Cytokine Receptor Antagonists Research Articles

Interplay of Cytokines and Chemokines in Aspergillosis.

Aspergillosis is a fungal infection caused by various species of Aspergillus, most notably A. fumigatus. This fungus causes a spectrum of diseases, including allergic bronchopulmonary aspergillosis, aspergilloma, chronic pulmonary aspergillosis, and invasive aspergillosis. The clinical manifestations and severity of aspergillosis can vary depending on individual immune status and the specific species of Aspergillus involved. The recognition of Aspergillus involves pathogen-associated molecular patterns (PAMPs) such as glucan, galactomannan, mannose, and conidial surface proteins. These are recognized by the pathogen recognition receptors present on immune cells such as Toll-like receptors (TLR-1,2,3,4, etc.) and C-type lectins (Dectin-1 and Dectin-2). We discuss the roles of cytokines and pathogen recognition in aspergillosis from both the perspective of human and experimental infection. Several cytokines and chemokines have been implicated in the immune response to Aspergillus infection, including interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), CCR4, CCR17, and other interleukins. For example, allergic bronchopulmonary aspergillosis (ABPA) is characterized by Th2 and Th9 cell-type immunity and involves interleukin (IL)-4, IL-5, IL-13, and IL-10. In contrast, it has been observed that invasive aspergillosis involves Th1 and Th17 cell-type immunity via IFN-γ, IL-1, IL-6, and IL-17. These cytokines activate various immune cells and stimulate the production of other immune molecules, such as antimicrobial peptides and reactive oxygen species, which aid in the clearance of the fungal pathogen. Moreover, they help to initiate and coordinate the immune response, recruit immune cells to the site of infection, and promote clearance of the fungus. Insight into the host response from both human and animal studies may aid in understanding the immune response in aspergillosis, possibly leading to harnessing the power of cytokines or cytokine (receptor) antagonists and transforming them into precise immunotherapeutic strategies. This could advance personalized medicine.

Omicron related COVID-19 prevention and treatment measures for patients with hematological malignancy and strategies for modifying hematologic treatment regimes

The Omicron variant of SARS-CoV-2 has rapidly become the dominant strain worldwide due to its high transmissibility, although it appears to be less pathogenic than previous strains. However, individuals with hematological malignancy (HM) and COVID-19 remain susceptible to severe infection and mortality, especially those with chronic lymphocytic leukemia (CLL) and those undergoing chimeric antigen receptor T-cell (CAR-T) treatment. Hematologists should thoroughly assess the severity of the patient’s hematological disease and the potential risk of SARS-CoV-2 infection before initiating chemotherapy or immunosuppressive treatment. Vaccination and booster doses are strongly recommended and patients with a poor vaccine response may benefit from long-acting COVID-19 neutralizing monoclonal antibodies (such as Evusheld). Early use of small molecule antiviral drugs is recommended for managing mild COVID-19 in HM patients and those with severe immunodeficiency may benefit from SARS-CoV-2 neutralizing monoclonal antibody therapy and high-titer COVID-19 convalescent plasma (CCP). For moderate to severe cases, low-dose glucocorticoids in combination with early antiviral treatment can be administered, with cytokine receptor antagonists or JAK inhibitors added if the condition persists or worsens. In the treatment of hematological malignancies, delaying chemotherapy is preferable for CLL, acute leukemia (AL), and low-risk myelodysplastic syndrome (MDS), but if the disease progresses, appropriate adjustments in dosage and frequency of treatment are required, with the avoidance of anti-CD20 monoclonal antibody, CAR-T and hematopoietic stem cell transplantation (HSCT). Patients with chronic myelocytic leukemia (CML) and myeloproliferative neoplasms (MPNs) can continue current treatment. What’s more, non-drug protective measures, the development of new vaccines and antiviral drugs, and monitoring of mutations in immunocompromised populations are particularly important.

Moderate to severe atopic dermatitis in children: focus on systemic Th2 cytokine receptor antagonists and Janus kinase inhibitors.

