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Pathophysiology, Clinical Presentation, and Treatment of Psoriasis : A Review

  • 1 Keck School of Medicine, Department of Dermatology, University of Southern California Los Angeles
  • 2 Department of Medicine, Imperial College London, London, United Kingdom

Importance   Approximately 125 million people worldwide have psoriasis. Patients with psoriasis experience substantial morbidity and increased rates of inflammatory arthritis, cardiometabolic diseases, and mental health disorders.

Observations   Plaque psoriasis is the most common variant of psoriasis. The most rapid advancements addressing plaque psoriasis have been in its pathogenesis, genetics, comorbidities, and biologic treatments. Plaque psoriasis is associated with a number of comorbidities including psoriatic arthritis, cardiometabolic diseases, and depression. For patients with mild psoriasis, topical agents remain the mainstay of treatment, and they include topical corticosteroids, vitamin D analogues, calcineurin inhibitors, and keratolytics. The American Academy of Dermatology-National Psoriasis Foundation guidelines recommend biologics as an option for first-line treatment of moderate to severe plaque psoriasis because of their efficacy in treating it and acceptable safety profiles. Specifically, inhibitors to tumor necrosis factor α (TNF-α) include etanercept, adalimumab, certolizumab, and infliximab. Other biologics inhibit cytokines such as the p40 subunit of the cytokines IL-12 and IL-23 (ustekinumab), IL-17 (secukinumab, ixekizumab, bimekizumab, and brodalumab), and the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab, and mirikizumab). Biologics that inhibit TNF-α, p40IL-12/23, and IL-17 are also approved for the treatment of psoriatic arthritis. Oral treatments include traditional agents such as methotrexate, acitretin, cyclosporine, and the advanced small molecule apremilast, which is a phosphodiesterase 4 inhibitor. The most commonly prescribed light therapy used to treat plaque psoriasis is narrowband UV-B phototherapy.

Conclusions and Relevance   Psoriasis is an inflammatory skin disease that is associated with multiple comorbidities and substantially diminishes patients’ quality of life. Topical therapies remain the cornerstone for treating mild psoriasis. Therapeutic advancements for moderate to severe plaque psoriasis include biologics that inhibit TNF-α, p40IL-12/23, IL-17, and p19IL-23, as well as an oral phosphodiesterase 4 inhibitor.

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Armstrong AW , Read C. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis : A Review . JAMA. 2020;323(19):1945–1960. doi:10.1001/jama.2020.4006

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Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review


  • 1 Keck School of Medicine, Department of Dermatology, University of Southern California Los Angeles.
  • 2 Department of Medicine, Imperial College London, London, United Kingdom.
  • PMID: 32427307
  • DOI: 10.1001/jama.2020.4006

Importance: Approximately 125 million people worldwide have psoriasis. Patients with psoriasis experience substantial morbidity and increased rates of inflammatory arthritis, cardiometabolic diseases, and mental health disorders.

Observations: Plaque psoriasis is the most common variant of psoriasis. The most rapid advancements addressing plaque psoriasis have been in its pathogenesis, genetics, comorbidities, and biologic treatments. Plaque psoriasis is associated with a number of comorbidities including psoriatic arthritis, cardiometabolic diseases, and depression. For patients with mild psoriasis, topical agents remain the mainstay of treatment, and they include topical corticosteroids, vitamin D analogues, calcineurin inhibitors, and keratolytics. The American Academy of Dermatology-National Psoriasis Foundation guidelines recommend biologics as an option for first-line treatment of moderate to severe plaque psoriasis because of their efficacy in treating it and acceptable safety profiles. Specifically, inhibitors to tumor necrosis factor α (TNF-α) include etanercept, adalimumab, certolizumab, and infliximab. Other biologics inhibit cytokines such as the p40 subunit of the cytokines IL-12 and IL-13 (ustekinumab), IL-17 (secukinumab, ixekizumab, bimekizumab, and brodalumab), and the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab, and mirikizumab). Biologics that inhibit TNF-α, p40IL-12/23, and IL-17 are also approved for the treatment of psoriatic arthritis. Oral treatments include traditional agents such as methotrexate, acitretin, cyclosporine, and the advanced small molecule apremilast, which is a phosphodiesterase 4 inhibitor. The most commonly prescribed light therapy used to treat plaque psoriasis is narrowband UV-B phototherapy.

Conclusions and relevance: Psoriasis is an inflammatory skin disease that is associated with multiple comorbidities and substantially diminishes patients' quality of life. Topical therapies remain the cornerstone for treating mild psoriasis. Therapeutic advancements for moderate to severe plaque psoriasis include biologics that inhibit TNF-α, p40IL-12/23, IL-17, and p19IL-23, as well as an oral phosphodiesterase 4 inhibitor.

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  • Published: 23 May 2023

A detailed review of pathophysiology, epidemiology, cellular and molecular pathways involved in the development and prognosis of Parkinson's disease with insights into screening models

  • Ayesha Sayyaed 1 ,
  • Nikita Saraswat   ORCID: orcid.org/0000-0001-6009-6700 1 ,
  • Neeraj Vyawahare 1 &
  • Ashish Kulkarni 1  

Bulletin of the National Research Centre volume  47 , Article number:  70 ( 2023 ) Cite this article

5704 Accesses

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Parkinson's disease is a neurodegenerative disorder of the central nervous system that is one of the mental disorders that cause tremors, rigidity, and bradykinesia. Many factors determine the development of disease. A comprehensive physical examination and medical history of the patient should be part of the differential diagnosis for Parkinson’s disease (PD). According to epidemiology, Parkinson’s disease majorly affects elderly persons and frequency of affecting men is more as compared to women where the worldwide burden of Parkinson’s disease (PD) increased more than twice in the past 20 years.

Main body of the abstract

In this review paper, we discussed screening models, recent clinical trials, cellular and molecular pathways, and genetic variants (mutations) responsible for induction of Parkinson’s disease. The paper also aims to study the pathophysiology, epidemiology, general mechanism of action, risk factors, neurotoxin models, cellular and molecular pathway, clinical trials genetic variants of Parkinson’s disease. These models correspond to our research into the pathogenesis of Parkinson’s disease. The collected data for the review have been obtained by studying the combination of research and review papers from different databases such as PubMed, Elsevier, Web of Science, Medline, Science Direct, Medica Database, Elton B. Stephens Company (EBSCO), and Google open-access publications from the years 2017–2023, using search keywords such as “Cellular and molecular pathways, Clinical trials, Genetic mutation, Genetic models, Neurotoxin, Parkinson’s disease, Pathophysiology.”

Short Conclusion

Microglia and astrocytes can cause neuroinflammation, which can speed the course of pathogenic damage to substantia nigra (SN). The mechanism of Parkinson’s disease (PD) that causes tremors, rigidity, and bradykinesia is a decrease in striatal dopamine. Genes prominently CYP1A2 (Cytochrome P450 A2), GRIN2A , and SNCA are Parkinson’s disease (PD) hazard factor modifiers. The most well-known neurotoxin is 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which destroys dopaminergic neurons, resulting in the development of Parkinson’s disease (PD). Dopamine auto-oxidation in dopaminergic (DA) neurons is a significant source of reactive oxygen species (ROS) that causes neuronal oxidative stress. Most common genes which when affected by mutation lead to development and progression of Parkinson’s disease (PD) are LRRK2 , SNCA (alpha-synuclein protein) , DJ-1, PRKN (Parkin protein), PINK1 , GBA1 , and VPS35 . The commonly used neurotoxin models for inducing Parkinson's disease are 6-hydroxydopamine (6-OHDA), rotenone, paraquat, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and genetic models. Anti-apoptic drugs, gene mutation therapy, cell-based therapy, and plasma therapy were all discontinued due to insufficient efficacy. Because it is unclear how aging affects these molecular pathways and cellular functions, future research into these pathways and their interactions with one another in healthy and diseased states is essential to creating disease-specific therapeutics.

A neurodegenerative condition known as Parkinson’s disease (PD) causes tremors, stiffness, and lack of motion. As the patient becomes older, molecular changes in the substantia nigra (SN) exhibit signs of increasing neuronal loss. Particularly in the late stage of PD, non-motor symptoms are very rare, such as confusion and dysautonomia. Some individuals utilize time as a precise scientific diagnostic and can get distinctive pathologic substrates underlying the condition. Some people will reserve the word for people who suffer from idiopathic Parkinsonism brought on by Lewy body (LB) framework inclusion in SN and cells from other parts of the brain. The diagnosis of PD responds to dopaminergic medication because decreases in dopamine levels and LB are present within the remaining neurons. Those suffering with the typical fundamental signs have an incredible response to levodopa for the clinical diagnosis of PD. However, there are different types of PD in the early stage of the disease. Motor signs are challenging. There is a 24% error rate in clinical and pathological series. The difficulties in detecting this PD in its initial stages are highlighted by two studies. Researchers found that the first clinical diagnosis was appropriate in 65% of patients within 5 years of the disease's development in a prospective clinical and pathological study. Like this, 8–9% of 800 individuals with mild early-onset PD were later found to have an alternate diagnosis based on multidimensional, clinical diagnostic criteria in the tocopherol potent antioxidant treatment for PD analysis (Tolosa et al. 2021 ). The UK PD brain bank criteria are the standard clinical criteria that will increase the specificity greatly of a clinical diagnosis of the disease. However, up to 10% of people who are diagnosed with the disease during their lifetime may still require categorization at the time of death (Sonustun et al. 2022 ).

Population-dependent research has found that about 20% of PD patients who have already received treatment have not yet been diagnosed with the condition, while about 15% of patients diagnosed with PD within a community don’t know the criteria which will be strong for a diagnosis for the disease (Bai et al. 2021 May). The most frequent misdiagnosis in clinical morphological research concerns different types of degenerative Parkinsonism, such as multisystem atrophy or degeneration, degenerative supranuclear palsy. Recent studies in clinical PD have shown that extensive tremors, (visual) hallucinations, and cognitive fluctuations are among the other common features to distinguish between dementia and PD with LB (Perren et al. 2020 ).

Here, we critically evaluate the capability of further investigation for the diagnosis and therapy for patient’s with PD by reviewing published data on the clinical differential diagnosis for different types of Parkinsonism. Further, craniocerebral trauma and exposure to pesticide and fungicides, which include paraquat and rotenone, as well as imperative frightening device infection seem to be related to the pathogenic nature of PD (Senturk 2020 ).

However, we have recognized that nearly 10% of genetic cases lead to the development of PD. We have also discussed some of the more common genetic PD rodent models in this paper. Since numerous scientists thought herbicides and pesticides could increase the symptoms of PD, lots of research was conducted to evaluate several elements of paraquat and rotenone in animal models (Liu et al. 2020 ). Levodopa is the gold-standard medication for treating PD. It is a precursor for dopamine that can cross the blood–brain barrier (BBB). There are several medications that are frequently used in combination with L-dopa, and they are classified based on how they work to increase dopamine production; these medications include monoamine oxidase-B (MAO-B), catechol-O-methyl transferase (COMT) inhibitors as well as dopaminergic agonists, such as amantadine (Koga et al. 2021 ). The motor symptoms of PD can be recovered through pharmacological treatment. However, in addition to several motor control elements being resistant to pharmacological treatment, the effectiveness of dopaminergic medicines diminishes with time (Mylius et al. 2021 ). Moreover, current therapies only work to relieve symptoms and cannot prevent the further development of disease (Pereira et al. 2019 ).

In recent years, neurotrophic element therapy and cellular transplantation have become innovative therapies for those suffering from PD. However, the common of these methods involves extremely invasive localization surgery, which has risks. Neuropharmacological remedies and workout are complementary, and it generates more interest as a PD method of treatment. Ultimately, a slew of large-scale epidemiological research indicated that exercise is good for PD. Lau et al. revealed that workout might reduce chances of developing neurological impairments in PD (Feng et al. 2020 ). Exercise can improve motor and nonmotor signs of individuals with PD as a supplementary and alternative therapy. Different types of workout training have been included in scientific research, including gait training, cardio exercise, complementary exercise, innovative resistance training, and balance training. This might slow the disease's course and enhance its quality of life, helping a growing number of PD patients (Silva et al. 2021 ).

Materials and methods

In this paper, we have studied recent research on PD, neurotoxicity-induced models, techniques for the induction of disease, molecular pathways, therapeutic clinical trials, genetic mutation for PD. We thoroughly used search engines like PubMed, Elsevier, Web Science, Google Scholar, Science Direct, Medline Plus, Google Open Access, Europe PMC, Hub Med, Scopus, Semantic Scholar, Shodhaganga, Science Open, and ScienceDirect. Keywords search during the review were "Parkinson's disease, Neurotoxicity models, Pathophysiology in PD, Clinical trials in PD, Genetic mutation in PD, Cellular and molecular pathways in PD, Neurodegenerative disease, Epidemiology of PD, Central nervous system, Oxidative stress in PD, Diagnosis of PD." In addition, articles were also obtained from authentic online websites and official magazines. The review contained information from published sources on PD and its models.

Data abstraction and analysis

Literature research was made on database abstractions like PubMed and Medline Plus by using keywords like "Cellular and molecular pathways, Clinical trials, Neurotoxin and genetic models, PD, Pathophysiology." We have attempted to review the published research and reviews on PD, including its pathophysiology, epidemiology, risk factors, mechanism of action, models observed, and cellular and molecular pathways, genetic mutation. This paper also focuses on the research conducted from 2017 to 2023 on patients suffering from PD.


Since the early 1800s, PD has become widely recognized and, when the disease is reported, physicians gave PD its name (Skidmore et al. 2022 ). Sometimes PD, known as "paralysis agitans," is rare in young adults, particularly individuals under 40 (Xu et al. 2020 Feb). Around 60,000 new instances of PD are reported each year, with an estimated one million Americans suffering from the condition. According to estimates, 7–10 million people worldwide have PD, which affects men 1.5 times more frequently than women. In accordance with a population-based analysis of Medicare users, those 65 and older had an average frequency of PD of 1.6% (Draoui et al. 2020 ).

