SARS-CoV-2 infection and persistence in the human body and brain at autopsy.

Coronavirus disease 2019 (COVID-19) is known to cause multi-organ dysfunction1-3 during acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with some patients experiencing prolonged symptoms, termed post-acute sequelae of SARS-CoV-2 (refs. 4,5). However, the burden of infection outside the respiratory tract and time to viral clearance are not well characterized, particularly in the brain3,6-14. Here we carried out complete autopsies on 44 patients who died with COVID-19, with extensive sampling of the central nervous system in 11 of these patients, to map and quantify the distribution, replication and cell-type specificity of SARS-CoV-2 across the human body, including the brain, from acute infection to more than seven months following symptom onset. We show that SARS-CoV-2 is widely distributed, predominantly among patients who died with severe COVID-19, and that virus replication is present in multiple respiratory and non-respiratory tissues, including the brain, early in infection. Further, we detected persistent SARS-CoV-2 RNA in multiple anatomic sites, including throughout the brain, as late as 230 days following symptom onset in one case. Despite extensive distribution of SARS-CoV-2 RNA throughout the body, we observed little evidence of inflammation or direct viral cytopathology outside the respiratory tract. Our data indicate that in some patients SARS-CoV-2 can cause systemic infection and persist in the body for months.

Histopathology and SARS-CoV-2 Cellular Localization in Eye Tissues of COVID-19 Autopsies.

Ophthalmic manifestations and tissue tropism of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been reported in association with coronavirus disease 2019 (COVID-19), but the pathology and cellular localization of SARS-CoV-2 are not well characterized. The objective of this study was to evaluate macroscopic and microscopic changes and investigate cellular localization of SARS-CoV-2 across ocular tissues at autopsy. Ocular tissues were obtained from 25 patients with COVID-19 at autopsy. SARS-CoV-2 nucleocapsid gene RNA was previously quantified by droplet digital PCR from one eye. Herein, contralateral eyes from 21 patients were fixed in formalin and subject to histopathologic examination. Sections of the droplet digital PCR-positive eyes from four other patients were evaluated by in situ hybridization to determine the cellular localization of SARS-CoV-2 spike gene RNA. Histopathologic abnormalities, including cytoid bodies, vascular changes, and retinal edema, with minimal or no inflammation in ocular tissues were observed in all 21 cases evaluated. In situ hybridization localized SARS-CoV-2 RNA to neuronal cells of the retinal inner and outer layers, ganglion cells, corneal epithelia, scleral fibroblasts, and oligodendrocytes of the optic nerve. In conclusion, a range of common histopathologic alterations were identified within ocular tissue, and SARS-CoV-2 RNA was localized to multiple cell types. Further studies will be required to determine whether the alterations observed were caused by SARS-CoV-2 infection, the host immune response, and/or preexisting comorbidities.

The role of Janus kinase signaling in the pathology of atopic dermatitis.

Atopic dermatitis (AD) is a heterogeneous, chronic, relapsing, inflammatory skin disease associated with considerable physical, psychological, and economic burden. The pathology of AD includes complex interactions involving abnormalities in immune and skin barrier genes, skin barrier disruption, immune dysregulation, microbiome disturbance, and other environmental factors. Many of the cytokines involved in AD pathology, including IL-4, IL-13, IL-22, IL-31, thymic stromal lymphopoietin, and IFN-γ, signal through the Janus kinase (JAK)-signal transducer and activation of transcription (STAT) pathway. The JAK family includes JAK1, JAK2, JAK3, and tyrosine kinase 2; the STAT family includes STAT1, STAT2, STAT3, STAT4, STAT5A/B, and STAT6. Activation of the JAK-STAT pathway has been implicated in the pathology of several immune-mediated inflammatory diseases, including AD. However, the exact mechanisms of JAK-STAT involvement in AD have not been fully characterized. This review aims to discuss current knowledge about the role of the JAK-STAT signaling pathway and, specifically, the role of JAK1 in the pathology and symptomology of AD.

Solid State and Solution Structures of Lanthanide Nitrate Complexes of Tris-(1-napthylphosphine oxide).

