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This article provides an overview of the clinical presentation and diagnosis of select pediatric primary systemic vasculitides. Important advances in understanding the pathogenesis of these rare diseases also are discussed and efforts to harmonize treatment through consensus-based guidelines and multicenter and international collaborations highlighted.

Objective A working group was established to develop a core domain set (CDS) for Chronic Nonbacterial Osteomyelitis (CNO) and Synovitis, Acne, Pustulosis, Hyperostosis, Osteitis (SAPHO) following the OMERACT filter 2.1. Methods A scoping review to identify disease-related manifestations was performed, followed by a special interest group (SIG) session at OMERACT2020 to begin the CNO/SAPHO CDS framework. Results Candidate items were identified from the scoping review and most fell under Life Impact and Pathophysiology Manifestation core areas. A SIG agreed on the need to develop a CDS for CNO and SAPHO (100%) and for children and adults (91%). Conclusion Based on candidate items identified, qualitative research and Delphi surveys will be performed as next steps.

IntroductionProspective comparative effectiveness research in chronic nonbacterial osteomyelitis (CNO) is lacking.ObjectivesStudy objectives were to: 1) determine the use and safety of each consensus treatment plan (CTP) regimen for CNO, 2) the feasibility of usingchronic nonbacterialosteomyelitis international registry (CHOIR) data for comparative effectiveness research, and 3) develop and validate a CNO clinical disease activity score (CDAS) using CHOIR.MethodsConsenting children or young adults with CNO were enrolled into CHOIR. Demographic, clinical, and imaging data were prospectively collected. The CNO CDAS was developed through a Delphi survey and nominal group technique. External validation surveys were administered to CHOIR participants.Results140 (76%) CHOIR participants enrolled between August 2018 and September 2020 received at least one CTP regimen. Baseline characteristics from the three groups were well matched. Patient pain, patient global assessment, and clinical CNO lesion count were key variables included in the CNO CDAS. The CDAS showed a strong correlation with patient/parent report of difficulty using a limb, back, or jaw and patient/parent report of disease severity, but a weak correlation with patient/parent report of fatigue, sadness, and worry. The change in CDAS was significant in patients reporting disease worsening or improvement. The CDAS significantly decreased after initiating second-line treatments from median 12 (8-15.5) to 5 (3-12). While second-line treatments were well tolerated, psoriasis was the most common adverse event.ConclusionThe CNO CDAS was developed and validated for disease monitoring and assessment of treatment effectiveness. CHOIR provided a comprehensive framework for future comparative effectiveness research.Key messagesThechronic nonbacterialosteomyelitis international registry (CHOIR) provides comprehensive prospective data for comparison of treatment effectivenessThe clinical disease activity score (CDAS) has content and construct validity to assess CNO

