Canakinumab investigated for treating familial Mediterranean fever

ABSTRACT

Introduction: Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory syndrome. The treatment of choice is colchicine. However, ~40% of patients are only partial responders and 5–10% are non-responders. Advances in the understanding of the role of pyrin in the regulation of interleukin (IL)-1β activation has led to use of anti-IL-1 agents for colchicine-resistant FMF.

Areas covered: The authors performed a literature search of anti-IL-1 treatment for FMF, particularly canakinumab, a humanized IL-1β antibody, by searching PubMed/Medline/Scopus since 2001 and proceedings of major rheumatologic conferences since 2011 for unpublished studies.

Expert opinion: Many reports of successful treatments with anti-IL-1 agents were published since 2007. In 2011, the first case reports of successful treatment with canakinumab were reported. Successful phase II trials reported in 2014 and 2015 led to a double-blind, randomized, placebo-controlled phase III trial in patients with colchicine-resistant FMF. Significantly more canakinumab treated patients attained the very stringent primary outcome measure and secondary outcomes vs. those treated with placebo. The safety profile was similar to canakinumab trials for other indications. Canakinumab appears to be an excellent alternative for the vast majority of patients with colchicine-resistant FMF, with an adequate safety profile.     

Rilonacept for the treatment of cryopyrin-associated periodic syndromes (CAPS)

Background: Cryopyrin-associated periodic syndromes (CAPS) encompass a group of rare inherited, autoinflammatory disorders that represent a spectrum of one disease with varying degrees of severity. Until recently, there was no effective treatment for CAPS, but identification of the genetic basis of CAPS highlighted the pathogenic role of IL-1β. Objectives: Rilonacept is a recently FDA approved biologic therapy for CAPS with high affinity for IL-1β. Limited pharmacological data has been reported to date. Methods: A review of the phamacokinetics and pharmacodynamics data as well as the results of a pilot study and Phase III placebo-controlled trials of rilonacept in CAPS. Unpublished data on an open-label extension study in adult and pediatric subjects is also reviewed. Results: Rilonacept produced rapid and profound improvements in symptoms and also reduced high-sesitivity C-reactive protein levels and normalized elevated serum amyloid A concentrations, an important risk factor for amyloidosis. The primary adverse events were injection- site reactions and upper respiratory tract infections. Conclusion: Rilonacept, the only IL-1 Trap, is the first of many novel IL-1-targeted therapies being developed. In a very short time it has changed the lives of CAPS patients.     

In vivo regulation of interleukin 1β in patients with cryopyrin-associated periodic syndromes

The investigation of interleukin 1β (IL-1β) in human inflammatory diseases is hampered by the fact that it is virtually undetectable in human plasma. We demonstrate that by administering the anti–human IL-1β antibody canakinumab (ACZ885) to humans, the resulting formation of IL-1β–antibody complexes allowed the detection of in vivo–produced IL-1β. A two-compartment mathematical model was generated that predicted a constitutive production rate of 6 ng/d IL-1β in healthy subjects. In contrast, patients with cryopyrin-associated periodic syndromes (CAPS), a rare monogenetic disease driven by uncontrolled caspase-1 activity and IL-1 production, produced a mean of 31 ng/d. Treatment with canakinumab not only induced long-lasting complete clinical response but also reduced the production rate of IL-1β to normal levels within 8 wk of treatment, suggesting that IL-1β production in these patients was mainly IL-1β driven. The model further indicated that IL-1β is the only cytokine driving disease severity and duration of response to canakinumab. A correction for natural IL-1 antagonists was not required to fit the data. Together, the study allowed new insights into the production and regulation of IL-1β in man. It also indicated that CAPS is entirely mediated by IL-1β and that canakinumab treatment restores physiological IL-1β production.IL-1α and β, which were originally described as leukocytic pyrogens (1), are important regulators of the response to tissue damage and infections and mediate symptoms of fever, fatigue, pain, arthritis, and the hepatic acute phase responses including synthesis of C-reactive protein (CRP) and serum amyloid A protein (SAA) (2). Although studies using recombinant IL-1 in cancer patients confirmed the causative role of IL-1 for many of these symptoms (3), its direct investigation in man is hampered by the inability to detect IL-1 in biological fluids. cryopyrin-associated periodic syndromes (CAPS) is a clinical disease syndrome resulting from heterozygous gain-of-function mutations in NLRP3, the gene encoding cryopyrin. These mutations are supposed to promote release of IL-1, thereby providing an excellent paradigm for studying human IL-1 in vivo (4, 5). CAPS patients present with a spectrum of autoinflammatory diseases (6–11) involving almost all organ systems. NLRP3 mutations result in overactivation of caspase 1, the enzyme which cleaves the precursors of IL-1β, IL-18, and IL-33, members of the IL-1 family of cytokines, into their active forms (12). Although pro–IL-1α is not a substrate of caspase 1, recent studies in mice indicate that secretion of bioactive IL-1α requires functional NLRP3 (13) and activated caspase-1 (14). The recombinant IL-1 receptor antagonist (IL-1Ra) anakinra and the IL-1 receptor type I (IL-1RI) fusion protein rilonacept (IL-1 trap) have both induced clinical response in CAPS, demonstrating that signaling via the IL-1RI is crucial for the pathogenesis of CAPS (15–17). This strongly implies that neither IL-18 nor IL-33 plays significant roles in the disease, as neither of these two cytokines signals via the IL-1RI, and suggests that the disease is caused by overproduction of IL-1. By administering the human anti–IL-1β antibody canakinumab to CAPS patients, we provide evidence in this paper that IL-1β is pivotal in the pathogenesis of CAPS. Treatment with the antibody allowed the detection of IL-β and the creation of a mathematical model, which indicates that the in vivo production rate of IL-1β is fivefold higher in CAPS as compared with healthy subjects. Furthermore, in vivo IL-β production could be completely restored in these patients after canakinumab treatment.     