Coordination complexes of lanthanide metals with tris-1-naphthylphosphine oxide (Nap3PO, L) have not been previously reported in the literature. We describe here the formation of lanthanide(III) nitrate complexes Ln(NO3)3L4 (Ln = Eu to Lu) and the structures of [Ln(NO3)3L2]·2L (Ln = Eu, Dy, Ho, Er) and L. The core structure of the complexes is an eight-coordinate [Ln(NO3)3L2] with the third and fourth ligands H-bonded via their oxygen atoms to one of the naphthyl rings. The structures are compared with those of the analogous complexes of triphenylphosphine oxide and show that the Ln-O(P) bond in the Nap3PO complexes is slightly longer than expected on the basis of differences in coordination numbers. The reaction solutions, investigated by 31P and 13C NMR spectroscopy in CD3CN, show that coordination of L occurs across the lanthanide series, even though complexes can only be isolated from Eu onwards. Analysis of the 31P NMR paramagnetic shifts shows that there is a break in the solution structures with a difference between the lighter lanthanides (La-Eu) and heavier metals (Tb-Lu) which implies a minor difference in structures. The isolated complexes are very poorly soluble, but in CDCl3, NMR measurements show dissociation into [Ln(NO3)3L2] and 2L occurs.

Clinical and Immunologic Correlates of Vasodilatory Shock Among Ebola Virus-Infected Nonhuman Primates in a Critical Care Model.

BACKGROUND: Existing models of Ebola virus infection have not fully characterized the pathophysiology of shock in connection with daily virologic, clinical, and immunologic parameters. We implemented a nonhuman primate critical care model to investigate these associations. METHODS: Two rhesus macaques received a target dose of 1000 plaque-forming units of Ebola virus intramuscularly with supportive care initiated on day 3. High-dimensional spectral cytometry was used to phenotype neutrophils and peripheral blood mononuclear cells daily. RESULTS: We observed progressive vasodilatory shock with preserved cardiac function following viremia onset on day 5. Multiorgan dysfunction began on day 6 coincident with the nadir of circulating neutrophils. Consumptive coagulopathy and anemia occurred on days 7 to 8 along with irreversible shock, followed by death. The monocyte repertoire began shifting on day 4 with a decline in classical and expansion of double-negative monocytes. A selective loss of CXCR3-positive B and T cells, expansion of naive B cells, and activation of natural killer cells followed viremia onset. CONCLUSIONS: Our model allows for high-fidelity characterization of the pathophysiology of acute Ebola virus infection with host innate and adaptive immune responses, which may advance host-targeted therapy design and evaluation for use after the onset of multiorgan failure.

Adult spinal deformity patients revised for pseudarthrosis have comparable two-year outcomes to those not undergoing any revision surgery.

PURPOSE: This study aimed to evaluate whether adult spinal deformity patients undergoing revision for symptomatic pseudarthrosis have comparable two-year outcomes as patients who do not experience pseudarthrosis. METHODS: Patients whose indexed procedure was revision for pseudarthrosis (pseudo) were compared with patients who underwent a primary procedure and did not have pseudarthrosis by 2Y post-op (non-pseudo). Patients were propensity-matched (PSM) based on baseline (BL) sagittal alignment, specifically C7SVA and CrSVA-Hip. Key outcomes were 2Y PROs (SRS and ODI) and reoperation. All patients had a minimum follow-up period of two years. RESULTS: A total of 224 patients with min 2-year FU were included (pseudo = 42, non-pseudo = 182). Compared to non-pseudo, pseudo-patients were more often female (P = 0.0018) and had worse BL sagittal alignment, including T1PA (P = 0.02], C2-C7 SVA [P = 0.0002], and CrSVA-Hip [P = 0.004]. After 37 PSM pairs were generated, there was no significant difference in demographics, BL and 2Y alignment, or operative/procedural variables. PSM pairs did not report any significantly different PROs at BL. Consistently, at 2Y, there were no significant differences in PROs, including SRS function [3.9(0.2) vs 3.7(0.2), P = 0.44], pain [4.0 (0.2) vs. 3.57 (0.2), P = 0.12], and ODI [25.7 (5.2) vs 27.7 (3.7), P = 0.76]. There were no differences in 1Y (10.8% vs 10.8%, P > 0.99) and 2Y (13.2% vs 15.8%, P = 0.64) reoperation, PJK rate (2.6% vs 10.5%, P = 0.62), or implant failure (2.6% vs 10.5%, P = 0.37). Notably, only 2 patients (5.4%) had recurrent pseudarthrosis following revision. Kaplan-Meier curves indicated that patients undergoing intervention for pseudarthrosis had comparable overall reoperation-free survival (log-rank test, χ2 = 0.1975 and P = 0.66). CONCLUSIONS: Patients undergoing revision for pseudarthrosis have comparable PROs and clinical outcomes as patients who never experienced pseudarthrosis. Recurrence of symptomatic pseudarthrosis was infrequent.

