Adverse cardiovascular events in rheumatoid arthritis patients treated with JAK inhibitors: An analysis of postmarketing spontaneous safety reports.

OBJECTIVES: The ORAL Surveillance trial, a postmarketing safety clinical trial, found an increased risk of adverse cardiovascular events and venous thromboembolism (VTE) in patients treated with Janus Kinase (JAK) inhibitors compared to tumor necrosis factor (TNF) inhibitors. However, additional studies yielded mixed results and data on other JAK inhibitors are limited. METHODS: A retrospective, pharmacovigilance study using the FDA adverse event reporting system (FAERS) to assess reporting of adverse cardiovascular events following treatment with JAK inhibitors in rheumatoid arthritis (RA) patients between January 2015 and June 2023. To identify disproportionately increased reporting, an adjusted reporting odds ratio (adj.ROR) was calculated with a multivariable logistic regression model. RESULTS: We identified safety reports of 75,407 RA patients treated with JAK inhibitors (tofacitinib, n = 52,181; upadacitinib, n = 21,006; baricitinib, n = 2,220) and 303,278 patients treated with biologic disease-modifying antirheumatic drugs (bDMARDs; TNF inhibitors, rituximab, and tocilizumab). The mean age was 61.2(±12) and 59.0(±13), respectively; 82 % and 81 % were women. Compared to bDMARDs, JAK inhibitors were associated with an increased reporting of VTE [n = 1,393, adj.ROR=2.11 (1.97-2.25)], stroke [n = 973, adj.ROR=1.25 (1.16-1.34)], ischemic heart disease [IHD, n = 999, adj.ROR=1.23 (1.13-1.33)], peripheral edema [n = 2699, adj.ROR=1.22 (1.17-1.28)], and tachyarrhythmias [n = 370, adj.ROR=1.15 (1.00-1.33)]. Most of the events occurred in the first year after treatment initiation. When different JAK inhibitors were compared, VTE, stroke, and IHD were more frequently reported with upadacitinib and baricitinib than tofacitinib. When stratified by age category, all safety signals were statistically significant in patients aged≤65 years. CONCLUSION: In this global postmarketing study, JAK inhibitors are associated with increased reporting of VTE, stroke, IHD, and tachyarrhythmias. These adverse events were reported following all JAK inhibitors that were studied, suggesting a class effect.

The real-world safety profile of sodium-glucose co-transporter-2 inhibitors among older adults (≥ 75 years): a retrospective, pharmacovigilance study.

BACKGROUND: As indications for sodium-glucose co-transporter-2 inhibitors (SGLT2i) are expanding, a growing number of older adults have become candidates for treatment. We studied the safety profile of SGLT2i among older adults. METHODS: A retrospective, pharmacovigilance study of the FDA's global database of safety reports. To assess reporting of pre-specified adverse events following SGLT2i among adults (< 75 years) and older adults (≥ 75), we performed a disproportionality analysis using the sex-adjusted reporting odds ratio (adj.ROR). RESULTS: We identified safety reports of 129,795 patients who received non-insulin anti-diabetic drugs (NIAD), including 24,253 who were treated with SGLT2i (median age 60 [IQR: 51-68] years, 2,339 [9.6%] aged ≥ 75 years). Compared to other NIAD, SGLT2i were significantly associated with amputations (adj.ROR = 355.1 [95%CI: 258.8 - 487.3] vs adj.ROR = 250.2 [79.3 - 789.5]), Fournier gangrene (adj.ROR = 45.0 [34.5 - 58.8] vs adj.ROR = 88.0 [27.0 - 286.6]), diabetic ketoacidosis (adj.ROR = 32.3 [30.0 - 34.8] vs adj.ROR = 23.3 [19.2 - 28.3]), genitourinary infections (adj.ROR = 10.3 [9.4 - 11.2] vs adj.ROR = 8.6 [7.2 - 10.3]), nocturia (adj.ROR = 5.5 [3.7 - 8.2] vs adj.ROR = 6.7 [2.8 - 15.7]), dehydration (adj.ROR = 2.5 [2.3 - 2.8] vs adj.ROR = 2.6 [2.1 - 3.3]), and fractures (adj.ROR = 1.7 [1.4 - 2.1] vs adj.ROR = 1.5 [1.02 - 2.1]) in both adults and older adults, respectively. None of these safety signals was significantly greater in older adults (Pinteraction threshold of 0.05). Acute kidney injury was associated with SGLT2i in adults (adj.ROR = 1.97 [1.85 - 2.09]) but not in older adults (adj.ROR = 0.71 [0.59 - 0.84]). Falls, hypotension, and syncope were not associated with SGLT2i among either adults or older adults. CONCLUSION: In this global post-marketing study, none of the adverse events was reported more frequently among older adults. Our findings provide reassurance regarding SGLT2i treatment in older adults, although careful monitoring is warranted.

