A recommended paradigm for vaccination of rheumatic disease patients with the SARS-CoV-2 vaccine.

Autoimmune and autoinflammatory rheumatic disorders (ARD) are treated with antimetabolites, calcineurin inhibitors and biologic agents either neutralizing cytokines [Tumor Necrosis Factor (TNF), Interleukin (IL)-1, IL-6, IL-17, B-cell activating factor] or being directed against B-cells (anti-CD-20), costimulatory molecules or JAK kinases. Similarly for the influenza or pneumococcal vaccines, there is limited data on the effectiveness of vaccination against SARS-CoV-2 infection and COVID-19 prevention for this susceptible patient population. Moreover, preliminary data from vaccinated organ transplanted, inflammatory bowel and connective tissue disease patients suggests only limited immunogenicity after the first vaccine dose, particularly in patients on immunosuppressive regimens. Herein a set of recommendations for the vaccination of immune suppressed patients with the SARS-CoV-2 vaccines is proposed aimed at achieving optimal vaccine benefit without interfering with disease activity status. Moreover, rare autoimmune adverse events related to vaccinations are discussed.

Pumpless Extracorporeal Hemadsorption Technique: A New Method for Early Cytokine Elimination?

In recent years, extracorporeal hemadsorption (HA) techniques capable of adsorbing pro- and anti-inflammatory cytokines are increasingly used in various clinical situations. The therapeutic benefit of cytokine elimination likely depends on timing. Although treatment seems to be most effective when started within the first 24 h, therapy is often delayed as it must be combined with another extracorporeal circuit. Thus, using a pumpless extracorporeal HA technique might be a valuable option in order to expedite the commencement of cytokine elimination in critically ill patients.

Medium Cut-Off Dialysis Membranes: Can They Have Impact on Outcome of COVID-19 Hemodialysis Patients?

INTRODUCTION: Severe acute respiratory syndrome coronavirus-2 may lead to high levels of expression of inflammatory cytokines. Medium cut-off (MCO) membranes may make greater clearances for large-middle molecules (including cytokines) than low-flux (LF) membranes. In this study, we aimed to evaluate the impact of MCO membranes on outcome of COVID-19 patients on hemodialysis (HD). METHODS: Sixty COVID-19 HD patients were included in this study. The patients were categorized into 2 groups regarding type of HD membranes. Clinical data were taken from medical records. RESULTS: Initial crp and ferritin levels, which are surragates of cytokine storm and severity of disease in COVID-19, were significantly higher in MCO membrane group compared to LF group (p = 0.037 and 0.000, respectively). Although there were more patients with severe disease in MCO group, there were no significant differences regarding need for intensive care unit and death. CONCLUSION: It may be an option to use MCO membranes in HD patients with COVID-19 in order to reduce cytokine levels and prevent cytokine storm.

Cytokine Adsorption to Polymyxin B-Immobilized Fiber: An in vitro Study.

BACKGROUND: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are episodes of acute respiratory worsening characterized by diffuse alveolar damage superimposed on usual interstitial pneumonia. Direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) is reported to have beneficial effects on the respiratory status and outcome in patients with AE-IPF although its mechanism of action is not fully elucidated. OBJECTIVE: To investigate whether and how the PMX-immobilized fiber (PMX-F) adsorbs cytokines because reduction of the serum levels of various cytokines has been noted in AE-IPF patients receiving PMX-DHP. METHODS: The propensity of recombinant cytokines for adsorption onto PMX-F was examined by incubating cytokines with heparin-coated or uncoated PMX-F for 2 h at 37°C. Cytokines were quantitated by multiplex bead array assay or ELISA. RESULTS: Interleukin (IL)-8, RANTES, platelet-derived growth factor-bb, and transforming growth factor-ß were substantially adsorbed onto PMX-F without heparin coating. The adsorbed cytokines could be eluted with PMX sulfate, indicating that the PMX moiety is involved in cytokine adsorption. Importantly, although IL-1ß, monocyte chemoattractant protein-1, fibroblast growth factor 2, and vascular endothelial growth factor-A were adsorbed onto PMX-F to lesser extents, the adsorption was enhanced by heparin coating of PMX-F. Furthermore, heparin-coated PMX-F acquired the capability to adsorb IL-6, IL-12, and tumor necrosis factor α. An affinity of heparin to PMX was determined (Kd = 0.061 ± 0.032 mg/mL), which accounts for the enhanced cytokine adsorption onto PMX-F upon heparin coating. CONCLUSIONS: Various cytokines involved in inflammation, fibrosis, and vascular permeability were shown to be adsorbed onto PMX-F. Removal of multiple cytokines may be associated with positive impacts of PMX-DHP in patients with AE-IPF.

