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.     

Therapeutic agents for patients with rheumatoid arthritis and an inadequate response to tumour necrosis factor-α antagonists

Background: Rheumatoid arthritis (RA) is a disabling autoimmune disease; unless adequately controlled, patients have a poor long-term prognosis. Tumour necrosis factor (TNF)-α antagonists have provided relief for many RA patients; however, despite their efficacy, some patients do not respond or fail to maintain initial response. In the UK, patients with an inadequate response to TNF-α antagonists have limited options, as the National Institute of Clinical Excellence (NICE) currently only recommend switching to an alternative TNF-α antagonists if discontinuation occurs due to safety during the first 6 months of treatment. The EU has approved three biological agents, rituximab, abatacept, and tocilizumab, for patients with RA with an inadequate response to TNF-α antagonists. Objective: This review examines the clinical experience with two therapies targeting key immune cells involved in RA – rituximab (lyses B-cells), and abatacept (T-cell co-stimulation modulator) – specifically focusing on patients with an inadequate response to TNF-α blockade. Methods: Phase II/III clinical trials and original studies were identified using Medline and Pubmed; articles assessing the efficacy and/or safety of rituximab or abatacept in patients with RA refractory to TNF-α blockade were reviewed. Conclusions: Clinical data for rituximab and abatacept demonstrate that both reduce disease activity in TNF-α antagonist inadequate responders, suggesting that agents with alternative mechanisms of action, such as those targeting key immune cells, may be useful in this patient population.     

Tocilizumab: is there life beyond anti‐TNF blockade?

Anti-TNF-α therapy has become the most effective biological treatment for rheumatoid arthritis. Despite having changed the prognosis of the disease establishing new targets for treatment strategy, there are several aspects that still remain unmatched. About 30% of the patients with rheumatoid arthritis have a less than satisfactory response to anti-TNF therapy, which has led the way for the pursuit of new targets and approaches to treatment. IL-6 is one of these alternative targets and data from the more recent clinical trials involving tocilizumab (an anti-IL-6 soluble receptor antibody) suggest advantages in relation to some clinical aspects which are not addressed by anti-TNF-α treatment.     

Mavrilimumab,a human monoclonal GM-CSF receptor-α antibody for the management of rheumatoid arthritis: a novel approach to therapy

Introduction: Mavrilimumab, formerly known as CAM-3001, a GM-CSF receptor-α antibody, is the first human monoclonal antibody to be used in Phase II studies (2011) to modulate the innate immunity pathway targeting GM-CSF signaling in moderate rheumatoid arthritis (RA).

Areas covered: Analysis of available clinical trial data on GM-CSF receptor-α antibody and medical literature search using MEDLINE for molecular mechanisms of pathogenesis of RA and its treatment forms the basis of this expert opinion review. The mavrilimumab Phase II double blind, randomized, placebo-controlled ascending dose trial demonstrated statistically significant achievement of primary and secondary end points in patients with moderate RA. The trial demonstrated significant clinical benefit in the 100 mg mavrilimumab cohort compared to the placebo group.

Expert opinion: The novel molecular targeting mechanism of mavrilimumab together with its demonstrated clinical efficacy, tolerability and safety profile in Phase II clinical trials in moderate RA, suggests significant potential utility for this drug to induce clinical remission, reduce flares and improve morbidity and mortality in patients with RA.     

AE37: a novel T-cell-eliciting vaccine for breast cancer

Introduction: Immunotherapy, including vaccines targeting the human EGFR2 (HER-2/neu) protein, is an active area of investigation in combatting breast cancer. Several vaccines are currently undergoing clinical trials, most of which are CD8⁺ T-cell-eliciting vaccines. AE37 is a promising primarily CD4⁺ T-cell-eliciting HER-2/neu breast cancer vaccine currently in clinical trials.

Areas covered: This article reviews preclinical investigations as well as findings from completed and ongoing Phase I and Phase II clinical trials of the AE37 vaccine.