Pharmacokinetic and Pharmacodynamic Characteristics of Single-dose Canakinumab in Patients With Type 2 Diabetes Mellitus

PurposeInterleukin (IL)-1β, an inflammatory molecule, contributes to the development of atherothrombosis and worsening of islet β-cell function. Canakinumab, a human monoclonal antibody, targets IL-1β–dependent inflammation and reduces the vascular inflammatory biomarker, high-sensitivity C-reactive protein (hsCRP), and other inflammatory cardiovascular biomarkers. Here, we aimed to assess the pharmacokinetic (PK) and pharmacodynamic characteristics, including the effect on hsCRP, of canakinumab in patients with type 2 diabetes mellitus (T2DM) after a 2-hour single-dose intravenous infusion.MethodsThis multicenter, randomized, double-blind, placebo-controlled, dose-escalation study was conducted in patients with T2DM (diagnosed ≥6 months before screening) on a stable daily dose of metformin. Patients were randomly assigned to receive a single intravenous dose of canakinumab 0.03, 0.1, 0.3, 1.5, or 10 mg/kg or placebo. The study was initially designed with 1 small cohort (15 patients, 0.3 mg/kg) on a stable dose of metformin ≥500 mg/d for an initial tolerability evaluation; all other patients were on a stable dose of ≥850 mg/d of metformin. The PK profile was assessed at 0 and 2 hours and at days 2, 14, 28, 56, 84, and 168. Changes in hsCRP and hemoglobin (Hb) A_1c levels were assessed at weeks 4, 8, 12, and 24.FindingsOf the 231 enrolled patients, 222 completed the study. Median hsCRP values at screening ranged from 1.8 to 3.2 mg/L, and the median daily dose of metformin ranged from 1000 to 2000 mg. Exposure to canakinumab was dose proportional. The mean half-life ranged from 17 to 26 days, and mean systemic clearance ranged from 0.094 to 0.128 mL/h/kg. Dose-related reductions in hsCRP were significantly greater with canakinumab compared with those with placebo at week 4 (−0.2 mg/L, −0.5 mg/L, −1.5 mg/L, and −1.7 mg/L with the 0.1-, 0.3-, 1.5-, and 10-mg/kg doses, respectively; all, P < 0.05). Significant reductions in hsCRP were maintained up to week 12 with the 2 highest doses of canakinumab (−0.8 mg/L with 1.5 mg/kg and −1.3 mg/L with 10 mg/kg; both, P < 0.05). A placebo-adjusted decrease in HbA1c of 0.31% at week 12 was reported with canakinumab 10 mg/kg (P = 0.038), and a reduction of 0.23% at week 4 was found with canakinumab 1.5 mg/kg (P = 0.011).ImplicationsThe findings from this study suggest that IL-1β blockade after single-dose administration of canakinumab at 1.5 and 10 mg/kg provided sustained suppression of hsCRP levels for 12 weeks in patients with T2DM. ClinicalTrials.gov identifier: NCT00900146.     