Atopic dermatitis (AD) is a lifelong disease that markedly impairs quality of life. AD is considered a starting point of the "atopic march," which begins at a young age and may progress to systemic allergic diseases. Moreover, it is strongly associated with comorbid allergic and inflammatory diseases including arthritis and inflammatory bowel disease. Understanding the pathogenesis of AD is essential for the development of targeted therapies. Epidermal barrier dysfunction, immune deviation toward a T helper 2 proinflammatory profile, and microbiome dysbiosis play important roles via complex interactions. The systemic involvement of type 2 inflammation, wheather acute or chronic, and whether extrinsic or intrinsic, is evident in any type of AD. Studies on AD endotypes with unique biological mechanisms have been conducted according to clinical phenotypes, such as race or age, but the endotype for each phenotype, or endophenotype, has not yet been clearly identified. Therefore, AD is still being treated according to severity rather than endotype. Infancy-onset and severe AD are known risk factors leading to atopic march. In addition, up to 40% of adult AD are cases of infancy-onset AD that persist into adulthood, and these are often accompanied by other allergic diseases. Therefore, early intervention strategies to identify high-risk infants and young children, repair an impaired skin barrier, and control systemic inflamation may improve long-term outcomes in AD patients. However, to the best of our knowledge, no study has evaluated the effectiveness of early intervention on atopic march using systemic therapy in high-risk infants. This narrative review addresses the latest knowledge of systemic treatment, including Th2 cytokine receptor antagonists and Janus kinase inhibitors, for children with moderate to severe AD that is refractory to topical treatment.

A filarial parasite-encoded human IL-10 receptor antagonist reveals a novel strategy to modulate host responses.

Interleukin (IL)-10 is the primary cytokine driving the modulation of the host response in filarial infections. We performed binding assays with Brugia malayi antigen extracts and human IL-10R1. Bm5539 was the top-binding hit. We identified a short sequence, termed truncated Bm5339, that has structural similarities to the human IL-10 functional dimer. Sequence comparisons revealed that other filarial parasites possess Bm5539 orthologues. Using recombinant Bm5539 in a modified Luciferase Immunoprecipitation System assay, we confirmed that both the truncated and full-length forms of the protein can bind to human IL-10R1. Truncated Bm5539 could inhibit human IL-10-driven phosphorylation of STAT3, thereby demonstrating that Bm5539 acts as an IL-10 antagonist, most likely through competitive binding to the receptor. We provide a structural basis for these observations using computational modeling and simulations. This parasite-encoded cytokine receptor antagonist provides an additional lens through which parasite-induced modulation of the host immune response can be examined.

Angiopoietin-2 Inhibition of Thrombomodulin-Mediated Anticoagulation-A Novel Mechanism That May Contribute to Hypercoagulation in Critically Ill COVID-19 Patients.

Hypercoagulation and endothelial dysfunction play central roles in severe forms of COVID-19 infections, but the molecular mechanisms involved are unclear. Increased plasma levels of the inflammatory cytokine and TIE2 receptor antagonist Angiopoietin-2 were reported in severely ill COVID-19 patients. In vitro experiments suggest that Angiopoietin-2 bind and inhibits thrombomodulin. Thrombomodulin is expressed on the luminal surface of endothelial cells where it is an important member of the intrinsic anticoagulant pathway through activation of protein C. Using clinical data, mouse models, and in vitro assays, we tested if Angiopoietin-2 plays a causal role in COVID-19-associated hypercoagulation through direct inhibition of thrombin/thrombomodulin-mediated physiological anticoagulation. Angiopoietin-2 was measured in 61 patients at admission, and after 10 days in the 40 patients remaining in the ICU. We found that Angiopoietin-2 levels were increased in COVID-19 patients in correlation with disease severity, hypercoagulation, and mortality. In support of a direct effect of Angiopoietin-2 on coagulation, we found that injected Angiopoietin-2 in mice associated to thrombomodulin and resulted in a shortened tail bleeding time, decreased circulating levels of activated protein C, and increased plasma thrombin/antithrombin complexes. Conversely, bleeding time was increased in endothelial-specific Angiopoietin-2 knockout mice, while knockout of Tie2 had no effect on tail bleeding. Using in vitro assays, we found that Angiopoietin-2 inhibited thrombomodulin-mediated anticoagulation and protein C activation in human donor plasma. Our data suggest a novel in vivo mechanism for Angiopoietin-2 in COVID-19-associated hypercoagulation, implicating that Angiopoietin-2 inhibitors may be effective in the treatment of hypercoagulation in severe COVID-19 infection.

Engineered protein nanodrug as an emerging therapeutic tool.

