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.     

Optimizing the expediency of TNFi in rheumatoid arthritis: offering a TNFi holiday in patients having reached low-disease activity in the maintenance phase

Introduction: The treatment of rheumatoid arthritis (RA) has been revolutionized since the introduction of biological disease-modifying antirheumatic drugs such as tumour necrosis factor alpha inhibitors (TNFi), and clinical remission has become a realistic target in the treatment strategy. Discontinuation strategies of TNFi therapy after reaching sustained remission or low-disease activity (LDA) have been emerging. These strategies are important considering the risk–benefit profile of TNFi, as well as looking at them from a cost-economic point of view.

Areas covered: This article presents an overview of recent major studies on TNFi withdrawal, and tapering and about the safety of doing so.

Expert opinion: Although data are still limited, tapering or discontinuing TNFi in some RA patients may well be possible, especially in the early RA patients who are methotrexate naive. Also, a substantial group of longer established RA patients can stop or taper TNFi, particularly when ultrasonography signals are negative. However, before making the decision of implementing it in the routine care for RA patients, more predictors for successful discontinuation are desired.     

The use of ustekinumab in autoimmune disease

Importance of the field: The advent of biologic therapies has revolutionized the treatment of autoimmune diseases including psoriasis, autoimmune arthritides and inflammatory bowel disease. With recent advances in our understanding of the immunogenetic pathways involved in the pathogenesis of these conditions, newer, more targeted biologic therapies have been developed. Ustekinumab is an antibody to the common p40 subunit of IL-12 and IL-23, which has been studied in the treatment of psoriasis, psoriatic arthritis, Crohn's disease and multiple sclerosis.

Areas covered in this review: This review details the efficacy and safety of ustekinumab in all clinical studies to date, using PubMed listed publications and official product websites.

What the reader will gain: Readers will gain a comprehensive understanding of the mechanism of action of ustekinuamb, its pharmacodynamic and pharmacokinetic profile, and its clinical efficacy and safety in the treatment of psoriasis, psoriatic arthritis, Crohn's disease and multiple sclerosis.

Take home message: Ustekinumab has shown significant efficacy in the treatment of chronic plaque psoriasis in Phase III studies, and promising results in Phase II studies in psoriatic arthritis. Efficacy has been shown in Crohn's disease only in non-responders to infliximab. Ustekinumab did not show benefit in the treatment of multiple sclerosis.     

Tumour necrosis factor inhibitors in the treatment of psoriatic arthritis: a view on effectiveness,clinical practice and toxicity

Introduction: Psoriatic arthritis is a common and often severe chronic joint disorder associated with the skin disease psoriasis (PsO). Treatment options for psoriatic arthritis patients have changed considerably over the last decade with the widespread use of biological therapies, in particular tumour necrosis factor inhibitors. Current clinical experience based on large registries and careful observations now allows us to understand the true value of these interventions in daily clinical practice.

Areas covered: Literature searches were performed targeting effectiveness, drug survival, toxicity and safety of biological therapies as well as treatment strategies specifically focused on patients with psoriatic arthritis.

Expert opinion: Tumour necrosis factor inhibition is a powerful and effective option for the treatment of severe psoriatic arthritis. The different available drugs have good survival rates and show an excellent balance between effectiveness and toxicity. Switching of inhibitor is feasible, but treatment changes should be carefully considered. Novel biological therapies are introduced into the market and will further provide better perspectives for the patient. New questions are also emerging: How to handle long-term remission, can biological therapies be successfully stopped and are co-morbidities sufficiently managed? These questions should be addressed for optimal long-term management of a severe chronic disease.     

Ustekinumab for the treatment of psoriasis and psoriatic arthritis: a drug evaluation and literature review

Introduction: Psoriasis (PsO) is an inflammatory disorder characterized by proliferation of keratinocytes, and it may be associated with a systemic inflammatory articular disorder, psoriatic arthritis (PsA). The presentations of PsO and PsA are heterogeneous, and our understanding of pathogenesis has led to a better understanding of the role of the interleukin (IL)-23/T-helper 17 (Th17) axis.

Areas covered: Ustekinumab is a monoclonal antibody against IL-12 and IL-23. The pathogenesis of PsO and PsA is a multifactorial process involving genetic, environmental, and lifestyle factors. IL-23 signaling and activation of Th17 cells leads to a self-perpetuating inflammatory loop resulting in continuous keratinocyte proliferation and synovitis. Treatment options are varied, ranging from topical therapy to injection of targeted biologic disease-modifying antirheumatic drugs (bDMARDs). Evidence on the use of ustekinumab in the management of PsO is strong, but it is not as impressive in management of PsA.

