Treatment of atopic dermatitis with upadacitinib: adcare single center experience.

Introduction: The role of upadacitinib in the management of moderate to severe atopic dermatitis seems promising, but more data on its efficacy and safety are needed. This study endeavors to assess the practical impact and safety of upadacitinib in patients with moderate to severe atopic dermatitis. The study aims to evaluate the efficacy and safety of upadacitinib in the treatment of moderate to severe atopic dermatitis, focusing on analyzing patient responses to the treatment. Methods: In this study, adult patients diagnosed with moderate to severe atopic dermatitis received upadacitinib at daily doses of 15 mg or 30 mg, as prescribed by their attending physicians. The therapeutic efficacy of upadacitinib was meticulously assessed using established clinical metrics. Simultaneously, a comprehensive safety assessment was conducted through monthly monitoring, including the evaluation of potential effects of upadacitinib intake on hepatic function, lipid profile, and hematopoiesis using the pertinent laboratory tests. Results: Sixteen participants were enrolled in the study. At 1month follow-up, there was a significant reduction in the mean Eczema Area and Severity Index (EASI) score to 18.8 points, which further increased to 24 points at the 4-month mark. Additionally, 9 participants (56%) demonstrated an EASI-50 response after 1 month of treatment, with this response increasing to 9 participants (90%) after 4 months. Furthermore, enhanced therapeutic responses were observed at 4 months, with 6 patients (38%) achieving an EASI-75 response at 1month and 8 patients (80%) achieving this milestone at the 4-month follow-up. This study highlights the potential of upadacitinib as an effective treatment option for moderate to severe atopic dermatitis. While it demonstrates improved symptom management, close monitoring for potential adverse events, particularly infections and the known risks of Janus kinase inhibitors, is essential. Further research is essential to determine the long-term safety and efficacy of upadacitinib.

Real-world clinical effectiveness of Tixagevimab/Cilgavimab and Regdanvimab monoclonal antibodies for COVID-19 treatment in Omicron variant-dominant period.

Several virus-neutralizing monoclonal antibodies (mAbs) have become new tools in the treatment of the coronavirus disease (COVID-19), but their effectiveness against the rapidly mutating virus is questionable. The present study investigated the effectiveness of Tixagevimab/Cilgavimab and Regdanvimab for mild and moderate COVID-19 treatment in real-world clinical practice during the Omicron variant-dominant period. Patients with known risk factors for disease progression and increasing disease severity were enrolled in the study within the first 7 days of symptom onset. Seventy-seven patients were divided into four groups: first 15 patients received 300 mg Tixagevimab/Cilgavimab intravenously (IV) and 23 patients got the same drug 300 mg intramuscularly (IM), the next 15 patients was on the same combination in dose of 600 mg IV, and 24 patients were on Regdanvimab at a dose of 40 mg/kg IV. By Day 4, 100% of Tixagevimab/Cilgavimab IV patients showed negative polymerase chain reaction results for SARS-CoV-2 Ribonucleic acid (RNA) regardless of the mAbs dose while in the Regdanvimab group 29% of the patients were positive for SARS-CoV-2 virus RNA. The testing for virus neutralizing antibodies (nAbs) to various Omicron sublineages (BA.1, BA.2, and BA.5) showed that an increase in nAb levels was detected in blood serum immediately after the drug administration only in Tixagevimab/Cilgavimab 300 mg and 600 mg IV groups. In the group of intravenous Regdanvimab, a significant increase in the level of nAbs to the Wuhan variant was detected immediately after the drug administration, while no increase in nAbs to different Omicron sublineages was observed. Clinical trial registration: https://clinicaltrials.gov/, identifier NCT05982704.

Positive experience with TNF-α inhibitor in toxic epidermal necrolysis resistant to high-dose systemic corticosteroids.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, potentially life-threatening syndromes characterized by the development of necrotic epidermal and mucosal lesions. The most common etiologic cause of SJS/TEN is drug-induced mechanisms. The group of drugs with high potential risk includes sulfonamides, anticonvulsants, non-steroidal anti-inflammatory drugs (NSAIDs), allopurinol, phenobarbital, etc. There is no gold standard treatment algorithm for SJS/TEN. In medical practice, systemic glucocorticosteroids (sGCS), intravenous immunoglobulin (IVIG), plasmapheresis, and cyclosporine are used empirically and in various combinations. Recently published studies have demonstrated the efficacy of TNF-α inhibitors as a promising approach in SJS/TEN, including cases resistant to high-dose sGCS, with etanercept and infliximab being the most commonly used drugs. In a large multicenter study by Zhang J et al. (XXXX), 242 patients treated with etanercept, sGCS, or a combination of both had lower mortality compared to the control group. A shorter skin healing time was documented compared to sGCS monotherapy, thus reducing the risk of secondary infections. The published data show a high efficacy with THF-α inhibitor blockade, but the safety of TNF-α inhibitors in patients with SJS/TEN is still questionable due to the paucity of available information. As all clinical research data should be accumulated to provide reliable evidence that the use of TNF-α inhibitors may be beneficial in SJS/TEN, we report a case of etoricoxib-associated SJS with progression to TEN in a 50-year-old woman who was refractory to high-dose sGCS therapy.

