Biologic therapies for refractory juvenile dermatomyositis: five years of experience of the Childhood Arthritis and Rheumatology Research Alliance in North America.

BACKGROUND: The prognosis of children with juvenile dermatomyositis (JDM) has improved remarkably since the 1960's with the use of corticosteroid and immunosuppressive therapy. Yet there remain a minority of children who have refractory disease. Since 2003 the sporadic use of biologics (genetically-engineered proteins that usually are derived from human genes) for inflammatory myositis has been reported. In 2011-2016 we investigated our collective experience of biologics in JDM through the Childhood Arthritis and Rheumatology Research Alliance (CARRA). METHODS: The JDM biologic study group developed a survey on the CARRA member experience using biologics for Juvenile DM utilizing Delphi consensus methods in 2011-2012. The survey was completed online by the CARRA members interested in JDM in 2012. A second survey was similarly developed that provided more opportunity to describe their experiences with biologics in JDM in detail and was completed by CARRA members in Feb 2013. During three CARRA meetings in 2013-2015, nominal group techniques were used for achieving consensus on the current choices of biologic drugs. A final survey was performed at the 2016 CARRA meeting. RESULTS: One hundred and five of a potential 231 pediatric rheumatologists (42%) responded to the first survey in 2012. Thirty-five of 90 had never used a biologic for Juvenile DM at that time. Fifty-five of 91 (denominators vary) had used biologics for JDM in their practice with 32%, 5%, and 4% using rituximab, etanercept, and infliximab, respectively, and 17% having used more than one of the three drugs. Ten percent used a biologic as monotherapy, 19% a biologic in combination with methotrexate (mtx), 52% a biologic in combination with mtx and corticosteroids, 42% a combination of a biologic, mtx, corticosteroids (steroids), and an immunosuppressive drug, and 43% a combination of a biologic, IVIG and mtx. The results of the second survey supported these findings in considerably more detail with multiple combinations of drugs used with biologics and supported the use of rituximab, abatacept, anti-TNFα drugs, and tocilizumab in that order. One hundred percent recommended that CARRA continue studying biologics for JDM. The CARRA meeting survey in 2016 again supported the study and use of these four biologic drug groups. CONCLUSIONS: Our CARRA JDM biologic work group developed and performed three surveys demonstrating that pediatric rheumatologists in North America have been using multiple biologics for refractory JDM in numerous scenarios from 2011 to 2016. These survey results and our consensus meetings determined our choice of four biologic therapies (rituximab, abatacept, tocilizumab and anti-TNFα drugs) to consider for refractory JDM treatment when indicated and to evaluate for comparative effectiveness and safety in the future. Significance and Innovations This is the first report that provides a substantial clinical experience of a large group of pediatric rheumatologists with biologics for refractory JDM over five years. This experience with biologic therapies for refractory JDM may aid pediatric rheumatologists in the current treatment of these children and form a basis for further clinical research into the comparative effectiveness and safety of biologics for refractory JDM.

Efficacy of mycophenolate mofetil in adolescent patients with lupus nephritis: evidence from a two-phase, prospective randomized trial.

The safety and efficacy of mycophenolate mofetil (MMF) were evaluated in adolescent patients with systemic lupus erythematosus and active or active/chronic class III-V lupus nephritis. During the 24-week induction phase, patients were randomized to oral MMF (target dose 3.0 g/day) or intravenous cyclophosphamide (IVC) (0.5-1.0 g/m(2)/month), plus prednisone. Response was defined as a decrease in 24-hour urine protein:creatinine ratio (P:Cr) to < 3 in patients with baseline nephrotic range proteinuria, or by ≥ 50% if subnephrotic baseline proteinuria, and stabilization (± 25%) or improvement in serum creatinine. In the 36-month maintenance phase, induction therapy responders were randomized 1:1 to MMF (1.0 g twice daily) or oral azathioprine (AZA) (2 mg/kg/day), plus prednisone. In the induction phase, 10 patients received MMF and 14 received IVC; 15 (62.5%) achieved treatment response (MMF, 7 (70%); IVC, 8/15 (57.1%); p = 0.53, odds ratio (95% confidence interval) 2.0 (0.2, 15.5)). There was a non-statistically significant difference in maintenance of response to MMF (7/8; 87.5%) versus AZA (3/8; 37.5%). Seven patients withdrew (MMF, 2; AZA, 5). During both phases, rates of serious adverse events were similar in both arms. During both phases treatment response with MMF was as effective as the comparator.

Atypical and incomplete Kawasaki disease.