Expert opinion: IL-12/23 inhibition appears to be a good first-line option for plaque PsO, but efficacy in PsA does not compare favorably to IL-17 inhibition. In general, poorer responses to therapy with any bDMARD in PsA cohorts highlight psoriatic disease heterogeneity. Until new knowledge can remedy the failure of monotherapy, synergistic methods may have to be explored, including combination biologic therapy.     

Safety profile of biological therapies for treating rheumatoid arthritis

Introduction: Biological agents such as tumor necrosis factor inhibitors (TNFi), abatacept, rituximab and tocilizumab have proven efficacy in RA. However, these agents are also associated with adverse events so further data is essential to detect them at the earliest stage possible.

Areas covered: Herein, the authors review the safety profile of biological therapy, including TNFi and non-TNF agents including abatacept (ABA), rituximab (RTX) and tocilizumab (TCZ). The authors analyze both published articles and congress communications including clinical trials, meta-analyses, observational studies, data from registries and spontaneous clinical reports. The authors classify studies according to the most common and relevant adverse events associated with biological agents.

Expert opinion: Biological therapies have a reasonable safety profile and, globally, the benefits far outweigh the possible risk of adverse events. Currently, the risk of serious infections is low and no increased risk in solid malignancies or cardiovascular events have been found after a long clinical experience with these therapies. However, there are still potential risks as well as concerns of immunogenicity induced by TNFi. More studies are required to understand these risks, design safer drugs, and implement pharmacogenomics into the clinic. This will lead to a more personalized medicine in the future.     

Monoclonal antibodies for the treatment of osteoarthritis

ABSTRACT

Introduction: Osteoarthritis (OA) is a multifactorial chronic joint disease, and so far, there are no approved disease-modifying anti-OA drugs (DMOADs). There is an urgent need to develop therapies for different phenotypes of OA. Monoclonal antibodies (mAb) may slow structural progression, control inflammation and relieve pain, and thus have the potential to be DMOADs.

Areas covered: In this review, the authors searched the literature on PubMed, EMBASE and the Cochrane Library using keywords, including mAbs, biological agents, OA and osteoarthritis, electronically up to May 2016. They also included abstracts of international conferences. Furthermore, they reviewed experimental and clinical studies of various mAbs targeting different pathological mechanisms of OA, including ADAMTS, Interleukine-1, tumour necrosis factor, never growth factor and vascular endothelial growth factor.

Expert opinion: MAbs for the treatment of OA are under intense investigation and the results for some mAbs (e.g., anti-nerve growth factor mAbs, anti- vascular endothelial growth factor mAbs) are promising. The authors believe that mAb therapy can be a targeted therapeutic approach for the treatment of OA. Future clinical trials are required to evaluate the therapeutic efficacy of these agents by the appropriate selection of specific phenotype for targeted therapy based on the mechanism of drug action.     

Economical aspect of biological therapy in inflammatory conditions in Hungary

Introduction: There has been a burst in the use of biological therapies in the past decade resulting in increasing costs. In 2006 – 2010 the following biological agents were available in Hungary: adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab, tocilizumab, and ustekinumab. All biological agents except rituximab were first line therapies; rituximab was a second line option in rheumatoid arthritis.

Areas covered: Data of the financing system related to health care services from the data warehouse of the Hungarian National Health Insurance Fund were in inflammatory conditions. Our analysis showed a constant increase in number of patients and overall cost of biological therapy as well as annual cost of biological agents. Distribution of first choice of biological therapy was compared in different diseases. Time from diagnosis to start of biological therapy showed relatively high deviations.

Expert opinion: In order to achieve both health benefit and cost-effectiveness it is crucial that biological therapy is initiated early enough in the course of the disease, after the failure of non-biological therapies. Health authorities in close collaboration with clinical decision-makers should ensure that early detection of the disease and early initiation of appropriate therapies—including non-biological and biological therapies—are carried out in the health care systems.     

Joint tenderness and swelling in biologic‐treated inflammatory arthritis patients – A tricky trade off?

