Performance of 2019 EULAR/ACR Classification Criteria for Systemic Lupus Erythematosus in Children and Adults : A Retrospective Observational Study

Background: The European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) recently developed a systemic lupus erythematosus (SLE) classification criteria (EULAR/ACR-2019) with high sensitivity and specificity. The aim of this study was to validate and compare the performance of the newly developed criteria to that of the ACR-1997 and the 2012 Systemic Lupus International Collaborating Clinics (SLICC-2012) criteria in juvenile-onset SLE (jSLE) and adult-onset SLE (aSLE) patients.Methods: We conducted a retrospective study of SLE patients (221 children and adult) and controls (214 children and adult) with defined rheumatic diseases to establish the ACR-1997, SLICC-2012 and EULAR/ACR-2019 criteria. The performance of the three criteria was statistically analyzed.Results: For jSLE, sensitivities of ACR-1997, SLICC-2012 and EULAR/ACR-2019 criteria were 63.3%, 94.6% and 98.2% (P < 0.001), with specificities 99.5%, 98.6% and 93.5% (P < 0.001), respectively. For aSLE, sensitivities of ACR-1997, SLICC-2012 and EULAR/ACR-2019 criteria were 72.9%, 96.8% and 99.1% (P < 0.001), with specificities 97.2%, 92.5% and 90.2% (P = 0.013), respectively. In ANA positive juvenile patients, a EULAR/ACR score ≥13 instead of a score ≥10 resulted in higher specificity (93.1% vs. 75.9%), despite slightly lower sensitivity (92.2% vs. 99.5%). In both jSLE and aSLE patients, the SLICC-2012 and EULAR/ACR-2019 criteria had increased sensitivity for major organ involvement than ACR-1997.Conclusion: The EULAR/ACR-2019 criteria showed similar sensitivity to jSLE and aSLE patients and was more sensitive than ACR-1997 and SLICC-2012 criteria, allowing earlier recognition of patients with single or major organ involvement. The adoption of a EULAR/ACR total score ≥13 in this study, instead of the initially proposed ≥10 score, was more appropriate to classify jSLE.

Impact of glucocorticoids on the incidence of lupus-related major organ damage: a systematic literature review and meta-regression analysis of longitudinal observational studies

ObjectiveIn systemic lupus erythematosus (SLE), disease activity and glucocorticoid (GC) exposure are known to contribute to irreversible organ damage. We aimed to examine the association between GC exposure and organ damage occurrence.MethodsWe conducted a literature search (PubMed (Medline), Embase and Cochrane January 1966–October 2021). We identified original longitudinal observational studies reporting GC exposure as the proportion of users and/or GC use with dose information as well as the occurrence of new major organ damage as defined in the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index. Meta-regression analyses were performed. Reviews, case-reports and studies with <5 years of follow-up, <50 patients, different outcomes and special populations were excluded.ResultsWe selected 49 articles including 16 224 patients, 14 755 (90.9%) female with a mean age and disease duration of 35.1 years and of 37.1 months. The mean follow-up time was 104.9 months. For individual damage items, the average daily GC dose was associated with the occurrence of overall cardiovascular events and with osteoporosis with fractures. A higher average cumulative dose adjusted (or not)/number of follow-up years and a higher proportion of patients on GC were associated with the occurrence of osteonecrosis.ConclusionsWe confirm associations of GC use with three specific damage items. In treating patients with SLE, our aim should be to maximise the efficacy of GC and to minimise their harms.

A European pharmacotherapeutic agent Roflumilast exploring integrated preclinical and clinical evidences for SARS CoV-2 mediated inflammation to organ damage

COVID-19 has spread globally, affecting almost 160 million individuals. Elderly and pre-existing patients (such as diabetes, heart disease and asthma), seems more susceptible to serious illness with COVID-19. Roflumilast was licensed for usage in the European Union in July 2010 as a phosphodiesterase-4 (PDE4) inhibitor. Roflumilast has been shown to decrease bleomycin-induced lung fibrosis, lung hydroxyproline, right heart thickning in animal prophylactic. The current study reviewed existing data that the PDE-4 inhibitor protects not just renal tissues but also other major organ systems after COVID-19 infection by decreasing immune cell infiltration. These immune-balancing effects of roflumilast were related with a decrease in oxidative and inflammatory burden, caspase-3 suppression, and increased PKA/cAMP levels in renal and other organ tissue.

