Search Results (255)

The treatment of arteritic anterior ischemic optic neuropathy (AAION), non-arteritic ischemic optic neuropathy (NAAION), and posterior ischemic optic neuropathy (PION) is a topic of ongoing research with mixed evidence on some pharmacotherapies and a need for more consensus. This manuscript provides an overview of these conditions’ current, potential future, and attempted pharmacotherapies. AAION’s current treatment regimen consists of high-dose steroids, with methotrexate, tocilizumab, and abatacept, being the most viable steroid-sparing therapy candidates. As for NAAION, the treatments being tried are vast, with mixed evidence supporting each modality. Similarly, despite the various treatment options explored, there still needs to be a universally effective therapy for PION. More research is needed to formulate an agreed-upon treatment regimen for these conditions. Full article

Objective: This study aimed to assess changes in the morphology of the retina and cornea in patients treated and hospitalized during the acute active phase of SARS-CoV-2 infection. Methods: A total of 24 patients with symptomatic early COVID-19 disease and 38 healthy participants from a control group were enrolled in our study. Among them, 20 received oxygen therapy at flow rates ranging from 1–10 L, while four received high-flow intranasal oxygen therapy (HFNOT). Some patients were treated with other types of therapy, such as Remdesivir, COVID-19 convalescent plasma therapy, or Tocilizumab. In the study, we focused on the analysis of optical coherence tomography (OCT) images of the cornea and retina including corneal thickness, central retinal thickness, retinal nerve fiber layer (RNFL), and optic disc parameters. The measurements were acquired using Spectral-domain OCT REVO FC 130. Results: The analysis did not show significant changes between the examined ophthalmological parameters before and after therapy. Furthermore, there were no detected significant differences between the tested parameters of the retina and cornea in COVID-19-positive patients compared to the control group. Conclusions: No ophthalmological manifestations of COVID-19 disease were observed during the study. Taking into account the results of other publications, the lack of an unambiguous position on this topic requires further research. Full article

Introduction: Systemic lupus erythematosus (SLE) is a multifaceted autoimmune disorder characterized by significant autoantibodies, particularly targeting nuclear antigens. SLE pathogenesis involves genetic, environmental, and hormonal factors. The disease course includes flares and remission and involves various organs. Recent therapeutic progresses, including biologics, have improved management and prognosis, though the long-term impact of novel therapies remains to be determined. Biologics in SLE: Rituximab, the earliest B-cell-oriented biologic, binds CD20 and depletes CD20+ B cells, leading to remission in some SLE patients. Belimumab is a B-cell-activating factor (BAFF) inhibitor with a recent additional indication for lupus nephritis. The CALIBRATE and BLISS-BELIEVE studies investigated combinations of these drugs with conventional therapies, showing varied efficacy. Ocrelizumab and obinutuzumab, newer CD20-oriented SLE therapies, together with ofatumumab and veltuzumab, are also promising. The latest trials highlight their efficacy and safety. Anifrolumab, targeting type-I interferon receptors, was evaluated in the TULIP 1/2 trials. The ongoing TULIP LTE trial supports the long-term safety and efficacy of anifrolumab. Additionally, the IRIS Phase III trial is exploring anifrolumab for lupus nephritis, showing favorable renal responses. Tocilizumab and secukinumab are being assessed for SLE, with mixed outcomes. Several biologics targeting the C5 complement protein, together with immunomodulators and immunotherapeutics, are also under investigation for potential benefits in SLE. Discussion: Biologics in SLE target specific immune components, aiming to improve disease control and reduce the side effects of conventional therapy. However, trial outcomes vary due to factors like inclusion criteria and trial design. Conclusions: Biotechnology progress enables targeted biologic therapies for SLE, reducing disease activity and improving patients’ quality of life. Full article