Pathophysiology of Parkinson’s disease and role of Lewy bodies in dopaminergic neurons

  • Pathophysiology

Lewy body (LB), a pathologic characteristic of dopaminergic neurons, is improved in PD, which is described as pathophysiological as degradation or dopaminergic neuronal loss located in the SN. Several years may pass before there is any sign of a pathologic change. This lack of dopamine-producing neurons impairs motor function significantly. Aggregation of LB contains a wide range of proteins including ubiquitin alpha-synuclein and ubiquitin, which impair optimal neuron function. Aging and environmental stress, according to new guidelines, both contribute to neuropathology. Environmental contamination (e.g., pesticides), the strain of the growing-old process, or misuse of pills causes a low-stage illness inside the mind ("inflammation"), persistent. Cellular aging in neurons in the brain over time is caused by this inflammatory process (Crowley et al. 2019 ). Details about the pathophysiology of PD are shown in Fig.  1 .

figure 1

Pathophysiology PD. (Parkinson’s disease is mainly characterized by the neuronal loss within the SN of the brain, which causes motor and non-motor signs such as tremors, bradykinesia, and stiffness.) (Feng et al. 2020 )

Degradation of neurons is triggered by gene mutations that encode for central nervous system (CNS) proteins. In particular, SNCA (alpha-synuclein protein) turns self-aggregates and abnormal. This inflexible alpha-synuclein is a crucial element of LB, the cellular accumulation that characterizes PD (Sun and Armstrong 2021 ). Atypical protein-disrupting systems, like the ubiquitin–proteasome device, are also made more difficult. PD can result from a variety of dysfunctional processes, such as mitochondrial disease or unique oxidative stress caused by reactive oxygen species (ROS), which results in neuronal degeneration (Roeh et al. 2019 ).

Role of substantia nigra, dopaminergic transmission, and D1, D2 receptors in Parkinson’s disease

A dopaminergic imbalance causes the novel neurodegenerative disease PD to cause mobility deficits (inhibitory D2 and excitatory D1 receptors). However, K + channels enhance these. Dopamine: In PD, the substantia nigra degenerates, destroying the nigrostriatal pathway. The neurochemical basis of PD is the ensuing reduction in striatal dopamine. The impairment in striatal dopaminergic transmission seems to depend on and be sufficient for the emergence of PD motor symptoms. Dopamine is the precursor of levodopa. Individual dopamine does not cross the BBB. Levodopa is actively transported into the brain, where levodopa is converted into dopamine in the brain. In the periphery of the brain, medication decarboxylated dopamine. Because of that, it requires a large dose of levodopa (Ishiguro et al. 2021 ). In the peripheral tissues and gastrointestinal tract (GIT), the metabolism of levodopa decreases and enhances with carbidopa and increases the bioavailability of levodopa in the CNS. Because of that, levodopa administered with carbidopa should enhance the effect of levodopa on the CNS (Jaiswal et al. 2021 ).

Clinical features in the development and progression of Parkinson’s disease

Since James PD in the nineteenth century, the important component of the disease has been motor symptoms of PD, which was later improved by Jean-Martin Charcot (Flynn et al. 2023 ). These PD signs encompass molecular stress, bradykinesia, rest tremor, gait, and postural impairment. The patients are categorized as a subtype of disease which, in having patients with PD motor actions, are heterogeneous (Marchetti 2020 ). The average time between the beginning of Parkinsonian and Parkinsonian motor signs occurrence is 12–14 years. It is an example of how that premature stage can be increased (Greener 2021 ). The pathology of PD is thought to be ongoing throughout the motor period, including dopaminergic neurons as well as the CNS and peripheral system areas in the substantia nigra paras compacta (SNpc) (Wuthrich and Rapee 2019 ).

The development of PD is described by impairment of motor function, which can primarily be treated with symptomatic treatment options. However, headaches associated with prolonged durations of symptomatic therapy, like dyskinesia, fluctuations, psychosis, motor and non-motor symptoms, dyskinesia, and psychosis, may arise as the disease progresses (Islam et al. 2021 ). Treatment-resist motor and non-motor symptoms in the last stage of PD are differentiated, with axial motor signs including movement problems, falls, gait freezing, speech difficulties, and swallowing. In the last stage of PD, non-motor signs such as symptomatic postural hypotension are frequent, constipation needing regular laxatives and urine incontinence (Neag et al. 2020 ). After 20 years with the disease, 83% of PD patients have dementia. These levodopa-resistant late-stage PD signs and symptoms significantly increase impairment and are reliable indicators of death and the necessity for hospitalization (Bjørklund et al. 2019 ).

Role of environmental, genetic, and epigenetic factors in causing Parkinson’s disease

Age is the potential risk of PD. This pattern has significant implications for public health: By 2030, the number of patients of PD is predicted to rise by more than 50% because of an aging population, as well as a rise in life expectancy globally (Masato et al. 2021 ). Environmental exposures are also risk factors for PD. These factors have been demonstrated that significantly alter the risk of PD in a meta-analysis of individual capability threat elements (Borghammer et al. 2022 ). The hypothesis that smoking may provide protection against the disease has arisen because of the factors that lower the risk of PD with smoking. The results of extensive case–control research and modern research, however, indicated that PD patients can avoid smoking more rapidly and that the correlations with smoking may be brought on by a reduced reactivity to nicotine during the prodromal stage of PD. The consequences of at least five potential population-based studies showed a negative correlation between blood urate attention and PD risk, a finding that is possibly more resolute in men than in women (Gao et al. 2020 ). Heating and manganese exposures were not related to an elevated risk of PD, according to a comparable meta-analysis. Single epidemiologic results show that exposure to solvents, especially trichloroethylene, and the use of antipsychotics by elderly people, particularly benzamides, phenothiazines, risperidone, or haloperidol, would likely increase the risk of PD (Smeyne et al. 2021 ).

Although there are multiple factors that might increase the possibility of developing PD, their complex interactions are increasing to be recognized. For instance, circumstantial findings of this study showed that exposure to brain trauma and Paraquat both increased the chances of PD (Xicoy et al. 2021). Further research has found genetic factors on environmental risk factors. For example, single-nucleotide polymorphisms in CYP1A2, that encode the isoform of Cytochrome P450 that causes metabolism of GRIN2A , that codes for a component of the N-methyl-D-aspartate (NMDA) receptor, affect the threat caused by drinking coffee. Moreover, the shape of a polymorphism blended with a repeat dinucleotide within the gene promoter of SNCA  (alpha-synuclein protein) affects the risk of PD correlated with head trauma (Rocha et al. 2022 ). Environmental, genetic, epigenetic, and other risk factors for PD are shown in Fig.  2 .

figure 2

Risk factors for PD (Parkinson’s disease is a central nervous system disorder that affects the movement, often including tremors, bradykinesia, and rigidity.) (Adams et al. 2023 )

Screening rodent models for induction of Parkinson’s disease

Many neurotoxin animal models are currently used in rodents and mice, such as 6-Hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), but pesticides are primarily used. They have increased some events and symptoms that may result in PD by inducing neurotoxicity. These toxin-based PD models have some advantages and disadvantages (Tran et al. 2021 ). Table 1  shows the required dose and route of administration of neurotoxin.

Conventional 6-hydroxydopamine model in induction of Parkinson’s disease

6-Hydroxydopamine (6-OHDA) is a conventional and classical animal model for PD. Inject 6- 6-OHDA directly into the SNpc of the brain because this compound does not cross the BBB (Kayis et al. 2023 ). In the region of the mouse or rat brain, it has approximately 60% of the tyrosine hydroxylase-containing neurons present, with the lack of striatum containing the tyrosine hydroxylase-positive terminals. It is widely believed and has been tested that the tyrosine hydroxylase-advantageous terminals were dead before the tyrosine hydroxylase-advantageous neuronal cells within the SNpc, which reflect PD symptoms. Hence, most researchers have injected this 6-OHDA immediately within the SN to observe retrograde of degeneration (Belvisi et al. 2022 ). 6-OHDA enters the cytosol via the dopaminergic neuron transporter, where it may self-oxidize and induce oxidative pressure inside the cell. It has been shown the 6-OHDA and interaction, although neither leading to nor producing clumps or LB clusters like those found in PD (Fabbri et al. 2019 ). The bilateral injection of 6-OHDA into the SNpc causes not only the most severe aphasia, seizures; moreover, it is more common for people to turn to apomorphine or amphetamine after unilateral 6-OHDA can measure the severity of the precipitated striatal loss or SNpc, and this behavior to enhance the efficacy of treatments for PD (Kambey et al. 2021 ). 6-OHDA is produced in the metabolism of endogenous dopamine; hence, 6-OHDA is a neurotoxin compound; it causes lesions within the dopaminergic neurons which makes it potential for the endogenous toxin in the initiation of the PD neurodegeneration (Park et al. 2019 ). 6-OHDA induced neurotoxicity produces symptoms of PD, as shown in Fig.  3 .

figure 3

6-OHDA induced PD in a specific way. It has been suggested that oxidative stress causes neuroinflammation (Luca et al. 2020 )

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-based model for inducing oxidative stress

Originally, MPTP became an unintentional visitor in the catalytic process, and while it may cause some concern in certain areas, it turned into ROS. Oxidative pressure, energy failure, infection, and energy failure have been are shown symptoms of PD (Dumurgier and Tzourio 2020 ). MPTP is the popular animal model of PD. MPTP has induced neurotoxicity in PD and shows all of the symptoms of PD in guinea pigs, monkeys, and other animal models, as well as a specific range of signs and symptoms observed in mice models, but there is no longer in rodents because rats were resistant to the MPTP (Neshige et al. 2021 ).

Role of Rotenone in Parkinson’s disease induction by inducing the synthesis of Lewy bodies, inflammation, and alpha-synuclein aggregation

Rotenone is an insecticide as well as herbicide; as compared to paraquat it is a pure herbicide. It easily crosses BBB as well as is also highly lipophilic. Rotenone induces all the symptoms of PD, including behavioral changes, inflammation, complex-I blockage, α-synuclein aggregation, development of LB, digestive issues, and oxidative stress (Jia et al. 2020 ). This model's apparent strength is that it has been shown to produce α-synuclein aggregation and LB formation. While using rotenone as a PD model enhances dopaminergic neuron (DA) oxidation, there is little proof that it leads to degradation of the dopaminergic pathway (Yin et al. 2021 ). The mechanism of rotenone as a neurotoxicity inducer in PD is shown in Fig.  4 .

figure 4

Rotenone-induced ROS generation and cell death are depicted schematically as the causes of PD (Adamson et al. 2022 )

Methamphetamine in substantia nigra paras compacta neurodegeneration

Methamphetamine is a derivative of amphetamine; some effects such as induced neurotoxic effects on the CNS lead to some structural changes. Numerous research studies have shown that selective damage to serotonergic nerves or dopaminergic nerve endings leads to neuronal loss in rodents after hypothermia (Guo et al. 2022 ) though it was not a universally accepted hypothesis. These genes ( LRRK2 and SNCA , autosomal-dominant PD; PRKN, PINK1, DJ - 1 , and autosomal–recessive PD) are potential and prominent therapeutic targets in animal models. We first need to understand how these animal models work to that extent. For example, neither of the above mutations are knocked out or overexpressed in humans (Hamed et al. 2019 ). In accordance with this approach, a protein's degree of expression might contain the key to understanding the nature of that protein. Research has demonstrated that wiping out alpha-synuclein has no effect on DA retention or development (Sitzia 202 2).

Autosomal–recessive PD is caused by several mutations. These are PINK1 (mitochondrial-localized enzyme and new kinase 1 that are stimulated by tensin isoforms), Parkin (20% of individuals with early-onset PD and about 50% of gene mutations of PD), and DJ-1 (an oxidation–reduction reaction-sensitive antioxidant regulator and molecular stress). Rodent models of these genes do not show neurodegeneration. Recent reports show that exogenous Parkin depletion within adult mice is associated with the SNpc neurodegeneration. Therefore, the lack of neurotoxicity in rodents may be because rodents may have protective mechanisms that prevent the development of PD symptoms in these models (Palasz et al. 2019 ).

Pesticide paraquat and its damage to DNA

Epidemiological studies indicate that using pesticides increases the symptoms of PD, but since only 95 cases of PD have been associated with paraquat poisoning, this association may be very hypothetical in the case of paraquat (Agnihotri and Aruoma 2020 ). In agriculture, paraquat is frequently employed. Pesticide is used as a weed killer because paraquat causes damage to deoxyribonucleic acid (DNA), proteins, ribonucleic acid (RNA), and lipids through oxidative stress caused by redox reaction. This process also produces ROS, including the superoxide radical, hydrogen peroxide, and radical. Recent research on paraquat's effects on the nigrostriatal DA system is somewhat contradictory (Martínez-Chacón et al. 2021 ). Diagrammatic illustration mechanism of induction of neurotoxicity by paraquat in PD is shown in Fig.  5 .

figure 5

Illustration of the paraquat-induced neurotoxicity, ROS production, and c-Jun N-terminal kinase (JNK) activation that led to the dopaminergic cells' neuronal loss and PD-like symptoms (Colle and Farina 2021 )

Mutation-based genetic models for inducing Parkinson’s disease

The "new kids on the block" are certainly genetic models of PD. Even though PD was once thought to be a "sporadic" non-genetic condition, genetic alterations are uncommon and only account for roughly 10% of PD patients. Furthermore, DJ-1 , alpha-synuclein, LRRK2 autosomal-dominant PD and PINK1 -recessive PD, are significant genes which undergo mutations to cause PD thus are potential targets for therapy. The complexity of this PD is becoming more apparent, so we must first comprehend how these animal models function. For example, neither of the mentioned mutations above are completely absent or overexpressed within humans. However, model of PD in animals use overexpression and knockout techniques. The idea behind this is that understanding a protein's behavior may depend on how much of it is expressed. Consider alpha-synuclein as an example. Moreover, it was demonstrated that knocking down alpha-synuclein does not have an impact on dopaminergic neuron development or maintenance (Calabresi et al. 2023 ).

