Positioning ustekinumab in moderate-to-severe ulcerative colitis: new kid on the block

ABSTRACT

Introduction: Ulcerative colitis (UC) is a chronic relapsing disorder of the colonic tract. Dysregulated innate and adaptive immune pathways contribute to intestinal inflammation in IBD, and cytokines, including IL-12 and IL-23, play a key role. The blockade of both IL-12 and IL-23 may have an impact on different pathways of inflammation and could be effective for the treatment of inflammatory bowel diseases.

Ustekinumab is a fully human IgG1κ monoclonal antibody which binds to the shared p40 protein subunit of IL-12 and ?23. It is currently approved for several immune-mediated diseases such as moderate to severe plaque psoriasis, psoriatic arthritis, and Crohn’s disease, and has shown promising results in UC.

Areas covered: A review of the literature was performed to understand several aspects including the role of IL-12 and ?23 in UC, the potential therapeutic role of ustekinumab in inflammatory bowel disease, and the positioning of ustekinumab in the therapeutic algorithm of UC, based on extrapolated data from available randomized clinical trials.

Expert opinion: Ustekinumab is effective and safe in UC, and shows potential advantages compared to other drugs in moderate-to-severe UC.     

Biological therapy targeting the IL-23/IL-17 axis in inflammatory bowel disease

Introduction: As many inflammatory bowel disease (IBD) patients do not benefit from long-term anti-tumour necrosis factor treatment, new anti-inflammatories are urgently needed. After the discovery of the interleukin (IL) 23/17 axis being pivotal in IBD pathogenesis, many different compounds were developed, targeting different components within this pathway.

Areas covered: A literature search to March 2016 was performed to identify the most relevant reports on the role of the IL-23/IL-17 axis in IBD and on the different molecules targeting this pathway. First, the authors briefly summarize the immunology of the IL-23/IL-17 pathway to elucidate the mode of action of all different agents. Second, they describe all different molecules targeting this pathway. Besides discussing efficacy and safety data, they also explore immunogenicity, exposure during pregnancy and pharmacokinetics.

Expert opinion: A new era in IBD treatment has recently been initiated: besides immunomodulators and TNF-antagonists, anti-adhesion molecules and monoclonal antibodies targeting the IL-23/IL-17 pathway have been developed. Biomarkers for personalized medicine are urgently needed. This therapeutic (r)evolution will further improve disease-related and patient-reported outcome, though a lot of questions should still be addressed in future years.     

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.     

Pitrakinra for asthma

Importance of the field: In asthma IL-4 and IL-13 have been demonstrated to play major pathogenic roles and therefore their blockade would potentially represent a plausible therapeutic approach.

Areas covered in this review: Pitrakinra is a dual IL-4/IL-13 inhibitor currently under development for asthma and the existing preclinical and clinical data are discussed.

What the reader will gain: Inhaled pitrakinra demonstrated a good anti-inflammatory potential and a good safety profile on a short-term basis but its place in asthma therapy is still to be found.

Take home message: Specific anticytokine therapies might in the near future reshape asthma therapy.     

Role of neuropeptides in skin inflammation and its involvement in diabetic wound healing

Importance of the field: In 2010, the world prevalence of diabetes is 6.4%, affecting 285 million adults. Diabetic patients are at risk of developing neuropathy and delayed wound healing that can culminate in incurable diabetic foot ulcerations (DFUs) or even foot amputation.

Areas covered in this review: The contrast between cellular and molecular events of wound healing and diabetic wound healing processes is characterized. Neuropeptides released from the autonomous nervous system and skin cells reveal a major role in the immunity of wound healing. Therefore, the signaling pathways that induce pro/anti-inflammatory cytokines expression and its involvement in diabetic wound healing are discussed. The involvement of neuropeptides in the activation, growth, migration and maturation of skin cells, like keratinocytes, Langerhans cells, macrophages and mast cells, are described.

What the reader will gain: This review attempts to address the role of neuropeptides in skin inflammation, focusing on signal transduction, inflammatory mediators and pro/anti-inflammatory function, occurring in each cell type, as well as, its connection with diabetic wound healing.

Take home message: Understanding the role of neuropeptides in the skin, their application on skin wounds could be a potential therapy for skin pathologies, like the problematic and prevalent DFUs.     