Longitudinal Assessment and Prognostic Importance of Minimal Residual Disease (MRD) By Multiparametric Flow Cytometry in Patients with Systemic Light Chain (AL) Amyloidosis

Background: Minimal residual disease (MRD) assessment can provide an index of robust disease control, particularly if MRD negativity is sustained over time. Whereas MRD status has well-established prognostic implications in multiple myeloma, its role in light chain (AL) amyloidosis-a related but biologically distinct plasma cell disorder-is presently under investigation. Aims: The aims of our study were to evaluate (1) major organ deterioration-progression-free survival (MOD-PFS) based on MRD status and (2) MRD evolution patterns during disease surveillance for patients with AL amyloidosis in hematologic complete response (hemCR) after therapy. Methods: We established MRD status using multiparametric 10-color flow cytometry of bone marrow aspirates. At least 2 x 10 6 events were measured using a Beckman Coulter Navios Flow Cytometer and analyzed by Kaluza Software (sensitivity level of ≤10 -5). Sequential MRD testing was performed (≥12 months apart) for patients returning for follow-up. We evaluated hematologic and organ responses or progression based on consensus guidelines (Palladini, 2012). MOD-PFS was defined as time from hemCR achievement to major organ deterioration (i.e., the kidney or heart), hematologic progression or death from any cause (whichever occurred first). Presence of MRD was not used to guide treatment decisions. Results: A total of 96 patients with hemCR after therapy were tested, of whom 46 (48%) were MRD negative and 50 (52%) MRD positive on first assessment. The median estimated clone size for those with MRD positivity was 3.4 x 10 -4 (range 1.4 x 10 -5 to 5.7 x 10 -3). Baseline characteristics were similar between groups, except for greater use of daratumumab and ≥2 lines of therapy to achieve hemCR in the MRD-negative group. MRD positivity correlated with a higher level of involved free light chains (iFLC) in the serum at the time of MRD assessment (23.4 mg/L vs 17.3 mg/L, P = .011). In regard to organ responses, patients with MRD negativity had a significantly higher rate of renal response (91% vs 67%, P = .017) but a similar rate of cardiac response (74% vs 68%, P = .668). After a median follow-up of 50 months from hemCR achievement, the MRD-negative group demonstrated a superior MOD-PFS (HR 0.38, 95% CI 0.16-0.88, P = .034). Progression or organ deterioration events in the MRD-negative group occurred early after hemCR achievement, while in the MRD-positive group these events continued to occur over time. A total of 8 patients had died, including 4 in each group. Sequential MRD testing (median 12 months apart, range 12-28 months) was performed for 43 patients, of whom 16/19 (84%) had sustained MRD negativity; 21/24 (88%) had persistent MRD positivity; and 6/43 (14%) had MRD conversion. No patient received therapy between MRD assessments. Among those with sustained MRD negativity, there were 2 major organ deterioration events. The 3 patients who experienced loss of MRD negativity (which occurred at 12, 107 and 114 months after last treatment) had no progression or organ deterioration events. Of those with persistent MRD positivity, 13 (62%) had durable hemCR and organ responses; moreover, 4/14 (29%) and 1/11 (9%) of these patients attained even deeper renal and cardiac responses, respectively, in the interval between sequential MRD testing. Clone progression (defined as &gt;1-log growth in MRD clone size) was observed in 3/21 (14%) patients with persistent MRD positivity, none of whom demonstrated hematologic relapse. Conclusions: We evaluated the dynamics of MRD status in relation to clinical outcomes and found that patients with MRD negativity had longer survival free from hematologic progression, major organ deterioration or death. Longer prospective follow-up is needed to determine whether this translates into an overall survival benefit. MRD conversion occurred in a small proportion (14%) of patients, but was not linked to adverse outcomes. Understanding the role of cross-sectional MRD testing for clinical disease tracking in AL amyloidosis requires further analysis with larger sample size. Figure 1 Figure 1. Disclosures Sanchorawala: Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; Pfizer: Honoraria; Karyopharm: Research Funding; Sorrento: Research Funding; Celgene: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees; Caelum: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Membership on an entity's Board of Directors or advisory committees; Proclara: Membership on an entity's Board of Directors or advisory committees; Oncopeptide: Research Funding.