ImportanceMinimal data are available regarding the postdischarge treatment of multisystem inflammatory syndrome in children (MIS-C).ObjectivesTo evaluate clinical characteristics associated with duration of postdischarge glucocorticoid use and assess postdischarge clinical course, laboratory test result trajectories, and adverse events in a multicenter cohort with MIS-C.Design, Setting, and ParticipantsThis retrospective cohort study included patients with MIS-C hospitalized with severe illness and followed up for 3 months in an ambulatory setting. Patients younger than 21 years who were admitted between May 15, 2020, and May 31, 2021, at 13 US hospitals were included. Inclusion criteria were inpatient treatment comprising intravenous immunoglobulin, diagnosis of cardiovascular dysfunction (vasopressor requirement or left ventricular ejection fraction ≤55%), and availability of complete outpatient data for 3 months.ExposuresGlucocorticoid treatment.Main Outcomes and MeasuresMain outcomes were patient characteristics associated with postdischarge glucocorticoid treatment, laboratory test result trajectories, and adverse events. Multivariable regression was used to evaluate factors associated with postdischarge weight gain (≥2 kg in 3 months) and hyperglycemia during illness.ResultsAmong 186 patients, the median age was 10.4 years (IQR, 6.7-14.2 years); most were male (107 [57.5%]), Black non-Hispanic (60 [32.3%]), and Hispanic or Latino (59 [31.7%]). Most children were critically ill (intensive care unit admission, 163 [87.6%]; vasopressor receipt, 134 [72.0%]) and received inpatient glucocorticoid treatment (178 [95.7%]). Most were discharged with continued glucocorticoid treatment (173 [93.0%]); median discharge dose was 42 mg/d (IQR, 30-60 mg/d) or 1.1 mg/kg/d (IQR, 0.7-1.7 mg/kg/d). Inpatient severity of illness was not associated with duration of postdischarge glucocorticoid treatment. Outpatient treatment duration varied (median, 23 days; IQR, 15-32 days). Time to normalization of C-reactive protein and ferritin levels was similar for glucocorticoid duration of less than 3 weeks vs 3 or more weeks. Readmission occurred in 7 patients (3.8%); none was for cardiovascular dysfunction. Hyperglycemia developed in 14 patients (8.1%). Seventy-five patients (43%) gained 2 kg or more after discharge (median 4.1 kg; IQR, 3.0-6.0 kg). Inpatient high-dose intravenous and oral glucocorticoid therapy was associated with postdischarge weight gain (adjusted odds ratio, 6.91; 95% CI, 1.92-24.91).Conclusions and RelevanceIn this multicenter cohort of patients with MIS-C and cardiovascular dysfunction, postdischarge glucocorticoid treatment was often prolonged, but clinical outcomes were similar in patients prescribed shorter courses. Outpatient weight gain was common. Readmission was infrequent, with none for cardiovascular dysfunction. These findings suggest that strategies are needed to optimize postdischarge glucocorticoid courses for patients with MIS-C.

Purpose of Review To review the spectrum of cardiac manifestations and treatments of multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19). Recent Findings Studies demonstrate that up to 80% of children with MIS-C may have cardiac involvement on a spectrum of severity. Cardiac manifestations include myocarditis, coronary artery aneurysms, conduction abnormalities, and arrhythmias. Current treatments, including inotropic support, immunomodulatory therapy, and anti-coagulation, have been effective at resolving these cardiac findings in the majority of patients. COVID-19 can also cause myocarditis in the acute stage of illness and recent descriptions of COVID-19 vaccine myocarditis have occurred. Summary Cardiac manifestations are common in MIS-C and should be assessed for at presentation and during the clinical course as indicated.

PR3-ANCA vasculitis has a genetic association with HLA-DPB1. We explored immunologic and clinical features related to the interaction of HLA-DPB1*04:01 with a strongly binding PR3 peptide epitope (PR3Patients with ANCA vasculitis with active disease and disease in remission were followed longitudinally. Peripheral blood mononuclear cells from patients and healthy controls with HLA-DPB1*04:01 were tested for HLA-DPB1*04:01 expression and interaction with a PR3 peptide identifiedThe risk allele HLA-DPB1*04:01 has been associated with PR3-ANCA, but its immunopathologic role was unclear. These studies demonstrate that HLA-DPB1*04:01 and PR3

Activated PI3 kinase delta syndrome (APDS) is a combined immunodeficiency characterized by recurrent sinopulmonary infections, increased risk of herpesvirus infections, lymphoproliferation, autoimmunity, and increased risk of lymphoid malignancies. Gain-of-function mutations in PIK3CD and PIK3R1 result in increased phosphoinositide-3-kinase-delta activity which causes hyperactivation of lymphocytes and abnormal development and activation of T and B cells. Cytopenias are the most common autoimmune process occurring in patients with APDS and typically occur as a later manifestation of the disease. Here we present a female patient with an early autoimmune hemolytic anemia, hepatosplenomegaly, and frequent infections presenting in infancy, followed by development of significant lymphadenopathy before her diagnosis with APDS type 1. She had significant improvement in her infectious history with immunoglobulin replacement, and control of autoimmune hemolytic anemia with initiation of sirolimus after her diagnosis with APDS type 1. We utilize this case to review the literature on APDS and present the novel finding of early-onset autoimmune disease in the setting of APDS. Autoimmune cytopenias are seen in many primary immunodeficiencies, and workup of autoimmune cytopenias in young patients should include evaluation for underlying immune disorder.