Screening for Fabry's disease in a high-risk subpopulation of FMF.

BACKGROUND: Familial Mediterranean fever (FMF) is an autosomal recessive disease associated with mutations in the Mediterranean fever gene (MEFV) that manifests with recurrent episodes of febrile serositis. Fabry's disease (FD) is an X-linked lysosomal storage disease caused by mutations in the alpha-galactosidase A gene and presents with a wide range of gastrointestinal, skin, vascular, renal and neurological manifestations. FMF and FD share similar manifestations, which may lead to misdiagnosis of one as the other; mostly FD is misdiagnosed as FMF. Moreover, various overlapping manifestations may stem from comorbidities, commonly coupled to FMF (such as Behcet's disease, inflammatory bowel disease, glomerulonephritis, fibromyalgia, and multiple sclerosis), as well as from colchicine adverse effects, which may add to the diagnostic confusion. Thus, we postulated that screening FMF for FD will lead to the identification of patients falsely diagnosed with FMF or who, in addition to FMF, suffer from FD that was previously missed. METHODS: To identify missed FD among the FMF population, we performed chemical and genetic analyses for FD in blood samples obtained from a cohort of FMF patients followed in the specialized FMF center of our institution. To increase the likelihood of detecting patients with FD, we enriched the surveyed FMF population with patients exhibiting manifestations shared by patients with FD or who deviate from the typical FMF presentation. RESULTS AND CONCLUSIONS: Of 172 surveyed FMF patients in a cohort derived from a clinic dedicated to FMF, none had FD. Thus, the postulation of increased odds for detecting FD in patients with FMF was not confirmed. Further exploration for FD in FMF population, is nevertheless recommended.

Determining the origin of different variants associated with familial mediterranean fever by machine-learning.

A growing number of familial Mediterranean fever (FMF) patients in Israel do not have a single country of origin for all four grandparents. We aimed to predict the Mediterranean fever gene (MEFV) variant most likely to be found for an individual FMF patient, by a machine learning approach. This study was conducted at the Sheba Medical Center, a referral center for FMF in Israel. All Jewish referrals included in this study carried an FMF associated variant in MEFV as shown by genetic testing performed between 2001 and 2017. We introduced the term 'origin score' to capture the dose and different combinations of the grandparents' origin. A machine learning approach was used to analyze the data. In a total of 1781 referrals included in this study, the p.Met694Val variant was the most common, and the variants p.Glu148Gln and p.Val726Ala second and third most common, respectively. Of 26 countries of origin analyzed, those that increased the likelihood of a referral to carry specific variants were identified in North Africa for p.Met694Val, Europe for p.Val726Ala, and west Asia for p.Glu148Gln. Fourteen of the studied countries did not show a highly probable variant. Based on our results, it is possible to describe an association between modern day origins of the three most common MEFV variant types and a geographical region. A strong geographic association could arise from positive selection of a specific MEFV variant conferring resistance to endemic infectious agents.

CHA2DS2-VASC Score Predicts the Risk of Stroke in Patients Hospitalized to the Internal Medicine Department Without Known Atrial Fibrillation.

