• Download PDF
  • Share X Facebook Email LinkedIn
  • Permissions

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.

Read More About

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

Manage citations:

© 2024

Artificial Intelligence Resource Center

Cardiology in JAMA : Read the Latest

Browse and subscribe to JAMA Network podcasts!

Others Also Liked

Select your interests.

Customize your JAMA Network experience by selecting one or more topics from the list below.

  • Academic Medicine
  • Acid Base, Electrolytes, Fluids
  • Allergy and Clinical Immunology
  • American Indian or Alaska Natives
  • Anesthesiology
  • Anticoagulation
  • Art and Images in Psychiatry
  • Artificial Intelligence
  • Assisted Reproduction
  • Bleeding and Transfusion
  • Caring for the Critically Ill Patient
  • Challenges in Clinical Electrocardiography
  • Climate and Health
  • Climate Change
  • Clinical Challenge
  • Clinical Decision Support
  • Clinical Implications of Basic Neuroscience
  • Clinical Pharmacy and Pharmacology
  • Complementary and Alternative Medicine
  • Consensus Statements
  • Coronavirus (COVID-19)
  • Critical Care Medicine
  • Cultural Competency
  • Dental Medicine
  • Dermatology
  • Diabetes and Endocrinology
  • Diagnostic Test Interpretation
  • Drug Development
  • Electronic Health Records
  • Emergency Medicine
  • End of Life, Hospice, Palliative Care
  • Environmental Health
  • Equity, Diversity, and Inclusion
  • Facial Plastic Surgery
  • Gastroenterology and Hepatology
  • Genetics and Genomics
  • Genomics and Precision Health
  • Global Health
  • Guide to Statistics and Methods
  • Hair Disorders
  • Health Care Delivery Models
  • Health Care Economics, Insurance, Payment
  • Health Care Quality
  • Health Care Reform
  • Health Care Safety
  • Health Care Workforce
  • Health Disparities
  • Health Inequities
  • Health Policy
  • Health Systems Science
  • History of Medicine
  • Hypertension
  • Images in Neurology
  • Implementation Science
  • Infectious Diseases
  • Innovations in Health Care Delivery
  • JAMA Infographic
  • Law and Medicine
  • Leading Change
  • Less is More
  • LGBTQIA Medicine
  • Lifestyle Behaviors
  • Medical Coding
  • Medical Devices and Equipment
  • Medical Education
  • Medical Education and Training
  • Medical Journals and Publishing
  • Mobile Health and Telemedicine
  • Narrative Medicine
  • Neuroscience and Psychiatry
  • Notable Notes
  • Nutrition, Obesity, Exercise
  • Obstetrics and Gynecology
  • Occupational Health
  • Ophthalmology
  • Orthopedics
  • Otolaryngology
  • Pain Medicine
  • Palliative Care
  • Pathology and Laboratory Medicine
  • Patient Care
  • Patient Information
  • Performance Improvement
  • Performance Measures
  • Perioperative Care and Consultation
  • Pharmacoeconomics
  • Pharmacoepidemiology
  • Pharmacogenetics
  • Pharmacy and Clinical Pharmacology
  • Physical Medicine and Rehabilitation
  • Physical Therapy
  • Physician Leadership
  • Population Health
  • Primary Care
  • Professional Well-being
  • Professionalism
  • Psychiatry and Behavioral Health
  • Public Health
  • Pulmonary Medicine
  • Regulatory Agencies
  • Reproductive Health
  • Research, Methods, Statistics
  • Resuscitation
  • Rheumatology
  • Risk Management
  • Scientific Discovery and the Future of Medicine
  • Shared Decision Making and Communication
  • Sleep Medicine
  • Sports Medicine
  • Stem Cell Transplantation
  • Substance Use and Addiction Medicine
  • Surgical Innovation
  • Surgical Pearls
  • Teachable Moment
  • Technology and Finance
  • The Art of JAMA
  • The Arts and Medicine
  • The Rational Clinical Examination
  • Tobacco and e-Cigarettes
  • Translational Medicine
  • Trauma and Injury
  • Treatment Adherence
  • Ultrasonography
  • Users' Guide to the Medical Literature
  • Vaccination
  • Venous Thromboembolism
  • Veterans Health
  • Women's Health
  • Workflow and Process
  • Wound Care, Infection, Healing
  • Register for email alerts with links to free full-text articles
  • Access PDFs of free articles
  • Manage your interests
  • Save searches and receive search alerts

U.S. flag

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

  • Publications
  • Account settings
  • My Bibliography
  • Collections
  • Citation manager

Save citation to file

Email citation, add to collections.

  • Create a new collection
  • Add to an existing collection

Add to My Bibliography

Your saved search, create a file for external citation management software, your rss feed.

  • Search in PubMed
  • Search in NLM Catalog
  • Add to Search

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

Affiliations.

  • 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.

PubMed Disclaimer

Similar articles

  • State of the art and pharmacological pipeline of biologics for chronic plaque psoriasis. Gisondi P, Geat D, Pizzolato M, Girolomoni G. Gisondi P, et al. Curr Opin Pharmacol. 2019 Jun;46:90-99. doi: 10.1016/j.coph.2019.05.007. Epub 2019 Jun 15. Curr Opin Pharmacol. 2019. PMID: 31212119 Review.
  • Biologics for the primary care physician: Review and treatment of psoriasis. Schadler ED, Ortel B, Mehlis SL. Schadler ED, et al. Dis Mon. 2019 Mar;65(3):51-90. doi: 10.1016/j.disamonth.2018.06.001. Epub 2018 Jul 20. Dis Mon. 2019. PMID: 30037762 Review.
  • Psoriasis: a brief overview. Raharja A, Mahil SK, Barker JN. Raharja A, et al. Clin Med (Lond). 2021 May;21(3):170-173. doi: 10.7861/clinmed.2021-0257. Clin Med (Lond). 2021. PMID: 34001566 Free PMC article.
  • Newer Biologics for the Treatment of Plaque Psoriasis [Internet]. Subramonian A, Walter M. Subramonian A, et al. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2021 Sep. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2021 Sep. PMID: 36343118 Free Books & Documents. Review.
  • Latest Advances for the Treatment of Chronic Plaque Psoriasis with Biologics and Oral Small Molecules. Bellinato F, Gisondi P, Girolomoni G. Bellinato F, et al. Biologics. 2021 Jun 29;15:247-253. doi: 10.2147/BTT.S290309. eCollection 2021. Biologics. 2021. PMID: 34239295 Free PMC article. Review.
  • Rapid response on facial psoriasis to bimekizumab: case series. Bernardini N, Dattola A, Caldarola G, Orsini D, Assorgi C, D'Amore A, Maretti G, Richetta AG, Tolino E, Skroza N, Potenza C. Bernardini N, et al. Drugs Context. 2024 May 23;13:2024-1-4. doi: 10.7573/dic.2024-1-4. eCollection 2024. Drugs Context. 2024. PMID: 38817804 Free PMC article.
  • Rapid progression of condyloma acuminatum caused by IL-17A antibody treatment: a case report. Sun F, Yu Z. Sun F, et al. Front Med (Lausanne). 2024 May 15;11:1387620. doi: 10.3389/fmed.2024.1387620. eCollection 2024. Front Med (Lausanne). 2024. PMID: 38813385 Free PMC article.
  • Metabolic dysfunction associated steatotic liver disease in patients with plaque psoriasis: a case-control study and serological comparison. Lin Z, Shi YY, Yu LY, Ma CX, Pan SY, Dou Y, Zhou QJ, Cao Y. Lin Z, et al. Front Med (Lausanne). 2024 May 15;11:1400741. doi: 10.3389/fmed.2024.1400741. eCollection 2024. Front Med (Lausanne). 2024. PMID: 38813379 Free PMC article.
  • Targeting STING in dendritic cells alleviates psoriatic inflammation by suppressing IL-17A production. Sun X, Liu L, Wang J, Luo X, Wang M, Wang C, Chen J, Zhou Y, Yin H, Song Y, Xiong Y, Li H, Zhang M, Zhu B, Li X. Sun X, et al. Cell Mol Immunol. 2024 May 28. doi: 10.1038/s41423-024-01160-y. Online ahead of print. Cell Mol Immunol. 2024. PMID: 38806624
  • Reactive oxygen species-responsive supramolecular deucravacitinib self-assembly polymer micelles alleviate psoriatic skin inflammation by reducing mitochondrial oxidative stress. Yao L, Tian F, Meng Q, Guo L, Ma Z, Hu T, Liang Q, Li Z. Yao L, et al. Front Immunol. 2024 May 10;15:1407782. doi: 10.3389/fimmu.2024.1407782. eCollection 2024. Front Immunol. 2024. PMID: 38799436 Free PMC article.

Publication types

  • Search in MeSH

Related information

  • Cited in Books

LinkOut - more resources

Full text sources.

  • Ovid Technologies, Inc.
  • Silverchair Information Systems

Other Literature Sources

  • The Lens - Patent Citations
  • Genetic Alliance
  • MedlinePlus Health Information
  • Citation Manager

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

  • Open access
  • 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

1 Citations

Metrics details

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.

Epidemiology

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 ).

Conclusions

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/ .

Abbreviations

Blood–brain barrier

Cellular and molecular pathway

Central nervous system

Catechol-o-methyltransferase

Cytochrome P450A2

Damaged associated molecular pathway

Enteric nervous system

Glutamic acid decarboxylase

Glucocerebrosidase

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

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Nicotinamide adenine dinucleotide hydrogen

Nitric oxide

Nitric oxide synthase

Superoxide anion

6-Hydroxydopamine

Hydroxyl radical

Parkinson's disease

Reactive oxygen species

Subcutaneous route

Substantia nigra paras compacta

Tyrosine hydroxylase

Adams C, Suescun J, Haque A, Block K, Chandra S, Ellmore TM, Schiess MC (2023) Updated Parkinson’s disease motor subtypes classification and correlation to cerebrospinal homovanillic acid and 5-hydroxyindoleacetic acid levels. Clin Parkinsonism Related Disord 8:100187

Article   Google Scholar  

Adamson A, Buck SA, Freyberg Z, De Miranda BR (2022) Sex differences in dopaminergic vulnerability to environmental toxicants—implications for Parkinson’s disease. Curr Environ Health Rep 9(4):563–573

Article   PubMed   Google Scholar  

Agnihotri A, Aruoma OI (2020) Alzheimer’s disease and Parkinson’s disease: a nutritional toxicology perspective of the impact of oxidative stress, mitochondrial dysfunction, nutrigenomics and environmental chemicals. J Am Coll Nutr 39(1):16–27

Article   CAS   PubMed   Google Scholar  

Aryal B, Lee Y (2019) Disease model organism for Parkinson disease: drosophila melanogaster. BMB Rep 52(4):250

Article   CAS   PubMed   PubMed Central   Google Scholar  

Asemi-Rad A, Moafi M, Aliaghaei A, Abbaszadeh HA, Abdollahifar MA, Ebrahimi MJ, Heidari MH, Sadeghi Y (2022) The effect of dopaminergic neuron transplantation and melatonin co-administration on oxidative stress-induced cell death in Parkinson’s disease. Metab Brain Dis 37(8):2677–2685

Bai X, Liu X, Li X, Li W, Xie A (2021) Association between VPS13C rs2414739 polymorphism and Parkinson’s disease risk: A meta-analysis. Neurosci Lett 29(754):135879

Barker RA (2019) Designing stem-cell-based dopamine cell replacement trials for Parkinson’s disease. Nat Med 25(7):1045–1053

Belvisi D, Pellicciari R, Fabbrini A, Costanzo M, Ressa G, Pietracupa S, De Lucia M, Modugno N, Magrinelli F, Dallocchio C, Ercoli T (2022) Relationship between risk and protective factors and clinical features of Parkinson’s disease. Parkinsonism Relat Disord 98:80–85

Bjørklund G, Hofer T, Nurchi VM, Aaseth J (2019) Iron and other metals in the pathogenesis of Parkinson’s disease: toxic effects and possible detoxification. J Inorg Biochem 199:110717

