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.     

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

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

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

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

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.     

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.     

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.     

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.     

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.     

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.     

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.     

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).     

The effect on the patient flow in a local health care after implementing reverse triage in a primary care emergency department: a longitudinal follow-up study

Objective: Reverse triage means that patients who are not considered to be in need of medical services are not placed on the doctor’s list in an emergency department (ED) but are sent, after face-to-face evaluation by a triage nurse, to a more appropriate health care unit. It is not known how an abrupt application of such reverse triage in a combined primary care ED alters the demand for doctors’ services in collaborative parts of the health care system.

Design: An observational study.

Setting: Register-based retrospective quasi-experimental longitudinal follow-up study based on a before–after setting in a Finnish city.

Subjects: Patients who consulted different doctors in a local health care unit.

Main outcome measures: Numbers of monthly visits to different doctor groups in public and private primary care, and numbers of monthly referrals to secondary care ED from different sources of primary care were recorded before and after abrupt implementation of the reverse triage.

Results: The beginning of reverse triage decreased the number of patient visits to a primary ED doctor without increasing mortality. Simultaneously, there was an increase in doctor visits in the adjacent secondary care ED and local private sector. The number of patients who came to secondary care ED without a referral or with a referral from the private sector increased.

Conclusions: The data suggested that the reverse triage causes redistribution of the use of doctors’ services rather than a true decrease in the use of these services.     

Incidence of rheumatoid arthritis,psoriatic arthritis and polymyalgia rheumatica in an inland area of central Italy: results of the CAMPO-RHE study

Objective: The aim of the CAMPO-RHE study was to determine the incidence of rheumatoid arthritis (RA), psoriatic arthritis (PsA) and polymyalgia rheumatica (PMR) in patients attending a rheumatologic outpatient’s clinic of a new institution in Campobasso, Italy.

Methods: Campobasso is a small town of approximately 50,000 inhabitants located in the inland territory of central Italy (Molise), and Public Health is managed from a single health authority. In Italy, all citizens are registered with a National Health System of General Practitioner (GP) Physicians. Between the 1^st of June 2014 and the 31^st of May 2016, all consecutive adult patients, sent by a GP, of Campobasso with any diagnosis of musculoskeletal symptoms/signs/complaints were evaluated in a single rheumatology outpatient clinic of our Academic Unit. The clinic represents the first and unique reference for GPs about rheumatic diseases in the territory. Subjects were classified using the 2010 EULAR criteria for RA, the CASPAR criteria for PsA and the 2012 ACR classification criteria for PMR.

Results: 1003 adult patients, sent by GPs, with articular or musculoskeletal complaints visited our clinic. Of these, 409 inhabitants of the municipality of Campobasso were evaluated for the study. During the 2-year study period we diagnosed 18, 19 and 12 new cases of RA, PsA and PMR respectively, with a new incident cases rate of 21.4, 22.59 and 27.43/100,000/year on the population at risk.

Conclusion: The results of our study could contribute to better define the incidence of these rheumatic diseases classified with the new classification criteria.     

Factors associated with self-rated health in primary care

Background: Self-rated health (SRH) measures one’s current general health and is a widely used health indicator. Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships are suspected to influence SRH, but studies in primary health care settings are sparse.

Objective: To examine the associations between patients’ self-rated health and their sleep problems, somatic health complaints, and unmet needs in interpersonal relationships.

Design: We collected data via questionnaires for this cross-sectional study from general practice.

Setting: Primary health care in Norway.

Subjects: 1302 consecutive patients participated.

Main outcome measures: The questionnaire included a single question about SRH, the Bergen Insomnia Scale (BIS), five questions on somatic health complaints, and three questions from the Basic Psychological Needs Scale (BPNS) pertaining to the relationships domain. We analyzed our data using ordinal logistic regression models.

Results: Our response rate was 74%. The prevalence of fair/poor SRH was 26%, with no gender differences. We revealed a significant association between increasing age and reduced SRH. The study showed that sleep problems and somatic health complaints were strongly associated with SRH, and unmet needs in relationships were also significantly and independently associated with reduced SRH in a full model analysis.

Conclusion: Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships were all associated with reduced SRH. These factors are all modifiable and could be managed both within and outside a primary care setting in order to improve SRH.

• Key Points

• There was a high prevalence of reduced SRH in clinical general practice

• Sleep problems, somatic health complaints, and unmet needs in interpersonal relationships were all associated with reduced SRH

• These predictors are all modifiable with a potential to improve SRH

     

A systematic review to determine the optimal type and dosage of land-based exercises for treating knee osteoarthritis

Background: Exercise has been acknowledged as an effective non-pharmacological intervention for osteoarthritis. Consensus regarding the type of exercise i.e., aerobic or resistance, weight bearing or non-weight bearing, and dosage i.e., frequency, loading, duration, or intensity, is yet to be reached.

Objective: The purpose of this review was to address two questions: (1) is there a difference in clinical outcomes between different exercise programmes; and (2) what is the optimal dosage of exercises for people with knee osteoarthritis.

