Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies.

BACKGROUND: Idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterised by myositis-related autoantibodies plus infiltration of leucocytes into muscles and/or the skin, leading to the destruction of blood vessels and muscle fibres, chronic weakness and fatigue. While complement-mediated destruction of capillary endothelia is implicated in paediatric and adult dermatomyositis, the complex diversity of complement C4 in IIM pathology was unknown. METHODS: We elucidated the gene copy number (GCN) variations of total C4, C4A and C4B, long and short genes in 1644 Caucasian patients with IIM, plus 3526 matched healthy controls using real-time PCR or Southern blot analyses. Plasma complement levels were determined by single radial immunodiffusion. RESULTS: The large study populations helped establish the distribution patterns of various C4 GCN groups. Low GCNs of C4T (C4T=2+3) and C4A deficiency (C4A=0+1) were strongly correlated with increased risk of IIM with OR equalled to 2.58 (2.28-2.91), p=5.0×10-53 for C4T, and 2.82 (2.48-3.21), p=7.0×10-57 for C4A deficiency. Contingency and regression analyses showed that among patients with C4A deficiency, the presence of HLA-DR3 became insignificant as a risk factor in IIM except for inclusion body myositis (IBM), by which 98.2% had HLA-DR3 with an OR of 11.02 (1.44-84.4). Intragroup analyses of patients with IIM for C4 protein levels and IIM-related autoantibodies showed that those with anti-Jo-1 or with anti-PM/Scl had significantly lower C4 plasma concentrations than those without these autoantibodies. CONCLUSIONS: C4A deficiency is relevant in dermatomyositis, HLA-DRB1*03 is important in IBM and both C4A deficiency and HLA-DRB1*03 contribute interactively to risk of polymyositis.

COVID-19 associated Multisystem Inflammatory Syndrome in Children (MIS-C) guidelines; revisiting the Western New York approach as the pandemic evolves.

Multisystem inflammatory syndrome of children (MIS-C) continues to be a highly concerning diagnosis in those recently infected with SARS-CoV-2. The diagnosis of MIS-C cases will likely become even more challenging as vaccine uptake and natural immunity in previously infected persons leads to lower circulating rates of SARS-CoV-2 infection and will make cases sporadic. Febrile children presenting with cardiac dysfunction, symptoms overlapping Kawasaki disease or significant gastrointestinal complaints warrant a thorough screen in emergency departments, urgent care centers, and outpatient pediatric or family medicine practices. An increased index of suspicion and discussion regarding higher level of care (transferring to pediatric tertiary care centers or to intensive care) continues to be recommended. Herein we outline a broad approach with a multidisciplinary team for those meeting the case definition and believe such an approach is crucial for successful outcomes.

Follow-up and management of serologically active clinically quiescent cases in pediatric systemic lupus erythematosus.

OBJECTIVES: Our aim is to identify the presence of serologically active clinically quiescent (SACQ) episodes in pediatric systemic lupus erythematosus (SLE) patients. We aim to identify serologic biomarkers associated with SACQ episodes and discuss risks and benefits of escalating treatments. MATERIAL AND METHODS: We evaluated 25 pediatric SLE patients, 13 of whom experienced SACQ episodes. Serologically active clinically quiescent was defined as two consecutive clinic visits without any clinical symptoms or clinical examination findings of a lupus flare with a clinical Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score of zero, but either elevated anti-ds-DNA antibodies or low complement (C3 and/or C4) levels. RESULTS: Among the 13 patients who experienced a SACQ episode, there were a total of 24 episodes, with each patient experiencing 1-4 SACQ episodes. Erythrocyte sedimentation rate (ESR) was the most commonly elevated laboratory marker in a SACQ episode, followed by low hemoglobin levels, and then elevated anti-dsDNA antibodies. Of the 17 episodes treated during a SACQ episode, 15 (88%) did not progress to a clinical flare within six months, while two did. Furthermore, of the 7 patients who were not treated during their SACQ episode, 2 (29%) continued to be SACQ without flare, whereas 5 led to a clinical flare within six months. CONCLUSIONS: Serologically active clinically quiescent episodes were identified in pediatric SLE patients, suggesting that the presence of SACQ is not limited to adults with SLE. Serologic markers such as increased ESR, hemoglobin, and elevated anti-dsDNA antibodies are preliminarily associated with pediatric SACQ episodes. Treating these SACQ episodes in pediatric SLE patients was less likely to lead to a clinical flare within six months when compared to not treating (p < 0.05). More research with a larger sample size is needed to define SACQ episodes, determine the prevalence in pediatric SLE patients, and establish SACQ treatment guidelines.

