Emerging drugs for the treatment of axial spondyloarthritis

Introduction: The treatment of axial spondyloarthritis(axSpA) has been for nearly 15 years constricted to non-steroidal antirheumatic drugs and TNFα inhibitors. With the approval of secukinumab, a drug targeting the interleukin(IL)-17 axis became available. Nonetheless, an unmet need for further emerging therapeutic options remains.

Areas covered: This review summarizes the recent and ongoing clinical trials with novel drugs in axSpA. Besides secukinumab, further therapeutics directed against the IL-17A (e.g. ixekizumab) as well as the dual IL-17A and F inhibitor bimekizumab and the IL-17RA antibody brodalumab are in development. Furthermore, several drugs targeting the IL-12/-23 axis are being evaluated. Pan-JAK and JAK-1 inhibitors might offer another effective mode of action.

Expert opinion: The number of treatment options in axSpA is likely to be further extended in the coming years. Data of ongoing studies are needed to prove the efficacy of drugs directed against the IL-12/-23 axis as well as of JAK inhibition, whilst targeting the IL-17 axis was shown to be as effective as TNF inhibition by indirect comparison. There is an emerging need for trials aiming at identification of optimal treatment strategies in the scope of the treat-to-target concept in axSpA.     

New treatment options and emerging drugs for axial spondyloarthritis: biological and targeted synthetic agents

Introduction: Ankylosing spondylitis (AS) and axial spondyloarthritis (ax SpA) are chronic inflammatory diseases mainly involving the axial skeleton. Pharmacological treatments for AS and ax SpA usually include local glucocorticoid injections, NSAIDs and anti-TNFα agents. Since around 30% to 40% of patients are non responders or intolerant to anti-TNFα agents, we need new therapeutic options for AS and ax SpA.

Areas covered: This review describes the new biological agents that can be used or are in development for AS or ax SpA as well as emerging synthetic targeted drugs.

Expert opinion: Based on the rationale of the involvement of the IL-23/Th17 axis in AS, novel biological agents have been developed and include secukinumab, an anti-IL-17A agent and ustekinumab, an anti-IL-23 antibody. New compounds in the class of synthetic drugs are apremilast, a PDE4 inhibitor, and inhibitors of kinase pathways. Secukinumab gave positive results in the treatment of AS. Ustekinumab yielded promising results in AS in an open labeled study. Apremilast is not effective in AS while results with kinase inhibitors are preliminary. Future studies will clarify the place of secukinumab in the therapeutic management of AS, its influence on radiographic progression and its effects on the non radiographic form of the disease.     

Developments with experimental and investigational drugs for axial spondyloarthritis

Introduction: Axial spondyloarthritis (AxS pA) is a chronic inflammatory disease for which, until recently, there were no valid therapeutic alternatives to TNF-α blocking agents. This unmet clinical need led to explore several therapeutic targets, from proinflammatory cytokines to intracellular signaling systems. The recent approval of Secukinumab, an anti-IL-17A monoclonal antibody, marked a new step in the evolution of AxSpA treatment.

Areas covered: the authors review and discuss all the biological or synthetic agents that are currently developed or that have been tested in AxSpA. News from relevant press releases by manufacturers on past, current and future developments are also reported. Several agents that target IL-17 are currently between phase 2 and 3 of clinical development. Ustekinumab, a monoclonal antibody that blocks IL-23 and IL-12 is also in phase 3 after encouraging results from a pilot study.

Expert opinion: The advent of agents that target the IL-23/IL-17 axis promises to reshape the therapeutic landscape for AxSpA in the next few years. Open questions in the research agenda for these agents involve their positioning in the therapeutic strategy, their efficacy on the spectrum of skeletal and extraskeletal manifestations of AxSpA, their effect on new bone formation and their long-term tolerance.     

Current therapeutics for spondyloarthritis

Introduction: Ankylosing spondylitis (AS) belongs to a clinically related group of disorders named spondyloarthritis (SpA) that mainly affect the axial skeleton and present with specific extra-articular manifestations. The therapeutic management of AS and other SpA has considerably progressed over the past 10 years.

Areas covered: This paper provides a review of the available treatments for AS including traditional treatments (NSAIDs, sulfasalazine and methotrexate, local corticosteroids) and biological therapies (TNF-α antagonists), as well as nonpharmacological procedures (education and physical therapy) and specific recommendations for this therapeutic management.