Aspergillosis Complicating Severe Coronavirus Disease.

Aspergillosis complicating severe influenza infection has been increasingly detected worldwide. Recently, coronavirus disease-associated pulmonary aspergillosis (CAPA) has been detected through rapid reports, primarily from centers in Europe. We provide a case series of CAPA, adding 20 cases to the literature, with review of pathophysiology, diagnosis, and outcomes. The syndromes of pulmonary aspergillosis complicating severe viral infections are distinct from classic invasive aspergillosis, which is recognized most frequently in persons with neutropenia and in other immunocompromised persons. Combined with severe viral infection, aspergillosis comprises a constellation of airway-invasive and angio-invasive disease and results in risks associated with poor airway fungus clearance and killing, including virus- or inflammation-associated epithelial damage, systemic immunosuppression, and underlying lung disease. Radiologic abnormalities can vary, reflecting different pathologies. Prospective studies reporting poor outcomes in CAPA patients underscore the urgent need for strategies to improve diagnosis, prevention, and therapy.

Macrophages Subvert Adaptive Immunity to Urinary Tract Infection.

Urinary tract infection (UTI) is one of the most common bacterial infections with frequent recurrence being a major medical challenge. Development of effective therapies has been impeded by the lack of knowledge of events leading to adaptive immunity. Here, we establish conclusive evidence that an adaptive immune response is generated during UTI, yet this response does not establish sterilizing immunity. To investigate the underlying deficiency, we delineated the naïve bladder immune cell compartment, identifying resident macrophages as the most populous immune cell. To evaluate their impact on the establishment of adaptive immune responses following infection, we measured bacterial clearance in mice depleted of either circulating monocytes, which give rise to macrophages, or bladder resident macrophages. Surprisingly, mice depleted of resident macrophages, prior to primary infection, exhibited a nearly 2-log reduction in bacterial burden following secondary challenge compared to untreated animals. This increased bacterial clearance, in the context of a challenge infection, was dependent on lymphocytes. Macrophages were the predominant antigen presenting cell to acquire bacteria post-infection and in their absence, bacterial uptake by dendritic cells was increased almost 2-fold. These data suggest that bacterial uptake by tissue macrophages impedes development of adaptive immune responses during UTI, revealing a novel target for enhancing host responses to bacterial infection of the bladder.

Collecting lymphatic vessel permeability facilitates adipose tissue inflammation and distribution of antigen to lymph node-homing adipose tissue dendritic cells.

Collecting lymphatic vessels (CLVs), surrounded by fat and endowed with contractile muscle and valves, transport lymph from tissues after it is absorbed into lymphatic capillaries. CLVs are not known to participate in immune responses. In this study, we observed that the inherent permeability of CLVs allowed broad distribution of lymph components within surrounding fat for uptake by adjacent macrophages and dendritic cells (DCs) that actively interacted with CLVs. Endocytosis of lymph-derived Ags by these cells supported recall T cell responses in the fat and also generated Ag-bearing DCs for emigration into adjacent lymph nodes (LNs). Enhanced recruitment of DCs to inflammation-reactive LNs significantly relied on adipose tissue DCs to maintain sufficient numbers of Ag-bearing DCs as the LN expanded. Thus, CLVs coordinate inflammation and immunity within adipose depots and foster the generation of an unexpected pool of APCs for Ag transport into the adjacent LN.

