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Objective: Rheumatologic disease-associated hemophagocytic lymphohistiocytosis (HLH), a rare, life-threatening, systemic hyperinflammatory syndrome, occurs as a complication of underlying rheumatologic disease. Real-world evidence is lacking on emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon-γ, approved for treating patients with primary HLH., Methods: REAL-HLH, a retrospective medical chart review study conducted across 33 US hospitals, assessed real-world treatment patterns and outcomes in patients with HLH treated with one or more dose of emapalumab between November 20, 2018, and October 31, 2021. Data are presented for the subset of patients with rheumatologic disease-associated HLH., Results: Fifteen of 105 patients (14.3%) had rheumatologic disease-associated HLH. Of these, nine (60.0%) had systemic juvenile idiopathic arthritis, and one (6.7%) had adult-onset Still disease. Median (range) age at HLH diagnosis was 5 (0.9-39) years. Most patients (9 of 15; 60.0%) initiated emapalumab in an intensive care unit. Emapalumab was most frequently initiated for treating refractory or recurrent (10 of 15; 66.7%) disease. Most patients received HLH-related therapies before (10 of 15; 66.7%) and concurrently with (15 of 15; 100.0%) emapalumab. Emapalumab-containing regimens stabilized or achieved physician-determined normalization of most laboratory parameters, including absolute neutrophil count and absolute lymphocyte count (13 of 14; 92.9%), chemokine ligand 9 (9 of 11; 81.8%), and platelets and alanine transaminase (11 of 14; 78.6%), and reduced glucocorticoid dose by 80%. Overall survival and 12-month survival probability from emapalumab initiation were 86.7%., Conclusion: Emapalumab-containing regimens stabilized or normalized most key laboratory parameters, reduced glucocorticoid dose, and were associated with low disease-related mortality, thereby demonstrating potential benefits in patients with rheumatologic disease-associated HLH., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objective: Systemic juvenile idiopathic arthritis-associated lung disease (SJIA-LD) is a life-threatening disease complication. Key questions remain regarding clinical course and optimal treatment approaches. The objectives of the study were to detail management strategies after SJIA-LD detection, characterize overall disease courses, and measure long-term outcomes., Methods: This was a prospective cohort study. Clinical data were abstracted from the electronic medical record, including current clinical status and changes since diagnosis. Serum biomarkers were determined and correlated with presence of LD., Results: We enrolled 41 patients with SJIA-LD, 85% with at least one episode of macrophage activation syndrome and 41% with adverse reactions to a biologic. Although 93% of patients were alive at last follow-up (median 2.9 years), 37% progressed to requiring chronic oxygen or other ventilator support, and 65% of patients had abnormal overnight oximetry studies, which changed over time. Eighty-four percent of patients carried the HLA-DRB1*15 haplotype, significantly more than patients without LD. Patients with SJIA-LD also showed markedly elevated serum interleukin-18 (IL-18), variable C-X-C motif chemokine ligand 9 (CXCL9), and significantly elevated matrix metalloproteinase 7. Treatment strategies showed variable use of anti-IL-1/6 biologics and addition of other immunomodulatory treatments and lung-directed therapies. We found a broad range of current clinical status independent of time from diagnosis or continued biologic treatment. Multidomain measures of change showed imaging features were the least likely to improve with time., Conclusion: Patients with SJIA-LD had highly varied courses, with lower mortality than previously reported but frequent hypoxia and requirement for respiratory support. Treatment strategies were highly varied, highlighting an urgent need for focused clinical trials., (© 2023 American College of Rheumatology.)

Objective: To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA)., Methods: In a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data., Results: LD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features., Conclusions: A rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed., Competing Interests: Competing interests: VES reports personal fees from Novartis. GD reports personal fees from Novartis. SC reports personal fees from Novartis and grants from AB2 Bio. GS reports personal fees from Novartis. KB reports personal fees from Novartis. RQC is co-PI of an investigator-initiated clinical trial funded by SOBI. RD reports personal fees from Boehringer Ingelheim, other from NowVitals, personal fees and other from Triple Endoscopy, other from Earables, and NowVitals with patents and lung-related device development. AAG reports grants and personal fees from Novartis and grants from NovImmune. SL reports personal fees from Novartis. RS reports personal fees from Novartis, NovImmune and SOBI. SS reports personal fees from Novartis. MLS reports personal fees from Novartis. LRY reports other from Up-To-Date and other from Boehringer Ingelheim, outside the submitted work. EDM reports grants from Novartis., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

1. Tobacco smokers are well aware of the long term hazards of tobacco smoking, yet they continue to smoke. Presumably people smoke because of short term gains due to nicotine. 2. The mechanism by which nicotine is a drug reinforcer still needs a great deal of study. The specific aim of the present study was to determine the effects of tobacco smoking on the topographic EEG of 12 hr deprived heavy tobacco smokers. 3. Seven normal adult tobacco smokers of mixed sex were recruited into the study and compared with six normal nonsmokers of similar age and sex. 4. A Grass Model 8-24D EEG and 16 different scalp monopolar electrodes were used to record the EEG using both ears as reference before and after smoking. EKG lead II was recorded on channel 17. Blood pressure was measured by auscultation. Exhaled CO was measured using a CO detector. Computer analysis of the EEG data was run of line on a Zenith 386/25 microcomputer using RHYTHM 7.1. The same system was used to store the EEG in digitized form. The maximum number of 4 sec artifact free epochs in a 3 min recording period with eyes open and then closed was used before and after low and high nicotine tobacco or sham smoking. 5. The hypothesis of this research was confirmed, i.e., that tobacco smoking of high nicotine cigarettes (about 2.0 mg/cigarette) would cause a shift in EEG alpha rhythm to higher frequencies in more diffuse midline cortical structures. In other studies an increase in alpha rhythm has been correlated with an awake relaxed behavioral state. 6. A heart rate increase was a more sensitive index of tobacco smoking than an increase in arterial blood pressure. Exhaled smoking CO levels correlated with the nicotine and tar content of the cigarette.

The effects of estradiol (E2) and its 2- and 4-hydroxylated metabolites on gonadotrophin regulation in the female rat brain were examined. Neonatal female rats were injected from day 1 through 5 with E2, 2-OHE2 and 4-OHE2, at doses of 0.1, 1 and 10 micrograms/day. At 2, 6 and 24 h after the last estrogen injection, some animals from each treatment group were killed and the concentration of estrogen receptors (ERn) in their brain cell nuclei determined. The remaining animals were allowed to mature. Their vaginal smear patterns were examined from 7 to 9 and from 15 to 17 weeks of age. They were then ovariectomized and tested for their capacity to exhibit a luteinizing hormone (LH) surge in response to estrogen and progesterone injections. In a parallel series of experiments, the affinities of the three test estrogens for alpha-fetoprotein (AFP) were determined from in vitro competition studies with fetal rat serum. All three estrogens increased brain cell nuclear ERn concentrations, measured at 2 h after the final injection. E2 was more potent in this respect than either 4-OHE2 or 2-OHE2. E2 and 4-OHE2 competed for binding to AFP to an approximately equal extent. 2-OHE2, however, was a much weaker competitor for AFP than either of the other two compounds. The neonatal E2 and 4-OHE2 treatments reduced the number of animals showing regular cyclic vaginal smears, at all three doses tested. In contrast, 2-OHE2 significantly affected vaginal cyclicity only at a dose of 10 micrograms/day.(ABSTRACT TRUNCATED AT 250 WORDS)