Borghammer P, Just MK, Horsager J, Skjærbæk C, Raunio A, Kok EH, Savola S, Murayama S, Saito Y, Myllykangas L, Van Den Berge N (2022) A postmortem study suggests a revision of the dual-hit hypothesis of Parkinson’s disease. NPJ Parkinson’s Disease 8(1):166

Article   PubMed   PubMed Central   Google Scholar  

Bouchez C, Devin A (2019) Mitochondrial biogenesis and mitochondrial reactive oxygen species (ROS): a complex relationship regulated by the cAMP/PKA signaling pathway. Cells 8(4):287

Braidy N, Zarka M, Jugder BE, Welch J, Jayasena T, Chan DK, Sachdev P, Bridge W (2019) The precursor to glutathione (GSH), γ-Glutamylcysteine (GGC), can ameliorate oxidative damage and neuroinflammation induced by Aβ40 oligomers in human astrocytes. Front Aging Neurosci 11:177

Bryson S (2020) Gene therapy trial patients, in death, helping show what did and didn't work. Parkinson's News Today

Calabresi P, Mechelli A, Natale G, Volpicelli-Daley L, Di Lazzaro G, Ghiglieri V (2023) Alpha-synuclein in Parkinson’s disease and other synucleinopathies: from overt neurodegeneration back to early synaptic dysfunction. Cell Death Dis 14(3):176

Camargo CH, Della-Coletta MV, da Silva DJ, Teive HA (2019) Alpha-synucleinopathies: Parkinson's disease, dementia with lewy bodies, and multiple system atrophy. In: Handbook of research on critical examinations of neurodegenerative disorders 2019. IGI Global, pp 274–297

Chia SJ, Tan EK, Chao YX (2020) Historical perspective: models of Parkinson’s disease. Int J Mol Sci 21(7):2464

Choudhury SP, Bano S, Sen S, Suchal K, Kumar S, Nikolajeff F, Dey SK, Sharma V (2022) Altered neural cell junctions and ion-channels leading to disrupted neuron communication in Parkinson’s disease. NPJ Parkinson’s Disease. 8(1):66

Clinical Research. https://www.fda.gov/patients/drug-development-process/step-3-clinical-research . Accessed 26 Jan 2021.

Colle D, Farina M (2021) Oxidative stress in paraquat-induced damage to nervous tissues. In: Toxicology. Academic Press, pp 69–78

Crowley EK, Nolan YM, Sullivan AM (2019) Exercise as a therapeutic intervention for motor and non-motor symptoms in Parkinson’s disease: evidence from rodent models. Prog Neurobiol 172:2–22

da Silva WA, Oliveira KF, Vitorino LC, Romão LF, Allodi S, Correa CL (2021) Physical exercise increases the production of tyrosine hydroxylase and CDNF in the spinal cord of a Parkinson’s disease mouse model. Neurosci Lett 760:136089

Desai A, Benner L, Wu R, Gertsik L, Maruff P, Light GA, Uz T, Marek GJ, Zhu T (2021) Phase 1 randomized study on the safety, tolerability, and pharmacodynamic cognitive and electrophysiological effects of a dopamine D1 receptor positive allosteric modulator in patients with schizophrenia. Neuropsychopharmacology 46(6):1145–1151

Di Luca DG, Feldman M, Jimsheleishvili S, Margolesky J, Cordeiro JG, Diaz A, Shpiner DS, Moore HP, Singer C, Li H, Luca C (2020) Trends of inpatient palliative care use among hospitalized patients with Parkinson’s disease. Parkinsonism Relat Disord 77:13–17

Draoui A, El Hiba O, Aimrane A, El Khiat A, Gamrani H (2020) Parkinson’s disease: from bench to bedside. Revue Neurol 176(7–8):543–559

Article   CAS   Google Scholar  

Dumurgier J, Tzourio C (2020) Epidemiology of neurological diseases in older adults. Revue Neurol 176(9):642–648

Fabbri M, Coelho M, Abreu D, Guedes LC, Rosa MM, Godinho C, Cardoso R, Guimaraes I, Antonini A, Zibetti M, Lopiano L (2019) Dysphagia predicts poor outcome in late-stage Parkinson’s disease. Parkinsonism Relat Disord 64:73–81

Feng YS, Yang SD, Tan ZX, Wang MM, Xing Y, Dong F, Zhang F (2020) The benefits and mechanisms of exercise training for Parkinson’s disease. Life Sci 245:117345

Flynn MS, Robinson C, Patel S, Liu B, Green C, Pavlis M (2023) Clinicopathologic characteristics of melanoma in patients with parkinson disease. JID Innovations 3(2):100173

Fraint A, Pal DG, Tam E, et al (2018) Interest in genetic testing in Parkinson’s disease patients with deep brain stimulation. Neurology 90(15 Supplement):P4.069

Gao C, Liu J, Tan Y, Chen S (2020) Freezing of gait in Parkinson’s disease: pathophysiology, risk factors and treatments. Trans Neurodegener 9:1–22

Ghosh S, Won SJ, Wang J, Fong R, Butler NJM, Moss A, Wong C, Pan J, Sanchez J, Huynh A et al (2021) α-Synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism. Prog Neurobiol 202:102070

Greener M (2021) Parkinson’s disease: is pharmacotherapy on the move? Prescriber 32(8–9):26–31

Guo Z, Ruan Z, Zhang D, Liu X, Hou L, Wang Q (2022) Rotenone impairs learning and memory in mice through microglia-mediated blood brain barrier disruption and neuronal apoptosis. Chemosphere 291:132982

Article   ADS   CAS   PubMed   Google Scholar  

Hamed MA, Mohammed MA, Aboul Naser AF, Matloub AA, Fayed DB, Ali SA, Khalil WK (2019) Optimization of curcuminoids extraction for evaluation against Parkinson’s disease in rats. J Biological Act Products Nat 9(5):335–351

Hollville E, Joers V, Nakamura A, Swahari V, Tansey MG, Moy SS, Deshmukh M (2020) Characterization of a Cul9–Parkin double knockout mouse model for Parkinson’s disease. Sci Rep 10(1):1–3

Ishiguro M, Li Y, Yoshino H, Daida K, Ishiguro Y, Oyama G, Saiki S, Funayama M, Hattori N, Nishioka K (2021) Clinical manifestations of Parkinson’s disease harboring VPS35 retromer complex component p D620N with long-term follow-up. Parkinsonism Relat Disord 84:139–143

Islam MS, Azim F, Saju H, Zargaran A, Shirzad M, Kamal M, Fatema K, Rehman S, Azad MM, Ebrahimi-Barough S (2021) Pesticides and Parkinson’s disease: current and future perspective. J Chem Neuroanat 115:101966

Ivanova M (2020) Altered sphingolipids metabolism damaged mitochondrial functions: lessons learned from Gaucher and Fabry diseases. J Clin Med 9(4):1116

Jaiswal V, Alquraish D, Sarfraz Z, Sarfraz A, Nagpal S, Singh Shrestha P, Mukherjee D, Guntipalli P, Sánchez Velazco DF, Bhatnagar A, Savani S (2021) The influence of coronavirus disease-2019 (COVID-19) on Parkinson’s disease: an updated systematic review. J Prim Care Commun Health 12:21501327211039708

Jia F, Fellner A, Kumar KR (2022) Monogenic Parkinson’s disease: genotype, phenotype, pathophysiology, and genetic testing. Genes 13(3):471

Jia Y, Tan W, Zhou Y (2020) Transfer RNA-derived small RNAs: potential applications as novel biomarkers for disease diagnosis and prognosis. Ann Transl Med 8(17):1092

Jiménez-Gómez B, Ortega-Sáenz P, Gao L, González-Rodríguez P, García-Flores P, Chandel N, López-Barneo J (2023) Transgenic NADH dehydrogenase restores oxygen regulation of breathing in mitochondrial complex I-deficient mice. Nat Commun 14(1):1172

Article   ADS   PubMed   PubMed Central   Google Scholar  

Kambey PA, Chengcheng M, Xiaoxiao G, Abdulrahman AA, Kanwore K, Nadeem I, Jiao W, Gao D (2021) The orphan nuclear receptor Nurr1 agonist amodiaquine mediates neuroprotective effects in 6-OHDA Parkinson’s disease animal model by enhancing the phosphorylation of P38 mitogen-activated kinase but not PI3K/AKT signaling pathway. Metab Brain Dis 36:609–625

Kayis G, Yilmaz R, Arda B, Akbostancı MC (2023) Risk disclosure in prodromal Parkinson’s disease—a survey of neurologists. Parkinsonism Relat Disord 106:105240

Koga S, Zhou X, Dickson DW (2021) Machine learning-based decision tree classifier for the diagnosis of progressive supranuclear palsy and corticobasal degeneration. Neuropathol Appl Neurobiol 47(7):931–941

Liu C, Liu Z, Zhang Z, Li Y, Fang R, Li F, Zhang J (2020) A scientometric analysis and visualization of research on Parkinson’s disease associated with pesticide exposure. Front Public Health 8:91

Liu H, Liu H, Li T, Cui J, Fu Y, Ren J, Sun X, Jiang P, Yu S, Li C (2017) NR4A2 genetic variation and Parkinson’s disease: evidence from a systematic review and meta-analysis. Neurosci Lett 650:25–32

Mailloux RJ (2020) An update on mitochondrial reactive oxygen species production. Antioxidants 9(6):472

Marchetti B (2020) Nrf2/Wnt resilience orchestrates rejuvenation of glia-neuron dialogue in Parkinson’s disease. Redox Biol 36:101664

Martínez-Chacón G, Yakhine-Diop SM, González-Polo RA, Bravo-San Pedro JM, Pizarro-Estrella E, Niso-Santano M, Fuentes JM (2021) Links between paraquat and Parkinson’s disease. Handbook of Neurotoxicity, pp 1–9

Masato A, Plotegher N, Boassa D, Bubacco L (2019) Impaired dopamine metabolism in Parkinson’s disease pathogenesis. Mol Neurodegener 14(1):1–21

Masato A, Sandre M, Antonini A, Bubacco L (2021) Patients stratification strategies to optimize the effectiveness of scavenging biogenic aldehydes: towards a neuroprotective approach for Parkinson’s disease. Curr Neuropharmacol 19(10):1618

Merchant KM, Cedarbaum JM, Brundin P, Dave KD, Eberling J, Espay AJ, Hutten SJ, Javidnia M, Luthman J, Maetzler W et al (2019) A proposed roadmap for Parkinson’s disease proof of concept clinical trials investigating compounds targeting alpha-synuclein. J Parkinson’s Dis 9:31–61

Merkow RP, Schwartz TA, Nathens AB (2020) Practical guide to comparative effectiveness research using observational data. JAMA Surg 155(4):349–350

Millichap LE, Damiani E, Tiano L, Hargreaves IP (2021) Targetable pathways for alleviating mitochondrial dysfunction in neurodegeneration of metabolic and non-metabolic diseases. Int J Mol Sci 22(21):11444

Mullin S, Smith L, Lee K, D’Souza G, Woodgate P, Elflein J, Hällqvist J, Toffoli M, Streeter A, Hosking J et al (2020) Ambroxol for the treatment of patients with Parkinson disease with and without glucocerebrosidase gene mutations: a nonrandomized, non controlled trial. JAMA Neurol 77:427–434

Mylius V, Möller JC, Bohlhalter S, Ciampi-de-Andrade D, Perez-Lloret S (2021) Diagnosis and management of pain in Parkinson’s disease: a new approach. Drugs Aging 38:559–577

Nakamura T, Oh CK, Zhang X, Lipton SA (2021) Protein S-nitrosylation and oxidation contribute to protein misfolding in neurodegeneration. Free Radical Biol Med 172:562–577

Neag MA, Mitre AO, Catinean A, Mitre CI (2020) An overview on the mechanisms of neuroprotection and neurotoxicity of isoflurane and sevoflurane in experimental studies. Brain Res Bull 165:281–289