The novel coronavirus, SARS-CoV-2, can present with a wide range of neurological manifestations, in both adult and pediatric populations. We describe here the case of a previously healthy 8-year-old girl who presented with seizures, encephalopathy, and rapidly progressive, diffuse, and ultimately fatal cerebral edema in the setting of acute COVID-19 infection. CSF analysis, microbiological testing, and neuropathology yielded no evidence of infection or acute inflammation within the central nervous system. Acute fulminant cerebral edema (AFCE) is an often fatal pediatric clinical entity consisting of fever, encephalopathy, and new-onset seizures followed by rapid, diffuse, and medically-refractory cerebral edema. AFCE occurs as a rare complication of a variety of common pediatric infections and a CNS pathogen is identified in only a minority of cases, suggesting a para-infectious mechanism of edema. This report suggests that COVID-19 infection can precipitate AFCE, and highlights the need for high suspicion and early recognition thereof.

Eosinophilic granulomatosis with polyangiitis (EGPA) (formerly Churg-Strauss syndrome) is a small vessel vasculitis associated with asthma and eosinophilia. Despite its rarity, continuous gains are being made in understanding the disease with knowledge advancements regarding its epidemiology, heterogeneous clinical manifestations, management, and outcomes. Large knowledge gaps remain, however, particularly surrounding pathophysiologic and diagnostic uncertainties. There is still an incomplete understanding of the interplay between the eosinophilic and vasculitic processes that are features of disease pathogenesis. EGPA is also a conceptually difficult disorder given its dual categorization with hypereosinophilic syndromes and systemic vasculitides and the absence of a biomarker that can reliably distinguish between the two. In addition, recent evidence points to distinct, but partly overlapping, disease phenotypes, yet there is insufficient understanding to inform phenotype-tailored therapies. EGPA also remains a diagnostic challenge in part because asthma may be the primary or predominant manifestation for years, and the chronic corticosteroid requirement may mask other disease features. Efforts are ongoing to better elucidate pathophysiologic mechanisms, resolve classification issues, better characterize disease manifestations, and further clarify disease subcategorization, all of which will translate into better diagnosis and treatment with the possibility of specifically adapted therapies.

Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant disorder with variable expressivity [1] and results from mutations in the PSTPIP1 gene. The PSTPIP1 protein is a cytoskeletal protein within hematopoietic cells that serves as a scaffold for the binding of other cellular proteins, such as pyrin, protein tyrosine phosphatases, c-Abl, CD2, and WASP. Through these interactions, PSTPIP1 regulates several cellular functions including IL-lβ release, cytoskeleton organization, cell migration, and T-cell activation [2, 3]. Depending on the mutation location within the PSTPIP1 gene and consequent alterations in protein-protein interactions, a spectrum of autoinflammatory disorders may result and are collectively referred to as PSTPIP1-associated inflammatory diseases (PAID). While the underlying pathogenesis is not completely understood, the PAID spectrum is characterized by dysregulated IL-lβ release and neutrophil responses [4] and clinically manifests as recurrent bouts of untriggered inflammation involving various organ systems [5]. PAPA syndrome is only one entity within the PAID spectrum and classically presents with sterile pyogenic arthritis, pyoderma gangrenosum (PG), and cystic acne. Due to heterogeneous presentations, delays in diagnosis and misdiagnoses as autoimmune or immunodeficiency conditions are common. Given the rarity of PAPA syndrome and other disorders in the PAID spectrum, no guideline-based treatment approaches exist and previous reports highlight the significant variability in responses to monotherapy with two of the most common long-term therapies utilized: IL-1β antagonists and TNF-α inhibitors [2, 6]. Other anti-inflammatory agents are reserved for treatment failures, and dual therapy, except in combination with steroids, is rarely reported for treatment of PAPA syndrome [3, 6]. Early diagnosis and initiation of effective treatment to induce remission, however, are vital to decreasing the morbidity and mortality associated with these autoinflammatory disorders. We present here a case of an adolescent female referred to our immunology clinic for suspected immunodeficiency, but who was subsequently diagnosed with and treated for PAPA syndrome with combination adalimumab and tacrolimus therapy. To our knowledge, this is the first report of the effective and safe use of tacrolimus in combination with adalimumab for PAPA syndrome. Case Presentation A 12-year-old female was referred to our immunology clinic for evaluation of a possible immunodeficiency given her history of recurrent infections since 1 year of age. Her pertinent clinical history is summarized in Figure 1a. She initially developed recurrent purulent otitis media (OM), requiring multiple sets of tympanostomy tubes. At 5-years-old, she developed erythema, bruising, swelling, and pain of her left ankle that was initially attributed to trauma. Over several months, her symptoms extended to involve her bilateral ankles, knees, wrists, and hands. Following a rheumatology evaluation, she was diagnosed with seronegative polyarticular juvenile idiopathic arthritis (JIA). After failing therapy with naproxen, methotrexate was attempted but discontinued after four months due to an increase in OM. Her arthritis interestingly resolved spontaneously over the next several months without further treatment. Open in a separate window Figure 1: a) Our patient’s clinical history was significant for recurrent episodes of purulent otitis media, polyarticular juvenile idiopathic arthritis (JIA), two episodes of pyogenic sterile arthritis and osteomyelitis of the right elbow, and various cutaneous manifestations including recurrent episodes of cellulitis and abscesses, pyoderma gangrenosum (PG), and nodulocystic acne. Arrows indicate initiation of adalimumab and addition of tacrolimus. * represents PG flare during lapse of adalimumab therapy for 6–8 weeks. b) Dermatopathology from biopsy of left breast lesion revealed a mixed lobular panniculitis with interstitial neutrophils and lymphocytes and features consistent with a neutrophilic dermatosis. c) Erythematous, violaceous ulcerated plaque that represents PG lesion prior to treatment. d) PG lesion following treatment with adalimumab with reduction in erythema, ulceration, and size. e) PG lesion following addition of tacrolimus to adalimumab has healed into a hypertrophic scar.