Expert opinion: NSAIDs remain the first-line treatment in patients with AS, especially with axial disease. There is an increasing amount of evidence showing the short-term and long-term efficacy of TNF-α antagonists in AS, with the control of pain, extra-articular manifestations and spinal inflammation as evidenced by MRI. By contrast, there is no proof for the control of radiographic progression at the spine with these agents. An early diagnosis is now possible using the new classification criteria for SpA. However, it remains to be established if an early intervention might control the progression of the disease. Since about 20 – 25% of patients are considered as nonmajor responders to TNF-α blockers, there is an unmet need for developing new biological therapies. Targeting the IL-17 pathway may be an interesting option. International recommendations for the management of AS by the Assessment of Spondyloarthritis (ASAS) group were recently updated and discussed the respective place of each current therapeutic option in AS.     

Safety of treatment options for spondyloarthritis: a narrative review

Introduction: Spondyloarthritis (SpA) are chronic inflammatory diseases with overlapping pathogenic mechanisms and clinical features. Treatment armamentarium against SpA includes non-steroidal anti-inflammatory drugs, glucocorticoids, conventional disease-modifying antirheumatic drugs (DMARDs, including sulfasalazine, methotrexate, leflunomide, cyclosporine), targeted synthetic DMARDs (apremilast) and biological DMARDs (TNF inhibitors, anti-IL 12/23 and anti-IL-17 agents).

Areas covered: A narrative review of published literature on safety profile of available SpA treatment options was performed. Readers will be provided with a comprehensive overview on frequent and rare adverse events associated with each drug listed in current SpA treatment recommendations.

Expert opinion: The overall safety profile of such molecules is good and serious adverse events are rare but need to be promptly recognized and treated. However, the monitoring of adverse events is a major challenge for clinicians because it is not adequately addressed by current treatment recommendations. A tailored treatment is crucial and rheumatologists must accurately select patients in order to identify those more susceptible to develop adverse events.     

IL-23／IL-17轴对寻常型银屑病病情的影响

目的：通过观察甲砜霉素联合异维A酸胶丸治疗寻常型银屑病的疗效,检测患者血清辅助T细胞17（ Th17）相关因子白介素17（IL-17）、白介素22（IL-22）和白介素23（IL-23）水平的变化,分析其与疾病严重程度及转归的关系,探讨银屑病可能的发病机制。方法治疗组为寻常型银屑病40例,对照组为健康体检者40例;治疗组给予甲砜霉素、异维A酸胶丸口服及丁酸氢化可的松乳膏外用。以4周为1个疗程,2个疗程后进行疗效判定。治疗组治疗前后分别检测血清IL-17、IL-22和IL-23的水平,与对照组进行比较,分析IL-17、IL-22、IL-23与严重程度指数（psoriasis area and severity index,PASI）相关性。结果治疗组治疗前后血清IL-17、IL-22、IL-23水平较对照组高,差异有统计学意义（P＜0．01）,治疗8周后IL-17、IL-22、IL-23水平较治疗前明显下降（ P＜0.01）。治疗组治疗前IL-17、IL-22与IL-23表达水平与PASI评分之间均呈正相关（ r分别为0.77、0．76、0．60,P均＜0．05）。结论 IL-23／IL-17轴可能在寻常型银屑病的发病机制中起重要作用,IL-17、IL-22、IL-23可以作为判断寻常型银屑病严重程度的重要指标,降低IL-17、IL-22、IL-23表达可能成为治疗寻常型银屑病的新的方向。     

Pharmacological management of SAPHO syndrome

The SAPHO (synovitis, acne, pustulosis, hyperostosis and osteitis) syndrome (SaS) includes different skeletal manifestations such as recurrent multifocal osteomyelitis, osteitis and arthritis, which are frequently associated with different forms of skin pustulosis (palmoplantar pustulosis, pustular psoriasis and severe acne). This syndrome is strictly related to the spondyloarthopathies (particularly to psoriatic arthritis) and many SaS cases fulfil the classification criteria for the spondyloarthopathies. Because SaS is an uncommon disease, current knowledge regarding its therapy is based on limited experiences gained by treating mainly small groups of patients. As a consequence, its treatment is still empiric. Several drugs (including NSAIDs, corticosteroids, sulfasalazine, methotrexate, ciclosporin, leflunomide, calcitonin and so on) have been administered and obtained conflicting results. The use of antibiotics, due to the isolation of Propionibacterium acnes from the bone biopsies of several subjects with SaS, has not represented a turning point in therapy, although some patients are responsive to this treatment. Initial reports concerning the administration of bisphosphonates (pamidronate and zoledronic acid) and of an anti-TNF-α agent (infliximab) are very promising for the future. In any case, larger, multi-centre, controlled, double-blind studies are required to emerge from the present pioneering phase.     

