Psoriatic disease treatment nowadays: unmet needs among the “jungle of biologic drugs and small molecules”
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Rheumatology is the branch of medicine dealing with the diagnosis and treatment of articular and connective tissue diseases. Outstanding progresses have been done in the last few decades regarding diseases pathogenesis and new diagnostic processes as well as innovative therapies . Indubitably, the evolution in psoriatic arthritis (PsA) knowledge represents an emblematic example . Indeed, fundamental advances in understanding PsA pathogenesis and natural history have deeply changed its perception by both patients and physicians . In the past, psoriasis was considered just a mere esthetic concern due to a primary defect in keratinocytes, leading to their hyper-proliferation. Nowadays, it is well known that psoriasis and PsA have to be considered a systemic disease, not limited to the skin and joints, but linked to increased cardiovascular risk, obesity, and metabolic syndrome through a shared chronic pro-inflammatory background, establishing the concept of psoriatic disease (PsD) . PsD often requires a multidisciplinary approach through the collaboration of dermatologist, rheumatologist, immunologist, etc. . In addition, being a chronic inflammatory multifactorial disease and dysregulation of immune cells (Th1 and Th17 above all) have been reported as key features of PsD pathogenesis . In this context, a major role is played by inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-17, IL-22, and IL-23 [6, 7]. Advances in PsD pathogenesis have put the basis for the development of new effective drugs for its treatment. Particularly, monoclonal antibody and fusion protein able to inhibit the effects of pro-inflammatory cytokines involved in PsD development, the so-called biologic drugs, have completely revolutionized disease management . It is relevant, for example, that 40 years ago topical treatments such as corticosteroid, salicylic acid, and coal tar represented the main stay of psoriasis therapies, whereas nowadays different new systemic drugs are available such as biologics like anti-TNF-α (adalimumab, etanercept, golimumab, certolizumab, infliximab), anti-IL-12–23 (ustekinumab), and anti-IL-17 (ixekizumab, secukinumab) [8, 9, 10]. Moreover, literature is constantly enriching of clinical trials and surveys regarding newer biologic drugs which will be soon available for psoriasis and PsA treatment such as anti-IL-17 receptor (brodalumab) , anti-IL-23 (guselkumab, tildrakizumab) [12, 13], and anti-CD6 (itolizumab) . However, PsD treatment scenario is going to become more and more complex and wide apart from the development of biologic drugs. A new era will be introduced by the so-called small molecules which are able to act at the basis of the pro-inflammatory cascade which dominates PsD pathogenesis, preventing the production of inflammatory cytokines. This is the case of molecules such as phosphodiesterase 4 (PDE4) inhibitor (apremilast) and Janus kinase (JAK) inhibitor (tofacitinib) .
The intracellular enzyme, PDE4, hydrolyzes cyclic adenosine monophosphate (cAMP) into the intracellular second messenger AMP and activates protein kinase A, leading to regulation of anti-inflammatory and pro-inflammatory cytokines, chemokines, and leukotriene B4 .
Further, in PsD, a coordinate involvement of the JAK-STAT phosphoproteins pathway has been found . Apremilast and tofacitinib, targeting respectively PDE4 and JAK molecules, have been showed efficacious on psoriasis and PsA [18, 19, 20, 21].
Therefore, insights into the pathogenesis of PsD increasing the understanding of the action of cytokines and their associated transduction pathways have indubitably yielded a number of new therapeutic targets [22, 23].
The introduction of biological agents has changed the way we treat PsD, providing more efficacious and directed therapy for this complex disease. However, PsD is a chronic condition and, therefore, requires long-term management with safe and effective therapy. Although the number of available drugs is continuously growing, there still exist some limitations such as predicting side-effect profile, immunogenicity, and primary lack or secondary loss of efficacy . Indeed, there is a great interest in concepts such as precision medicine  and pharmacogenomics  in order to find biomarkers which can help and guide the clinician in the treatment choice, predicting higher or lower percentage of efficacy and side effects, also to put the basis for a real tailored and patient-centered therapy. Indeed, head to head studies between different biologic drugs are limited as well as data on how long any treatment should be given and when and how to terminate . These drugs, which present different targets, dosage, and treatment schedules, are used following clinical experience and trials data. However, real-life patients are very different from those enrolled in clinical trials, often presenting comorbidities and/or polypharmacotherapy which can strongly influence biologic treatment outcomes [28, 29]. Moreover, PsD may present different phenotypes apart from the most common form of skin manifestations and articular subsets  for which the majority of clinical trials is conducted for. As a result, there is a strict need of fixed rules or shared guidelines which regulate therapy choice between biologics for PsD, highlighting first-line treatments for different patients and their peculiarities (e.g., following different body area involved, being a naïve patient or not, subjects with previous biologic drug failure, comorbidities, articular phenotype, psoriasis subtype, etc.), supporting an algorithm which suggests which drug to choose when a patient with PsD qualifies for systemic therapy. In addition, with a particular regard on cutaneous involvement, many other aspects still remain to be addressed such as treatment goals, adjusting biologics dose and intervals, and the issue of anti-drug antibody.
For all these reasons, the development of new biologic drugs and small molecules for PsD has not only increased the power and the effectiveness of treatment weapons against it but also enhanced the complexity of management strategies creating a “biologic and small molecules jungle” where the clinician can move only following limited evidences and clinical experiences. Hence, a continuous collaborative effort of investigation in order to clarify the complexity of the pathogenetic mechanisms and clinical aspects should be encouraged. This is indubitably the time to develop new surveys, empowering precision medicine and pharmacogenomics strategies, to highlight markers which can guide and help clinician in PsD treatment choice in order to personalize therapy for the right patient in the right time.
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