Background Chronic nonbacterial osteomyelitis (CNO) is a severe and occult autoinflammatory bone disease of unknown cause. Early diagnosis is challenging, and CNO may debilitate affected children when left untreated. Currently, evidence-based and validated diagnostic and classification criteria for CRMO/CNO are lacking. The insidious disease course, increasing disease incidence, and significant delay in diagnosis highlight the need for the development of classification criteria that leads to more precise and early selection of patients for clinical trials1,2. Objectives To identify candidate items towards developing classification criteria for CNO using anonymous survey and nominal group technique. Methods An international collaborative effort was formed within the pediatric and adult rheumatology communities to conduct the following phases: 1) to generate candidate criteria items by a Delphi survey among international rheumatologists; 2) to reduce candidate criteria items through consensus processes involving physicians managing CNO and patients or caregivers of children with CNO. This study was approved by Seattle Children’s Hospital Institutional Review Board. Results In Phase 1, 259 pediatric rheumatologists (30%, N=865) participated in an online questionnaire about features most relevant to the classification of CNO. Of those, 77 (30%) practiced in Europe, 132 (51%) in North America, and 50 (19%) in other continents. A total of 138 (53%) responders had >10 years of practicing experience and 108 (42%) had managed >10 CNO patients. There were 33 candidate criteria items initially identified. In Phase 2, candidate items were presented to 39 rheumatologists and 7 parents and items were refined or eliminated through item reduction techniques. Seventy-seven (94%, N=82) workgroup members then participated in a second survey to rank the remaining items by their distinguishing power of CNO from mimicking conditions. Figure 1 shows the mean score for the remaining 31 candidate criteria. Multifocal lesions, ruling out malignancy and infection and typical location on imaging had the greatest means. CRP and/or ESR greater than 3x the normal upper limit had the greatest negative means. Discriminatory Score +3/-3 (increases/decreases the likelihood of CRMO the most) +2/-2 (increases/decreases the likelihood of CRMO moderately) +1/-1 (increases/decreases the likelihood of CRMO slightly) 0 (no difference) Conclusion Through surveys and consensus technique, candidate items towards developing classification criteria for CNO were identified. This list of items will guide the design of a feasible patient data collection form towards weighting of each item in the classification criteria. References [1] Roderick MR, Shah R, Rogers V, Finn A, Ramanan AV. Chronic recurrent multifocal osteomyelitis (CRMO)–advancing the diagnosis. Pediatric Rheumatology. 2016 Dec;14(1):47. [2] Jansson A, Renner ED, Ramser J, Mayer A, Haban M, Meindl A, et al. Classification of non-bacterial osteitis: retrospective study of clinical, immunological and genetic aspects in 89 patients. Rheumatology. 2006 Jun 17;46(1):154-60. Acknowledgement CNO/CRMO Work Group, Childhood Arthritis and Rheumatology Research Alliance Disclosure of Interests Melissa Oliver: None declared, Eveline Wu: None declared, Raymond Naden Speakers bureau: Was a speaker at conferences paid by pharmaceutical companies several times in the past, but not in the last 7 years., Matthew Hollander: None declared, Polly Ferguson: None declared, Fatma Dedeoglu Consultant for: Attended a scientific meeting for Novartis in 2017. Overall monetary amount was less than $5000., Seza Ozen Consultant for: Seza Ozen is receiving consultancy fees from Novartis, Speakers bureau: Roche, Yongdong Zhao Grant/research support from: I have grant support from Bristol-Myer Squibb