Functional proteins are the most versatile macromolecules. They can be obtained by extraction from natural sources or by genetic engineering technologies. The outstanding selectivity, specificity, binding activity, and biocompatibility endow engineered proteins with outstanding performance for disease therapy. Nevertheless, their stability is dramatically impaired in blood circulation, hindering clinical translations. Thus, many strategies have been developed to improve the stability, efficacy, bioavailability, and productivity of therapeutic proteins for clinical applications. In this review, we summarize the recent progress in the fabrication and application of therapeutic proteins. We first introduce various strategies for improving therapeutic efficacy via bioengineering and nanoassembly. Furthermore, we highlight their diverse applications as growth factors, nanovaccines, antibody-based drugs, bioimaging molecules, and cytokine receptor antagonists. Finally, a summary and perspective for the future development of therapeutic proteins are presented.

Targeting Cytokines for Morphine Tolerance: A Narrative Review.

Background:Despite its various side effects, morphine has been widely used in clinics for decades due to its powerful analgesic effect. Morphine tolerance is one of the major side effects, hindering its long-term usage for pain therapy. Currently, the thorough cellular and molecular mechanisms underlying morphine tolerance remain largely uncertain.MethodsWe searched the PubMed database with Medical subject headings (MeSH) including ‘morphine tolerance’, ‘cytokines’, ‘interleukin 1’, ‘interleukin 1 beta’, ‘interleukin 6’, ‘tumor necrosis factor alpha’, ‘interleukin 10’, ‘chemokines’. Manual searching was carried out by reviewing the reference lists of relevant studies obtained from the primary search. The searches covered the period from inception to November 1, 2017.ResultsThe expression levels of certain chemokines and pro-inflammatory cytokines were significantly increased in animal models of morphine tolerance. Cytokines and cytokine receptor antagonist showed potent effect of alleviating the development of morphine tolerance.ConclusionCytokines play a fundamental role in the development of morphine tolerance. Therapeutics targeting cytokines may become alternative strategies for the management of morphine tolerance.

Cenicriviroc, a cytokine receptor antagonist, potentiates all-trans retinoic acid in reducing liver injury in cholestatic rodents.

Cholestatic liver injury is mediated by bile acid-induced inflammatory responses. We hypothesized that superior therapeutic effects might be achieved by combining treatments that reduce the bile acid pool size with one that blocks inflammation. Bile duct-ligated (BDL) rats and Mdr2(Abcb4)-/- mice were treated with all-trans retinoic acid (atRA), a potent inhibitor of bile acid synthesis, 5mg/kg/d by gavage, or Cenicriviroc (CVC), a known antagonist of CCR2 and CCR5, 50mg/kg/d alone or in combination for 14 days and 1month respectively. All-trans retinoic acid alone reduced bile acid pool size and liver necrosis in BDL rats. However, the combination with CVC further reduced liver to body weight ratio, bile acid pool size, plasma liver enzyme, bilirubin, liver necrosis and fibrosis when compared to the atRA treatment. The assessment of hepatic hydroxyproline content further confirmed the reduced liver injury concurrent with reduction of pro-inflammatory cytokines emphasizing the synergistic effects of these two agents. Profiling of hepatic inflammatory cells revealed that combination therapy reduced neutrophils and T cells but not macrophages. The superior therapeutic effects of combination treatment were also confirmed in Mdr2-/- mice where a significant reduction in plasma liver enzymes, bilirubin, liver fibrosis, bile duct proliferation and hepatic infiltration of neutrophils and T cells and expression of cytokines were found. Multitargeted therapy is an important paradigm for treating cholestatic liver injury. The combination of CVC with atRA or other FXR activators may warrant a clinical trial in patients with cholestatic liver disease.

Lnterleukin-1 Receptor Antagonist.

The interleukin-1 receptor antagonist (IL-lra) is unusual in that it is the only known naturally occurring, cytokine receptor antagonist with no apparent agonist function. Over the last 5 years, since the cloning of the IL-lra cDNA sequence, there has been intensive research on the genetics, regulation, and potential therapeutic value of this protein. The later discovery of a second form of IL-lra in 1991 has complicated the picture. Whereas the originally described IL-lra is predominantly glycosylated and secreted (sIL-lra), the alternative isoform is unglycosylated and intracellular (icIL-lra). Although the biological roles of the two forms are still open to question, IL-lra is likely to be of great importance in the pathogenesis of both acute and chronic inflammatory diseases. A large body of evidence for this conclusion has come from animal models of inflammatory disease that respond well to administration of exogenous IL-lra. A role for recombinant IL-lra in the management of human disease is still under investigation. The two forms of IL-lra are encoded by a single gene by alternative usage of two first exons. Expression of sIL-lra and icIl-lra is regulated by two promoters. In this review I explore the genetics of the gene encoding IL-lra (IL-1RN) and the mechanisms of IL-lra gene activation to produce sIL-lra and icIL-lra. Also, possible biological roles for these immunomodulators in health and disease are discussed.