Extracorporeal Blood Purification and Organ Support in the Critically Ill Patient during COVID-19 Pandemic: Expert Review and Recommendation.

Critically ill COVID-19 patients are generally admitted to the ICU for respiratory insufficiency which can evolve into a multiple-organ dysfunction syndrome requiring extracorporeal organ support. Ongoing advances in technology and science and progress in information technology support the development of integrated multi-organ support platforms for personalized treatment according to the changing needs of the patient. Based on pathophysiological derangements observed in COVID-19 patients, a rationale emerges for sequential extracorporeal therapies designed to remove inflammatory mediators and support different organ systems. In the absence of vaccines or direct therapy for COVID-19, extracorporeal therapies could represent an option to prevent organ failure and improve survival. The enormous demand in care for COVID-19 patients requires an immediate response from the scientific community. Thus, a detailed review of the available technology is provided by experts followed by a series of recommendation based on current experience and opinions, while waiting for generation of robust evidence from trials.

Additive treatment considerations in COVID-19-The clinician's perspective on extracorporeal adjunctive purification techniques.

The aim of this document was to inform the scientific community of sparse preliminary results regarding advanced supportive therapies and technology-driven systems in addition to highlighting the benefits and possibilities of performing concise research during challenging times. Advanced organ support for lung and heart offers the possibility to buy the time needed for recovery. However, remaining a bridging strategy, extracorporeal life support cannot act as the ultimate treatment for the underlying COVID-19 disease. Appropriate patient selection criteria addressed by experts and scientific organizations, such as Extracorporeal Life Support Organization and World Health Organization, may provide significant help in the difficult decision-making and to reduce mortality in patients with profound respiratory and/or cardiac failure due to COVID-19. Severe, systemic cytokine-mediated inflammation associated with the SARS-CoV-2 has also been described. Effects of crosstalk between coagulation and inflammatory pathways appear to significantly affect disease progression and lead to poor outcomes. Multiple therapeutic strategies, including antibody therapies (such as Tocilizumab, Sarilumab, Siltuximab), therapeutic plasma exchange (TPE), and blood purification techniques for direct removal of cytokines, including filtration, dialysis (diffusion), and adsorption are available. Further, we believe, that research should be facilitated and promoted, particularly under the guidance of recognized scientific societies or expert-based multicenter investigation, with rapid communication of critical and relevant information to enhance better appraisal of patient profiles, complications, and treatment modalities.

CytoResc - "CytoSorb" Rescue for critically ill patients undergoing the COVID-19 Cytokine Storm: A structured summary of a study protocol for a randomized controlled trial.