This suggests that the degradation of dopaminergic neurons found in PD is not likely to be caused by the loss of alpha-synuclein. The precise role of alpha-synuclein, however, is unknown; it is difficult to determine its relationship to PD. LRRK2 is restricted to mucosal tissue, in contrast with the ubiquitous alpha-synuclein. Moreover, although LRRK2 knockout mice have been shown to not affect the LRRK2 animal model, it is not particularly useful in investigating DA nerve cell development and preservation. Melanogaster models have limited generalizability for the human state. Autosomal–recessive PD is caused by several mutations. These include PRKN (20% of instances of onset of PD and 50% cases of familial), DJ-1 (a redox-sensitive regulator of antioxidants and molecular chaperone) and PINK1 (phosphatase and tensin homolog-induced kinase 1; confined to the mitochondria). Animal models of these genes that are constitutively knocked out do not exhibit neurodegeneration. Meanwhile, a scientific study demonstrates that SNpc neurodegeneration is correlated with Parkin conditional deletion in adult mice (Aryal and Lee 2019 ).

Genetic studies on PD have shown a variety of monogenic variants of the disease and several genetic risk factors that raise the possibility of developing neuron degeneration (Tran et al. 2020 ). The most often advised method for people to diagnose the disease is molecular testing. Few genes that are significant in both the autosomal–recessive forms and autosomal dominant of PD have been reported in the last ten years (Jia et al. 2022 ). It has determined that mutations in the loci PARK1 to PARK13 (loci on 13 chromosomes) indicate linkage to PD by whole genome linkage screening to differentiate between chromosomal areas linked to the risk of PD or the period of PD onset (Selvaraj and Piramanayagam 2019 ).

Monogenic forms, which are pervasive but only make up around 30% of related cases, were brought on by a single mutation in a gene that was passed down either recessively or dominantly. Most of the gene mutations leading to increased ROS production, mitochondrial DNA damage (mtDNA damage), reduced mitochondrial membrane potential (MMP), decreased ATP levels, structural defects in the organelle, and mitochondrial network are related to mitochondrial dysfunction; these various phases of mitochondrial dysfunction have been responsible for of the development of PD (Liu et al. 2017 ). Parkinsonism is caused by the autosomal-dominant gene transformation of the UCHL1 , SNCA , LRRK2 , and GIGYF2 , and mutations in the, DJ-1 , PRKN , PINK1 , FBXO7 , PLA2G6 , and ATP13A2 , genes. ( Table 2 ) About 27% of those with early-onset PD (EOPD) have a mutation in one of the three genes ( LRRK2 , glucocerebrosidase or Parkin )(Papagiannakis et al. 2018 ).

Cellular and molecular pathways involved in the initiation and progression of Parkinson’s disease

Different genetic, epigenetic, environmental, molecular, cellular, and intracellular dysfunctional symptoms can be seen in this condition. The main molecule that makes up the LB at the molecular level is alpha-synuclein. Significant pathogenic correlation, pathogenesis of Ca 2+ , is linked to an oxidation–reduction imbalance in cells and an increment in reactive oxygen species (ROS) generation. There are seven most common PD-related genes ( VPS35 , DJ-1 , GBA1 , LRRK2 , PINK1 , PRKN and SNCA ). In the cerebral cortex of PD patients, various cellular and molecular biomarkers, such as neuroinflammation, autophagy, and oxidative stress, were detected. Factors that cause oxidative stress promote alpha-synuclein aggregation. In the nigrostriatal neuronal cell, in which it initially aggregates alpha-synuclein deposited, it appears in the GIT or enteric nervous system (ENS), olfactory bulb, and the LB (Fraint et al. 2018 ).

The earliest symptoms of PD are mitochondrial dysfunction and mitophagy. Melanin-concentrating hormone is essential for ATP synthesis, but it also affects calcium storage, cellular metabolism, the generation of damage-associated molecular patterns, damaged associated molecular pathways (DAMPs), the balance of ROS, programmed cell death, inflammatory processes, and immunity to programmed cell death. The loss of dopamine pathways by i) loss of the dopaminergic neuronal cells currently available for synaptic transmission in the SNpc is neuropathological characteristics of PD. ii) Alpha-synuclein, LB, clumps containing neurofibrillary tangles that contain microfibrils are developing (Camargo et al. 2019 ). Lack of dopamine neurotransmitters in the SNpc disrupts the circuitry that controls posture and movement, resulting in symptoms consisting of relaxed shaking and sluggish movement. PD non-motor symptoms include difficulties with sleep, anxiety, memory, autonomic nervous system, and the senses (Zampese and Surmeier 2020 ).

Buildup of oxidative stress due of presence of reactive oxygen species and its effects on generation of Parkinson’s disease

Reactive oxygen species in PD such as hydroxyl radical (OH•), superoxide anion (O 2 ), and hydrogen peroxide (H 2 O 2 ) are synthesized because within the mitochondria there is physiological metabolism of molecular oxygen.  In ETS (electron transport chain) the mitochondrial complexes I and III produce Superoxide anion which are very reactive and can easily cross the mitochondrial membrane where it is reduced to H 2 O 2 . Additionally, various nitric oxide synthases (NOS) create nitric oxide (NO), a transient reactive nitrogen species (RNS), which combines with thiols and reduced glutathione (GSH) to form disulfides, sulfenic, sulfonic, and s-nitrosothiols. Additionally, peroxynitrite (ONOO) can be created when oxygen (O 2 ) and nitric oxide (NO) are combined (Hollville et al. 2020 ) shown in Fig.  6 . An increase in ROS production in PD has shown failure in mitochondrial complex I, according to studies utilizing the paraquat and MPTP-like toxins, which are known to cause PD-like symptoms including dopaminergic neuronal cells to die and protein clusters are produced. A complex I impairment can result in a decrease in energy production as well as an increase in the synthesis of free radicals (Mailloux 2020 ).

figure 6

Radical species development. ROS are produced by a variety of metabolic processes, including oxidative phosphorylation, superoxide anion (O 2 •), Singlet oxygen (O 2 ), hydrogen peroxide (H 2 O 2 ), hydroxyl radical (OH•) nitric oxide (NO•) and mitochondrial-derived reactive oxygen species (mtROS), hydroxyl ion (OH-) (Trist et al. 2019 )

Although the specific causes of mitochondrial complex-I failure in PD are not fully recognized yet, it is reported that a GSH-to-oxidized glutathione (GSSG) ratio increases the formation of RNS as well as ROS species. However, the pathway by which the highest levels of GSSG might rise RNS as well as ROS generation was not discovered; it was demonstrated that glutathione redox state is necessary for the opening of the transition pore of mitochondrial permeability. For instance, GSSG causes the MPTP to open, which then triggers a Ca 2+ basis reduction within the potential of the inner membrane of Wang and Kang ( 2020 ). The reduced glutathione/ oxidized glutathione ratio can increase the generation of ROS or RNS by preventing mitochondrial complex-I from functioning and lowering the potential of the mitochondria. The protein’s sulfhydryl portion of the enzymes having thiol oxidation, which are involved in electron transport of mitochondria, is another way that low amounts of GSH may harm mitochondrial complex-I. In addition, high quantities of these reactive species can also damage crucial complex I residues and decrease the activity of the enzyme glutathione reductase, which is responsible for decreasing GSSG (Teleanu et al. 2022 ).

Recent clinical trials involved in evaluation of possible treatments for Parkinson’s disease

Clinical studies closely monitor the evaluation of novel medications. The US Food and Drug Administration states that the objective of phase-I is dose as well as safety; about 70% of drugs and therapies advance to phase II. About 33% of medications transfer to phase III after completing phase II, which examines the efficacy as well as adverse effects. Phase III is used to monitor adverse effects and investigate their potency. The ‘United States National Library of Medicine’ established the ‘web-based’ registry "clinical trials. gov" for ease in availability of data and information related to the clinical trials, such as the methodology, study design, outcomes, anticipated finish dates, etc. Worldwide sponsors of trial update and maintain the data (Nakamura et al. 2021 ). Clinical trial endpoints are related to the subject of comparing the impact of research, and results may be obtained by a number of means, including behavioral tests, positron emission tomography, magnetic resonance imaging (MRI), biological biomarkers, or electrophysiological monitoring (Jiménez-Gómez et al. 2023 ; Choudhury et al. 2022 ). Each clinical trial is assessed and planned for the advancement to reduce the possibility of negative outcomes (Bouchez and Devin 2019 ). For comparison research in clinical trials, post-approval is necessary. This allows safety, tolerance, and better quality of life, to be taken into account when obtaining effective data from a broader patient group (Nunes and Laranjinha 2021 ). In clinical trials, primary endpoints are necessary and sufficient to determine a drug's or therapy's effectiveness. The primary endpoints serve as the foundation for secondary endpoints, which are sufficient for claiming the efficacy of clinical trial study, and the tertiary endpoints, which provide detailed information (Braidy et al. 2019 ). To investigate PD treatments, we have searched for “clinical trials.gov” clinical trial pipeline data. These clinical studies are shown below among those identified (Table 3 ).

Based on the recent study status, which indicates updated/ongoing or stopped as of 2023, we selected 10 registered intervention clinical trials in phases I, II, and III as novel PD medicines after reviewing the data gathered from “clinical trials.gov.” The phase I/II or phase II/III trials in clinical trials.gov are regarded as being in phase I and II, respectively. The 10 trials, (41%) were in phase I and in phase II (53%), (6%) were in phase III in Fig.  7 . Stem cells have shown the potential of providing a huge supply of dopaminergic neurons which could be beneficial in treatment. Stem cells have also shown differentiation into dopaminergic neurons which will benefit post their transplantation in models of PD (Asemi-Rad et al. 2022 ).

figure 7

Clinical trial phases and treatment plans for treating PD. The relative contribution of phase I, phase II, and phase III trials to the total is depicted in ( A ) using a pie chart. In Clinical trials. gov, the phase I or phase II trials, respectively, are displayed. B A pie chart showing the percentages of every therapeutic approach to all the clinical trials for PD (Masato et al. 2019 ; Millichap et al. 2021 ; Clinical Research 2021 ; Merkow et al. 2020 ; Merchant et al. 2019 ; Ivanova 2020 ; Mullin et al. 2020 ; Parker et al. 2020 ; Barker 2019 ; Ghosh et al. 2021 ; Asemi-Rad et al. 2022 ; Desai et al. 2021 ; Bryson 2020 )

Neurological disorders have been popularly being treated using herbal and ayurvedic remedies since ages. Hence, it is crucial to isolate bioactive compounds to potentially alleviate these conditions (Staff et al. 2019 ; Saraswat et al. 2020a , 2020b ). In our current research by our laboratory, we are focusing on herbal extracts and their bioactive active compounds for treating PD in animal models (Sachan et al. 2022 ).


Parkinson’s disease is a progressive neurodegenerative disease condition that develops both motor and non-motor symptoms. The motor signs like tremors, resting, bradykinesia, and stiffness which have been determined to be striatal dopamine deficiency and nonmotor symptoms include disorders of sleep, sadness, and cognitive abnormalities. Unfortunately, there are no conclusive tests to support a Parkinson’s disease diagnosis, but identifying conditions with symptoms like Parkinson’s disease is a crucial first step in the diagnostic process.

In this paper, we reviewed recent researches and came to following conclusions. Improvement in both motor and non-motor symptoms for enhancing the lifestyle of patients is the main objective of the Parkinson’s disease treatment.

In the pathophysiology, it was concluded that the slow degradation of dopaminergic neuronal cells in the brain's substantia nigra is Parkinson’s disease main pathophysiological cause. There are many other risk factors associated with Parkinson’s disease, including age-related, genetic, epigenetic, and environmental variables. Single-nucleotide polymorphism in CYP1A2 (Cytochrome P450 A2) or GRIN2A strikes the major threat for Parkinson’s disease which is associated with coffee consumption and falls into the category of genetic modifiers for the environmental risks.

Parkinson’s disease has a significant mortality rate and is the widespread neurodegenerative disease. Induction of the disease by various models has been successfully studied for understanding the genesis, propagation and treatment. Hence, substances like 6-hydroxydopamine, paraquat, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, rotenone, and methamphetamine are successfully used for inducing neurotoxicity to develop signs and symptoms like Parkinson’s disease as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine targets mitochondrial cells and serves as an excellent model for how aberrant mitochondrial function can result in symptoms like those of Parkinson’s disease. Rotenone impairs motor function, depletes catecholamines, destroys nigral dopamine, and develops Lewy bodies. Among the neurotoxin models discussed in this review paper, pesticides like parquet and rotenone are commercially available and exhibit many of the symptoms of Parkinson’s disease, including motor impairment, a reduction in Lewy bodies, and the destruction of dopaminergic neurons.

Several geographically specific cellular and molecular mechanisms are actively involved in the development of Parkinson’s disease. In comparison with previous clinical trials for the treatment of Parkinson’s disease, small molecule such as alpha-synuclein aggregation therapy, and monoclonal antibody gene therapy, may show promise in the future. Dopamine auto-oxidation in dopaminergic neurons is a significant source of reactive oxygen species that causes neuronal oxidative stress. LRRK2 , SNCA (alpha-synuclein protein), DJ-1 , PRKN (Parkin protein), PINK1 , GBA1 , and VPS35 are the seven most common Parkinson’s disease-related genes which when affected by mutations leads to development and progression of disease.

