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Macrophage activation syndrome (MAS) is the name given to secondary hemophagocytic lymphohistiocytosis (sHLH) associated with rheumatic diseases. Previously, MAS has been best studied in children with systemic juvenile idiopathic arthritis (sJIA), who are at high risk of developing MAS. MAS/sHLH is a cytokine storm that results in multi-organ system failure and is frequently fatal. Early diagnosis and treatment is critical for improving survival. Various diagnostic tools have been developed for identifying MAS in the setting of sJIA, as well as for all forms of MAS/sHLH. These are largely based on clinical (e.g., fever) and laboratory features (e.g., cytopenias). None are perfectly sensitive and specific, however, increasing awareness of this condition is also paramount in making the diagnosis. Rare familial forms of HLH can also be diagnosed based on homozygous mutation in genes largely involved in perforin-mediated cytolytic function of lymphocytes (natural killer cells and CD8 T cells). Intriguingly, heterozygous defects in these same genes are frequently identified in patients with sHLH and MAS. Decreased cytolytic function results in prolonged interaction of the lytic lymphocytes and their target antigen presenting cells, thus resulting in the pro-inflammatory cytokine storm believed responsible for the multi-organ failure. Novel cytokine-targeted therapies are currently being explored for a less toxic yet effective alternative to chemotherapeutic approaches to treating children with sHLH/MAS. As increased recognition and diagnosis of MAS is on the rise, an earlier and cytokine-targeted approach to therapy will likely save many lives of children with this disorder.

OBJECTIVE To assess the benefit of the recombinant human interleukin-1 receptor antagonist anakinra in treating pediatric patients with secondary hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) associated with rheumatic and nonrheumatic conditions. METHODS A retrospective chart review of all anakinra-treated patients with secondary HLH/MAS was performed at Children's of Alabama from January 2008 through December 2016. Demographic, clinical, laboratory, and genetic characteristics, outcomes data, and information on concurrent treatments were collected from the records and analyzed using appropriate univariate statistical approaches to assess changes following treatment and associations between patient variables and outcomes. RESULTS Forty-four patients with secondary HLH/MAS being treated with anakinra were identified in the electronic medical records. The median duration of hospitalization was 15 days. The mean pretreatment serum ferritin level was 33,316 ng/ml and dropped to 14,435 ng/ml (57% decrease) within 15 days of the start of anakinra treatment. The overall mortality rate in the cohort was 27%. Earlier initiation of anakinra (within 5 days of hospitalization) was associated with reduced mortality (P = 0.046), whereas thrombocytopenia (platelet count

Objective Macrophage activation syndrome (MAS) is a life‐threatening complication of systemic juvenile idiopathic arthritis (sJIA). Early diagnosis is critical. Classification criteria for MAS in sJIA perform less well in the setting of cytokine‐directed therapies. The goal herein was to explore a simple ratio of serum ferritin to the erythrocyte sedimentation rate (ESR) for diagnosis of MAS in the setting of sJIA, and to assess ferritin alone as a screening tool for identifying MAS of multiple etiologies. Methods Data from a large international cohort of sJIA patients with and without MAS, and from hospitalized patients with systemic infection (SI), were assessed for the ferritin:ESR ratio and ferritin alone to identify MAS among sJIA patients. Moreover, data from a smaller cohort of MAS patients associated with multiple etiologies and febrile hospitalized controls were explored. For both cohorts and controls, receiver operating characteristic curves (ROCs) for the ferritin:ESR ratio and ferritin alone were constructed, and areas under the curves (AUCs) were calculated. The Youden index was used to determine the optimal ferritin:ESR ratio and ferritin alone cut points for diagnosis. Results A ferritin:ESR ratio of 21.5 was 82% sensitive and 78% specific for diagnosing sJIA‐MAS versus active sJIA without MAS. Ferritin alone with a set sensitivity of 95% (screening tool) had an 89.3% specificity of identifying all‐cause MAS versus febrile hospitalized children. Conclusion The ferritin:ESR ratio is a practical tool for diagnosing MAS among sJIA patients, and serum ferritin alone is a remarkable screening tool for identifying MAS among febrile hospitalized children.