A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression.

Schizophrenia, bipolar disorder and major depressive disorder (MDD) have all been associated with aberrant blood cytokine levels; however, neither the pattern of cytokine alterations nor the impact of clinical status have been compared across disorders. We performed a meta-analysis of blood cytokines in acutely and chronically ill patients with these major psychiatric disorders. Articles were identified by searching the PubMed, PsycInfo and Web of Science, and the reference lists of these studies. Sixty-eight studies met the inclusion criteria (40 schizophrenia, 10 bipolar disorder and 18 MDD) for acutely ill patients. Forty-six studies met the inclusion criteria (18 schizophrenia, 16 bipolar disorder and 12 MDD) for chronically ill patients. Levels of two cytokines (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α)), one soluble cytokine receptor (sIL-2R), and one cytokine receptor antagonist (IL-1RA) were significantly increased in acutely ill patients with schizophrenia, bipolar mania and MDD compared with controls (P<0.01). Following treatment of the acute illness, IL-6 levels significantly decreased in both schizophrenia and MDD (P<0.01); sIL-2R levels increased in schizophrenia; and IL-1RA levels in bipolar mania decreased. In chronically ill patients, the levels of IL-6 were significantly increased in schizophrenia, euthymic (but not depressed) bipolar disorder and MDD compared with controls (P<0.01). The levels of IL-1β and sIL-2R were significantly increased in both chronic schizophrenia and euthymic bipolar disorder. Overall, there were similarities in the pattern of cytokine alterations in schizophrenia, bipolar disorder and MDD during acute and chronic phases of illness, raising the possibility of common underlying pathways for immune dysfunction. Effects of treatment on cytokines were more robust for schizophrenia and MDD, but were more frequently studied than for acute mania. These findings have important implications for our understanding of the pathophysiology and treatment of major psychiatric disorders.

Profile of Cytokines (IL-1β, TNF- α and IL-10) in Eyelid Tumors

Introduction: Tissue cytokine levels (IL-1β, TNF-α and IL-10) have been utilized for screening, diagnosis, prognostication and treatment of tumors. The current study, therefore, purports to measure the levels of common cancer associated cytokines in histopathologically confirmed tissue samples of eyelid tumors. The compilation of this information is planned with a view to facilitate further studies which will enable the use of specific cytokines for screening, diagnosis, prognostication and treatment of these tumors. Material and Method: This is a prospective observational cross-sectional case-control study conducted on all immunocompetent cases of eyelid neoplasia that underwent surgical treatment over a one year period. Tissue from other non-inflammatory, nonneoplastic eyelid disorders were recruited as controls. Commercially available “Ready-SET-Go! ELISA Kit” was used to determine the levels of the cytokines (IL-1β, TNF-α, IL-10) in pg/ml. Results were expressed as the mean (SEM). Statistical analysis was done using SPSS software, version 17.0 employing ‘Chi square test’, ‘unpaired t-test’ and Pearson’s correlation coefficient. Results: On comparing the mean cytokine levels of the two groups with surgically excised tissue of 25 patients of eyelid neoplasia of either sex as cases and 26 age and sex matched tissue samples as controls, t-test revealed significantly different and higher level of IL1β (16.71 ± 2.75 vs. 14.60 ± 3.71, t=2.3, p=0.025), TNF-α (19.11 ± 3.2 vs. 16.73 ± 4.44, t=2.18, p=0.033) and IL-10 (24.86 ± 5.94 vs. 21.60 ± 4.60, t=2.19, p=0.032) in cases as compared to controls. Discussion: The mean cytokine levels of IL-1β, TNF-α, IL-10 were raised in cases by 12.62%, 12.45% and 13.11% respectively (p<0.05) in comparison to controls. Conclusion: Significantly higher levels of cytokines IL-1β, TNF-α and IL-10 are present in the tissues of eyelid neoplasia. This represents a higher association with tumorigenesis. Development of anti-cytokine molecules, cytokine receptor agonists and antagonists for modifying the disease processes and their application to provide treatment in eyelid tumors is a potential area for research in eyelid tumors.