According to our opinion, the purpose of clinical studies should be to postpone motor difficulties before they manifest ever lasting effects. Finding new multitarget medications or therapies without side effects is becoming more difficult, whereas the rate of Parkinson’s disease occurrence globally is rising quickly. Future investigations of these molecular pathways will be essential for designing disease-specific therapeutics.

Availability of data and material

Web: http://pubmed.ncbi.nlm.nih.gov/ .


Blood–brain barrier

Cellular and molecular pathway

Central nervous system


Cytochrome P450A2

Damaged associated molecular pathway

Enteric nervous system

Glutamic acid decarboxylase


Glutamate ionotropic receptor NMDA type subunit 2A

Oxidized glutathione

Hydrogen peroxide

Intracerebral route

Intraperitoneal route

C-Jun N-terminal kinase

Leucine-rich repeat kinase

Monoamine oxidase-B

Mechanism of action


Nicotinamide adenine dinucleotide hydrogen

Nitric oxide

Nitric oxide synthase

Superoxide anion


Hydroxyl radical

Parkinson's disease

Reactive oxygen species

Subcutaneous route

Substantia nigra paras compacta

Tyrosine hydroxylase

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Sayyaed, A., Saraswat, N., Vyawahare, N. et al. A detailed review of pathophysiology, epidemiology, cellular and molecular pathways involved in the development and prognosis of Parkinson's disease with insights into screening models. Bull Natl Res Cent 47 , 70 (2023). https://doi.org/10.1186/s42269-023-01047-4

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Obstructive sleep apnea and acute lower respiratory tract infections: a narrative literature review.

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1. Introduction

2. literature search strategy, 3. obstructive sleep apnea and community-acquired pneumonia, 4. obstructive sleep apnea and influenza pneumonia, 5. obstructive sleep apnea and covid-19 pneumonia, 6. obstructive sleep apnea and lower respiratory tract infections: pathophysiology, 6.1. altered immunity, 6.2. risk of aspiration, 6.3. the role of obesity and other comorbidities, 7. obstructive sleep apnea and lower respiratory tract infections: treatment, 7.1. settings of care and empiric antibiotics, 7.2. specific risks guiding empiric antibiotic therapy, 7.3. antibiotic pharmacokinetics, side effects, and resistance, 8. discussion, 9. conclusions, supplementary materials, author contributions, institutional review board statement, informed consent statement, data availability statement, acknowledgments, conflicts of interest.

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(“Obstructive Sleep Apnea” OR “Sleep Apnea Syndromes” OR “Sleep-related breathing disorder” OR OSA) AND (pneumonia OR “acute pneumonia” OR “bacterial pneumonia” OR “community acquired pneumonia” OR CAP OR “lung infection” OR “respiratory infection” OR “bronchopneumonia”)
(“Obstructive Sleep Apnea” OR “Sleep Apnea Syndromes” OR “Sleep-related breathing disorder” OR OSA) AND (influenza OR “Influenza A” OR “Influenza B” OR “H1N1” OR “swine flu” OR “avian influenza” OR “H5N1” OR “seasonal influenza” OR “viral pneumonia” OR flu)
(“Obstructive Sleep Apnea” OR “Sleep Apnea Syndromes” OR “Sleep-related breathing disorder” OR OSA) AND (COVID-19 OR “SARS-CoV-2” OR “2019-nCoV” OR “coronavirus disease 2019” OR “novel coronavirus” OR “viral pneumonia”)
Author and DateDesignTotal N (OSA N)Inclusion and Exclusion CriteriaOutcomesKey FindingsLimitations
Keto et al., 2023 [ ]Case-control from Finland50,648 (25,324)I: ICD code for OSA. E: OSA in the two years preceding the index date.LRTI, recurring LRTI.↑ LRTI in the year preceding OSA RR 1.35, and during the year after OSA RR 1.39.No PSG data, no data on OSA treatment, no BMI data.
Grant et al., 2023 [ ]Retrospective cohort from healthcare plans database38.62M PY (1.29M PY)I: Minimum 1 year of enrollment in health plan. E: Death date before January 1st of the index year; Overlapping pneumonia inpatient admissions.All-cause pneumonia, invasive pneumococcal disease, pneumococcal pneumonia.OSA: ↑ pneumonia (18–49 y RR 3.6, 50–64 y RR 3.6, ≥65 y RR 3.4), ↑ invasive pneumococcal disease (18–49 y RR 5.7, 50–64 y RR 4.2, ≥65 y RR 4.2).No PSG data, no data on OSA treatment, no BMI data.
Lutsey et al., 2023 [ ]Post-hoc analysis of the multicentric prospective cohort1586 (772)I: Valid PSG data; Self-identify as White. E: CSA; Already had the outcome of interest at the time of visit.Hospitalization: with pneumonia; with respiratory infection; with any infection.OSA not linked to outcomes; T90 > 5% ↑ hospitalized pneumonia HR 1.59, ↑ hospitalized respiratory infection HR 1.53, ↑ hospitalized any infection HR 1.25.No data on OSA treatment, mostly White population.
Chiner et al., 2016 [ ]Single center case-control123
I: Cases: Hospitalized for CAP; Controls: Hospitalized for non-respiratory/non-ENT infection. E: Previous OSA diagnosis and CPAP.Pneumonia, PSI.AHI ≥ 10: ↑ pneumonia OR 2.86; AHI ≥ 30: ↑ pneumonia OR 3.184; AHI positively correlated with PSI.Small sample size, no data on OSA treatment.
Su et al., 2014 [ ]Retrospective cohort from Taiwan34,100 (6816)I: ICD codes for OSA; E: ICD codes for pneumonia, lung abscess, empyema.Pneumonia.OSA: ↑ pneumonia HR 1.19; OSA requiring CPAP: ↑ pneumonia HR 1.32.No PSG data, no BMI data.
Lindenauer et al., 2014 [ ]Multicenter, retrospective cohort 250,907 (15,569)I: ICD code for pneumonia; Chest radiography; Antibiotics within 48 h of admission. E: Transfers; Hospital LOS under 2 days; Cystic fibrosis; Pneumonia not present at admission.ICU, MV, hospital mortality, hospital LOS, costs.OSA: ↑ ICU OR 1.54, ↑ MV OR 1.68, ↑ hospital LOS RR 1.14, ↑ cost RR 1.22, ↓ mortality OR 0.90.No PSG data, no data on OSA treatment, no BMI data.
Beumer et al., 2019 [ ]Two center, retrospective cohort199 (9)I: Symptoms and positive influenza PCR; Transfers if not received antibiotics or antivirals.ICU, ICU mortality.OSA/CSA: ↑ ICU admission OR 9.73., not linked to mortality.Small sample size, no PSG data, no data on OSA treatment.
Boattini et al., 2023 [ ]Post-hoc analysis of a multicentric, retrospective cohort356 (23)I: Positive influenza or RSV PCR; Symptoms; Pulmonary infiltrate on imaging. E: Viral co-infections.NIV failure, hospital mortality.OSA/OHS: ↑ NIV failure OR 4.66, not linked to mortality.No PSG data, no data on OSA treatment, no BMI data, no adjustments for obesity.
Mok et al., 2020 [ ]Single center, retrospective cohort 53 (53)I: ICD codes for OSA, influenza. E: No PSG data; No OSA treatment data; CSA on PSG.Hospitalization, complications, hospital LOS.OSA non-CPAP vs. CPAP: ↑ hospitalization OR 4.7. Severity of OSA not linked to hospitalization in CPAP-non adherent.Small sample size, no adjustments for obesity and comorbidities.
Tsai et al., 2022 [ ]Retrospective cohort from Taiwan32,540 (6508)I: Cases: ICD codes for OSA; Controls: No OSA; Randomly selected, matched by income, gender, urbanization, and age. E: influenza pneumonia before OSA.Influenza-associated SARI.OSA: ↑ influenza-SARI HR 1.98, ↑ cumulative incidence of influenza-SARI.No PSG data, no data on OSA treatment, no BMI data.
Chen et al., 2021 [ ]Retrospective cohort from Taiwan27,501 (5483)I: Cases: ICD codes for OSA; Controls: No OSA; Randomly selected, matched by age, sex, index years, and comorbidities. E: UPPP; influenza before OSA.Influenza, composite (pneumonia, hospitalization).OSA: ↑ influenza HR 1.18, ↑ pneumonia or hospitalization 1.79.No PSG data, no data on OSA treatment, no BMI data.
Mashaqi et al., 2021 [ ]Multicentric, retrospective cohort 1738 (139)I: Hospitalized; ICD codes, PSG report, self-report, STOP-BANG for OSA; ICD codes COVID-19. E: ICD for CSA and unspecified sleep apnea.MV, ICU, hospital mortality, hospital LOS.OSA not linked to ICU admission, hospital LOS, MV, or mortality.No PSG data, no data on OSA treatment.
Maas et al., 2021 [ ]Multicentric, retrospective cohort 5544,884 (~44,877)I: All patient encounters; January to June 2020.COVID-19, hospitalization, respiratory failure.OSA: ↑ COVID-19, OR 8.6, ↑ hospitalization, OR 1.65, ↑ respiratory failure, OR 1.98.No PSG data, no data on OSA treatment.
Strausz et al., 2021 [ ]Retrospective cohort from FinnGen biobank445 (38)I: All positive COVID-19 PCR from FinnGen biobank.Hospitalization, COVID-19.OSA not linked with COVID-19, ↑ hospitalization, OR 2.93. Link attenuated after adjustment for BMI in meta-analysis.Small sample size, no PSG data, no data on OSA treatment.
Rögnvaldsson et al., 2022 [ ]Retrospective cohort from Iceland4756 (185)I: Positive COVID-19 PCR. E: Nursing home; COVID-19 during hospitalization or rehabilitation.Composite (hospitalization, mortality).OSA: ↑ composite outcome (hospitalization and mortality) OR 2.0. OSA and CPAP: ↑ composite outcome (hospitalization and mortality) OR 2.4.No PSG data for the control group, no BMI data for 30% of controls and 2% of the OSA group.
Cade et al., 2020 [ ]Multicentric, retrospective cohort4668 (443)I: Positive COVID-19 PCR; A minimum of two clinical notes, two encounters, and three ICD diagnoses.Mortality, composite (mortality, MV, ICU), hospitalization.OSA or CPAP not linked with mortality, MV, ICU, and hospitalization.No PSG data, no data on OSA treatment.
PenaOrbea et al., 2021 [ ]Multicentric, retrospective control and case-control5402 (2664)I: Positive COVID-19 PCR; PSG record available.COVID-19, WHO-designated COVID-19 clinical outcomes, composite (hospitalization, mortality).AHI, T90, SaO , ETCO and CPAP not linked with COVID-19. T90 and SaO : ↑ WHO-designated COVID-19 outcomes ↑ hospitalization, ↑ mortality.Included only patients who had indications for PSG.
Oh et al., 2021 [ ]Retrospective cohort from South Korea124,330 (550)I: ICD codes for COVID-19, chronic respiratory diseases. E: COVID-19 still hospitalized as of June 26, 2020.COVID-19; hospital mortality.OSA: ↑ COVID-19, OR 1.65, not linked to mortality.No PSG data, no data on OSA treatment, no BMI data.
Gottlieb et al., 2020 [ ]Retrospective cohort from Chicago, IL.8673 (288)I: Positive COVID-19 PCR. E: Interhospital transfers.Hospitalization, ICU.OSA not linked to hospitalization, ↑ ICU, OR 1.58.No PSG data, no data on OSA treatment.
Kendzerska et al., 2023 [ ]Retrospective cohort from Ontario, CA.4,912,229 (324,029)I: Alive at the start of the pandemic; Followed until March 31, 2021, or death.COVID-19, ED, hospitalization, ICU, 30-day mortality.OSA: ↑ COVID-19, csHR 1.17, ↑ ED, csHR 1.62, ↑ hospitalizations csHR 1.50, ↑ ICU csHR 1.53, not linked to mortality.No PSG data, no data on OSA treatment, no BMI data.
Peker et al., 2021 [ ]Multicenter, prospective, observational clinical trial320 (121)I: Positive COVID-19 PCR and/or clinical/radiologic.Clinical improvement, clinical worsening, hospitalization, oxygen, ICU.OSA: ↑ delayed clinical improvement, OR 0.42, ↑ oxygen OR 1.95, ↑ clinical worsening.No PSG data, no data on OSA treatment.
Girardin et al., 2021 [ ]Retrospective cohort from NYC and LI4446 (290)I: Positive COVID-19 PCR.Hospital mortality.OSA not linked to mortality.No PSG data, no data on OSA treatment, no BMI data.
Gimeno-Miguel et al., 2021 [ ]Retrospective cohort from Aragon, ES.68,913 (1231)I: Positive COVID-19 PCR/antigen; E: Patients diagnosed from March to May 2020.Composite (hospitalization, 30-day mortality)OSA: ↑ composite outcome (hospitalization and 30-day mortality) in women OR 1.43, but not in men.No PSG data, no data on OSA treatment, no BMI data.
Cariou et al., 2020 [ ]Multicentric, retrospective cohort 1317 (114)I: Positive COVID-19 PCR or clinical/radiological diagnosis, hospitalized, diabetics.Composite (MV, 7-day mortality), mortality on day 7, MV on day 7, ICU, discharge on day 7.OSA: ↑ mortality by day 7 OR 2.80, not linked to composite outcome (intubation and death within 7 days of admission).No PSG data, no data on OSA treatment, diabetic population.
Ioannou et al., 2020 [ ]Longitudinal cohort from VA registry.10,131 (2720)I: VA enrollees who had COVID-19 PCR test; E: VA employees.Hospitalization, MV, mortality.OSA: ↑ MV HR, 1.22, not linked to hospitalization, mortality.No PSG data, no data on OSA treatment, male veterans.
Izquierdo et al., 2020 [ ]Multicentric, retrospective cohort 10,504 (212)I: Positive COVID-19 PCR or clinical/radiological diagnosis.ICU.OSA not linked to ICU admission.No PSG data, no data on OSA treatment, no BMI data, no adjustments for obesity and comorbidities.
Lohia et al., 2021 [ ]Multicentric, retrospective cohort1871 (63)I: Adults; Positive COVID-19 PCR; E: Readmission; Ambulatory surgery, pregnant, transferred-for-ECMO patients.Mortality, MV, ICU.OSA ↑ mortality OR 2.59, ↑ ICU OR 1.95, ↑ MV OR 2.20.Small OSA sample size, no data on OSA treatment, mostly African Americans.
Prasad et al., 2024 [ ]Retrospective cohort from VA registry20,357 (6112)I: Tested for COVID-19 by PCR; Until 16 December 2023.COVID-19, LFNC, HFNC, NIV, MV, 30-day readmission; hospital LOS, ICU LOS, adapted WHO severity scale.OSA ↑ COVID-19 OR 1.37, ↑ NIV OR 1.83, not linked to LFNC, HFNC, MV, 30-day readmission. CPAP adherence not linked to outcomes.No PSG data.
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Nemet, M.; Vukoja, M. Obstructive Sleep Apnea and Acute Lower Respiratory Tract Infections: A Narrative Literature Review. Antibiotics 2024 , 13 , 532. https://doi.org/10.3390/antibiotics13060532