BACKGROUND: The CHA2DS2-VASC score is used to assess the risk of cerebrovascular accident (CVA) in patients with atrial fibrillation (AF) or atrial flutter (AFL). OBJECTIVES: We aimed to determine whether this score can determine the risk of CVA during the first year after hospitalization, in patients without known AF/AFL. DESIGN: Single-center retrospective cohort. PATIENTS: We included all patients aged ≥ 50 who were hospitalized between January 1, 2008, and December 31, 2018, to the internal medicine departments at the Chaim Sheba Medical Center, Israel. Exclusion criteria included history or new diagnosis of CVA, TIA, and AF/AFL and use of anticoagulation at any time. MAIN MEASURES: Patients were stratified into 3 groups according to their CHA2DS2-VASC score (0-1, 2, or ≥ 3). The primary outcome was hospitalization with CVA/TIA within one year of the index hospitalization. KEY RESULTS: Of the patients, 52,206 were included in the study. CVA/TIA occurred in 0.7%, 1.3%, and 1.7% of patients with a CHA2DS2-VASC score of 0-1, 2, and ≥ 3, respectively. Compared to a CHA2DS2-VASC score of 0-1, the HR for CVA/TIA occurrence for CHA2DS2-VASC scores of 2 and ≥ 3 was 1.77 (CI 1.42, 2.22) and 2.33 (CI 1.9, 2.85), respectively (p < 0.001 for both comparisons). Each additional CHA2DS2-VASC point increased the probability for readmission with CVA/TIA within 1-year by 26% (HR 1.26, CI 1.19, 1.32, p < 0.001). Similar trends were seen in subgroup analyses by gender, age, and renal function. CONCLUSIONS: The CHA2DS2-VASC score is a predictor for CVA/TIA during the first year after hospitalization in patients without AF. High CHA2DS2-VASC scores warrant work-up for occult AF/AFL and other risk factors for CVA/TIA.

Physiological Effects of Wearing N95 Respirator on Medical Staff During Prolong Work Hours in Covid-19 Departments.

OBJECTIVE: The objective of the current study was to determine gas exchange abnormalities and physiological changes among healthcare workers during a 4-hour emergency department (ED) shift while wearing the N95 respirator. METHODS: Single-center prospective observational study. Comparisons of paired measurements were performed using a non-parametric Wilcoxon matched-pairs signed-rank test. Results: Forty-one subjects were included. Prolonged N95 respirator use was associated with a significant decline in plasma pH (7.35 mmHg vs 7.34 mmHg, P = 0.02), PvO 2 (23.2 mmHg vs 18.6 mmHg, P < 0.001) and a concurrent increase in EtCO 2 (32.5 mmHg vs 38.5 mmHg, P < 0.0001). PvCO 2 and bicarbonate levels did not differ. No significant change was observed for heart rate or oxygen saturation. CONCLUSION: Using an N95 respirator for prolonged periods by healthcare professionals may provoke changes in gas exchange. The clinical significance of these changes remains to be determined.

The Preferential Use of Anakinra in Various Settings of FMF: A Review Applied to an Updated Treatment-Related Perspective of the Disease.

Familial Mediterranean fever (FMF), the most frequent monogenic autoinflammatory disease, is manifested with recurrent and chronic inflammation and amyloid A (AA) amyloidosis, driven by overproduction of interleukin 1 (IL-1) through an activated pyrin inflammasome. Consequently, non-responsiveness to colchicine, the cornerstone of FMF treatment, is nowadays addressed by IL-1- blockers. Each of the two IL-1 blockers currently used in FMF, anakinra and canakinumab, has its own merits for FMF care. Here we focus on anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist, and explore the literature by using PubMed regarding the utility of anakinra in certain conditions of FMF. Occasionally we enrich published data with our own experience. To facilitate insights to anakinra role, the paper briefs some clinical, genetic, pathogenetic, and management aspects of FMF. The clinical settings of FMF covered in this review include colchicine resistance, AA amyloidosis, renal transplantation, protracted febrile myalgia, on- demand use, leg pain, arthritis, temporary suspension of colchicine, pediatric patients, and pregnancy and lactation. In many of these instances, either because of safety concerns or a necessity for only transient and short-term use, anakinra, due to its short half-life, is the preferred IL-1 blocker.

Safety of the BNT162b2 mRNA COVID-19 vaccine in patients with familial Mediterranean fever.