Intracranial complications associated with spinal surgery.

PURPOSE: Though rare, intracranial complications have been reported as a result from spinal surgery. Most if not all of these are a result of intracranial hypotension from durotomy and cerebrospinal fluid (CSF) leak. We aimed to characterize these complications across a large postoperative population at our institution. METHODS: We conducted a retrospective review of all patients who underwent spinal surgery at our institution by four neurosurgeons from July 2008 to August 2013. RESULTS: Our review yielded 1113 consecutive patients who underwent spinal surgery for a total of 1396 procedures. Intracranial imaging using either computed tomography or magnetic resonance imaging was obtained on 59 (4.2%) patients after a procedure due to neurologic change. Six patients (0.4%) were found to have intracranial findings of subdural hygroma (4 patients), remote cerebellar hemorrhage (1 patient), or subdural hematoma (1 patient). CONCLUSION: Intracranial complications from spinal surgery are a rare event. We demonstrate an incidence of 0.4% of total intracranial pathology after spinal surgery. A strong clinical suspicion must be maintained after durotomy or CSF leak due to these infrequent but potentially life-threatening complications.

The active metabolite of spleen tyrosine kinase inhibitor fostamatinib abrogates the CD4⁺ T cell-priming capacity of dendritic cells.

OBJECTIVES: Spleen tyrosine kinase (SYK) is a core signalling protein that drives inflammatory responses and is fundamental to the propagation of signals via numerous immune receptors, including the B cell receptor and Fc receptors (FcRs). Fostamatinib, a small molecule SYK inhibitor, has shown evidence of ameliorating inflammation in RA patients. We sought to understand how the active metabolite of fostamatinib, R406, affects the inflammatory response at the cellular level. METHODS: Antigen-specific in vivo systems and in vitro fluorescence microscopy were combined to investigate the effects of fostamatinib on antigen-specific interactions between dendritic cells (DCs) and CD4(+) T cells. RESULTS: Although it has previously been shown that R406 reduces the response of DCs to immune complexes (ICs), we found that fostamatinib failed to reduce specific CD4(+) T cell proliferation in mice after immunization with ICs. However, we observed in vitro that R406 reduces both the area and duration of cellular interactions between IC-activated DCs and specific CD4(+) T cells during the initial phase of cellular crosstalk. This led to diminished proliferation of antigen-specific CD4(+) T cells after R406 treatment compared with vehicle controls. This decreased proliferative capacity of CD4(+) T cells was accompanied by reduced expression of the co-stimulatory molecules, inducible T cell co-stimulator (ICOS) and PD-1, and abrogation of the production of inflammatory cytokines such as IFN-γ and IL-17. CONCLUSION: Our findings indicate a potential mechanism by which this compound may be effective in inhibiting FcR-driven CD4(+) T cell responses.

Normal dendritic cell mobilization to lymph nodes under conditions of severe lymphatic hypoplasia.

To address the requirement for lymphatic capillaries in dendritic cell (DC) mobilization from skin to lymph nodes (LNs), we used mice bearing one inactivated allele of vascular endothelial growth factor receptor 3 (VEGFR3) where skin lymphatic capillaries are reported absent. Unexpectedly, DC mobilization from the back skin to draining LNs was similar in magnitude, and kinetics to control mice and humoral immunity appeared intact. By contrast, DC migration from body extremities, including ear and forepaws, was ablated. An evaluation in different regions of skin revealed rare patches of lymphatic capillaries only in body trunk areas where migration was intact. That is, whereas the ear skin was totally devoid of lymphatic capillaries, residual capillaries in the back skin were present though retained only at ∼10% normal density. This reduction in density markedly reduced the clearance of soluble tracers, indicating that normal cell migration was spared under conditions when lymphatic transport function was poor. Residual lymphatic capillaries expressed slightly higher levels of CCL21 and migration of skin DCs to LNs remained dependent on CCR7 in Chy mice. DC migration from the ear could be rescued by the introduction of a limited number of lymphatic capillaries through skin transplantation. Thus, the development of lymphatic capillaries in the skin of body extremities was more severely impacted by a mutant copy of VEGFR3 than trunk skin, but lymphatic transport function was markedly reduced throughout the skin, demonstrating that even under conditions when a marked loss in lymphatic capillary density reduces lymph transport, DC migration from skin to LNs remains normal.

