Risk of infection associated with anti-TNF-α therapy

ABSTRACT

Introduction: The advent, more than two decades ago, of monoclonal antibodies and soluble receptors targeting tumor necrosis factor (TNF)-α has revolutionized the therapeutic approach to otherwise difficult-to-treat autoimmune and inflammatory diseases. However, due to the pleiotropic functions played by this pro-inflammatory cytokine (with particular relevance in granuloma maintenance), TNF-α blockade may increase the incidence of serious infections.

Areas covered: The present review summarizes the biological rationale supporting the impact of anti-TNF-α therapy on the host’s susceptibility to infection. The structure, mode of action, and indications of available agents are reviewed, as well as the clinical evidence coming from clinical trials and observational registries. We discuss the impact of patient- and disease-related factors influencing the occurrence of infection. Finally, strategies for risk minimization are also covered, with particular attention to recommendations for screening of latent tuberculosis infection and management of chronic hepatitis B infection.

Expert commentary: Methodological limitations (confounding by indication bias, patient dropout, or switching therapies) should be considered when interpreting observational data. Clinicians must individualize the infection risk assessment not only on the basis of the specific anti-TNF-α agent used or the expected duration of therapy, but also by taking into account the baseline susceptibility of a given patient.     

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.     

The therapeutic potential of TNF-α antagonists for skin psoriasis comorbidities

Importance of the field: Alopecia, psoriatic arthritis, the metabolic syndrome, inflammatory bowel diseases and cardiovascular diseases may occur as skin psoriatic comorbidities. TNF-α antagonists are used to treat psoriasis. Adalimumab is one of the recognized active agents for this indication.

Areas covered in this review: The current peer-reviewed publications and presentation of original findings.

What the reader will gain: Adalimumab is active on recalcitrant psoriasis and some of its comorbidities, particularly arthropathies and Crohn's disease. However, the progression of the radiological alterations is limited with regression of the bony erosions. Psoriatic enthesopathy also regresses. Mortality associated with psoriasis arthropathy is on the decline. Crohn's disease, the most frequent inflammatory bowel comorbidity of psoriasis, is responsive to adalimumab. The effect of adalimumab on the metabolic syndrome and cardiovascular involvement is more erratic. The spectacular effects of adalimumab may be associated with some adverse effects. In particular, despite a marked reduction in the psoriasis area-and-severity index (PASI) score some new acute lesions of cutaneous psoriasis may develop corresponding to paradoxical psoriasis. Other potential adverse effects include infections, granulomas, rapid growth of cancers and occurrence of lymphomas.

Take home message: Adalimumab frequently controls moderate-to-severe forms of cutaneous psoriasis and some of its comorbidities.     

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.     

Monoclonal antibodies and antibody fragments: state of the art and future perspectives in the treatment of non-haematological tumors

Introduction: The use of monoclonal antibodies is one of the strategies for targeting the specific key points of the main pathways of cancer growth and survival, but only a few antibodies have offered a clear clinical benefit in the treatment of non-haematological malignancies.

Areas covered: This review summarizes the general properties of monoclonal antibodies, including structure, nomenclature and production techniques. The antibodies approved for use in clinical practice for the treatment of non-haematological tumors and those antibodies still being developed in this setting are briefly described. The types of antibody fragments are also reported.

Expert opinion: Monoclonal antibodies were initially developed in order to avoid the cytotoxic effects of chemotherapy on healthy tissues. However antibodies have not yet replaced chemotherapy agents, since the combination of both kinds of drugs have usually appeared to achieve higher benefit compared with chemotherapy alone. The research for the development of new monoclonal antibodies aims to identify further targets and to provide innovative antibody constructs.     

Kinoid of human tumor necrosis factor-alpha for rheumatoid arthritis

Introduction: Anti-TNF-α drugs have dramatically changed treatment of rheumatoid arthritis (RA) in terms of both clinical control and articular damage prevention. Despite this, they hold some important drawbacks, such as frequent therapeutic failures and high costs. Anti-TNF-α active immunization, with a therapeutic vaccine against TNF-α, is a promising alternative anti-TNF-α targeting strategy, potentially devoid of treatment limitations of some of current anti-TNF blocking agents.

Areas covered: This review covers the preclinical proof-of-concept of anti-TNF-α vaccination with the kinoid of human TNF-α (TNFK) and analyzes the body of evidence forming the rationale for the application of this strategy in RA and other TNF-α-dependent diseases. We describe the theoretical bases of anti-TNF-α active immunization and of experimental data supporting the applicability of TNFK to human disease in terms of both safety and efficacy.