Esophageal adenocarcinoma (EAC) is a subtype of esophageal cancer that is difficult to treat, with overall poor survival and frequent recurrence despite curative-intent treatment strategies. There is limited understanding of EAC resistance mechanisms to chemotherapy or radiation. We have found that the AMP-activated protein kinase (AMPK) can serve a pro-survival function in EAC cells in response to cytotoxic treatments. Treatment with the IL-6 inhibitor tocilizumab, which previously has been shown to inhibit EAC organoid growth, resulted in the activation of AMPK in the OE33 EAC cell line, which was accompanied by a decrease in MTORC1 signaling and an increase in oxidative mitochondrial metabolism, both known downstream effects of AMPK activation to promote cell survival under conditions of metabolic stress. This increase in oxidative metabolism was abrogated in cells with a genetic knockdown of AMPK expression. Furthermore, we found that AMPK was activated in OE33 cells following treatment with cisplatin or ionizing radiation. Treatment with the AMPK inhibitor Compound C or genetic knockdown of AMPK expression enhanced cell death in a synergistic manner with chemotherapeutics or ionizing radiation. These findings were recapitulated in human patient-derived EAC organoids, suggesting that AMPK may be a common pro-survival mechanism to confer treatment resistance in EAC and may serve as a novel target to enhance the efficacy of current and future treatment strategies. Full article

Background: Coronavirus Disease-2019 (COVID-19) has posed formidable challenges to healthcare systems. Exploring novel biomarkers that can provide valuable prognostic insights, particularly in critically ill patients, has a significant importance. Against this backdrop, our study aims to elucidate the associations between serum chloride levels and clinical outcomes. Methods: A total of 499 patients were enrolled into the study. The serum chloride levels of patients upon hospital admission were recorded and then categorized into three groups (hypochloremia, normochloremia, and hyperchloremia) for the evaluation of clinical outcomes. Additionally, serum C-reactive protein, procalcitonin, and D-dimer measurements were recorded for further evaluation. Results: A total of 390 (78.1%) patients tested positive for COVID-19 via polymerase chain reaction testing. Non-contrast thorax computed tomography scans were indicative of COVID-19 compatibility for all patients. A total of 210 (42%) patients were female and 289 (58%) were male. A total of 214 (42.8%) patients necessitated tocilizumab intervention; 250 (50.1%) were at an intensive care unit (ICU), with 166 (66.4%) of them receiving tocilizumab. A total of 65 (13%) patients died, 40 (61.5%) of whom received tocilizumab; 41 (63%) were in the ICU. Serum chloride levels upon admission were markedly lower and elevated D-dimer levels were apparent in tocilizumab users, patients requiring ICU care, and patients who died. Conclusions: our findings provide robust evidence supporting the value of serum chloride levels as a prognostic biomarker in critically ill COVID-19 patients. Full article

Circular (circ) RNAs are non-coding RNAs with important functions in the nervous system, cardiovascular system, and cancer. Their role in atherosclerosis and myocardial infarction (MI) remains poorly described. We aim to investigate the potential circRNAs in immune cells during atherogenesis and examine the most regulated during MI and the modulation by interleukin (IL)-6 receptor inhibition by tocilizumab. Wild-type (WT) and ApoE^−/− mice were fed an atherogenic diet for 10 weeks, and the circRNA profile was analyzed by circRNA microarray. Whole blood from patients with ST-elevated MI (STEMI) and randomized to tocilizumab (n = 21) or placebo (n = 19) was collected at admission, 3–7 days, and at 6 months, in addition to samples from healthy controls (n = 13). Primers for human circRNA were designed, and circRNA levels were measured using RT-qPCR. mRNA regulation of predicted circRNA targets was investigated by RNA sequencing. The expression of 867 circRNAs differed between atherogenic and WT mice. In STEMI patients, circUBAC2 was significantly lower than in healthy controls. CircANKRD42 and circUBAC2 levels were inversely correlated with troponin T, and for circUBAC2, an inverse correlation was also seen with final infarct size at 6 months. The predicted mRNA targets for circUBAC2 and circANKRD42 were investigated and altered levels of transcripts involved in the regulation of inflammatory/immune cells, apoptosis, and mitochondrial function were found. Finally, tocilizumab induced an up-regulation of circANKRD42 and circUBAC2 3–7 days after percutaneous coronary intervention. CircRNA levels were dysregulated in STEMI, potentially influencing the immune system, apoptosis, and mitochondrial function. Full article