Pharmacological therapy of spondyloarthritis

Introduction: The current pharmacological therapy of spondyloarthritis (SpA) includes several drugs: Non-steroidal anti-inflammatory drugs, corticosteroids, traditional disease-modifying antirheumatic drugs and biologic drugs.

Areas covered: A systematic literature search was completed using the largest electronic databases (Medline, Embase and Cochrane), starting from 1995, with the aim to review data on traditional and biologic agents commercialised for SpA treatment. Randomised controlled trials and large observational studies were considered. In addition, studies performed in SpA patients treated with other, still unapproved, drugs (rituximab, anti-IL6 agents, apremilast, IL17 inhibitors and anakinra) were also taken into account.

Expert opinion: Biologic agents, especially anti-TNF drugs, have resulted in significant progress in improving clinical symptoms and signs, reducing inflammatory features in laboratory tests and imaging findings, and recovering all functional indexes. Anti-TNF drugs have radically changed the evolution of radiographic progression in peripheral joints; the first disappointing data concerning their efficacy on new bone formation of axial SpA has been recently challenged by studies enrolling patients who have been earlier diagnosed and treated. The opportunity to extend the interval of administration or to reduce the doses of anti-TNF agents can favourably influence the costs. Ustekinumab, the first non-anti-TNF biologic drug commercialised for psoriatic arthritis, offers new chances to patients that are unresponsive to anti-TNF.     

Novel therapies in the treatment of spondyloarthritis

Spondyloarthritis represents one of the commonest groups of inflammatory arthritides with onset in the third and fourth decades and primarily affecting the axial skeleton. Current treatment is primarily symptomatic, non-steroidal anti-inflammatory drugs being used most commonly. No therapeutics have been shown to prevent structural damage. The development of validated and standardised outcome instruments and a composite criterion of response should encourage evaluation of new therapeutics. Anti-TNF-α-directed therapeutics have been shown to be dramatically effective in short-term (12 week) placebo-controlled trials in both ankylosing spondylitis and psoriatic arthritis whilst observational cohorts describe efficacy that is maintained for over one year. Treatment has been well-tolerated, with mycobacterial infections being the primary concern. Significant costs and the requirement for continuous therapy are likely to spur the development of orally bioavailable agents targeting TNF-α expression.     

5th annual conference on Cytokines and Inflammation

The concept of anticytokine therapies for the treatment of inflammatory diseases has been proven with the successful launch of therapeutics targeting TNF and IL-1, and with numerous additional anticytokine strategies in development. The 5th annual conference on Cytokines and Inflammation provided a timely update on this topic with sections devoted to cytokine biology, chemokines, new technologies for cytokine-based therapy and small-molecule agonists and antagonists. This brief review summarizes key findings from the conference.     

An overview of investigational new drugs for treating ankylosing spondylitis

Introduction: Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic condition. Pharmacological treatment relies on nonsteroidal anti-inflammatory drugs, disease-modifying anti-rheumatic drugs (in case of peripheral involvement) and anti-TNF agents in case of inadequate response. To date, there are no alternate options, and about 30% of the patients do not adequately respond to anti-TNF therapy.

Areas covered: This overview is based on recent publications and programmed studies. The author provides the reader with an overview of AS, its current management and provide details of novel insights into the disorder. From there, the authors highlight novel treatments under investigation before providing their expert opinion on the field.

Expert opinion: The first results with biodrugs targeting the IL-23/Th17 pathway are encouraging, and secukinumab will likely be available in the forthcoming years to treat AS. Other targets may be evaluated in this axis. The author believes that additional head-to-head studies are needed find the place of these new drugs in AS treatment strategies. Further studies are also needed to better evaluate their long-term outcome and safety.     

Pharmacological treatment for generalized anxiety disorder in adults: an update

Introduction: Modest response and remission rates for the selective serotonin reuptake inhibitors and the serotonin-norepinephrine reuptake inhibitors, coupled with mounting evidence that the tolerability of the antidepressants (ADs) may have been overstated in the literature, has contributed to changes in prescribing patterns for generalized anxiety disorder (GAD). New interest in the absence of evidence that supports these standard therapies as superior to benzodiazepines stimulated a review of the literature.