Juvenile idiopathic arthritis (JIA) comprises a group of heterogeneous diseases further divided into various categories based on shared clinical presentation, laboratory markers, and disease prognosis. Extra-articular complications include uveitis and growth abnormalities. Disease course and prognosis vary with respect to each JIA category and subsequently guide respective treatment. Over the past few decades, considerable treatment advances have significantly reduced the morbidity associated with childhood arthritis. Nevertheless, the treatments are not curative; many children continue to have active disease into adulthood. Emphasis is placed on the initiation of early aggressive therapy in hopes of delaying disease progression and inducing remission.

Background Evidence remains contradictory regarding second-line therapy in patients with Kawasaki disease (KD) refractory to initial intravenous immunoglobulin (IVIg). The objective of this study aims to evaluate the efficacy and safety of three treatments [i.e. a second IVIg infusion, methylprednisolone (IVMP), and infliximab (IFX)] in patients with refractory KD. Methods A systematic search of PubMed, Embase, Cochrane, and ClinicalTrials.gov using predefined MeSH terms was performed from 1990 through 2017. Relevance screening was performed by two independent reviewers. Inclusion criteria included English-only, original clinical data. Eight studies met the inclusion criteria. Fever resolution, coronary lesions, and adverse event outcomes were extracted and pooled for analysis. Results Of the 388 patients included from the 8 studies analyzed, a majority received a second IVIg dose (n = 263, 68%). Fever resolution was comparable between IVIg (72%) and IVMP (73%). IFX (88%) significantly increased fever resolution by approximately 20% compared to IVIg re-dose (RR 1.2; [95% CI: 1.1–1.4]; p = 0.03) and IVMP (RR 1.2; [95% CI: 1.0–1.5]; p = 0.04). Clinical significance of differences in coronary outcomes remains unclear. Conclusions This combined analysis was limited due to variability in design and data reporting methods between the studies and risk of bias. In the absence of a clinical trial, IFX monotherapy as second-line treatment should be considered in patients who fail to respond to initial IVIg. This conclusion is based on a systematic review of the literature with pooled outcome data analysis suggesting IFX is more effective in fever resolution compared to a second IVIg dose and IVMP.

BackgroundNeurological involvement has been reported in up to 80% of adults with Primary Sjogren’s syndrome (pSS) with psychiatric abnormalities including anxiety, depression, and cognitive dysfunction being common. Psychosis due to pSS has been reported in adult patients but has never been previously reported in the adolescent/pediatric literature. Here we describe for the first time four cases of adolescent Sjogren’s syndrome that presented with psychotic symptoms. Rituximab treatment was followed by improvement of psychiatric symptoms in all patients.Case presentation1: 16 year old female without significant past medical history presented to the emergency department with 4 days of abnormal behavior, tremors, insomnia, polyphagia, polyuria, and suicidal ideation.2: 16 year old female with a 4 year history of severe anxiety, OCD, and tic disorder treated with fluoxetine with partial benefit presented with an abrupt and severe worsening of anxiety, OCD and new auditory hallucinations.3: 19 year old female without significant past medical history presented with a 3 day history of progressively altered behavior, incoherent speech, insomnia, headache, and tangential thoughts.4: 17 year old female without significant past medical history presented with new onset suicidal ideation, paranoia, confusion, and emotional lability.ConclusionPsychosis is more common in autoimmune disease than previously known. To our knowledge, the four teenage women described above are the first reported patients with adolescent pSS manifesting as psychosis. pSS should be considered in the differential diagnosis of young patients with new psychiatric disorders, even in the absence of sicca symptoms. Psychiatric symptoms improved with rituximab infusions in all 4 of our patients, which suggests rituximab may be an effective treatment option that should be considered early after the diagnosis of pSS-associated psychiatric disturbance.