Neshige S, Ohshita T, Neshige R, Maruyama H (2021) Influence of current and previous smoking on current phenotype in Parkinson’s disease. J Neurol Sci 427:117534

Nunes C, Laranjinha J (2021) Nitric oxide and dopamine metabolism converge via mitochondrial dysfunction in the mechanisms of neurodegeneration in Parkinson’s disease. Arch Biochem Biophys 704:108877

Palasz E, Niewiadomski W, Gasiorowska A, Mietelska-Porowska A, Niewiadomska G (2019) Neuroplasticity and neuroprotective effect of treadmill training in the chronic mouse model of Parkinson’s disease. Neural Plasticity 2019:8215017

Papagiannakis N, Koros C, Stamelou M et al (2018) Alpha-synuclein dimerization in erythrocytes of patients with genetic and nongenetic forms of Parkinson’s Disease. Neurosci Lett 672:145–149

Park JH, Kim DH, Kwon DY, Choi M, Kim S, Jung JH, Han K, Park YG (2019) Trends in the incidence and prevalence of Parkinson’s disease in Korea: a nationwide, population-based study. BMC Geriatr 19:1

Parker JE, Martinez A, Deutsch GK, Prabhakar V, Listing M, Kapphahn KI, Anidi CM, Neuville R, Coburn M, Shah N, Bronte-Stewart HM (2020) Safety of plasma infusions in Parkinson’s disease. Mon Disord 35(11):1905–1913

Pereira AP, Marinho V, Gupta D, Magalhães F, Ayres C, Teixeira S (2019) Music therapy and dance as gait rehabilitation in patients with Parkinson disease: a review of evidence. J Geriatr Psychiatry Neurol 32(1):49–56

Rocha EM, Keeney MT, Di Maio R, De Miranda BR, Greenamyre JT (2022) LRRK2 and idiopathic Parkinson’s disease. Trends Neurosci 45(3):224–236

Roeh A, Kirchner SK, Malchow B, Maurus I, Schmitt A, Falkai P, Hasan A (2019) Depression in somatic disorders: is there a beneficial effect of exercise? Front Psychol 10:141

Sachan N, Saraswat N, Chandra P, Khalid M, Kabra A (2022) Isolation of Thymol from Trachyspermum ammi Fruits for Treatment of Diabetes and Diabetic Neuropathy in STZ-Induced Rats. BioMed Res Int 2022:8263999

Saraswat N, Sachan N, Chandra P (2020a) A review on ethnobotanical, phytochemical, pharmacological and traditional aspects of indigenous Indian herb Trachyspermum ammi (L). Curr Tradit Med 6(3):172–187

Saraswat N, Sachan N, Chandra P (2020b) Anti-diabetic, diabetic neuropathy protective action and mechanism of action involving oxidative pathway of chlorogenic acid isolated from Selinum vaginatum roots in rats. Heliyon 6(10):e05137

Selvaraj S, Piramanayagam S (2019) Impact of gene mutation in the development of Parkinson’s disease. Genes Diseases 6(2):120–128

Senturk ZK (2020) Early diagnosis of Parkinson’s disease using machine learning algorithms. Med Hypotheses 138:109603

Sitzia G (2022) The circuit and synaptic organization of the basal ganglia output: mechanistic insights on movement disorders and action control

Skidmore FM, Monroe WS, Hurt CP, Nicholas AP, Gerstenecker A, Anthony T, Jololian L, Cutter G, Bashir A, Denny T, Standaert D (2022) The emerging postural instability phenotype in idiopathic Parkinson disease. NPJ Parkinson’s Disease 8(1):28

Smeyne RJ, Noyce AJ, Byrne M, Savica R, Marras C (2021) Infection and risk of Parkinson’s disease. J Parkinsons Dis 11(1):31–43

Sonustun B, Altay MF, Strand C, Ebanks K, Hondhamuni G, Warner TT, Lashuel HA, Bandopadhyay R (2022) Pathological relevance of post-translationally modified alpha-synuclein (pSer87, pSer129, nTyr39) in idiopathic Parkinson’s disease and Multiple System Atrophy. Cells 11(5):906

Staff NP, Jones DT, Singer W (2019) Mesenchymal stromal cell therapies for neurodegenerative diseases. Mayo Clinic proceedings. Retrieved January 26, 2022.

Sun C, Armstrong MJ (2021) Treatment of Parkinson’s disease with cognitive impairment: current approaches and future directions. Behav Sci 11(4):54

Teleanu DM, Niculescu AG, Lungu II, Radu CI, Vladâcenco O, Roza E, Costăchescu B, Grumezescu AM, Teleanu RI (2022) An overview of oxidative stress, neuroinflammation, and neurodegenerative diseases. Int J Mol Sci 23(11):5938

Tolosa E, Garrido A, Scholz SW, Poewe W (2021) Challenges in the diagnosis of Parkinson’s disease. Lancet Neurol 20(5):385–397

Tran J, Anastacio H, Bardy C (2020) Genetic predispositions of Parkinson’s disease revealed in patient-derived brain cells. NPJ Parkinson’s Disease 6(1):8

Tran TN, Le Ha UN, Nguyen TM, Nguyen TD, Vo KN, Dang TH, Trinh PM, Truong D (2021) The effect of non-motor symptoms on health-related quality of life in patients with young onset Parkinson’s disease: a single center vietnamese cross-sectional study. Clin Parkinsonism Related Disord 5:100118

Trist BG, Hare DJ, Double KL (2019) Oxidative stress in the aging substantia nigra and the etiology of Parkinson’s disease. Aging Cell 18(6):e13031

Vaccari C, El Dib R, Gomaa H, Lopes LC, de Camargo JL (2019) Paraquat and Parkinson’s disease: a systematic review and meta-analysis of observational studies. J Toxicol Environ Health Part B 22(5–6):172–202

Van der Perren A, Gelders G, Fenyi A, Bousset L, Brito F, Peelaerts W, Van den Haute C, Gentleman S, Melki R, Baekelandt V (2020) The structural differences between patient-derived α-synuclein strains dictate characteristics of Parkinson’s disease, multiple system atrophy and dementia with lewy bodies. Acta Neuropathol 139:977–1000

Wang W, Kang PM (2020) Oxidative stress and antioxidant treatments in cardiovascular diseases. Antioxidants 9(12):1292

Wuthrich VM, Rapee RM (2019) Telephone-delivered cognitive behavioural therapy for treating symptoms of anxiety and depression in Parkinson’s disease: a pilot trial. Clin Gerontol 42(4):444–453

Xicoy H, Klemann CJ, De Witte W, Martens MB, Martens GJ, Poelmans G (2021) Shared genetic etiology between Parkinson’s disease and blood levels of specific lipids. NPJ Parkinson’s Disease 7(1):23

Xu Y, Cai X, Qu S, Zhang J, Zhang Z, Yao Z, Huang Y, Zhong Z (2020) Madopar combined with acupuncture improves motor and non-motor symptoms in Parkinson’s disease patients: a multicenter randomized controlled trial. Eur J Integr Med 1(34):101049

Yin R, Xue J, Tan Y, Fang C, Hu C, Yang Q, Mei X, Qi D (2021) The positive role and mechanism of herbal medicine in Parkinson’s disease. Oxid Med Cell Longevity 2021:9923331

Zampese E, Surmeier DJ (2020) Calcium, bioenergetics, and Parkinson’s disease. Cells 9(9):2045

Download references

Acknowledgements

We are thankful for entire Pharmacology Department at Dr. DY Patil College of Pharmacy, Akurdi, for successful completion of work.

Not applicable.

Author information

Authors and affiliations.

Department of Pharmacology, Dr. D.Y. Patil College of Pharmacy, Akurdi, D.Y. Patil Educational Complex, Sector Pradhikaran, Nigdi, Pune, Maharashtra, 411044, India

Ayesha Sayyaed, Nikita Saraswat, Neeraj Vyawahare & Ashish Kulkarni

You can also search for this author in PubMed   Google Scholar

Contributions

AS complied the paper, worked on English, grammar, and collected information regarding genetic studies. NS was responsible for filtering the useful information and mechanisms enlisted. NV contributed in the basic idea of paper and collected all data regarding recent clinical trials with their interpretations. AK was responsible for all high-quality diagrams, epidemiological data, and information regarding risk factors.

Corresponding author

Correspondence to Nikita Saraswat .

Ethics declarations

Ethics approval and consent to participate.

No ethical approval or consent to participate was required for this manuscript.

Consent for publication

Yes, all the researches studied have been duly cited and we have all the open access rights to access these studies.

Competing interests

No, the authors declare that they have no competing interests.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ .

Reprints and permissions

About this article

Cite this article.

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

Download citation

Received : 08 March 2023

Accepted : 13 May 2023

Published : 23 May 2023

DOI : https://doi.org/10.1186/s42269-023-01047-4

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

  • Cellular and molecular pathways
  • Clinical trials
  • Genetic mutation
  • Genetic models
  • Parkinson’s disease

free research paper on pathophysiology

Spartanburg Community College Library

  • Spartanburg Community College Library
  • SCC Research Guides

NUR 120 - Care Plan and Pathophysiology Paper

  • 7. Write Your Paper

ask a librarian email questions

Write Your Paper/Project

Getting started.

  • Writing Fundamentals from Writer's Reference Center This has links to articles on writing any document, paraphrasing, quotations, writing a thesis statement, outline, body paragraphs, conclusion, and writing about themes, characters, form, symbols, etc.
  • Choosing a Research Topic and Creating a Thesis This guide from the SCC Library provides students information on how to choose a research topic for an assignment including what makes a good research topic, concept mapping, background research, and narrowing a topic and most importantly information about creating a thesis.
  • Choosing a Topic (Tutorial) This SCC Library tutorial will walk you through how to choose an appropriate topic for a research assignment and help you turn your research topic into a thesis statement.

APA Formatting for Papers

If you're using MLA Format for your paper - see our MLA Guide

  • Formatting Your Title Page and Paper-APA This guide from SCC Library provides you instructions in MS Word on how to format the title page and paper in APA for student papers.
  • Formatting Your Reference Page-APA This guide from SCC Library provides you instructions in MS Word for formatting references page correctly including proper font and hanging in-dent.
  • Sample Paper in APA Format This sample paper shows how an APA paper should look.

Incorporating Sources into a Research Project & Avoiding Plagiarism

  • Organizing Your Research This guide from the SCC Library provides information on creating research note cards, source tables, and research outlines to help organize your sources so that you can incorporate them into your paper.
  • Incorporating Sources into a Research Project This guide from the SCC Library provides resources on how to properly include sources in a research project without plagiarism, whether through good note-taking, following the research process, or using direct quotations, paraphrasing, or summarizing, etc.
  • How to Paraphrase: Avoid Plagiarism in Research Papers with Paraphrases & Quotations (3 min. video) This video explains how to paraphrase information correctly to avoid plagiarism.
  • English Composition I: The Writer's Circle, Lesson 9, Part 4, Integrating Research (Video) This video talk about citing sources to avoid plagiarizing. (1 min)

Additional Resources

  • Purdue Online Writing Lab (OWL) This site contains resources for writing, research, grammar, mechanics, and style guides (MLA & APA).

free research paper on pathophysiology

The Learning Center (TLC)

Student working with tutor

  • Free live online tutoring and writing help, available 24/7 -  TutorMe  (accessed through D2L).
  • Visit the TLC in-person at Giles or other campuses. Visit the  TLC Portal Page (SCC Log in Required)  for hours and English and Computer tutor availability.
  • Email your paper/project to them at  [email protected] . They offer a 48 hour turn-around on papers (excluding weekends and holidays), and ask that you send a copy of the assignment as well. The paper needs to be Microsoft Word format (don't share a copy of your OneDrive/cloud account), and please include your due date and SCC college ID number in the email.

Visit the The Learning Center located in the P. Dan Hull Building, rooms E2, E5, E6.  See TLC Portal Page (SCC log in required) for additional locations. Contact The Learning Center for more information .