Expert opinion: Based on preclinical efficacy and safety data supporting its feasibility in a Phase I – II trial in Crohn's disease, anti-TNF-α vaccination with TNFK has entered the phase of clinical development and promises to be a valuable anti-TNF-α targeting strategy in human disease. The focus is made in the first clinical trial in RA (Phase II) on the efficacy in active RA patients having developed antibodies against anti-TNF mAbs.     

Adecatumumab: an anti-EpCAM monoclonal antibody,from the bench to the bedside

Importance of the field: In developing new anticancer drugs, the identification of relevant targets is a key issue of growing importance. Ideally, an anticancer drug target should be specific to cancer cells, in order to both increase efficacy and decrease toxicity of the compound.

Areas covered in this review: Epithelial cell adhesion molecule (EpCAM) is a membrane protein with proto-oncogenic properties that is expressed in a number of endothelium-derived cancers and is a promising anticancer drug target. Adecatumumab is a monoclonal, fully human IgG1 antibody that targets EpCAM, development of which is at present reaching Phase III trials.

What the reader will gain: From a review of literature, we here update the rationale for using EpCAM as an anticancer target for monoclonal antibodies, with a special focus on adecatumumab. The fully human nature of adecatumumab is also discussed to put the drug in perspective with other related anti-EpCAM monoclonal antibodies, such as edrecolomab and catumaxomab. Adecatumumab studies are recapitulated, in order to provide the reader with a comprehensive view of the development of this promising anticancer agent.

Take home message: Adecatumumab is a promising fully human monoclonal antibody targeting EpCAM which is expressed in almost all adenocarcinomas and its activity is not dependent of K-Ras status.     

Tumor necrosis factor biologics beyond psoriasis in dermatology

Introduction: TNF-α is a cytokine essential for immune response and its receptors has been shown to be dysregulated in a variety of diseases including psoriasis vulgaris. There are a number of TNF-α inhibitors approved for psoriasis, however there is a growing body of literature supporting their use in a wide variety of dermatological conditions.

Areas covered: The use of biologic TNF-α antagonists in conditions for which they have not yet been approved by the FDA (‘off-label’ uses) and the literature that supports the most appropriate agents and conditions for use. A PubMed/MEDLINE search was performed with the keywords ‘TNFα antagonist’, ‘biologic therapy’, ‘off-label’ and ‘unapproved’. The list of references and citing articles of the articles retrieved were also used as sources. This complete list was evaluated for inclusion, based on relevance to the proposed goal of this review.

Expert opinion: There are a large number of conditions for which biologic antagonists of TNFα are effective, beyond those already approved by the FDA. The various agents vary in their efficacy in treatment, with infliximab consistently the most effective, particularly in granulomatous diseases. Although effectiveness varies among these conditions, biologic antagonists of TNF-α are promising for the treatment of these 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.     

Recent Advances in Monoclonal Antibody Therapies for Multiple Sclerosis

ABSTRACT

Introduction: Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating disease of the CNS and results in neurological disability. Existing immunomodulatory and immunosuppressive approaches lower the number of relapses but do not cure or reverse existing deficits nor improve long-term disability in MS patients.

Areas Covered: Monogenic antibodies were described as treatment options for MS, however the immunogenicity of mouse antibodies hampered the efficacy of potential therapeutics in humans. Availability of improved antibody production technologies resulted in a paradigm shift in MS treatment strategies. In this review, an overview of immunotherapies for MS that use conventional monoclonal antibodies reactive to immune system and their properties and mechanisms of action will be discussed, including recent advances in MS therapeutics and highlight natural autoantibodies (NAbs) that directly target CNS cells.

Expert Opinion: Recent challenges for MS therapy are the identification of relevant molecular and cellular targets, time frame of treatment, and antibody toxicity profiles to identify safe treatment options for MS patients. The application of monoclonal antibody therapies with better biological efficacy associated with minimum side effects possesses huge clinical potential. Advances in monoclonal antibody technologies that directly target cells of nervous system may promote the CNS regeneration field from bench to bedside.     

Golimumab — a new tool in the armoury against inflammatory arthritis

Abstract

The development of biological drugs blocking tumour necrosis factor-alpha (TNF-α) has had a dramatic impact on the treatment of inflammatory arthritis in recent years. Golimumab is a fully human monoclonal antibody which inhibits TNF-α. It is licensed for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. In this review we evaluate the results of phase III studies using golimumab and explore the place of golimumab in the treatment of these diseases.     