Nemet M, Vukoja M. Obstructive Sleep Apnea and Acute Lower Respiratory Tract Infections: A Narrative Literature Review. Antibiotics . 2024; 13(6):532. https://doi.org/10.3390/antibiotics13060532

Nemet, Marko, and Marija Vukoja. 2024. "Obstructive Sleep Apnea and Acute Lower Respiratory Tract Infections: A Narrative Literature Review" Antibiotics 13, no. 6: 532. https://doi.org/10.3390/antibiotics13060532

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Psoriasis Pathogenesis and Treatment

Research on psoriasis pathogenesis has largely increased knowledge on skin biology in general. In the past 15 years, breakthroughs in the understanding of the pathogenesis of psoriasis have been translated into targeted and highly effective therapies providing fundamental insights into the pathogenesis of chronic inflammatory diseases with a dominant IL-23/Th17 axis. This review discusses the mechanisms involved in the initiation and development of the disease, as well as the therapeutic options that have arisen from the dissection of the inflammatory psoriatic pathways. Our discussion begins by addressing the inflammatory pathways and key cell types initiating and perpetuating psoriatic inflammation. Next, we describe the role of genetics, associated epigenetic mechanisms, and the interaction of the skin flora in the pathophysiology of psoriasis. Finally, we include a comprehensive review of well-established widely available therapies and novel targeted drugs.

1. Definition and Epidemiology

Psoriasis is a chronic inflammatory skin disease with a strong genetic predisposition and autoimmune pathogenic traits. The worldwide prevalence is about 2%, but varies according to regions [ 1 ]. It shows a lower prevalence in Asian and some African populations, and up to 11% in Caucasian and Scandinavian populations [ 2 , 3 , 4 , 5 ].

1.1. Clinical Classification

The dermatologic manifestations of psoriasis are varied; psoriasis vulgaris is also called plaque-type psoriasis, and is the most prevalent type. The terms psoriasis and psoriasis vulgaris are used interchangeably in the scientific literature; nonetheless, there are important distinctions among the different clinical subtypes (See Figure 1 ).

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Object name is ijms-20-01475-g001a.jpg

Clinical manifestations of psoriasis. ( A , B ) Psoriasis vulgaris presents with erythematous scaly plaques on the trunk and extensor surfaces of the limbs. ( C ) Generalized pustular psoriasis. ( D ) Pustular psoriasis localized to the soles of the feet. This variant typically affects the palms of the hands as well; hence, psoriasis pustulosa palmoplantaris. ( E , F ) Inverse psoriasis affects the folds of the skin (i.e., axillary, intergluteal, inframammary, and genital involvement).

1.2. Psoriasis Vulgaris

About 90% of psoriasis cases correspond to chronic plaque-type psoriasis. The classical clinical manifestations are sharply demarcated, erythematous, pruritic plaques covered in silvery scales. The plaques can coalesce and cover large areas of skin. Common locations include the trunk, the extensor surfaces of the limbs, and the scalp [ 6 , 7 ].

1.3. Inverse Psoriasis

Also called flexural psoriasis, inverse psoriasis affects intertriginous locations, and is characterized clinically by slightly erosive erythematous plaques and patches.

1.4. Guttate Psoriasis

Guttate psoriasis is a variant with an acute onset of small erythematous plaques. It usually affects children or adolescents, and is often triggered by group-A streptococcal infections of tonsils. About one-third of patients with guttate psoriasis will develop plaque psoriasis throughout their adult life [ 8 , 9 ].

1.5. Pustular psoriasis

Pustular psoriasis is characterized by multiple, coalescing sterile pustules. Pustular psoriasis can be localized or generalized. Two distinct localized phenotypes have been described: psoriasis pustulosa palmoplantaris (PPP) and acrodermatitis continua of Hallopeau. Both of them affect the hands and feet; PPP is restricted to the palms and soles, and ACS is more distally located at the tips of fingers and toes, and affects the nail apparatus. Generalized pustular psoriasis presents with an acute and rapidly progressive course characterized by diffuse redness and subcorneal pustules, and is often accompanied by systemic symptoms [ 10 ].

Erythrodermic psoriasis is an acute condition in which over 90% of the total body surface is erythematous and inflamed. Erythroderma can develop on any kind of psoriasis type, and requires emergency treatment ( Figure 2 ).

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Erythrodermic psoriasis.

1.6. Comorbidities in Psoriasis

Psoriasis typically affects the skin, but may also affect the joints, and has been associated with a number of diseases. Inflammation is not limited to the psoriatic skin, and has been shown to affect different organ systems. Thus, it has been postulated that psoriasis is a systemic entity rather than a solely dermatological disease. When compared to control subjects, psoriasis patients exhibit increased hyperlipidemia, hypertension, coronary artery disease, type 2 diabetes, and increased body mass index. The metabolic syndrome, which comprises the aforementioned conditions in a single patient, was two times more frequent in psoriasis patients [ 11 , 12 ]. Coronary plaques are also twice as common in psoriasis patients when compared to control subjects [ 13 ]. Several large studies have shown a higher prevalence of diabetes and cardiovascular disease correlating with the severity of psoriasis [ 14 , 15 , 16 , 17 , 18 ]. There are divided opinions regarding the contribution of psoriasis as an independent cardiovascular risk factor [ 19 , 20 ]; however, the collective evidence supports that psoriasis independently increases risk for myocardial infarction, stroke, and death due to cardiovascular disease (CVD) [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. In addition, the risk was found to apply also to patients with mild psoriasis to a lower extent [ 21 , 27 ].

Vascular inflammation assessed via 18F-fluorodeoxyglucose positron emission tomography-computed tomography (18F-FDG PET/CT) found psoriasis duration to be a negative predicting factor. It was suggested that the cumulative effects of low-grade chronic inflammation might accelerate vascular disease development [ 29 ]. In a study by Metha et al., systemic and vascular inflammation in six patients with moderate to severe psoriasis was quantified by FDG-PET/CT. Inflammation foci were registered as expected in the skin, joints, and tendons. In addition, FDG uptake in the liver and aorta revealed subclinical systemic inflammation [ 30 ]. Furthermore, standardized uptake values were reduced in the liver, spleen, and aorta following treatment with ustekinumab {Kim, 2018 #359}. A new biomarker to assess CVD risk in psoriasis patients was proposed by nuclear magnetic resonance spectroscopy [ 31 ]. The signal originating from glycan N-acetylglucosamine residues called GlycA in psoriasis patients was associated with psoriasis severity and subclinical CVD, and was shown to be reduced in response to the effective treatment of psoriasis.

Psoriatic inflammation of the joints results in psoriatic arthritis (PsA). The skin manifestations generally precede PsA, which shares the inflammatory chronicity of psoriasis and requires systemic therapies due to a potential destructive progression. Psoriatic arthritis develops in up to 40% of psoriasis patients [ 32 , 33 , 34 , 35 , 36 , 37 , 38 ]; around 15% of psoriasis patients are thought to have undiagnosed PsA [ 39 ]. It presents clinically with dactylitis and enthesitis in oligoarticular or polyarticular patterns. The polyarticular variant is frequently associated with nail involvement [ 40 ]. Nails are specialized dermal appendages that can also be affected by psoriatic inflammation. Nail psoriasis is reported to affect more than half of psoriasis patients, and can present as the only psoriasis manifestation in 5–10% of patients [ 41 ]. The clinical presentation of nail psoriasis depends on the structure affected by the inflammatory process. Nail matrix involvement presents as pitting, leukonychia, and onychodystrophy, whereas inflammation of the nail bed presents as oil-drop discoloration, splinter hemorrhages, and onycholysis ( Figure 3 ) [ 42 ]. Psoriatic nail involvement is associated with joint involvement, and up to 80% of patients with PsA have nail manifestations [ 43 , 44 ].

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Onycholysis and oil drop changes on psoriatic nail involvement.

In addition to an increased risk for cardiometabolic disease, psoriasis has been associated with a higher prevalence of gastrointestinal and chronic kidney disease. Susceptibility loci shared between psoriasis and inflammatory bowel disease support this association in particular with regard to Crohn’s disease [ 45 , 46 ]. An association with mild liver disease, which correlates with imaging studies, has been reported [ 30 , 47 ]. Psoriasis might be a risk factor for chronic kidney disease and end-stage renal disease, independent of traditional risk factors (demographic, cardiovascular, or drug-related) [ 48 ].

Taken together, the different factors contributing to psoriasis as a systemic disease can have a dramatic effect on the quality of life of patients and their burden of disease. Psoriasis impairment to psychological quality of life is comparable to cancer, myocardial infarction, and depression [ 49 ]. The high burden of disease is thought to be owed to the symptoms of the disease, which include pain, pruritus, and bleeding, in addition to the aforementioned associated diseases [ 50 ]. The impact of psoriasis on psychological and mental health is currently an important consideration due to the implications of the disease on social well-being and treatment. Patients with psoriasis have an increased prevalence of depression and anxiety and suicidal ideation. Interestingly, psoriasis treatment leads to improvement in anxiety symptoms [ 51 , 52 ].

2. Pathogenesis

The hallmark of psoriasis is sustained inflammation that leads to uncontrolled keratinocyte proliferation and dysfunctional differentiation. The histology of the psoriatic plaque shows acanthosis (epidermal hyperplasia), which overlies inflammatory infiltrates composed of dermal dendritic cells, macrophages, T cells, and neutrophils ( Figure 4 ). Neovascularization is also a prominent feature. The inflammatory pathways active in plaque psoriasis and the rest of the clinical variants overlap, but also display discrete differences that account for the different phenotype and treatment outcomes.

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Histopathology of psoriasis. ( A ) Psoriasis vulgaris characteristically shows acanthosis, parakeratosis, and dermal inflammatory infiltrates. ( B ) In pustular psoriasis, acanthotic changes are accompanied by epidermal predominantly neutrophilic infiltrates, which cause pustule formation.

2.1. Main Cytokines and Cell Types in Plaque Psoriasis

Disturbances in the innate and adaptive cutaneous immune responses are responsible for the development and sustainment of psoriatic inflammation [ 53 , 54 ]. An activation of the innate immune system driven by endogenous danger signals and cytokines characteristically coexists with an autoinflammatory perpetuation in some patients, and T cell-driven autoimmune reactions in others. Thus, psoriasis shows traits of an autoimmune disease on an (auto)inflammatory background [ 55 ], with both mechanisms overlapping and even potentiating one another.

The main clinical findings in psoriasis are evident at the outermost layer of the skin, which is made up of keratinocytes. However, the development of the psoriatic plaque is not restricted to inflammation in the epidermal layer, but rather is shaped by the interaction of keratinocytes with many different cell types (innate and adaptive immune cells, vasculature) spanning the dermal layer of the skin. The pathogenesis of psoriasis can be conceptualized into an initiation phase possibly triggered by trauma (Koebner phenomenon), infection, or drugs [ 53 ] and a maintenance phase characterized by a chronic clinical progression (see Figure 5 ).

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The pathogenesis of psoriasis.

It is well known that dendritic cells play a major role in the initial stages of disease. Dendritic cells are professional antigen-presenting cells. However, their activation in psoriasis is not entirely clear. One of the proposed mechanisms involves the recognition of antimicrobial peptides (AMPs), which are secreted by keratinocytes in response to injury and are characteristically overexpressed in psoriatic skin. Among the most studied psoriasis-associated AMPs are LL37, β-defensins, and S100 proteins [ 56 ]. LL37 or cathelicidin has been attributed a pathogenic role in psoriasis. It is released by damaged keratinocytes, and subsequently forms complexes with self-genetic material from other damaged cells. LL37 bound to DNA stimulates toll-like receptor (TLR) 9 in plasmacytoid dendritic cells (pDCs) [ 57 ]. The activation of pDC is key in starting the development of the psoriatic plaque, and is characterized by the production of type I IFN (IFN-α and IFN-β). Type I IFN signaling promotes myeloid dendritic cells (mDC) phenotypic maturation, and has been implicated in Th1 and Th17 differentiation and function, including IFN-γ and interleukin (IL)-17 production, respectively [ 58 , 59 , 60 ].

Whilst LL37–DNA complexes stimulate pDCs through TLR9, LL37 bound to RNA stimulates pDCs through TLR7. In addition, LL37–RNA complexes act on mDCs via TLR8 [ 56 , 57 ]. Activated mDCs migrate into draining lymph nodes and secrete tumor necrosis factor (TNF)-α, IL-23, and IL-12, with the latter two modulating the differentiation and proliferation of Th17 and Th1 cell subsets, respectively. Furthermore, slan + monocytes, which are important pro-inflammatory cells found in psoriasis skin lesions, respond to LL37–RNA activation by secreting high amounts of TNF-α, IL-12, and IL-23 [ 61 ].

