Tildrakizumab for treating psoriasis

Introduction: Agents that block inflammatory pathways other than tumor necrosis factor (TNF) have represented new options for treating psoriasis in recent years. IL-23 is involved in regulating Th17 cells and is a potent activator of keratinocyte proliferation. Targeting IL-23p19 alone may be a promising treatment approach in patients with moderate-to-severe chronic plaque psoriasis, with a downregulation of Th17 and Th22 cell responses, while IL-12 blockade is not required to achieve efficacy in these patients.

Areas covered: The authors review and provide an update on tildrakizumab, a humanized IgG1 monoclonal antibody that blocks the p19 subunit of IL-23.

Expert opinion: Total skin clearance is an important treatment goal that has both measurable and clinically meaningful benefits. Meeting patient needs about total clearance, IL-23p19 inhibitors will obtain a specific position in the crowded psoriasis market. On the other hand, PASI 75 and PASI 90 response achieved by tildrakizumab in the phase II and III trials are less than the response achieved by the IL-17A inhibitors and other p19 competitors, possibly due to a less intensive dosing regimen, although direct comparisons cannot be made without a head-to-head randomized clinical trial. The main advantage of tildrakizumab is that it is dosed in a maintenance regimen of 12 weeks, and similar to ustekinumab, this is likely to encourage adherence and aid persistence to the drug.     

Anti-inflammatory effects of the new generation synthetic surfactant CHF5633 on Ureaplasma-induced cytokine responses in human monocytes

Background: Synthetic surfactants represent a promising alternative to animal-derived preparations in the treatment of neonatal respiratory distress syndrome. The synthetic surfactant CHF5633 has proven biophysical effectiveness and, moreover, demonstrated anti-inflammatory effects in LPS-stimulated monocytes. With ureaplasmas being relevant pathogens in preterm lung inflammation, the present study addressed immunomodulatory features on Ureaplasma-induced monocyte cytokine responses.

Methods: Ureaplasma parvum-stimulated monocytes were exposed to CHF5633. TNF-α, IL-1β, IL-8, IL-10, TLR2 and TLR4 expression were analyzed using qPCR and flow cytometry.

Results: CHF5633 did not induce pro-inflammation, and did not aggravate Ureaplasma-induced pro-inflammatory cytokine responses. It suppressed U. parvum-induced intracellular TNF-α (p < 0.05) and IL-1β (p < 0.05) in neonatal monocytes and inhibited Ureaplasma-induced TNF-α mRNA (p < 0.05), TNF-α protein (p < 0.001), and IL-1β (p = 0.05) in adult monocytes. Ureaplasma-modulated IL-8, IL-10, TLR2 and TLR4 were unaffected.

Conclusion: CHF5633 does neither act pro-apoptotic nor pro-inflammatory in native and Ureaplasma-infected monocytes. Suppression of Ureaplasma-induced TNF-α and IL-1β underlines anti-inflammatory features of CHF5633.     

Biologics for treating axial spondyloarthritis

Introduction: Spondyloarthritis (SpA) encompasses a heterogeneous group of diseases sharing genetic, immunological, clinical and imaging features. Axial spondyloarthritis (axSpA) refers to a subgroup characterised predominately by inflammation of the axial skeleton with subsequent symptoms of chronic (often inflammatory) back pain and sacroiliitis. There is a strong association with the major histocompatibility complex (MHC) class I allele human leukocyte antigen (HLA) B27. In the last decade, there has been significant progress in earlier detection of the disease and the molecular mechanisms involved in its pathogenesis. The subsequent introduction of anti-tumour necrosis factor (TNF) has revolutionised the treatment of patients with axSpA.

Areas covered: In this article, we review the current biologic therapies for axSpA, the emergence of biosimilars, predictors of response, primary and secondary failure and new biologics on the horizon.