Glycated hemoglobin level dynamics in COVID-19 survivors: 12 months follow-up study after discharge from hospital.

INTRODUCTION: One of the stages of reproduction of SARS-CoV-2 is the S-protein glycosylation to facilitate penetration into target cells. It has been suggested that SARS-CoV-2 is able to enter erythrocytes, interact with heme and porphyrin, which could influence HbA1c levels. Assessment of HbA1c levels in individuals with acute COVID-19 and after recovery may show clinical relevance of this hypothesis. AIM: To assess HbA1c levels in patients with COVID-19 in the acute phase and in early (6-8 weeks) and late (52±2 weeks) periods after recovery. MATERIALS AND METHODS: We conducted a multicenter prospective study, which included patients hospitalized in Endocrinology Research Centre and the City Clinical Hospital № 52" diagnosed with COVID-19, virus identified/ not identified. Patients were divided into three groups according to baseline HbA1c level and the presence or absence of previous history of diabetes previous history of diabetes mellitus (DM): HbA1c ≤ 6.0%, HbA1c > 6.0% and patients with DM. Patients were examined during the acute COVID-19 phase and in early (6-8 weeks) and late (52±2 weeks) periods after recovery. Oral glucose tolerance test was performed in the group with initial HbA1c > 6.0% to clarify the diagnosis. RESULTS: We included 194 patients in the study. During the follow-up, 52 patients were examined in 6-8 week period: 7 with HbA1c ≤ 6.0%, 34 with HbA1c > 6.0%, 11-with previously diagnosed DM. Carbohydrate metabolism assessment in the later stages (52±2 weeks) after recovery was performed in 78 patients: 33 patients with HbA1c ≤ 6.0%, 36 patients with HbA1c > 6.0% and 9 patients with previously established diabetes. HbA1c median in patients with HbA1c ≤ 6.0% was 5.7% [5.3;5.8], with HbA1c>6.0% -6.4% [6.2; 6.6], with previously diagnosed DM-7.7% [7.2; 8.9]. Statistically significant decrease in HbA1c over time 6-8 weeks after extracts were obtained in both groups of individuals without a history of DM (Wilcoxon test, p<0.05). After 52±2 weeks we observed HbA1c decrease in all three groups (Fridman test, p<0.05): in patients with HbA1c ≤ 6.0% median HbA1c was 5.5[5.3;5.7], with HbA1c>6.0% - 6.1[6.15;6.54], with previously diagnosed DM-7.8 [5.83; 8.08]. Development of DM after 52±2 weeks was recorded in 7.24% of all examined patients without a history of DM, which is 16.6% of the total number of patients examined in dynamics with HbA1c > 6.0%. CONCLUSION: HbA1c elevation during the acute phase of COVID-19 may be false due to the effect of SARS-CoV-2 on hemoglobin kinetics and/or detection on the surface of the SARS-CoV-2 virion highly glycosylated S-proteins by high performance liquid chromatography determinations. Upon detection HbA1c > 6.0% in patients with COVID-19 in the active phase of the disease without concomitant hyperglycemia re-determine the level of HbA1c after recovery is recommended.

SARS-CoV-2 evolution in a patient with secondary B-cell immunodeficiency: A clinical case.

The article highlights the course of long-term SARS-CoV-2 infection in a patient with a secondary immunodeficiency developed with B-cell-depleting therapy of the underlying disease. Analysis of the intrapatient virus evolution revealed an inpatient S:G75A mutation that alters the 72GTNGTKR78 motif of the S-protein, with a possible role in binding to alternative cellular receptors. Therapy with a ready-made COVID-19-globulin preparation (native human immunoglobulin G (IgG) derived from the plasma of convalescent COVID-19-patients) resulted in rapid improvement of the patient's condition, fast, and stable elimination of the virus, and passive immunization of the patient for at least 30 days. The results suggest the use of products containing neutralizing antibodies opens new prospects for treatment algorithms for patients with persistent coronavirus infection, as well as for passive immunization schemes for patients with a presumably reduced specific response to vaccination.

