Psoriasis, Psoriatic Arthritis, IL-23 and Skyrizi: Understanding Chronic Inflammation and Targeted Biological Therapy

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The role of the IL-23/IL-17 inflammatory pathway in psoriasis, psoriatic arthritis and related immune-mediated diseases, and how Skyrizi (risankizumab) helps control chronic inflammation.

Introduction: Chronic Inflammation as a Common Biological Link

Psoriasis and psoriatic arthritis are systemic immune-mediated inflammatory diseases that extend beyond the skin and joints. Both involve dysregulation of the immune system, with inflammatory signaling molecules known as cytokines playing important roles in maintaining chronic inflammation.

Among these cytokines, interleukin-23 (IL-23) and interleukin-17 (IL-17) are particularly important in the development and progression of psoriatic disease.

The IL-23/IL-17 signaling pathway regulates immune-cell activity and inflammatory responses. When dysregulated, it contributes to persistent inflammation, tissue injury and structural changes in affected organs.

The development of targeted biological therapies has significantly changed the treatment of psoriasis and psoriatic arthritis. One such therapy is Skyrizi (risankizumab), a humanized monoclonal antibody designed to selectively inhibit IL-23.

By blocking a specific component of the inflammatory network, Skyrizi reduces disease activity without functioning as a corticosteroid or a traditional broad-spectrum immunosuppressant.

Understanding how IL-23 inhibition influences downstream inflammatory pathways helps explain the therapeutic benefits of Skyrizi and its role in treating several chronic immune-mediated diseases.

1. The IL-23/IL-17 Axis: A Central Pathway in Chronic Inflammation

IL-23 is an inflammatory cytokine produced primarily by activated immune cells, including dendritic cells and macrophages. It supports the maintenance and activity of certain inflammatory immune-cell populations, particularly T-helper 17 (Th17) cells.

These cells produce cytokines such as IL-17A, IL-17F and IL-22, which participate in immune defense and inflammatory responses.

In psoriasis, excessive activity within this pathway promotes abnormal skin-cell proliferation, immune-cell recruitment and the development of characteristic inflammatory plaques.

In psoriatic arthritis, related mechanisms contribute to inflammation of joints, tendons, ligaments and surrounding tissues, potentially resulting in progressive structural damage.

Diseases associated with IL-17 inflammatory signaling

Increased or dysregulated IL-17 activity has been identified in several inflammatory and immune-mediated diseases:

  • Psoriasis: Chronic inflammatory skin disease involving abnormal keratinocyte proliferation.

  • Psoriatic arthritis: Inflammatory disease affecting joints, tendons and entheses.

  • Ankylosing spondylitis and axial spondyloarthritis: Inflammatory conditions predominantly affecting the spine and sacroiliac joints.

  • Rheumatoid arthritis: Systemic autoimmune disease characterized by persistent synovial inflammation.

  • Multiple sclerosis: Immune-mediated inflammatory disease affecting the central nervous system.

  • Inflammatory bowel disease: Including Crohn's disease and ulcerative colitis.

  • Asthma and COPD: Certain inflammatory phenotypes involve IL-17-associated immune responses.

However, the role of IL-17 differs substantially between diseases. Its involvement does not necessarily mean that IL-23 inhibition will be therapeutically effective.

For example, IL-23 inhibitors are effective in psoriasis and peripheral psoriatic arthritis but have not demonstrated comparable efficacy in axial spondyloarthritis. Furthermore, direct IL-17 inhibition can worsen inflammatory bowel disease in some patients.

This illustrates the complexity of inflammatory signaling and the importance of disease-specific treatment strategies.

2. Skyrizi: Selective Inhibition of IL-23

Skyrizi (risankizumab) is a humanized immunoglobulin G1 (IgG1) monoclonal antibody that selectively binds to the p19 subunit of interleukin-23.

IL-23 consists of two protein subunits, p19 and p40. By binding p19, Skyrizi prevents IL-23 from interacting with its receptor and activating downstream inflammatory signaling.