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.     

Considerations,challenges and future of anti-TNF therapy in treating inflammatory bowel disease

ABSTRACT

Introduction: Crohn’s disease (CD) and ulcerative colitis (UC) are chronic disabling conditions. Monoclonal antibody therapy directed against tumor necrosis factor-alpha (anti-TNF) has revolutionized the care of patients with inflammatory bowel disease (IBD).

Areas covered: Considerations before starting anti-TNF therapy are highlighted: the best time to start with anti-TNF therapy, either alone or in combination with an immunomodulator, the choice of an anti-TNF agent and the contra-indications to anti-TNF therapy. Primary nonresponse and secondary loss of response are discussed. De-escalating therapy, the role of therapeutic drug monitoring and the use of biosimilars, are handled. Finally, the future directions of anti-TNF therapy are emphasized.

Expert opinion: Anti-TNF therapy remains the cornerstone in the treatment of IBD. When initiating long-term therapy, safety and cost issues are of great importance. The therapeutic armamentarium in the treatment of IBD is rapidly growing. Therefore, the challenge is to optimize the use and refine the exact position of anti-TNF therapy in the near future, with personalized medicine as the ultimate goal.     

Risankizumab for the treatment of moderate to severe psoriasis

Introduction: Psoriasis is a chronic inflammatory skin disorder pathogenically mediated by multiple cytokines, including interleukin (IL)-23, IL-17, and TNF. An emerging class of therapeutics that selectively blocks IL-23 has been developed. Among these new agents, risankizumab is now being investigated in phase III clinical trials, and the preliminary data are promising in inducing an excellent clinical response.

Areas covered: This review aims to describe the pathogenic role of IL-23 in psoriasis and to collect clinical data related to the efficacy and safety of risankizumab, an anti-IL-23p19 agent, in the treatment of psoriasis.

Expert opinion: Risankizumab showed high response rates in reaching complete or almost complete clearance of psoriasis. When compared to other similarly effective drugs, it may show some advantages related to its mechanism of action (direct blockade of the main pathogenic pathway), safety (no impact on the immune surveillance against Candida infection), therapeutic regimen (every-12-week injections), and effectiveness in the treatment of immune-mediated psoriasis comorbid conditions, such as psoriatic arthritis and Crohn’s disease.     

New biologic therapeutics for ulcerative colitis and Crohn's disease

Introduction: Some inflammatory bowel disease (IBD) patients especially those with refractory Crohn's disease (CD) or relapsing ulcerative colitis (UC) do not respond to current therapies. The newly introduced biological drugs have got some interest due to their specificity and selectivity in modulation of inflammatory elements.

Areas covered: In 46 included randomized, placebo-controlled clinical trials, the efficacy and safety of different biologic drugs have been evaluated in moderately to severely active CD or UC patients. Current investigated drugs include new anti-TNF drugs (adalimumab, certolizumab pegol, etanercept, onercept and golimumab), anti-CD20 (rituximab), T-cell inhibitors (abatacept) and anti-α4 integrins (natalizumab and vedolizumab). Adalimumab, certolizumab, and golimumab showed significant efficacy in induction of remission and maintenance in CD and UC patients with a rate of adverse events similar to placebo in the major trials. Natalizumab and vedolizumab were effective in the treatment of moderately to severely active CD and UC patients. However, vedolizumab caused less adverse effects than natalizumab. onercept, etanercept, rituximab and abatacept were all well tolerated but were not effective in CD or UC patients.

Expert opinion: Anti-TNF drugs, except for onercept and etanercept, and anti-α4 integrins exhibit beneficial therapeutic effects. Although they were all well tolerated, the incidence of progressive multifocal leukoencephalopathy associated with natalizumab should not be missed.     

Investigating cell therapy for inflammatory bowel disease

ABSTRACT

Introduction: Advances in immuno-modulatory therapies, including anti-TNF-α therapies, have greatly increased the chance to achieve long-term remission of inflammatory bowel disease (IBD) patients. However, as the importance of mucosal healing has been demonstrated in a number of clinical studies, new cell-based therapies that can regenerate and fully restore the intestinal mucosal functions are currently under development.