Tocilizumab, netakimab, and baricitinib in patients with mild-to-moderate COVID-19: An observational study.

OBJECTIVE: The aim of the study was to assess inflammatory markers and clinical outcomes in adult patients admitted to hospital with mild-to-moderate COVID-19 and treated with a combination of standard-of-care (SOC) and targeted immunosuppressive therapy including anti-IL-17A (netakimab), anti-IL-6R (tocilizumab), or JAK1/JAK2 inhibitor (baricitinib) or with a standard-of-care therapy alone. METHODS: The observational cohort study included 154 adults hospitalized between February and August, 2020 with RT-PCR-confirmed SARS-CoV-2 with National Early Warning Score2 (NEWS2) < 7 and C-reactive protein (CRP) levels ≤ 140 mg/L on the day of the start of the therapy or observation. Patients were divided into the following groups: I) 4 mg baricitinib, 1 or 2 times a day for an average of 5 days (n = 38); II) 120 mg netakimab, one dose (n = 48); III) 400 mg tocilizumab, one dose (n = 34), IV) SOC only: hydroxychloroquine, antiviral, antibacterial, anticoagulant, and dexamethasone (n = 34). RESULTS: CRP levels significantly decreased after 72 h in the tocilizumab (p = 1 x 10-5) and netakimab (p = 8 x 10-4) groups and remained low after 120 h. The effect was stronger with tocilizumab compared to other groups (p = 0.028). A significant decrease in lactate dehydrogenase (LDH) levels was observed 72 h after netakimab therapy (p = 0.029). NEWS2 scores significantly improved 72 h after tocilizumab (p = 6.8 x 10-5) and netakimab (p = 0.01) therapy, and 120 h after the start of tocilizumab (p = 8.6 x 10-5), netakimab (p = 0.001), or baricitinib (p = 4.6 x 10-4) therapy, but not in the SOC group. Blood neutrophil counts (p = 6.4 x 10-4) and neutrophil-to-lymphocyte ratios (p = 0.006) significantly increased 72 h after netakimab therapy and remained high after 120 h. The percentage of patients discharged 5-7 days after the start of therapy was higher in the tocilizumab (44.1%) and netakimab (41.7%) groups than in the baricitinib (31.6%) and SOC (23.5%) groups. Compared to SOC (3 of the 34; 8.8%), mortality was lower in netakimab (0 of the 48; 0%, RR = 0.1 (95% CI: 0.0054 to 1.91)), tocilizumab (0 of the 34; 0%, RR = 0.14 (95% CI: 0.0077 to 2.67)), and baricitinib (1 of the 38; 2.6%, RR = 0.3 (95% CI: 0.033 to 2.73)) groups. CONCLUSION: In hospitalized patients with mild-to-moderate COVID-19, the combination of SOC with anti-IL-17A or anti-IL-6R therapy were superior or comparable to the combination with JAK1/JAK2 inhibitor, and all three were superior to SOC alone. Whereas previous studies did not demonstrate significant benefit of anti-IL-17A therapy for severe COVID-19, our data suggest that such therapy could be a rational choice for mild-to-moderate disease, considering the generally high safety profile of IL-17A blockers. The significant increase in blood neutrophil count in the netakimab group may reflect efflux of neutrophils from inflamed tissues. We therefore hypothesize that neutrophil count and neutrophil-to-lymphocyte ratio could serve as markers of therapeutic efficiency for IL-17A-blocking antibodies in the context of active inflammation.

Comprehensive Cytokine Profiling of Patients with COVID-19 Receiving Tocilizumab Therapy.

