Biologic agents in nail psoriasis: efficacy data and considerations

Introduction: Nail psoriasis plays a major role in the overall assessment of psoriatic disease. Four biologic agents are officially labeled for the treatment of moderate to severe, stable plaque psoriasis (adalimumab, etanercept, infliximab, ustekinumab) and have enriched subsequently the therapeutic armamentarium against psoriatic nails. However, evidence for the efficacy of these agents for nail psoriasis is under investigation.

Areas covered: In this review an effort has been made to summarize evidence regarding the efficacy of biologics in nail psoriasis. A systemic search for reports of biologic agents in psoriatic patients with nail involvement was carried out (MEDLINE and CENTRAL in the Cochrane Library). Relevant data are thoroughly presented.

Expert opinion: All four biologic agents have shown efficacy on psoriatic nail disease. However, published data are heterogeneous, based on studies assessing the therapeutic efficacy with different scoring indexes and at different time points, depending on the time table of each drug administration. Therefore, the need for consensus on core outcome to be used is mandatory. Additionally, optimization of the scoring systems and the conduction of further trials of high quality and validity could lead to more accurate conclusions on the efficacy of biologic agents in the treatment of nail psoriasis.     

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.     

Bimekizumab for the treatment of psoriatic disease

ABSTRACT

Introduction: Psoriasis and psoriatic arthritis are common diseases with significant physical and emotional burden. Several biologics are FDA-approved to treat psoriasis and psoriatic arthritis, though some patients remain refractory to, or have lost response to, therapy and/or cannot tolerate the associated risks and side effects. Bimekizumab is a new biologic that inhibits both IL-17A and IL-17F. It is currently in phase III clinical trials. To date, phase II studies show promise in its ability to rapidly resolve symptoms while remaining safe and well-tolerated.

Areas covered: This review serves to summarize the literature regarding the use of bimekizumab for psoriasis and psoriatic arthritis. Bimekizumab has undergone phase I and phase II clinical trials with results showing significant disease improvement or resolution, as well as safety and tolerability. Phase III studies are now actively enrolling.

Expert opinion: Bimekizumab is a burgeoning biologic offering significant promise through its unique bispecific targeting of both IL-17A and IL-17F. Clinical trials have shown the potential of rapid symptom improvement after treatment with bimekizumab, with some patients seeing improvement after only two weeks. To date, bimekizumab has been shown to be safe and well-tolerated by patients, without any associated significant adverse events.     

Clinical evaluation of natalizumab for formulary consideration

Importance of the field: Natalizumab is a monotherapy for relapsing forms of multiple sclerosis (MS) and maintaining remission in Crohn's disease (CD). Evaluation of natalizumab's clinical relevance must be performed before considering its place in treatment of these diseases.

Areas covered in this review: MEDLINE and PubMed searches were performed using the keywords multiple sclerosis, Crohn's disease, natalizumab and clinical trials. The manufacturer's product information was consulted to extract additional data. Pivotal clinical trials included: Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis (AFFIRM), Safety and Efficacy of Natalizumab in Combination With Interferon Beta-1a in Patients With Relapsing Remitting Multiple Sclerosis (SENTINEL), Efficacy of Natalizumab as Active Crohn's Therapy (ENACT)-1 and 2 and Efficacy of Natalizumab in Crohn's Disease Response and Remission (ENCORE).

What the reader will gain: AFFIRM and SENTINEL showed improvements in progression of MS. ENACT-1 failed to show a significant effect, but the follow-up trials ENACT-2 and ENCORE were able to demonstrate a response to natalizumab.

Take home message: Two trials on efficacy of Tysabri for treatment of MS demonstrated positive results. Efficacy for CD was mixed. More research demonstrating head-to-head evidence against other agents is necessary to determine if Tysabri's benefits are significant.     

Briakinumab

Background: Psoriasis is a chronic, autoimmune, T-cell mediated, inflammatory disease. An improved understanding of the pathogenesis of the autoimmune response has led to the development of targeted biologic therapies. Briakinumab is a human monocolonal antibody that blocks the activity of the cytokines IL-12 and IL-23. Immune dysregulation has been implicated in multiple inflammatory disorders and briakinumab has been investigated for the treatment of psoriasis, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. Objectives: This review focuses on briakinumab and its use in chronic plaque-type psoriasis. Methods: A literature review was performed, searching Medline and the clinicaltrials.gov database for all articles with the keywords ABT-874, IL-12/IL-23 and psoriasis. Conclusions: Although limited by small sample sizes, length of follow-up, and a lack of direct comparisons with other psoriasis treatments, initial data regarding the safety and efficacy of briakinumab for the treatment of psoriasis is promising. Ongoing Phase III trials may provide additional information regarding the relative efficacy and safety of briakinumab.     

