Impact of Baseline Corticosteroids on Immunotherapy Efficacy in Patients With Advanced Melanoma.

This is a 2-center, retrospective study which aimed to evaluate the effect of baseline corticosteroid use on immunotherapy efficacy in patients with advanced melanoma. We included all patients with advanced unresectable and metastatic melanoma on single-agent programmed cell death protein 1 (PD-1) inhibitors at the Cancer Centre of Southeastern Ontario and London Regional Cancer Program. We defined baseline corticosteroid use as prednisone-equivalent of ≥10 mg within 30 days of immunotherapy initiation. Our study had 166 patients in total, and 25 were taking corticosteroids at the initiation of the PD-1 inhibitor. Baseline prednisone-equivalent ≥10 mg did not have effect on median overall survival (hazard ratio=1.590, 95% confidence interval: 0.773-3.270, P=0.208). However, a higher dose of baseline prednisone-equivalent ≥50 mg was independently associated with poor median overall survival (hazard ratio=2.313, 95% confidence interval: 1.103-4.830, P=0.026) when compared with baseline prednisone-equivalent 0-49 mg, even when controlled for confounders including baseline Eastern Cooperative Oncology Group ≥2 and baseline brain metastasis. Consideration should be made to decrease the use of unnecessary steroids as much as possible before initiation of PD-1 inhibitor treatment.

Cytokine changes during immune-related adverse events and corticosteroid treatment in melanoma patients receiving immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICIs) often cause immune-related adverse events (irAEs), most of which are treated with corticosteroids despite evidence suggesting that corticosteroids may blunt antitumor efficacy. We sought to identify cytokine changes that correlate with irAEs and study the impact of corticosteroid treatment on cytokine levels. METHODS: We analyzed expression of 34 cytokines in 52 melanoma patients who developed irAEs during therapy with ICIs. Luminex serum assay was performed at baseline, 1, 2, and 3 months after starting ICI. Baseline cytokine levels and longitudinal log2 fold-change was compared with incidence and grade of irAEs. Cytokine patterns were compared between patients based on development of irAEs and steroid treatment. RESULTS: There were no differences in baseline cytokine levels between patients who developed grade 1-2 irAEs (N = 28) vs. grade 3-4 irAEs (N = 24). Dermatitis patients (N = 8) had significantly higher baseline Ang-1 (p = 0.006) and CD40L (p = 0.005). Pneumonitis patients (N = 4) had significantly higher baseline IL-17 (p = 0.009). Colitis patients (N = 8) had a trend toward decreased GCSF (p = 0.08). Through Spearman's correlation analysis, patients who developed irAEs without receiving corticosteroids (N = 23) exhibited harmonization of cytokine fold-change, with 0/276 pairwise comparisons demonstrating significant divergence. In contrast, corticosteroid treatment in patients with irAEs (N = 15) altered fold-change to a discordant pattern (42/276 diverged, 15.2%). This discordant cytokine pattern in patients receiving corticosteroids is similar to the cytokine pattern in patients who did not develop irAEs (N = 8) during the longitudinal profiling period (41/276, 14.9%). CONCLUSIONS: Baseline levels of certain cytokines correlate with specific irAEs in melanoma patients receiving ICIs. irAEs drive a concordant pattern of cytokine fold-change, which is disrupted by corticosteroid treatment.

The Perfect Storm: A Rheumatologist's Point of View on COVID-19 Infection.

The new coronavirus infection (Covid-19) is a pandemic that has affected the whole world and progresses with high morbidity and mortality. It has a high contagion rate and a course capable of rapid lung involvement with severe acute respiratory distress syndrome (ARDS) and pulmonary insufficiency. A severe clinical picture develops as a result of a "perfect cytokine storm" which results from possible immunological mechanisms triggered by the viral infection. Immune system dysregulation and possible autoinflammatory and autoimmune mechanisms are responsible for a higher amount of cytokines release from immune cells. Although no clear treatment of Covid-19 infection has emerged yet, it is argued that some disease-modifying anti-rheumatic drugs (DMARDs) may be effective in addition to anti-viral treatments. These drugs (anti-malarial drugs, colchicum dispert, biologics) have been well known to rheumatologists for years because they are used in the treatment of many inflammatory rheumatologic diseases. Another important issue is whether DMARDs, which can cause severe immunosuppression, pose a risk for Covid-19 infection and whether they have been discontinued beforehand. Although there are insufficient data on this subject, considering the risk of disease reactivation, patients may continue their DMARDs treatment under the supervision of a rheumatologist. In this article, the possible immunological mechanisms in the pathogenesis of Covid-19 infection and the efficacy and safety of various DMARDs used in the treatment are discussed from a rheumatologist's perspective in the light of recent literature data.