Coronavirus disease 2019 (COVID-19) is characterized by immune activation in response to viral spread, in severe cases leading to the development of cytokine storm syndrome (CSS) and increased mortality. Despite its importance in prognosis, the pathophysiological mechanisms of CSS in COVID-19 remain to be defined. Towards this goal, we analyzed cytokine profiles and their interrelation in regard to anti-cytokine treatment with tocilizumab in 98 hospitalized patients with COVID-19. We performed a multiplex measurement of 41 circulating cytokines in the plasma of patients on admission and 3-5 days after, during the follow-up. Then we analyzed the patient groups separated in two ways: according to the clusterization of their blood cytokines and based on the administration of tocilizumab therapy. Patients with and without CSS formed distinct clusters according to their cytokine concentration changes. However, the tocilizumab therapy, administered based on the standard clinical and laboratory criteria, did not fully correspond to those clusters of CSS. Furthermore, among all cytokines, IL-6, IL-1RA, IL-10, and G-CSF demonstrated the most prominent differences between patients with and without clinical endpoints, while only IL-1RA was prognostically significant in both groups of patients with and without tocilizumab therapy, decreasing in the former and increasing in the latter during the follow-up period. Thus, CSS in COVID-19, characterized by a correlated release of multiple cytokines, does not fully correspond to the standard parameters of disease severity. Analysis of the cytokine signature, including the IL-1RA level in addition to standard clinical and laboratory parameters may be useful to define the onset of a cytokine storm in COVID-19 as well as the indications for anti-cytokine therapy.

Temporal Clinical and Laboratory Response to Interleukin-6 Receptor Blockade With Tocilizumab in 89 Hospitalized Patients With COVID-19 Pneumonia.

BACKGROUND: Pandemic COVID-19 pneumonia due to SARS-2 is an important cause of morbidity and mortality. Emerging evidence links poor outcomes to an inflammatory cytokine storm. METHODS: We treated 89 hospitalized patients with COVID-19 pneumonia and heightened systemic inflammation (elevated serum C reactive protein and interleukin-6 levels) with an infusion of tocilizumab (TCZ), a human monoclonal IgG1 antibody to the interleukin-6 receptor. RESULTS: Clinical and laboratory evidence of improvement was evident when baseline and 1-2-day post-infusion indices were compared. Among the 72 patients receiving supplemental oxygen without mechanical ventilation, severity of condition on the NEWS2 scale scores fell from 5 to 2 (P<0.001), C reactive protein levels fell from 95 to 14 mg/L (P<0.001), and lymphocyte counts rose from 900 to 1000/uL (P=0.036). Sixty-three of 72 patients were discharged from the hospital, one patient died, and eight patients remained in the hospital at the time of this writing. Among the 17 patients receiving mechanical ventilation, despite a rapid decrease in CRP levels from 89 to 35 mg/L (P=0.014) and early improvements in NEWS2 scores in 10 of 17 patients, 10 patients ultimately died and the other seven remain in the hospital at the time of this writing. Overall, mortality was only seen in patients who had markedly elevated CRP levels (>30 mg/L) and low lymphocyte counts (<1000/uL) before TCZ administration. CONCLUSIONS: Inflammation and lymphocytopenia are linked to mortality in COVID-19. Inhibition of IL-6 activity by administration of tocilizumab, an anti-IL-6 receptor antibody, is associated with rapid improvement in both CRP and lymphocyte counts and in clinical indices. Controlled clinical trials are needed to confirm the utility of IL-6 blockade in this setting. Additional interventions will be needed for patients requiring mechanical ventilation.

Pheochromocytoma surgery: epidemiologic peculiarities in children.

Manifestations of pheochromocytoma have some specific features in children. The aim of this study was to explore epidemiologic differences of the disease course in children and adults, the principal causes of pheochromocytoma recurrence, and the optimal extent of an operative intervention in a group of patients with initial manifestation of their tumor during childhood. A total of 520 patients with pheochromocytoma underwent surgery from 1957 to 2001. The mean age of the patients was 39.3 +/- 9.2 years; 50 patients (9.6%) were 16 years or under (children's group). There were 213 males (41%) in the general group and 32 males (62%) in the children's group. Bilateral adrenal lesions were present in 68 patients (13.1%), including 16 of the 50 children (32%). The tumors were extraadrenal in 36 patients (6.9%), including 9 of the 50 children (18%). The combination of pheochromocytoma and a hereditary syndrome was present in 36 cases (6.9%). Follow-up was obtained in 260 patients, including 46 children. Length of follow-up varied from 4 to 25 years (average 8.4 +/- 1.9 years). The pheochromocytoma recurred in 49 patients (18.8% of surveyed patients), with a true recurrence (a tumor in the region of the primary operation or metastases) in 16 patients (6.15%). A true pheochromocytoma recurrence was noted in 6 of the 50 children (12.0%). Organ-sparing tactics for multicentric adrenal lesions was a principal cause of the true recurrence. Therefore we believe it is necessary to perform a radical operation, which includes adrenalectomy and removal of the tumor, in patients with a high risk of recurrence.