Canakinumab for secondary prevention of atherosclerotic disease

Introduction: The widespread prevalence of cardiovascular disease (CVD) and its impact on morbidity and mortality requires effective secondary prevention measures. For years, inflammation has been advocated as a key mediator of atherosclerosis and its associated complications. Drugs for secondary prevention of CVD events include interventions aimed at risk factors control and antithrombotic management, but there is no drug currently recommended that specifically targets inflammation. Recently, the inflammatory hypothesis of atherosclerosis has been confirmed by a randomized clinical trial of canakinumab, a monoclonal antibody that blocks an inflammatory pathway mediated by interleukin-1β.

Areas covered: This article reviews the pharmacology of canakinumab, its current clinical development status and upcoming regulatory perspectives.

Expert opinion: In the CANTOS trial, canakinumab 150 mg met the pre-specified criteria of statistical significance, showing a reduction in combined cardiovascular events, myocardial infarction, re-hospitalization due to urgent revascularization and any coronary revascularization, but no impact on all-cause or cardiovascular death. There were more death attributed to sepsis or infection with canakinumab than placebo, but fewer reports of arthritis, gout, osteaoarthritis and cancer-related death. Because interleukin-1β is only one of the potential pro-inflammatory pathways that may serve as a target for atherothrombotic protection, other anti-inflammatory drugs may be the object of future investigations. If approved, the initial penetration of canakinumab will face hurdles in view of cost issues, but costs are likely to decrease if the drug loses its present status of orphan drug with the new indication.     

Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies

The inflammasome is a cytoplasmic multiprotein complex that promotes proinflammatory cytokine maturation in response to host- and pathogen-derived signals. Missense mutations in cryopyrin (NLRP3) result in a hyperactive inflammasome that drives overproduction of the proinflammatory cytokines IL-1β and IL-18, leading to the cryopyrin-associated periodic syndromes (CAPS) disease spectrum. Mouse lines harboring CAPS-associated mutations in Nlrp3 have elevated levels of IL-1β and IL-18 and closely mimic human disease. To examine the role of inflammasome-driven IL-18 in murine CAPS, we bred Nlrp3 mutations onto an Il18r-null background. Deletion of Il18r resulted in partial phenotypic rescue that abolished skin and visceral disease in young mice and normalized serum cytokines to a greater extent than breeding to Il1r-null mice. Significant systemic inflammation developed in aging Nlrp3 mutant Il18r-null mice, indicating that IL-1 and IL-18 drive pathology at different stages of the disease process. Ongoing inflammation in double-cytokine knockout CAPS mice implicated a role for caspase-1–mediated pyroptosis and confirmed that CAPS is inflammasome dependent. Our results have important implications for patients with CAPS and residual disease, emphasizing the need to explore other NLRP3-mediated pathways and the potential for inflammasome-targeted therapy.     

Tralokinumab for uncontrolled asthma

Introduction: Asthma is a chronic inflammatory disease of the airways mainly related to allergen exposure, in which various cytokine-specific pathways interact among themselves to promote IgE hyperproduction, bronchial hyperresponsiveness, eosinophil local recruitment and airways remodeling. IL-13 is known for its prominent pathogenic role in this disease and therapeutic blocking approaches are underway.

Areas covered: Anti-IL-13 antibodies are currently investigated in clinical studies in uncontrolled asthma. Tralokinumab is a human IgG4 anti IL-13 antibody which was recently evaluated in a Phase II study demonstrating the maximal efficacy in a subset of asthma patients characterized by the highest sputum IL-13 levels. The results of this study are discussed in this paper.

Expert opinion: The IL-13 blockade with various therapeutic approaches such as tralokinumab has the potential to improve the asthma control in patients subsets in whom the blocked cytokine is demonstrated to be overexpressed.     

Darbepoetin alfa in anemia of myelodysplastic syndromes: present and beyond

Importance of the field: Anemia is the leading clinical manifestation in myelodysplastic syndromes (MDS), significantly altering quality of life. Darbepoetin alfa has recently been added to the armentarium of erythropoiesis stimulating agents (ESAs) for the treatment of anemia in MDS.