Expert opinion: There have been significant advances in the treatment of axSpA. Beyond the clear efficacy of anti-TNF inhibition, IL-17 offers an alternative therapeutic target and there is promise from inhibition of the IL-17/IL-23 pathway and small molecules, such as Janus kinase (JAK) inhibitors. Biosimilars have offered greater affordability and choice within this increasingly growing field of therapeutics.     

Guselkumab for the treatment of psoriasis

Introduction: Psoriasis is a chronic immune mediated disease in which the interplay of T cells and keratinocytes seems to play a key role. In this context, the interleukin (IL)-23/IL-17 axis is currently considered to be crucial in the pathogenesis of psoriasis and the selective inhibition of IL-23 may be viewed as an improvement of treatments blocking both IL-23 and IL-12, since its upstream actions.

Areas covered: The authors performed a thorough and updated review on guselkumab, a fully human IgG1λ monoclonal antibody that blocks the p19 subunit of IL-23, analyzing efficacy and safety data from phase I, II and III trials.

Expert opinion: Guselkumab represents a very promising therapy, providing an alternative mechanism of action with high efficacy and safety profiles, sustained total skin clearance, and rapid onset of effect also to psoriasis patients who previously failed or experienced an inadequate response to anti-TNF-α or anti-IL12/23. Guselkumab will definitively shift therapeutic goals of psoriasis management from PASI 75 to PASI 90 and 100 due to its exciting trials results, also favored by its increased treatment adherence due to its administering regimen (100 mg injection at week 0, 4 and then every 8 weeks).     

Ixekizumab: an anti- IL-17A monoclonal antibody for the treatment of psoriatic arthritis

Introduction: Psoriatic arthritis (PsA) is an inflammatory rheumatic disease that manifests itself with synovitis, dactylitis, enthesitis and also axial involvement. Interleukin-17A has been identified as a master cytokine in the inflammatory response and pathogenesis of PsA and spondyloarthritis in general. Ixekizumab is a new humanized monoclonal antibody that blocks the biological activity of IL-17A. This biological agent has previously demonstrated a high level of efficacy in psoriasis.

Areas covered: This review discusses the basic immunology of the IL-17 cytokine family, the contribution of IL-17A to the immunopathogenesis of PsA, the clinical trials that evaluated ixekizumab in patients with PsA (SPIRIT program) and the safety of this agent.

Expert opinion: Ixekizumab demonstrated its efficacy in different aspects of PsA including peripheral joint involvement, dactylitis, skin symptoms and patient reported outcomes in the 2 phase III trials from the SPIRIT program. Its safety profile was consistent with previous observations in patients with psoriasis. The role of IL-17A in the management of patients with PsA needs further clarification. According to EULAR recommendations for the management of PsA, IL-17A inhibitors may be used as second line biological DMARDs after TNF inhibitors.     

Itolizumab,a novel anti-CD6 monoclonal antibody: a safe and efficacious biologic agent for management of psoriasis

Introduction: Psoriasis, a chronic immune-mediated skin disorder is associated with significant physical, psychological, and quality of life impairments. Along with well-documented genetic and environmental factors, immunological factors also contribute to the pathogenesis of psoriasis. Among the immunological factors, CD6 – dependent T-cell proliferation to form Th1 and Th17 cells play a major role in the pathogenesis of psoriasis. Itolizumab is the first humanized IgG1 monoclonal antibody, which selectively targets CD6.

Areas covered: The current article presents the pharmacology of itolizumab and provides a review of the currently available data on the efficacy and safety of itolizumab for management of moderate to severe plaque psoriasis.

Expert opinion: The use of biologics to attenuate the immune-mediated pathological events in psoriasis is a relatively well-established clinical practice. However, the safety and efficacy of biologics continues to be an unsettled topic of ongoing research. While available data seems to suggest that itolizumab may be a safer option, additional studies with higher sample sizes and active comparators are needed before definitive conclusions can be drawn on the place of itolizumab in the management of psoriasis.     