Synonymous with secondary hemophagocytic lymphohistiocytosis, macrophage activation syndrome (MAS) is a term used by rheumatologists to describe a potentially life-threatening complication of systemic inflammatory disorders, most commonly systemic juvenile idiopathic arthritis (sJIA) and systemic lupus erythematosus (SLE). Clinical and laboratory features of MAS include sustained fever, hyperferritinemia, pancytopenia, fibrinolytic coagulopathy, and liver dysfunction. Soluble interleukin-2 receptor alpha chain (sCD25) and sCD163 may be elevated, and histopathology often reveals characteristic increased hemophagocytic activity in the bone marrow (and other tissues), with positive CD163 (histiocyte) staining. A common hypothesis as to the pathophysiology of many cases of MAS proposes a defect in lymphocyte cytolytic activity. Specific heterozygous gene mutations in familial HLH-associated cytolytic pathway genes (e.g., PRF1, UNC13D) have been linked to a substantial subset of MAS patients. In addition, the pro-inflammatory cytokine environment, particularly IL-6, has been shown to decrease NK cell cytolytic function. The inability of NK cells and cytolytic CD8 T cells to lyse infected and otherwise activated antigen presenting cells results in prolonged cell-to-cell (innate and adaptive immune cells) interactions and amplification of a pro-inflammatory cytokine cascade. The cytokine storm results in activation of macrophages, causing hemophagocytosis, as well as contributing to multi-organ dysfunction. In addition to macrophages, dendritic cells likely play a critical role in antigen presentation to cytolytic lymphocytes, as well as contributing to cytokine expression. Several cytokines, including tumor necrosis factor, interferon-gamma, and numerous interleukins (i.e., IL-1, IL-6, IL-18, IL-33), have been implicated in the cytokine cascade. In addition to broadly immunosuppressive therapies, novel cytokine targeted treatments are being explored to dampen the overly active immune response that is responsible for much of the pathology seen in MAS.

In rheumatology circles, macrophage activation syndrome (MAS) describes a potentially life-threatening complication of systemic inflammatory disorders, frequently making matters worse for those with systemic juvenile idiopathic arthritis (sJIA) and its adult counterpart, adult-onset Still disease (AOSD). A dysfunctional immune response results in continuous activation and expansion of T lymphocytes and macrophages, leading to an overproduction of proinflammatory cytokines (a cytokine storm) and resulting in multiorgan dysfunction. Like the related disorder, secondary hemophagocytic lymphohistiocytosis (HLH), MAS features include high, unremitting fever, hyperferritinemia, hepatosplenomegaly, lymphadenopathy, pancytopenia, and hypofibrinogenemia. Other laboratory abnormalities include elevated liver enzymes, D-dimers, lactate dehydrogenase, and triglycerides (TGC). Soluble interleukin 2 receptor α (sCD25) may be elevated, but testing is often not available at an on-site laboratory and therefore is not routinely done at the time of diagnosis1,2,3,4. Histopathology often reveals characteristic increased hemophagocytic activity in the bone marrow (and other tissues), with positive CD163 (histiocyte) staining, although this feature is often not present in initial stages and is neither highly sensitive nor specific for MAS5,6. Most commonly studied as a complication of sJIA, the reported prevalence of MAS is estimated to be about 10%; however, reports suggest subclinical MAS may be present in 30%–40% of patients with sJIA7,8. There are several diagnostic challenges in the early recognition of MAS, particularly in distinguishing it from a flare of sJIA or AOSD. Moreover, there is no single pathognomonic feature of MAS, and many clinical features and laboratory abnormalities overlap with those of systemic inflammatory disorders, making it difficult to distinguish the underlying disease from the life-threatening comorbidity1,2,3,4. Further, until very recently, there were no universal validated criteria to aid in diagnosis. However, patient data–based classification criteria … Address correspondence to Dr. R.Q. Cron, Children’s of Alabama, Division of Rheumatology, 1600 7th Ave. S., CPP #M10, Birmingham, Alabama 35233-1711, USA; E-mail: rcron{at}peds.uab.edu