Areas covered in this review: We review here the efficacy and safety data on the use of darbepoetin alfa in the management of anemia in MDS patients. Published reports covering the period from 2005 till today were reviewed, as well as updated guidelines on the use of ESAs.

What the reader will gain: Darbepoetin alfa administered, during correction phase, once a week or at longer intervals, yielded erythroid response rates comparing favourably with those obtained with recombinant human erythropoietin (rHuEPO) in lower-risk MDS. During maintenance phase, intervals between injections can be further increased in many responders. Quality of life was consistently improved in responders and the drug was overall well tolerated.

Take home message: Those results, together with recent studies showing improved long-term outcomes in responders, support the use of darbepoetin, among other ESAs, for the treatment of anemia of lower-risk MDS, as recommended by international guidelines.     

Zalutumumab in head and neck cancer

Introduction: Plaque psoriasis is a chronic inflammatory disease that can result in significant physical, psychological and quality of life impairments. Until recently, biologic treatment for psoriasis was limited to tumor necrosis factor-α inhibitors and an interleukin (IL)-12/23 p40 subunit inhibitor. Newly developed biologics targeting the pro-inflammatory IL-17A cytokine have shown success in providing higher levels of clinical efficacy in patients with psoriasis. Secukinumab, a member of this novel class of IL-17 inhibitors, is the latest biologic to receive US FDA approval for the treatment of moderate-to-severe plaque psoriasis.

Areas covered: This comprehensive review will cover the pharmacology, efficacy, safety and future role of secukinumab and other IL-17 blockers in the treatment of plaque psoriasis.

Expert opinion: While biologics have revolutionized patient care for chronic plaque psoriasis, they are associated with loss of response over time. When treatment failure occurs with existing biologics, physicians are left with few alternative treatment options to offer patients. The introduction of secukinumab has provided an additional therapeutic agent that offers improved skin clearance, better health related quality of life and a favorable side-effect profile.     

Icterus Index Determined with the Spectrophotometer,Corrected for Turbidity and Hemoglobin

Background. Alterations in body temperature may influence immune system function and consequently affect the risk of infection and inflammatory diseases. Lipopolysaccharide (LPS) from gram-negative bacteria induces production of inflammatory cytokines after ligand binding to Toll-like receptor 4 (TLR4) on immune cells (especially monocytes/ macrophages). Our aim was to explore how clinically relevant hypo- and hyperthermia affect this signalling in an ex vivo whole blood model, and investigate if the cytokine response was correlated with monocyte TLR4 expression level. Methods. Blood from 11 healthy volunteers was incubated with LPS 10 ng/ml for 6 h at 33, 37 or 40°C. The concentrations of selected pro-inflammatory (tumour necrosis factor-α (TNF-α) and interleukin (IL)-1β) and anti-inflammatory (IL-10) cytokines were measured in plasma, and the surface expression of TLR4 was quantified on CD14 + monocytes. Results. Monocyte TLR4 expression and plasma IL-1β were inversely related to temperature. The TNF-α production was unaffected by hypothermia but increased significantly during hyperthermia, whereas plasma IL-10 was significantly reduced during both hypo- and hyperthermic incubation. No correlation was found between TLR4 expression and cytokine concentrations. During hypothermia, the TNF-α/IL-10 and IL-1β/IL-10 ratios increased seven and nine times, respectively. Hyperthermia increased the TNF-α/IL-10 ratio, but to a lesser extent (doubling), whereas the IL-1β/IL-10 ratio remained unchanged. Conclusion. Hypothermia significantly changed the cytokine ratios in the pro-inflammatory direction. In comparison, the effect of hyperthermia was sparse, with a modest increase in the TNF-α/IL-10 ratio only. No association was found between LPS-stimulated cytokine production and TLR4 expression on CD14 + monocytes.     

Update on biologicals for treatment of juvenile idiopathic arthritis

Introduction: The development of biologics has markedly changed the treatment of JIA. Complete control of the disease and remission has today become the main goal of treatment preventing long-term damage and disability.

Areas covered: This review gives an overview of the current treatment options using biologics in JIA. The biologic drugs are discussed on the basis of recent clinical trials.