A new class of biologic agents facing the therapeutic paradigm in psoriasis: anti-IL-23 agents.

Introduction: Psoriasis is a chronic inflammatory skin disease whose pathogenesis is driven by multiple cytokine-mediated pathways. In this immunologic setting, the centrality of the IL-23/IL-17 axis and its therapeutic relevance has emerged.

Areas covered: This review is aimed at collecting preliminary data on IL23p19 blockers developed for the treatment of plaque psoriasis. Three agents, guselkumab, risankizumab, and tildrakizumab, are currently being tested in phase III trials, while LY2525623 is currently being tested in phase II trials. Treatment with these agents resulted in a marked improvement in disease severity, confirming the pathogenic relevance of IL-23 in psoriasis.

Expert opinion: Selective neutralization of IL-23 is an advantageous strategy for treating psoriasis. Preliminary data from phase II and III trials have shown the capability of this therapeutic class in inducing complete clearance or almost complete clearance in many patients: the highest PASI 90 rates were achieved by guselkumab, tildrakizumab, and risankizumab in 73.3%, 74% and 77% of cases, respectively. Moreover, the highest PASI 100 rates were achieved in 33%, 14%, and 48% of patients treated with guselkumab, tildrakizumab, and risankizumab, respectively. Further studies are needed to confirm this remarkable efficacy over long-term treatment periods.     

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.     

Regulatory T CD4 + CD25+ lymphocytes increase in symptomatic carotid artery stenosis

Background: Atherosclerosis is a multifactorial disease characterized by an immune-inflammatory remodeling of the arterial wall. Treg and Th17 subpopulations are detectable inside atherosclerotic plaque; however, their behavior in symptomatic carotid artery stenosis (CAS) is not fully elucidated. The aim of this study was to evaluate Th17 and Treg subsets and their ratio in patients affected by symptomatic and asymptomatic CAS.

Methods: 14 patients with symptomatic CAS (CAS-S group), 41 patients with asymptomatic CAS (CAS-A group), 32 subjects with traditional cardiovascular risk factors (RF group), and 10 healthy subjects (HS group) were enrolled. Th17 and Treg frequency was determined by flow cytometry and by histology and immunohistochemistry. Interleukin (IL)-10, IL-17, and metalloproteinase (MMP)-12 levels were measured by ELISA.

Results: Th17 were significantly increased in CAS-A versus RF and versus HS. Tregs were significantly increased in CAS-S versus CAS-A. Tregs/Th17 ratio was significantly reduced in CAS-A versus RF and versus HS, whereas it was significantly increased in CAS-S versus CAS-A.

Conclusions: The results of this study suggest that Th17 are related to the late stages of CAS but not to plaque instability. Moreover, Treg expansion seems to represent a specific cellular pattern displayed by patients with symptomatic CAS and associated with brain injury.

• KEY MESSAGES

• Tregs expansion seems to represent a specific cellular pattern displayed by patients with symptomatic CAS and associated with CD4+ effector depletion and brain ischemic injury.

• Th17 lymphocytes are related to the late stages of CAS but not to plaque instability.

     

Anti-IL17 therapies for psoriasis

Introduction: Interleukin-17 (IL-17) is a proinflammatory cytokine considered to play a significant role in the immunopathogenesis of plaque psoriasis. As a result, focus in clinical trials has undergone a shift towards disease specific targets, with the goals of more effective treatment and reduction in the incidence of serious adverse events.

Areas covered: Two monoclonal antibodies targeting IL-17A (secukinumab, ixekizumab) and one against the IL-17 receptor (brodalumab) are approved for the treatment of moderate-to-severe plaque psoriasis. Herein, the clinical efficacy, safety and tolerability of each is reviewed by summarizing the existing literature (found via PubMed database).