  • << Previous: 6. Evaluate Your Sources
  • Next: Contact Us >>
  • 1. Getting Started
  • 2. Explore Your Topic
  • 3. Search for Information
  • 4. Find Sources
  • List of Nursing Journals
  • 5. Cite Your Sources
  • 6. Evaluate Your Sources

Questions? Ask a Librarian

SCC Librarian and student working together

  • Last Updated: May 8, 2024 9:31 AM
  • URL: https://libguides.sccsc.edu/nur120-pathophysiology

Giles Campus | 864.592.4764 | Toll Free 866.542.2779 | Contact Us

Copyright © 2024 Spartanburg Community College. All rights reserved.

Info for Library Staff | Guide Search

Return to SCC Website

MERRIMACK COLLEGE MCQUADE LIBRARY

Pathophysiology.

  • Getting Started
  • Types of Articles
  • Primary versus Secondary Sources
  • Academic Integrity
  • APA Style and Grammar Guidelines
  • Purdue Online Writing Lab: APA Style and Formatting Guide
  • Merrimack College Writing Center

APA Formatting & Citations (7th edition)

APA (American Psychological Association) style is most commonly used to write papers and cite sources within the social sciences.

If you are asked to use APA format, be sure to consult the Publication manual of the American Psychological Association, located in McQuade Library's reference collection:

free research paper on pathophysiology

The Purdue Online Writing Lab (OWL) is the gold standard for online tools to teach you about citations and formatting.

From the website you can learn to:

  • Format in-text, and full bibliographical citations for a variety of source types
  • Follow formatting and style guidelines for a variety of assignments

Perdue OWL: APA Formatting and Style Guide

  • APA 7th Edition Quick Reference Guide
  • APA 7th Edition Title Page Guide
  • APA Running Head
  • Purdue Owl - APA Formatting Videos
  • Sample APA Papers
  • APA Title Page Setup
  • All authors' names should be inverted (i.e., last names should be provided first).
  • Authors' first and middle names should be written as initials.
  • Give the last name and first/middle initials for all authors of a particular work up to and including 20 authors
  • Reference list entries should be alphabetized by the last name of the first author of each work.
  • For multiple articles by the same author, or authors listed in the same order, list the entries in chronological order, from earliest to most recent.
  • When referring to the titles of books, chapters, articles, reports, webpages,   or other sources, capitalize only the first letter of the first word of the title and subtitle, the first word after a colon or a dash in the title, and proper nouns.
  • Italicize titles of longer works (e.g., books, edited collections, names of newspapers, and so on).
  • Do not italicize, underline, or put quotes around the titles of shorter works such as chapters in books or essays in edited collections.
  • Present journal titles in full.
  • Italicize journal titles.
  • Maintain any nonstandard punctuation and capitalization that is used by the journal in its title.
  • Capitalize all major words in the titles of journals. Note that this differs from the rule for titling other common sources (like books, reports, webpages, and so on) described above.
  • Capitalize the first word of the titles and subtitles of journal articles, as well as the first word after a colon or a dash in the title, and any proper nouns.
  • Do not italicize or underline the article title.
  • Do not enclose the article title in quotes. 
  • All lines after the first line of each entry in your reference list should be indented one-half inch from the left margin. This is called hanging indentation.
  • << Previous: Academic Integrity
  • Last Updated: Apr 23, 2024 3:29 PM
  • URL: https://libguides.merrimack.edu/pathophysiology

Information

  • Author Services

Initiatives

You are accessing a machine-readable page. In order to be human-readable, please install an RSS reader.

All articles published by MDPI are made immediately available worldwide under an open access license. No special permission is required to reuse all or part of the article published by MDPI, including figures and tables. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited. For more information, please refer to https://www.mdpi.com/openaccess .

Feature papers represent the most advanced research with significant potential for high impact in the field. A Feature Paper should be a substantial original Article that involves several techniques or approaches, provides an outlook for future research directions and describes possible research applications.

Feature papers are submitted upon individual invitation or recommendation by the scientific editors and must receive positive feedback from the reviewers.

Editor’s Choice articles are based on recommendations by the scientific editors of MDPI journals from around the world. Editors select a small number of articles recently published in the journal that they believe will be particularly interesting to readers, or important in the respective research area. The aim is to provide a snapshot of some of the most exciting work published in the various research areas of the journal.

Original Submission Date Received: .

  • Active Journals
  • Find a Journal
  • Proceedings Series
  • For Authors
  • For Reviewers
  • For Editors
  • For Librarians
  • For Publishers
  • For Societies
  • For Conference Organizers
  • Open Access Policy
  • Institutional Open Access Program
  • Special Issues Guidelines
  • Editorial Process
  • Research and Publication Ethics
  • Article Processing Charges
  • Testimonials
  • Preprints.org
  • SciProfiles
  • Encyclopedia

antibiotics-logo

Article Menu

free research paper on pathophysiology

  • Subscribe SciFeed
  • Recommended Articles
  • Google Scholar
  • on Google Scholar
  • Table of Contents

Find support for a specific problem in the support section of our website.

Please let us know what you think of our products and services.

Visit our dedicated information section to learn more about MDPI.

JSmol Viewer

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

free research paper on pathophysiology

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.