Sweet’s syndrome (SS) is classically considered a hypersensitivity reaction often associated with autoimmune disorders and malignancy. SS has also been increasingly reported to occur with immunodeficiencies. We present a case of treatment-refractory, systemic SS as the initial manifestation in a young child with common variable immunodeficiency (CVID). We also review current literature about SS and concurrent immunodeficiencies and autoimmunity in CVID patients. Few case reports exist regarding the co-occurrence of Sweet’s syndrome and primary immunodeficiencies. SS is characterized by a pro-inflammatory state with a neutrophil predominance resulting in a spectrum of clinical manifestations. CVID is a multifactorial antibody deficiency that can be associated with autoimmunity, which some studies have proposed to be secondary to altered CD21 expression. SS occurring in patients with CVID has been infrequently reported, and one case study demonstrated improvement of Sweet’s associated skin lesions with immunoglobulin replacement. In our case, the patient had multi-system SS refractory to multiple immunomodulatory therapies. To our knowledge, this is the first report of the effective and safe use of intravenous tocilizumab and oral lenalidomide to treat SS in a child with CVID. Immunoglobulin replacement reduced the frequency of infections and may have contributed to the opportunity to wean the immunosuppressive therapies for Sweet’s syndrome. Sweet’s syndrome as an initial manifestation of co-occurring immunodeficiencies is rare, and providers need a high index of suspicion. In addition, treatment of SS associated with an immunodeficiency can be a challenge. Treatment with immunoglobulin replacement reduces the frequency of infections, and in some patients with concurrent SS may improve skin lesions and reduce the need for immunomodulator therapy. Further study is necessary to better understand the pathogenesis of CVID in patients with SS and to identify possible biomarkers that predict who with SS are at risk for developing hypogammaglobulinemia.

ANCA vasculitis is an autoimmune disease with increased expression of the autoantigen genes, myeloperoxidase (MPO) and proteinase 3 (PRTN3), but their origin and significance of expression is less distinct. To clarify this, we measured MPO and PRTN3 messenger RNA in monocytes, normal-density neutrophils, and in enriched leukocytes from peripheral blood mononuclear cells. Increased autoantigen gene expression was detected in normal-density neutrophils and enriched leukocytes from patients during active disease compared to healthy individuals, with the largest difference in enriched leukocytes. RNA-seq of enriched leukocytes comparing active-remission pairs identified a gene signature for low-density neutrophils. Cell sorting revealed low-density neutrophils contained mature and immature neutrophils depending on the presence or absence of CD10. Both populations contributed to autoantigen expression but the frequency of immature cells in low-density neutrophils did not correlate with low-density neutrophil MPO or PRTN3 expression. Low-density neutrophils were refractory to MPO-ANCA induced oxidative burst, suggesting an alternative role for low-density neutrophils in ANCA vasculitis pathogenesis. In contrast, normal-density neutrophils were activated by MPO-ANCA and monoclonal anti-PR3 antibody. Normal-density neutrophil activation correlated with MPO and PRTN3 mRNA. Increased autoantigen gene expression originating from the mature low-density and normal-density neutrophils suggests transcriptional dysregulation is a hallmark of ANCA vasculitis. Thus, the correlation between autoantigen gene expression and antibody-mediated normal-density neutrophil activation connects autoantigen gene expression with disease pathogenesis.