OBJECTIVES: Approximately 8 - 10 % of COVID-19 patients present with a serious clinical course and need for hospitalization, 8% of hospitalized patients need ICU-treatment. Currently, no causal therapy is available and treatment is purely supportive. The main reason for death in critically ill patients is acute respiratory failure. However, in a number of patients a severe hyperinflammatory response with excessively elevated proinflammatory cytokines causes vasoplegic shock resistant to vasopressor therapy. A new polystyrene-based hemoadsorber (CytoSorb®, Cytosorbents Inc., New Jersey, USA) has been shown to adsorb effectively cytokines and other middle molecular weight toxins this way reducing their blood concentrations. This has been routinely used in clinical practice in the EU for other conditions where a cytokine storm occurs and an observational study has just been completed on COVID-19 patients. We hypothesized that the extracorporeal elimination of cytokines in critically ill COVID-19 patients with suspected hyperinflammation and shock may stabilize hemodynamics and improve outcome. The primary endpoint is time until resolution of vasoplegic shock, which is a well implemented, clinically relevant endpoint in critical care studies. TRIAL DESIGN: Phase IIb, multicenter, prospective, open-label, randomized, 1:1 parallel group pilot study comparing the additional use of "CytoSorb" to standard of care without "CytoSorb". PARTICIPANTS: Patients are recruited from the Intensive Care Units (ICUs) of 7 participating centers in Germany (approximately 10 ICUs). All patients aged 18- 80 with positive polymerase chain reaction (PCR) test for SARS-CoV-2, a C-reactive protein (CRP) ≥ 100 mg/l, a Procalcitonin (PCT) < 2 ng/l, and suspected cytokine storm defined via a vasoplegic shock (Norepinephrine > 0.2 µg/min/kg to achieve a Mean Arterial Pressure ≥ 65mmHg). Patients are included irrespective of indication for renal replacement therapy. Suspected or proven bacterial cause for vasoplegic shock is a contraindication. INTERVENTION AND COMPARATOR: Within 24 hours after meeting the inclusion criteria patients will be randomized to receive either standard of care or standard of care and additional "CytoSorb" therapy via a shaldon catheter for 3-7 days. Filter exchange is done every 24 hours. If patients receive antibiotics, an additional dose of antibiotics is administered after each change of "CytoSorb" filter in order to prevent underdosing due to "CytoSorb" treatment. MAIN OUTCOMES: Primary outcome is time to resolution of vasoplegic shock (defined as no need for vasopressors for at least 8 hours in order to sustain a MAP ≥ 65mmHg) in days. Secondary outcomes are 7 day mortality after fulfilling the inclusion criteria, mortality until hospital discharge, Interleukin-6 (IL-6) measurement on day 1 and 3, need for mechanical ventilation, duration of mechanical ventilation, duration of ICU-stay, catecholamine dose on day 1/2/3 after start of "CytoSorb" and acute kidney injury. RANDOMIZATION: An electronic randomization will be performed using the study software secuTrial® administered by the Clinical Study Center (CSC) of the Charité - Universitätsmedizin Berlin, Germany. Randomization is done in blocks by 4 stratified by including center. BLINDING (MASKING): The trial will be non-blinded for the clinicians and patients. The statistician will receive a blinded data set, so that all analyses will be conducted blinded. NUMBERS TO BE RANDOMIZED (SAMPLE SIZE): As this is a pilot study with the goal to examine the feasibility of the study design as well as the intervention effect, no formal sample size calculation was conducted. A total number of approximately 80-100 patients is planned (40-50 patients per group). Safety assessment is done after the inclusion of each 10 patients per randomization group. TRIAL STATUS: Please see the study protocol version from April 24 2020. Recruitment of patients is still pending. TRIAL REGISTRATION: The study was registered on April 27 2020 in the German Registry of Clinical Trials (DRKS) under the number DRKS00021447. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

A case of complete atrioventricular block in secondary hemophagocytic syndrome/hemophagocytic lymphohistiocytosis recovered by plasma exchange and cytokine absorbing therapy with AN69ST continuous hemodiafiltration.

We report a case of incipient systemic lupus erythematosus (SLE) that rapidly progressed to complete atrioventricular block (cAVB). A 20-year-old man was admitted with facial erythema, painless oral aphtha, polyarthritis, and myalgia of each extremity. On admission, he developed first-degree atrioventricular block, pericarditis, pleuritis, renal failure, hemophagocytic lymphohistiocytosis, neurophychiatric SLE (left cerebellar infarction), and Staphylococcus aureus bacteremia. He was subsequently diagnosed with SLE based on several positive findings on immunological tests (including positive for antinuclear antibody). Despite immediate glucocorticoid pulse therapy and plasma exchange (PE) along with antibiotic, he developed cAVB that required temporary pacing on day 2. Because it was thought that hypercytokinemia exacerbated pericarditis, which progressed to myocarditis and cAVB, we decided to PE and cytokine-adsorbing therapy with AN69ST-continuous hemodiafiltration (CHDF). Other than renal failure, his organ dysfunctions improved with the multidisciplinary therapy. CAVB improved and temporary pacing was no longer required on day 11. Even a first-degree atrioventricular block can rapidly progress to cAVB; therefore, strict attention to electrocardiogram is necessary in severe SLE cases. When presenting with organ dysfunctions caused by hypercytokinemia such as severe SLE cases or SLE with severe infection cases, use of the combination of PE and AN69ST-CHDF might be beneficial.

Cytokine Removal in Critically Ill Patients Requiring Surgical Therapy for Infective Endocarditis (RECReATE): An Investigator-initiated Prospective Randomized Controlled Clinical Trial Comparing Two Established Clinical Protocols.