Gene copy-number variations (CNVs) of complement C4 and C4A deficiency in genetic risk and pathogenesis of juvenile dermatomyositis.

OBJECTIVE: Complement-mediated vasculopathy of muscle and skin are clinical features of juvenile dermatomyositis (JDM). We assess gene copy-number variations (CNVs) for complement C4 and its isotypes, C4A and C4B, in genetic risks and pathogenesis of JDM. METHODS: The study population included 105 patients with JDM and 500 healthy European Americans. Gene copy-numbers (GCNs) for total C4, C4A, C4B and HLA-DRB1 genotypes were determined by Southern blots and qPCRs. Processed activation product C4d bound to erythrocytes (E-C4d) was measured by flow cytometry. Global gene-expression microarrays were performed in 19 patients with JDM and seven controls using PAXgene-blood RNA. Differential expression levels for selected genes were validated by qPCR. RESULTS: Significantly lower GCNs and differences in distribution of GCN groups for total C4 and C4A were observed in JDM versus controls. Lower GCN of C4A in JDM remained among HLA DR3-positive subjects (p=0.015). Homozygous or heterozygous C4A-deficiency was present in 40.0% of patients with JDM compared with 18.2% of controls (OR=3.00 (1.87 to 4.79), p=8.2×10(-6)). Patients with JDM had higher levels of E-C4d than controls (p=0.004). In JDM, C4A-deficient subjects had higher levels of E-C4d (p=0.0003) and higher frequency of elevated levels of multiple serum muscle enzymes at diagnosis (p=0.0025). Microarray profiling of blood RNA revealed upregulation of type I interferon-stimulated genes and lower abundance of transcripts for T-cell and chemokine function genes in JDM, but this was less prominent among C4A-deficient or DR3-positive patients. CONCLUSIONS: Complement C4A deficiency appears to be an important factor for the genetic risk and pathogenesis of JDM, particularly in patients with a DR3-positive background.

Disease Course, Treatments, and Outcomes of Children With Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease.

OBJECTIVE: Systemic juvenile idiopathic arthritis-associated lung disease (SJIA-LD) is a life-threatening disease complication. Key questions remain regarding clinical course and optimal treatment approaches. The objectives of the study were to detail management strategies after SJIA-LD detection, characterize overall disease courses, and measure long-term outcomes. METHODS: This was a prospective cohort study. Clinical data were abstracted from the electronic medical record, including current clinical status and changes since diagnosis. Serum biomarkers were determined and correlated with presence of LD. RESULTS: We enrolled 41 patients with SJIA-LD, 85% with at least one episode of macrophage activation syndrome and 41% with adverse reactions to a biologic. Although 93% of patients were alive at last follow-up (median 2.9 years), 37% progressed to requiring chronic oxygen or other ventilator support, and 65% of patients had abnormal overnight oximetry studies, which changed over time. Eighty-four percent of patients carried the HLA-DRB1*15 haplotype, significantly more than patients without LD. Patients with SJIA-LD also showed markedly elevated serum interleukin-18 (IL-18), variable C-X-C motif chemokine ligand 9 (CXCL9), and significantly elevated matrix metalloproteinase 7. Treatment strategies showed variable use of anti-IL-1/6 biologics and addition of other immunomodulatory treatments and lung-directed therapies. We found a broad range of current clinical status independent of time from diagnosis or continued biologic treatment. Multidomain measures of change showed imaging features were the least likely to improve with time. CONCLUSION: Patients with SJIA-LD had highly varied courses, with lower mortality than previously reported but frequent hypoxia and requirement for respiratory support. Treatment strategies were highly varied, highlighting an urgent need for focused clinical trials.