Bone metastases, a common and debilitating consequence of advanced cancers, involve a complex interplay between malignant cells and the bone microenvironment. Central to this interaction are interleukins (ILs), a group of cytokines with critical roles in immune modulation and inflammation. This review explores the dualistic nature of pro-inflammatory and anti-inflammatory interleukins in bone metastases, emphasizing their molecular mechanisms, pathological impacts, and therapeutic potential. Pro-inflammatory interleukins, such as IL-1, IL-6, and IL-8, have been identified as key drivers in promoting osteoclastogenesis, tumor proliferation, and angiogenesis. These cytokines create a favorable environment for cancer cell survival and bone degradation, contributing to the progression of metastatic lesions. Conversely, anti-inflammatory interleukins, including IL-4, IL-10, and IL-13, exhibit protective roles by modulating immune responses and inhibiting osteoclast activity. Understanding these opposing effects is crucial for developing targeted therapies aimed at disrupting the pathological processes in bone metastases. Key signaling pathways, including NF-κB, JAK/STAT, and MAPK, mediate the actions of these interleukins, influencing tumor cell survival, immune cell recruitment, and bone remodeling. Targeting these pathways presents promising therapeutic avenues. Current treatment strategies, such as the use of denosumab, tocilizumab, and emerging agents like bimekizumab and ANV419, highlight the potential of interleukin-targeted therapies in mitigating bone metastases. However, challenges such as therapeutic resistance, side effects, and long-term efficacy remain significant hurdles. This review also addresses the potential of interleukins as diagnostic and prognostic biomarkers, offering insights into patient stratification and personalized treatment approaches. Interleukins have multifaceted roles that depend on the context, including the environment, cell types, and cellular interactions. Despite substantial progress, gaps in research persist, particularly regarding the precise mechanisms by which interleukins influence the bone metastatic niche and their broader clinical implications. While not exhaustive, this overview underscores the critical roles of interleukins in bone metastases and highlights the need for continued research to fully elucidate their complex interactions and therapeutic potential. Addressing these gaps will be essential for advancing our understanding and treatment of bone metastases in cancer patients. Full article

Chronic wounds pose a significant clinical challenge due to their complex pathophysiology and the burden of long-term management. Monoclonal antibodies (mAbs) are emerging as a novel therapeutic option in managing difficult wounds, although comprehensive data on their use in wound care are lacking. This study aimed to explore existing scientific knowledge of mAbs in treating chronic wounds based on a rationale of direct inhibition of the main molecules involved in the underlying inflammatory pathophysiology. We performed a literature review excluding primary inflammatory conditions with potential ulcerative outcomes (e.g., hidradenitis suppurativa). mAbs were effective in treating wounds from 16 different etiologies. The most commonly treated conditions were pyoderma gangrenosum (treated with 12 different mAbs), lipoid necrobiosis, and cutaneous vasculitis (each treated with 3 different mAbs). Fourteen mAbs were analyzed in total. Rituximab was effective in 43.75% of cases (7/16 diseases), followed by tocilizumab (25%, 4/16 diseases), and both etanercept and adalimumab (18.75%, 3/16 conditions each). mAbs offer therapeutic potential for chronic wounds unresponsive to standard treatments. However, due to the complex molecular nature of wound healing, no single target molecule can be identified. Therefore, the use of mAbs should be considered as a translational approach for limited cases of multi-resistant conditions. Full article

Background: Pulmonary involvement in systemic juvenile idiopathic arthritis (SJIA) is a rare but dangerous complication. The main risk factors are already known, such as macrophage activation syndrome, a refractory course of systemic juvenile arthritis, infusion reaction to interleukin 1 and/or interleukin 6 blockers, trisomy 21, and eosinophilia. However, information about respiratory system involvement (RSI) at the onset of SJIA is scarce. Our study aimed to evaluate the specific features of children with SJIA with RSI and their outcomes. Methods: In a single-center retrospective cohort study, we compared the information from the medical records of 200 children with SJIA according to ILAR criteria or SJIA-like disease (probable/possible SJIA) with and without signs of RSI (dyspnea, shortness of breath, pleurisy, acute respiratory distress syndrome, and interstitial lung disease (ILD)) at the disease onset and evaluated their outcomes (remission, development of chronic ILD, clubbing, and pulmonary arterial hypertension). Results: A quarter (25%) of the SJIA patients had signs of the RSI at onset and they more often had rash; hepato- and splenomegaly; heart (pericarditis, myocarditis), central nervous system, and kidney involvement; hemorrhagic syndrome; macrophage activation syndrome (MAS, 44.4% vs. 9.0%, p = 0.0000001); and, rarely, arthritis with fewer active joints, compared to patients without RSI. Five patients (10% from the group having RSI at the onset of SJIA and 2.5% from the whole SJIA cohort) developed fibrosing ILD. All of them had a severe relapsed/chronic course of MAS; 80% of them had a tocilizumab infusion reaction and further switched to canakinumab. Unfortunately, one patient with Down’s syndrome had gone. Conclusion: Patients with any signs of RSI at the onset of the SJIA are required to be closely monitored due to the high risk of the following fibrosing ILD development. They required prompt control of MAS, monitoring eosinophilia, and routine checks of night oxygen saturation for the prevention/early detection of chronic ILD. Full article