Expert opinion: Clinical trials have shown the AE37 vaccine to be safe and capable of generating peptide-specific, durable immune responses. This has been shown in patients with any level of HER-2/neu expression. Early clinical findings suggest there may be benefit to AE37 vaccination in preventing breast cancer recurrence.     

Immunogenicity of anti-TNFα therapy in psoriasis: a clinical issue?

Introduction: Immunogenicity of antitumor necrosis factor-alpha (TNFα) agents has been proven to play a significant role in the variability of clinical responses among patients with chronic inflammatory diseases. However, its clinical impact on the outcome of patients with psoriasis and psoriatic arthritis receiving anti-TNFα treatment is not yet fully clear. Despite the high rates of efficacy of anti-TNFα agents in psoriasis, a substantial proportion of patients remain who experience a primary or secondary failure or significant side effects, which are potentially ascribable to immunogenicity.

Areas covered: Topics include immunologic response elicited by anti-TNFα agents, the impact of immunogenicity on treatment response to anti-TNFα and the role played by immunogenicity in the lack of efficacy of anti-TNFα agents (infliximab, adalimumab and etanercept) in psoriasis.

Expert opinion: Based on data available in the literature and the clinical experience of the authors, this article suggests the optimal approach to drug monitoring and antidrug antibody assay and the most effective use of biologic immunotherapies in this setting. Immunogenicity should be taken into account in the adoption of therapeutic choices in psoriatic patients, such as anti-TNFα agent intensification, or switching to another anti-TNFα agent or a drug with a different mechanism of action.     

“Better but not best”: a qualitative exploration of the experiences of occupational gain for people with inflammatory arthritis receiving anti-TNFα treatment

Abstract

Objectives: To investigate whether patients with improved clinical markers during their anti-TNFα treatment experience improvements in their functional and psychological ability to undertake activities. Methods: Patients receiving anti-TNFα treatment for rheumatoid arthritis (RA) or ankylosing spondylitis (AS) were recruited from outpatient clinics in East Anglia and North West England. Purposive sampling recruited variety in demographic and treatment experiences. Data were collected through in-depth qualitative interviews and analysed using an interpretive phenomenological framework. Twenty-seven patients were recruited; 19 with RA, eight with AS, and aged from 21 to 73 years. Results: While people generally experienced an improvement in their functional ability, known as occupational gain, they continued to experience difficulties through previous biomechanical damage, continuing symptoms of inflammatory arthritis, or concerns about anti-TNFα treatment. These disruptions affected how participants retained or regained employment. Lack of healthcare support, including an absence of occupational therapy intervention, resulted in people testing new boundaries through a process of unsupported trial and error. Conclusion: Occupational gain was not maximised for people on anti-TNFα treatment. Improved referral pathways to occupational therapy could facilitate the management of continuing functional difficulties, thereby maximising the benefit of treatment to people with inflammatory arthritis.

• Implications for Rehabilitation

• This study challenges the assumption that functional improvement for people with rheumatoid arthritis (RA) and ankylosing spondylitis (AS) receiving anti-TNF a treatment experience is relatively trouble-free.

• Rheumatology provision needs to be more closely informed by and aligned with the needs of these service users to maximise the benefit from what is an expensive treatment option.

• People with RA and AS would both benefit from more focused occupational therapy interventions addressing the impact of occupational performance on occupational engagement.

     

TNF参与内毒素诱导肥大细胞HMGB1释放

目的探讨肿瘤坏死因子-α(TNF-α)在内毒素诱导肥大细胞高迁移率族蛋白B1(HMGB1)释放中的作用。方法采用小鼠肥大细胞株P815培养物,观察100μg/L脂多糖(LPS)诱导后培养上清液中HMGB1、TNF-α含量的变化,不同剂量抗TNF-α中和抗体IgG对LPS诱导HMGB1释放的影响,及TNF-α对HMGB1释放的诱导作用。HMGB1含量采用酶联免疫吸附试验检测。结果培养上清液中HMGB1含量随LPS诱导时间而升高,而TNF-α含量于诱导6 h时达到峰值;5、25 mg/L抗TNF-α抗体对LPS诱导HMGB1释放有明显的抑制作用(P0.05);TNF-α显示具有诱导肥大细胞释放HMGB1的作用,并呈时间、剂量相关性。结论 TNF-α参与内毒素诱导肥大细胞释放HMGB1的过程。     

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.     