Area covered: In this review, we feature the recent challenges of cell-based therapies that are applied to the treatment of IBD. In particular, we will focus on hematopoietic stem cells (HSC), mesenchymal stem cells (MSCs) and intestinal stem cells (ISCs) as the candidate source for cell-based therapy targeted to treat IBD. The current status, as well as the expected advantages and disadvantages of those transplantations will be summarized and discussed.

Expert opinion: Transplantation of HSC, MSC and ISC may have different levels of potential in their ability to exert an immunomodulatory or pro-regenerative effect. Combined cell therapies, such as co-transplantation of MSC and ISC, may provide improved therapeutic outcome compared to transplantation of a single cell population. Those cell-based therapies may not only improve the disease activity or tissue regeneration, but may also have the potential to decrease the risk of developing colitis-associated cancers.     

Canakinumab for treatment of cryopyrin-associated periodic syndrome

Importance of the field: Autoinflammatory syndromes such as cryopyrin-associated periodic syndromes (CAPS) place a heavy burden on affected individuals as well as on their families due to significant morbidity and increased mortality. The inflammatory response in CAPS is caused by an overwhelming activation of the pro-inflammatory cytokine IL-1, which was identified as a promising treatment target.

Areas covered in this review: This article focuses on the pathogenic background and different clinical manifestations in CAPS. Furthermore, the development program and characteristics of canakinumab, a recently approved fully human anti-IL-1β mAb for the treatment of CAPS, are described and compared to other available IL-1 blocking agents.

What the reader will gain: Canakinumab targets selectively human IL-1ß with high affinity and prevents the cytokine from interaction to its receptor and, thus, effectively blocks the inflammatory response in CAPS. In all studies performed, canakinumab showed a rapid improvement of symptoms of CAPS and a complete clinical response was achieved in most patients. Inflammatory markers such as C-reactive protein and serum amyloid-A protein were reduced to normal levels within few days. In comparison to other IL-1 blockers, canakinumab provides a longer plasma half-life and less injection site reactions.

Take home message: Canakinumab offers the possibility of permanent disease control, almost symptom-free life, and hopefully less long-term morbidity and mortality in patients with CAPS.     

Assessment of anti-inflammatory efficacy of acupuncture in patients with inflammatory bowel disease: A systematic review and meta-analysis

BackgroundInflammation has a significant role in the onset and progression of inflammatory bowel disease (IBD). Increasing attention has been paid to the use of acupuncture in IBD patients; however, its regulatory effects on inflammatory factors in IBD still require validation. Here, we systematically evaluated the effects of acupuncture on inflammatory factors in IBD patients.MethodsEight electronic databases were searched for studies that met the inclusion criteria. After evaluating the quality of the studies selected by two reviewers, the meta-analysis was performed to assess the efficacy of acupuncture in IBD patients and the impact on inflammatory factors (TNF-α, IL-1, IL-8 and IL-10).ResultsFour randomized controlled trials with a total of 228 patients satisfied the inclusion criteria. Acupuncture has a positive therapeutic impact on IBD (MD = 1.22, 95% CI [1.07, 1.39], P = 0.003). Moreover, it regulates the levels of TNF-α (MD =−60.58, 95% CI [−100.30, −20.89], P = 0.003), IL-8 (MD =−56.40, 95% CI [−60.02, −52.14], P < 0.00001) and IL-10 (MD =35.96, 95% CI [11.02, 60.91], P = 0.005) in IBD patients. However, the P value of meta-analysis in IL-1 great than 0.05.(MD =−27.90, 95% CI [−97.82, 42.02], P = 0.11).ConclusionAcupuncture has a positive therapeutic impact on IBD and can effectively regulate inflammatory factors in IBD patients. TNF-α, IL-8 and IL-10 are more appropriate inflammatory indicators for clinically evaluating the anti-inflammatory response in the blood of IBD patients by acupuncture.     

Prevalence,incidence and mortality of inflammatory bowel disease in Catalonia. A population-based analysis

Abstract

Introduction: Few recent data on the epidemiology of inflammatory bowel disease (IBD) are available, especially in Southern Europe.

Aim: To evaluate the prevalence, incidence and mortality of IBD in Catalonia during the period 2011–2016.

