Objective
There is wide variation in therapeutic approaches to systemic juvenile idiopathic arthritis (JIA) among North American rheumatologists. Understanding the comparative effectiveness of the ...diverse therapeutic options available for treatment of systemic JIA can result in better health outcomes. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans and standardized assessment schedules for use in clinical practice to facilitate such studies.
Methods
Case‐based surveys were administered to CARRA members to identify prevailing treatments for new‐onset systemic JIA. A 2‐day consensus conference in April 2010 employed modified nominal group technique to formulate preliminary treatment plans and determine important data elements for collection. Followup surveys were employed to refine the plans and assess clinical acceptability.
Results
The initial case‐based survey identified significant variability among current treatment approaches for new‐onset systemic JIA, underscoring the utility of standardized plans to evaluate comparative effectiveness. We developed 4 consensus treatment plans for the first 9 months of therapy, as well as case definitions and clinical and laboratory monitoring schedules. The 4 treatment regimens included glucocorticoids only, or therapy with methotrexate, anakinra, or tocilizumab, with or without glucocorticoids. This approach was approved by >78% of the CARRA membership.
Conclusion
Four standardized treatment plans were developed for new‐onset systemic JIA. Coupled with data collection at defined intervals, use of these treatment plans will create the opportunity to evaluate comparative effectiveness in an observational setting to optimize initial management of systemic JIA.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The United States pediatric rheumatology workforce is committed to a mission of providing children access to pediatric rheumatology care. With a limited number and distribution of pediatric ...rheumatologists, telemedicine has been proposed as one way to meet this mission, yet the adoption of this modality has been slower than expected. The purpose of this study was to explore the parent perspective on barriers to accessing pediatric rheumatology care and to explore the acceptability of telemedicine and other alternative care models.
Over a period of six weeks, all new and return English-speaking parents/guardians of patients visiting a single center were offered an opportunity to complete a survey which assessed barriers to care and interest in alternative models of care. Responses were analyzed using descriptive statistics.
Survey response rate was 72% (159/221). Twenty-eight percent (45/159) traveled more than three hours to the pediatric rheumatology clinic, and 43% (65/152) reported travel as inconvenient. An overwhelming majority of respondents (95%, 144/152) reported a preference for in-person visits over the option of telemedicine. This preference was similar regardless of whether respondents reported travel to the clinic as inconvenient vs convenient (inconvenient 92%, 60/65; convenient 97%, 84/87; p = 0.2881) and despite those reporting travel as inconvenient also reporting greater difficulty with several barriers to care. Those familiar with telemedicine were more likely to report a preference for telemedicine over in-person visits (27%, 3/11 vs 3%, 4/140; p = 0.0087). The option of an outreach clinic was acceptable to a majority (63%, 97/154); however, adult rheumatology and shared-care options were less acceptable (22%, 35/156 and 34%, 53/156 respectively).
Among survey respondents, in-person visits were preferred over the option of telemedicine, even when travel was noted to be inconvenient. Telemedicine familiarity increased its acceptability. Outreach clinics were acceptable to a majority. Ultimately, the parent perspective can shape acceptable ways to address barriers and provide accessible care.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
In this randomized, placebo-controlled trial of 133 children with polyarticular juvenile rheumatoid arthritis who had a response to a 16-week course of treatment with adalimumab, a monoclonal ...antibody to tumor necrosis factor, disease flares were less common when adalimumab was continued than when it was withdrawn. Fourteen patients had serious adverse events, including seven patients with serious infections.
In children with polyarticular juvenile rheumatoid arthritis who had a response to a 16-week course of treatment with adalimumab, a monoclonal antibody to tumor necrosis factor, disease flares were less common when adalimumab was continued than when it was withdrawn.
Juvenile rheumatoid arthritis is the most common rheumatic disease of childhood and is an important cause of disability among children.
1
Weekly methotrexate (oral or parenteral), at dosages of up to 15 mg per square meter of body-surface area per week for parenteral administration, has been established as an effective therapy in polyarticular juvenile rheumatoid arthritis.
2
,
3
During the past decade, the use of tumor necrosis factor (TNF) antagonists in adult rheumatoid arthritis has shifted the paradigm of care.
4
–
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More recently, TNF blockade has been shown to be an efficacious treatment option for polyarticular juvenile rheumatoid arthritis.
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Adalimumab (Humira, Abbott . . .
Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are ...well-established, yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here, we report a non-conventional, T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis. Reconstitution of lymphopenic hosts with Nod2
CD4
T cells or retina-specific autoreactive CD4
T cells lacking Nod2 reveals a T cell-autonomous, Rip2-independent mechanism for Nod2 in uveitis. In naive animals, Nod2 operates downstream of TCR ligation to suppress activation of memory CD4
T cells that associate with an autoreactive-like profile involving IL-17 and Ccr7. Interestingly, CD4
T cells from two Blau syndrome patients show elevated IL-17 and increased CCR7. Our data define Nod2 as a T cell-intrinsic rheostat of Th17 immunity, and open new avenues for T cell-based therapies for Nod2-associated disorders such as Blau syndrome.