Areas covered: A literature search was conducted in the MedLine database with search terms ‘generalized anxiety disorder’ and ‘treatment’ for purposes of including relevant literature related to pharmacologic treatment of GAD. Aside from a review of pivotal literature, the authors also included newer studies that evaluated novel drug treatments. Last, the database was searched for benzodiazepine comparisons to standard therapy secondary to concerns that such literature is sparse. The review of newer modalities and the decision to include related literature was also based on the strength of the evidence and the status of their approval for the treatment of GAD.

Expert opinion: Although ADs remain the most frequently prescribed medications for GAD, alternative and off-label therapies such as pregabalin, the atypical antipsychotics and vortioxetine are garnering interest. Based on the evidence available to us, it is our recommendation that along with the ADs, benzodiazepines be considered a possible first-line therapy in eligible patients based on the discretion and clinical judgment of the treating physician.     

Management of patients with inflammatory bowel disease and spondyloarthritis

Introduction: More than half of the patients with inflammatory bowel disease (IBD) experience at least one extra-intestinal manifestation (EIM). The most common EIM in patients with IBD is spondyloarthritis (SpA). Microscopic intestinal inflammation is documented in almost 50% of the patients with SpA.

Areas covered: We give an overview of the classification, the epidemiology and the diagnosis of IBD and SpA. The treatment goals, the pharmacologic management options and the available treatment guidelines in IBD patients with SpA are discussed.

Expert commentary: The coexistence of IBD and SpA generates challenges and opportunities for both the gastroenterologist and the rheumatologist. The potential of drugs with a gut-specific mode of action in the treatment of IBD-related arthritis warrants further exploration.     

Pharmacological management of late-onset hypogonadism

Introduction: The frequency of late-onset hypogonadism (LOH) ranges between 2 and 15%. Up to 85% of LOH is due to a functional impairment of the hypothalamus–pituitary–testicular axis, mostly secondary to metabolic conditions.

Areas covered: This paper provides a comprehensive review of all the available medications for treating LOH, including antiestrogens, gonadotropins and testosterone therapy (TTh). In addition, the evidence on clinical outcomes of these treatments is provided by meta-analyzing the results from the available randomized clinical trials.

Expert commentary: The present data indicate that antiestrogens are able to increase testosterone levels without changing gonadotropins or even increasing them. Therefore, they may maintain, and even to stimulate spermatogenesis. However, their efficacy in treating LOH-associated symptoms has been scarcely tested and their use in LOH is off-label. In contrast, gonadotropins are indicated for hypogonadism, in particular when fertility is required. Information on the effects of gonadotropins on LOH is scanty and the impractical administration limits their use. TTh can be administered with different modalities, making it a suitable option for LOH, when fertility is not desired. The available meta-analyses show that TTh is able to improve sexual function and body composition, with more evident results obtained with transdermal and injectable preparations.     

Retinoic acid receptor-related orphan receptor gamma-t (RORγt) inhibitors in clinical development for the treatment of autoimmune diseases: a patent review (2016-present)

ABSTRACT

Introduction: RORγt is critical for the differentiation of Th17 cells and the production of IL-17. Inhibition of RORγt is considered as a promising strategy to treat Th17-mediated autoimmune diseases. Quite a number of RORγt inhibitors have been progressed into clinical trials, besides much biological interests in this attractive target.

Areas covered: This article reviews the progress of RORγt inhibitors (antagonists and inverse agonists) that are active in clinical development based on an analysis of the related patents published by the corresponding companies in the period of January 2016 through May 2019.

Expert opinion: The development of RORγt inhibitors has gone through a boom period in the past three years. However, with a little bit frustration, some of the frontrunner clinical compounds were either discontinued or suspended for further development possibly due to some safety concerns or lack of efficacy in humans. There is a need to probe deeply into these concerns in the on-going pre-clinical and clinical studies. Given the effectiveness of a few recently FDA-approved anti-IL-17(R) antibodies on psoriasis, the discovery of RORγt inhibitors continues to be an exciting field for the development of novel treatment approaches.     

The safety of brodalumab for the treatment of psoriasis

ABSTRACT

Introduction: Brodalumab is a newly developed targeted biologic agent for the treatment of psoriasis that blocks IL-17 receptor A.