Monoclonal antibodies in oncology therapeutics: present and future indications

Introduction: Over the last decade, the field of oncology has undergone revolutionary changes. One of the major reasons contributing to this change is the improvement in our understanding of the biology of cancer. Recognition of novel targets on the cancer cell has enabled development of tools to attack those targets. Monoclonal antibodies represent such a therapy that has rapidly been adapted in almost all major cancer subtypes.

Areas covered: This review intends to give a comprehensive overview of monoclonal antibodies, including mechanism of action, the currently approved agents and future targets. The authors reviewed published data as well as information from the ongoing clinical trials.

Expert opinion: Monoclonal antibodies represent a major new advance in oncology therapy but there remains significant room for improvement.     

Inflammatory cytokines: from discoveries to therapies in IBD

ABSTRACT

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.     

Overview of the use of the anti-TNF agent infliximab in chronic inflammatory diseases

Anti-inflammatory therapy with monoclonal antibodies (mAbs) directed against tumour necrosis factor (TNF)-α has emerged as a major advancement in the treatment of various immune mediated diseases such as rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and Crohn’s disease. TNF-α seems to play a major pathogenic role in these chronic immune-mediated inflammatory diseases. Infliximab (Remicade^®, Centocor, Inc., Malvern, PA, USA), a chimaeric mAb, binds to soluble and membrane bound TNF-α, but not to TNF-β. Infliximab is able to effectively regulate and mediate inflammatory processes involved in a number of different disease states. Many clinical trials in these diseases have demonstrated that biological therapy with mAbs directed against TNF-α is effective and relatively safe.     

The Hydro-alcoholic Extract of Achillea wilhelmsii C. Koch Ameliorates Acetic Acid-induced Ulcerative Colitis through TLR-4

Achillea wilhelmsii contains several anti-inflammatory and antioxidant phytochemicals, proposing protecting effect on inflammatory responses in autoimmune diseases such as inflammatory bowel diseases. However, its protective and anti-inflammatory activities against Ulcerative Colitis are unknown. This study intended to verify whether A. wilhelmsii is able to improve colitis via mediating inflammatory cytokines. Colitis was induced by intrarectal administration of acetic acid 4% in rats, except in sham group. Animals were treated with the hydro-alcoholic extract of A. wilhelmsii at concentrations of 50, 100, 200 mg/kg for 48 h. The other groups included the control (only treated with acetic acid), sham group (normal saline), and a standard group (Dexamethasone). Microscopic and histopathologic examinations were conducted in inflamed colonic tissue. Both macroscopic and microscopic examinations of colitis tissue were carried out. Tissue concentrations of interleukin (IL)-6 and tumor necrosis factor (TNF)-α were assessed by Eliza kits, while myeloperoxidase (MPO) was measured spectrophotometrically. mRNA expression of toll-like receptor (TLR)-4 was assessed in Real time-PCR. A. wilhelmsii ameliorated macroscopic and microscopic symptoms of induced colitis. The extract also downregulated pro-inflammatory mediators including IL-6, TNF-α, and MPO in the colon tissue. Substantial decline was recorded in mucosal TLR-4 expression, signifying considerable reduction of IL-6, and TNF-α production. This is the first report indicating that A. wilhelmsii abrogates experimental colitis through its anti-inflammatory activity, which in particular might be correlated with downregulation of TLR-4 expression.

     

Biologics that inhibit the Th17 pathway and related cytokines to treat inflammatory disorders

Introduction: Advances in the understanding of TNF-α and IL-17 synergistic functions have recently led to the concept that patients who do not respond or who respond inadequately to TNF-α inhibitors may have IL-17-driven diseases, opening up the way for a new class of therapeutic development: Th17-inhibitors.

Areas covered: In this review, the authors discuss the central role that the IL-23/Th17 axis plays in the pathogenesis of several inflammatory diseases, such as psoriasis, highlighting its position as a relevant therapeutic target. In particular, the authors start by giving a brief historical excursus on biologic agent development up until the success of TNF-α inhibitors, and continue with an overview of IL12/23 pathway inhibition. Next, they describe Th17 cell biology, focusing on the role of IL-17 in host defense and in human immune-inflammatory diseases, discussing the use and side effects of IL-17 inhibitors.