Expert opinion: While JIA is a group of heterogeneous diseases, differences in their biology turned out to influence treatment success with different biologics. TNF inhibitors emerged to be the most commonly used biologics for the treatment of JIA. First they were successful for the treatment of rheumatoid factor positive and negative polyarticular JIA. TNF inhibitors have also been studied in patients with enthesitis-related arthritis, psoriatic arthritis, and extended olioarthritis, and approval of at least etanercept is expected. Second-line biologics are abatacept and tocilizumab. For systemic onset JIA, tocilizumab, and the IL-1 inhibitors anakinra and canakinumab have been successfully studied. In the treatment of JIA, biologics have emerged as potent drugs to control the disease. New advancements will be crucial for further improvement of treatment options in JIA.     

Evaluating the role of IL-12 based therapies in ovarian cancer: a review of the literature

Introduction: Immunotherapy, in its entirety, represents a promising field at the forefront of cancer. Treatment with potent cytokine IL-12 has provided science with many challenges, but has also demonstrated promise as therapeutic strategy in ovarian cancer.

Areas covered: This review examines the anti-tumor mechanism of action of IL-12 and the development of IL-12 as a potential therapeutic option in a variety of malignancies. It also reviews the immunogenicity of ovarian cancer and covers preclinical and clinical trials that have contributed to the advancement of IL-12 as a potential therapy for ovarian malignancy. The obstacles that researchers have overcome and currently face regarding the use of IL-12 in clinical ovarian cancer trials are also discussed.

Expert opinion: IL-12, as a therapeutic modality, is mechanistically logical and shows great promise in preclinical trials. Further clinical studies are warranted to optimize the potential of IL-12 as a treatment strategy for ovarian cancer.     

Ixekizumab: an anti- IL-17A monoclonal antibody for the treatment of psoriatic arthritis

Introduction: Psoriatic arthritis (PsA) is an inflammatory rheumatic disease that manifests itself with synovitis, dactylitis, enthesitis and also axial involvement. Interleukin-17A has been identified as a master cytokine in the inflammatory response and pathogenesis of PsA and spondyloarthritis in general. Ixekizumab is a new humanized monoclonal antibody that blocks the biological activity of IL-17A. This biological agent has previously demonstrated a high level of efficacy in psoriasis.

Areas covered: This review discusses the basic immunology of the IL-17 cytokine family, the contribution of IL-17A to the immunopathogenesis of PsA, the clinical trials that evaluated ixekizumab in patients with PsA (SPIRIT program) and the safety of this agent.

Expert opinion: Ixekizumab demonstrated its efficacy in different aspects of PsA including peripheral joint involvement, dactylitis, skin symptoms and patient reported outcomes in the 2 phase III trials from the SPIRIT program. Its safety profile was consistent with previous observations in patients with psoriasis. The role of IL-17A in the management of patients with PsA needs further clarification. According to EULAR recommendations for the management of PsA, IL-17A inhibitors may be used as second line biological DMARDs after TNF inhibitors.     

Interleukin-21: updated review of Phase I and II clinical trials in metastatic renal cell carcinoma,metastatic melanoma and relapsed/refractory indolent non-Hodgkin's lymphoma

Importance to the field: In advanced renal cell cancer and malignant melanoma, the current FDA approved immune modulators, such as IL-2, are the only agents which provide a durable complete remission. These responses, however, occur in < 10% of treated patients and their applicability is limited to selected patients because of their toxicity. The identification of new immunotherapeutic agents with an improved response rate and toxicity profile would represent a significant advancement in the treatment of these malignancies.

Areas covered in this review: This is a comprehensive review of IL-21 including its pharmacology and current developmental status. A literature review was performed using all PubMed listed publications involving IL-21, including original research articles, reviews and abstracts. It also includes a review of current ongoing trials and information from the official product website.

What the reader will gain: Recombinant IL-21 (rIL-21) is a new immune modulator currently undergoing Phase I and II testing. It is a cytokine with a four helix structure that has structural and sequence homology to IL-2 and -15, but also possesses many unique biological properties. In this review, we evaluate the development, pharmacologic properties, safety profile and current clinical efficacy of rIL-21.

Take home message: rIL-21 has an acceptable safety profile and encouraging single agent activity in early phase renal cell carcinoma and melanoma clinical trials.     