Objective
There is no standardized approach to the initial treatment of polyarticular juvenile idiopathic arthritis (JIA) among pediatric rheumatologists. Understanding the comparative effectiveness ...of the diverse therapeutic options available will result in better health outcomes for polyarticular JIA. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) developed consensus treatment plans (CTPs) for use in clinical practice to facilitate such studies.
Methods
A case‐based survey was administered to CARRA members to identify the common treatment approaches for new‐onset polyarticular JIA. Two face‐to‐face consensus conferences employed modified nominal group technique to identify treatment strategies, operational case definition, end points, and data elements to be collected. A core workgroup reviewed the relevant literature, refined plans, and developed medication dosing and monitoring recommendations.
Results
The initial case‐based survey identified significant variability among treatment approaches for new‐onset polyarticular JIA. We developed 3 CTPs based on treatment strategies for the first 12 months of therapy, as well as case definitions and clinical and laboratory monitoring schedules. The CTPs include a step‐up plan (nonbiologic disease‐modifying antirheumatic drug DMARD followed by a biologic DMARD), an early combination plan (nonbiologic and biologic DMARD combined within a month of treatment initiation), and a biologic only plan. This approach was approved by 96% of the CARRA JIA Research Committee members attending the 2013 CARRA face‐to‐face meeting.
Conclusion
Three standardized CTPs were developed for new‐onset polyarticular JIA. Coupled with data collection at defined intervals, use of these CTPs will enable the study of their comparative effectiveness in an observational setting to optimize initial management of polyarticular JIA.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Weekly adalimumab dosing is used to treat juvenile idiopathic arthritis (JIA), uveitis, and other pediatric rheumatic diseases, but the safety of such dosing has not previously been studied. A ...retrospective chart review was conducted to assess the safety of weekly adalimumab. Demographic and clinical data were collected. Basic descriptive analysis was performed to assess for adverse events from weekly adalimumab. Sixty-nine patients at the University of Minnesota or Gillette Children’s Hospital were identified as treated with weekly adalimumab. Sixty (87%) were eligible for the chart review. Weekly adalimumab was used most commonly to treat uveitis (28%, 17/60) and rheumatoid factor-negative polyarticular JIA (25%, 15/60). Mean age at the start of weekly dosing was 13.9 years. The majority of patients were concurrently treated with a non-steroidal anti-inflammatory drug and methotrexate. Fifty-three (90%) patients continued weekly dosing for greater than 3 months. The mean duration of weekly adalimumab was 2 years. Throughout the duration of weekly dosing, 24/60 (40%) patients had documented minor infections not requiring antimicrobials and 24/60 (40%) had documented infections requiring antimicrobial treatment. Only three patients (5%) had an infection requiring hospitalization. Two patients (3%) developed autoimmune disease. Laboratory abnormalities and injection site reactions were rare. Weekly adalimumab was used most commonly to treat uveitis and rheumatoid factor-negative polyarticular JIA, and mean duration of weekly dosing was 2 years. Serious adverse events were rare.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Susac syndrome is an immune-mediated, ischemia-producing, occlusive microvascular endotheliopathy that threatens the brain, retina, and inner ear. There is a need for disease assessment tools that ...can help clinicians and patients to more easily, accurately, and uniformly track the clinical course and outcome of Susac syndrome. Ideally, such tools should simultaneously facilitate the clinical care and study of Susac syndrome and improve the value of future case reports. To meet this need, two novel clinical assessment tools were developed: the Susac Symptoms Form and the Susac Disease Damage Score. The former is a comprehensive self-report form that is completed by patients/families to serially document the clinical status of a patient. The latter documents the extent of damage perceived by individual patients/families and their physicians. Both forms were initially trialed with two particularly representative and instructive patients. The results of this trial are shared in this report.
Patient 1 is a 21-year-old Caucasian female who presented with an acute onset of headache, paresthesias, cognitive dysfunction, and emotional lability. Patient 2 is a 14-year-old Caucasian female who presented with an acute onset of headache, cognitive dysfunction, urinary incontinence, ataxia, and personality change. Both patients fulfilled criteria for a definite diagnosis of Susac syndrome: both eventually developed brain, retinal, and inner ear involvement, and both had typical "snowball lesions" on magnetic resonance imaging. The Susac Symptoms Form documented initial improvement in both patients, was sufficiently sensitive in detecting a subsequent relapse in the second patient, and succinctly documented the long-term clinical course in both patients. The Disease Damage Score documented minimal disease damage in the first patient and more significant damage in the second.