Scurvy in a Pediatric Patient Unable to Bear Weight: A Case Report.

Pediatric scurvy is uncommon in the twenty-first century but cases have been reported in children with neurodevelopmental issues and restricted diets. We are reporting a two-year and nine-month-old boy who had a coronavirus disease (COVID) infection and then presented with a refusal to walk. By careful history-taking, he was found to have a restricted diet, speech delay, and gum bleeding suggestive of scurvy, which was confirmed by extremely low levels of ascorbic acid. In this case, the diagnosis of scurvy was established before establishing the diagnosis of neurodevelopmental delay. Treatment with ascorbic acid resulted in a remarkable improvement in his symptoms. This case highlights the importance of collecting a thorough history, connecting exam findings to the history, and including scurvy in differential diagnoses for the presentation of inability to bear weight.

Autoimmunity in people with cystic fibrosis.

Cystic fibrosis (CF) clinicians may see patients who have difficult-to-manage symptoms that do not have a clear CF-related etiology, such as unusual gastrointestinal (GI) complaints, vasculitis, or arthritis. Alterations in immunity, inflammation and intraluminal dysbiosis create a milieu that may lead to autoimmunity, and the CF transmembrane regulator protein may have a direct role as well. While autoantibodies and other autoimmune markers may develop, these may or may not lead to organ involvement, therefore they are helpful but not sufficient to establish an autoimmune diagnosis. Autoimmune involvement of the GI tract is the best-established association. Next steps to understand autoimmunity in CF should include a more in-depth assessment of the community perspective on its impact. In addition, bringing together specialists in various fields including, but not limited to, pulmonology, gastroenterology, immunology, and rheumatology, would lead to cross-dissemination and help define the path forward in basic science and clinical practice.

The Importance of Differentiating Oligoarticular Juvenile Idiopathic Arthritis From Lyme Arthritis in Pediatric Patients.

Objective This study aims to compare clinical and laboratory features between Lyme arthritis (LA) and oligoarticular juvenile idiopathic arthritis (oligoarticular JIA) by examining several potential predictors in pediatric patients. This study also aims to improve and increase awareness of ways to detect LA and oligoarticular JIA in pediatric patients who present with clinical features of joint pain. Methods A medical chart review was conducted among pediatric patients diagnosed with LA or oligoarticular JIA at John R. Oishei Children's Hospital of Buffalo between January 2014 and September 2018. Patients' diagnoses were identified using the International Classification of Disease 10th Revision code for LA (ICD 10 code A69.23) and oligoarticular JIA (ICD 10 code M08.40). Patients with LA were only included in this study if they (1) exhibited arthritis, (2) tested positive for Lyme antibodies, (3) indicated a positive western blot (WB) of five or more out of 10 Borrelia burgdorferi proteins by IgG antibodies or at least two of three B. burgdorferi proteins by IgM antibodies, and (4) at the age of 16 or below at the time of diagnosis. Patients with oligoarticular JIA were included in this study if they (1) exhibited arthritis affecting one to four joints for at least six weeks in the first six months of diagnosis and (2) are at the age of 16 or below at the time of diagnosis after ruling out LA and reactive arthritis. In this study, clinical presentations, physical exam findings during initial healthcare visits, and demographics including age, sex, and race of patients were obtained. In addition, laboratory results including white blood cells (WBCs), hemoglobin (Hgb), platelet count, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, Lyme antibodies through enzyme-linked immunosorbent assay (ELISA) and WB, synovial fluid analysis for red blood cells (RBCs), nucleated cells, and polymerase chain reaction (PCR) for B. burgdorferi DNA were also collected and analyzed. Results In our data, ESR and CRP were significantly higher in LA compared to oligoarticular JIA (P=0.0053 and 0.0005, respectively). The mean WBC in the synovial joint fluid was significantly higher in LA compared to oligoarticular JIA (P=0.002). Conclusion LA shares features with oligoarticular JIA. This overlap prevents the creation of a clinically useful predictive model for LA. Therefore, Lyme testing should be performed on all patients presenting with monoarticular and oligoarticular arthritis. In addition, ESR, CRP, and WBC in the synovial joint fluid were significantly higher in LA compared to oligoarticular JIA in our findings. While this difference is not definitive by any means, it may help distinguish between the two in cases where the diagnosis is not clear-cut, and the values of ESR, CRP, and WBC in the joint aspirate may help guide clinical judgment in cases that lack a definitive diagnosis.