Lactoferrin Protects Hyperoxia-Induced Lung and Kidney Systemic Inflammation in an In Vivo Imaging Model of NF-κB/Luciferase Transgenic Mice

Purpose

High levels of oxygen are usually used in ventilatory support and extracorporeal membrane oxygenation (ECMO) in the intensive care unit of hospitals. Hyperoxia may induce the production of reactive oxygen species (ROS) that can cause lung damage and even systemic injury. In this study, the NF-κB/luciferase transgenic mouse model with non-invasive real-time in vivo imaging was established to test the functions of lactoferrin (LF) in antioxidant and anti-inflammation.

Procedures

The NF-κB/luciferase transgenic mice were used to assess the effects of oral administration of LF on attenuation of the systemic inflammatory response and organ damage after 72 h of hyperoxia (FiO₂?>?95 %) exposure via monitoring using an in vivo imaging system (IVIS).

Results

Using luciferase IVIS imaging, we found that the lungs and kidneys were the most evidently affected organs after hyperoxia treatment. The groups treated with low dose (150 mg/kg) or high dose (300 mg/kg) of LF had lower luciferase expression and less injury, with a dose-dependent effect on the lungs and kidneys. Moreover, ROS, mitogen-activated protein kinases (MAPK), and pro-inflammatory cytokine (TNF-α, IL-1ß, and IL-6) expression levels were all significantly decreased (P?<?0.01), and the protein level of IκB was statistically increased (P?<?0.01) after LF treatment.

Conclusions

Our results suggest that hyperoxia can induce systemic inflammation, and the oral administration of LF as a natural antioxidant decreases the production of ROS, attenuates inflammation, and lessens kidney and lung injuries from hyperoxia via the use of live image monitoring of the response in NF-kB/luciferase transgenic mice.

     

Abciximab as an adjunctive therapy for patients undergoing percutaneous coronary interventions

Introduction: Platelets play a central role in the pathophysiology of acute coronary syndromes (ACS) and activation of platelet glycoprotein (GP) IIb/IIIa receptor is critical to platelet aggregation. Abciximab, a human murine chimeric antibody to the GPIIb/IIIa receptor, is an important biological therapy in the management of patients presenting with ACS.

Areas covered: The objective of this review is to define the role of abciximab in the management of ACS by interpreting the available data from randomized clinical trials using abciximab in various clinical scenarios, particularly in percutaneous coronary intervention (PCI). We also review different modes of delivery and describe the adverse effects of abciximab including thrombocytopenia. Where possible, we attempt to compare abciximab to the other available GPIIb/IIIa inhibitors. We hope the reader will gain a better understanding of the benefits and risks of abciximab and the important role it has in the management of cardiology patients.

Expert opinion: Abciximab was a breakthrough drug in the management of high risk ACS patients undergoing PCI. However, with newer available therapies and improvement in PCI technology, dose and delivery of this drug have evolved as we try to extract maximum benefit while minimizing the adverse effects associated with it.     

Anti-inflammatory effects of the new generation synthetic surfactant CHF5633 on Ureaplasma-induced cytokine responses in human monocytes

Background: Synthetic surfactants represent a promising alternative to animal-derived preparations in the treatment of neonatal respiratory distress syndrome. The synthetic surfactant CHF5633 has proven biophysical effectiveness and, moreover, demonstrated anti-inflammatory effects in LPS-stimulated monocytes. With ureaplasmas being relevant pathogens in preterm lung inflammation, the present study addressed immunomodulatory features on Ureaplasma-induced monocyte cytokine responses.

Methods: Ureaplasma parvum-stimulated monocytes were exposed to CHF5633. TNF-α, IL-1β, IL-8, IL-10, TLR2 and TLR4 expression were analyzed using qPCR and flow cytometry.

Results: CHF5633 did not induce pro-inflammation, and did not aggravate Ureaplasma-induced pro-inflammatory cytokine responses. It suppressed U. parvum-induced intracellular TNF-α (p < 0.05) and IL-1β (p < 0.05) in neonatal monocytes and inhibited Ureaplasma-induced TNF-α mRNA (p < 0.05), TNF-α protein (p < 0.001), and IL-1β (p = 0.05) in adult monocytes. Ureaplasma-modulated IL-8, IL-10, TLR2 and TLR4 were unaffected.

Conclusion: CHF5633 does neither act pro-apoptotic nor pro-inflammatory in native and Ureaplasma-infected monocytes. Suppression of Ureaplasma-induced TNF-α and IL-1β underlines anti-inflammatory features of CHF5633.     