Divergent Effects of a Transient Corticosteroid Therapy on Virus-Specific Quiescent and Effector CD8+ T Cells.

We investigated the influence of a transient treatment of corticosteroid on CD8+ T cells during herpesvirus infection. Dexamethasone, a synthetic corticosteroid, induced apoptosis of naïve and memory CD8+ T cells but virus-specific effector cells were spared. CD8+ T cell susceptibility was directly correlated with the expression of nr3c1. Both α-(HSV1) and γ-(MHV68) herpesvirus infection expanded CD8+ T cells down regulated nr3c1 indicating corticosteroid-mediated effects were not limited to one pathogen or the specific clonotype. Dexamethasone compromised anti-viral immunity to subsequent infections, likely through reductions in the naïve cell pool. Dexamethasone augmented the function and inflammatory tissue homing potential of effector cells via upregulation of CXCR3. Accordingly, an antibody neutralization of CXCR3 diminished dexamethasone-induced migration of CD8+ T cells to tissues resulting in increased virus burden. Our study therefore suggests that even a transient corticosteroid therapy influences both ongoing CD8+ T cell responses as well as the size of the naïve and memory repertoire.

Corticosteroid signaling at the brain-immune interface impedes coping with severe psychological stress.

The immune system supports brain plasticity and homeostasis, yet it is prone to changes following psychological stress. Thus, it remains unclear whether and how stress-induced immune alterations contribute to the development of mental pathologies. Here, we show that following severe stress in mice, leukocyte trafficking through the choroid plexus (CP), a compartment that mediates physiological immune-brain communication, is impaired. Blocking glucocorticoid receptor signaling, either systemically or locally through its genetic knockdown at the CP, facilitated the recruitment of Gata3- and Foxp3-expressing T cells to the brain and attenuated post-traumatic behavioral deficits. These findings functionally link post-traumatic stress behavior with elevated stress-related corticosteroid signaling at the brain-immune interface and suggest a novel therapeutic target to attenuate the consequences of severe psychological stress.

Relationship between clinical course of nivolumab-related myositis and immune status in a patient with Hodgkin's lymphoma after allogeneic hematopoietic stem cell transplantation.

Although programmed cell death (PD)-1 blockade induces immune-related adverse events (irAEs), little is known about the safety of PD-1 blockade after allogeneic hematopoietic stem cell transplantation (HSCT). Here, we describe immune system changes during nivolumab-related myositis in a patient with Hodgkin's lymphoma after allogeneic HSCT; to our knowledge, this is the first such report in the literature. At the onset of myositis, the patient lost lower limb mobility against gravity, and had an activated immune profile with increased cytotoxic CD107a and granzyme B expression, as well as pro-inflammatory cytokines, interferon-γ, tumor necrosis factor-α, interleukin-2 in T and NK cells compared to healthy donor. Pulse steroid therapy decreased creatine kinase levels and induced PD-1 expression and regulatory T cells, but did not improve myositis; previously activated markers remained high. Four-week corticosteroid therapy decreased previously activated markers and the myositis improved. These findings provide new insights into nivolumab-induced irAE pathogenesis and suggest possible optimal treatments for irAEs.

Targeted PCR Array Analysis of Genes in Innate Immunity and Glucocorticoid Signaling Pathways in Mice Cochleae Following Acoustic Trauma.

AIM: To comprehensively analyze cochlear gene expressions related to innate immunity and glucocorticoid signaling at onset of acute noise-induced hearing loss (NIHL). BACKGROUND: Recent studies suggested innate immunity is involved in the cochlear pathology of NIHL. Glucocorticoids may modulate immune actions in cochleae. METHODS: Mice were exposed to 120 dB-octave band noise for 2 hours. Twelve hours later, a targeted PCR array analyzed cochlear expressions of 84 key genes in inflammation and immune pathways and 84 genes in the glucocorticoid signaling pathway. Real-time RT-PCR was used to analyze expression of two immune-related genes, Ccl12 and Glycam1, in noise-exposed cochleae with or without dexamethasone. RESULT: In inflammatory and immune gene pathways, 31.0% (26/84 genes) were significantly upregulated (>2-fold change) or downregulated (<0.5-fold change) (p < 0.05) in noise-exposed cochleae compared with controls. Sixteen of these differentially expressed genes (DEGs) encoded chemokines. DEGs included Ccl12, Ccl2, Ccl4, Ccl7, Cxcl1, Cxcl10, and Ptgs2 (upregulated genes), and Ccr7, Cxcr2, Kng1, Ltb, and Tnfsf14 (downregulated genes). In the glucocorticoid signaling pathway, 92.9% (78/84 genes) were unchanged in noise-exposed cochleae without dexamethasone administration. Cochlear expressions of Ccl12 and Glycam1 were significantly upregulated by noise and downregulated by dexamethasone. CONCLUSION: The targeted PCR array demonstrated that several dozen genes involved in innate immunity are actively regulated in cochleae with NIHL. The glucocorticoid signaling pathway was not endogenously regulated at 12 hours post-noise trauma. Systemic dexamethasone downregulated Ccl12 and Glycam1, which are upregulated in noise-exposed cochleae. These data may provide a basis for genomic medicine treatment of acute sensorineural hearing loss.