The activation of the adaptive immune response via the distinct T cell subsets drives the maintenance phase of psoriatic inflammation [ 62 ]. Th17 cytokines, namely IL-17, IL-21, and IL-22 activate keratinocyte proliferation in the epidermis.

The inflammatory milieu activates keratinocyte proliferation via TNF-α, IL-17, and IFN-γ. Keratinocytes are also activated by LL37 and DNA, and greatly increase the production of type I IFNs [ 57 ]. Furthermore, they participate actively in the inflammatory cascade through cytokine (IL-1, IL-6, and TNF-α), chemokine, and AMP secretion.

A widely used psoriasis-like inflammation mouse model relies on the effect of the TLR7/8 agonist imiquimod, and is thus in support of the TLR7/8 disease initiation model. In addition, the response to imiquimod was blocked in mice deficient of IL-23 or IL-17R, which highlights the involvement of the IL-23/IL-17 axis in skin inflammation and psoriasis-like pathology [ 63 ].

The TNFα–IL-23–Th17 inflammatory pathway characterizes plaque-type psoriasis. The IL-17 cytokine family is composed of six members: IL-17A–F. They are produced by different cell types, and are important regulators of inflammatory responses [ 64 ]. So far, the clinically relevant signaling in psoriasis is mediated mostly by IL-17A and IL-17F; both act through the same receptor, but have different potencies. IL-17A exerts a stronger effect than IL-17F, and the IL-17A/IL-17F heterodimer has an intermediate effect. IL-17A binds to its trimeric receptor complex composed of two IL-17RA subunits and one IL-17RC subunit, resulting in the recruitment of the ACT1 adaptor protein. The interaction between ACT1 and the IL-17 receptor complex leads to the activation of a series of intracellular kinases including: extracellular signal-regulated kinase (ERK), p38 MAPK, TGF-beta-activated Kinase 1 (TAK1), I-kappa B kinase (IKK), and glycogen synthase kinase 3 beta (GSK-3 beta). These kinases enable NFκB, AP-1, and C/EBP transcription of pro-inflammatory cytokines, chemokines, and antimicrobial peptides. Th1 and Th2 cytokines act through Janus kinase (JAK)-STAT signaling pathways, whereas Th17 responses are mediated by ACT1 and NFκB [ 65 ]. Alternatively, γδ T cells are able to produce IL-17A independently of the IL-23 stimulus [ 66 ].

Drugs targeting TNFα, IL-23, and IL-17 and signaling pathways such as JAK/STAT are effective in the clinical management of plaque psoriasis. However, alternate inflammatory pathways may be valid for distinct psoriatic variants.

2.2. Pathophysiology in Variants

Whereas the TNFα–IL23–Th17 axis plays a central role in T cell-mediated plaque psoriasis, the innate immune system appears to play a more prominent role in the pustular variants of psoriasis [ 55 ]. Different pathomechanisms are associated with distinct psoriasis subtypes.

In guttate psoriasis, streptococcal superantigens are thought to stimulate the expansion of T cells in the skin [ 67 ]. It was shown that there is a considerable sequence homology between streptococcal M proteins and human keratin 17 proteins. Molecular mimicry may play a role in patients with the major histocompatibility HLA-Cw6 allele, since CD8(+) T cell IFN-γ responses were elicited by K17 and M6 peptides in said patients [ 68 , 69 ].

Pustular psoriasis is characterized by the increased expression of IL-1β, IL-36α, and IL-36γ transcripts, which have been found in pustular psoriasis compared to psoriasis vulgaris [ 70 ]. Nevertheless, IL-17 signaling is also involved in pustular psoriasis and patients with generalized pustular psoriasis without IL-36R mutations responded to anti-IL-17 treatments [ 71 , 72 ].

In nail psoriasis and psoriatic arthritis (PsA), an increased expression of TNF-α, NFκB, IL-6, and IL-8 in psoriasis-affected nails is consistent with the inflammatory markers found on lesional psoriatic skin [ 73 ]. The pathophysiology of PsA and psoriasis is shared as synovial tissue in psoriatic arthritis expresses pro-inflammatory cytokines: IL-1, IFN-γ, and TNFα [ 74 , 75 ]. Infiltrating cells in psoriasis arthritis, tissues, and synovial fluid revealed large clonal expansions of CD8 + T cells. Joint pathology, specifically bone destruction, is partly mediated via IL-17A signaling, which induces the receptor activator of nuclear factor kappa b ligand (RANKL), and in turn activating osteoclasts. Pro-inflammatory cytokines IL-1β and TNF-α act in synergy with the local milleu [ 76 ].

2.3. Autoimmunity in Psoriasis

Psoriasis shows clear autoimmune-related pathomechanisms. This very important area of research will allow for a deeper understanding of to which extent autoantigen-specific T cells contribute to the development, chronification, and overall course of the disease.

LL37 is one of two well-studied T cell autoantigens in psoriasis. CD4 + and CD8 + T cells specific for LL37 were found in two-thirds of patients with moderate to severe plaque psoriasis in a study. LL37-specific T cells produce IFN-γ, and CD4 + T cells produce IL-17, IL-21, and IL-22 as well. LL37-specific T cells can be found in lesional skin or in the blood, where they correlate with disease activity [ 77 ]. CD8 + T cells activated through LL37 engage in epidermotropism, autoantigen recognition, and the further secretion of Th17 cytokines. The melanocytic protein ADAMTSL5 was found to be an HLA-C*06:02-restricted autoantigen recognized by an autoreactive CD8 + T cell TCR. This finding establishes melanocytes as autoimmune target cells, but does not exclude other cellular targets [ 78 ].

Other autoantigen candidates include lipid antigens generated by phospholipase A2 (PLA2) group IVD (PLA2G4D) and hair follicle-derived keratin 17 [ 79 , 80 ]. Interestingly, keratin 17 exposure only lead to CD8+ T cell proliferation in patients with the HLA-Cw*0602 allele (see above) [ 81 ].

2.4. Genetics

Psoriasis has a genetic component that is supported by patterns of familial aggregation. First and second-degree relatives of psoriasis patients have an increased incidence of developing psoriasis, while monozygotic twins have a two to threefold increased risk compared to dizygotic twins [ 82 , 83 ]. Determining the precise effect of genetics in shaping innate and adaptive immune responses has proven problematic for psoriasis and other numerous immune-mediated diseases [ 84 , 85 ]. The genetic variants associated with psoriasis are involved in different biological processes, including immune functions such as antigen presentation, inflammation, and keratinocyte biology [ 55 ].

2.4.1. Antigen Presentation

Genome-wide linkage studies of psoriasis-affected families have so far detected at least 60 chromosomal loci linked to psoriatic susceptibility [ 86 , 87 , 88 ]; the most prominent locus is PSORS1, which has been attributed up to 50% of the heritability of the disease [ 89 ]. PSORS1 is located on chromosome 6p21 within the major histocompatibility complex (MHC), which is specifically in the class I telomeric region of HLA-B, and spans an approximately 220 kb-long segment and corresponds to HLA-Cw6 (C*06:02). HLA-Cw6 is strongly linked to early and acute onset psoriasis [ 90 , 91 ]. The HLA-C*06:02 allele is present in more than 60% of patients, and increases the risk for psoriasis nine to 23-fold [ 92 ]. Nevertheless, no link between late-onset psoriasis or pustular psoriasis and PSORS1 could be established, possibly reflecting a genetically heterogenic background associated with different clinical phenotypes [ 93 ]. PSORS2 spans the CARD14 gene, while PSORS4 is located in the epidermal differentiation complex [ 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 ].

The results of numerous genome-wide association studies (GWAS) in psoriasis are consistent with the prominent role of PSORS1 as a risk factor, but have also revealed over 50 single-nucleotide polymorphisms (SNPs) to be associated to psoriasis [ 102 , 103 , 104 ]. Variants involving the adaptive and immune system are a constant result in these studies [ 53 , 103 , 105 ].

2.4.2. Genetic Variants Implicated in Aberrant Keratinocyte Proliferation and Differentiation

The immunogenetics of IL-23 are strongly associated with psoriasis. IL-23 is a dimer composed of a specific subunit, p19, and a p40 subunit, which is shared with IL-12. IL-23 signals through a heterodimeric receptor expressed by both innate and adaptive immune cells, which include Th17, natural killer T, γδ T cells, and RORγt + innate lymphoid cells. The IL-23R signals through JAK2/TYK2 and STAT3 [ 106 ]. SNPs in the regions coding for the IL-23 cytokine (both the p40 and p19 subunit) as well as the IL-23R have been identified to convey psoriasis risk [ 107 , 108 , 109 ]. Furthermore, these variants have been found to be associated with Crohn’s disease, psoriatic arthritis, and ankylosing spondylitis [ 110 ] [ 74 , 75 ]. IL-23 drives the expansion of Th17 T cells that produce IL-17A/F, which is another set of cytokines whose role is pivotal in the pathogenesis of psoriasis. Monoclonal antibodies targeting both the common p40 and the specific p19 subunit of IL-23 have proven to have high clinical efficacy [ 109 ].

As mentioned above, STAT3 is found in downstream signaling by IL-23, and is therefore essential in T cell development and Th17 polarization. STAT3 has also been detected in psoriasis GWAS, and its variants are associated with psoriasis risk [ 107 , 111 ]. Furthermore, transcription factor Runx1 induces Th17 differentiation by interacting with RORγt. Interestingly, the interaction of Runx1 with Foxp3 results in reduced IL-17 expression [ 112 ].

CARD14 mapping was shown to correspond to PSORS2. The CARD family encompasses scaffolding proteins that activate NF-kB. It was suggested that in psoriasis patients with respective CARD14 mutations, a triggering event can result in an aberrant NF-kB over activation [ 96 ]. CARD14 is expressed in keratinocytes and in psoriatic skin; it is upregulated in the suprabasal epidermal layers and downregulated in the basal layers. In healthy skin, CARD14 is mainly localized in the basal layer. Mutations in CARD14 have been shown to be associated with psoriasis, as well as with familial pityriasis rubra pilaris (PRP) [ 113 ].

The NF-kB signaling pathway is involved in the production of both IL-17 and TNF-α, and thus participates in adaptive and innate immune responses [ 73 ]; it is upregulated in psoriatic lesions and is responsive to treatment [ 114 ]. Gene variations in NFKBIA, TNIP1 , and TRAF3PI2 affecting NF-kB regulatory proteins have been linked to psoriasis via GWAS [ 102 , 115 , 116 , 117 ]. TRAF3PI2 codes for the ACT1 adaptor protein and the specific variant TRAF3IP2 p. Asp10Asn was associated to both psoriasis and psoriatic arthritis [ 117 ].

The different clinical psoriasis variants may have additional genetic modifiers. For instance, mutations in the antagonist to the IL-36 receptor (IL-36RN), belonging to the IL-1 pro-inflammatory cytokine family, have been linked to pustular psoriasis [ 118 , 119 ]. Recessive mutations in IL36RN , coding for the IL-36 receptor antagonist, have been associated with generalized pustular psoriasis (GPP). This mutation is also found in palmar plantar pustulosis and acrodermatitis continua of Hallopeau. Furthermore, in patients with pre-existing plaque-type psoriasis, the gain of function mutation in CARD14 , p.Asp176His, was found to be a predisposing factor for developing GPP [ 120 ].

In addition to studies of genetic variants, the profiling of gene expression in psoriasis has aided in the understanding of the relevant pathophysiological pathways. Transcriptomic studies of psoriatic skin have revealed differentially expressed genes (DEGs) when compared to healthy skin, and also between lesional and nonlesional psoriatic skin [ 121 , 122 ]. Further underscoring their relevance in psoriasis pathogenesis, IL-17A genes were found to be upregulated in nonlesional psoriatic skin compared to healthy skin. This finding suggests that nonlesional psoriatic skin is also subclinically affected, and supports the concept of the widespread inflammation that is present in psoriasis [ 123 ]. In addition, data showing the upregulation of Th2 genes in nonlesional psoriatic skin may reflect the activation of T cell regulatory compensation mechanisms in an effort to override the inflammatory cascade [ 123 ]. ‘Cross-disease’ transcriptomics have aided in differentiating nonspecific DEGs present in inflammatory skin conditions (such as atopic dermatitis and squamous cell carcinoma) from DEGs specific to psoriasis. The latter are induced by IL-17A and are expressed by keratinocytes [ 124 ].

Despite solid evidence of genetic relevance in the pathogenesis of psoriasis, no single genetic variant seems to be sufficient to account on its own for the development of disease. Hence, a multifactorial setting including multiple genetic mutations and environmental factors, which have been attributed up to 30% of disease risk, ought to be considered [ 125 ].