This reduces IL-23-dependent immune activation and can decrease the inflammatory activity associated with the Th17 pathway, including downstream effects involving IL-17 and IL-22.

However, IL-17 can also be produced through IL-23-independent mechanisms. Therefore, Skyrizi does not completely eliminate IL-17 activity.

Approved therapeutic applications

Skyrizi is FDA-approved in the United States for adults with:

  • Moderate-to-severe plaque psoriasis: Reducing inflammatory skin lesions and improving skin clearance.

  • Active psoriatic arthritis: Reducing joint inflammation, pain and disease activity.

  • Moderately-to-severely active Crohn's disease: Controlling intestinal inflammation and helping achieve or maintain remission.

  • Moderately-to-severely active ulcerative colitis: Reducing intestinal inflammatory activity and maintaining clinical remission.

Approval criteria and prescribing indications may differ between countries.

Why Skyrizi is not a steroid

Unlike corticosteroids, which influence numerous inflammatory and metabolic pathways, Skyrizi selectively targets IL-23.

It is also different from traditional broad-spectrum immunosuppressants such as cyclosporine.

This targeted mechanism allows substantial suppression of specific inflammatory pathways while preserving many other immune functions.

Nevertheless, Skyrizi remains an immunomodulating medication and can increase susceptibility to certain infections.

3. The Relationship Between IL-23, IL-17 and IL-6

Interleukin-6 (IL-6) is another important inflammatory cytokine involved in immune activation, acute-phase responses and chronic inflammatory disorders.

Elevated IL-6 activity has been associated with inflammatory arthritis and other immune-mediated conditions.

Although Skyrizi does not directly inhibit IL-6, reductions in overall inflammatory activity may be accompanied by decreases in IL-6 levels in some patients.

This effect is indirect and is not a consistent or established treatment effect in every patient.

Medications such as tocilizumab specifically block IL-6 receptor signaling, whereas risankizumab acts selectively on IL-23.

Consequently, any changes in IL-6 during Skyrizi treatment represent possible secondary immunological effects rather than direct IL-6 inhibition.

The IL-23, IL-17 and IL-6 pathways interact within complex inflammatory networks, but they remain distinct therapeutic targets.

4. How Skyrizi Reduces Inflammation in Psoriasis and Psoriatic Arthritis

The therapeutic effects of Skyrizi result from selectively interrupting IL-23-dependent inflammatory signaling.

Effects on psoriasis

In plaque psoriasis, excessive activation of the IL-23/IL-17 pathway promotes inflammatory-cell recruitment, abnormal keratinocyte proliferation and the formation of thickened, scaly skin lesions.

By blocking IL-23, Skyrizi reduces inflammatory signaling responsible for maintaining these lesions.

Clinical trials have demonstrated substantial improvements in skin clearance, including high rates of PASI 90 and PASI 100 responses in appropriately selected patients.

PASI refers to the Psoriasis Area and Severity Index, a standardized measure of psoriasis severity.

A PASI 90 response indicates at least a 90% improvement from baseline, while PASI 100 represents complete clearance according to that measure.

Effects on psoriatic arthritis

Psoriatic arthritis involves inflammation affecting joints, tendon insertions and other musculoskeletal structures.

IL-23-dependent inflammatory signaling contributes to several aspects of peripheral psoriatic arthritis.

Skyrizi can reduce joint tenderness and swelling, improve physical function and reduce overall disease activity.

Clinical trials have also demonstrated inhibition of radiographic progression of joint damage in certain patient populations.

However, its effectiveness for predominantly axial disease remains uncertain, and it is not an established treatment for axial spondyloarthritis.

Long-term control of inflammation

Because psoriasis and psoriatic arthritis are chronic conditions, sustained inflammatory control is important.

Long-term treatment may help maintain skin clearance, reduce joint symptoms and improve quality of life.

Responses vary between individuals, and treatment effectiveness should be assessed through regular clinical evaluation.