Objective: To compare the pattern of joint responses in patients with rheumatoid arthritis and psoriatic arthritis treated with TNF inhibitor (TNFi) therapy. Methods: A total of 182 PsA/Rheumatoid arthritis (RA) patients attending the rheumatology unit of a tertiary referral centre in Ireland were recruited and prospectively followed up by the attendant rheumatologists. Clinical progress of the patients was noted at baseline and 6 months after starting TNFi therapy. Results: A total of 114 RA and 68 PsA patients were assessed; 20% of the patients had one of either tender joints or swollen joints after 6 months of therapy. Rheumatoid arthritis patients had a significantly higher proportion of non‐tender swollen joints compared with PsA patients, whereas PsA patients had a higher proportion of tender non‐swollen joints (p < 0.05). Conclusion: Residual joint swelling was found more commonly in RA patients than in PsA patients following TNFi therapy, whereas residual tender joints occurred more frequently in PsA; this may reflect enthesiopathy or periostitis.     

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.     

Targeted biological therapies for pain

Introduction: Chronic pain is often resistant to currently used drugs. The effect of these is frequently self-limiting, with increasing level of side effects caused by increased doses. Biological pain therapies provide a means to target molecules to specific types of neural cells in spatially limited areas. Targeted biological therapies utilize agents acting at specific sites, or virus or cell vectors allowing expression and secretion of transgenic substances in small anatomical compartments. Biological approaches to treatment of chronic pain may be able to provide greater analgesic efficacy, avoiding many of the limitations associated with current analgesics.

Areas covered: The most important targets and tools for biological therapy of pain. Basic approaches, preclinical trials and the clinical studies successfully completed. The rationale and tools for biological therapies.

Expert opinion: Biological therapy of pain holds great promise and is rapidly developing. Despite the significant numbers of preclinical studies in the last two decades only a single biological agent, the cone snail toxin ziconotide, has been advanced through all stages and licensed for clinical use. Biological therapy of pain is thus here to stay, but will need more substantial proof of efficacy and safety before being widely accepted and routinely used.     

Synergy of molecular targeted approaches and immunotherapy in melanoma: preclinical basis and clinical perspectives

Introduction: Targeted therapy and immunotherapies are the novel pharmacologic treatment strategies for metastatic melanoma. BRAF and MEK inhibitors effectively block the hyperactivation of the MAPK pathway in BRAF mutant melanomas and also have several other effects on melanoma cells and on the immune response. The aim of this work is to discuss the rationale, evidence and perspectives of approaches combining target and immunotherapy against melanoma.

Areas covered: We first review the effects of BRAF and MEK inhibitors on melanoma cells and on the different components of the immune system. Afterwards, we summarize the results of the preclinical and clinical studies that have combined targeted therapy and immunotherapy for the treatment of melanoma.

Expert opinion: Clinical applications of immunotherapy strategies have recently changed the therapeutic mainstay for metastatic melanoma. Biologic and initial preclinical data support their integration with innovative molecular targeted therapies, opening enormous perspectives for researchers in the effort of finding a definitive cure. Main open challenges are the definition of reliable research models, assessment of effective schedules, safety issues and designing of personalized approaches.     

Ramucirumab for the treatment of gastric or gastro-esophageal junction cancer

ABSTRACT

Introduction: Gastric cancer remains one of the most lethal malignancy, accounting for an estimated 783,000 deaths worldwide in 2018. Although there are several approved drugs for the treatment of gastric cancer, the survival of patients with advanced disease remains dismal. Ramucirumab, a vascular endothelial growth factor receptor-2 inhibitor, is an important new targeted drug approved for gastric and gastroesophageal adenocarcinoma (GEJ) in second-line setting.

Areas covered: In this article, we have reviewed the role of ramucirumab in the management of gastric and GEJ adenocarcinoma. A comprehensive review of various clinical trials is presented that support the use of ramucirumab in gastric cancer.

Expert opinion: In our opinion, ramucirumab should be considered as a standard of care option, either alone or with paclitaxel, after progression on first-line therapy for advanced or metastatic disease. The results of large, randomized phase III clinical trials show benefit of ramucirumab on median overall survival (OS). However, the benefit is limited, with only about two months OS benefit of using ramucirumab with paclitaxel compared to paclitaxel alone. Novel combination therapies, such as ramucirumab with other targeted agents and immune checkpoint inhibitors in ongoing clinical trials, may provide important information to further improve the patient outcomes.     

The comparative immunogenicity of biologic therapy and its clinical relevance in psoriatic arthritis: a systematic review of the literature

Introduction: Biologic agents have demonstrated efficacy in treating patients with psoriatic arthritis (PsA). Biologic agents also have an intrinsic capacity to induce an immune response in patients that could result in unwanted adverse events and/or treatment failure.

