Alexa Adams

Update on the pathogenesis and treatment of systemic onset juvenile rheumatoid arthritis

Purpose of reviewAlthough systemic onset juvenile rheumatoid arthritis accounts for only about 20% of most reported series, children with systemic onset juvenile rheumatoid arthritis are often the most difficult to treat. Many children with persistent systemic onset juvenile rheumatoid arthritis have marked physical and emotional disability as a result of both disease and treatment-related morbidities. This review highlights recent studies that better elucidate the etiopathogenesis of systemic onset juvenile rheumatoid arthritis. New therapies derived from better understanding of cytokines, cytokine gene expression, and their complex interactions, which result in inflammation, are improving our ability to control active disease while reducing or reliance on corticosteroids. Recent findingsRecent advances in our understanding of the etiopathogenesis of systemic onset juvenile rheumatoid arthritis have led to therapies that specifically target the cytokines found in abnormal quantities in children with active disease. Biologic agents that directly target interleukin-1a, interleukin-6, and tumor necrosis factor α are currently in use, and additional agents that modulate interleukin-18, myeloid-related proteins 8 and 14, natural killer cell function, and macrophage migration inhibitory factor production are under investigation. SummaryAnakinra, monoclonal antibody to interleukin-6 receptor, and thalidomide each have led to significant clinical improvement with fewer side effects than resulted when corticosteroids were the mainstay of therapy.

Prolonged improvement of childhood onset systemic lupus erythematosus following systematic administration of rituximab and cyclophosphamide

BackgroundAlthough the combination of cyclophosphamide and rituximab has been utilized in case reports, there are no previous reports of the long term outcome of SLE treated systematically with this regimen. We report a pilot study to evaluate the efficacy of a systematically administered course of rituximab and cyclophosphamide over an eighteen month period to provide sustained improvement in childhood onset systemic lupus erythematosus (SLE).FindingsTwelve patients with childhood onset lupus nephritis or corticosteroid resistant SLE received systematic treatment with a combination of rituximab (750 mg/M2 up to 1 gram) and cyclophosphamide (750 mg/M2: no patient exceeded 1.8 M2). Two administrations of rituximab and cyclophosphamide, two weeks apart, were administered at the start of study, six months later, and eighteen months later. Clinical data were collected and analyzed after sixty months of follow up. There was sustained improvement in all clinical parameters with a dramatic reduction in both mean SLEDAI score (10.1 to 1 at one year and 0 at five years p<0.005) and mean daily prednisone dosage (29.7 mg/day to 12.7 by one year and 7.0 mg/day at five years p<0.005), with sustained improvement in mean C3 (55.5 mg/ml to 113 at one year and 107.5 at five years p<0.001) which was maintained through sixty months of follow up. Serum immunoglobulin levels were transiently depressed but mean values were within the normal range for both IgG and IgM at one and five years. Few complications were observed (two episodes of febrile neutropenia during the first year of treatment were the only serious adverse events) and patients routinely reported sustained wellbeing.ConclusionsThis pilot study demonstrates that a systematically administered course of rituximab and cyclophosphamide over an eighteen month period provided sustained relief for patients with childhood onset SLE which was maintained over a sixty month period, while minimizing the need for corticosteroids, without excessive toxicity.

Pharmacotherapy of lupus nephritis in children: a recommended treatment approach.

Systemic lupus erythematosus (SLE) is a multisystem inflammatory disease of unknown aetiology, which is characterised by recurrent disease flares that may affect any organ system. Renal involvement remains one of the chief causes of morbidity and mortality in children with lupus. Nephritis occurs in approximately two-thirds of patients, ranging from mild glomerulitis to life-threatening occurrences of diffuse proliferative glomerulonephritis. As lupus nephritis is a condition of no single aetiology, there is no single cure. Corticosteroids, although still the first line of treatment, are increasingly being superseded by cytotoxic drugs, in particular cyclophosphamide and corticosteroid-sparing agents. Newer agents such as mycophenolate mofetil, although effective in the treatment of lupus in adults, are less effective in children. Standard of care for highly active lupus nephritis in children remains intravenous cyclophosphamide, although preliminary experience suggests that the addition of rituximab may allow for remission induction with a reduction in cumulative cyclophosphamide dose. Combination therapies and newer agents appear promising for the future as our understanding of the immune system and its dysregulation in SLE improves. In this review, we discuss the current standards of care, newer therapies currently in use, and emerging treatments still undergoing development and investigation. We conclude by discussing our guidelines for treatment at the present time and suggestions for the comprehensive care of children with lupus nephritis.

The impact of disease activity and tumour necrosis factor-α inhibitor therapy on cytokine levels in juvenile idiopathic arthritis.