Primary immunodeficiencies are a group of genetically determined disorders with diverse presentations. The purpose of this review is to provide a practical and brief description of a select number of these diseases and to discuss the important role the radiologist can have in making an early diagnosis and in detecting and following disease complications. The role of diagnostic imaging and informed performance and interpretation are vital in the diagnosis, surveillance and management of all primary immunodeficiency disorders.

Small-vessel vasculitides (SVV) are a group of complex and chronic systemic autoimmune disorders associated with significant morbidity. Renal involvement is a major determinant of long-term outcome in all SVV. Depending on the disorder, SVV can be associated with frequent, and often life-threatening, relapses and increased burden from long-term exposure to toxic therapies and accumulating, irreversible organ damage. Prompt diagnosis or determination of active disease and quick initiation of appropriate treatment are therefore paramount in the management of SVV. For rapidly progressive glomerulonephritis or other severe, life-threatening manifestations in either anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) or cryoglobulinemic vasculitis (CV), we recommend intravenous pulse methylprednisolone, plasmapheresis, and intravenous monthly cyclophosphamide. Hemodialysis is also used when indicated. Dose adjustments are made based on the patient’s weight, degree of renal impairment, and tolerability. Corticosteroids and plasmapheresis are tapered according to the patient’s response. Although a clearer role for rituximab in the treatment of AAV and CV is emerging, we reserve rituximab for disease relapse or disease refractory to the aforementioned treatments. We also use rituximab in less severe disease and for maintenance of remission in AAV and CV when indicated. Corticosteroids are a mainstay of therapy in IgA nephropathy (IgAN) and vasculitis (IgAV). In rapidly progressive glomerulonephritis due to IgAN or IgAV, we recommend intravenous cyclophosphamide. Again, dose adjustments are made based on the patient’s weight, degree of renal impairment, and tolerability.

Hemophagocytic lymphohistiocytosis (HLH) comprises a spectrum of conditions uniformly characterized by a hyperinflammatory state with overproduction of pro-inflammatory cytokines. HLH may be subdivided into a primary, familial form and a secondary, acquired form. Despite their etiological diversity, both HLH subtypes are phenotypically similar with overwhelming inflammation manifested by fever, hepatosplenomegaly, and cytopenias. Lymphadenopathy, rash, and variable neurological symptoms may also be present. Inherited and acquired forms of HLH are potentially fatal if left untreated. Even with aggressive therapy, HLH is associated with high morbidity and mortality. Early diagnosis and prompt initiation of treatment are essential for survival and to reduce overall morbidity. Early diagnosis, however, is often challenging due to the rarity of the disease and lack of specific clinical and laboratory features. The purpose of this chapter is to review the current understanding of the pathophysiology, presentation, evaluation, and treatment of HLH with a focus on MAS.

Pyoderma gangrenosum is a neutrophilic dermatosis that is rare in infancy, with only 20 cases reported in the literature. We present a case of infantile pyoderma gangrenosum refractory to topical steroids, tacrolimus, and dapsone as well as systemic steroids and infliximab that is currently well controlled with the addition of oral tacrolimus. To our knowledge, this is the first report of the effective, safe use of oral tacrolimus in combination with infliximab for infantile pyoderma gangrenosum. We review all current cases of infantile pyoderma gangrenosum, as well as tacrolimus and its role in the treatment of this condition.

Granulomatous-lymphocytic interstitial lung disease (GLILD) has classically been associated with common variable immune deficiency (CVID), but is increasingly being reported in other immunodeficiencies. We describe the second reported case of GLILD in a patient with 22q11.2 deletion syndrome (22q11.2DS) and review the recent literature surrounding GLILD. GLILD is characterized by granulomata and lymphoproliferation. Consensus statements and retrospective and case-control studies have better elucidated the clinicopathological and radiographic manifestations of GLILD, allowing for its differentiation from similar conditions like sarcoidosis. Gaps of knowledge remain, however, particularly regarding optimal management strategies. Combination therapies targeting T and B cell populations have recently shown favorable results. GLILD is associated with poorer outcomes in CVID. Its recognition as a rare complication of 22q11.2DS and other immunodeficiencies therefore has important therapeutic and prognostic implications. Additional research is needed to better understand the natural history and pathogenesis of GLILD and to develop evidence-based practice guidelines.

