Abstract
The intersection of granulomatosis and autoinflammatory disease is a rare occurrence that can be generally subdivided into purely granulomatous phenotypes and disease spectra that are ...inclusive of granulomatous features. NOD2 (nucleotide-binding oligomerization domain-containing protein 2)-related disease, which includes Blau syndrome and early-onset sarcoidosis, is the prototypic example of granulomatous inflammation in the context of monogenic autoinflammation. Granulomatous inflammation has also been observed in two related autoinflammatory diseases caused by mutations in PLCG2 (phospholipase Cγ2). More recently, mutations in LACC1 (laccase domain-containing protein 1) have been identified as the cause of a monogenic form of systemic juvenile idiopathic arthritis, which does not itself manifest granulomatous inflammation, but the same LACC1 mutations have also been shown to cause an early-onset, familial form of a well-known granulomatous condition, Crohn’s disease (CD). Rare genetic variants of PLCG2 have also been shown to cause a monogenic form of CD, and moreover common variants of all three of these genes have been implicated in polygenic forms of CD. Additionally, common variants of NOD2 and LACC1 have been implicated in susceptibility to leprosy, a granulomatous infection. Although no specific mechanistic link exists between these three genes, they form an intriguing web of susceptibility to both monogenic and polygenic autoinflammatory and granulomatous phenotypes.
Objective
To develop treatment recommendations for children with juvenile idiopathic arthritis manifesting as non‐systemic polyarthritis, sacroiliitis, or enthesitis.
Methods
The Patient/Population, ...Intervention, Comparison, and Outcomes (PICO) questions were developed and refined by members of the guideline development teams. A systematic review was conducted to compile evidence for the benefits and harms associated with treatments for these conditions. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of evidence. A group consensus process was conducted among the Voting Panel to generate the final recommendations and grade their strength. A Parent and Patient Panel used a similar consensus approach to provide patient/caregiver preferences for key questions.
Results
Thirty‐nine recommendations were developed (8 strong and 31 conditional). The quality of supporting evidence was very low or low for 90% of the recommendations. Recommendations are provided for the use of nonsteroidal antiinflammatory drugs, disease‐modifying antirheumatic drugs, biologics, and intraarticular and oral glucocorticoids. Recommendations for the use of physical and occupational therapy are also provided. Specific recommendations for polyarthritis address general medication use, initial and subsequent treatment, and adjunctive therapies. Good disease control, with therapeutic escalation to achieve low disease activity, was recommended. The sacroiliitis and enthesitis recommendations primarily address initial therapy and adjunctive therapies.
Conclusion
This guideline provides direction for clinicians, caregivers, and patients making treatment decisions. Clinicians, caregivers, and patients should use a shared decision‐making process that accounts for patients’ values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objective
To provide updated guidelines for pharmacologic management of juvenile idiopathic arthritis (JIA), focusing on treatment of oligoarthritis, temporomandibular joint (TMJ) arthritis, and ...systemic JIA with and without macrophage activation syndrome. Recommendations regarding tapering and discontinuing treatment in inactive systemic JIA are also provided.
Methods
We developed clinically relevant Patient/Population, Intervention, Comparison, and Outcomes questions. After conducting a systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the quality of evidence (high, moderate, low, or very low). A Voting Panel including clinicians and patients/caregivers achieved consensus on the direction (for or against) and strength (strong or conditional) of recommendations.
Results
Similar to those published in 2019, these JIA recommendations are based on clinical phenotypes of JIA, rather than a specific classification schema. This guideline provides recommendations for initial and subsequent treatment of JIA with oligoarthritis, TMJ arthritis, and systemic JIA as well as for tapering and discontinuing treatment in subjects with inactive systemic JIA. Other aspects of disease management, including factors that influence treatment choice and medication tapering, are discussed. Evidence for all recommendations was graded as low or very low in quality. For that reason, more than half of the recommendations are conditional.
Conclusion
This clinical practice guideline complements the 2019 American College of Rheumatology JIA and uveitis guidelines, which addressed polyarthritis, sacroiliitis, enthesitis, and uveitis. It serves as a tool to support clinicians, patients, and caregivers in decision‐making. The recommendations take into consideration the severity of both articular and nonarticular manifestations as well as patient quality of life. Although evidence is generally low quality and many recommendations are conditional, the inclusion of caregivers and patients in the decision‐making process strengthens the relevance and applicability of the guideline. It is important to remember that these are recommendations. Clinical decisions, as always, should be made by the treating clinician and patient/caregiver.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Elevation of serum IL-18 in adult-onset Still's disease (AOSD) and systemic JIA (sJIA) suggests the role of the inflammasome in these diseases. Gasdermin D is a pore-forming protein playing central ...roles in inflammasome-mediated inflammation, but its role in rheumatic disease is unknown. We aimed to elucidate the auto-inflammatory mechanisms in AOSD and sJIA.
Patients with AOSD, sJIA, hemophagocytic lymphohistiocytosis (HLH) and Behçet's disease followed at Yokohama City University (YCU), or US National Institutes of Health (NIH) were included in the study. Disease activity was evaluated by the modified Pouchot score. Ferritin and N-terminal gasdermin D levels in serum and culture supernatant were measured by ELISA. Primary monocytes (Mo) were stimulated with GM-CSF or M-CSF and differentiated into M1 macrophages (Mφ) or M2Mφ, respectively. The number of Mo/Mφ and their viability were monitored over time.