Practical guide to treating children with juvenile idiopathic arthritis

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatological disease of childhood. Symptom control is important in the initial management. Following definitive diagnosis methotrexate remains the first-line treatment for children with JIA. For those in whom methotrexate is ineffective, in whom it is not tolerated or in children whose disease affects the spine biologic agents play an important role. Biologics are a new group of treatments including monoclonal antibodies, soluble cytokine receptors or receptor antagonists that target key pathways of the immune system implicated in inflammation. These new drugs provide symptomatic relief, improvement in disease activity, prevention of damage, and promote normal growth and development for children with JIA. In order to optimize outcomes for children with JIA the British Society of Paediatric and Adolescent Rheumatology (BSPAR) recommends that whenever possible management and treatment initiation should be undertaken at a specialist centre within a clinical network.

Circulating Soluble Cytokine Receptors and Colorectal Cancer Risk

Soluble cytokine receptors and receptor antagonist of proinflammatory cytokines can modify cytokine signaling and may affect cancer risk. In a case-cohort study nested within the Women's Health Initiative cohort of postmenopausal women, we assessed the associations of plasma levels of interleukin (IL)-1 receptor antagonist (IL-1Ra) and the soluble receptors of IL-1 (sIL-1R2), IL-6 (sIL-6R and sgp130), and TNF (sTNFR1 and sTNFR2) with risk of colorectal cancer in 433 cases and 821 subcohort subjects. Baseline levels of estradiol, insulin, leptin, IL-6, and TNF-α measured previously were also available for data analysis. After adjusting for significant covariates, including age, race, smoking, colonoscopy history, waist circumference, and levels of estrogen, insulin, and leptin, relatively high levels of sIL-6R and sIL-1R2 were associated with reduced colorectal cancer risk [HRs comparing extreme quartiles (HRQ4-Q1) for sIL-6R, 0.56; 95% confidence interval (CI), 0.38-0.83; HRQ4-Q1 for sIL-1R2, 0.44; 95% CI, 0.29-0.67]. The associations with IL-1Ra, sgp130, sTNFR1, and sTNFR2 were null. The inverse association of sIL-1R2 with colorectal cancer risk persisted in cases diagnosed ≤5 and >5 years from baseline blood draw; the association with sIL-6R, however, was not evident in the latter group, possibly indicating that relatively low levels of sIL-6R in cases might be due to undiagnosed cancer at the time of blood draw. High circulating levels of sIL-1R2 may be protective against colorectal carcinogenesis and/or be a marker of reduced risk for the disease. sIL-1R2 has potential to be a chemopreventive and/or immunotherapeutic agent in inflammation-related diseases.

Autologous conditioned serum for the treatment of osteoarthritis and other possible applications in musculoskeletal disorders

The therapeutic use of interleukin 1 (IL-1) cytokine receptor antagonists (IL-1RA) has promoted the development of new biological therapies for osteoarthritis (OA). Autologous conditioned serum (ACS) is an alternative, safe and well-tolerated treatment in OA. Sources of data We performed a comprehensive search of PubMed, Medline, Cochrane, CINAHL, Embase, SportDiscus, Pedro and Google scholar databases using keywords such as 'interleukin 1', 'osteoarthritis' and 'autologous conditioned serum'. ACS, containing endogenous anti-inflammatory cytokines including IL-1RA and several growth factors, could reduce pain and increase function and mobility in mild to moderate knee OA. AREA OF CONTROVERSY: Given the limited data available on the composition of ACS, the mechanisms through which ACS produces clinical improvement, the duration of its effect and the changes in cytokine levels after repeated injections are still unknown. Growing points Although previous clinical data are encouraging and confirm the safety of this modality, given the limitations of current studies, there should be additional, controlled trials to further confirm efficacy for the use of ACS in OA treatment. AREA TIMELY FOR DEVELOPING RESEARCH: ACS can lead to enhancement of tissue regeneration and to reduction of degenerative mechanisms.