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.     

Ixekizumab for the treatment of psoriasis: up-to-date

ABSTRACT

Introduction: Ixekizumab (an IL-17A antagonist) is a biologic therapeutic licensed for use in moderate-to-severe plaque psoriasis and psoriatic arthritis. IL-17 antagonists (also including Secukinumab and Brodalumab) represent a new generation of biologic therapy with rapid and high response rates, quickly becoming a crucial part of the psoriasis treatment armamentarium.

Areas covered: In this review, we describe how IL-17A antagonists disrupt inflammatory cascades in psoriasis and summarize results from clinical trials examining the safety and efficacy of ixekizumab against placebo and comparators.

Expert opinion: Ixekizumab induces a 75% reduction in psoriasis area severity index (PASI 75) in 89% of patients after 12 weeks and after 1 year, PASI 75 is maintained in 80% of patients. Ixekizumab is superior to both etanercept and ustekinumab, however, further comparator trials are needed to determine superiority between newer agents. Network meta-analysis suggests that ixekizumab is one of the most rapid and efficacious agents for treating psoriasis, but ideally more long-term real-world data are needed to determine the persistence of response. Candida may be commonly encountered during treatment and IL-17 agents should be avoided in patients with inflammatory bowel disease. Overall, ixekizumab represents an efficacious and well-studied therapeutic that can offer biologic-naïve and bio-failure patients durable disease control.     

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.     

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.     

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.     

Remestemcel-L: human mesenchymal stem cells as an emerging therapy for Crohn's disease

Introduction: Human mesenchymal stem cells (Prochymal brand of remestemcel-L) have been developed for experimental use in Crohn's disease and other conditions. Mesenchymal stems cells (MSCs) have been shown to inhibit inflammatory responses of innate and adaptive immune cells as well as have reparative effects on inflamed tissues. Promising preliminary therapeutic results of MSCs on gastrointestinal graft-versus-host disease have lead to Phase III trials for active Crohn's disease.

Areas covered: This review examines the discovery and characterization of mesenchymal stem cells, their immune effects, their use in animal models of disease, the production and administration of remestemcel-L and the published results of trials of remestemcel-L and alternative MSCs in Crohn's disease.

Expert opinion: The Prochymal brand of remestemcel-L represents the successful pharmaceutical development of mesenchymal stem cells for potential therapy in human disease. While preliminary results show promise of this therapy in terms of efficacy and safety, robust trials confirming efficacy results, explanation of the mechanism of response and estimates of effect compared to other biologics and immunosuppressants will be needed before this is an approved and widely accepted therapy.     

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.     

Zalutumumab in head and neck cancer

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

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

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

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.     

Efficacy and safety of ustekinumab and etanercept for the treatment of psoriasis

Importance of the field: TNF-α inhibitors such as etanercept have been used for psoriasis for years. A fairly well defined efficacy and safety profile has developed. A new biologic agent, ustekinumab, an IL-12 and IL-23 inhibitor, has recently been released in the US for the treatment of moderate-to-severe psoriasis. The purpose of this article is to compare the efficacy and safety profiles of ustekinumab and etanercept.

Areas covered in this review: We examined safety and efficacy data regarding ustekinumab and etanercept from clinical reports, a head-to-head trial, review articles, and databases and registries from the last 20 years.

What the reader will gain: Evidence is reviewed about the efficacy for the treatment of psoriasis as well as the safety profiles for both agents, ustekinumab and etanercept.

Take home message: Both drugs have data to confirm efficacy and safety in patients with moderate-to-severe psoriasis in the short-term. The limited long-term data on the safety profile of ustekinumab requires careful judgment on the clinician's part, weighing well-defined benefits and potential unknown risks.     

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.     

Rituximab biosimilar CT-P10 for the treatment of rheumatoid arthritis

ABSTRACT

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by long-standing inflammation in multiple joints. Rituximab, a monoclonal antibody, which binds to CD20, is effective in suppressing disease activity and preventing joint damage in RA. CT-P10 was developed as a biosimilar of rituximab and approved for use to treat hematologic malignancies and immune diseases including RA.

Area covered: This article describes the need for this biosimilar and summarizes the non-clinical studies verifying the physicochemical and biologic similarities and the clinical studies confirming the clinical similarity of CT-P10 to rituximab in patients with RA.

Expert opinion: CT-P10 had been evaluated and proven the efficacy and safety in RA in Phase I and III randomized controlled trial with extension studies including a switching regimen. Therefore, CT-P10 is recommended in the treatment of RA.     

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.     

Update on biologicals for treatment of juvenile idiopathic arthritis

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

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

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