Immune gamma globulin (IgG) has a long history in the treatment of both primary immune deficiency and autoimmune disorders. Disease indications continue to expand and new-generation products increase the versatility of delivery. This review encompasses a historical perspective as well as current and future implications of human immune globulin for the treatment of immune-mediated illness.

A 14-year-old girl presented with progressive upper and lower extremity weakness. Symptoms started 5 months prior with intermittent bilateral calf pain coincident with onset of lower extremity weakness. Initial evaluation revealed normal complete blood count, complelete metabolic panel, inflammatory markers, muscle enzymes and MRI brain and spine with/without contrast. Electromyography demonstrated an acute to subacute polyradiculitis affecting the upper and lower extremities. She was admitted for expedited evaluation. Examination was significant for lower extremity weakness and absent reflexes. Lumbar puncture (LP) showed lymphocytic pleocytosis and markedly elevated protein. Thorough infectious, oncological and rheumatological evaluations were all unremarkable. Most notable was that CSF Neuromyelitis Optica IgG and paraneoplastic antibody panel were negative, and serum ACE was normal. She was started on intravenous immunoglobulin for empiric treatment of chronic inflammatory demyelinating polyneuropathy (CIDP). While hospitalised, she developed left eye blurred vision. Ophthalmological examination demonstrated bilateral optic nerve oedema. Repeat MRI brain showed enhancement of multiple cranial nerves (figure 1). Initial MRI spine was reinterpreted as diffuse enhancement and …

Importance Soy isoflavone supplements are used to treat several chronic diseases, although the data supporting their use are limited. Some data suggest that supplementation with soy isoflavone may be an effective treatment for patients with poor asthma control. Objective To determine whether a soy isoflavone supplement improves asthma control in adolescent and adult patients with poorly controlled disease. Design, Setting, and Participants Multicenter, randomized, double-blind, placebo-controlled trial conducted between May 2010 and August 2012 at 19 adult and pediatric pulmonary and allergy centers in the American Lung Association Asthma Clinical Research Centers network. Three hundred eighty-six adults and children aged 12 years or older with symptomatic asthma while taking a controller medicine and low dietary soy intake were randomized, and 345 (89%) completed spirometry at week 24. Interventions Participants were randomly assigned to receive soy isoflavone supplement containing 100 mg of total isoflavones (n=193) or matching placebo (n=193) in 2 divided doses administered daily for 24 weeks. Main Outcomes and Measures The primary outcome measure was change in forced expiratory volume in the first second (FEV 1 ) at 24 weeks. Secondary outcome measures were symptoms, episodes of poor asthma control, Asthma Control Test score (range, 5-25; higher scores indicate better control), and systemic and airway biomarkers of inflammation. Results Mean changes in prebronchodilator FEV 1 over 24 weeks were 0.03 L (95% CI, −0.01 to 0.08 L) in the placebo group and 0.01 L (95% CI, −0.07 to 0.07 L) in the soy isoflavone group, which were not significantly different ( P = .36). Mean changes in symptom scores on the Asthma Control Test (placebo, 1.98 [95% CI, 1.42-2.54] vs soy isoflavones, 2.20 [95% CI, 1.53-2.87]; positive values indicate a reduction in symptoms), number of episodes of poor asthma control (placebo, 3.3 [95% CI, 2.7-4.1] vs soy isoflavones, 3.0 [95% CI, 2.4-3.7]), and changes in exhaled nitric oxide (placebo, −3.48 ppb [95% CI, −5.99 to −0.97 ppb] vs soy isoflavones, 1.39 ppb [95% CI, −1.73 to 4.51 ppb]) did not significantly improve more with the soy isoflavone supplement than with placebo. Mean plasma genistein level increased from 4.87 ng/mL to 37.67 ng/mL ( P Conclusions and Relevance Among adults and children aged 12 years or older with poorly controlled asthma while taking a controller medication, use of a soy isoflavone supplement, compared with placebo, did not result in improved lung function or clinical outcomes. These findings suggest that this supplement should not be used for patients with poorly controlled asthma. Trial Registration clinicaltrials.gov Identifier:NCT01052116