Areas covered: In this systematic literature review, the authors document the incidence of immune responses, primarily anti-drug antibodies (ADA), to the biologic therapeutic agents currently in clinical practice for the treatment of PsA. The authors discuss the importance of these responses with respect to clinical practice.

Expert opinion: Our evaluation of the published literature shows that the immune responses to the various biologic therapeutic agents currently being used to treat PsA are similar to those observed for these agents in other rheumatic diseases. Moreover, similar to observations in other rheumatic diseases, the incidence of ADA formation to biologic agents in patients with PsA is often decreased when patients are given concomitant treatment with disease-modifying anti-rheumatic drugs. These data strongly suggest that the immune response is a characteristic of the biologic agent. Using therapeutic drug monitoring may be an approach to assess the immune response to the agent and to mitigate the potential impact on efficacy and safety, and consequently optimize treatment.     

Farletuzumab in epithelial ovarian carcinoma

Importance of the field: Ovarian cancer is the leading cause of death from a gynecologic malignancy. Recurrence is both common and lethal, necessitating the development of novel targeted therapies. Farletuzumab (MORAb-003) is a humanized mAb with high affinity for folate receptor α (FRα), a 38 kDa GPI-anchored protein that is overexpressed in 90% of epithelial ovarian cancers.

Areas covered in this review: Preclinical and clinical trials, published or presented at national meetings from 2006 to the present, are presented in this review.

What the reader will gain: Preclinical studies have demonstrated robust antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in vitro, inhibition of tumor growth in ovarian tumor xenografts and a safe toxicology profile in non-human primates. Phase I and II studies have demonstrated single agent and combination therapy efficacy with minimal drug-specific toxicity. The Phase III development plan in ovarian cancer patients includes combination chemotherapy studies in both platinum-sensitive (recently launched) and platinum-resistant (planned) recurrent disease.

Take home message: FRα is overexpressed in ovarian cancers but largely absent from normal tissue, making it an attractive therapeutic target. Farletuzumab is a novel inhibitor of FRα and has shown clinical efficacy in early phase trials.     

Biological therapies for psoriasis

Introduction: Biological therapies have revolutionized moderate-to-severe psoriasis treatment. Increased understanding of disease pathogenesis has yielded multiple therapeutic targets involving the IL-23/Th17 pathway, while current therapies continue to be monitored for long-term efficacy and safety.

Areas covered: This review details current understanding of psoriasis immunopathogenesis specifically related to therapeutic targets. Approved and emerging biological psoriasis therapies targeting TNF-α, IL-12/23p40, IL-17 and IL-23p19 are covered. Biological agent uses in special circumstances are reviewed together with the emerging debate on biosimilar therapies and their potential future role in psoriasis and other inflammatory diseases.

Expert opinion: Psoriasis treatment has expanded and has become more effective due to increased understanding of disease pathogenesis. However, lack of efficacy in select psoriasis patients, safety concerns and limited treatment efficacy in psoriasis variants (e.g., pustular) are areas which still need improvement. As such, pharmacogenomics will be of vital importance in future for individualized psoriasis care. Further, a better understanding of the multiple psoriasis comorbidities, especially cardiovascular disease, continues to be of significant interest in the psoriasis community. Last, the emergence of biosimilar agents has the potential to change psoriasis treatment, especially as it relates to better access for the psoriasis community worldwide.     

B-cell-targeted therapy in adult glomerulonephritis

Introduction: There are many mechanisms through which B lymphocytes have been implicated in the pathogenesis of glomerulonephritis. There are a number of trials and clinical studies in glomerulonephritis involving depletion of CD20⁺ B lymphocytes using rituximab. Newer anti-CD20 agents are currently under evaluation, as are drugs targeting alternative B-cell targets such as B lymphocyte stimulator. Such selective, targeted B-cell therapies, if shown to be effective, may be of value in minimising toxicity from more conventional agents.

Areas covered: This article reviews the role of B cells as a target for therapy in adult renal disease resulting from primary glomerulonephritis and that occurring secondary to systemic disease. It will not address intracellular signalling or co-stimulatory pathways as therapeutic targets.

Expert opinion: There are indications for B-cell targeted therapies in a number of adult glomerulonephritides, with varying degrees of evidence. Further understanding of the mechanisms of B-cell depletion and repletion, and interplay with B-cell survival factors, is necessary in order to identify patients who will respond favourably.     

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.