  • Benjafield, A.V.; Ayas, N.T.; Eastwood, P.R.; Heinzer, R.; Ip, M.S.M.; Morrell, M.J.; Nunez, C.M.; Patel, S.R.; Penzel, T.; Pépin, J.L.; et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: A literature-based analysis. Lancet Respir. Med. 2019 , 7 , 687–698. [ Google Scholar ] [ CrossRef ]
  • Heinzer, R.; Vat, S.; Marques-Vidal, P.; Marti-Soler, H.; Andries, D.; Tobback, N.; Mooser, V.; Preisig, M.; Malhotra, A.; Waeber, G.; et al. Prevalence of sleep-disordered breathing in the general population: The HypnoLaus study. Lancet Respir. Med. 2015 , 3 , 310–318. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Dempsey, J.A.; Veasey, S.C.; Morgan, B.J.; O’Donnell, C.P. Pathophysiology of sleep apnea. Physiol. Rev. 2010 , 90 , 47–112. [ Google Scholar ] [ CrossRef ]
  • Eckert, D.J.; Malhotra, A. Pathophysiology of adult obstructive sleep apnea. Proc. Am. Thorac. Soc. 2008 , 5 , 144–153. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Randerath, W.; Bassetti, C.L.; Bonsignore, M.R.; Farre, R.; Ferini-Strambi, L.; Grote, L.; Hedner, J.; Kohler, M.; Martinez-Garcia, M.A.; Mihaicuta, S.; et al. Challenges and perspectives in obstructive sleep apnoea: Report by an ad hoc working group of the Sleep Disordered Breathing Group of the European Respiratory Society and the European Sleep Research Society. Eur. Respir. J. 2018 , 52 , 1702616. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Bonsignore, M.R.; Baiamonte, P.; Mazzuca, E.; Castrogiovanni, A.; Marrone, O. Obstructive sleep apnea and comorbidities: A dangerous liaison. Multidiscip. Respir. Med. 2019 , 14 , 8. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Kim, J.Y.; Ko, I.; Kim, D.K. Association of Obstructive Sleep Apnea with the Risk of Affective Disorders. JAMA Otolaryngol. Head. Neck Surg. 2019 , 145 , 1020–1026. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Feldman, C.; Shaddock, E. Epidemiology of lower respiratory tract infections in adults. Expert. Rev. Respir. Med. 2019 , 13 , 63–77. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • International Respiratory Coalition (IRC). Lower Respiratory Tract Infections. Available online: https://international-respiratory-coalition.org/diseases/lower-respiratory-tract-infections/ (accessed on 10 April 2024).
  • The Top 10 Causes of Death. Available online: https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death (accessed on 10 April 2024).
  • Docherty, A.B.; Harrison, E.M.; Green, C.A.; Hardwick, H.E.; Pius, R.; Norman, L.; Holden, K.A.; Read, J.M.; Dondelinger, F.; Carson, G.; et al. Features of 20 133 UK patients in hospital with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol: Prospective observational cohort study. BMJ 2020 , 369 , m1985. [ Google Scholar ] [ CrossRef ]
  • Mizgerd, J.P. Acute lower respiratory tract infection. N. Engl. J. Med. 2008 , 358 , 716–727. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Ludwig, K.; Huppertz, T.; Radsak, M.; Gouveris, H. Cellular Immune Dysfunction in Obstructive Sleep Apnea. Front. Surg. 2022 , 9 , 890377. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Faverio, P.; Zanini, U.; Monzani, A.; Parati, G.; Luppi, F.; Lombardi, C.; Perger, E. Sleep-Disordered Breathing and Chronic Respiratory Infections: A Narrative Review in Adult and Pediatric Population. Int. J. Mol. Sci. 2023 , 24 , 5504. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Keto, J.; Feuth, T.; Linna, M.; Saaresranta, T. Lower respiratory tract infections among newly diagnosed sleep apnea patients. BMC Pulm. Med. 2023 , 23 , 332. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Grant, L.R.; Meche, A.; McGrath, L.; Miles, A.; Alfred, T.; Yan, Q.; Chilson, E. Risk of Pneumococcal Disease in US Adults by Age and Risk Profile. Open Forum Infect. Dis. 2023 , 10 , ofad192. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Lutsey, P.L.; Zineldin, I.; Misialek, J.R.; Full, K.M.; Lakshminarayan, K.; Ishigami, J.; Cowan, L.T.; Matsushita, K.; Demmer, R.T. OSA and Subsequent Risk of Hospitalization with Pneumonia, Respiratory Infection, and Total Infection: The Atherosclerosis Risk in Communities Study. Chest 2023 , 163 , 942–952. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Chiner, E.; Llombart, M.; Valls, J.; Pastor, E.; Sancho-Chust, J.N.; Andreu, A.L.; Sánchez-de-la-Torre, M.; Barbé, F. Association between Obstructive Sleep Apnea and Community-Acquired Pneumonia. PLoS ONE 2016 , 11 , e0152749. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Su, V.Y.; Liu, C.J.; Wang, H.K.; Wu, L.A.; Chang, S.C.; Perng, D.W.; Su, W.J.; Chen, Y.M.; Lin, E.Y.; Chen, T.J.; et al. Sleep apnea and risk of pneumonia: A nationwide population-based study. CMAJ 2014 , 186 , 415–421. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Lindenauer, P.K.; Stefan, M.S.; Johnson, K.G.; Priya, A.; Pekow, P.S.; Rothberg, M.B. Prevalence, treatment, and outcomes associated with OSA among patients hospitalized with pneumonia. Chest 2014 , 145 , 1032–1038. [ Google Scholar ] [ CrossRef ]
  • Beumer, M.C.; Koch, R.M.; van Beuningen, D.; OudeLashof, A.M.; van de Veerdonk, F.L.; Kolwijck, E.; van der Hoeven, J.G.; Bergmans, D.C.; Hoedemaekers, C.W.E. Influenza virus and factors that are associated with ICU admission, pulmonary co-infections and ICU mortality. J. Crit. Care 2019 , 50 , 59–65. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Boattini, M.; Charrier, L.; Almeida, A.; Christaki, E.; Moreira Marques, T.; Tosatto, V.; Bianco, G.; Iannaccone, M.; Tsiolakkis, G.; Karagiannis, C.; et al. Burden of primary influenza and respiratory syncytial virus pneumonia in hospitalised adults: Insights from a 2-year multi-centre cohort study (2017–2018). Intern. Med. J. 2023 , 53 , 404–408. [ Google Scholar ] [ CrossRef ]
  • Mok, E.M.; Greenough, G.; Pollack, C.C. Untreated obstructive sleep apnea is associated with increased hospitalization from influenza infection. J. Clin. Sleep Med. 2020 , 16 , 2003–2007. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Tsai, M.S.; Chen, H.C.; Li, H.Y.; Tsai, Y.T.; Yang, Y.H.; Liu, C.Y.; Lee, Y.C.; Hsu, C.M.; Lee, L.A. Sleep Apnea and Risk of Influenza-Associated Severe Acute Respiratory Infection: Real-World Evidence. Nat. Sci. Sleep 2022 , 14 , 901–909. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Chen, T.Y.; Chang, R.; Chiu, L.T.; Hung, Y.M.; Wei, J.C. Obstructive sleep apnea and influenza infection: A nationwide population-based cohort study. Sleep Med. 2021 , 81 , 202–209. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Mashaqi, S.; Lee-Iannotti, J.; Rangan, P.; Celaya, M.P.; Gozal, D.; Quan, S.F.; Parthasarathy, S. Obstructive sleep apnea and COVID-19 clinical outcomes during hospitalization: A cohort study. J. Clin. Sleep Med. 2021 , 17 , 2197–2204. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Maas, M.B.; Kim, M.; Malkani, R.G.; Abbott, S.M.; Zee, P.C. Obstructive Sleep Apnea and Risk of COVID-19 Infection, Hospitalization and Respiratory Failure. Sleep Breath 2021 , 25 , 1155–1157. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Strausz, S.; Kiiskinen, T.; Broberg, M.; Ruotsalainen, S.; Koskela, J.; Bachour, A.; Palotie, A.; Palotie, T.; Ripatti, S.; Ollila, H.M. Sleep apnoea is a risk factor for severe COVID-19. BMJ Open Respir. Res. 2021 , 8 , e000845. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Rögnvaldsson, K.G.; Eyþórsson, E.S.; Emilsson, Ö.I.; Eysteinsdóttir, B.; Pálsson, R.; Gottfreðsson, M.; Guðmundsson, G.; Steingrímsson, V. Obstructive sleep apnea is an independent risk factor for severe COVID-19: A population-based study. Sleep 2022 , 45 , zsab272. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Cade, B.E.; Dashti, H.S.; Hassan, S.M.; Redline, S.; Karlson, E.W. Sleep Apnea and COVID-19 Mortality and Hospitalization. Am. J. Respir. Crit. Care Med. 2020 , 202 , 1462–1464. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Pena Orbea, C.; Wang, L.; Shah, V.; Jehi, L.; Milinovich, A.; Foldvary-Schaefer, N.; Chung, M.K.; Mashaqi, S.; Aboussouan, L.; Seidel, K.; et al. Association of Sleep-Related Hypoxia with Risk of COVID-19 Hospitalizations and Mortality in a Large Integrated Health System. JAMA Netw. Open 2021 , 4 , e2134241. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Oh, T.K.; Song, I.A. Impact of coronavirus disease-2019 on chronic respiratory disease in South Korea: An NHIS COVID-19 database cohort study. BMC Pulm. Med. 2021 , 21 , 12. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Gottlieb, M.; Sansom, S.; Frankenberger, C.; Ward, E.; Hota, B. Clinical Course and Factors Associated with Hospitalization and Critical Illness Among COVID-19 Patients in Chicago, Illinois. Acad. Emerg. Med. 2020 , 27 , 963–973. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Kendzerska, T.; Povitz, M.; Gershon, A.S.; Ryan, C.M.; Talarico, R.; Franco Avecilla, D.A.; Robillard, R.; Ayas, N.T.; Pendharkar, S.R. Association of clinically significant obstructive sleep apnoea with risks of contracting COVID-19 and serious COVID-19 complications: A retrospective population-based study of health administrative data. Thorax 2023 , 78 , 933–941. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Peker, Y.; Celik, Y.; Arbatli, S.; Isik, S.R.; Balcan, B.; Karataş, F.; Uzel, F.I.; Tabak, L.; Çetin, B.; Baygül, A.; et al. Effect of High-Risk Obstructive Sleep Apnea on Clinical Outcomes in Adults with Coronavirus Disease 2019: A Multicenter, Prospective, Observational Clinical Trial. Ann. Am. Thorac. Soc. 2021 , 18 , 1548–1559. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Girardin, J.L.; Seixas, A.; Ramos Cejudo, J.; Osorio, R.S.; Avirappattu, G.; Reid, M.; Parthasarathy, S. Contribution of pulmonary diseases to COVID-19 mortality in a diverse urban community of New York. Chron. Respir. Dis. 2021 , 18 , 1479973120986806. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Gimeno-Miguel, A.; Bliek-Bueno, K.; Poblador-Plou, B.; Carmona-Pírez, J.; Poncel-Falcó, A.; González-Rubio, F.; Ioakeim-Skoufa, I.; Pico-Soler, V.; Aza-Pascual-Salcedo, M.; Prados-Torres, A.; et al. Chronic diseases associated with increased likelihood of hospitalization and mortality in 68,913 COVID-19 confirmed cases in Spain: A population-based cohort study. PLoS ONE 2021 , 16 , e0259822. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Cariou, B.; Hadjadj, S.; Wargny, M.; Pichelin, M.; Al-Salameh, A.; Allix, I.; Amadou, C.; Arnault, G.; Baudoux, F.; Bauduceau, B.; et al. Phenotypic characteristics and prognosis of inpatients with COVID-19 and diabetes: The CORONADO study. Diabetologia 2020 , 63 , 1500–1515. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Ioannou, G.N.; Locke, E.; Green, P.; Berry, K.; O’Hare, A.M.; Shah, J.A.; Crothers, K.; Eastment, M.C.; Dominitz, J.A.; Fan, V.S. Risk Factors for Hospitalization, Mechanical Ventilation, or Death Among 10 131 US Veterans With SARS-CoV-2 Infection. JAMA Netw. Open 2020 , 3 , e2022310. [ Google Scholar ] [ CrossRef ]
  • Izquierdo, J.L.; Ancochea, J.; Soriano, J.B. Clinical Characteristics and Prognostic Factors for Intensive Care Unit Admission of Patients with COVID-19: Retrospective Study Using Machine Learning and Natural Language Processing. J. Med. Internet Res. 2020 , 22 , e21801. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Lohia, P.; Sreeram, K.; Nguyen, P.; Choudhary, A.; Khicher, S.; Yarandi, H.; Kapur, S.; Badr, M.S. Preexisting respiratory diseases and clinical outcomes in COVID-19: A multihospital cohort study on predominantly African American population. Respir. Res. 2021 , 22 , 37. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Prasad, B.; Mechineni, A.; Talugula, S.; Gardner, J.; Rubinstein, I.; Gordon, H.S. Impact of Obstructive Sleep Apnea on Health Outcomes in Veterans Hospitalized with COVID-19 Infection. Ann. Am. Thorac. Soc. 2024; online ahead of print . [ Google Scholar ] [ CrossRef ]
  • Bailly, S.; Galerneau, L.M.; Ruckly, S.; Seiller, A.; Terzi, N.; Schwebel, C.; Dupuis, C.; Tamisier, R.; Mourvillier, B.; Pepin, J.L.; et al. Impact of obstructive sleep apnea on the obesity paradox in critically ill patients. J. Crit. Care 2020 , 56 , 120–124. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Bolona, E.; Hahn, P.Y.; Afessa, B. Intensive care unit and hospital mortality in patients with obstructive sleep apnea. J. Crit. Care 2015 , 30 , 178–180. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Kim, H.; Webster, R.G.; Webby, R.J. Influenza Virus: Dealing with a Drifting and Shifting Pathogen. Viral Immunol. 2018 , 31 , 174–183. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Tyrrell, C.S.; Allen, J.L.Y.; Gkrania-Klotsas, E. Influenza: Epidemiology and hospital management. Medicine 2021 , 49 , 797–804. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Veerapandian, R.; Snyder, J.D.; Samarasinghe, A.E. Influenza in Asthmatics: For Better or for Worse? Front. Immunol. 2018 , 9 , 1843. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Rennard, S.; Decramer, M.; Calverley, P.M.; Pride, N.B.; Soriano, J.B.; Vermeire, P.A.; Vestbo, J. Impact of COPD in North America and Europe in 2000: Subjects’ perspective of Confronting COPD International Survey. Eur. Respir. J. 2002 , 20 , 799–805. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Williamson, E.J.; Walker, A.J.; Bhaskaran, K.; Bacon, S.; Bates, C.; Morton, C.E.; Curtis, H.J.; Mehrkar, A.; Evans, D.; Inglesby, P.; et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature 2020 , 584 , 430–436. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Denson, J.L.; Gillet, A.S.; Zu, Y.; Brown, M.; Pham, T.; Yoshida, Y.; Mauvais-Jarvis, F.; Douglas, I.S.; Moore, M.; Tea, K.; et al. Metabolic Syndrome and Acute Respiratory Distress Syndrome in Hospitalized Patients With COVID-19. JAMA Netw. Open 2021 , 4 , e2140568. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Miller, M.A.; Cappuccio, F.P. A systematic review of COVID-19 and obstructive sleep apnoea. Sleep Med. Rev. 2021 , 55 , 101382. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Bellou, V.; Tzoulaki, I.; van Smeden, M.; Moons, K.G.M.; Evangelou, E.; Belbasis, L. Prognostic factors for adverse outcomes in patients with COVID-19: A field-wide systematic review and meta-analysis. Eur. Respir. J. 2022 , 59 , 2002964. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Vardavas, C.I.; Mathioudakis, A.G.; Nikitara, K.; Stamatelopoulos, K.; Georgiopoulos, G.; Phalkey, R.; Leonardi-Bee, J.; Fernandez, E.; Carnicer-Pont, D.; Vestbo, J.; et al. Prognostic factors for mortality, intensive care unit and hospital admission due to SARS-CoV-2: A systematic review and meta-analysis of cohort studies in Europe. Eur. Respir. Rev. 2022 , 31 , 220098. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Hariyanto, T.I.; Kurniawan, A. Obstructive sleep apnea (OSA) and outcomes from coronavirus disease 2019 (COVID-19) pneumonia: A systematic review and meta-analysis. Sleep Med. 2021 , 82 , 47–53. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Hu, M.; Han, X.; Ren, J.; Wang, Y.; Yang, H. Significant association of obstructive sleep apnoea with increased risk for fatal COVID-19: A quantitative meta-analysis based on adjusted effect estimates. Sleep Med. Rev. 2022 , 63 , 101624. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Mandel, L.H.; Colleen, G.; Abedian, S.; Ammar, N.; Charles Bailey, L.; Bennett, T.D.; Daniel Brannock, M.; Brosnahan, S.B.; Chen, Y.; Chute, C.G.; et al. Risk of post-acute sequelae of SARS-CoV-2 infection associated with pre-coronavirus disease obstructive sleep apnea diagnoses: An electronic health record-based analysis from the RECOVER initiative. Sleep 2023 , 46 , zsad126. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Labarca, G.; Henríquez-Beltrán, M.; Lamperti, L.; Nova-Lamperti, E.; Sanhueza, S.; Cabrera, C.; Quiroga, R.; Antilef, B.; Ormazábal, V.; Zúñiga, F.; et al. Impact of Obstructive Sleep Apnea (OSA) in COVID-19 Survivors, Symptoms Changes Between 4-Months and 1 Year After the COVID-19 Infection. Front. Med. 2022 , 9 , 884218. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Chervin, R.D. Sleepiness, fatigue, tiredness, and lack of energy in obstructive sleep apnea. Chest 2000 , 118 , 372–379. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • O’Mahoney, L.L.; Routen, A.; Gillies, C.; Ekezie, W.; Welford, A.; Zhang, A.; Karamchandani, U.; Simms-Williams, N.; Cassambai, S.; Ardavani, A.; et al. The prevalence and long-term health effects of Long Covid among hospitalised and non-hospitalised populations: A systematic review and meta-analysis. eClinicalMedicine 2023 , 55 , 101762. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Wulf Hanson, S.; Abbafati, C.; Aerts, J.G.; Al-Aly, Z.; Ashbaugh, C.; Ballouz, T.; Blyuss, O.; Bobkova, P.; Bonsel, G.; Borzakova, S.; et al. Estimated Global Proportions of Individuals with Persistent Fatigue, Cognitive, and Respiratory Symptom Clusters Following Symptomatic COVID-19 in 2020 and 2021. JAMA 2022 , 328 , 1604–1615. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Yaffe, K.; Laffan, A.M.; Harrison, S.L.; Redline, S.; Spira, A.P.; Ensrud, K.E.; Ancoli-Israel, S.; Stone, K.L. Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women. JAMA 2011 , 306 , 613–619. [ Google Scholar ] [ CrossRef ]
  • Huang, L.; Yao, Q.; Gu, X.; Wang, Q.; Ren, L.; Wang, Y.; Hu, P.; Guo, L.; Liu, M.; Xu, J.; et al. 1-year outcomes in hospital survivors with COVID-19: A longitudinal cohort study. Lancet 2021 , 398 , 747–758. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Wheaton, A.G.; Perry, G.S.; Chapman, D.P.; Croft, J.B. Sleep disordered breathing and depression among U.S. adults: National Health and Nutrition Examination Survey, 2005–2008. Sleep 2012 , 35 , 461–467. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Rezaeitalab, F.; Moharrari, F.; Saberi, S.; Asadpour, H.; Rezaeetalab, F. The correlation of anxiety and depression with obstructive sleep apnea syndrome. J. Res. Med. Sci. 2014 , 19 , 205–210. [ Google Scholar ] [ PubMed ]
  • Menzler, K.; Mayr, P.; Knake, S.; Cassel, W.; Viniol, C.; Reitz, L.; Tsalouchidou, P.E.; Janzen, A.; Anschuetz, K.; Mross, P.; et al. Undiagnosed obstructive sleep apnea syndrome as a treatable cause of new-onset sleepiness in some post-COVID patients. Eur. J. Neurol. 2024 , 31 , e16159. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Punjabi, N.M.; Caffo, B.S.; Goodwin, J.L.; Gottlieb, D.J.; Newman, A.B.; O’Connor, G.T.; Rapoport, D.M.; Redline, S.; Resnick, H.E.; Robbins, J.A.; et al. Sleep-disordered breathing and mortality: A prospective cohort study. PLoS Med. 2009 , 6 , e1000132. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Kheirandish-Gozal, L.; Gozal, D. Obstructive Sleep Apnea and Inflammation: Proof of Concept Based on Two Illustrative Cytokines. Int. J. Mol. Sci. 2019 , 20 , 459. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Dewan, N.A.; Nieto, F.J.; Somers, V.K. Intermittent hypoxemia and OSA: Implications for comorbidities. Chest 2015 , 147 , 266–274. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Kimoff, R.J. Sleep fragmentation in obstructive sleep apnea. Sleep 1996 , 19 , S61–S66. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Jun, J.; Savransky, V.; Nanayakkara, A.; Bevans, S.; Li, J.; Smith, P.L.; Polotsky, V.Y. Intermittent hypoxia has organ-specific effects on oxidative stress. Am. J. Physiol. Regul. Integr. Comp. Physiol. 2008 , 295 , R1274–R1281. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Imani, M.M.; Sadeghi, M.; Khazaie, H.; Emami, M.; Sadeghi Bahmani, D.; Brand, S. Evaluation of Serum and Plasma Interleukin-6 Levels in Obstructive Sleep Apnea Syndrome: A Meta-Analysis and Meta-Regression. Front. Immunol. 2020 , 11 , 1343. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Van der Touw, T.; Andronicos, N.M.; Smart, N. Is C-reactive protein elevated in obstructive sleep apnea? A systematic review and meta-analysis. Biomarkers 2019 , 24 , 429–435. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Freund, A.; Orjalo, A.V.; Desprez, P.Y.; Campisi, J. Inflammatory networks during cellular senescence: Causes and consequences. Trends Mol. Med. 2010 , 16 , 238–246. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Santoro, A.; Bientinesi, E.; Monti, D. Immunosenescence and inflammaging in the aging process: Age-related diseases or longevity? Ageing Res. Rev. 2021 , 71 , 101422. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Shukla, S.D.; Walters, E.H.; Simpson, J.L.; Keely, S.; Wark, P.A.B.; O’Toole, R.F.; Hansbro, P.M. Hypoxia-inducible factor and bacterial infections in chronic obstructive pulmonary disease. Respirology 2020 , 25 , 53–63. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Prabhakar, N.R.; Peng, Y.J.; Nanduri, J. Hypoxia-inducible factors and obstructive sleep apnea. J. Clin. Investig. 2020 , 130 , 5042–5051. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Besedovsky, L.; Lange, T.; Born, J. Sleep and immune function. Pflugers Arch. 2012 , 463 , 121–137. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Ibarra-Coronado, E.G.; Pantaleón-Martínez, A.M.; Velazquéz-Moctezuma, J.; Prospéro-García, O.; Méndez-Díaz, M.; Pérez-Tapia, M.; Pavón, L.; Morales-Montor, J. The Bidirectional Relationship between Sleep and Immunity against Infections. J. Immunol. Res. 2015 , 2015 , 678164. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Dopp, J.M.; Wiegert, N.A.; Moran, J.J.; Muller, D.; Weber, S.; Hayney, M.S. Humoral immune responses to influenza vaccination in patients with obstructive sleep apnea. Pharmacotherapy 2007 , 27 , 1483–1489. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Tufik, S.; Andersen, M.L.; Rosa, D.S.; Tufik, S.B.; Pires, G.N. Effects of Obstructive Sleep Apnea on SARS-CoV-2 Antibody Response After Vaccination Against COVID-19 in Older Adults. Nat. Sci. Sleep 2022 , 14 , 1203–1211. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Quach, H.Q.; Warner, N.D.; Ovsyannikova, I.G.; Covassin, N.; Poland, G.A.; Somers, V.K.; Kennedy, R.B. Excessive daytime sleepiness is associated with impaired antibody response to influenza vaccination in older male adults. Front. Cell Infect. Microbiol. 2023 , 13 , 1229035. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Dimitrov, S.; Lange, T.; Tieken, S.; Fehm, H.L.; Born, J. Sleep associated regulation of T helper 1/T helper 2 cytokine balance in humans. Brain Behav. Immun. 2004 , 18 , 341–348. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Patel, S.R.; Malhotra, A.; Gao, X.; Hu, F.B.; Neuman, M.I.; Fawzi, W.W. A prospective study of sleep duration and pneumonia risk in women. Sleep 2012 , 35 , 97–101. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Resta, O.; Foschino Barbaro, M.P.; Bonfitto, P.; Talamo, S.; Mastrosimone, V.; Stefano, A.; Giliberti, T. Hypercapnia in obstructive sleep apnoea syndrome. Neth. J. Med. 2000 , 56 , 215–222. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Budhiraja, R.; Siddiqi, T.A.; Quan, S.F. Sleep disorders in chronic obstructive pulmonary disease: Etiology, impact, and management. J. Clin. Sleep Med. 2015 , 11 , 259–270. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Macavei, V.M.; Spurling, K.J.; Loft, J.; Makker, H.K. Diagnostic predictors of obesity-hypoventilation syndrome in patients suspected of having sleep disordered breathing. J. Clin. Sleep Med. 2013 , 9 , 879–884. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Gates, K.L.; Howell, H.A.; Nair, A.; Vohwinkel, C.U.; Welch, L.C.; Beitel, G.J.; Hauser, A.R.; Sznajder, J.I.; Sporn, P.H. Hypercapnia impairs lung neutrophil function and increases mortality in murine pseudomonas pneumonia. Am. J. Respir. Cell Mol. Biol. 2013 , 49 , 821–828. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Zhu, Q.; Hua, L.; Chen, L.; Mu, T.; Dong, D.; Xu, J.; Shen, C. Causal association between obstructive sleep apnea and gastroesophageal reflux disease: A bidirectional two-sample Mendelian randomization study. Front. Genet. 2023 , 14 , 1111144. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Wu, Z.H.; Yang, X.P.; Niu, X.; Xiao, X.Y.; Chen, X. The relationship between obstructive sleep apnea hypopnea syndrome and gastroesophageal reflux disease: A meta-analysis. Sleep Breath 2019 , 23 , 389–397. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Emilsson, Ö.I.; Bengtsson, A.; Franklin, K.A.; Torén, K.; Benediktsdóttir, B.; Farkhooy, A.; Weyler, J.; Dom, S.; De Backer, W.; Gislason, T.; et al. Nocturnal gastro-oesophageal reflux, asthma and symptoms of OSA: A longitudinal, general population study. Eur. Respir. J. 2013 , 41 , 1347–1354. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • You, C.R.; Oh, J.H.; Seo, M.; Lee, H.Y.; Joo, H.; Jung, S.H.; Lee, S.H.; Choi, M.G. Association Between Non-erosive Reflux Disease and High Risk of Obstructive Sleep Apnea in Korean Population. J. Neurogastroenterol. Motil. 2014 , 20 , 197–204. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Hsu, W.T.; Lai, C.C.; Wang, Y.H.; Tseng, P.H.; Wang, K.; Wang, C.Y.; Chen, L. Risk of pneumonia in patients with gastroesophageal reflux disease: A population-based cohort study. PLoS ONE 2017 , 12 , e0183808. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Fohl, A.L.; Regal, R.E. Proton pump inhibitor-associated pneumonia: Not a breath of fresh air after all? World J. Gastrointest. Pharmacol. Ther. 2011 , 2 , 17–26. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Nguyen, A.T.; Jobin, V.; Payne, R.; Beauregard, J.; Naor, N.; Kimoff, R.J. Laryngeal and velopharyngeal sensory impairment in obstructive sleep apnea. Sleep 2005 , 28 , 585–593. [ Google Scholar ] [ CrossRef ]
  • Ghannouchi, I.; Speyer, R.; Doma, K.; Cordier, R.; Verin, E. Swallowing function and chronic respiratory diseases: Systematic review. Respir. Med. 2016 , 117 , 54–64. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Pizzorni, N.; Radovanovic, D.; Pecis, M.; Lorusso, R.; Annoni, F.; Bartorelli, A.; Rizzi, M.; Schindler, A.; Santus, P. Dysphagia symptoms in obstructive sleep apnea: Prevalence and clinical correlates. Respir. Res. 2021 , 22 , 117. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Teramoto, S.; Sudo, E.; Matsuse, T.; Ohga, E.; Ishii, T.; Ouchi, Y.; Fukuchi, Y. Impaired swallowing reflex in patients with obstructive sleep apnea syndrome. Chest 1999 , 116 , 17–21. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Javaheri, S.; Barbe, F.; Campos-Rodriguez, F.; Dempsey, J.A.; Khayat, R.; Javaheri, S.; Malhotra, A.; Martinez-Garcia, M.A.; Mehra, R.; Pack, A.I.; et al. Sleep Apnea: Types, Mechanisms, and Clinical Cardiovascular Consequences. J. Am. Coll. Cardiol. 2017 , 69 , 841–858. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Gleeson, K.; Eggli, D.F.; Maxwell, S.L. Quantitative aspiration during sleep in normal subjects. Chest 1997 , 111 , 1266–1272. [ Google Scholar ] [ CrossRef ]
  • Beal, M.; Chesson, A.; Garcia, T.; Caldito, G.; Stucker, F.; Nathan, C.O. A pilot study of quantitative aspiration in patients with symptoms of obstructive sleep apnea: Comparison to a historic control group. Laryngoscope 2004 , 114 , 965–968. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Sato, K.; Chitose, S.I.; Sato, K.; Sato, F.; Ono, T.; Umeno, H. Recurrent aspiration pneumonia precipitated by obstructive sleep apnea. Auris Nasus Larynx 2021 , 48 , 659–665. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Peppard, P.E.; Young, T.; Barnet, J.H.; Palta, M.; Hagen, E.W.; Hla, K.M. Increased prevalence of sleep-disordered breathing in adults. Am. J. Epidemiol. 2013 , 177 , 1006–1014. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Jehan, S.; Zizi, F.; Pandi-Perumal, S.R.; Wall, S.; Auguste, E.; Myers, A.K.; Jean-Louis, G.; McFarlane, S.I. Obstructive Sleep Apnea and Obesity: Implications for Public Health. Sleep Med. Disord. 2017 , 1 , 00019. [ Google Scholar ] [ PubMed ]