Abstract 4487: Inverse associations between soluble cytokine receptors and colorectal cancer risk

Abstract Laboratory studies have suggested that soluble receptors of proinflammatory cytokines could be anti-inflammatory by acting as decoy receptors, blocking binding of the cytokines to their membrane receptors, and hence inhibiting cytokine signaling. Thus, relatively high levels of soluble cytokine receptors and receptor antagonists may be protective factors against colorectal cancer, which is an inflammation-associated disease. This case-cohort study nested within the Women's Health Initiative Observational Study of postmenopausal women 50-79 years of age at baseline (1993-1998) examined whether baseline plasma levels of IL-1 receptor antagonist (IL-1Ra) and the soluble receptors of IL-6 (sIL-6R and sgp130), TNF (sTNF-R1 and sTNF-R2), and IL-1 (sIL-1R2) were inversely associated with colorectal cancer risk. Analytes were measured in 433 incident colorectal cancer cases and 823 subcohort members using multiplex assays (Millipore, Billerica, MA). Circulating levels of IL-6, TNF-α, insulin, and estradiol measured previously were also available for data analyses. IL-1Ra and the 5 soluble receptors did not correlate with each other or with their ligands (all correlations r &amp;lt; 0.3), with the exception of sTNFR2, which was moderately correlated with sTNFR1 (r=0.51) and TNF-α (r=0.43). The table below shows the hazard ratios for colorectal cancer risk, when each analyte was entered separately into a Cox regression model adjusting for other colorectal cancer risk factors. Colorectal cancer risk decreased significantly with increasing levels of sIL-6R and sIL-1R2. The ratios of IL-6 or TNF-α to their soluble receptors were not associated with colorectal cancer risk. There were also no significant interactions between pairs of soluble receptors or between soluble receptors and their ligands. Increased circulating levels of sIL-6R and sIL-1R2 may confer protection against colorectal cancer. If our results are confirmed, these soluble receptors can be considered for chemoprevention. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4487. doi:1538-7445.AM2012-4487

Second trimester maternal plasma levels of cytokines IL-1Ra, Il-6 and IL-10 and preterm birth

To examine the interaction of the cytokines interleukin-1 receptor antagonist (IL)-1Ra, IL-6 and IL-10 to predict preterm birth (PTB) in pregnant Hispanic women (n=470). In this prospective study, demographic data were obtained prenatally and birth outcome data were obtained from the medical chart. Cytokines were measured from plasma obtained at 22 to 24 weeks gestation. Data analysis utilized logistic regression. PTB was predicted by level of IL-1Ra (odds ratio (OR)=2.55; 95% confidence interval (CI)=1.24, 5.24). The interaction between IL-1Ra and IL-6 and between IL-1Ra and IL-10 was significant (Wald=4.01, P=0.04 and Wald=8.84, P<0.003, respectively) and was also predictive of PTB. As IL-1Ra levels increased while IL-10 levels were low, the probability of PTB greatly increased. The interactions of select cytokines and cytokine receptor antagonists were associated with PTB. Future research should focus on the changes in cytokines during pregnancy to identify critical periods of change, and examine predictors of the cytokine response.