Corticosteroid suppression of antiviral immunity increases bacterial loads and mucus production in COPD exacerbations.

Inhaled corticosteroids (ICS) have limited efficacy in reducing chronic obstructive pulmonary disease (COPD) exacerbations and increase pneumonia risk, through unknown mechanisms. Rhinoviruses precipitate most exacerbations and increase susceptibility to secondary bacterial infections. Here, we show that the ICS fluticasone propionate (FP) impairs innate and acquired antiviral immune responses leading to delayed virus clearance and previously unrecognised adverse effects of enhanced mucus, impaired antimicrobial peptide secretion and increased pulmonary bacterial load during virus-induced exacerbations. Exogenous interferon-ß reverses these effects. FP suppression of interferon may occur through inhibition of TLR3- and RIG-I virus-sensing pathways. Mice deficient in the type I interferon-α/ß receptor (IFNAR1-/-) have suppressed antimicrobial peptide and enhanced mucin responses to rhinovirus infection. This study identifies type I interferon as a central regulator of antibacterial immunity and mucus production. Suppression of interferon by ICS during virus-induced COPD exacerbations likely mediates pneumonia risk and raises suggestion that inhaled interferon-ß therapy may protect.

Steroid Allergy: Clinical Features and the Importance of Excipient Testing in a Diagnostic Algorithm.

BACKGROUND: True corticosteroid (CS) allergy is rare. Instead, many patients may be allergic to excipients found in various CS preparations. Excipient testing is frequently overlooked. It might lead to unnecessary CS avoidance or dangerous re-exposure. OBJECTIVE: The objective of this study was to evaluate the clinical characteristics and frequency of excipient allergy in patients with confirmed type I hypersensitivity to systemic CS preparations. METHODS: Patients with a confirmed diagnosis of allergy (positive skin test or drug provocation test [DPT]) or tolerance (negative DPT to CS) over the past 10 years were studied. Patient characteristics, index CS, route of administration, clinical indications, symptoms of index reaction, and outcomes of CS/excipient allergy testing were analyzed. RESULTS: Sixty-four patients underwent CS allergy testing. True CS allergy was confirmed in 9 of 64 (14%) patients. The majority (5/9, 56%) with positive skin tests or DPT were actually allergic to the excipients (2 to carboxymethylcellulose and 3 to polyethylene glycol) rather than the CS. Respiratory manifestations were significantly associated with confirmed allergy (odds ratio = 6.79 [95% confidence interval = 1.36-34.03], P = .02). CONCLUSIONS: Patients with respiratory manifestations were significantly more likely to be truly allergic. CS allergies are rare and may be overdiagnosed without excipient testing. We suggest the use of Carmellose eye drops as a readily available source of carboxymethylcellulose for testing and propose a comprehensive diagnostic algorithm for suspected CS allergy.

More than a decade follow-up in patients with severe or difficult-to-treat asthma: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) II.