The pathophysiology of sepsis — 2021 update: Part 2, organ dysfunction and assessment

Disclaimer In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose This is the second article in a 2-part series discussing the pathophysiology of sepsis. Part 1 of the series reviewed the immunologic response and overlapping pathways of inflammation and coagulation that contribute to the widespread organ dysfunction. In this article (part 2), major organ systems and their dysfunction in sepsis are reviewed, with discussion of scoring systems used to identify patterns and abnormal vital signs and laboratory values associated with sepsis. Summary Sepsis is a dysregulated host response to infection that produces significant morbidity, and patients with shock due to sepsis have circulatory and cellular and metabolic abnormalities that lead to a higher mortality. Cardiovascular dysfunction produces vasodilation, reduced cardiac output and hypotension/shock requiring fluids, vasopressors, and advanced hemodynamic monitoring. Respiratory dysfunction may require mechanical ventilation and attention to volume status. Renal dysfunction is a frequent manifestation of sepsis. Hematologic dysfunction produces low platelets and either elevation or reduction of leucocytes, so consideration of the neutrophil:lymphocyte ratio may be useful. Procoagulant and antifibrinolytic activity leads to coagulation that is stimulated by inflammation. Hepatic dysfunction manifest as elevated bilirubin is often a late finding in sepsis and may cause reductions in production of essential proteins. Neurologic dysfunction may result from local endothelial injury and systemic inflammation through activity of the vagus nerve. Conclusion Timely recognition and team response with efficient use of therapies can improve patient outcome, and pharmacists with a complete understanding of the pathophysiologic mechanisms and treatments are valuable members of that team.

Metabolic Syndrome and Sarcopenia

Skeletal muscle is a major organ of insulin-induced glucose metabolism. In addition, loss of muscle mass is closely linked to insulin resistance (IR) and metabolic syndrome (Met-S). Skeletal muscle loss and accumulation of intramuscular fat are associated with a variety of pathologies through a combination of factors, including oxidative stress, inflammatory cytokines, mitochondrial dysfunction, IR, and inactivity. Sarcopenia, defined by a loss of muscle mass and a decline in muscle quality and muscle function, is common in the elderly and is also often seen in patients with acute or chronic muscle-wasting diseases. The relationship between Met-S and sarcopenia has been attracting a great deal of attention these days. Persistent inflammation, fat deposition, and IR are thought to play a complex role in the association between Met-S and sarcopenia. Met-S and sarcopenia adversely affect QOL and contribute to increased frailty, weakness, dependence, and morbidity and mortality. Patients with Met-S and sarcopenia at the same time have a higher risk of several adverse health events than those with either Met-S or sarcopenia. Met-S can also be associated with sarcopenic obesity. In this review, the relationship between Met-S and sarcopenia will be outlined from the viewpoints of molecular mechanism and clinical impact.

Regulatory Perspectives on Juvenile Animal Toxicologic Pathology

The Society of Toxicologic Pathology’s Annual Virtual Symposium (2021) included a session on "Regulatory Perspectives on Juvenile Animal Toxicologic Pathology." The following narrative summarizes the key concepts from the four talks included in this symposium session chaired by Drs Deepa Rao and Alan Hoberman. These encompass an overview of various global regulations impacting the conduct of juvenile animal studies in pharmaceutical drug development and chemical toxicity assessments in a talk by Dr Alan Hoberman. Given the numerous regulatory guidances and legal statutes that have covered the conduct of juvenile animal studies and the recent harmonization of these guidances for pharmaceuticals, Dr Paul Brown provided an update on the harmonization of these guidances for pharmaceuticals, in the recently finalized version of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use S11 guidance document, “Nonclinical Safety Testing in Support of Development of Pediatric Medicines.” The first two talks on regulations were followed by two talks focused on an evaluation of the postnatal development of two major organ systems relevant in juvenile animals. Dr Aurore Varela covered study design and endpoints impacting the skeletal system (bone), while Dr Brad Bolon presented a talk on the study design and conduct of neuropathology evaluations for the developing nervous system.