Mechanisms of autoimmunity in human diseases: a critical review of current dogma.

PURPOSE OF REVIEW: Autoimmune diseases such as rheumatoid arthritis (RA) pose an increasing, worldwide economic and health burden. Significantly, no cure exists for the majority of autoimmune diseases and consequently treatment is largely aimed at controlling disease symptoms. Therefore, there exists a critical need to develop new approaches that directly address the cause of disease, leading to disease remission and ultimately cure. RECENT FINDINGS: The organs, cells and molecules involved in the breach of self-tolerance have been partially defined in experimental models of autoimmunity. However, the broad applicability of this dogma in clinical disease is only partially understood. This gap between analyses of established disease and investigating early disease pathogenesis argues for the need for complementary studies in mice and humans. SUMMARY: Through a combination of clinical and experimental systems, novel autoantigens and neoepitopes involved in RA have been revealed. These have clear utility in predisease diagnosis and offer the possibility of antigen-specific immunotherapy. Ongoing experimental and clinical studies, for example using dendritic cell transfer, will facilitate a clearer understanding of the molecules, cells and organs that should be targeted to reinstate immunological tolerance. Antigen-specific immunotherapy therefore offers disease intervention without broad immunosuppression, and most importantly increases the likelihood of achieving true disease remission and cure.

Monocyte trafficking in acute and chronic inflammation.

Environmental signals at the site of inflammation mediate rapid monocyte mobilization and dictate differentiation programs whereby these cells give rise to macrophages or dendritic cells. Monocytes participate in tissue healing, clearance of pathogens and dead cells, and initiation of adaptive immunity. However, recruited monocytes can also contribute to the pathogenesis of infection and chronic inflammatory disease, such as atherosclerosis. Here, we explore monocyte trafficking in the context of acute inflammation, relying predominantly on data from microbial infection models. These mechanisms will be compared to monocyte trafficking during chronic inflammation in experimental models of atherosclerosis. Recent developments suggest that monocyte trafficking shares common themes in diverse inflammatory diseases; however, important differences exist between monocyte migratory pathways in acute and chronic inflammation.

Revision of Harrington rod constructs: a single-center's experience with this homogenous adult spinal deformity population at a minimum 2-year follow-up.

PURPOSE: To evaluate radiographic and clinical outcomes following revision surgery after HRC fusions. METHODS: Single-institution, retrospective study of patients revised following HRC with minimum 2-year follow-up post-revision. Demographics, perioperative information, radiographic parameters, complications, and Oswestry disability index (ODI) scores were collected. Radiographic parameters included global alignment, coronal and sagittal measurements pre and postoperatively, as well as final follow-up time points. RESULTS: 26 patients were included with a mean follow-up of 3.3 ± 1.1 years. Mean age was 55.5 ± 7.8 years, BMI 25.2 ± 5.8, and 22 (85%) were females. Instrumented levels increased from 9.7 ± 2.8 to 16.0 ± 2.2. Five (19.2%) patients underwent lumbar pedicle subtraction osteotomies, and 23 (88.4%) had interbody fusions. Patients significantly improved in all radiographic parameters at immediate and final follow-up (p < 0.005), except for thoracic kyphosis and pelvic incidence (p > 0.05). Correction was maintained from immediate postop to final follow-up (p > 0.05). 20 (76.9%) of patients experienced a complication at some point within the follow-up period with the most common being a lumbar nerve root deficit (n = 7). However, only one patient had a nerve root deficit at final follow-up, that being a 4/5 unilateral anterior tibialis function. 5 (19.2%) patients required further revision within a mean of 1.8 ± 1.1 years. On average, patients had an improvement in ODI score by final follow-up (35.6 ± 16.8 vs 25.4 ± 19.8, p = 0.035). CONCLUSION: Patients revised for HRCs significantly improve, both clinically and radiographically by final follow-up. This group did have a propensity for distal lumbar root neurological issues, which were common but all patients except for one, recovered to full strength by two-year follow-up.