BACKGROUND: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR I) study demonstrated high morbidity in patients with severe or difficult-to-treat asthma despite standard-of-care treatment. OBJECTIVE: We sought to determine the long-term natural history of disease and outcomes in patients in TENOR I after more than a decade. METHODS: TENOR I was a multicenter observational study (2001-2004) of 4756 patients with severe or difficult-to-treat asthma. TENOR II was a follow-up study of TENOR I patients using a single cross-sectional visit in 2013/2014. Overall, the sites participating in TENOR II originally enrolled 1230 patients in TENOR I. Clinical and patient-reported outcomes were assessed, including very poorly controlled asthma based on National Heart, Lung, and Blood Institute guidelines. RESULTS: A total of 341 (27.7%) patients were enrolled in TENOR II and were representative of the TENOR I cohort. The most frequent comorbidities were rhinitis (84.0%), sinusitis (47.8%), and gastroesophageal reflux disease (46.3%). Mean percent predicted prebronchodilator and postbronchodilator FEV1 were 72.7% (SD, 21.4%) and 78.2% (SD, 20.7%), respectively. A total of 231 (72.9%) of 317 patients had positive test responses to 1 or more allergen-specific IgEs. The mean blood eosinophil count was 200/µL (SD, 144/µL). Eighty-eight (25.8%) patients experienced an asthma exacerbation in the prior 3 months requiring hospital attention, oral corticosteroids, or both. More than half (197/339 [58.1%]) had very poorly controlled asthma. Medication use suggested undertreatment. CONCLUSION: TENOR II provides longitudinal data to characterize disease progression, heterogeneity, and severity in patients with severe or difficult-to-treat asthma. Findings show continued morbidity, including a high degree of comorbid conditions, allergic sensitization, exacerbations, and very poorly controlled asthma, including reduced lung function.

Reduced frequency of murine cytomegalovirus retinitis in C57BL/6 mice correlates with low levels of suppressor of cytokine signaling (SOCS)1 and SOCS3 expression within the eye during corticosteroid-induced immunosuppression.

AIDS-related human cytomegalovirus retinitis remains a leading cause of blindness worldwide. We compared two C57BL/6 mouse models of experimental murine cytomegalovirus (MCMV) retinitis for intraocular expression of suppressors of cytokine signaling (SOCS)1 and SOCS3, host proteins that are inducible negative feedback regulators of cytokine signaling. These mouse models differed in method of immune suppression, one by retrovirus-induced immune suppression (MAIDS) and the other by corticosteroid-induced immune suppression. Following subretinal injection of MCMV to induce retinitis, intraocular SOCS1 and SOCS3 were only mildly stimulated, and often without significance, within MCMV-infected eyes during the progression of MCMV retinitis in corticosteroid-immunosuppressed mice, contrary to MCMV-infected eyes of mice with MAIDS that showed significant high stimulation of SOCS1 and SOCS3 expression in agreement with previous findings. Frequency and severity of retinitis as well as amounts of intraocular infectious MCMV in corticosteroid-immunosuppressed mice were also unexpectedly lower than values previously reported for MAIDS animals during MCMV retinitis. These data reveal a major difference between two mouse models of experimental MCMV retinitis and suggest a possible link between the amplitude of SOCS1 and SOCS3 stimulation and severity of disease in these models.

A influência dos corticosteroides nos tecidos periodontais: aspectos morfológicos e resposta imunológica / The influence of corticosteroids on periodontal tissues: morphological aspects and immune response

O uso crônico de alguns medicamentos, em especial os corticosteroides, pode alterar a morfologia e a fisiologia dos tecidos periodontais, podendo induzir de forma exacerbada o crescimento gengival e gerar efeitos deletérios sobre a resposta imunológica dos tecidos frente a uma agressão de origem microbiana. Os corticosteroides agem reprimindo a ação de células do sistema imune e, em longo prazo, geram aumento da atividade osteoclástica associada com a redução da atividade osteoblástica, acelerando a perda óssea de maneira progressiva. O objetivo deste trabalho foi discutir, através de uma revisão da literatura, a influência dos medicamentos corticosteroides nos tecidos periodontais, abordando aspectos morfológicos e a resposta imunológica a nível local.

The chronic use of some medications, especially corticosteroids, can alter the morphology and physiology of periodontal tissues and can enhance the gingival growth and create deleterious effects on the immune tissue response facing an assault of microbial origin. Corticosteroids act by suppressing the immune system cell activity and in the long-term, produce increased osteoclastic activity associated with reduced osteoblastic activity, accelerating bone loss in a progressive manner. The objective of this study was to discuss the influence of corticosteroid medications in periodontal tissues, addressing morphology and the immune response locally.

A Transcriptome-driven Analysis of Epithelial Brushings and Bronchial Biopsies to Define Asthma Phenotypes in U-BIOPRED.