Background Henoch-Schonlein purpura (HSP) is a small vessel vasculitis that is characterized by non-thrombocytopenic purpura, abdominal pain, arthritis, and glomerulonephritis. Typically, HSP is self-limited requiring only supportive care, but more severe cases may require corticosteroid (CS) treatment. Rarely, a subset of these patients has persistent rash, arthritis, abdominal involvement, or renal disease despite treatment with CS, or has disease recurrence on CS tapering. Refractory HSP has been effectively treated with a variety of CS sparing therapies. For life-threatening refractory HSP, the B cell depleting agent, rituximab (RTX), has been reported as beneficial for children with substantial renal or central nervous system involvement. However, RTX use for children with less severe HSP, but chronic CS dependent disease refractory to CS sparing immunomodulatory agents, has been less well explored. Herein, we describe 8 children treated with RTX for chronic refractory HSP and report a reduction in recurrent hospitalizations and eventual CS discontinuation. Methods This is a retrospective analysis of eight children who were treated with RTX for chronic CS dependent HSP during the years 2006–2014 at a single institution. A chart review of the electronic medical record was performed to determine the presenting symptoms, the type and duration of treatment received, and the number of hospitalizations prior to and after RTX. The number of hospitalizations and oral corticosteroid burden were analyzed using the Wilcoxon signed rank test. Results Prior to receiving RTX, seven patients had at least one hospitalization for HSP (median 1.5, range 0–3). Following RTX, only two patients were hospitalized, each a single time for recurrent abdominal pain. The median oral CS burden was 0.345 mg/kg/day before RTX and 0 mg/kg/day at 6 months (p = 0.078), 1 year (p = 0.0625), and 2 years (p = 0.03) following RTX infusion. Seven out of eight children met remission criteria, defined as no active rash, arthritis, nephritis (hematuria and proteinuria), or gastrointestinal distress following RTX. No serious adverse events were noted. Conclusion Overall, RTX effectively reduced the number of hospital admissions and oral CS burden. RTX also helped most all children achieve clinical remission. RTX appears to be an effective and safe alternative for chronic CS dependent and immunomodulatory refractory childhood HSP.

Juvenile idiopathic arthritis (JIA) comprises a group of heterogeneous diseases further divided into various categories based on shared clinical presentation, laboratory markers, and disease prognosis. Extra-articular complications include uveitis and growth abnormalities. Disease course and prognosis vary with respect to each JIA category and subsequently guide respective treatment. Over the past few decades, considerable treatment advances have significantly reduced the morbidity associated with childhood arthritis. Nevertheless, the treatments are not curative; many children continue to have active disease into adulthood. Emphasis is placed on the initiation of early aggressive therapy in hopes of delaying disease progression and inducing remission.

Anti-tumor necrosis factor α (TNFα) medications have revolutionized the care of children and adults with chronic arthritis. They are quick acting, highly effective, and remarkably safe, particularly in children with juvenile idiopathic arthritis (JIA). Anti-TNFα agents come in 2 basic varieties: monoclonal antibodies to TNFα (e.g., infliximab, adalimumab) and a fusion protein containing a TNF receptor (etanercept). Although hypersensitivity reactions are not uncommon with some of the TNFα antibodies (e.g., infliximab), there are only rare reports of anaphylaxis to subcutaneous injections of etanercept in adults with rheumatoid arthritis. Herein, we report 2 cases of anaphylaxis in children with JIA after etanercept injections. Although rare, pediatricians need to be aware of this potentially dangerous occurrence.