Immunologic Advances Reveal New Targets in Psoriasis and Psoriatic Arthritis

A recent review in Discovery Medicine discusses how insights into the molecular mechanisms underlying psoriatic arthritis (PsA) have led to the development of new targeted therapies for this condition. In the review, Drs Mahta Mortezavi and Christopher T. Ritchlin of the University of Rochester Medical Center describe how interleukin-23 (IL-23)/IL-17 axis-elicited responses to infection or trauma as mediated by osteoclasts, keratinocytes, and neutrophils drive the pathobiology of PsA.¹

Clinical Presentations

PsA is a systemic musculoskeletal disease with a wide range of clinical presentations, including peripheral or axial arthritis, inflammation at sites where ligaments and tendons attach to bone, diffuse swelling of a finger or toe, and plaque psoriasis. Its severity can range from mild to disabling. PsA is distinguished from other inflammatory arthritides by abnormal bone turnover leading to osteoporosis and extensive resorption accompanied by new bone formation.

Treatment Strategies

Prior to the introduction of anti-tumor necrosis factor (anti-TNF) biologics in the late 1990s, a frequently employed strategy for addressing disease activity in patients with psoriatic arthritis was the use of methotrexate or other disease-modifying antirheumatic drugs (DMARDs). This treatment approach was based on the disease-modifying capability of these agents in rheumatoid arthritis. However, studies failed to demonstrate any significant difference between methotrexate and placebo in PsA.

Anti-TNF agents such as etanercept, adalimumab, infliximab, golimumab, and certolizumab have been shown to safely reduce symptoms and inhibit the radiographic progression of joint space narrowing and bone erosion in PsA, and thus have become the gold standard for treatment.² However, up to 50% of patients with PsA are either intolerant of anti-TNF therapy or fail to achieve an adequate response, and the majority of patients who fail therapy with anti-TNF biologics do not respond to a switch in TNF agents.³ The existence of a substantial proportion of patients who remain inadequately treated has necessitated the continued development of new therapies.

The review describes several agents with the potential to improve outcomes in PsA. Ustekinumab, a humanized IgG monoclonal antibody that binds to the P40 subunit common to IL-12 and IL-23, has been found to be safe and efficacious in psoriasis and PsA. An integrated analysis of radiographic data from phase 3 trials showed that ustekinumab inhibits radiographic progression of disease. The agent is currently considered a second-line therapy in PsA due to its cost.

Secukinumab, ixekizumab, and brodalumab are IL-17 inhibitors that have led to improvements in PsA; however, clinical trials on brodalumab were discontinued due to a higher-than-expected incidence of suicide and suicidal ideation. It is unknown whether the risk of suicidal ideation applies to the entire drug class. Other drugs that interfere with the IL-17 pathway have not shown a similar association.

Additional agents presently under development for PsA include humanized IgG monoclonal antibodies that target the p19 subunit of IL-23 such as BI655066, guselkumab, and tildrakizumab.

Conclusion

The authors wrote in conclusion, “Exciting new discoveries regarding the centrality of the IL23/Th17 pathway in the pathogenesis of psoriasis and psoriatic arthritis catalyzed the development of new targets, which hold great promise for patients with psoriatic skin and joint inflammation.”

References

Mortezavi M, Ritchlin C. Immunologic advances reveal new targets in psoriasis and psoriatic arthritis. Discov Med. 2015;20(110):169-175.
Mease P. A short history of biological therapy for psoriatic arthritis. Clin Exp Rheumatol. 2015;33(5 Suppl 93):S104-S108.
Fagerli KM, Lie E, van der Heijde D, et al. Switching between TNF inhibitors in psoriatic arthritis: data from the NOR-DMARD study. Ann Rheum Dis. 2013;72(11):1840-1844. doi:10.1136/annrheumdis-2012-203018.