Patients with active AOSD and sJIA had increased levels of serum gasdermin D N-terminal, which correlated with serum ferritin and IL-18 levels. Mo-derived Mφ from active AOSD patients showed reduced cell viability and increased cell death. The number of cultured Mφ cells on day nine was negatively correlated with the serum ferritin and gasdermin D levels. Higher ferritin and gasdermin D levels were observed in the M1Mφ culture supernatant of active AOSD patients. Gasdermin D inhibitors reduced the pyroptosis-mediated ferritin release in Mo.
Elevation of serum gasdermin D N-terminal provides evidence for inflammasome activation triggering gasdermin D-mediated Mo and Mφ pyroptosis in AOSD and possibly sJIA.
Background
Fever of unknown origin (FUO) continues to challenge clinicians to determine an etiology and the need for treatment. This study explored the most common etiologies, characteristics, and ...average cost of hospitalization for FUO in a pediatric population at an urban, tertiary care hospital in Washington, DC.
Methods
Records from patients admitted to Children’s National Health System between September 2008 and April 2014 with an admission ICD-9 code for fever (780.6) were reviewed. The charts of patients 2–18 years of age with no underlying diagnosis and a temperature greater than 38.3 ºC for 7 days or more at time of hospitalization were included. Final diagnoses, features of admission, and total hospital charges were abstracted.
Results
110 patients qualified for this study. The majority of patients (
n
= 42, 38.2%) were discharged without a diagnosis. This was followed closely by infection, accounting for 37.2% (
n
= 41) of patients. Rheumatologic disease was next (
n
= 16, 14.5%), followed by miscellaneous (
n
= 6, 5.4%) and oncologic diagnoses (
n
= 5, 4.5%). The average cost of hospitalization was 40,295 US dollars.
Conclusions
This study aligns with some of the most recent publications which report undiagnosed cases as the most common outcome in patients hospitalized with FUO. Understanding that, often no diagnosis is found may reassure patients, families, and clinicians. The cost associated with hospitalization for FUO may cause clinicians to reconsider inpatient admission for diagnostic work-up of fever, particularly given the evidence demonstrating that many patients are discharged without a diagnosis.
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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
Why did child abuse become a less significant problem after 1910? This article focuses on frame contestation, and how child-protection organizations gradually lost control of the narrative about ...fragile families to a competing set of groups—those that emphasized “family saving.” Like many interest groups, the SPCCs developed an “issue frame” in their efforts to publicize their mission, which sought to define a problem (child abuse), attribute blame for that situation (inadequate parents), propose a solution (the removal of children from parents), and encourage others to support their cause. After 1900, however, “family saving” groups identified a problem related to child abuse (fragile families), portrayed poverty as a cause of family instability, and supported policies that sought to preserve families. While advocating for policies that strengthened families, however, they undercut child protectors’ most crucial weapon against child abuse, namely, the removal of affected children from inadequate parents.
MA is a rare, autosomal recessive disorder characterized by episodes of inflammation and periodic fevers. In its most severe form, it can result in facial dysmorphism, growth inhibition, ataxia, ...liver dysfunction, intellectual disability, and at times can be fatal. A number of case reports exist stating that SCT is curative in these patients. We present the case of a patient diagnosed with MA at birth, who underwent SCT at the age of 14 months with intent to cure. She achieved complete engraftment and urine mevalonate became undetectable. However, 18 months following transplant, she developed frequent episodes of fevers, rashes, arthritis, and a rising urinary mevalonate. She was subsequently diagnosed with relapse. She now requires treatment with steroids and canakinumab to manage her disease. This case is the first report of disease relapse following transplant for MA. It runs contrary to prior reports that SCT is fully curative of MA and suggests that transplant may instead provide a means of decreasing disease severity without entirely eradicating the condition.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
This study of the Baltimore anti-smoke movement illustrates how Americans altered their approach to environmental regulation during the Progressive Era. After citizen groups came to recognize the ...limits of common-law regulation, they became enamored with administrative regulation and the promise of rationalized, professional agencies. While Baltimore did mirror the national regulatory trends, the city's unique circumstances limited its capacity to reduce the sooty, black smoke that provoked episodes of public activism. Fearful about the city's economic future, regulators exempted manufacturing from the city's early anti-smoke measures. Furthermore, although railroads were major polluters, they balked at electrifying the bulk of their tracks. Finally, the anti-smoke movement was narrowly based in the northeastern, more affluent parts of the city and failed to expand its support to working-class whites and African Americans. Hence, while the ideas about what constituted appropriate regulation ”modernized” in Baltimore, the city did not alter its regulatory practices until the 1930s, long after other cities had done so: In the heart of a beautiful residence section of our city, there rises a towering factory structure in the most gruesome ugliness, belching volumes upon volumes of black and angry smoke, flooding our very houses with showers of soot... It is the sworn duty of our legislators to protect the citizens in all their rights, and it is to be hoped that the crying need of protection from this unbearable smoke nuisance will now be recognized.
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BFBNIB, INZLJ, NMLJ, NUK, PNG, UL, UM, UPUK, ZRSKP
Screening of the NCI diversity set of compounds has led to the identification of 5 (NSC-117199), which inhibits the protein tyrosine phosphatase (PTP) Shp2 with an IC50 of 47 μM. A focused library ...incorporating an isatin scaffold was designed and evaluated for inhibition of Shp2 and Shp1 PTP activities. Several compounds were identified that selectively inhibit Shp2 over Shp1 and PTP1B with low to submicromolar activity. A model for the binding of the active compounds is proposed.
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