DIRA, DITRA, and New Insights Into Pathways of Skin Inflammation

Dermatology has a long-standing affinity for acronyms. From AGEP (acute generalized exanthematous pustulosis) to XP (xeroderma pigmentosum), acronyms have become a part of our dermatology lexicon, perhaps occasionally to the consternation of our colleagues in other specialties. In this issue, Brau-Javier et al1 describe a patient with a severe pustular skin disease called “DIRA”—an acronym for “deficiency of the interleukin 1 (IL-1) receptor antagonist,” which we first described in 9 pediatric patients in 2009.2 As its name suggests, DIRA is a new autoinflammatory disease linked to activation of the IL-1 pathway (Figure), joining the ranks of other IL-1–associated conditions with a prominent dermatologic component, foremost the cryopyrin-associated periodic fever syndromes (CAPS)—familial cold–induced autoinflammatory syndrome (FCAS), Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease (NOMID).3 Figure The pathogenesis of DIRA (deficiency of the interleukin 1 [IL-1] receptor [IL-1R] antagonist) and DITRA (deficiency of the IL-36 receptor [IL-36R] antagonist). Loss of the IL-1R antagonist leads to unopposed proinflammatory signaling by IL-1α ... CAPS is caused by gain of function mutations that lead to oversecretion of the well-established fever causing cytokine IL-1Β, and all 3 disorders manifest in the skin as neutrophilic urticaria. In contrast, DIRA presents in the neonatal period with a severe neutrophilic “pustular” skin eruption, skin pathergy, and nail dystrophy, as well as elevated acute-phase reactants, sterile osteomyelitis, and periostitis. DIRA is caused by loss of function of the IL-1 receptor (IL-1R) antagonist, the first endogenous cytokine receptor antagonist identified that blocks IL-1 signaling (Figure). Absence of the IL-1R antagonist results in unopposed proinflammatory signaling via the cytokines IL-1α and IL-1β on the IL-1R type I (IL-1R1). DIRA is a rare condition that you may never encounter in your practice, so why bother filing away another acronym in the deep recesses of your dermatologic cortex? First, as Brau-Javier et al1 demonstrate, just as with CAPS, DIRA is exquisitely responsive to IL-1 blockade. Responses are similar to those seen following anti–IL-1 treatment for NOMID, the most severe form of CAPS; children who have been ill since infancy now feel well for the first time; others confined to wheelchairs because of disabling joint pain are able to walk; and growth curves begin to arc upward again for the first time in years. Interleukin 1–blocking therapy is now the standard of care for CAPS, and 3 Food and Drug Administration–approved agents, anakinra, rilonacept, and canakinumab, are currently available that provide targeted inhibition of IL-1 signaling.4 Second, understanding DIRA may yield new insights into the mechanism of other challenging pustular skin conditions. The cutaneous and systemic features of DIRA bear similarity to features seen in pustular psoriasis and SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis), suggesting that IL-1 signaling may play a role in these conditions as well.

Pharmacotherapy of severe asthma

Severe asthma is a complex and heterogeneous phenotype where management can be challenging. While many patients with severe asthma respond to high-dose inhaled corticosteroids in combination with a long-acting beta-agonist, there remains a significant subset of patients that require oral corticosteroids to control symptoms. Alternative therapies are needed to help reduce the need for continuous oral corticosteroids; however, there are currently very few effective options. Several new alternatives to oral corticosteroids have been evaluated in severe asthma as add-on to conventional therapy. These include macrolide antibiotics, omalizumab, tumor necrosis factor-alpha inhibitors, cytokine receptor antagonists, and bronchial thermoplasty. The challenge with these entities is determining the appropriate phenotype of severe asthma where effectiveness is demonstrated, given the significant heterogeneity of the disease. Therefore, there is a crucial need to better understand the mechanisms and pathophysiology of severe asthma so more effective immunomodulators and biologic therapies can emerge.

Immunomodulators in asthma therapy

New developments in the field of allergy and immunology have yielded a variety of novel therapeutic approaches in recent years, and more agents are at the clinical trial stage. Among the therapeutic approaches discussed in this review are Toll-like receptor agonists, immunostimulatory oligodeoxynucleotides, orally and parenterally administered cytokine blockers, and specific cytokine receptor antagonists. Transcription factor modulators targeting syk kinase, peroxisome proliferator-activated receptor-gamma, and nuclear factor-kappaB are also being evaluated in the treatment of asthma. The anti-IgE monoclonal antibody omalizumab has established effectiveness in patients with allergic asthma, but the criteria for selecting patients who are most likely to benefit from it are less clear. This review summarizes data from human clinical trials with immunomodulators to discuss the rationale for their use, their efficacy, and adverse events associated with them.

Tratamento do trabalho de parto prematuro

The main purpose of using uterulytic in preterm delivery is to prolong gestation in order to allow the administration of glucocorticoid to the mother and/or to accomplish the mother's transference to a tertiary hospital center. Decisions on uterolytic use and choice require correct diagnosis of preterm delivery, as well as the knowledge of gestational age, maternal-fetal medical condition, and medicine's efficacy, side-effects and cost. All the uterolytics have side-effects, and some of them are potentially lethal. Studies suggest that beta-adrenergic receptor agonists, calcium blockers and cytokine receptor antagonists are effective to prolong gestation for at least 48 hours. Among these three agents, atosiban (a cytokine receptor antagonist) is safer, though it presents a high cost. Magnesium sulfate is not efficient to prolong gestation and presents significant side-effects. Cyclooxygenase inhibitors also present significant side-effects. Up till now, there is not enough evidence to recommend the use of nitric oxide donors to inhibit preterm delivery. There is no basis for the use of antibiotics to avoid prematurity in face of preterm labor.