OBJECTIVES: Evidence suggests a possible association between the COVID-19 vaccine and autoimmune disease flares or new onset of various autoinflammatory manifestations, such as pericarditis and myocarditis. The objective of this study was to assess the safety of an mRNA-based BNT162b2 anti-COVID-19 vaccine in individuals with FMF, a prototypic autoinflammatory disease. METHODS: Patients participating in this study fulfilled the criteria for diagnosis of FMF, were older than 18 years and received at least one dose of the vaccine. Data on baseline characteristics, features of FMF, post-vaccination side effects, and disease flares were acquired using electronic medical files and telephone interviews. RESULTS: A total of 273 FMF patients were recruited for the study. >95% were vaccinated with two doses of the vaccine. The rates of local reactions following the first and second vaccine doses were 65.5% and 60%, respectively, and 26% and 50.4%, respectively, for systemic adverse events. These rates are lower than those reported for the general population from real-world and clinical trial settings. Postvaccination FMF activity remained stable in most patients. None of the patients reported an attack of pericarditis or myocarditis, considered the most serious vaccine-associated adverse events. Patients with a more active FMF disease and patients harboring the M694V mutation had a significantly higher rate of post-vaccination systemic side effects and attacks. CONCLUSION: The BNT162b2 mRNA COVID-19 vaccine is safe in patients with FMF. Our results support the administration of this vaccine to FMF patients according to guidelines applicable to the general population.

Clinical and prognostic significance of elevated ferritin levels in hospitalised adults.

PURPOSE OF THE STUDY: Elevated ferritin levels are associated with a variety of infectious, malignant and inflammatory diseases. We aimed to investigate the prognostic value of markedly elevated ferritin levels in hospitalised patients with various medical conditions. STUDY DESIGN: Retrospective analysis of patients with a ferritin level higher than 2000 ng/mL hospitalised in Sheba Medical Center between 1 January 2007 and 31 December 2015. Medical conditions of these patients were recorded. In-hospital, 30-day and 1-year mortality rates were evaluated according to ferritin ranges and clinical categories. RESULTS: The study included 722 patients (63.4% men) with a mean age of 63.9±16.7 years. The most common clinical conditions associated with markedly elevated ferritin were infectious diseases and malignancies. The highest mean ferritin levels were associated with rheumatological/inflammatory conditions (16 241.3 ng/dL), particularly in patients with macrophage activation syndrome (MAS) (96 615.5 ng/dL). In-hospital, 30-day and 1-year mortality rates were 32.3%, 46.7% and 70.8%, respectively. The highest in-hospital, 30-day and 1-year mortality rates were observed among patients with solid malignancies (40.1%, 64.7% and 90.3%, respectively), whereas the lowest rates were found among patients with rheumatological/inflammatory conditions, including MAS (21.4%, 38.1% and 45.2%, respectively). Ferritin levels were not associated with mortality. CONCLUSIONS: In hospitalised patients, ferritin levels higher than 2000 ng/mL are mainly associated with infectious and malignant diseases but do not predict mortality.

Hyperglycaemic disorders associated with PCSK9 inhibitors: a real-world, pharmacovigilance study.

AIMS: While genetic and biological studies indicated a potential association between proprotein-convertase subtilisin/kexin type 9 inhibitors (PCSK9i) and hyperglycaemia, real-world data are limited. Therefore, we sought to investigate this association using the FDA adverse event reporting system (FAERS). METHODS AND RESULTS: The FAERS database (2015-2020) was retrospectively queried to characterize reporting of hyperglycaemic adverse events (AEs) with PCSK9i. Disproportionality analyses were performed using the adjusted reporting odds ratio (adj.ROR), and the lower bound of the information component (IC) 95% credibility interval (IC025 > 0 is deemed significant). Among 7 295 624 eligible patients, 71 748 reports of evolocumab and 15 976 of alirocumab were identified. Compared to the full database, PCSK9i treatment was associated with increased reporting of hyperglycaemic AEs [n = 1841, adj.ROR = 1.14 (1.07-1.22), IC025 = 0.13]. Hyperglycaemic AEs were primarily mild hyperglycaemia [n = 1469, adj. ROR = 1.48 (1.36-1.62), IC025 = 0.51] rather than diabetes [n = 372, adj. ROR = 0.67 (0.60-0.74), IC025 = -0.90]. Among PCSK9i agents, evolocumab, but not alirocumab, was associated with hyperglycaemic AEs [n = 1587, adj. ROR = 1.24 (1.15-1.32), IC025 = 0.20; n = 254, adj. ROR = 0.73 (0.60-0.88), IC025 = -0.38, respectively]. Hyperglycaemic AEs were reported more often with PCSK9i compared to ezetimibe [adj.ROR = 1.99 (1.35-2.94)], and less often compared to statins [adj.ROR = 0.26 (0.25-0.28)]. Notably, hyperglycaemic AEs were reported more frequently by diabetic than by non-diabetic patients (P < 0.001), mostly occurred within 6 months of treatment and were reversible upon drug discontinuation. CONCLUSION: In a real-world setting, PCSK9i treatment was associated with increased reporting of mild hyperglycaemia, but not diabetes. While initial monitoring is warranted, the favourable glycaemic safety profile compared to statins supports their essential role in the management of lipid disorders.