Material and methods: Data on the prevalence, incidence and mortality of IBD were obtained from the Catalan Health Surveillance System (CHSS). Crude incidence and prevalence rates were calculated for all the Catalan population. Trends in age-sex-adjusted rates were also estimated, and logistic regression was used to calculate the adjusted mortality odds ratio (OR). Data for Crohn’s disease (CD) and ulcerative colitis (UC) were analyzed separately.

Results: The prevalence per 100,000 inhabitants in 2016 was 353.9 for UC and 191.4 for CD. The total number of IBD patients rose from 29543 in 2011 to 40614 in 2016. IBD was associated with significantly elevated adjusted mortality ratios: 1.28 (95% CI: 1.6–1.4) for UC and 1.85 (95% CI: 1.62–2.12) for CD.

Conclusions: IBD prevalence is very high and is increasing rapidly in Catalonia. Both CD and UC are associated with significantly higher mortality rates.

• Key message

• Crohn disease and ulcerative colitis present a small but significant increase in mortality compared to non-inflammatory bowel disease.

• The prevalence of inflammatory bowel disease is increasing rapidly in Catalonia.

• Data on prevalence and incidence suggest that the number of patients may double in approximately 10 years.

     

NK cell subsets and their role in allergy

Introduction: NK cells represent a distinct lymphocyte population with extensive cytolytic activity and a variety of other functions, including regulation of hemopoiesis, suppressor functions and immunoglobulin production. Recently, reports suggest that NK cells also display potent regulatory functions via secretion of cytokines or cell-contact-dependent mechanisms. Thus NK cells may regulate innate and adaptive immune responses and play a role in immune homeostasis.

Areas covered: NK cells play important roles in viral infections, autoimmunity, pregnancy, cancer and bone marrow transplantation. Although the role of NK cells in allergic diseases is poorly described, recent findings suggest their role in allergy.

Expert opinion: Recent developments in the study of NK cell subsets have support their role in allergic diseases that contribute to allergen-specific immune suppression, allergen-specific T_H1 cell generation as well as IgE and other Ig production.     

Induced and natural regulatory T cells in human cancer

Introduction: Evidence suggests that FOXP3⁺CD25^highCD4⁺ regulatory T cells (Treg) which accumulate in cancer may have beneficial or unfavorable effects on prognosis. The presence in tumor-associated inflammatory infiltrates of two subsets of Treg with distinct phenotypic and functional profiles might explain these conflicting observations.

Areas covered: Human inducible (i) Treg arising by tumor-driven conversion of conventional CD4⁺ T cells are highly suppressive, therapy-resistant Treg which down-regulate anti-tumor immune responses, promoting tumor growth. Natural (n) Treg, normally responsible for maintaining peripheral tolerance, control cancer-associated inflammation, which favors tumor progression. This division of labor between nTreg and iTreg is not absolute, and overlap may be common. Nevertheless, iTreg play a critical and major role in cancer and cancer therapy. The tumor microenvironment determines the type, frequency and suppression levels of accumulating Treg.

Expert opinion: In cancer, a selective removal or silencing of iTreg and not of nTreg should be a therapeutic goal. However, the implementation of this challenging strategy requires further studies of cellular and molecular crosstalk among immune cells in the tumor microenvironment.     

Modulation of toll-like receptor function has therapeutic potential in autoimmune disease

Importance of the field: The role of toll-like receptors (TLRs) in the immune response to exogenous pathogens is well characterized. These receptors have been suggested to be involved in the initiation and/or perpetuation of many inflammatory autoimmune diseases and have become attractive candidates for the modulation of inflammation.

Areas covered in this review: This review discusses the evidence to support a potential role for TLRs in inflammatory diseases, focusing on rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. The approaches to targeting TLR activation are outlined.

What the reader will gain: An appreciation for the role of TLRs in inflammatory diseases and in particular the contribution of specific TLRs in rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. This review focuses on recent developments in targeting TLR activity from ligand binding through to the resultant signaling.

Take home message: As initiators of immune responses, TLRs have previously been targeted to increase the immune response with some success. However, targeting TLRs to attenuate immune responses for the treatment of chronic inflammatory diseases will require further evidence of the mechanisms of TLR involvement in the pathophysiology and a better understanding of the potential effects of modulating TLR physiology over a sustained period.     