INTRODUCTION: Infective endocarditis (IE) and other severe infections induce significant changes in the immune response in a considerable number of affected patients. Numerous IE patients develop a persistent functional immunological phenotype that can best be characterized by a profound anti-inflammation and/ or functional "anergy." This is pronounced in patients with unresolved infectious foci and was previously referred to as "injury-associated immunosuppression" (IAI). IAI can be assessed by measurement of the monocytic human leukocyte antigen-DR (mHLA-DR) expression, a global functional marker of immune competence. Persistence of IAI is associated with prolonged intensive care unit length of stay, increased secondary infection rates, and death. Immunomodulation to reverse IAI was shown beneficial in early immunostimulatory (randomized controlled) clinical trials. METHODS: Prospective 1:1 randomized controlled clinical study to compare the course of mHLA-DR in patients scheduled for cardiac surgery for IE. Patients will receive either best standard of care plus cytokine adsorption during surgery while on cardiopulmonary bypass (protocol A) versus best standard of care alone, that is, surgery without cytokine adsorption (protocol B). A total of 54 patients will be recruited and randomized. The primary endpoint is a change in quantitative expression of mHLA-DR (antibodies per cell on CD14+ monocytes/ macrophages, assessed using a quantitative standardized assay) from baseline (preoperation [pre-OP], visit 1) to day 1 post-OP (visit 4). DISCUSSION: This randomized controlled clinical trial (RECReATE) will compare 2 clinical treatment protocols and will investigate whether cytokine adsorption restores monocytic immune competence (reflected by increased mHLA-DR expression) in patients with IE undergoing cardiac surgery. TRIAL REGISTRATION: This protocol was registered in ClinicalTrials.gov, under number NCT03892174, first listed on March 27, 2019.

Cytokine and Cancer Biomarkers Detection: The Dawn of Electrochemical Paper-Based Biosensor.

Although the established ELISA-based sensing platforms have many benefits, the importance of cytokine and cancer biomarkers detection for point-of-care diagnostics has propelled the search for more specific, sensitive, simple, accessible, yet economical sensor. Paper-based biosensor holds promise for future in-situ applications and can provide rapid analysis and data without the need to conduct in a laboratory. Electrochemical detection plays a vital role in interpreting results obtained from qualitative assessment to quantitative determination. In this review, various factors affecting the design of an electrochemical paper-based biosensor are highlighted and discussed in depth. Different detection methods, along with the latest development in utilizing them in cytokine and cancer biomarkers detection, are reviewed. Lastly, the fabrication of portable electrochemical paper-based biosensor is ideal in deliberating positive societal implications in developing countries with limited resources and accessibility to healthcare services.

Coupled Plasma Filtration Adsorption for Treatment of Capillary Leak Syndrome Superimposed to Acute Generalized Exanthematous Pustolosis: A Case Report.

Coupled plasma filtration adsorption (CPFA) is an extracorporeal supportive therapy based on nonspecific adsorption of pro- and anti-inflammatory mediators combined with continuous renal replacement therapy. The main field of CPFA application is septic shock, and there are limited data about its efficacy in the treatment of other acute conditions characterized by a dysregulation in immune homeostasis. Capillary leak syndrome (CLS) defines a life-threatening condition sustained by hypercytokinemia and characterized by abrupt onset of increased capillary permeability leading to severe generalized edema and hypovolemic shock refractory to fluid administration. Therapy for CLS is not specific and, at present time, it consists in the use of steroids or intravenous immunoglobulins. We present the case of a 34-year-old woman who developed CLS superimposed to acute generalized exanthematous pustulosis after initiating therapy with hydroxychloroquine for undifferentiated connective tissue disease. CLS did not respond to steroids and intravenous immunoglobulins, while it was successfully treated with CPFA. This observation supports the possible role of CPFA in restoring a proper immunologic homeostasis not only in sepsis but also in other devastating conditions sustained by hypercytokinemia.

Nicotinamide phosphoribosyltransferase purification using SUMO expression system.