Aggregate Response Benefit in Skin Clearance and Itch Reduction With Upadacitinib or Dupilumab in Patients With Moderate-to-Severe Atopic Dermatitis®.

Background: In patients with moderate-to-severe atopic Dermatitis® (AD), greater skin clearance and itch reduction are associated with more pronounced improvements in quality of life (QoL). Objective: To characterize the aggregate response benefit with upadacitinib versus dupilumab or placebo in patients with moderate-to-severe AD. Methods: Degree of skin clearance and itch response in 3 phase 3 studies (Heads Up [NCT03738397] and Measure Up 1/2 [integrated; NCT03569293/NCT03607422]) were assessed by the Eczema Area and Severity Index (EASI) and Worst Pruritus Numerical Rating Scale (WP-NRS), respectively, using mutually exclusive categories. The aggregate response benefit with upadacitinib over dupilumab or placebo was determined by summing incremental differences for each EASI or WP-NRS category across the full distribution of patient responses. Results: Comparisons across EASI improvement threshold distributions, EASI severity levels, and WP-NRS categories demonstrated an aggregate response benefit favoring upadacitinib over dupilumab as early as week 4 and continuing at weeks 16 and 24. Similar trends were observed for upadacitinib 15 and 30 mg versus placebo. Conclusions: The aggregate response benefit in skin clearance and itch reduction favored upadacitinib 30 mg over dupilumab and upadacitinib 15 or 30 mg over placebo. These benefits may translate to overall greater improvements in patient QoL.

Knee flexion compensation in postoperative adult spinal deformity patients: implications for sagittal balance and clinical outcomes.

PURPOSE: To determine whether maintaining good sagittal balance with significant knee flexion (KF) constitutes a suboptimal outcome after adult spinal deformity (ASD) correction. METHODS: This single-center, single-surgeon retrospective study, assessed ASD patients who underwent posterior spinal fusion between 2014 and 2020. Inclusion criteria included meeting at least one of the following: PI-LL ≥ 25°, T1PA ≥ 20°, or CrSVA-H ≥ 2 cm. Those with lower-extremity contractures were excluded. Patients were classified into four groups based on their 6-week postoperative cranio-hip balance and KF angle, and followed for at least 2 years: Malaligned with Knee Flexion (MKF+) (CrSVA-H > 20 mm + KFA > 10), Malaligned without Knee Flexion (MKF-) (CrSVA-H > 20 mm + KFA < 10), Aligned without Knee Flexion (AKF-) (CrSVA-H < 20 mm + KFA < 10), and Aligned with Knee Flexion (AKF+) (CrSVA-H < 20 mm + KFA > 10). The primary outcomes of this study included one and two year reoperation rates. Secondy outcomes included clinical and patient reported outcomes. RESULTS: 263 patients (mean age 60.0 ± 0.9 years, 74.5% female, and mean Edmonton Frailty Score 3.3 ± 0.2) were included. 60.8% (160/263 patients) exhibited good sagittal alignment at 6-week postop without KF. Significant differences were observed in 1-year (p = 0.0482) and 2-year reoperation rates (p = 0.0374) across sub-cohorts, with the lowest and highest rates in the AKF- cohort (5%, n = 8) and MKF + cohort (16.7%, n = 4), respectively. Multivariable Cox regression demonstrated the AKF- cohort exhibited significantly better reoperation outcomes compared to other groups: AKF + (HR: 5.24, p = 0.025), MKF + (HR: 31.7, p < 0.0001), and MKF- (HR: 11.8, p < 0.0001). CONCLUSION: Our findings demonstrate that patients relying on knee flexion compensation in the early postoperative period have inferior outcomes compared to those achieving sagittal balance without knee flexion. When compared to malaligned patients, those with CrSVA-H < 20 mm and KFA > 10 degrees experience fewer early reoperations but similar delayed reoperation rates. This insight emphasizes the importance of considering knee compensation perioperatively when managing sagittal imbalance in clinical practice.