Management of severe complications in Behçet’s disease with TNF inhibitors

Introduction: The efficacy of anti-TNFα agents has been recently evaluated in many studies in Behçet’s disease (BD), particularly in ocular and life-threatening manifestations such as neurological and vascular disease.

Areas covered: The following article aims to summarize the currently available efficacy and safety data of anti-TNFα agents in BD.

Expert opinion: Most studies have shown dramatic and rapid efficacy with anti-TNFα agents on the main BD-associated issues including posterior uveitis, gastro-intestinal and neurological complications as well as major vessel disease. Experts in the field do recommend the use of anti-TNF agents (either infliximab or adalimumab) as a first-line therapy in severe posterior uveitis in BD and now use anti-TNFα treatment in BD-associated life threatening manifestations. However, data is mainly based on retrospective cohorts or open-label prospective studies. Controlled studies (versus conventional immunosuppressants such as azathioprine and cyclophosphamide) are warranted to properly evaluate their efficacy as first line therapeutic in life-threatening manifestations of BD.     

Trastuzumab emtansine: a novel antibody-drug conjugate for HER2-positive breast cancer

Introduction: Trastuzumab emtansine (T-DM1) is an antibody–drug conjugate (ADC) that combines intracellular delivery of the potent cytotoxic agent, DM1 (a derivative of maytansine) with the antitumor activity of trastuzumab. While there are several ADCs in Phase III development, T-DM1 is the only one in which the targeting antibody has antitumor properties. T-DM1 is also the only ADC that is directed toward the human EGFR 2 (HER2). Effective therapies are limited in HER2-positive advanced or metastatic breast cancer (MBC), particularly following progression on available HER2-targeted therapies.

Areas covered: The mechanisms of action, preclinical efficacy and clinical profile of T-DM1 are reported. The latest preclinical and clinical data for T-DM1 are examined.

Expert opinion: T-DM1 has significant antitumor potency in vitro and in vivo, which is maintained in tumors resistant to trastuzumab or lapatinib. In Phase I and II trials, T-DM1 provided objective tumor responses and was well tolerated across various lines of therapy in patients with HER2-positive MBC. In addition, it showed similar efficacy to trastuzumab plus docetaxel in first-line MBC. Ongoing trials (including two Phase III studies) are investigating T-DM1 as single-agent therapy or combined with other chemotherapeutic or biologic agents, and the results should help to define the place of T-DM1 within current treatment algorithms for HER2-positive disease.     

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.     

Albinterferon-alfa 2b: a new treatment option for hepatitis C

Importance of the field: HCV infection affects 180 million people worldwide. Standard therapy combines weekly injections of pegIFN and daily ribavirin (RBV). Albinterferon (albIFN)-α2b is the most advanced in the development of an IFN-based compound.

Areas covered in this review: The rationale for albIFN-α2b is to combine IFN-α antiviral activity with prolonged presence of human serum albumin in human blood. Initial experimental studies on albIFN-α2b were published in 2002. This review provides results of preclinical and subsequent clinical trials. Results of two Phase III clinical trials were presented in 2009 and will be published shortly.

What the reader will gain: This review discusses the current status of knowledge on the efficacy and safety of albIFN-α2b. Phase III clinical trials demonstrated comparable efficacy of albIFN-α2b given every 2 weeks to weekly pegIFN-α2a, both in combination with RBV. However, the most promising seems to be every 4 weeks dosage.

Take home message: Treatment with albIFN-α2b combined with RBV can provide comparable efficacy with the current standard of care medication with a reduced number of injections. Lower frequency of some adverse events and improved quality of life can be expected in patients receiving albIFN-α2b every 4 weeks.     