Kawasaki disease (KD) is the most common systemic vasculitis in childhood after Henoch-Schonlein purpura, and the most common cause of acquired heart disease among children living in Western countries. Its diagnosis relies on clinical findings; laboratory tests are useful to rule out other causes of unexplained fever but are not specific for the diagnosis of KD. Numerous efforts to produce a diagnostic algorithm have been made, but without success. Expert opinion is therefore required in doubtful cases, especially those that lack classical criteria (the so-called atypical or incomplete cases). Renal, gastrointestinal, neurologic, pulmonary and ocular involvements have all been described. Infants may be at higher risk of complications since recognising manifestations of the disease might be more difficult in this group. Approaches to treatment and follow-up of KD are changing in parallel with changes in concepts of what constitutes classical and incomplete KD. Guiding this evolution is the probability that the diagnosis is actually KD, the duration of the child's illness and the desired effects of therapy. Until a gold standard for diagnosing KD is available, these therapeutic decisions will continue to be made on an individual basis.

Family-based association analysis implicates IL-4 in susceptibility to Kawasaki disease.

Several compelling lines of evidence suggest an important influence of genetic variation in susceptibility to Kawasaki disease (KD), an acute vasculitis that causes coronary artery aneurysms in children. We performed a family-based genotyping study to test for association between KD and 58 genes involved in cardiovascular disease and inflammation. By analysis of a cohort of 209 KD trios using the transmission disequilibrium test, we documented the asymmetric transmission of five alleles including the interleukin-4 (IL-4) C(-589)T allele (P=0.03). Asymmetric transmission of the IL-4 C(-589)T was replicated in a second, independent cohort of 60 trios (P=0.05, combined P=0.002). Haplotypes of alleles in IL-4, colony-stimulating factor 2 (CSF2), IL-13, and transcription factor 7 (TCF7), all located in the interleukin gene cluster on 5q31, were also asymmetrically transmitted. The reported associations of KD with atopic dermatitis and allergy, elevated serum IgE levels, eosinophilia, and increased circulating numbers of monocyte/macrophages expressing the low-affinity IgE receptor (FCepsilonR2) may be related to effects of IL-4. Thus, the largest family-based genotyping study of KD patients to date suggests that genetic variation in the IL-4 gene, or regions linked to IL-4, plays an important role in KD pathogenesis and disease susceptibility.

Vasculitis in childhood.

Inadequate understanding of the pathogenesis and etiology of vascular inflammation continues to hinder progress in the diagnosis and treatment of pediatric vasculitis. The greatest amount of work is being done in the most common vasculitides of childhood, including Kawasaki disease and Henoch-Schönlein purpura. Discussion of rarer types of vasculitis, on the other hand, such as antineutrophil cytoplasmic antibody-positive small vessel diseases, is largely restricted to case reports. Most aspects of the care of children with Wegener granulomatosis and microscopic polyangiitis are derived by extrapolating from data about adults. Virtually no data are available concerning ways in which these diseases may be different in children.

Psoriatic eruption in Kawasaki disease.

We describe 10 patients who developed a psoriatic skin eruption during either the acute or convalescent phase of Kawasaki disease. The skin eruption was pustular in 3 patients, but more typical psoriasiform skin lesions were seen in the remaining 7 patients. No patient has yet developed chronic psoriasis.

Ticlopidine plus aspirin for coronary thrombosis in Kawasaki disease.

Selective inhibitors of the adenosine 5'-diphosphate pathway of platelet activation have been used rarely in children in the United States. We report the successful use of ticlopidine, together with aspirin, in a 7-month-old infant with Kawasaki disease complicated by a thrombus in a giant coronary aneurysm that failed to resolve with thrombolytic therapy. Kawasaki disease, coronary aneurysms, antithrombotic therapy, ticlopidine, children.

Report of the National Institutes of Health Workshop on Kawasaki Disease.

The National Institute of Allergy and Infectious Disease, National Institutes of Health convened a workshop on Kawasaki disease, May 1997, co-chaired by Drs. Karyl Barron and Stanford Shulman. The goal of the workshop was to review the latest scientific advances relating to the epidemiology, etiology, pathogenesis, treatment, and complications of Kawasaki disease, along with future therapeutic options and proposed future research directions.

Outcomes of children treated for Lyme disease.

OBJECTIVE: To study the outcome of Lyme disease (LD) in children identified in a total population survey of an endemic island. METHODS: We conducted a population-based retrospective cohort study off the coast of Massachusetts. Twenty-five children who met the Centers for Disease Control case definition for prior LD were compared with 26 children without LD from the same community. All children with LD received antibiotics during the acute phase of their disease. All 51 children were invited for a clinical evaluation, including 12-lead electrocardiogram (EKG), and measurement of antibodies to Borrelia burgdorferi by antibody-capture ELISA and Western blot. RESULTS: At a mean of 3.2 years from the initial manifestation of LD, children with prior LD did not have a higher prevalence of musculoskeletal or neurological symptoms, examination abnormalities, abnormal EKG, or behavioral difficulties, compared to children with no history of LD. CONCLUSION: Children who receive appropriate antimicrobial therapy for LD appear to have no demonstrable longterm morbidity.