Nicotinamide phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the salvage pathway required for nicotinamide adenine dinucleotide synthesis. The secreted NAMPT protein serves as a master regulatory cytokine involved in activation of evolutionarily conserved inflammatory networks. Appreciation of the role of NAMPT as a damage-associated molecular pattern protein (DAMP) has linked its activities to several disorders via Toll-like receptor 4 (TLR4) binding and inflammatory cascade activation. Information is currently lacking concerning the precise mode of the NAMPT protein functionality due to limited availability of purified protein for use in in vitro and in vivo studies. Here we report successful NAMPT expression using the pET-SUMO expression vector in E. coli strain SHuffle containing a hexa-His tag for purification. The Ulp1 protease was used to cleave the SUMO and hexa-His tags, and the protein was purified by immobilized-metal affinity chromatography. The protein yield was ~4 mg/L and initial biophysical characterization of the protein using circular dichroism revealed the secondary structural elements, while dynamic light scattering demonstrated the presence of oligomeric units. The NAMPT-SUMO showed a predominantly dimeric protein with functional enzymatic activity. Finally, we report NAMPT solubilization in n-dodecyl-ß-d-maltopyranoside (DDM) detergent in monomeric form, thus enhancing the opportunity for further structural and functional investigations.

Clinical Effect of the Acrylonitrile-Co-Methallyl Sulfonate Surface-Treated Membrane as a Cytokine Adsorption Therapy for Sepsis due to Acute Panperitonitis: A Retrospective Cohort Study.

INTRODUCTION: Sepsis is a systemic inflammatory response syndrome caused by infectious diseases, with cytokines possibly having an important role in the disease mechanism. Acrylonitrile-co-methallyl sulfonate surface-treated (AN69ST) membrane is expected to improve the outcomes of patients with sepsis through cytokine adsorption. OBJECTIVE: This study aimed to investigate the clinical effect of the AN69ST membrane in comparison to standard continuous renal replacement therapy (CRRT) membranes for panperitonitis due to lower gastrointestinal perforation. METHODS: Using the Diagnosis Procedure Combination database, we identified adult patients with sepsis due to panperitonitis receiving any CRRT. Propensity score matching was used to compare patients who received CRRT with the AN69ST membrane (AN69ST group) and those who received CRRT with other membranes (non-AN69ST group). The primary outcome measure was in-hospital mortality. RESULTS: A total of 528 and 1,445 patients were included in the AN69ST group and in the non-AN69ST group, respectively. Propensity score matching resulted in 521 pairs. There was no significant difference in in-hospital mortality (32.1 vs. 35.5%; p = 0.265) and 30-day mortality (41.3 vs. 42.8%, p = 0.074) between the AN69ST group and the non-AN69ST group. CONCLUSION: There is no significant difference in-hospital mortality between CRRT with the AN69ST membrane and CRRT with standard CRRT membranes for panperitonitis due to lower gastrointestinal perforation. These results indicate that the AN69ST membrane is not superior to the standard CRRT membrane.

Compartmentalized profiling of amniotic fluid cytokines in women with preterm labor.

OBJECTIVE: Amniotic fluid cytokines have been implicated in the mechanisms of preterm labor and birth. Cytokines can be packaged within or on the surface of extracellular vesicles. The main aim of this study was to test whether the protein abundance internal to and on the surface of extracellular vesicles changes in the presence of sterile intra-amniotic inflammation and proven intra-amniotic infection in women with preterm labor as compared to the women with preterm labor without either intra-amniotic inflammation or proven intra-amniotic infection. STUDY DESIGN: Women who had an episode of preterm labor and underwent an amniocentesis for the diagnosis of intra-amniotic infection or intra-amniotic inflammation were classified into three groups: 1) preterm labor without either intra-amniotic inflammation or proven intra-amniotic infection, 2) preterm labor with sterile intra-amniotic inflammation, and 3) preterm labor with intra-amniotic infection. The concentrations of 38 proteins were determined on the extracellular vesicle surface, within the vesicles, and in the soluble fraction of amniotic fluid. RESULTS: 1) Intra-amniotic inflammation, regardless of detected microbes, was associated with an increased abundance of amniotic fluid cytokines on the extracellular vesicle surface, within vesicles, and in the soluble fraction. These changes were most prominent in women with proven intra-amniotic infection. 2) Cytokine changes on the surface of extracellular vesicles were correlated with those determined in the soluble fraction; yet the magnitude of the increase was significantly different between these compartments. 3) The performance of prediction models of early preterm delivery based on measurements on the extracellular vesicle surface was equivalent to those based on the soluble fraction. CONCLUSIONS: Differential packaging of amniotic fluid cytokines in extracellular vesicles during preterm labor with sterile intra-amniotic inflammation or proven intra-amniotic infection is reported herein for the first time. The current study provides insights into the biology of the intra-amniotic fluid ad may aid in the development of biomarkers for obstetrical disease.