A Pediatric Case of Granulomatous Myositis and Response to Treatment.

Idiopathic inflammatory myopathy encompasses a group of acquired, heterogeneous, systemic diseases of the skeletal muscle, including adult polymyositis, adult dermatomyositis, juvenile dermatomyositis, juvenile polymyositis, inclusion body myositis, and necrotizing myopathy, all resulting in muscle weakness. Granulomatous myositis (GM) is a rare myopathy disorder histologically characterized by the development of endomyseal and/or perimyseal granulomas in striated muscle. GM is often associated with sarcoidosis. GM has also been associated with myasthenia gravis, inflammatory bowel disease, thymoma, and malignancy. We are reporting a rare case of a 13-year-old girl with GM without associated disease that was refractory to multiple medications, and responded well to rituximab.

Atypical Power Doppler Ultrasound Findings in Juvenile Idiopathic Inflammatory Myositis (JIIM) Flare.

Juvenile idiopathic inflammatory myositis (JIIM) is a multisystem inflammatory disease that impacts the muscles, skin, and blood vessels. Gray-scale power Doppler ultrasound is a technique that can be used to assist the diagnosis of JIIM and myositis in general. We report a case of an atypical symptomatic JIIM myositis flare that shows increased muscle echogenicity without the corresponding increase (complete absence) of Doppler flow.

Isolated Facet Joint Arthritis in Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is a group of childhood inflammatory arthropathies which has variable clinical presentations and can affect multiple joints including the spine. Arthritis in facet joints is rare and very unusual to be the only presentation of JIA. We report a 16-year-old female who presented with back pain and stiffness, in which CT of the lumbar spine showed evidence of facet joint erosion and pelvis MRI showed facet joint arthritis consistent with juvenile idiopathic arthritis.

Complete Renal Recovery in Pediatric Patient with C3 Glomerulonephritis: A Case Report.

C3 glomerulonephritis (C3GN) is a rare kidney disease resulting from dysregulation of the alternative complement cascade. Without treatment, approximately 70% of affected children and 30-50% of affected adults will develop worsening of proteinuria and progress to end-stage renal disease within 10 years of diagnosis. Here, we describe a 9-year-old Sudanese girl with no significant past medical history who presented to the Emergency Department with a 2-month history of fatigue, poor oral intake, and worsening facial and lower extremity edema, and subsequently found to have anemia, hypoalbuminemia, microscopic hematuria, and proteinuria. Additional laboratory testing revealed that the patient had low C3, high C3 nephritic factor (C3NeF), and high factor H. Renal function was normal. The diagnosis of C3GN was confirmed by renal biopsy. The patient was treated with ACE inhibitor, mycophenolate mofetil (600 mg per m2 per dose, every 12 h), in combination with "pulse" methylprednisolone at 30 mg/kg/day IV bolus (maximum 1 g) for 3 consecutive days, followed by 2 months of daily oral prednisolone (2 mg/kg/day) and alternate-day prednisolone weaning from 1 mg/kg to 0.1 mg/kg for additional 12 months. Mycophenolate was continued throughout her treatment course and for maintenance therapy. In response to treatment, anemia, microscopic hematuria, hypoalbuminemia, and proteinuria resolved. Complete complement profile before and at 6 months therapy showed normalization of C3NeF, complement regulatory factor H and C3. This present case provides evidence of the full responsiveness of a rare form of complement dysregulation C3GN to a combination of mycophenolate and corticosteroids. The disease has NOT recurred in >2 years after initial presentation.

Renal Involvement and Its Treatment in Pediatric Patients With Proteinase-3 Anti-Neutrophil Cytoplasmic Antibody Positive Granulomatosis With Polyangiitis: A Case Series.