  • Anderson, M.R.; Shashaty, M.G.S. Impact of Obesity in Critical Illness. Chest 2021 , 160 , 2135–2145. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Zhao, Y.; Li, Z.; Yang, T.; Wang, M.; Xi, X. Is body mass index associated with outcomes of mechanically ventilated adult patients in intensive critical units? A systematic review and meta-analysis. PLoS ONE 2018 , 13 , e0198669. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Kahlon, S.; Eurich, D.T.; Padwal, R.S.; Malhotra, A.; Minhas-Sandhu, J.K.; Marrie, T.J.; Majumdar, S.R. Obesity and outcomes in patients hospitalized with pneumonia. Clin. Microbiol. Infect. 2013 , 19 , 709–716. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Botros, N.; Concato, J.; Mohsenin, V.; Selim, B.; Doctor, K.; Yaggi, H.K. Obstructive sleep apnea as a risk factor for type 2 diabetes. Am. J. Med. 2009 , 122 , 1122–1127. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Peppard, P.E.; Young, T.; Palta, M.; Skatrud, J. Prospective study of the association between sleep-disordered breathing and hypertension. N. Engl. J. Med. 2000 , 342 , 1378–1384. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Marin, J.M.; Carrizo, S.J.; Vicente, E.; Agusti, A.G. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: An observational study. Lancet 2005 , 365 , 1046–1053. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Gottlieb, D.J.; Yenokyan, G.; Newman, A.B.; O’Connor, G.T.; Punjabi, N.M.; Quan, S.F.; Redline, S.; Resnick, H.E.; Tong, E.K.; Diener-West, M.; et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: The sleep heart health study. Circulation 2010 , 122 , 352–360. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Teodorescu, M.; Broytman, O.; Curran-Everett, D.; Sorkness, R.L.; Crisafi, G.; Bleecker, E.R.; Erzurum, S.; Gaston, B.M.; Wenzel, S.E.; Jarjour, N.N. Obstructive Sleep Apnea Risk, Asthma Burden, and Lower Airway Inflammation in Adults in the Severe Asthma Research Program (SARP) II. J. Allergy Clin. Immunol. Pract. 2015 , 3 , 566–575.e561. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Kimmel, P.L.; Miller, G.; Mendelson, W.B. Sleep apnea syndrome in chronic renal disease. Am. J. Med. 1989 , 86 , 308–314. [ Google Scholar ] [ CrossRef ]
  • Torres, A.; Peetermans, W.E.; Viegi, G.; Blasi, F. Risk factors for community-acquired pneumonia in adults in Europe: A literature review. Thorax 2013 , 68 , 1057–1065. [ Google Scholar ] [ CrossRef ]
  • Naqvi, S.B.; Collins, A.J. Infectious complications in chronic kidney disease. Adv. Chronic Kidney Dis. 2006 , 13 , 199–204. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Viasus, D.; Garcia-Vidal, C.; Manresa, F.; Dorca, J.; Gudiol, F.; Carratalà, J. Risk stratification and prognosis of acute cardiac events in hospitalized adults with community-acquired pneumonia. J. Infect. 2013 , 66 , 27–33. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Johnsen, R.H.; Heerfordt, C.K.; Boel, J.B.; Dessau, R.B.; Ostergaard, C.; Sivapalan, P.; Eklöf, J.; Jensen, J.S. Inhaled corticosteroids and risk of lower respiratory tract infection with Moraxella catarrhalis in patients with chronic obstructive pulmonary disease. BMJ Open Respir. Res. 2023 , 10 , e001726. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Metlay, J.P.; Waterer, G.W.; Long, A.C.; Anzueto, A.; Brozek, J.; Crothers, K.; Cooley, L.A.; Dean, N.C.; Fine, M.J.; Flanders, S.A.; et al. Diagnosis and Treatment of Adults with Community-acquired Pneumonia. An Official Clinical Practice Guideline of the American Thoracic Society and Infectious Diseases Society of America. Am. J. Respir. Crit. Care Med. 2019 , 200 , e45–e67. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Kim, M.A.; Park, J.S.; Lee, C.W.; Choi, W.I. Pneumonia severity index in viral community acquired pneumonia in adults. PLoS ONE 2019 , 14 , e0210102. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Restrepo, M.I.; Babu, B.L.; Reyes, L.F.; Chalmers, J.D.; Soni, N.J.; Sibila, O.; Faverio, P.; Cilloniz, C.; Rodriguez-Cintron, W.; Aliberti, S. Burden and risk factors for Pseudomonas aeruginosa community-acquired pneumonia: A multinational point prevalence study of hospitalised patients. Eur. Respir. J. 2018 , 52 , 1701190. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Srivali, N.; Chongnarungsin, D.; Ungprasert, P.; Edmonds, L.C. Two cases of Legionnaires’ disease associated with continuous positive airway pressure therapy. Sleep Med. 2013 , 14 , 1038. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Schnirman, R.; Nur, N.; Bonitati, A.; Carino, G. A case of legionella pneumonia caused by home use of continuous positive airway pressure. SAGE Open Med. Case Rep. 2017 , 5 , 2050313x17744981. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Brady, M.F.; Awosika, A.O.; Sundareshan, V. Legionnaires’ Disease. In StatPearls ; StatPearls Publishing LLC.: Treasure Island, FL, USA, 2024. [ Google Scholar ]
  • Kato, H.; Hagihara, M.; Asai, N.; Shibata, Y.; Koizumi, Y.; Yamagishi, Y.; Mikamo, H. Meta-analysis of fluoroquinolones versus macrolides for treatment of legionella pneumonia. J. Infect. Chemother. 2021 , 27 , 424–433. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Cesar, L.; Gonzalez, C.; Calia, F.M. Bacteriologic flora of aspiration-induced pulmonary infections. Arch. Intern. Med. 1975 , 135 , 711–714. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Influenza Antiviral Medications: Summary for Clinicians|CDC. Available online: https://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm#highrisk (accessed on 4 May 2024).
  • People with Certain Medical Conditions|CDC. Available online: https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html (accessed on 4 May 2024).
  • Zhang, X.B.; Chen, X.Y.; Chiu, K.Y.; He, X.Z.; Wang, J.M.; Zeng, H.Q.; Zeng, Y. Intermittent Hypoxia Inhibits Hepatic CYP1a2 Expression and Delays Aminophylline Metabolism. Evid. Based Complement. Alternat Med. 2022 , 2022 , 2782702. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Fradette, C.; Du Souich, P. Effect of hypoxia on cytochrome P450 activity and expression. Curr. Drug Metab. 2004 , 5 , 257–271. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Fohner, A.E.; Sparreboom, A.; Altman, R.B.; Klein, T.E. PharmGKB summary: Macrolide antibiotic pathway, pharmacokinetics/pharmacodynamics. Pharmacogenet. Genom. 2017 , 27 , 164–167. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Mesarwi, O.A.; Loomba, R.; Malhotra, A. Obstructive Sleep Apnea, Hypoxia, and Nonalcoholic Fatty Liver Disease. Am. J. Respir. Crit. Care Med. 2019 , 199 , 830–841. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Elbarbry, F. Vancomycin Dosing and Monitoring: Critical Evaluation of the Current Practice. Eur. J. Drug Metab. Pharmacokinet. 2018 , 43 , 259–268. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Munar, M.Y.; Singh, H. Drug dosing adjustments in patients with chronic kidney disease. Am. Fam. Physician 2007 , 75 , 1487–1496. [ Google Scholar ] [ PubMed ]
  • Gorelik, E.; Masarwa, R.; Perlman, A.; Rotshild, V.; Abbasi, M.; Muszkat, M.; Matok, I. Fluoroquinolones and Cardiovascular Risk: A Systematic Review, Meta-analysis and Network Meta-analysis. Drug Saf. 2019 , 42 , 529–538. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Guo, D.; Cai, Y.; Chai, D.; Liang, B.; Bai, N.; Wang, R. The cardiotoxicity of macrolides: A systematic review. Pharmazie 2010 , 65 , 631–640. [ Google Scholar ] [ PubMed ]
  • Filippone, E.J.; Kraft, W.K.; Farber, J.L. The Nephrotoxicity of Vancomycin. Clin. Pharmacol. Ther. 2017 , 102 , 459–469. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Frieri, M.; Kumar, K.; Boutin, A. Antibiotic resistance. J. Infect. Public Health 2017 , 10 , 369–378. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • McIsaac, D.I.; Gershon, A.; Wijeysundera, D.; Bryson, G.L.; Badner, N.; van Walraven, C. Identifying Obstructive Sleep Apnea in Administrative Data: A Study of Diagnostic Accuracy. Anesthesiology 2015 , 123 , 253–263. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Steinhauer, K.; Goroncy-Bermes, P. Investigation of the hygienic safety of continuous positive airways pressure devices after reprocessing. J. Hosp. Infect. 2005 , 61 , 168–175. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Ortolano, G.A.; Schaffer, J.; McAlister, M.B.; Stanchfield, I.; Hill, E.; Vandenburgh, L.; Lewis, M.; John, S.; Canonica, F.P.; Cervia, J.S. Filters reduce the risk of bacterial transmission from contaminated heated humidifiers used with CPAP for obstructive sleep apnea. J. Clin. Sleep Med. 2007 , 3 , 700–705. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Sanner, B.M.; Fluerenbrock, N.; Kleiber-Imbeck, A.; Mueller, J.B.; Zidek, W. Effect of continuous positive airway pressure therapy on infectious complications in patients with obstructive sleep apnea syndrome. Respiration 2001 , 68 , 483–487. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Jao, L.Y.; Su, W.L.; Chang, H.C.; Lan, C.C.; Wu, Y.K.; Yang, M.C. Pneumocystis jirovecii pneumonia presenting as a solitary pulmonary granuloma due to unclean continuous positive airway pressure equipment: A case report. J. Clin. Sleep Med. 2022 , 18 , 1717–1721. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Caiano Gil, J.; Calisto, R.; Amado, J.; Barreto, V. Eikenella corrodens and Porphyromonas asaccharolytica pleural empyema in a diabetic patient with obstructive sleep apnea syndrome on noninvasive ventilation. Rev. Port. Pneumol. 2013 , 19 , 76–79. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Patel, S.R. Providing Cleaning Recommendations for Positive Airway Pressure Devices. Ann. Am. Thorac. Soc. 2024 , 21 , 27–29. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Mercieca, L.; Pullicino, R.; Camilleri, K.; Abela, R.; Mangion, S.A.; Cassar, J.; Zammit, M.; Gatt, C.; Deguara, C.; Barbara, C.; et al. Continuous Positive Airway Pressure: Is it a route for infection in those with Obstructive Sleep Apnoea? Sleep Sci. 2017 , 10 , 28–34. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Gavidia, R.; Shieu, M.M.; Dunietz, G.L.; Braley, T.J. Respiratory infection risk in positive airway pressure therapy users: A retrospective cohort study. J. Clin. Sleep Med. 2023 , 19 , 1769–1773. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Mutti, C.; Azzi, N.; Soglia, M.; Pollara, I.; Alessandrini, F.; Parrino, L. Obstructive sleep apnea, cpap and COVID-19: A brief review. Acta Biomed. 2020 , 91 , e2020196. [ Google Scholar ] [ CrossRef ]
  • Feng, Z.; Glasser, J.W.; Hill, A.N. On the benefits of flattening the curve: A perspective. Math. Biosci. 2020 , 326 , 108389. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Klompas, M.; Baker, M.A.; Rhee, C. Airborne Transmission of SARS-CoV-2: Theoretical Considerations and Available Evidence. JAMA 2020 , 324 , 441–442. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Drummond, M. Sleep labs, lung function tests and COVID-19 pandemic—Only emergencies allowed! Pulmonology 2020 , 26 , 244–245. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Barker, J.; Oyefeso, O.; Koeckerling, D.; Mudalige, N.L.; Pan, D. COVID-19: Community CPAP and NIV should be stopped unless medically necessary to support life. Thorax 2020 , 75 , 367. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Sampol, J.; Sáez, M.; Martí, S.; Pallero, M.; Barrecheguren, M.; Ferrer, J.; Sampol, G. Impact of home CPAP-treated obstructive sleep apnea on COVID-19 outcomes in hospitalized patients. J. Clin. Sleep Med. 2022 , 18 , 1857–1864. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Pépin, J.L.; Bailly, S.; Borel, J.C.; Logerot, S.; Sapène, M.; Martinot, J.B.; Lévy, P.; Tamisier, R. Detecting COVID-19 and other respiratory infections in obstructive sleep apnoea patients through CPAP device telemonitoring. Digit. Health 2021 , 7 , 20552076211002957. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Pneumococcal Vaccination: Who and When to Vaccinate|CDC. Available online: https://www.cdc.gov/vaccines/vpd/pneumo/hcp/who-when-to-vaccinate.html#adults-19-64 (accessed on 10 April 2024).
  • Influenza Vaccination: A Summary for Clinicians|CDC. Available online: https://www.cdc.gov/flu/professionals/vaccination/vax-summary.htm#vaccinated (accessed on 10 April 2024).
  • People at Higher Risk of Flu Complications|CDC. Available online: https://www.cdc.gov/flu/highrisk/index.htm (accessed on 10 April 2024).
  • Kaku, Y.; Okumura, K.; Padilla-Blanco, M.; Kosugi, Y.; Uriu, K.; Hinay, A.A., Jr.; Chen, L.; Plianchaisuk, A.; Kobiyama, K.; Ishii, K.J.; et al. Virological characteristics of the SARS-CoV-2 JN.1 variant. Lancet Infect. Dis. 2024 , 24 , e82. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Song, X.D.; Yang, G.J.; Jiang, X.L.; Wang, X.J.; Zhang, Y.W.; Wu, J.; Wang, M.M.; Chen, R.R.; He, X.J.; Dong, G.; et al. Seroprevalence of SARS-CoV-2 neutralising antibodies and cross-reactivity to JN.1 one year after the BA.5/BF.7 wave in China. Lancet Reg. Health West. Pac. 2024 , 44 , 101040. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Jeworowski, L.M.; Mühlemann, B.; Walper, F.; Schmidt, M.L.; Jansen, J.; Krumbholz, A.; Simon-Lorière, E.; Jones, T.C.; Corman, V.M.; Drosten, C. Humoral immune escape by current SARS-CoV-2 variants BA.2.86 and JN.1, December 2023. Euro Surveill. 2024 , 29 , 2300740. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Troeger, C.; Blacker, B.; Khalil, I.A.; Rao, P.C.; Cao, J.; Zimsen, S.R.M.; Albertson, S.B.; Deshpande, A.; Farag, T.; Abebe, Z.; et al. Estimates of the global, regional, and national morbidity, mortality, and aetiologies of lower respiratory infections in 195 countries, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Infect. Dis. 2018 , 18 , 1191–1210. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Ford, N.D.; Patel, S.A.; Narayan, K.M. Obesity in Low- and Middle-Income Countries: Burden, Drivers, and Emerging Challenges. Annu. Rev. Public Health 2017 , 38 , 145–164. [ Google Scholar ] [ CrossRef ] [ PubMed ]
  • Roche, J.; Rae, D.E.; Redman, K.N.; Knutson, K.L.; von Schantz, M.; Gómez-Olivé, F.X.; Scheuermaier, K. Sleep disorders in low- and middle-income countries: A call for action. J. Clin. Sleep Med. 2021 , 17 , 2341–2342. [ Google Scholar ] [ CrossRef ] [ PubMed ]
(“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
(85)
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.
The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