Pulmonary drug delivery offers a minimally invasive and efficient method for treating lung conditions, leveraging the lungs’ extensive surface area and blood flow for rapid drug absorption. Nebulized therapies aim to deliver drugs directly to the lung tissue. This study investigates the histological impact of nebulized tocilizumab—a monoclonal antibody targeting IL-6, traditionally administered intravenously for rheumatoid arthritis and severe COVID-19—on a murine model. Thirty BALB/c mice were nebulized with tocilizumab (10 mg, 5 mg, and 2.5 mg) and six controls were nebulized with saline solution. They were euthanized 48 h later, and their organs (lungs, nasal mucosa, and liver) were analyzed by a microscopic histological evaluation. The results indicate that all the mice survived the 48 h post-nebulization period without systemic compromise. The macroscopic examination showed no abnormalities, and the histopathological analysis revealed greater lung vascular changes in the control group than in the nebulized animals, which is attributable to the euthanasia with carbon dioxide. Additionally, increased alveolar macrophages were observed in the nebulized groups compared to controls. No significant histological changes were observed in the liver, indicating the safety of nebulized tocilizumab. In conclusion, these findings suggest the potential of nebulized tocilizumab for treating pulmonary inflammation, warranting further research to establish its efficacy and safety in clinical settings. Full article

An older age is associated with severe progression and poor prognosis in coronavirus disease 2019 (COVID-19), and mechanical ventilation is often required. The specific characteristics of older patients undergoing mechanical ventilation and their prognostic factors are largely unknown. We aimed to identify potential prognostic factors in this group to inform treatment decisions. This retrospective cohort study collected data from patients with COVID-19 at 22 medical centers. Univariate and multivariate Cox regression analyses were performed to assess factors that influence mortality. We allocated 434 patients in geriatric (≥80 years) and elderly (65–79 years) groups. The former group scored significantly higher than the elderly group in the clinical frailty scale and sequential organ failure assessment, indicating more severe organ dysfunction. Significantly lower administration rates of tocilizumab and extracorporeal membrane oxygenation and higher intensive care unit (ICU) and in-hospital mortality were noted in the geriatric group. The factors associated with ICU and in-hospital mortality included high creatinine levels, the use of continuous renal replacement therapy, prone positioning, and the administration of life-sustaining treatments. These results highlight significant age-related differences in the management and prognosis of critically ill older patients with COVID-19. Increased mortality rates and organ dysfunction in geriatric patients undergoing mechanical ventilation necessitate age-appropriate treatment strategies to improve their prognoses. Full article

Granulomatous tubulointerstitial nephritis (GTIN) attributed to early onset sarcoidosis is an ultrarare finding in an allograft kidney biopsy. We present the case of a young man with allograft dysfunction who had GTIN upon biopsy. We performed a thorough case review based on recovered records from early childhood and reassessed genetic testing results. We revised his underlying diagnosis from cryopyrin-associated periodic syndrome to early-onset sarcoidosis with wild-type NOD2 and established a rationale to use the interleukin-6 (IL-6) receptor blocker tocilizumab (TCZ). This suppressed his inflammatory disease and stabilised kidney function. We performed a literature review related to the emerging role of IL-6 pathway blockade in kidney transplantation. We identified 18 reports with 417 unique patients treated with TCZ for indications including HLA-desensitisation, transplant immunosuppression induction, treatment of chronic antibody-mediated rejection, and treatment of subclinical rejection. Both TCZ and the direct IL-6 inhibitor clazakizumab are being studied in ongoing randomised control trials. Full article