We describe three pediatric patients between the ages of 10 and 14 years old who were diagnosed with granulomatosis with polyangiitis (GPA) between 2014 and 2019. Each case involves variations in presentation, symptomatology, diagnostics, and induction and maintenance therapy regimens. Patient 1 presented with significant renal involvement, hypertensive emergency, and focal alveolar hemorrhage, a rare presentation of GPA that causes up to 60% mortality.Patient 2 presented with minimal renal involvement and a diffuse petechial rash, which is the most common cutaneous presentation of GPA. Finally, patient 3 presented with significant renal involvement and later on with symptoms of idiopathic intracranial hypertension (IIH), a unique and rare presentation associated with GPA. Despite the heterogeneity of these cases, the similar therapy regimens used in each case successfully achieved induction and maintenance of disease remission, providing an evidentiary basis for these treatment regimens even in severe and unusual pediatric GPA cases.

Response to treatment with intra-articular triamcinolone hexacetonide and triamcinolone acetonide in oligo articular juvenile idiopathic arthritis.

BACKGROUND: Oligo-articular juvenile idiopathic arthritis (Oligo JIA) is the most common subtype of juvenile idiopathic arthritis. Intra-articular corticosteroid (IAC) injection is a mainstay treatment of oligo JIA providing pain relief, improving mobility and preventing further joint destruction in the majority of patients. In 2015, production of triamcinolone hexacetonide (TH) an intra-articular corticosteroid was discontinued in the United States leading to use of triamcinolone acetonide (TA) as an alternative. In this study, we compared response to treatment in children with oligo JIA who underwent therapy with intra-articular TA and TH injection. METHODS: Our study is a retrospective chart review of children with oligo JIA who were treated with IAC injections with TH between January 2012 and June 2015 and TA between J uly 2015 and December 2018. The two groups were followed at John R. Oishei Children's Hospital of Buffalo and were evaluated for response to treatment, side effects and predictors of response including duration of disease before treatment, erythrocyte sedimentation rate (ESR), and c-reactive protein (CRP). Response to treatment was defined as at least 6 months follow up without evidence of active arthritis in injected joints. Patients were considered to be non-responders if they continued to show active arthritis during their first follow up after joint injection. The primary objective was to evaluate whether there was a significant difference in rate of response between TH and TA. RESULTS: Forty-nine patients, 38 female and 11 male with oligo JIA were included in the study. The average age was 6.7 years. A total of 111 joints were injected includin g 78 knees, 13 ankles, 9 wrists, 4 hips, 4 elbows, 2 TMJ and one subtalar joint. In the TA group, 49% (29/59) did not show response to injection compared to 27% (14/52) in the TH group. After 6 months, response rates were better for individuals injected with TH compared to TA (73% vs. 51%). In general, response to intra-articular TH was superior to TA with P = .016 using chi-square test of independence. This difference in outcome was not influenced by other variables such as duration of illness before treatment (P value 0.784) or elevated ESR and CRP. No difference in side effects between the two groups were noted. CONCLUSION: Our results in conjunction with prior published data suggests that TH intra-articular joint injection in oligo JIA is superior to TA, although future controlled trials are necessary for confirmation. An effective, long lasting treatment can have a great impact on the outcome of these children.

Pulmonary Involvement in Acute Rheumatic Fever: A Case Report and Literature Review.