5. IL-23 Inhibition and the Blood–Brain Barrier

The blood–brain barrier (BBB) is a specialized biological interface that regulates the movement of substances from the bloodstream into the central nervous system.

It is formed primarily by tightly connected endothelial cells supported by pericytes, astrocytes and other components of the neurovascular unit.

Risankizumab is a large monoclonal antibody with a molecular weight of approximately 150 kilodaltons.

Because of its molecular size and physicochemical characteristics, passive penetration across an intact blood–brain barrier is expected to be extremely limited.

Why Skyrizi has limited brain penetration

Molecular size: Monoclonal antibodies are substantially larger than most small-molecule medications capable of crossing biological membranes.

Tight cellular junctions: The blood–brain barrier restricts movement of large circulating proteins into brain tissue.

Lack of specialized transport mechanisms: Risankizumab is not engineered to use receptor-mediated transport systems, such as transferrin-receptor transport, to facilitate brain entry.

Nevertheless, antibody penetration into the central nervous system is not absolutely zero. Limited transport may occur, and barrier permeability can change under certain pathological conditions.

Implications for neurological inflammation

Systemic inflammatory pathways can influence neurological function through interactions between peripheral immunity, circulating inflammatory mediators and the central nervous system.

However, Skyrizi has not been established as a treatment for multiple sclerosis or other primary neurological inflammatory disorders.

Its limited expected penetration into the brain is an important pharmacological characteristic but does not establish therapeutic effectiveness against neurological inflammation.

6. Interactions with Other Anti-Inflammatory Medications

Patients with psoriasis or psoriatic arthritis frequently require additional medications for pain, inflammation or associated medical conditions.

NSAIDs and corticosteroids

Skyrizi does not have a generally recognized major direct pharmacokinetic interaction with common nonsteroidal anti-inflammatory drugs such as ibuprofen or naproxen.

However, NSAIDs carry independent risks, including gastrointestinal bleeding and kidney injury.

Corticosteroids may sometimes be prescribed for other inflammatory conditions, but their use alongside biological therapy requires consideration of infection risk and other adverse effects.

Combining Skyrizi with other biologics

Combining Skyrizi with other biological immunomodulators, including TNF inhibitors such as adalimumab (Humira), is not routinely recommended without specialist supervision.

Such combinations may increase susceptibility to serious infections and may lack sufficient supporting safety data.

Infection risks and vaccination

Although Skyrizi selectively targets IL-23, it still modifies immune responses.

Patients should be evaluated for tuberculosis before starting treatment, and active clinically important infections should be addressed.

Live vaccines should generally be avoided during treatment.

Vaccination status and other infection-related precautions should be reviewed with the prescribing specialist.

7. Clinical Implications for Patients with Multiple Inflammatory Diseases

Patients who have psoriasis, psoriatic arthritis and additional immune-mediated inflammatory conditions often require a multidisciplinary treatment strategy.

Although several diseases may share inflammatory pathways, this does not necessarily mean that one medication can adequately treat all of them.

For example, Skyrizi is effective for several IL-23-dependent inflammatory conditions, including plaque psoriasis, peripheral psoriatic arthritis, Crohn's disease and ulcerative colitis.

However, patients with axial inflammatory symptoms require careful evaluation because IL-23 inhibition has not demonstrated consistent efficacy in axial spondyloarthritis.

Similarly, the involvement of IL-17 in rheumatoid arthritis, multiple sclerosis or certain respiratory inflammatory disorders does not establish Skyrizi as an appropriate treatment for those conditions.

Treatment decisions should therefore be based on specific clinical manifestations, established therapeutic indications and individual patient characteristics.

Coordination between dermatologists, rheumatologists, gastroenterologists and other relevant specialists may be particularly important.

8. Future Research: IL-23 Inhibition and Immune Regulation

The development of selective IL-23 inhibitors has expanded understanding of chronic immune-mediated inflammation.

Ongoing research continues to investigate the complex interactions between IL-23, IL-17, IL-22 and other cytokines involved in inflammatory disease.

