial agents used 90.3%, immunosuppressive treatment adjustment 75.6%, anti-hypertensive 24.4% and vasopressors 12.2%. Twelve patients (48%) fully recovered and 40% partially recovered while three patients died during their PICU stay. The causes of death were macrophage activation syndrome complicated by sepsis in two patients and advanced pulmonary hypertension in one patient. CONCLUSION: Our data showed that children with rheumatic diseases, particularly SLE, are mostly admitted to PICU with serious disease exacerbation or severe infection. To improve the outcome, early diagnosis of critical condition and proper intervention are fundamental in reducing mortality.

Evaluation of effectiveness of a paediatric simulation course in procedural skills for paediatric residents - A pilot study.

OBJECTIVE: To explore the effects of simulation training on paediatric residents' confidence and skills in managing advanced skills in critical care. METHODS: The study was conducted at Alfaisal University, Riyadh, Saudi Arabia, from March to June 2016, and comprised junior residents in paediatrics. All paediatric residents (years 1 and 2) were recruited into two workshops, held one week apart. The first workshop covered lumbar puncture/ cerebrospinal fluid interpretation, oral intubation, bone marrow aspiration, and critical airway management. The second workshop covered chest tube insertion, pleural tap, insertion of central line, and arthrocentesis. The participants were surveyed using a 5-point Likert scale survey pre- and post-course, assessing their confidence. Their practical skills were assessed using a pre-objective structured clinical examination on the same day and post-course objective structured clinical examination a week later on selected skills. The outcome measures were: (1) pre-/post-course confidence rating, and (2) pre-/post-course objective structured clinical examination results. Data was analysed using SPSS 20. RESULTS: Of the 16 participants, 8(50%) were boys and 8(50%) girls. Besides, 13(81%) residents were in year-1 and 3(19%) in year-2. Median post-course confidence level ranks for all the skills were higher (p<0.05). There was no improvement in mean pre-objective structured clinical examination scores (2.31±2.66/ 7.46±3.02) and post- objective structured clinical examination scores (22.54±4.39/ 31.85±6.90) in Year 1 residents (p<0.001). CONCLUSIONS: Simulation course was significantly successful in improving residents' clinical skills and confidence in performing critical tasks.

Monogenic interferonopathies: Phenotypic and genotypic findings of CANDLE syndrome and its overlap with C1q deficient SLE.

OBJECTIVE: To report the clinical and genetic features of the first cases of chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome in an Arab population and to compare them with patients of C1q deficient systemic lupus erythematosus (SLE). MATERIALS AND METHODS: This is a retrospective case series of patients with CANDLE syndrome and C1q deficient SLE seen at a single tertiary hospital. Medical records were reviewed for demographic data, clinical and laboratory features, histopathology and imaging findings, and response to therapeutic intervention. Descriptive data were summarized. RESULTS: Three patients from unrelated families fulfilled the clinical manifestations of CANDLE syndrome. The disease onset was within the first 4 months of age. Two patients had uncommon features including uveitis, pulmonary involvement, aseptic meningitis and global delay. Skin biopsy showed heterogeneous findings. Genomic DNA screening was homozygous for mutation in PSMB8, (NM_004159.4:c.212C>T, p.T71M) in one patient and inconclusive for the other two patients. The comparison group was three patients with familial C1q deficient SLE from three unrelated families, who were born to consanguineous parents with at least one affected sibling. They presented with extensive mucocutaneous lesions, discoid rash and scarring alopecia. They required frequent admissions due to infections. CONCLUSION: This is the first report of CANDLE syndrome in an Arab population; our patients had heterogeneous phenotypic and genetic features with overlap manifestations with C1q deficient SLE. Both are monogenic interferonopathies. However, C1q deficient SLE had more systemic inflammatory disease.

Outcome of childhood lupus nephritis in Saudi children.