Adalimumab in the treatment of plaque-type psoriasis and psoriatic arthritis

Introduction: Psoriasis and psoriatic arthritis (PsA) are chronic immune-mediated diseases, and TNF-α (tumor necrosis factor) is a pro-inflammatory cytokine that plays a critical role in the pathogenesis of these conditions. Adalimumab is an anti-TNF-α drug widely used for the treatment of both psoriasis and PsA. Controlled clinical trials demonstrated that adalimumab is characterized by a high degree of clinical response. The aim of this review is to report the safety, efficacy, and recent findings in the treatment of psoriasis and PsA with adalimumab.

Areas covered: This article reviews the results of Phase II, III, controlled, and observational clinical studies on adalimumab in the treatment of psoriasis and PsA. A systematic search was conducted using the Pubmed Medline database for primary articles.

Expert opinion: Treatment of psoriasis and PsA represents a therapeutic challenge for dermatologists and rheumatologists. The efficacy, tolerability, and safety profiles suggest adalimumab as a suitable anti-psoriatic drug in the long-term treatment of psoriasis and PsA. Management of long-term treatment, loss of efficacy, and comorbidities has been described.     

Belimumab,an anti-BLyS human monoclonal antibody for potential treatment of inflammatory autoimmune diseases

Background: B lymphocyte stimulator (BLyS) is a factor determining the survival of B cells, and elevated levels in serum or locally have been observed in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients. Belimumab (LymphoStat-B), a human monoclonal antibody that inhibits BlyS, was developed for the treatment of these diseases. Objective: To summarize preclinical development, efficacy and safety of belimumab in treatment of RA and SLE. Methods: Articles found in a PubMed search and data presented in abstract form at international conferences up to August 2008 are described. Results/conclusions: Belimumab was well tolerated in treatment of RA over 24 weeks and SLE over 3 years. It significantly decreased rheumatoid factor (RF) levels, and modestly reduced symptoms of RA, especially in some subgroups such as patients with high disease activity, positive RF and no anti-TNF treatment experience. It also significantly reduced symptoms of SLE, and decreased anti-double-stranded DNA autoantibodies among patients with positive baseline anti-double-stranded DNA or antinuclear antibodies during a long-period treatment. These results suggest that careful patient selection is necessary to achieve optimal outcomes.     

Necitumumab in the treatment of advanced non-small cell lung cancer: translation from preclinical to clinical development

Introduction: Treatment outcomes in unselected patients with advanced NSCLC remain disappointing with platinum-based chemotherapy. The addition of monoclonal antibodies targeting EGFR to standard first-line therapy is a validated strategy and has been associated with statistically significant survival advantage in advanced NSCLC. Necitumunab is a fully human IgG1 monoclonal antibody targeting EGFR, having the potential benefit of lower hypersensitivity reaction risk as compared with cetuximab and also equivalent antibody-dependent cell-mediated cytotoxicity.

Areas covered: This paper reviews literature on preclinical and early clinical development of necitumumab that is available in PubMed and published abstracts from conferences, as well as ongoing trials as specified by clinicaltrials.gov. Recently, the Phase III clinical trial evaluating the addition of necitumumab to pemetrexed and cisplatin in non-squamous NSCLC was prematurely closed due to concerns about the increased risk of thromboembolic events in the experimental arm. Accrual in the Phase III trial of necitumumab in combination with gemcitabine and cisplatin in squamous NSCLC is ongoing.

Expert opinion: Results of the ongoing large randomized trials will be instrumental in determining the drug's clinical significance and, with the analysis of potential molecular predictive factors, are expected to bring valuable additions to future therapeutic strategies in NSCLC.     