2.5. Epigenetics

The quest for the missing heritability associated with psoriasis candidate genes has fueled the search for epigenetic modifications. Epigenetic mechanisms modify gene expression without changing the genomic sequence; some examples include: long noncoding RNA (lncRNA), microRNA (miRNA) silencing, and cytosine and guanine (CpG) methylation.

lncRNA are at least 200 nucleotides long, and are not transcribed to protein. At least 971 lncRNAs have been found to be differentially expressed in psoriatic plaques compared to normal skin [ 126 , 127 , 128 , 129 , 130 , 131 ]. Thereof, three differentially expressed lncRNAs in proximity to known psoriasis susceptibility loci at CARD14, LCE3B/LCE3C , and IL-23R , and are thought to modulate their function [ 127 ].

miRNAs are small, evolutionarily conserved, noncoding RNAs that base pair with complementary sequences within mRNA molecules, and regulate gene expression at the posttranscriptional level, usually downregulating expression. Most of the studies of miRNAs in association with psoriasis address the plaque-type variant (see Table 1 ), and so far, more than 250 miRNAs are aberrantly expressed in psoriatic skin [ 132 , 133 , 134 , 135 ]. A prominent role has been attributed to miR-31, which is upregulated in psoriatic skin and regulates NF-κB signaling as well as the leukocyte-attracting and endothelial cell-activating signals produced by keratinocytes [ 135 ]. miR-21 is an oncomiR with a role in inflammation, and has been found to be elevated in psoriatic skin. Increased miR-21 has been localized not only to the epidermis, but is also found in the dermal inflammatory infiltrates, and correlates with elevated TNF-α mRNA expression [ 136 ]. miR-221 and miR-222 are among other upregulated miRNAs in psoriatic skin [ 132 ]. The aberrant expression of miR-21, miR-221, and miR-222 correlates with a downregulation of the tissue inhibitor of metalloprotease 3 (TIMP3) [ 137 , 138 ]. TIMP3 is a member of the matrix metalloprotease family with a wide range of functions. Increased levels of said miRs are thought to result in unopposed matrix metalloprotease activity, leading to inflammation (partly via TNF-α-mediated signaling) and epidermal proliferation [ 138 ]. miR-210 was found to be highly expressed in psoriasis patients, and induced Th17 and Th1 differentiation while inhibiting Th2 differentiation through STAT6 and LYN repression [ 139 ].

MicroRNAs (miRNAs) increased in psoriasis.

miRNATarget GenesTissue/Cell Type (Human)Function
miR-21 Skin, PBMCsKeratinocyte differentiation and proliferation, T cell activation, inflammation [ ]
miR-31 SkinNF-κB activity, keratinocyte differentiation and proliferation [ ]
miR-135b SkinKeratinocyte differentiation and proliferation [ ]
miR-146a SkinHematopoiesis, inflammation, and keratinocyte proliferation [ , ]
miR-155 SkinInflammation [ ]
miR-203 SkinSTAT3 signaling, keratinocyte differentiation and proliferation, and inflammation [ ]
miR-210 PBMCsRegulatory T cell activation
Induction of Th17 and Th1 differentiation [ , ]
miR-221/222 SkinImmune cell activation
Keratinocyte proliferation [ ]
miR-424 SkinKeratinocyte differentiation and proliferation [ ]

Serum levels of miR-33, miR-126, and miR-143, among others, have been proposed as potential biomarkers of disease [ 140 , 141 ]. However, the studies have so far failed to consistently present elevations of a single miRNA in psoriatic patients. Thus, alterations of miRNA expression are better interpreted in the context of miRNA profiles, which have been reported to shift following psoriasis treatments [ 132 ]. Thus, miRNA expression profiles could potentially be used to predict response to treatment and personalize therapies.

DNA methylation is another epigenetic mechanism that can alter gene expression in a transient or heritable fashion, and primarily involves the covalent modification of cytosine and guanine (CpG) sequences. CpG methylation is usually repressive unless it inhibits transcriptional repressors, in which case it results in gene activation. Around 1100 differentially methylated CpG sites were detected between psoriatic and control skin. Of these sites, 12 corresponded to genes regulating epidermal differentiation, and were upregulated due to a lower methylation pattern. Said changes in DNA methylation reverted to baseline under anti-TNF-α treatment, indicating that CpG methylation in psoriasis is dynamic [ 148 , 149 ]. Further research will shed light on the functional relevance of epigenetic regulation in psoriasis.

2.6. Microbiome

The skin microbiome exerts an active role in immune regulation and pathogen defense by stimulating the production of antibacterial peptides and through biofilm formation. A differential colonizing microbiota in comparison to healthy skin has been found in several dermatologic diseases, including atopic dermatitis, psoriasis, and acne vulgaris [ 150 , 151 ]. It is hypothesized that an aberrant immune activation triggered by skin microbiota is involved in the pathogenesis of autoimmune diseases. For instance, there is growing evidence that the steady-state microbiome plays a role in autoimmune diseases such as in inflammatory bowel disease [ 152 ].

The overall microbial diversity is increased in the psoriatic plaque [ 151 ]. However, an increase in Firmicutes and Actinobacteria phyla were found in psoriatic plaques ( Table 2 ) [ 153 ]. Proteobacteria were found to be higher in healthy skin when compared to psoriatic patients [ 153 , 154 ]. Nevertheless, Proteobacteria were found to be increased in the trunk skin biopsies of psoriatic lesions [ 151 ]. A combined increase in Corynebacterium, Propionibacterium, Staphylococcus, and Streptococcus was found in psoriatic skin; however, in another study, Staphylococci were significantly lower in psoriatic skin compared to healthy controls [ 151 , 154 ].

Psoriasis microbiome. ↑ increased. > higher than.

StudySample ( )MethodPsoriasisHealthy SkinComments
Gao et al., 2008 [ ]Skin swabs
(six psoriatic patients)
broad range PCR↑ diversity
↑ Firmicutes
↑ Actinobacteria
↑ Proteobacteria
Healthy controls taken from previous study [ ].
Alekseyenko et al., 2013 [ ]Skin swabs
(54 psoriasis patients, 37 controls)
High-throughput 16S rRNA gene sequencing↑ Actinobacteria/Firmicutes
↑ Corynebacterium, Propionibacterium, Staphylococcus, Streptococcus↑ Corynebacterium, Streptococcus, Staphylococcus
↑ ProteobacteriaOTUs Acidobacteria and Schlegella were strongly associated with psoriasis status. Samples were site-matched.
Fahlen et al., 2012 [ ]Skin biopsies
(10 psoriasis patients, 10 healthy controls)
Pyrosequencing targeting the V3-V4 regions of the 16S rRNA geneStreptococcus > Staphylococcus
↑ Proteobacteria (trunk skin)
↑Propionibacteria/Staph. (limb skin)
↑ ActinobacteriaIncluded dermis and adnexal structures. Bacterial diversity was increased in the control group (unmatched sites), but not statistically significant.
Firmicutes, Proteobacteria, and Actinobacteria predominant in healthy and psoriatic skin.
Takemoto et al., 2015 [ ]Psoriatic scale samples (12 psoriatic patients, 12 healthy controls)Pyrosequencing for fungal rRNAgene sequences↑ fungal diversity
↓ Malassezia
↑ MalasseziaFungal microbiome study Malassezia were the most abundant species in psoriatic and healthy skin.

Certain fungi such as Malassezia and Candida albicans, and viruses such as the human papilloma virus have been associated with psoriasis [ 155 ]. So far, Malassezia proved to be the most abundant fungus in psoriatic and healthy skin. Nevertheless, the colonization level of Malassezia in psoriasis patients was lower than that in healthy controls [ 156 ]. Further studies are required to explain the role of the microbiome signature and the dynamics among different commensal and pathogenic phyla [ 157 ].

Psoriasis is a chronic relapsing disease, which often necessitates a long-term therapy. The choice of therapy for psoriasis is determined by disease severity, comorbidities, and access to health care. Psoriatic patients are frequently categorized into two groups: mild or moderate to severe psoriasis, depending on the clinical severity of the lesions, the percentage of affected body surface area, and patient quality of life [ 159 ]. Clinical disease severity and response to treatment can be graded through a number of different scores. The PASI score has been extensively used in clinical trials, especially those pertaining to the development of the biologic drugs, and will be used throughout this review.

Mild to moderate psoriasis can be treated topically with a combination of glucocorticoids, vitamin D analogues, and phototherapy. Moderate to severe psoriasis often requires systemic treatment. The presence of comorbidities such as psoriasis arthritis is also highly relevant in treatment selection. In this review, we will address the systemic therapies as small-molecule (traditional and new) and biologic drugs.

A number of case reports and case series have suggested that tonsillectomy has a therapeutic effect in patients with guttate psoriasis and plaque psoriasis [ 69 , 160 , 161 ]. A systematic review concluded that the evidence is insufficient to make general therapeutic recommendations for tonsillectomy, except for selected patients with recalcitrant psoriasis, which is clearly associated to tonsillitis [ 162 ]. A recent study stated that HLA-Cw*0602 homozygosity in patients with plaque psoriasis may predict a favorable outcome to tonsillectomy [ 163 ]. To date, a single randomized, controlled clinical trial showed that tonsillectomy produced a significant improvement in patients with plaque psoriasis in a two-year follow-up timespan [ 164 ]. Furthermore, the same cohort was evaluated to assess the impact of the clinical improvement after tonsillectomy on quality of life. The study reported a 50% improvement in health-related quality of life, and a mean 59% improvement in psoriasis-induced stress. Tonsillectomy was considered worthwhile by 87% of patients who underwent the procedure [ 165 ].

3.1. Small-Molecule Therapies

In the past years, an accelerated development in psoriasis therapies has resulted in advanced targeted biological drugs. Methotrexate (MTX), cyclosporin A, and retinoids are traditional systemic treatment options for psoriasis. All of the former are oral drugs with the exception of MTX, which is also available for subcutaneous administration. They will be briefly discussed in this review (see Table 3 ). The section ends with an overview on dimethyl fumarate and apremilast, which are newer drugs that have been approved for psoriasis.

Drugs available for psoriasis therapy.

MethotrexateDihydrofolate reductase inhibition blocks purine biosynthesis; induction of lymphocyte apoptosiss.c./oral
CyclosporinCalcineurin inhibition leading to reduced IL-2Oral
AcitretinNormalization of keratinocyte proliferation/differentiation through retinoid receptor bindingOral
FumarateIntracellular glutathione, modulation of Nrf2, NF-κB, and HIF-1α; promoting a shift from a pro-inflammatory Th1/Th17 response to an anti-inflammatory/regulatory Th2 response.Oral
ApremilastPDE4 inhibitor increases in tracellular cAMP levels in immune and non-immune cell types modulating inflammationOral
EtanerceptDimeric human fusion protein mimicking TNF-αR s.c.
InfliximabChimeric IgG1κ monoclonal antibody that binds to soluble and transmembrane forms of TNF-α i.v.
AdalimumabHuman monoclonal antibody against TNF-α s.c.
CertolizumabFab portion of humanized monoclonal antibody against TNF-α conjugated to polyethylene glycol s.c.
UstekinumabHuman IgG1k monoclonal antibody that binds with specificity to the p40 protein subunit used by both the interleukin (IL)-12 and IL-23 cytokines IL-12/IL-23 p40 s.c.
TildrakizumabHumanized IgG1κ, which selectively blocks IL-23 by binding to its p19 subunit s.c.
GuselkumabHuman immunoglobulin G1 lambda (IgG1λ) monoclonal antibody that selectively blocks IL-23 by binding to its p19 subunit s.c.
RisankizumabHumanized IgG1 monoclonal antibody that inhibits interleukin-23 by specifically targeting the p19 subunit s.c.
SecukinumabHuman IgG1κ monoclonal antibody against IL-17A s.c.
IxekizumabHumanized, immunoglobulin G4κ monoclonal antibody selectively binds and neutralizes IL-17A s.c.
BrodalumabHuman monoclonal IgG2 antibody directed at the IL-17RA s.c.

MTX is a folic acid analogue that inhibits DNA synthesis by blocking thymidine and purine biosynthesis. The initial recommended dose of 7.5–10 mg/weekly may be increased to a maximum of 25 mg/weekly [ 166 , 167 ]. A recent retrospective study reported successful treatment response (defined by PASI decrease of 50% to 75% and absolute DLQI value) was reached by 33%, 47%, and 64% of patients at three, six, and 12 months, respectively [ 168 ]. There is conflicting evidence regarding MTX effectiveness on psoriatic arthritis. A recent publication reported 22.4% of patients achieved minimal arthritic disease activity, and 27.2% reached a PASI 75 at week 12 [ 169 ]. Furthermore, HLA-Cw6 has been suggested as a potential marker for patients who may benefit from MTX treatment [ 170 ]. The most common side effects include nausea, leucopenia, and liver transaminase elevation. Despite the potential side effects and its teratotoxicity, it remains a frequently used cost-effective first-line drug, and the close monitoring of liver function and full blood count make a long-term administration feasible.

Cyclosporine is a T cell-inhibiting immunosuppressant from the group of the calcineurin inhibitors. Cyclosporine is effective as a remission inducer in psoriasis and as maintenance therapy for up to two years [ 171 ]. Hypertension, renal toxicity, and non-melanoma skin cancer are significant potential side effects. Nephrotoxicity is related to the duration of treatment and the dose. Cyclosporine is employed as an intermittent short-term therapy. The dosage is 2.5 to 5.0 mg/kg of body weight for up to 10 to 16 weeks. Tapering of the drug is recommended to prevent relapse [ 171 ].

Retinoids are natural or synthetic vitamin A-related molecules. Acitretin is the retinoid used in the treatment of psoriasis. It affects transcriptional processes by acting through nuclear receptors and normalizes keratinocyte proliferation and differentiation [ 172 , 173 ]. A multicenter, randomized study reported 22.2% and 44.4% of patients reaching PASI 75 and PASI 50 at 24 weeks [ 174 ]. Acitretin is initially administered at 0.3–0.5 mg/kg of body weight per day. The maximum dosage is 1 mg/kg body weight/daily. Cheilitis is the most common side effect appearing dose dependently in all patients. Other adverse effects include conjunctivitis, effluvium, hepatitis, and teratogenicity.