The aim of this study was to evaluate prospectively cytokine levels and disease activity in juvenile idiopathic arthritis (JIA) patients treated with and without tumour necrosis factor (TNF)‐α inhibitors. TNF‐α inhibitor‐naive JIA subjects were followed prospectively for 6 months. Cytokine levels of TNF‐α, interleukin (IL)−1β, IL‐6, IL‐8, IL‐10 and IL‐17 were measured at baseline for JIA subjects and healthy controls (HCs). Cytokine levels were then measured at four time‐points after initiation of TNF‐α inhibition for anti‐TNF‐α‐treated (anti‐TNF) JIA subjects, and at two subsequent time‐points for other JIA (non‐TNF) subjects. JIA disease activity by Childhood Health Assessment Questionnaire (CHAQ) disability index/pain score and physician joint count/global assessment was recorded. Sixteen anti‐TNF, 31 non‐TNF and 16 HCs were analysed. Among JIA subjects, those with higher baseline disease activity (subsequent anti‐TNFs) had higher baseline TNF‐α, IL‐6 and IL‐8 than those with lower disease activity (non‐TNFs) (P < 0·05). TNF‐α and IL‐10 increased, and IL‐6 and IL‐8 no longer remained significantly higher after TNF‐α inhibitor initiation in anti‐TNF subjects. Subgroup analysis of etanercept versus adalimumab‐treated subjects showed that TNF‐α and IL‐17 increased significantly in etanercept but not adalimumab‐treated subjects, despite clinical improvement in both groups of subjects. JIA subjects with increased disease activity at baseline had higher serum proinflammatory cytokines. TNF‐α inhibition resulted in suppression of IL‐6 and IL‐8 in parallel with clinical improvement in all anti‐TNF‐treated subjects, but was also associated with elevated TNF‐α and IL‐17 in etanercept‐treated subjects.

Takayasu arteritis presenting in the context of active tuberculosis: a pediatric case.

Takayasu arteritis (TA) is a large-vessel vasculitis, most commonly presenting in young adults and more rarely in pediatric patients. An apparent association between TA and Mycobacterium tuberculosis has been noted previously, although this potential relationship is not yet understood. We present the case of a 16-year-old Haitian girl diagnosed with TA, originally presenting in the context of active tuberculosis. Our patient has been treated with antituberculosis therapy, corticosteroids, methotrexate, and rituximab to control her continued active vasculitis. With this case report, we seek to promote further exploration of the apparent association between TA and tuberculosis, as further clarification of the nature of this relationship may lead to the development of more targeted therapies and better outcomes for TA patients.

Unrecognized Celiac Disease in Children Presenting for Rheumatology Evaluation

BACKGROUND AND OBJECTIVES: Current clinical guidelines do not consider patients with rheumatic conditions to be at high risk for celiac disease (CD) despite numerous reported associations between the two in adults and children. The objective of this study was to evaluate the prevalence of CD among patients presenting for pediatric rheumatology evaluation. METHODS: A total of 2125 patients presenting for initial evaluation by the Division of Pediatric Rheumatology at the Hospital for Special Surgery between June 2006 and December 2013 were screened for CD as a part of the standard initial serologic evaluation. The charts of these patients were evaluated retrospectively at the end of this period. RESULTS: 36 patients (30 girls, 6 boys, mean age 9.4 ± 4.3 years, range 2–16 years) received a diagnosis of CD after serologic testing and evaluation by pediatric gastroenterology. Eight additional patients with known diagnoses of CD presented during this time period. The total prevalence of CD over this 6.5-year period was 2.0%. The most common presenting complaints among patients diagnosed with CD were myalgias, arthralgias, and rash. Less frequently, patients reported gastrointestinal complaints including abdominal pain, nausea, and diarrhea. All patients reported improvement or complete resolution of their musculoskeletal symptoms after initiation of a gluten-free diet. CONCLUSIONS: This study identified 36 new cases of CD among children presenting for rheumatology evaluation, for an overall prevalence rate of 2.0%. The majority of patients who ultimately received a diagnosis of CD presented with extraintestinal manifestations. These results underscore the importance of screening children presenting for rheumatology evaluation for CD.

A17: A Prospective Study Comparing Infectious Risks, Disease Activity, and Cytokine Alterations in Children with Juvenile Idiopathic Arthritis Treated with and without Tumor Necrosis Factor‐alpha Inhibitors

Tumor necrosis factor‐alpha (TNF‐α) inhibitors are effective in the treatment of juvenile idiopathic arthritis (JIA), but may increase infection rates due to immunosuppression. However, as JIA results from immune system dysfunction, high disease activity may also render patients vulnerable to infection.