Coronary artery dimensions may be misclassified as normal in Kawasaki disease.

BACKGROUND: Current American Heart Association guidelines indicate that patients with Kawasaki disease and no coronary artery abnormalities on echocardiography at any stage of illness may be discharged from cardiologic follow-up 1 year after onset of illness. METHODS AND RESULTS: To determine whether coronary artery dimensions in patients with Kawasaki disease whose vessels are classified as "normal" by Japanese Ministry of Health criteria have a distribution similar to expected population norms when adjusting for body surface area, we studied 125 patients during 4 intervals from onset of illness: (1) 10 days or less, (2) 2 weeks (11 to 21 days), (3) 6 weeks (22 days to 3 months), and (4) 1 year (4 months to 1.5 years). Using two-dimensional echocardiography, we measured the internal lumen diameter of the left main, proximal left anterior descending, and proximal right coronary arteries. Mean body surface area-adjusted dimensions of the proximal left anterior descending and right coronary arteries were significantly larger (P < .01) in patients with Kawasaki disease than those in subjects in all periods, except for a marginal difference at 6 weeks for the proximal right coronary artery (P = .02); for the left main coronary artery, this difference achieved statistical significance in the period of 10 days or less, with a trend at 2 weeks (P = .02). Among patients classified as having normal coronary arteries on all echocardiograms by the Japanese Ministry of Health criteria, 27% had at least 1 body surface area-adjusted coronary dimension more than 2 standard deviations above the expected mean. CONCLUSIONS: Coronary artery dilation in Kawasaki disease is thus more prevalent than previously reported, highlighting the need for systematic long-term surveillance of this population.

A predictive instrument for coronary artery aneurysms in Kawasaki disease. US Multicenter Kawasaki Disease Study Group.

To construct a predictive instrument for developing coronary artery abnormalities in patients with acute Kawasaki disease treated with aspirin and intravenous gamma globulin within the first 10 days of illness, data available from a multicenter database of patients with acute Kawasaki disease were analyzed. A development data set (n = 212) was used to construct a sequential risk classification instrument based on easily measured baseline laboratory test results and temperature. The instrument was then validated in 3 test data sets (n = 192, 264, and 92, respectively). Risk factors used in the sequential classification instrument included baseline neutrophil and band counts, hemoglobin concentration, platelet count, and temperature on the day after infusion of intravenous gamma globulin. In the development data set, the instrument classified 123 of 212 patients (58%) as low risk; none developed coronary artery abnormalities. Among 89 patients classified as high risk, 3 of 36 female (8.3%) and 9 of 53 male patients (17.0%) developed coronary artery abnormalities. The instrument performed similarly in the 3 test data sets; no patient in any data set classified as low risk developed coronary artery abnormalities. This simple instrument allows the clinician to identify within 1 day of treatment low-risk children in whom extensive and frequent cardiac testing may be unnecessary, as well as high-risk children who require closer monitoring and may be candidates for additional therapies.

Intravenous immunoglobulin in the treatment of polyarticular juvenile rheumatoid arthritis: a phase I/II study. Pediatric Rheumatology Collaborative Study Group.

OBJECTIVE: To obtain preliminary information about the safety and efficacy of intravenous immune globulin (IVIG: Iveegam, Immuno AG, Vienna) in the treatment of polyarticular juvenile rheumatoid arthritis (poly-JRA) resistant to other forms therapy. METHODS: We used a multicentered, phase I/II blinded-withdrawal design with stratified entry. All patients began by receiving open infusions of IVIG at a dose between 1.5 and 2.0 g/kg/infusion (100 g maximum) bimonthly for the first 2 months, then monthly for up to 6 months. Beginning at Month 3, those who met the criteria for "clinically important improvement" were randomized to receive monthly infusions for 4 months of either placebo or IVIG in a double blind (DB) phase. Patients were permitted nonsteroidal antiinflammatory drugs, slow acting antirheumatic drugs, and low dose (< 10 mg/day) prednisone at constant doses. An "early escape" provision in the DB allowed those who showed "clinically important worsening" to again receive IVIG (if taking placebo) or a higher dose of IVIG (if taking the lower dose of IVIG). RESULTS: Efficacy. Twenty-five children entered the trial and 19 (76%) met the criteria for "clinically important improvement" during the open phase (OP) and entered the DB. Three patients completed the OP but failed to meet the criteria for response, and 3 patients dropped out of the OP, none of whom showed benefit from IVIG. Treatment effect sizes produced by IVIG were moderate to large for all variables in the OP. Patients who continued IVIG in the DB continued to show improvement over that achieved in the OP. Those given placebo showed a rapid loss of efficacy, suggesting IVIG has a limited duration of effect after discontinuation. Safety. No patient developed serious or unexpected adverse side effects in the open or DB phases, and none dropped out of the study due to toxicity or side effects. CONCLUSION: Substantial clinical improvement from IVIG is produced in about three-fourths of patients with poly-JRA during open administration, but the duration of the beneficial effect is short after discontinuation. Those with disease < 3 years' duration may be more likely to respond than those who have had their disease for > 5 years. Short term safety is excellent.