Expert opinion: The IL-23/Th17 signaling pathway plays a central role in the pathogenesis of several inflammatory diseases, such as psoriasis. Recent data has demonstrated that biologics neutralizing IL-17 (ixekizumab, secukinumab) or its receptor (brodalumab) are highly effective with a positive safety profile in treating moderate to severe psoriasis, offering new treatment possibilities, especially for patients who do not respond adequately to anti-TNF-α therapies.     

Plasma IgA antibody levels to malondialdehyde acetaldehyde-adducts are associated with inflammatory mediators,obesity and type 2 diabetes

Abstract

Aim. Obesity and type 2 diabetes (T2D) associate with increased oxidative stress. Malondialdehyde acetaldehyde (MAA) adducts have been suggested to be one of the antigenic epitopes in MDA-LDL responsible for the antibody recognition. Our aim was to investigate the associations between plasma IgA antibodies to MAA-LDL, inflammatory markers, adipokines, obesity, and T2D.

Methods. IgA to MAA-LDL were measured in a subsample (n = 1507) of the Finnish Health 2000 survey. The associations between antibody levels, obesity, TNF-α, IL-6, high-sensitivity (hs) CRP, resistin, adiponectin, fasting plasma (fp) glucose, fp-insulin, glycosylated hemoglobin (Hb-A1C), and T2D were investigated.

Results. IgA to MAA-LDL associated positively with fasting plasma insulin. IgA to MAA-LDL were higher among subjects with T2D (P < 0.001) compared to subjects with normal glucose metabolism. IgA to MAA-LDL associated with obesity, but was not independently (P = 0.002, not significant after correction for multiple tests) associated with T2D in logistic regression analysis. IgA to MAA-LDL, obesity, and TNF-α all associated with markers of glucose metabolism.

Conclusions. T2D subjects had increased IgA to MAA-LDL compared to subjects with normal glucose metabolism. The data suggest that the associations between IgA to MAA-LDL and markers of glucose metabolism were independent of TNF-α but dependent on components of the metabolic syndrome.     

Brodalumab-an IL-17RA monoclonal antibody for psoriasis and psoriatic arthritis

Introduction: IL-17 is a growing target for autoimmune and inflammatory diseases. Brodalumab is a fully human anti-IL-17RA monoclonal antibody that has been investigated in a range of disease including psoriasis, psoriatic arthritis, rheumatoid arthritis, inflammatory bowel disease and asthma.

Areas covered: This review aims to summarize up-to-date pharmacological properties of brodalumab and the clinical efficacy and safety data presented in clinical trials. The focus of this review will be on psoriasis, psoriatic arthritis and rheumatoid arthritis although we will briefly touch on the other indications in which the drug has been studied as we feel it adds to our understanding of the IL-17 pathway and highlights areas where research is still needed.

Expert opinion: Brodalumab has shown good efficacy in psoriasis in small but extended studies with a moderate effect on psoriatic arthritis. Brodalumab studies are clearly negative in rheumatoid arthritis and inflammatory bowel disease. The data are equivocal in asthma; however, further studies in this disease are justifiable. The safety profile of this drug thus far is not worrisome although longer studies in more patients are needed.     

The evolving role of monoclonal antibodies in the treatment of patients with advanced renal cell carcinoma: a systematic review

ABSTRACT

Introduction: While the majority of the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors currently used for the therapy of metastatic renal cell carcinoma (mRCC) are small molecule agents inhibiting multiple targets, monoclonal antibodies are inhibitors of specific targets, which may decrease off-target effects while preserving on-target activity. A few monoclonal antibodies have already been approved for mRCC (bevacizumab, nivolumab), while many others may play an important role in the therapeutic scenario of mRCC.

Areas covered: This review describes emerging monoclonal antibodies for treating RCC. Currently, bevacizumab, a VEGF monoclonal antibody, is approved in combination with interferon for the therapy of metastatic RCC, while nivolumab, a Programmed Death (PD)-1 inhibitor, is approved following prior VEGF inhibitor treatment. Other PD-1 and PD-ligand (L)-1 inhibitors are undergoing clinical development.

Expert opinion: Combinations of inhibitors of the PD1/PD-L1 axis with VEGF inhibitors or cytotoxic T-lymphocyte antigen (CTLA)-4 inhibitors have shown promising efficacy in mRCC. The development of biomarkers predictive for benefit and rational tolerable combinations are both important pillars of research to improve outcomes in RCC.