Important areas of investigation include:

  • Long-term effectiveness of IL-23 inhibition in psoriasis and psoriatic arthritis.

  • Mechanisms responsible for differences in treatment response between patients.

  • The relationship between IL-23-dependent and IL-23-independent IL-17 production.

  • The effects of targeted treatment on inflammatory biomarkers and immune-cell populations.

  • The potential role of IL-23 inhibition in additional immune-mediated conditions.

  • Strategies for selecting the most appropriate biological therapy based on individual disease characteristics.

A particularly important research objective is identifying why some patients respond exceptionally well to IL-23 inhibition while others require treatment targeting different inflammatory pathways.

Improved understanding of these mechanisms may support more individualized and effective treatment approaches.

Conclusion

The identification of the IL-23/IL-17 inflammatory pathway has substantially advanced understanding of psoriasis, psoriatic arthritis and several other immune-mediated inflammatory diseases.

Skyrizi represents an important development in targeted biological therapy because it selectively inhibits the p19 subunit of IL-23, reducing inflammatory activity in plaque psoriasis, psoriatic arthritis, Crohn's disease and ulcerative colitis.

Unlike corticosteroids or traditional broad-spectrum immunosuppressants, Skyrizi acts on a specific cytokine pathway central to several chronic inflammatory disorders.

Its effects on downstream inflammatory signaling, including IL-17-associated responses, help explain its clinical effectiveness in controlling skin and joint inflammation.

Although IL-23, IL-17 and IL-6 interact within complex immunological networks, they remain distinct therapeutic targets, and the effects of inhibiting one pathway cannot automatically be generalized to every inflammatory disease.

Skyrizi is an effective, targeted biological treatment that can provide sustained control of inflammation in several established immune-mediated conditions, particularly psoriasis and psoriatic arthritis.

Continued research into IL-23-dependent immune signaling may further improve treatment selection, long-term disease control and understanding of chronic inflammatory disorders.


References:

SKYRIZI is a biologic prescription for people 6+ with moderate to severe plaque psoriasis (Ps) or for people 6+ with active psoriatic arthritis (PsA)
https://www.skyrizi.com/psoriasis-psoriatic-arthritis/about-skyrizi/what-is-skyrizi 

Co-Occurrence of Psoriasis/Psoriatic Arthritis and Antiphospholipid Syndrome: A Series of Nine Patients from a Single Centre and Literature Review
https://pubmed.ncbi.nlm.nih.gov/41647271/

Skyrizi Overview
https://www.ema.europa.eu/en/medicines/human/EPAR/skyrizi

Risankizumab (Skyrizi)
https://rheumatology.org/patients/risankizumab-skyrizi 

Effect of interleukin 23 inhibitors (risankizumab and guselkumab) on cardiovascular and cerebrovascular risk in psoriasis patients
https://www.researchgate.net/publication/395921786_Effect_of_interleukin_23_inhibitors_risankizumab_and_guselkumab_on_cardiovascular_and_cerebrovascular_risk_in_psoriasis_patients

Generation of a Protective T-Cell Response Following Coronavirus Infection of the Central Nervous System Is Not Dependent on IL-12/23 Signaling
https://pmc.ncbi.nlm.nih.gov/articles/PMC2570712/

Astrocyte-specific expression of interleukin 23 leads to an aggravated phenotype and enhanced inflammatory response with B cell accumulation in the EAE model
https://link.springer.com/article/10.1186/s12974-021-02140-z

Risankizumab Mechanism of Action
https://elicit.com/mechanism-of-action/risankizumab

Risankizumab: Mechanism of action, clinical and translational science
https://pmc.ncbi.nlm.nih.gov/articles/PMC10777435/

Medical disclaimer: This article is intended for scientific and educational purposes and does not replace individualized medical advice. Decisions involving biological therapies, immunosuppressants or other medications should be made in consultation with qualified healthcare professionals.

© 2020-2030 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right. Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

 

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