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by immune dysregulation due to a defect in lymphocyte apoptosis. The clinical manifestations may be noted in multiple family members and include lymphadenopathy, splenomegaly, increased risk of lymphoma, and autoimmune disease, which typically involves hematopoietic cell lines manifesting as multilineage cytopenias. Since the disease was first characterized in the early 1990s, there have been many advances in the diagnosis and management of this syndrome. The inherited genetic defect of many ALPS patients has involved (FAS) pathway signaling proteins, but there remain those patients who carry undefined genetic defects. Despite ALPS having historically been considered a primary immune defect presenting in early childhood, adult onset presentation is increasingly becoming recognized and more so in genetically undefined patients and those with somatic FAS mutations. Thus, future research may identify novel pathways and/or regulatory proteins important in lymphocyte activation and apoptosis.

The complement system is a major, multifunctional part of innate immunity and serves as a bridge between the innate and adaptive immune systems. It consists of more than 30 distinct proteins that interact with one another in a specific sequence. There are three pathways of complement activation: the classical, the lectin, and the alternative pathways. The three pathways are initiated by distinct mechanisms, but they all generate the same core set of effector molecules. Inherited complete deficiencies in complement components are generally very rare and predispose to infections and autoimmune disease. One of the better described associations is between deficiencies in early classical pathway components and the development of systemic lupus erythematosus. The goal of this review will be to discuss the associations between and the causal mechanisms of complement deficiencies and systemic lupus erythematosus.

Background/Purpose: Localized scleroderma (LS) is a chronic inflammatory and fibrosing skin disease. We present baseline data on the juvenile LS (jLS) cohort from the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry, a multicenter observational pediatric rheumatic disease registry. Methods: Descriptive statistics were used for demographic, clinical and laboratory features. Data analysis included the two-sample t-test, chi-square test, Fisher's exact test, and analysis of variance as appropriate. Results: Of 259 children in the database, 78% were female and 81% were Caucasian. Mean age at onset was 8.3 yr (± 4.2). Mean age at first pediatric rheumatology (PRH) evaluation was 9.5 yr (± 4.2), yet 37% had ≥5 yr delay from onset to first PRH visit. Linear scleroderma (LiS) was the most common subtype (54%), followed by circumscribed morphea (CM) (15%), generalized morphea (GM) (8%), eosinophilic fasciitis (2%), and pansclerotic morphea (1%). 20% of children had mixed subtype, and LiS-CM was the most frequent combination (60%). Among LiS patients with face-scalp localization (40%), neurologic and ocular diseases were reported in 7% and 4%, respectively. ANA positivity was found in 50% tested and was not associated with subtype, age at onset, extracutaneous manifestations, or features of disease damage. Children with new lesions were more likely to have an elevated creatine kinase (CK) (p=0.02) or aldolase (p=0.02); muscle atrophy (p=0.04) and extremity shortening (p=0.02) were also associated with an elevated CK. Children with any functional limitation (baseline worst ever ACR functional class II, III, and IV) (28%) had earlier first PRH visit (mean 0.88 yr ± 0.89) compared to those without limitation (class I) (mean 1.4 yr ± 1.8, p=0.03). The association was also significant when evaluating ≥1 yr (p=0.04), ≥2 yr (p=0.02), and ≥5 yr delay (p=0.02) in first PRH visit. Poorer function also correlated with presence of muscle atrophy, joint contracture, and extremity shortening (all p

Purpose Recent studies have implicated low vitamin D levels with greater disease activity in pediatric systemic lupus erythematosus (SLE) and we have reported an association between low vitamin D levels and greater disease activity in juvenile dermatomyositis. The objective of this study was to explore whether standardized vitamin D supplementation of low levels of 25-hydroxyvitamin D [25(OH)D] might be associated with improvements in disease activity.