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

Article Metrics

Article access statistics, supplementary material.

ZIP-Document (ZIP, 196 KiB)

Further Information

Mdpi initiatives, follow mdpi.

MDPI

Subscribe to receive issue release notifications and newsletters from MDPI journals

U.S. flag

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

  • Publications
  • Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

  • Advanced Search
  • Journal List
  • Int J Mol Sci

Logo of ijms

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 ).

An external file that holds a picture, illustration, etc.
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 ).

An external file that holds a picture, illustration, etc.
Object name is ijms-20-01475-g002.jpg

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 ].

An external file that holds a picture, illustration, etc.
Object name is ijms-20-01475-g003.jpg

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.

An external file that holds a picture, illustration, etc.
Object name is ijms-20-01475-g004.jpg

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 ).

An external file that holds a picture, illustration, etc.
Object name is ijms-20-01475-g005.jpg

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.

DrugMechanismApplication
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.

Acknowledgments

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.

IMAGES

  1. 📌 Paper Example on Pathophysiology of Sickle Cell Disease

    free research paper on pathophysiology

  2. Pathology notes

    free research paper on pathophysiology

  3. Pathology

    free research paper on pathophysiology

  4. 7 Pathophysiology

    free research paper on pathophysiology

  5. 📚 Research Paper on Pathophysiology of Schizophrenia

    free research paper on pathophysiology

  6. Pathophysiology

    free research paper on pathophysiology

VIDEO

  1. Pathophysiology An introduction

  2. How to Download free Research Paper using Extension Paper Panda and open access

  3. Pathophysiology question paper B PHARMA ERA UNIVERSITY

  4. Dr. Ramesh Kumar Marya

  5. Best Tool to Read IEEE Paper in seconds

  6. Selective research

COMMENTS

  1. Pathophysiology

    Pathophysiology is an international, peer-reviewed, open access journal on the etiology, development, and elimination of pathological processes. Pathophysiology is the official journal of the International Society for Pathophysiology (ISP) and is published quarterly online by MDPI (from Volume 27, Issue 1 - 2020).. Open Access — free for readers, with article processing charges (APC) paid by ...

  2. Pathophysiology and Treatment of Stroke: Present Status and Future

    In the US in 2005, the average age of incidence of stroke was 69.2 years [ 2, 29, 30 ]. Recent research has indicated that people aged 20-54 years are at increasing risk of stroke, probably due to pre-existing secondary factors [ 31 ]. Women are at equal or greater risk of stroke than men, irrespective of age [ 32 ].

  3. Pathophysiology of Coronary Artery Disease

    Abstract. During the past decade, our understanding of the pathophysiology of coronary artery disease (CAD) has undergone a remarkable evolution. We review here how these advances have altered our concepts of and clinical approaches to both the chronic and acute phases of CAD. Previously considered a cholesterol storage disease, we currently ...

  4. Osteoporosis: Pathophysiology and therapeutic options

    Pathophysiology of Osteoporosis. Osteoporosis is a classic example of a multifactorial disease with a complex interplay of genetic, intrinsic, exogenous, and life style factors contributing to an individual's risk of the disease. ... A randomized dose-response trial in free-living pubertal females. J Nutr. 2016; 146:1298-1306. [Google Scholar]

  5. Sepsis—Pathophysiology and Therapeutic Concepts

    Sepsis-Induced Acute Kidney Injury. The pathophysiology of the development of sepsis-associated acute kidney injury (sa-AKI) is still poorly understood. Progress in research is slow and often based on extrapolations from postmortem observations, cell cultures, and animal models.

  6. Pathophysiology of COVID-19: Mechanisms Underlying Disease Severity and

    The global epidemiology of coronavirus disease 2019 (COVID-19) suggests a wide spectrum of clinical severity, ranging from asymptomatic to fatal. Al-though the clinical and laboratory characteristics of COVID-19 patients have been well characterized, the pathophysiological mechanisms underlying dis-ease severity and progression remain unclear.

  7. Pathophysiology of Hypertension

    Abstract. Dr Irvine Page proposed the Mosaic Theory of Hypertension in the 1940s advocating that hypertension is the result of many factors that interact to raise blood pressure and cause end-organ damage. Over the years, Dr Page modified his paradigm, and new concepts regarding oxidative stress, inflammation, genetics, sodium homeostasis, and ...

  8. Cancers

    Feature papers represent the most advanced research with significant potential for high impact in the field. ... in terms of ten-year biochemical-relapse-free survival and disease-free survival, with a longer follow-up (median of 107.6 months (IQR: 78.35; 136.10)) than that used in previous studies, and they identified a Gleason Score ≥8 as ...

  9. Pathophysiology

    Special Issue on Brain Injury. Edited by Dr.Jonathan Steven Alexander. February 2013. View all special issues and article collections. View all issues. Read the latest articles of Pathophysiology at ScienceDirect.com, Elsevier's leading platform of peer-reviewed scholarly literature.

  10. The Journal of Physiology

    Editor-in-Chief: Kim Barrett. JOURNAL METRICS >. The Journal of Physiology publishes research in all areas of physiology and pathophysiology that illustrates new physiological principles, mechanisms or premises. Papers on work at the molecular level, cell membrane, single cells, tissues or organs, and on systems physiology are all encouraged.

  11. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A

    Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A Review April W. Armstrong, MD, MPH 1 ; Charlotte Read, MBBS, BSc 1,2 Author Affiliations Article Information

  12. Pathophysiology, Clinical Presentation, and Treatment of Psoriasis: A

    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 ...

  13. Pathophysiology

    Pathophysiology. The pathophysiology of atherosclerosis per se, is complex, mainly involving an ongoing inflammatory and tissue remodeling process that is thought to be triggered by the accumulation of oxidized lipids and activated pro-fibrotic subintimal smooth muscle cells and immune cells (mainly macrophages and T-lymphocytes) within the intimal space of arteries [7-9].

  14. Full article: What's new in chronic pain pathophysiology

    ABSTRACT. The understanding of pain pathophysiology is continuously evolving. Identifying underlying cellular and subcellular pathways helps create opportunities for targeted therapies that may prove to be effective interventions. This article is an update on four areas of developing knowledge as it pertains to clinical management of patients ...

  15. Pathophysiology of a scientific paper

    Research paper writers understand the basic scientific writing skills[1,2] as it is vital to comprehend the anatomy and physiology of the various sections of the scientific paper. This article highlights the pathophysiological characteristics which should be avoided while writing the various sections of the scientific paper.

  16. A detailed review of pathophysiology, epidemiology, cellular and

    Background 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 ...

  17. Pathophysiology

    Pathophysiology. Pathophysiology involves either cortical or subcortical pathology, as established with neurophysiologic and imaging studies. Rasmussen's syndrome is an autoimmune disease involving one hemisphere, with cortical inflammation and atrophy, and thus this is a secondary myoclonus. Pathophysiology is unknown.

  18. 7. Write Your Paper

    This guide is designed to help you complete the care plan and pathophysiology research paper in Nursing 120. Write Your Paper/Project ... Free live online tutoring and writing help, available 24/7 - TutorMe (accessed through D2L). Visit the TLC in-person at Giles or other campuses.

  19. Human Anatomy and Pathophysiology

    Advances in the pathophysiology of human organs or anatomical districts. Bioengineering the human body. Bioethical aspects in biomedical research about human anatomy and pathobiology. Clinical, surgical, and radiological anatomy: new insights. From human anatomy to pathophysiology: experimental models. Effects of physical exercise on the ...

  20. APA

    Purdue Owl - APA Formatting Videos. Sample APA Papers. APA Title Page Setup. APA Tips: All authors' names should be inverted (i.e., last names should be provided first). Authors' first and middle names should be written as initials. Give the last name and first/middle initials for all authors of a particular work up to and including 20 authors.

  21. Multiple Sclerosis: Pathogenesis, Symptoms, Diagnoses and Cell-Based

    Abstract. Multiple sclerosis (MS) is a chronic inflammatory disease characterized by central nervous system (CNS) lesions that can lead to severe physical or cognitive disability as well as neurological defects. Although the etiology and pathogenesis of MS remains unclear, the present documents illustrate that the cause of MS is multifactorial ...

  22. Antibiotics

    Both obstructive sleep apnea (OSA) and acute lower respiratory tract infections (LRTIs) are important global health issues. The pathophysiological links between OSA and LRTIs include altered immune responses due to chronic intermittent hypoxia and sleep fragmentation, increased aspiration risk, and a high burden of comorbidities. In this narrative review, we evaluated the current evidence on ...

  23. Psoriasis Pathogenesis and Treatment

    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.