Expert commentary: The development and approval of the IL-17 inhibitor agents secukinumab, ixekizumab, and brodalumab has expanded psoriatic treatment with effective options, validating the importance of the pro-inflammatory role of IL-17 psoriatic pathophysiology. Biologic treatment options for psoriasis will continue to grow, especially IL-17 and IL-23 related agents, with an increasing specificity of agents to be available in the future.     

Certolizumab pegol for the treatment of psoriasis

Introduction: Psoriasis is a chronic immunomediated and inflammatory disease involving mainly skin and joints, often associated with several metabolic and non-metabolic comorbidities. TNF-alpha inhibitors have shown long-term efficacy and safety/tolerability in psoriasis, and preliminary data support the use of certolizumab pegol (CZP) as well.

Areas covered: The authors review the pharmacological properties of CZP, as well as its safety data and efficacy profile. They also review the quality of life outcomes related to CZP in psoriasis. The authors also provide their expert opinion on the subject.

Expert opinion: CZP is a promising treatment for psoriasis owing to its rapid reduction of disease activity, long-term therapeutic efficacy – both in bio-naive and non-bio-naive patients, long term safety and low rate of site injection reactions. CZP seems to be a promising therapeutic option for psoriasis patients, although further evidence supporting the continuing clinical program for development of CZP in psoriasis is needed.     

Dupilumab for the treatment of asthma

Introduction: Dupilumab is a fully human IgG4 monoclonal antibody directed against the α subunit of the interleukin (IL)-4 receptor (IL-4Rα). Since the activation of IL-4Rα is utilized by both IL-4 and IL-13 to mediate their pathophysiological effects, dupilumab behaves as a dual antagonist of these two sister cytokines, which blocks IL-4/IL-13-dependent signal transduction.

Areas covered: Herein, the authors review the cellular and molecular pathways activated by IL-4 and IL-13, which are relevant to asthma pathobiology. They also review: the mechanism of action of dupilumab, the phase I, II and III studies evaluating the pharmacokinetics as well as the safety, tolerability and clinical efficacy of dupilumab in asthma therapy.

Expert opinion: Supported by a strategic mechanism of action, as well as by convincing preliminary clinical results, dupilumab currently appears to be a very promising biological drug for the treatment of severe uncontrolled asthma. It also may have benefits to comorbidities of asthma including atopic dermatitis, chronic sinusitis and nasal polyposis.     

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

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

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

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

Subcutaneous anti-TNF alfa induced sustained minimal disease activity and remission in psoriatic arthritis patients: a retrospective study

Objective: The aim of the present study was to assess the rate of sustained Minimal Disease Activity (MDA) and remission in a group of psoriatic arthritis (PsA) patients treated with TNFα blockers.

Methods: We perform a retrospective study on our database of PsA patients treated with adalimumab, etanercept and golimumab, with a minimum of 12 months of follow up. Patients were considered in sustained MDA when they met at least 5/7 of the criteria previously defined for at least 12 months of follow up. DAS28-CRP < 2.6, DAPSA score ≤ 4 and patient global assessment (PGA) ≤ 20 mm were also evaluated as remission criteria. Concordance between the remission criteria and MDA was also performed.

Results: Of the 81 patients treated with TNFα blockers, at baseline no patients were in MDA or had a DAPSA score ≤ 4, while 17 (20.9%) had a DAS28-CRP score < 2.6. PGA ≤ 20 was recorded in 6 patients (7%). Sustained MDA was achieved in 35 (43.2%) patients while sustained DAPSA, DAS28-CRP and PGA remission were obtained respectively in 19.7%, 35.8% and 44.4% of patients. No difference was found between the three anti-TNFα in respect to the probability of achieve MDA.

Conclusions: In this retrospective study, sustained MDA was achieved in 43.2% of patients treated with TNFα blockers. Moreover, sustained remission was achieved in a consistent number of patients, configuring this as an achievable target for PsA patients.     