Methods: A systematic review was conducted. A study of published (AMED, CINAHL, MEDLINE, EMBASE, PubMed, and the Cochrane Library) and unpublished literature (WHO International Clinical Trials Registry Platform, current controlled trials and the United States National Institute of Health Trials Registry, and Open Grey) was undertaken in January 2013. Studies assessing the clinical outcomes of different types and dosages of exercise for people with osteoarthritis of the knee were included. Methodological quality was assessed using the critical appraisal skills programme (CASP) randomized controlled trial (RCT) appraisal tool.

Results: Ten studies assessing 958 knees from 916 participants were included. Exercise significantly improved pain and function for people with knee osteoarthritis. There was no significant difference in outcomes for different types of exercise i.e., aerobic versus resistance, weight bearing versus non-weight bearing. There was no significant difference in respect to the intensity of exercise i.e., high- versus lower-intensity resistance or aerobic exercises. The quality of the literature was moderate to high.

Conclusions: While exercise appears to improve symptoms and optimize function for people with knee osteoarthritis, the optimal form and dosage of exercise remains unknown.

Funding: None.

PROSPERO Registration Number: CRD42012002811.     

General practitioners’ views on leadership roles and challenges in primary health care: a qualitative study

Objective: To explore general practitioners’ (GPs) views on leadership roles and leadership challenges in general practice and primary health care.

Design: We conducted focus groups (FGs) with 17 GPs.

Setting: Norwegian primary health care.

Subjects: 17 GPs who attended a 5 d course on leadership in primary health care.

Results: Our study suggests that the GPs experience a need for more preparation and formal training for the leadership role, and that they experienced tensions between the clinical and leadership role. GPs recognized the need to take on leadership roles in primary care, but their lack of leadership training and credentials, and the way in which their practices were organized and financed were barriers towards their involvement.

Conclusions: GPs experience tensions between the clinical and leadership role and note a lack of leadership training and awareness. There is a need for a more structured educational and career path for GPs, in which doctors are offered training and preparation in advance.

• KEY POINTS

• Little is known about doctors’ experiences and views about leadership in general practice and primary health care. Our study suggests that:

• There is a lack of preparation and formal training for the leadership role.

• GPs experience tensions between the clinical and leadership role.

• GPs recognize leadership challenges at a system level and that doctors should take on leadership roles in primary health care.

     

Resolution of cannabis hyperemesis syndrome with topical capsaicin in the emergency department: a case series

Background: Cannabinoid hyperemesis syndrome (CHS) is characterized by symptoms of cyclic abdominal pain, nausea, and vomiting in the setting of prolonged cannabis use. The transient receptor potential vanilloid 1 (TRPV1) receptor may be involved in this syndrome. Topical capsaicin is a proposed treatment for CHS; it binds TRPV1 with high specificity, impairing substance P signaling in the area postrema and nucleus tractus solitarius via overstimulation of TRPV1. This may explain its apparent antiemetic effect in this syndrome.

Purpose: We describe a series of thirteen cases of suspected cannabis hyperemesis syndrome treated with capsaicin in the emergency departments of two academic medical centers.

Methods: A query of the electronic health record at both centers identified thirteen patients with documented daily cannabis use and symptoms consistent with CHS who were administered topical capsaicin cream for symptom management.

Results: All 13 patients experienced symptom relief after administration of capsaicin cream.

Conclusion: Topical capsaicin was associated with improvement in symptoms of CHS after other treatments failed.     

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.     

Serum osmolal gap in clinical practice: usefulness and limitations

Background: Although serum osmolal gap can be a useful diagnostic tool, clinicians are not familiar with its use in clinical practice.

Objectives: The review presents in a series of questions-answers and under a clinical point of view the current data regarding the use of osmolal gap.

Discussion: The definition and the best formula used for the calculation of osmolal gap, the main causes of increased osmolal gap with or without increased anion gap metabolic acidosis, as well as the role of concurrent lactic acidosis or ketoacidosis are presented under a clinical point of view.

Conclusions: The calculation of osmolal gap is crucial in the differential diagnosis of many patients presenting in emergency departments with possible drug or substance overdose as well as in comatose hospitalized patients.     

Secukinumab in moderate-to-severe plaque psoriasis: a multi-center,retrospective, real-life study up to 52 weeks observation

Objectives: To evaluate efficacy and safety of the anti-IL-17 drug secukinumab in a real-life large cohort of patients with moderate-to-severe plaque psoriasis in Central Italy.

Methods: Multicenter, retrospective study with an observation period of up to 52 weeks. Efficacy was assessed by Psoriasis Area and Severity Index (PASI) score; clinical and laboratory examinations were performed at baseline and at weeks 4, 12, 24, 36, and 52.

Results: A 90% and a 100% PASI score reduction (PASI90 and PASI100) were reported in 67.5% and 55% of patients at week 12, respectively. A rapid improvement of skin lesions was observed particularly in young patients and in patients naïve to biologics: at week 4, the achievement of PASI90 and PASI100 was higher in younger patients (odds ratio [OR] 0.95, and 0.95; p = 0.003, and 0.005, respectively); PASI90 was achieved by 42.0% of patients naïve to biologics and by 17.0% of patients with prior exposure to biologics (PBT) (OR 0.24; p = 0.001); and PASI100 was reached by 25.5% of naïve patients and 9.8% of PBT (OR 0.28; p = 0.015).The drug was well tolerated.

Conclusion: Secukinumab was effective in this real-life analysis, with rapid clinical improvement and long-term maintenance of results.