Tendon healing and platelet-rich plasma therapies

Importance of the field: The therapeutic use of platelet-rich plasma (PRP) is an autologous biotechnology that relies on the local delivery of a wide range of growth factors and cytokines with the aim of enhancing tissue healing. Understanding both tendon healing and PRP therapies is an area of research that is critically important in developing optimal formulations and protocols to achieve the intended therapeutic effects.

Areas covered in this review: We summarise recent information on the mechanisms inherent to the earliest response to tendon injury. We then describe the positive effect of PRP therapies on tendon healing. Research on tendinopathy has produced several biological hypotheses based on histopathological, biochemical and clinical findings showing that cell apoptosis, angiofibroblastic features or abnormal biochemical adaptations underlie the condition.

What the reader will gain: The article provides insights into early healing mechanisms and the influence of PRP therapies on inflammation, cell migration, angiogenesis and the proliferation and synthesis of extracellular matrix. The knowledge gained helps to better understand and optimize tendon therapies.

Take home message: The use of endogenous therapies has a positive effect on experimental tendon healing. However, several obstacles need to be addressed to optimise medical practice in this field.     

Chemokine CCL18 predicts intraventricular hemorrhage in very preterm infants

Abstract

Background. Intraventricular hemorrhage (IVH) in very preterm infants is a common disease associated with long-term consequences. Risk factors of IVH remain to be further defined.

Aims. To determine whether specific immunoproteins at birth predict the risk of IVH and whether their receptors are localized at the bleeding site.

Methods. A prospective cohort consisted of 163 infants born before 32 weeks of gestation. Altogether 107 cord blood immunoproteins and 12 cytokines from peripheral blood obtained 1 and 7 days after birth were analyzed. Serial brain ultrasounds were assessed. Immunohistochemistry of a chemokine receptor from 14 autopsies was studied.

Results. Low levels of cord chemokine CCL18 (chemokine (C-C motif) ligand 18) robustly predicted the risk of IVH grade II–IV when ante- and neonatal risk factors were considered. Cord CCL18 increased from 32 weeks to term. During the first week after very preterm birth CCL18 increased as the risk of new IVH cases decreased. CCL18 receptor, CCR3, was detectable in choroid plexus, periventricular capillary endothelium, ependymal cells, and in germinal matrix.

Conclusion. Low cord blood CCL18 is an independent risk factor of IVH. CCL18 may inhibit signal transduction of its receptor in periventricular cells. Defining the function and regulation of CCL18 may help to decrease the risk of IVH.     

Therapeutic peptides in inflammatory bowel disease

Introduction: Therapeutic peptides in inflammatory bowel diseases essentially comprise cytokines affecting immune response, growth factors and monoclonal antibodies directed against key targets of mucosal inflammation, in particular, tumor necrosis factor-α (TNF-α). The latter have revolutionized standard medical treatment which previously was restricted to mesalamine, corticosteroids or classical immunosuppressants.

Areas covered: We review current evidence of the use of the so-called biologicals, including the well-established TNF-α antagonists and novel peptides and monoclonal antibodies developed for these diseases. The focus is on controlled clinical trials and meta-analyses, if available. Limitations and biases of these studies are important but tend to be ignored. Safety is also an important issue with opportunistic infections and lymphoma as relevant risks. There is significant heterogeneity between different countries, guidelines and opinions within the scientific community regarding clinical indications, even apart from pharmacoeconomics and reimbursement.

Expert opinion: TNF blockers have greatly extended medical options in inflammatory bowel diseases. Their more or less extensive use in nearly all patients or only a few selected indications is a matter of debate. It proved difficult to reproduce this success with other antibody targets as well as with immunomodulatory cytokines and growth factors. The most promising novel peptide is vedolizumab, an antibody against α4β7 integrin.     

The role of integrin antagonists in the treatment of inflammatory bowel disease

Introduction: Ulcerative colitis (UC) and Crohn’s disease are chronic inflammatory diseases of the bowel associated with complex inflammatory cascades within the mucosal lining of the gut.

Areas covered: INTEGRINS and their use as therapies in UC and Crohn’s.

Expert Opinion: The anti-adhesion molecules are a welcome addition to the armamentarium of medical therapies for inflammatory bowel disease.