Lasing in 15 atm CO2 cell optically pumped by a Fe:ZnSe laser.

10 µm lasing is studied in a compact CO2-He cell pressurized up to 15 atm when optically pumped by a ∼50 mJ Fe:ZnSe laser tunable around 4.3 µm. The optimal pump wavelength and partial pressure of CO2 for generating 10 µm pulses are found to be ∼4.4 µm and 0.75 atm, respectively. Without cavity optimization, the optical-to-optical conversion efficiency reached ∼10% at a total pressure of 7 atm. The gain lifetime is measured to be ∼1 µs at pressures above 10 atm, indicating the feasibility of using high-pressure optically pumped CO2 for the efficient amplification of picosecond 10 µm pulses.

Automated processing of thermal imaging to detect COVID-19.

Rapid and sensitive screening tools for SARS-CoV-2 infection are essential to limit the spread of COVID-19 and to properly allocate national resources. Here, we developed a new point-of-care, non-contact thermal imaging tool to detect COVID-19, based on advanced image processing algorithms. We captured thermal images of the backs of individuals with and without COVID-19 using a portable thermal camera that connects directly to smartphones. Our novel image processing algorithms automatically extracted multiple texture and shape features of the thermal images and achieved an area under the curve (AUC) of 0.85 in COVID-19 detection with up to 92% sensitivity. Thermal imaging scores were inversely correlated with clinical variables associated with COVID-19 disease progression. In summary, we show, for the first time, that a hand-held thermal imaging device can be used to detect COVID-19. Non-invasive thermal imaging could be used to screen for COVID-19 in out-of-hospital settings, especially in low-income regions with limited imaging resources.

Effect of interleukin-1 inhibition in a cohort of patients with colchicine-resistant familial Mediterranean fever treated consecutively with anakinra and canakinumab.

OBJECTIVES: To evaluate the efficacy of IL-1 blockers in a cohort of patients with colchicine-resistant familial Mediterranean fever (crFMF) treated consecutively with anakinra and canakinumab. METHODS: Patients with crFMF treated with anakinra and canakinumab in any order were identified using the computerised database of Sheba Medical Centre. Background characteristics of the patients, reason for switching IL-1 inhibitor, and frequency of attacks under colchicine only, anakinra, and canakinumab were extracted from the computerised patient files. Patients were then interviewed for patient-reported outcomes. RESULTS: A total of 46 patients in our clinic were prescribed canakinumab for crFMF after previous anakinra treatment, whereas no patients who switched treatment from canakinumab to anakinra were identified. Of those, 23/46 patients (50%) discontinued anakinra due to inadequate response (11 of them with secondary failure after a good initial response). Frequency of flares was significantly decreased following switch to canakinumab from anakinra treatment (p<0.01). After the switch to canakinumab, the median duration of flares, the severity of pain during a flare, and the patient's global assessment of disease activity were all significantly decreased (p≤0.01), according to the reports from the patients. CONCLUSIONS: Canakinumab is an effective treatment for FMF after failure of anakinra due to any cause.

Familial Mediterranean fever (FMF)-response to TNF-blockers used for treatment of FMF patients with concurrent inflammatory diseases.