The Susac Symptoms Form and the Disease Damage Score are useful disease assessment tools, both for clinical care and research purposes. Their use could enhance the value of future case reports on Susac syndrome and could improve opportunities to learn from a series of such reports.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background Non-criteria antiphospholipid antibodies (NC-aPL) are a relatively undefined subgroup of antiphospholipid antibodies (aPL). Knowledge about NC-aPL in adults is limited and even less is ...known in pediatric patients. Routine tests for antiphospholipid syndrome (APS)--a clinical state marked by the presence of aPL in association with vascular thrombosis--usually include lupus anticoagulant (LAC), anti-cardiolipin (aCL) and -beta-2 glycoprotein I (abeta2GPI). LAC is a functional screen for prothrombotic aPL, while the latter tests identify specific autoantibodies. Specific targets of NC-aPL include, but are not limited to, phosphatidylethanolamine, phosphatidylserine, and prothrombin. Presentation of cases We present single-center data from eight pediatric patients with NC-aPL identified during a three-year period. All patients had presenting features raising suspicion for APS. Most patients were female with a primary rheumatic disease. One patient had a stroke. Another patient had alveolar hemorrhage and pulmonary hypertension. Raynaud's phenomenon, rashes involving distal extremities, and headaches were common. Most patients had a positive LAC, yet their routine aPL tests were negative, prompting testing for NC-aPL. Conclusions Our findings suggest NC-aPL are associated with typical signs and symptoms of APS in pediatric patients. Pediatricians and pediatric subspecialists should consider NC-aPL when clinical suspicion is high and routine aPL tests are negative, particularly when LAC is positive. While guidelines for NC-aPL do not yet exist for children or adults, these autoantibodies have pathogenic potential. Actionable items could include evaluation for the presence of other (primary) rheumatic diseases, and consultation with hematologists and/or obstetricians regarding anticoagulation/platelet inhibition and thrombosis education. Future guidelines regarding NC-aPL will only be generated by gathering more data, ideally prospectively. Keywords: Non-criteria antiphospholipid antibodies, Antiphospholipid syndrome, Rheumatic disease, Lupus anticoagulant
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and a leading cause of childhood disability. The objective of this study was to characterize the PK, safety, and ...taste acceptability of tofacitinib in patients with JIA.
This Phase 1, open-label, multiple-dose (twice daily BID for 5 days) study of tofacitinib in patients with active (≥ 5 joints) polyarticular course JIA was conducted from March 2013-December 2015. Patients were allocated to one of three age-based cohorts: Cohort 1, 12 to < 18 years; Cohort 2, 6 to < 12 years; and Cohort 3, 2 to < 6 years. Tofacitinib was administered according to age and body weight as tablets or oral solution (grape flavor). PK were assessed on Day 5; safety was assessed at screening, Day 1, and Day 5. Taste acceptability of the oral solution was evaluated.
Twenty-six patients (age range 2-17 years) were enrolled: Cohort 1, N = 8; Cohort 2, N = 9; Cohort 3, N = 9; median tofacitinib doses were 5.0, 2.5, and 3.0 mg BID, respectively. The higher median tofacitinib dose in Cohort 3 versus Cohort 2 reflected implementation of an amended dosing scheme following an interim PK analysis after Cohort 2 recruitment. Geometric mean AUC at steady state (AUC
) was 156.6 ng•h/mL in Cohort 1, 118.8 ng•h/mL in Cohort 2, and 142.5 ng•h/mL in Cohort 3; C
(ng/mL) was 47.0, 41.7, and 66.2, respectively. C
, C
, and t
were similar in Cohorts 2 and 3, but higher in Cohort 1. Median time to C
(T
) was similar between cohorts. Apparent clearance and volume of distribution decreased with decreasing age. Tofacitinib was well tolerated, with no serious adverse events or discontinuations due to adverse events reported. Taste acceptability was confirmed.
PK findings from this study in children with polyarticular course JIA established dosing regimens and acceptable taste for use in subsequent studies within the tofacitinib pediatric development program.
ClinicalTrials.gov: NCT01513902 .
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Juvenile dermatomyositis (JDM) is the most common form of idiopathic inflammatory myopathy in children. While outcomes are generally thought to be good, persistence of skin rash is a common problem. ...The goal of this study was to describe the development of clinical treatment plans (CTP) for children with JDM characterized by persistent skin rash despite complete resolution of muscle involvement.
The Childhood Arthritis and Rheumatology Research Alliance, a North American consortium of pediatric rheumatologists and other healthcare providers, used a combination of Delphi surveys and nominal group consensus meetings to develop CTP that reflected consensus on typical treatments for patients with JDM with persistent skin rash.
Consensus was reached on patient characteristics and outcome assessment. Patients should have previously received corticosteroids and methotrexate (MTX). Three consensus treatment plans were developed. Plan A added intravenous immunoglobulin (IVIG) if it was not already being used. Plan B added mycophenolate mofetil, while Plan C added cyclosporine. Continuation of previous treatments, including corticosteroids, MTX, and IVIG, was permitted in plans B and C.
Three consensus CTP were developed for use in children with JDM and persistent skin rash despite complete resolution of muscle disease. These CTP reflect typical treatment approaches and are not to be considered treatment recommendations or standard of care. Using prospective data collection and statistical methods to account for nonrandom treatment assignment, it is expected that these CTP will be used to allow treatment comparisons, and ultimately determine the best treatment for these patients.
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