Evaluation of serum cystatin C and chromogranin A as markers of nephropathy in patients with Type 2 diabetes mellitus

Abstract

The chronic joint inflammation in axial spondyloarthritis (axSpA) is characterized by infiltration of activated macrophages. The haptoglobin–hemoglobin receptor CD163 and the mannose receptor CD206 are strongly expressed on M2c and M2a macrophages, respectively. We measured the soluble forms of the receptors (sCD163 and sCD206) in plasma (PL) in two axSpA cohorts. All patients fulfil the 2009 Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axSpA and/or the 1984 modified New York criteria for ankylosing spondylitis. The first cohort included anti-TNF-α treated patients with active axSpA (n?=?30); the second cohort included patients in early disease stages (n?=?38). Plasma sCD163 and sCD206 were both within the reference interval of healthy controls (HC), but sCD163 decreased slightly during anti-TNF-α treatment [baseline: 1.49?mg/L (IQR: 1.22–1.77?mg/L, 12?weeks: 1.29 (IQR: 1.09–1.57) mg/L, 20?weeks: 1.25 (IQR: 0.99–1.75) mg/L, 52?weeks: 1.39 (IQR: 1.15–1.78) mg/L], while sCD206 increased [baseline: 0.17 (IQR: 0.13–0.21) mg/L, 12?weeks: 0.19 (0.16–0.23) mg/L, 20?weeks: 0.20 (0.14–0.24) mg/L, 52: 0.19 (IQR: 0.14–0.23) mg/L], pointing toward a shift in polarization of involved macrophages. Plasma levels of sCD206 proved significantly higher in patients with early disease stages and definite radiological sacroiliitis (n?=?10). This was not the case for sCD163. A significant increase in response to anti-TNF-α treatment, could suggest sCD206 as a marker of response to anti-TNF-α treatment, however, the potential for the two macrophage markers as diagnostic and prognostic indicators of disease in axSpA is weak.     

Belimumab – an anti-BLyS human monoclonal antibody for rheumatoid arthritis

Introduction: B lymphocyte stimulator (BLyS) is a major regulatory factor that controls the development and survival of B cells. Elevated serum levels of BLyS have been associated with rheumatoid arthritis (RA). Belimumab is a fully human monoclonal antibody that inhibits BLyS and it is being developed for the treatment of RA. This review aims to summarize up-to-date pharmacological and clinical data of belimumab in the treatment of RA.

Areas covered: A literature search was performed on PubMed using keywords, including belimumab, LymphoStat-B, benlysta, BLyS inhibitor, rheumatoid arthritis and autoimmune disease. References of relevant studies were searched by hand. Abstracts of international conferences up to October 2012 were also included. Belimumab was well tolerated in the treatment of RA over 24 weeks. It significantly increased American College of Rheumatology (ACR)20 responses at week 24, especially in patients with high disease activity, positive rheumatoid factor, no anti-TNF treatment experience and those who had failed methotrexate therapy. However, belimumab failed to demonstrate significantly improved ACR50 and ACR70 responses in the single Phase II clinical trial of RA.

Expert opinion: These results suggest that the clinical efficacy of belimumab for RA needs to be further investigated in future clinical trials. Careful patient selection may be necessary for belimumab to achieve optimal clinical outcomes in RA.     

Aflibercept in lung cancer

Rheumatoid arthritis (RA) is a multisystem autoimmune disease, of unknown aetiology with high morbidity and significantly increased mortality. Over recent years, the introduction of targeted therapies with biologic agents have made major inroads to the outcomes in RA.The first such agents developed were TNF-α inhibitors. However, despite their high efficacy, up to 30% patients fail to respond adequately, or develop adverse reaction to TNF-α inhibitors. This suggests that other pathological mechanisms are involved, in addition to those mediated by TNF-α. Abnormal T-cell function has long been thought to play a key role in the pathogenesis of RA, stimulating both the production of pro-inflammatory cytokines and recruitment of other inflammatory cells, resulting in joint destruction and systemic disease. Abatacept, the first of a group of T-cell co-stimulation modulators, targeting T-cell activation, has recently been licensed for use in RA and shows promise as a useful drug to treat this major disabling disease.