RATIONALE: Asthma is a heterogeneous disease driven by diverse immunologic and inflammatory mechanisms. OBJECTIVES: Using transcriptomic profiling of airway tissues, we sought to define the molecular phenotypes of severe asthma. METHODS: The transcriptome derived from bronchial biopsies and epithelial brushings of 107 subjects with moderate to severe asthma were annotated by gene set variation analysis using 42 gene signatures relevant to asthma, inflammation, and immune function. Topological data analysis of clinical and histologic data was performed to derive clusters, and the nearest shrunken centroid algorithm was used for signature refinement. MEASUREMENTS AND MAIN RESULTS: Nine gene set variation analysis signatures expressed in bronchial biopsies and airway epithelial brushings distinguished two distinct asthma subtypes associated with high expression of T-helper cell type 2 cytokines and lack of corticosteroid response (group 1 and group 3). Group 1 had the highest submucosal eosinophils, as well as high fractional exhaled nitric oxide levels, exacerbation rates, and oral corticosteroid use, whereas group 3 patients showed the highest levels of sputum eosinophils and had a high body mass index. In contrast, group 2 and group 4 patients had an 86% and 64% probability, respectively, of having noneosinophilic inflammation. Using machine learning tools, we describe an inference scheme using the currently available inflammatory biomarkers sputum eosinophilia and fractional exhaled nitric oxide levels, along with oral corticosteroid use, that could predict the subtypes of gene expression within bronchial biopsies and epithelial cells with good sensitivity and specificity. CONCLUSIONS: This analysis demonstrates the usefulness of a transcriptomics-driven approach to phenotyping that segments patients who may benefit the most from specific agents that target T-helper cell type 2-mediated inflammation and/or corticosteroid insensitivity.

Systemic Allergy to Corticosteroids: Clinical Features and Cross Reactivity.

Systemic hypersensitivity (HS) to corticosteroids (CS) is paradoxical but does exist. Some patients with a previous contact allergy to topical CS may develop a systemic contact dermatitis (SCD) while receiving CS orally or intravenously. However, a previous contact sensitization is not mandatory for developing a systemic HS to CS. Acute or delayed urticaria can occur in immediate HS. Immediate HS can be due to excipients, mainly carboxymethylcellulose or to CS themselves. Delayed reactions, mainly maculopapular rash and acute generalized exanthematous pustulosis can occur. Skin tests with systemic CS have to be standardized. It is necessary to determine if IDT with CS frequently induce skin atrophy or not and if such skin atrophy is transient by doing prospective studies using an standardized method and a limited injected volume (0.02 ml). Patch tests can be done in delayed HS, with readings at day 2, 4 and 7. In SCD, the Baeck's classification of CS in 3 chemical groups could explain cross reactivity between systemic CS. However, this classification is not applicable to explain cross-reactions between in systemic HS. According to the literature, 52/79 patients had a HS reaction to a group confirmed by a positive allergological investigations, but had a negative provocation test with another CS belonging to the same group. In case of non-severe cutaneous adverse reactions and when skin tests are negative, provocation tests have to be performed to find an alternative CS, even if it belongs to the same chemical group as those responsible for the initial reaction.

Contact Hypersensitivity to European Baseline Series and Corticosteroid Series Haptens in a Population of Adult Patients with Contact Eczema.

Contact eczema (CE) is one of the most common skin diseases and is regarded as a reaction pattern. However, the skin can react in the same way to different stimuli, some of which may act together. The golden standard in the diagnosis of allergic contact dermatitis (ACD) is the patch test. Contact allergy to topical corticosteroids is known to be gradually rising, and this represents a significant problem in the treatment of contact eczema. The aim of this study was to evaluate the prevalence of contact allergy to European Baseline Series and Corticosteroid Series haptens in a population of patients with CE. A group of 126 patients with the clinical diagnosis of contact eczema were patch tested with 28 European Baseline Series allergens and 8 corticosteroid allergens in different concentrations and in different media: 80 (64.5%) women and 46 (36.5%) men, mean age 50.4 years. The average duration of CE was 6.9 years. In total, 65 patients (51.6%) demonstrated an allergic reaction to at least one European Baseline Series allergen, and 22 patients (17.4%) to at least one corticosteroid. The most common allergens giving positive results were nickel sulfate (26.2%), cobalt chloride (15.1%), budesonide (14.3%), potassium dichromate (13.5%), and myroxylon pereirae resin (MPR) (11.9%). According our data, the European Baseline Series tests allow the cause of ACD to be identified in over 50% of cases.

Top 10 Things Primary Care Physicians Should Know About Maintenance Immunosuppression for Transplant Recipients.

The success of organ transplantation allows many transplant recipients to return to life similar to nontransplant patients. Their need for regular health care, including preventive medicine, has switched the majority of responsibilities for their health care from transplant specialists to primary care physicians. To take care of transplant recipients, it is critical for primary care physicians to be familiar with immunosuppressive medications, their side effects, and common complications in transplant recipients. Ten subjects are reviewed here in order to assist primary care physicians in providing optimal care for transplant recipients.