Rheumatic pneumonia is a pulmonary complication of rheumatic fever, often with grave outcomes. It has been described sporadically in literature, most recently a decade ago. Here, we describe a case of a 12-year-old Native American girl presenting with chest pain, gastrointestinal complaints, and frequent nosebleeds. After the initial diagnosis with acute pericarditis, she was found to meet diagnostic criteria for rheumatic fever. Revised Jones criteria met included significantly elevated streptolysin O antibody and anti-DNase B, carditis, arthralgia, fever, and elevated inflammatory markers. Findings complicating the diagnosis were an elevated antinuclear antigen with a family history of systemic lupus erythematosus (SLE), hemoptysis, and a chest CT finding of right lower lobe alveolar hemorrhage as well as right-sided mediastinal adenopathy. The patient was discharged on day nine of admission after a course of high-dose methylprednisolone with prednisone taper, furosemide, enalapril, naproxen, monthly penicillin G injections, and multidisciplinary outpatient follow-up. A repeat chest CT scan three months later showed significant improvement. The pulmonary findings described in our patient are consistent with prior reports of rheumatic pneumonia, however, most prior cases described did not include high-resolution imaging. Our patient recovered well aside from complications secondary to mitral regurgitation, unlike many patients seen in our literature search who died due to early or later complications of pulmonary disease. Although acute rheumatic fever, and its pulmonary complications, is significantly less common than it once was, it remains a disease entity that should remain on the differential for multisystem rheumatic complaints.

Acetabula Osteoid Osteoma Mimicking Juvenile Idiopathic Arthritis and Chronic Recurrent Multifocal Osteomyelitis.

Osteoid osteoma (OO) is a benign bone tumor that usually presents between 10 and 35 years of age. The metaphysis and diaphysis of the femur and tibia are the typical locations. The diagnosis is usually straightforward when images reveal a radiolucent nidus surrounded by reactive sclerosis. However, the diagnosis is more difficult when it occurs at atypical locations with nonspecific and misleading appearance on images. OO may mimic juvenile idiopathic arthritis (JIA), bone infection, or malignancy. We present a 14-year-old male with a 4-month history of left hip pain. His pain was worse with playing hockey and lacrosse and in the morning and sometimes woke him up at night. His examination was significant for pain with flexion and external rotation of the left hip and for mild limitation of full external rotation. Blood work revealed normal complete blood count, erythrocyte sedimentation rate, and C-reactive protein. Left hip X-ray was unremarkable. Left hip MR arthrogram showed marked edema of the medial and posterior walls of the left acetabulum. CT-guided biopsy of the left acetabulum showed unremarkable flow cytometry and chronic inflammatory component raising concern about chronic recurrent multifocal osteomyelitis (CRMO). Bone scan revealed focal increased uptake in the left acetabulum and no additional abnormality. Repeat MRI with intravenous contrast showed a left hip effusion, focal synovial enhancement in the medial left hip, and acetabula edema. The patient failed treatment for presumed JIA and CRMO with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, methotrexate, and adalimumab. CT scan of the left hip was performed for further evaluation of the bone and showed 11 × 6 mm low attenuation focus with subtle internal nidus in the posteromedial aspect of the acetabular rim, suggestive of intra-articular OO. Radiofrequency ablation was performed with no complications, and the left hip pain improved. The atypical location resulted in delay of diagnosis for 12 months after presentation. We highlight the diagnostic pitfalls observed in atypical OO locations and the difficulties this creates with making the diagnosis. OO mimicking JIA has previously been described. We submit CRMO as another differential diagnosis which may be mimicked and demonstrate the vital role of CT scan in the diagnosis.

Rare Presentation of Pseudotumor Cerebri in a Pediatric Patient With Granulomatosis With Polyangiitis.

We present a case of an 11-year-old female with granulomatosis with polyangiitis (GPA) diagnosed one year prior to presentation, stage III chronic kidney disease (CKD), hypertension (HTN), obstructive sleep apnea (OSA), and chronic anemia who presented with headache, nausea, vomiting, and diplopia and was found to have idiopathic intracranial hypertension (IIH). IIH was reported in adults with GPA and for our knowledge has not been yet reported in pediatric cases of GPA.

A Rare Presentation of Multi-System Inflammatory Disease in Children Associated With Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).

Management of multi-system inflammatory disease in children (MIS-C) remains a challenge due to the evolving nature of the coronavirus disease 2019 (COVID-19) pandemic. This article reports a rare presentation of multi-system inflammatory disease in a previously healthy 16-month-old male who fully recovered with minimal residual cardiac insufficiency upon discharge. Our case is unique due to patient's young age, cardiac findings, and his response to our treatment protocol. A multi-disciplinary team in a tertiary center was involved with care.