Fumaric acid esters (FAEs) are small molecules with immunomodulatory and anti-inflammatory properties [ 175 , 176 ]. The exact mechanism of action has not been cleared, but is thought to involve an interaction with glutathione, which among other mechanisms, inhibits the transcriptional activity of NF-κB [ 177 , 178 ]. FAEs were initially available as a mix of dimethyl fumarate and monoethyl fumarate (DMF/MEF), the former being the main active compound in the formulation. DMF has been reported to decrease the migratory capacity of slan+ monocytes, and also inhibited the induction of Th1/Th17 responses [ 178 ]. DMF/MEF was approved in 1994 in Germany for the treatment of severe plaque psoriasis, and in 2008, the indication was expanded for moderate psoriasis [ 179 ]. This licensing was exclusive to Germany, where it remains a first-line drug; nevertheless, DMF/MEF was used as off-label treatment in other European countries [ 180 , 181 , 182 , 183 ]. A new FAE formulation containing exclusively the main active metabolite DMF became available in 2017, and was approved for psoriasis treatment in the European Union, Iceland, and Norway [ 184 ]. Although there are no studies comparing DMF/MEF directly to biologics, several studies document its efficacy [ 185 , 186 , 187 , 188 , 189 ]. A marked improvement is also seen in patients with psoriatic arthritis and nail psoriasis. The most common side effects are gastrointestinal symptoms and flushing, which are generally mild in severity, resolve over time, and are dose related [ 184 ]. In addition, FAEs may decrease lymphocyte and leukocyte counts. Therefore, it is recommended to perform a complete blood count before treatment initiation and monthly for DMF/MEF or every three months for DMF [ 184 ].

Apremilast, a phosphodiesterase-4 inhibitor, inhibits the hydrolyzation of the second messenger cAMP. This leads to the reduced expression of pro-inflammatory cytokines TNF-α, IFN0γ, and IL-12, and increased levels of IL-10. Apremilast was shown to have broad anti-inflammatory effects on keratinocytes, fibroblasts, and endothelial cells [ 190 ]. We studied apremilast in the context of slan + cells, which is a frequent dermal inflammatory dendritic cell type derived from blood circulating slan + nonclassical monocytes. Here, apremilast strongly reduced TNF-α and IL-12 production, but increased IL-23 secretion and IL-17 production in T cells stimulated by apremilast-treated slan + monocytes [ 191 ]. These dual effects on slan + antigen-presenting cells may constrain therapeutic responses. No routine monitoring of hematologic parameters is required for apremilast, which is a major advantage compared to the other small molecule drugs. Apremilast showed a 33.1% PASI 75 response at week 16. It is also effective for palmoplantar, scalp psoriasis, and nail psoriasis in addition to psoriatic arthritis [ 192 , 193 , 194 ]. The most common adverse events affected the gastrointestinal tract (nausea and diarrhea) and the upper respiratory tract (infections and nasopharyngitis). These effects were mild in nature and self-resolving over time.

The traditional systemic drugs are immunomodulators, which except for apremilast require close clinical monitoring due to the common side effects involving mainly the kidney and the liver. Methotrexate and cyclosporine are the only systemic therapies for psoriasis included in the World Health Organization (WHO) Model List of Essential Medicines, albeit for the indications of joint disease for the former and immunosuppression for the latter. The potential side effects of FAE and apremilast are usually not life-threatening, but might be sufficient to warrant discontinuation.

3.2. Biologics

In the context of psoriasis treatment, current use of the term biologics refers to complex engineered molecules including monoclonal antibodies and receptor fusion proteins. Biologics are different from the above-described systemic therapies in that they target specific inflammatory pathways and are administered subcutaneously (s.c.) (or intravenously i.e., infliximab) on different weekly schedules. Biologics presently target two pathways crucial in the development and chronicity of the psoriatic plaque: the IL-23/Th17 axis and TNF-α-signaling (see Table 3 ).

3.2.1. TNF-α

TNF-α inhibitors have been available for over a decade. They are considered the first-generation biologics, and are effective for plaque psoriasis and psoriatic arthritis. TNF-α inhibitors are still the standard used to evaluate drug efficacy in psoriasis clinical research. There are currently four drugs in this category: etanercept, infliximab, adalimumab, and certolizumab.

Etanercept is unique in the biologics category in that it is not a monoclonal antibody, but rather a recombinant human fusion protein. The receptor portion for the TNF-α ligand is fused to the Fc portion of an IgG1 antibody. It was the first TNF-α inhibitor approved by the United States Food and Drug Administration (FDA) for psoriasis. Infliximab is a chimeric monoclonal IgG1 antibody, and adalimumab is a fully human monoclonal IgG1 antibody. They neutralize TNF-α activity by binding to its soluble and membrane-bound form. These drugs are particularly employed to treat psoriatic arthritis, and show a similar efficacy. In the treatment of psoriasis, they show different PASI 75 response rates: 52% for etanercept, 59% for adalimumab, and 80% for infliximab. Infliximab shows superiority in terms of efficacy when compared to the other TNF-α inhibitors, and when compared with ustekinumab, it showed a similar performance [ 195 ]. The chimeric nature of infliximab might contribute to a higher immunogenic potential of the drug, which in turn might influence drug survival. Certolizumab pegol is a pegylated Fab’ fragment of a humanized monoclonal antibody against TNF-α. PEGylation is the covalent conjugation of proteins with polyethylene glycol (PEG), and is attributed a number of biopharmaceutical improvements, including increased half-life and reduced immunogenicity [ 196 ]. The initial indication for treating Crohn’s disease was extended to psoriatic arthritis and recently to plaque psoriasis. Certolizumab has shown an 83% PASI 75 response. Unlike other anti-TNF-α agents, it has no Fc domain, and is thus not actively transported across the placenta. Thus, certolizumab pegol is approved for use during pregnancy and breastfeeding.

3.2.2. IL23/Th17 axis

As previously mentioned, IL-23 drives the expansion of Th17 cells whose inflammatory effects are in turn mediated by IL-17A, IL-17F, and IL-22.

IL-23 is a dimer composed of p40 and p19. The first biologic to be approved for psoriasis vulgaris after the TNF-α inhibitors was ustekinumab, which is a monoclonal antibody directed against the p40 subunit. P40 is not exclusive to IL-23, but rather is shared with IL-12. IL-12 is a dimer consisting of p40 and p35, and is involved in the differentiation of naïve T cells into Th1 cells. By targeting p40, ustekinumab blocks two different T-cell activating mechanisms, namely Th1 and Th17 selection. Ustekinumab is also effective for the treatment of PsA and Chron’s disease. It is available in two dosages, 45 mg and 90 mg, depending on a threshold body weight of 100 kg. Ustekinumab has extensive safety data, few side effects, good clinical efficacy, and long treatment drug survival was reported. At 90 mg, ustekinumab showed a PASI 75 response in 72.4% and in 61.2% at 45 mg [ 197 ]. Studies using real-life data compared ustekinumab with the anti-TNF-α drugs, and ustekinumab was found to have a significant longer drug survival [ 198 , 199 , 200 ]. Frequent adverse events include nasopharyngitis, upper respiratory tract infections, fatigue, and headache. Among the serious adverse events listed in the label of ustekinumab are infections. Tuberculosis (TB) has only been reported in two psoriasis patients receiving ustekinumab [ 201 , 202 ]. The clinical efficacy of ustekinumab and the further clarification of its mechanism of action highlighted the crucial role of IL-23 in shaping the Th17 response. On the other hand, Th1 signaling is important for the response against bacterial and viral pathogens, and a study showed IL-12 signaling to have a protective effect in a model of imiquimod psoriasis-like inflammation [ 203 ]. This rationale fueled the development of drugs targeting p19, which is the IL-23-exclusive subunit. This more specific molecular targeting approach has also achieved successful clinical outcomes. Three fully human monoclonal antibodies with p19 specificity are available: guselkumab, tildrakizumab, and risankizumab. Guselkumab is licensed for psoriasis, and showed clinical superiority when compared to adalimumab, with 85.1% of patients reaching a PASI 75, and 73.3% receiving a PASI 90 response at week 16 [ 204 , 205 ]. Patients receiving tildrakizumab showed a 74% PASI 75, and 52% PASI 90 at week 16. Tildrakizumab was compared to etanercept, and was more likely to reach PASI 75 at weeks 16 and 28 [ 206 , 207 ]. Risankizumab showed the following PASI responses at week 12: 88% PASI 75, 81% PASI 90, and 48% PASI 100. Patients were followed for 48 weeks after the last injection at week 16, and one-fourth of them showed a maintained PASI 100 [ 208 ]. Whether IL-23 inhibition has the potential to modify the course of the disease after subsequent drug retrieval is currently under study.

So far, three human monoclonal antibodies targeting IL-17 are available. Secukinumab and ixekizumab block IL-17A; whereas brodalumab is directed against the IL-17 receptor A. IL-17-targeted biologics are fast acting, showing significant differences from placebo within the first week of treatment. Secukinumab was the first IL-17A inhibitor approved for psoriasis in 2015. A year later, the approval extended to include PsA and ankylosing spondylitis. At week 12, 81.6% of patients on secukinumab reached a PASI 75 response, and 28.6% reached a PASI 100 response [ 209 ]. At week 52, over 80% maintained PASI 75. Secukinumab showed a rapid onset of action, reflecting a significant likelihood of achieving PASI 75 as early as the first week of treatment when compared to ustekinumab, and surpassed the latter in clinical superiority at week 16 and 52 [ 210 , 211 ].

Ixekizumab also showed a significantly rapid onset of action in the first week when compared to placebo: a 50% PASI 75 response at week four, and 50% PASI 90 by week eight. At week 12, response rates were 89.1% for PASI 75 and 35.3% for PASI 100 [ 212 ]. Secukinumab and ixekizumab have proven effective for scalp and nail psoriasis, which are two clinical variants that are resistant to conventional topical therapies.

Brodalumab is a human monoclonal antibody that targets the IL-17 receptor type A, thus inhibiting the biological activity of IL-17A, IL-17F, interleukin-17A/F, and interleukin-17E (also called interleukin-25). Brodalumab showed an 83.3% PASI 75, 70.3% PASI 90, and 41.9% PASI 100 response rate at week 12, and a satisfactory safety profile [ 213 , 214 ]. After the discontinuation of treatment with secukinumab, 21% of patients maintained their response after one year and 10% after two years [ 215 ]. This finding suggests that targeting IL-17 signaling exerts some disease-modifying effect that might reestablish the homeostasis of the inflammatory pathways in a subset of psoriasis patients. Frequent adverse effects under IL-17 blockade include nasopharyngitis, headache, upper respiratory tract infection, and arthralgia. Furthermore, IL-17 signaling is critical for the acute defense against extracellular bacterial and fungal infections. Candida infections are more frequent in patients receiving anti-IL17 biologics secukinumab and ixekizumab compared to etanercept [ 209 ]. Nonetheless, candida infections were not severe, and did not warrant treatment interruption. The risk of tuberculosis reactivation is considered small under biologic therapies other than anti-TNF-α [ 216 ]. Anti-IL-17 biologics should not be used in psoriasis patients also suffering from Chron’s disease.

3.2.3. Biosimilars in Psoriasis

The introduction of biosimilars for different diseases is revolutionizing the pharmaceutical arsenal at hand. As patents for many biologics face expiration, biosimilar versions of these drugs are being developed, or are already entering the market. A biosimilar is a biological product that must fulfill two requirements: it must be highly similar to an approved biologic product and have no clinically meaningful differences in safety, purity, or potency when compared with the reference product. Guidelines for the development and approval of biosimilars have been issued by the European Medicines Agency, the FDA, and the World Health Organization. There are currently eight adalimumab biosimilars, four infliximab biosimilars, and two etanercept biosimilars approved in Europe. By lowering the costs of systemic treatment for psoriasis patients, biosimilars may also increase access to biologics.

3.2.4. Drugs in the Research Pipeline

Tofacitinib is an oral Janus kinase (JAK) inhibitor currently approved for the treatment of rheumatoid arthritis (RA) and PsA. Tofacitinib showed a 59% PASI 75 and 39% PASI 90 response rate at week 16, and was also effective for nail psoriasis; however, its development for psoriasis was halted for reasons unrelated to safety. Upadacitinib is another JAK inhibitor currently undergoing phase III clinical trials for the treatment of psoriatic arthritis. Piclidenoson, an adenosine A3 receptor inhibitor, serlopitant, a neurokinin-1 receptor antagonist, and RORγt inhibitors are each being tested as oral treatments for psoriasis [ 217 ]. Two different biologics targeting IL-17 and one targeting IL-23 are being currently tested. In addition, there are currently 13 registered phase III clinical trials testing biosimilars for adalimumab (eight), infliximab (three), and etanercept (two).

Psoriasis is a complex multifactorial disease for which various novel therapies have arisen in the past years. In spite of the refinement of the targeted therapies, psoriasis remains a treatable but so far not curable disease. The targeted therapies show high clinical efficacy for the inhibition of IL-23 and IL-17. Some degree of a persistent antipsoriatic effect by these therapies could be demonstrated after drug discontinuation, and argue for disease modification concept [ 208 , 215 ]. This important finding will be followed up in ongoing and future studies. However, in other cases, an initial clinical response is only short lived, requiring treatment with a different biologic. Clearly, more research is required to answer the question of why the drug survival of some biologics is limited. The therapeutic arsenal for psoriasis is likely to increase in the near future, with studies on orally applied new small molecules such as inhibitors targeting RORγt. In spite of the safety and efficacy of targeted therapies, due to economic factors, dosage regimes, and adverse effect profiles, broader-acting drugs remain the mainstay of psoriasis systemic therapy in many clinical scenarios around the world. The role of genetics remains to be elucidated not only in the context of predisposition to disease, but also in the profiling of distinct psoriatic types based on cytokine signatures, and in identifying therapy response markers. Clearly, psoriasis is currently the best understood and the best treatable Th17-biased chronic inflammatory disease. After achieving excellent clinical responses for the majority of patients with available therapeutic approaches, the stratification of psoriasis patients to the optimal drug and ensuring the sustainability of our treatments are the major tasks to be resolved.


We kindly thank Lukas Freund for his comments on the manuscript, Galina Grabe for providing the histology images, Anja Heid and Christine Dorschel for their technical support in gathering the clinical pictures.

This work was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) to KS – SFB TRR 156, SCHA 1693/1-1 and project number 259332240/RTG 2099.

Conflicts of Interest

The authors declare no conflict of interest.


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