Sarcopenia Increases the Risk of Major Organ Invasion in Patients with Papillary Thyroid Cancer

While sarcopenia is associated with poor overall survival and cancer-specific survival in solid cancer patients, the impact of sarcopenia on clinicopathologic features that can influence conventional papillary thyroid cancer (PTC) prognosis remains unclear. To investigate the impact of sarcopenia on aggressive clinicopathologic features in PTC patients, prospectively collected data on 305 patients who underwent surgery for PTC with preoperative staging ultrasonography and bioelectrical impedance analysis were retrospectively analyzed. Nine sarcopenia patients showed more patients aged 55 or older (p = 0.022), higher male proportion (p < 0.001), lower body-mass index (p = 0.015), higher incidence of major organ invasion (p = 0.001), higher T (p = 0.002) stage, higher TNM (p = 0.007) stage, and more tumor recurrence (p = 0.023) compared to the non-sarcopenia patients. Unadjusted and adjusted logistic regression analyses showed that sarcopenia (odds ratio (OR) 9.936, 95% confidence interval (CI) 2.052–48.111, p = 0.004), tumor size (OR 1.048, 95% CI 1.005–1.093, p = 0.027), and tumor multiplicity (OR 3.323, 95% CI 1.048–10.534, p = 0.041) significantly increased the risk of major organ invasion. Therefore, sarcopenia in PTC patients should raise suspicion for a more locally advanced disease and direct appropriate management.

Platinized graphene fiber electrodes uncover direct spleen-vagus communication

Neural interfacing nerve fascicles along the splenic neurovascular plexus (SNVP) is needed to better understand the spleen physiology, and for selective neuromodulation of this major organ. However, their small size and anatomical location have proven to be a significant challenge. Here, we use a reduced liquid crystalline graphene oxide (rGO) fiber coated with platinum (Pt) as a super-flexible suture-like electrode to interface multiple SNVP. The Pt-rGO fibers work as a handover knot electrodes over the small SNVP, allowing sensitive recording from four splenic nerve terminal branches (SN 1–4), to uncover differential activity and axon composition among them. Here, the asymmetric defasciculation of the SN branches is revealed by electron microscopy, and the functional compartmentalization in spleen innervation is evidenced in response to hypoxia and pharmacological modulation of mean arterial pressure. We demonstrate that electrical stimulation of cervical and sub-diaphragmatic vagus nerve (VN), evokes activity in a subset of SN terminal branches, providing evidence for a direct VN control over the spleen. This notion is supported by adenoviral tract-tracing of SN branches, revealing an unconventional direct brain-spleen projection. High-performance Pt-rGO fiber electrodes, may be used for the fine neural modulation of other small neurovascular plexus at the point of entry of major organs as a bioelectronic medical alternative.

A Case of a 49-Year-Old Man with Nonclassical Fabry Disease Diagnosed by Renal Biopsy

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the galactosidase A (GLA) gene that result in deficiency of α-GLA activity, leading to major organ failure and premature mortality. According to different disease courses, FD can be divided into classical and nonclassical phenotypes. The nonclassical FD phenotype is always absent of characteristic symptoms, which makes identifying it challenging. This article presents a 49-year-old man with a 10-year history of proteinuria and decreased glomerular filtration rate. An electrocardiogram showed a complete right bundle branch block and abnormal Q waves in high lateral, accompanied by dramatically elevated ST segment. Consequently, a renal biopsy was performed. Vacuolation was found in many podocytes in light microscopic examinations. Similarly, a myelin-like structure was detected by electron microscopy. Pathological findings were most consistent with FD. Consequently, genetic analysis, p.R301Q (c.902G&#x3e;A [p.Arg301Gln]), confirmed the FD diagnosis. Angiotensin receptor blocker and traditional Chinese medicine, but not enzyme replacement therapy, were prescribed due to financial constraints. The patient had stabilization of kidney disease 6 months later. The case showed that renal biopsy should be performed in patients with cardiac and renal symptoms, which could contribute toward the correct diagnosis for nonclassical FD type.