Organ system-involvement in SLE and relationship with demographic factors, disease duration and health-related quality of life in childhood SLE

Organ system-involvement in SLE and relationship with demographic factors, disease duration and health-related quality of life in childhood SLE Lakshmi N Moorthy, Maria J Baratelli, Margaret GE Peterson, Afton L Hassett, Alexa B Adams, Laura V Barinstein, Emma J MacDermott, Elizabeth C Chalom, Karen Onel, Linda I Ray, Jorge Lopez-Benitez, Christina Pelajo, Kathleen A Haines, Daniel J Kingsbury, Victoria W Cartwright, Philip J Hashkes, Nora G Singer, Gina A Montealegres, Ingrid Tomanova-Soltys, Andreas O Reiff, Sandy D Hong, Thomas JA Lehman

Simple screening tool for assessing attention deficit in pediatric lupus

Sir, The neuropsychiatric manifestations of childhood-onset systemic lupus erythematosus (cSLE) range from mild cognitive difficulties to depression to psychosis. Neurocognitive dysfunction affects 30%–60% of cSLE patients, impacting the areas of intelligence, academic achievement, arithmetic, reading comprehension, learning, visual memory, and complex problem solving. The Pediatric Automated Neuropsychological Assessment Metrics (Ped-ANAM) is validated, but it can take up to 35–55 minutes to administer. The ACR has defined cognitive dysfunction in SLE as one of the 19 neuropsychiatric syndromes of SLE, and recommends a battery of standard tests, which are impractical for clinical use. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) Ad-Hoc Neurocognitive Lupus Committee proposed a series of neuropsychological tests for cSLE, but the battery is time consuming. Neuropsychological tests are also associated with increased cost of test administration, and difficulty in scoring and interpretation. Attention difficulties are under-diagnosed and under-studied, but constitute an important component of cognitive dysfunction, and can impair educational and social functioning, self-esteem, and quality of life. We used the Gordon Diagnostic System (GDS), a brief screening tool for attention deficit, in cSLE outpatients. The GDS is a gamelike assessment device that aids in the diagnosis of attention deficit, especially ADHD, by yielding data about an individual’s ability to focus and sustain attention over time. The GDS is brief, portable, easy to use, and can be administered by any trained individual, thus offering a clear advantage over other standardized tests. In this bi-institutional prospective pilot study, approved by respective Institutional Review Boards, we evaluated seven cSLE patients (six female, one male, mean age: 13.0 3.2 years; range: 9–18 years) using three nine-minute tasks on the GDS: delay, vigilance, and distractibility. The ‘‘delay’’ task, a simple test for younger children, asks users to wait an appropriate length of time before pressing a central button on the machine in order to receive a point. The ‘‘vigilance’’ task requires users to press a button when they see a particular sequence of numbers flash on the electronic display of the GDS. The ‘‘distractibility’’ task is a more complex version of the vigilance task, in which irrelevant digits flash on either side of the display that shows the target digits; users are again asked to press the button when they see a particular sequence of digits appear. The GDS records the time between responses, the number of correct responses, incorrect responses (commissions), and failures to answer (omissions), as appropriate. Health-related quality of life in cSLE was assessed with the Simple Measure of Impact of Lupus Erythematosus in Youngsters (SMILEY), a validated cSLE-specific scale (data not shown). The mean scores for cSLE patients consistently fell into the lowest quartile for all GDS measures for which normative data are available (Table 1). This is the first time to our knowledge that the GDS has been used in cSLE. These findings are limited by the small sample size, and future studies are needed. The GDS may allow clinicians to identify attention problems earlier, and offer appropriate referrals in a timely fashion.

Chapter 5 Systemic Lupus Erythematosus: Etiology, Pathogenesis, Clinical Manifestations, and Management

Publisher Summary This chapter discusses the etiology, clinical manifestations, genetics, and treatments of systemic lupus erythematosus (SLE). SLE is an autoimmune disease characterized by widespread inflammation and resultant end-organ damage. The etiology of SLE remains unknown. Although great strides are being made toward clarifying the immune dysregulation seen in SLE, clinical disease expression is the end-result of varied environmental and immunologic stimuli acting on a genetically predisposed individual. Abnormalities of T cells, B cells, dendritic cells, F cγ receptors, pro-inflammatory cytokines, the complement pathway, and apoptosis play a role in the pathogenesis of SLE. As with any chronic medical condition, the treatment of SLE in children is a particular challenge. Treatment of SLE is individually tailored to each patients clinical manifestations. Corticosteroids remain the first line of treatment for SLE. However, depending upon the extent and severity of internal organ involvement, medication regimens can range from low-dose corticosteroids and anti-malarials to inpatient treatment with pulse methylprednisolone and cytotoxic medications such as cyclophosphamide and rituximab.