OBJECTIVE: Familial Mediterranean fever (FMF) is the most common interleukin 1 (IL-1)-driven monogenic autoinflammatory disease. Yet published data also suggest that tumor necrosis factor (TNF) may have a role in the pathogenesis of FMF and may serve as a target for treatment. In the present study we evaluate this hypothesis. METHODS: To this goal, we studied the incidental effect on FMF of TNF-directed treatment, administered to colchicine-refractory FMF patients for the management of a concurrent inflammatory disease. The rates of FMF patients and of treatments with complete or nearly complete FMF response were determined, based on the number of FMF attacks during TNF-blocker exposures. The possible effect of various FMF and non-FMF features on the outcome was determined using comparative analysis. Patients were identified and data were retrieved using electronic files from the FMF clinic. RESULTS: Twenty-six patients were identified, each receiving ≥1 of four TNF-blockers for a mean duration of 27.6±16.4months. The TNF-blockers were found to induce complete or nearly complete FMF response in 10 (38.5%) of the patients, and in 13 of 50 (26%) exposures. No clinical, genetic, demographic, or therapeutic feature could predict which FMF patient would respond favorably to TNF-blocker therapy. CONCLUSION: This study suggests that TNF-blockers may be beneficial for a small proportion of colchicine-resistant FMF patients.

Amyloid storm: acute kidney injury and massive proteinuria, rapidly progressing to end-stage kidney disease in AA amyloidosis of familial Mediterranean fever.

OBJECTIVE: Amyloid A nephropathy of FMF usually progresses over many years to end-stage renal disease (ESRD). We aim to describe an acute condition, termed here 'amyloid storm', typically manifesting with a rapid (≤2 weeks) increase in serum creatinine and urine protein, that has never been characterized in FMF amyloidosis. METHODS: This retrospective analysis features amyloid storm by comparing between FMF amyloidosis patients who have experienced an episode of amyloid storm (study group) and matched patients who have not (control group). The primary outcome was ESRD or death within 1 year from study entry. Featured data were retrieved from hospital files. RESULTS: The study and control groups, each comprising 20 patients, shared most baseline characteristics. However, they differed on the time from FMF onset to reaching serum creatinine of 1.2 mg/dl [26.5 years (s.d. 15.15) vs 41.55 (10.98), P = 0.001] and the time from the onset of proteinuria to study entry [8.8 years (s.d. 6.83) vs 15.75 (13.05), P = 0.04], culminating in younger age at study entry [39.95 years (s.d. 16.81) vs 48.9 (9.98), respectively, P = 0.05] and suggesting an accelerated progression of kidney disease in the study group. Within 1 year from study entry, 16 patients in the study and 3 in the control groups reached the primary endpoint (P = 0.000). The major triggers of amyloid storm were infections, occurring in 17 of 20 patients. CONCLUSION: Amyloid storm is a complication of FMF amyloidosis, induced by infection and associated with poor prognosis and death.

Measurements of nonlinear absorption of intense 10 µm laser pulses in n-Ge, GaAs, and ZnSe.

We study the nonlinear absorption of high-power 10 µm radiation propagating through n-Ge, GaAs, and ZnSe materials widely used in the long-wave infrared range. Measurements are performed using both nanosecond and picosecond CO2 laser pulses providing intensities up to 100MW/cm2 and 5GW/cm2, respectively. Nonlinear absorption coefficients in optical quality n-Ge are found to be the same for both pulse durations. The nonlinear absorption coefficient of these materials scales inverse proportionally to their bandgap energies, indicating increased photoionization in the smaller bandgap materials.

Saliva immunoglobulin free light chain analysis for monitoring disease activity and response to treatment in multiple sclerosis.

BACKGROUND: Immunoglobulin free light chains (FLC) have recently gained considerable interest as new promising intrathecal biomarkers of multiple sclerosis (MS). However, lumbar puncture is invasive and not practical for monitoring disease course. This study aimed to assess the utility of saliva FLC as a biomarker of disease activity and response to treatment in MS METHODS: Western blotting was used to study saliva FLC monomers and dimers. The intensity of immunoreactive FLC bands was quantified by electrophoresis analysis, and the obtained values were used as FLC indices to account for kappa and lambda FLC monomer and dimer levels. Firth's logistic regression analysis suitable to study small cohorts was applied to compare FLC levels between M.S. patients in relapse, MS patients in remission, and healthy controls. Association between FLC levels and clinical and radiological parameters was analyzed. RESULTS: 55 MS patients and 40 healthy controls were evaluated. Saliva FLC levels were significantly higher in relapse compared to remission. Logistic regression analysis employing a combination of FLC indices confirmed the significant difference between these two groups. The FLC levels were significantly reduced by treatment with corticosteroids. During remission, patients treated with disease-modifying therapies had lower levels of FLC compared to untreated patients. The increased FLC levels were associated with the presence of gadolinium-enhancing lesions, but not with MRI T2 lesion load and EDSS scores. During individual patient follow-up, the changes of the saliva FLC levels were in concordance with the disease activity status. CONCLUSIONS: Saliva FLC levels may be a useful biomarker for discriminating between stable remission and active disease. The developed test may serve as a new, non-invasive, and inexpensive tool for monitoring disease activity and response to treatment in MS.