Areas covered: This review sought to provide a detailed overview on safety of brodalumab for the treatment of psoriasis. A PubMed search was conducted for relevant literature. Here we review the efficacy and safety data from key phase II, phase III and open-label extension clinical trials, as well as systematic reviews and meta-analyses.

Expert opinion: The unique mechanism of action of brodalumab offers advantages on efficacy over other targeted treatments, with a quick onset of action and long-term maintenance of treatment response. Brodalumab has a favorable safety profile, similar to other IL-17 inhibitors. Infections, especially mucocutaneous candidiasis, must be monitored. Suicidal ideation was detected in brodalumab trials, although a causal relationship has not been revealed. Brodalumab is a highly efficacious and comparably safe therapeutic choice in patients with moderate to severe psoriasis, especially when rapid control of the disease is desired.     

Pharmacotherapeutic management of psoriasis in adolescents and children

ABSTRACT

Introduction: Psoriasis is a relatively common condition, with a lot of discordance in studies about the peak of onset. In a large German study, an almost linear prevalence increase was reported during childhood, ranging from 0.12% at 1 year to 1–2% at 18 years. According to recent studies, plaque psoriasis is the most common variant in childhood disease.

Areas covered: This article focuses on topical, systemic and biologic therapies used in childhood psoriasis. The authors performed a full literature PubMed research, while incorporating case reports and experience. Topical agents are considered the first step, but they always have little efficacy in the extensive form of the disease. In this case, systemic and particularly biological therapy must be evaluated. The most studied treatment in the pediatric population is etanercept, but adalimumab and ustekinumab are also approved in pediatric and adolescent populations.

Expert opinion: Larger studies are needed to further investigate the use of new compounds in childhood psoriasis. Recent evidence suggests that practitioners should consider interceding in the early immunologic psoriatic process to halt this march and stunt immunological scar development. An early investment would provide lasting effects and serious impact in long-term disease modification.     

Pharmacological management of atopic dermatitis in the elderly

ABSTRACT

Introduction

The prevalence of atopic dermatitis (AD) in geriatric populations of industrialized countries is currently estimated at 3-4% and continues to increase. AD is associated with significant morbidity, increased susceptibility to infection, and symptoms of pruritus and pain. Treatments may negatively affect elderly patients; thus, plans should be optimized for this population.     

单子叶植物内生菌多糖抗肿瘤免疫机制的研究

目的:研究单子叶植物内生菌多糖抗肿瘤活性免疫机制。方法:用MTT法检测单子叶内生菌多糖对荷瘤小鼠淋巴细胞上清中TNF-α、IL-2、IL-3活性的影响;用RT-PCR和凝胶图像吸收度分析系统检测IL-2mRNA、IL-3mRNA、TNFmRNA表达的影响。结果:单子叶植物内生菌多糖可提高荷瘤小鼠体内中的TNF、IL-2、IL-3含量显著明显增高(P<0.01或P<0.05)并使荷瘤小鼠巨噬细胞TNFmRNA和淋巴细胞IL-2、IL-3mRNA表达水平明显增强(P<0.05)。结论:单子叶植物内生菌多糖抗肿瘤活性机制可能与增强机体抗肿瘤免疫功能密切相关。     

Th17细胞相关细胞因子在结直肠癌患者体内的分布及临床意义

目的 探讨结直肠癌(CRC)患者体内Th17细胞相关细胞因子IL-17A、IL-17F、IL-23的表达情况及其临床意义.方法 选择30例CRC患者和15名健康者为对照,采用实时荧光定量PCR法检测肿瘤组织和正常瘤旁组织中细胞因子IL-17A、IL-17F、IL-23 mRNA表达水平,ELISA法检测外周血IL-17A、IL-23的水平;并作临床相关性分析.结果 肿瘤组织标本中IL-17A的mRNA、IL-23的mRNA相对表达量高于对照组瘤旁组织中的mRNA相对表达量,差异皆有统计学意义(P＜0.05);IL-17F的mRNA相对表达量低于对照组中的mRNA相对表达量,但两者差异无统计学意义(P＞0.05);外周血IL-17、IL-23水平均高于健康对照组,差异有统计学意义(P＜0.05).它们与患者的性别、年龄、肿瘤大小及肿瘤发生部位均无关(P＞0.05),而与有无淋巴结转移及临床分期有关(P＜0.05).结论 CRC患者体内存在着细胞因子IL-17A、IL-23的高表达,提示Th17细胞可能参与了结直肠癌的发生发展.