Association between cardiovascular diseases and mobility in persons with lower limb amputation: a systematic review

Purpose: Persons requiring a lower limb amputation often have cardiovascular diseases that reduce cardiac function, which may complicate recovery and rehabilitation after an amputation. This systematic review analysis the association between cardiovascular diseases and mobility in persons with a lower limb amputation.

Method: Four databases were searched for studies published before August 2016 using database-specific keywords and synonyms for amputation, cardiovascular diseases and mobility. Assessment of the publications was performed based on predefined criteria; first title and abstract and thereafter the full text.

Results: Of the 1704 titles and abstracts, 51 full texts were assessed. Ten studies were included. Cardiovascular diseases were associated with cardiac complications during rehabilitation. Prosthetic training improved cardiac function. Seven studies showed that cardiovascular diseases were associated with a smaller chance of becoming a prosthetic walker, and with poorer mobility outcomes.

Conclusion: Evidence for effects of cardiovascular diseases on mobility in persons with a lower limb amputation is heterogeneous. Cardiovascular diseases reduce the chance of becoming a prosthetic walker and reduce mobility outcomes after a lower limb amputation. More research with adequate quality about cardiovascular diseases in persons requiring a lower limb amputation is needed, to enable informed choices in the pre- and post-amputation rehabilitation.

• Implications for rehabilitation

• Data about the effect of cardiovascular diseases on mobility in persons with a lower limb amputation is limited.

• More research about cardiovascular diseases in persons requiring a lower limb amputation is needed, to enable informed choices in the pre- and post-amputation rehabilitation.

     

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.     

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.     

Biological therapies for eosinophilic asthma

Introduction: Severe uncontrolled asthma is by definition refractory to traditional therapies or can be controlled only with therapies that have intolerable side effects. Monoclonal antibodies that target interleukin (IL)-5/IL-5Rα, IgE, and IL-4Rα have shown favorable results in clinical trials, including reductions in asthma exacerbations and other important clinical outcomes. These biological agents offer treatment alternatives to patients with uncontrolled severe eosinophilic asthma.

Areas covered: This article reviews how the shifting emphasis toward identifying distinct asthma phenotypes has led to the approval of biological therapies that preferentially benefit patients with severe eosinophilic asthma. The clinical trials that led to the approval of these biologic treatments are discussed in detail.

Expert opinion: Biologic therapies targeting the IL-5, IgE, IL-4/IL-13 signaling pathways have been successful in clinical trials in subjects with severe eosinophilic asthma. Some of these agents have also been successful regardless of peripheral blood eosinophil counts. These treatments have shown a relatively favorable safety profile in clinical trials, although long-term safety data for some of these agents are limited. Due to the high costs associated with these medications, they should be reserved for select patients where they yield a therapeutic and pharmacoeconomic advantage.     

Adalimumab for treating childhood plaque psoriasis: a clinical trial evaluation

Introduction: Most systemic therapies have not been systematically investigated in moderate to severe childhood plaque psoriasis. Evidence on the efficacy and safety of systemic treatments is limited and therapeutic guidelines are lacking. Recently adalimumab, a fully human monoclonal antibody that binds tumor necrosis factor (TNF)- alpha, was investigated in childhood psoriasis. Adalimumab is licensed for many inflammatory conditions including chronic plaque psoriasis in adults.

Areas covered: A randomized phase III study published provided favourable efficacy and safety data of adalimumab in childhood psoriasis. The active comparator was methotrexate. After 16 weeks of treatment, a PASI 75 score was achieved in 58% of patients within the adalimumab 0.8 mg/kg group compared with 32% of patients within the methotrexate group. Safety data gave no evidence of drug-related serious adverse events and no organ toxicity. This is the first randomised controlled study of either adalimumab or methotrexate in children and adolescents with psoriasis.

Expert opinion: The aforementioned trial was the first to provide clinical data on adalimumab’s efficacy and safety in the short term when treating children and adolescents with psoriasis. Through the use of an active comparator, this study has opened the way for the future assessment of systemic therapies in children and adolescent with this condition.