Upadacitinib Rapidly Improves Patient-Reported Outcomes in Atopic Dermatitis: 16-Week Results from Phase 3 Clinical Trials (Measure Up 1 and 2).

INTRODUCTION: Atopic dermatitis (AD) is characterized by intense itch and other symptoms that negatively impact quality of life (QoL). This study evaluates the effect of upadacitinib (an oral selective Janus kinase inhibitor) monotherapy on patient-reported outcomes (PROs) among adults and adolescents with moderate-to-severe AD over 16 weeks. METHODS: This integrated analysis of the double-blind, placebo-controlled periods of phase 3 monotherapy clinical trials Measure Up 1 (NCT03569293) and Measure Up 2 (NCT03607422) assessed itch (Worst Pruritus Numerical Rating Scale [WP-NRS] and SCORing Atopic Dermatitis [SCORAD]), skin pain and symptom severity (AD Symptom Scale), symptom frequency (Patient-Oriented Eczema Measure), sleep (AD Impact Scale [ADerm-IS] and SCORAD), daily activities and emotional state (ADerm-IS), QoL (Dermatology Life Quality Index [DLQI] and Children's DLQI), mental health (Hospital Anxiety and Depression Scale), and patient impressions (Patient Global Impression of Severity, Patient Global Impression of Change, and Patient Global Impression of Treatment). RESULTS: Data from 1683 patients (upadacitinib 15 mg, n = 557; upadacitinib 30 mg, n = 567; placebo, n = 559) were analyzed. A greater proportion of patients receiving upadacitinib versus placebo experienced improvements in itch (≥ 4-point improvement on WP-NRS) by week 1 (upadacitinib 15 mg, 11.2%; upadacitinib 30 mg, 17.7%; placebo, 0.5%; P < 0.001), with response rates sustained through week 16 (upadacitinib 15 mg, 47.1%; upadacitinib 30 mg, 59.8%; placebo, 10.4%; P < 0.001). Improvements were similar for PROs assessing skin pain/symptoms, sleep, daily activities, QoL, emotional state, mental health, and patient impressions of disease severity and treatment. Responses generally improved rapidly (within 1-2 weeks), increased through weeks 4-6, and were maintained through week 16. CONCLUSIONS: Once-daily oral upadacitinib monotherapy improved response rates across PROs compared with placebo. Upadacitinib therapy resulted in rapid, sustained improvements in PROs measuring symptom burden and QoL in adults and adolescents with moderate-to-severe AD. TRIAL REGISTRATION: ClinicalTrials.gov identifiers, NCT03569293 and NCT03607422.

Atopic dermatitis, or eczema, is characterized by itchy, dry, inflamed skin. These symptoms often make it difficult for patients to get adequate sleep. Patients with atopic dermatitis may also experience anxiety, depression, reduced self-confidence, social isolation, disruption to daily activities like school and work, and decreased quality of life. Many atopic dermatitis symptoms, including itch and psychological impact, are difficult for doctors to assess. Thus, it is important to consider patients' descriptions of their symptoms and quality of life, particularly when assessing treatment benefit. Upadacitinib is an orally administered drug approved to treat moderate-to-severe atopic dermatitis. We investigated how upadacitinib (15 mg or 30 mg) given once daily to adults and adolescents with moderate-to-severe atopic dermatitis in the Measure Up 1 and 2 clinical trials impacts their symptoms and quality of life over a 16-week period. We compared changes in patient-reported itch, pain, sleep, daily activities, emotional state, mental health, and overall quality of life among patients in the clinical trials who received upadacitinib with those in the same studies who received a dummy (placebo) treatment. Upadacitinib improved patient-reported symptoms and quality of life early in the clinical trials, often within the first 1­2 weeks. The extent of the improvements increased through weeks 4­6 of treatment and lasted through week 16. Patients who received upadacitinib reported greater improvements in symptoms and quality of life than did patients who received placebo. Upadacitinib treatment resulted in rapid and lasting improvements in the well-being of patients with atopic dermatitis.