Our aim in this study is to report the long-term renal outcome of a cohort of Saudi children with systemic lupus erythematosus (SLE). All patients with childhood lupus nephritis (cLN) proved by renal biopsy seen between January 2000 and June 2015 were reviewed. The renal outcome was assessed according to serum creatinine level, protein/creatinine ratio at the last follow-up visit, and/or evidence of renal impairment during follow-up period and end-stage renal disease (ESRD). Additional outcome measures include accrual damage measured by pediatric adaptation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (pSDI), and death related to SLE was determined. A total of 84 (72 females) cLN patients with follow-up duration of 9.3 years (±5.2) were included in this study. The mean current age was 19.4 years (±5.5) and mean age at onset was 9.2 years (±2.4). The most frequent histopathological class was proliferative glomerulonephritis (64.3%) followed by membranous nephritis (27.4%). The mean activity and chronicity indices were 5.9 (±3.9) and 2.9 (±2.2), respectively. Renal microthrombosis was found in 9 (10.7%) patients. All patients treated with immunosuppressive medications; cyclophosphamide used in 64 followed by mycophenolate mofetil in 42, then azathioprine in 19 patients, while rituximab used in 24 patients. At the last follow-up visit, the mean serum creatinine was 147 umol/L (±197) and the mean protein/ creatinine ratio was 0.8 (± 1.1) while the mean total pSDI was 1.9 (±1.9) and mean renal SDI was 0.7 (±1.1). Sixteen (19%) patients had ESRD and eight of them had class IV nephritis. However, there was no significant difference in ESRD by histological class. The overall survival rates were five years: 94% and 10 years: 87%. Infection was the leading cause of mortality. Our patients had severe cLN and required intensive treatment. Despite the survival rate is comparable to other studies, ESRD is more frequent and this may be attributed to genetic or ethnic factors.

Phenotypic characteristics and outcome of juvenile dermatomyositis in Arab children.

This study describes the disease characteristics and outcome of Arab children with juvenile dermatomyositis (JDM) and compares the findings with other ethnicities. We retrospectively reviewed the hospital registries of the participating hospitals for children with JDM seen between 1990 and 2016 in three Arab countries. All patients fulfilled Bohan and Peter criteria for JDM, diagnosed before 14 years of age and were of Arab ethnicity. Clinical and laboratory features as well as the long-term outcomes including accrual disease damage were collected at the last follow-up visit. A total of 92 JDM patients (58 girls) were included. Mean age at the onset was 6 ± 3 years, with a mean follow-up duration of 5 ± 4.4 years. Forty-three patients (46.7%) had polycyclic disease course, 34 (36.9%) had a monocyclic course, while 15 (16.3%) had a continuous progressive course. Forty-five patients (48.9%) had arthritis, 14 (15.2%) patients had an upper airway and dysphagia, and 10 patients (10.9%) had lung involvement. Eight patients (8.7%) were admitted to the intensive care unit (ICU), 4 of them required mechanical ventilation. Methotrexate had been the most frequently used immunosuppressive drug (86%) and rituximab was used in eight patients. Additionally, 31 patients received IVIG. Most of the patients achieved a complete clinical response, but 16 ended up with permanent skin changes and 12 had a residual muscle weakness. Twenty-seven patients developed calcinosis. There were two deaths due to infection during the follow-up period. We report the largest phenotypic data on Arab children with JDM. Our patients have similar characteristics to previously described cohorts. Majority of the patients remained with inactive disease.

Safety and efficacy of combined cyclophosphamide and rituximab treatment in recalcitrant childhood lupus.

To report the safety and efficacy of combined cyclophosphamide and rituximab treatment in Saudi children with systemic lupus erythematosus (SLE). Medical records of all children with SLE treated with cyclophosphamide and rituximab between June 2007 and June 2012 at King Faisal Specialist Hospital and Research Center, Riyadh, were reviewed for demographic characteristics, age at diagnosis, concomitant treatments, indication of using rituximab and adverse events during the treatment period. Clinical and serologic response parameters included SLE Disease Activity Index (SLEDAI), complement, anti-ds DNA antibody and ANA levels, and mean daily corticosteroid dose assessed 3 months before combined cyclophosphamide and rituximab infusion course and at 6-month interval afterward. Sixteen patients (13 girls) with refractory SLE treated with cyclophosphamide and rituximab were included. The mean age at onset of SLE was 7.8 + 3.3 years, while the mean age at diagnosis was 8.1 + 3.4 years; the mean disease duration was 4.7 + 3.2 years. All patients were treated with corticosteroid and immunosuppressive drugs. Nephritis (8 patients) was the most frequent indication; other indications included refractory arthritis, thrombocytopenia, severe mucocutaneous lesions and central nervous system involvement. All patients received 2 doses, but 4 required 4-8 extra doses. All patients showed improvement in response parameters. There was significant reduction in SLEDAI (P < 0.0002) and corticosteroid dose (P < 0.005). A total of 4 adverse events were notified; 2 developed infusion-related reactions. One patient had severe soft tissue fungal infection, and other patient had pancreatitis. Our data showed beneficial therapeutic and steroid-sparing effects of rituximab as adjunctive treatment for children with refractory SLE including both renal and extrarenal manifestations. Although rituximab was well tolerated by the majority of patients, it may associated with various adverse events.