Targeting the IL-23/IL-17 axis for the treatment of psoriasis and psoriatic arthritis

Introduction: A growing amount of data supporting the pathogenic role of the IL-23/IL-17 axis in inflammatory/autoimmune disorders has provided the rationale to target the system for therapeutic purpose. Several compounds have been and are currently under intense investigation in psoriasis and psoriatic arthritis (PsA) yielding impressive results.

Areas covered: In this review article, we provide an overview of currently available data on the IL-23/IL-17 system as a target for treatment for psoriasis and PsA. We searched MEDLINE for articles on drug therapy for psoriasis and PsA published between 1 January 2010 and 31 May 2015. One of these agents, ustekinumab, has been recently approved for the treatment of psoriasis and PsA, and a number of IL-23/IL-17-targeted compounds under investigation in these diseases.

Expert opinion: As our knowledge of the role of the IL-23/IL-17 axis in the pathogenesis of psoriasis and PsA deepens, it enables the development of more targeted therapies in the management of these conditions. Early data on IL-23/IL-17 targeting drugs appear promising, although incomplete. Given the key role IL-23/IL-17 in host defence, the safety profile of targeted drugs should be thoroughly assessed in future studies.     

Omalizumab is effective in treating severe asthma in patients with severe cardiovascular complications and its effects on sCD200, d-dimer,CXCL8, 25-hydroxyvitamin D and IL-1β levels

Background: There have been concerns about the cardiovascular safety of omalizumab.

Objectives: In this study, the clinical status of the omalizumab receiving severe asthma patients and the cytokine expressions patterns were investigated.

Materials and methods: In a pilot study described below we examined the levels of serum eosinophil cationic peptid (ECP), CD200, d-dimer, 25-hydroxyvitamin D (25(OH)D), CXCL8 and IL-1β in asthma patients treated with anti-IgE therapy, to explore their relationship with disease activity, and the impact of anti-IgE therapy impact on those levels. Exercise stress testing and blood samples were taken at all follow up visits from the time of first diagnosis and after 20 months of treatment during the disease remission.

Results: Fractional exhaled nitric oxide concentrations and serum levels of sTRAIL, sCD200, D-dimer, ECP, total IgE, IL-1β and Hs-CRP were decreased while CXCL8, 25(OH)D were increased after starting the treatment of anti-IgE. Our first case of a patient, who had both protein C and S deficiency and hence a high risk for thromboembolism, documents for the first time the safety of omalizumab for asthmatic patients with concurrent risk factors contributing to arteriothrombotic events.

Conclusion: Omalizumab might be used carefully in patients with cardiovascular diseases.     

A new agent for tumour necrosis factor-alpha inhibition

Abstract

Background: Tumour necrosis factor-α (TNF-α) plays a central role in inflammatory cascade in Crohn's disease (CD). Our study aims to investigate the in vitro effects of dipyridamole (DP) on the TNF-α and interleukin-10 (IL-10) production in the intestinal mononuclear cells of CD patients. Material and Methods: Thirteen patients with CD and in 17 healthy individuals underwent colonoscopy and biopsy samples were taken. Cultured mononuclear cells were preincubated with DP1 (0.7 microg/ml), DP2 (1.25 microg/ml), methotrexate (MTX)1 (0.5 nmol/L) and MTX2 (1.5 nmol/L). These cells were then stimulated with lipopolysaccaride (LPS) and phytohemagglutinin (PHA). The levels of TNF-α and IL-10 in supernatants were measured with standard immunoassay monoclonal antibody method. Results: An appropriate cell culture could be obtained in 10 patients with CD and 12 healthy individuals. In LPS stimulated cells, MTX1 and MTX2 were superior to DP1 and DP2 in suppressing TNF-α in both groups. In PHA stimulated cells, while MTX1 was superior to DP1, MTX2 and DP2 had an equivalent effect in CD patients (p<0.05, p>0.05, respectively). In LPS-stimulated cells DP2 was significantly superior to MTX2 in increasing IL-10 levels in both groups (p<0.05). In PHA stimulated cells, DP1 and DP2 caused a higher increase in IL-10 levels compared with MTX1 and MTX2 in CD group (p<0.05). Conclusions: Dipyridamole suppresses TNF-α similar with MTX. It seems to be superior to MTX in increasing IL-10 levels. Addition of DP to anti-TNF medications may create a synergy in cytokine modulation.