Cytokine adsorption as a promising option for septic shock and multiple organ failure due to Candida infection and decompensated type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) represents one of the most common chronic diseases in childhood. It is associated with high morbidity and mortality rates due to metabolic dysregulation, immunosuppressive effects, and a predisposition to fungal infections. Candidiasis is a severe infection and its prevalence has increased throughout the last decades. We report the case of a 19-year-old female patient admitted to our intensive care unit with T1DM and Candida infection associated with severe metabolic acidosis. In the absence of response to high dose catecholamine cardiovascular therapy and the presence of severe metabolic acidosis, a CytoSorb cartridge was implemented into the extracorporeal dialysis circuit resulting in a stabilization of hemodynamics accompanied by a tremendous decrease in vasopressor requirements, control of the hyperinflammatory response, as well as a resolution of metabolic acidosis and regeneration of renal function. Treatment with CytoSorb was safe and feasible without technical problems. Notably, this is the first case description reporting on the effects of CytoSorb in a patient with Candida infection as part of T1DM.

Separating cytokine twins with a small molecule.

The cytokine macrophage migration inhibitory factor (MIF) has been characterized as a key immunomodulator and mediator of various diseases. Small molecule inhibitors based on the conserved enzymatic pocket of MIF have been valuable in elucidating MIF mechanisms and developing translational strategies. In contrast, our mechanistic understanding of the MIF homolog MIF-2/d-dopachrome tautomerase (d-DT) and its clinical translation has been hampered, partly because MIF-2-selective inhibitors have been elusive. Here, Tilstam et al. characterize a small-molecule inhibitor selective for MIF-2 that interferes with receptor binding and cell signaling. That could be a promising therapeutic lead and a valuable research tool.

Comprehensive immune profiling and immune-monitoring using body fluid of patients with metastatic gastric cancer.

BACKGROUND: The aim of this study is to profile the cytokines and immune cells of body fluid from metastatic gastric cancer (mGC), and evaluate the potential role as a prognostic factor and the feasibility as a predictive biomarker or monitoring source for immune checkpoint inhibitor. METHODS: Body fluid including ascites and pleural fluid were obtained from 55 mGC patients and 24 matched blood. VEGF-A, IL-10, and TGF-ß1 were measured and immune cells were profiled by fluorescence assisted cell sorting (FACS). RESULTS: VEGF-A and IL-10 were significantly higher in body fluid than in plasma of mGC. Proportion of T lymphocytes with CD69 or PD-1, memory T cell marked with CD45RO, and number of Foxp3+ T regulatory cells (Tregs) were significantly higher in body fluid than those in blood of mGC. Proportion of CD8 T lymphocyte with memory marker (CD45RO) and activation marker (HLA-DR), CD3 T lymphocyte with PD-1, and number of FoxP3+ Tregs were identified as independent prognostic factors. When patients were classified by molecular subgroups of primary tumor, VEGF-A was significantly higher in genomically stable (GS)-like group than that in chromosomal instability (CIN)-like group while PD-L1 positive tumor cells (%) showed opposite results. Monitoring immune dynamics using body fluid was also feasible. Early activated T cell marked with CD25 was significantly increased in chemotherapy treated group. CONCLUSIONS: By analyzing cytokines and proportion of immune cells in body fluid, prognosis of patients with mGC can be predicted. Immune monitoring using body fluid may provide more effective treatment for patients with mGC.

Inflammatory cytokines: from discoveries to therapies in IBD.

Introduction: Although the etiology of inflammatory bowel diseases (IBD) remains unknown, accumulating evidence suggests that the intestinal tissue damage in these disorders is due to a dynamic interplay between immune cells and non-immune cells, which is mediated by cytokines produced within the inflammatory microenvironment. Areas covered: We review the available data about the role of inflammatory cytokines in IBD pathophysiology and provide an overview of the therapeutic options to block the function of such molecules. Expert opinion: Genome studies, in vitro experiments with patients' samples and animal models of colitis, have largely advanced our understanding of how cytokines modulate the ongoing mucosal inflammation in IBD. However, not all the cytokines produced within the damaged gut seem to play a major role in the amplification and perpetuation of the IBD-associated inflammatory cascade. Indeed, while some of the anti-cytokine compounds are effective in some subgroups of IBD patients, others have no benefit. In this complex scenario, a major unmet need is the identification of biomarkers that can predict response to therapy and facilitate a personalized therapeutic approach, which maximizes the benefits and limits the adverse events.