Macrophage activation syndrome complicating rheumatic diseases in adults: case-based review.

Macrophage activation syndrome (MAS) is a life-threatening complication of rheumatologic diseases. Data regarding the clinical course, management and outcome of adults with MAS is limited. Therefore, we aimed to describe the clinical features, treatment and outcome of adult patients with MAS, and review the literature for previous cohorts. We retrospectively reviewed patients with MAS complicating rheumatologic diseases between the years 2007 and 2017. Through Pubmed, Medline and Scopus literature search we identified previous cases of adult patients with MAS. We identified 7 patients with MAS complicating rheumatologic diseases (5 females and 2 males). The median age of diagnosis was 32 (range 26-57) years. The median follow-up was 30 months (range 6.95-36.5) months. The underlying rheumatologic disease was adult onset Still's disease (AOSD) in 3 patients, systemic juvenile idiopathic arthritis (sJIA) in 2 patients, systemic lupus erythematosus (SLE) in 1 patient, and systemic vasculitis in 1 patient. Four patients developed MAS concurrently with the clinical development of the rheumatologic disease. All the patients were treated with systemic corticosteroids. Five patients were treated with cyclosporine A, one of which received combination therapy with anakinra, and one received tocilizumab. Two patients deceased during the hospitalization. We identified 92 patients from literature cohorts, 73 (79%) of them with AOSD. MAS developed concurrently with the underlying rheumatologic disease in 25 (27%) patients, and 30 (33%) patients deceased. Our cohort and previous cohorts demostrate that MAS often presents concurrently with the underlying rheumatologic disease and is associated with a high mortality rate. Further larger prospective studies are needed to determine the optimal management of MAS.

IFNγ potentiates TNFα/TNFR1 signaling to induce FAT10 expression in macrophages.

INTRODUCTION: The tight regulation of the cytokine network during macrophage activation is of prime importance to enable a fast and potent innate immune response against exogenous pathogens. The inflammation mediating ubiquitin-like protein HLA-F adjacent transcript number 10 (FAT10) was shown to be transcriptionally regulated by and also regulate the nuclear factor-κB (NFκB) signaling pathway. However, very little is known about the regulation of FAT10 gene expression during macrophage activation. RESULTS: RNA sequencing of interferon (IFN)γ-stimulated mouse peritoneal macrophages analyzed by ingenuity pathway analysis revealed significant involvement of tumor necrosis factor receptor 1 (TNFR1) signaling in addition to IFNγ signaling. Subsequently, IFNγ robustly upregulated FAT10 expression compared to a milder induction seen with TNFα or lipopolysaccharide (LPS) stimulation. While low dose IFNγ with TNFα synergistically elevated FAT10 expression, preincubation of macrophages with IFNγ strongly augmented TNFα-induced FAT10 expression. Moreover, a short preincubation with IFNγ, which did not elevate FAT10, was sufficient to potentiate the induction of FAT10 by TNFα. A double augmentation mechanism of TNFα signaling was demonstrated, where IFNγ rapidly induced the expression of TNFα and TNFR1, which further augmented the induction of TNFα and TNFR1 expression by TNFα. Importantly, the induction of FAT10 by IFNγ in macrophages from TNFα-deficient or TNFR1-deficient mice was completely inhibited compared to macrophages from wild type (WT) mice. Finally, we show that TNFα-induced FAT10 expression is dependent on NFκB signaling. CONCLUSION: IFNγ potentiates the TNFα/TNFR1 signaling pathway to induce FAT10 expression in mouse macrophages, mediated through NFκB network.