Treatment of immune globulin-resistant Kawasaki disease with pulsed doses of corticosteroids.

We describe four children with Kawasaki disease resistant to treatment with intravenously administered immune globulin who were treated with high doses of methylprednisolone. All four patients apparently responded with normalization of symptoms, and none had significant progression of coronary artery abnormalities or adverse events. We recommend pulse methylprednisolone therapy (30 mg/kg per day) during a 1- to 3-day period for patients with Kawasaki disease who do not respond to intravenous immune globulin therapy or who have recrudescent disease after adequate therapy.

Osteomyelitis and septic arthritis in children: appropriate use of imaging to guide treatment.

Modern imaging techniques have become essential components of the management of acute osteomyelitis and septic arthritis in children. This article addresses the role of these techniques, based on clinical practice guidelines recently developed at a children's hospital by an interdisciplinary group. The recommendations reflect a review of the literature and an analysis of our own experience with 84 children treated for musculoskeletal sepsis during the past 3 years. We attempt to optimize imaging resources by analyzing the unique aspects of these infections in the pediatric skeleton, the clinical needs at different stages of the disease, and the relative strengths and weaknesses of the various imaging procedures. Our goal was to define the use of imaging in cases of osteomyelitis and septic arthritis in children in specific clinical scenarios in which additional information is likely to lead to management modification.

Acquired C1 inhibitor deficiency as a result of an autoantibody to the reactive center region of C1 inhibitor.

An autoantibody that we hypothesize to react with the reactive center of the plasma serine proteinase inhibitor, C1 inhibitor (C1INH), has been found in a patient with acquired C1INH deficiency. The Ab blocks the ability of C1INH to inhibit the hydrolysis of N-carbobenzyloxy-L-lysine thiobenzylester by purified C1s. A cryoprecipitate from the patient's plasma as well as the Ig fraction were able to block C1INH inhibition of C1s. The immunoaffinity purified Ab to C1INH from the patient's plasma Ig fraction neutralizes the inhibitory activity of C1INH in a dose-dependent manner and blocks the ability of normal C1INH to form a complex with C1s. The neutralizing activity of the purified Ab is reversed by a synthetic peptide that corresponds to the amino acid sequence in the P1 to P15 positions of the reactive center of C1INH but not by a 34-amino-acid trypsin peptide or 37-amino-acid elastase peptide derived from the C-terminus of C1INH. Western blot analysis indicated that the Ab is an oligoclonal Ig with kappa light chains.

Kawasaki disease and its cardiac sequelae.

In 1967, Tomisaku Kawasaki described a syndrome of mucocutaneous inflammation in 50 Japanese children. Seven years later, he reported his experience in English, emphasizing that 1% to 2% of affected children died of cardiac failure. Since then, Kawasaki disease has been described worldwide in children of all racial groups and has been recognized as a leading cause of acquired heart disease among children in the United States (Figure 1). The disease affects mostly toddlers; about 80% of patients are less than five years old, and only rare cases are seen in adolescents over age 15. Intravenous gamma globulin has recently been demonstrated to reduce systemic inflammation and the prevalence of coronary artery aneurysms in patients with Kawasaki disease. The treatment, however, is effective only if administered early in the illness. Hence, prompt and accurate diagnosis is essential. The following cases offer a context in which to discuss some of the clinical issues surrounding Kawasaki disease.

Gamma globulin re-treatment in Kawasaki disease.

We retrospectively reviewed the effects of intravenous gamma-globulin (IVGG) re-treatment of 13 children with Kawasaki disease and persistent or recrudescent fever. Fever and mucocutaneous inflammation resolved within 48 hours in nine patients; fever abated in two other children after a third course of IVGG. We conclude that IVGG re-treatment of Kawasaki disease appears to be safe and may improve the clinical course.