TAFRO syndrome is an inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly. Despite great advancements in research on the TAFRO syndrome in the last decade, its diagnosis and treatment are still challenging for most clinicians because of its rarity and severity. Since the initial proposal of the TAFRO syndrome as a distinct disease entity in 2010, two independent diagnostic criteria have been developed. Although these are different in the concept of whether TAFRO syndrome is a subtype of idiopathic multicentric Castleman disease or not, they are similar except for the magnitude of lymph node histopathology. Because there have been no specific biomarkers, numerous diseases must be ruled out before the diagnosis of TAFRO syndrome is made. The standard of care has not been fully established, but interleukin-6 blockade therapy with siltuximab or tocilizumab and anti-inflammatory therapy with high-dose corticosteroids are the most commonly applied for the treatment of TAFRO syndrome. The other immune suppressive agents or combination cytotoxic chemotherapies are considered for patients who do not respond to the initial treatment. Whereas glowing awareness of this disease improves the clinical outcomes of patients with TAFRO syndrome, further worldwide collaborations are warranted. Full article

Objective: Chloroquine (CQ) and hydroxychloroquine (HCQ) were used as off-label treatments for SARS-CoV-2 infection during the first pandemic waves. The urgency of combatting COVID-19 led to the dissemination of medical recommendations with a scarce awareness of possible drug–drug interactions. This issue primarily concerned people already taking multiple medications, such as older individuals. We estimated the prevalence of drug interactions with CQ or HCQ in COVID-19 inpatients during the first pandemic waves and their possible association with hospitalization-related outcomes. Methods: This study considers 487 patients aged ≥60, hospitalized for COVID-19 from March to December 2020, and treated with CQ or HCQ. Data on acute and chronic therapies and hospitalization length and outcomes were derived from medical records. The presence of drugs potentially interacting with CQ and HCQ was identified based on published literature and drug databases. Results: In our sample (mean age 77.1 years, 47.8% females), 255 (52.4%) patients presented with one drug interaction with CQ or HCQ, and 114 (23.4%) had more than two interactions. The most frequent drugs potentially interacting with CQ or HCQ were lopinavir/ritonavir (50.4%), azithromycin (47.2%), tocilizumab (15.4%), levofloxacin (8.7%), clarithromycin (6.0%), amlodipine (3.3%), and trazodone (2.4%). No substantial differences in the duration and outcomes of the hospitalization emerged as a function of the presence of drug–drug interactions. Conclusions: Many older patients prescribed with CQ or HCQ, which have lately proved ineffective against COVID-19, were exposed to the risk of drug–drug interaction. This underlines that medical recommendations should undergo careful peer review before being widely disseminated, even in emergencies like a pandemic. Full article

COVID-19 infection is caused by the novel severe acute respiratory syndrome coronavirus 2 (SAR-CoV-2). This novel virus has transformed into different resistant variants (e.g., omicron; delta; alpha; epsilon) since its first emergence in 2019. The National Institutes of Health and Infectious Diseases Society of America guidelines currently recommend adding either baricitinib or tocilizumab to the standard of care for severe COVID-19 treatment. An outcome comparison between baricitinib and tocilizumab is needed to determine which agent is more appropriate and safer in clinical practice when deciding treatment. We aimed to compare mortality and clinical outcomes between tocilizumab and baricitinib in the management of severe COVID-19 infection. A total of 5638 adult patients from 16 acute care hospitals in a large healthcare system in Texas were included in this multicentered retrospective cohort study. The median age of the patients was 56 years and 46.67% of them were female. Severe COVID-19 patients were treated with standard of care and either tocilizumab or baricitinib. The primary outcome of hospital admission mortality rates was found to be higher with tocilizumab (odd ratio (OR) of 1.56; p = 0.001; 95% CI 1.19 to 2.008) compared to that with baricitinib (OR 0.65; p = 0.001; 95% CI 0.50 to 0.84). For one of the secondary outcomes, patients who received tocilizumab were 3.75 times more likely to be admitted to the ICU than those receiving baricitinib (p = 0.001; 95% CI 2.89 to 4.85). Among the 1199 COVID-19 patients who were admitted to the ICU, the ICU length of stay was shorter among patients receiving baricitinib with a mean difference of 4.42 days and a median difference of 2.54 days, compared to those receiving tocilizumab (p < 0.0001; 95% CI −5.97 to −2.62) as another secondary outcome. Our large retrospective observational study showed that baricitinib reduced mortality; the likelihood of ICU admission; and the ICU length of stay compared to tocilizumab in patients with severe COVID-19 infection. Full article