¹John P. and Kathrine G. McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, USA
²Center for Clinical Studies, Webster, TX, USA
³Department of Dermatology, The University of Texas Health Science Center at Houston, Houston, TX, USA

Conflict of interest: The authors declare that there are no conflicts of interest.
Funding sources: None.

Abstract: Psoriatic arthritis (PsA) is a chronic, inflammatory disease with heterogeneous clinical features. The pathogenesis of PsA involves a complex interplay of genetic, immunologic, and environmental factors, leading to the activation of the immune system and subsequent inflammation. Over the past decade, the understanding of the immune mechanisms underlying PsA has advanced significantly, particularly regarding the role of the interleukin-23/T helper 17 pathway in the disease process. Guselkumab, a novel IL-23 inhibitor, has emerged as a promising therapeutic option for PsA, offering an alternative to conventional therapies and other biologics. This review aims to summarize the current evidence on the efficacy, safety, and clinical utility of guselkumab in the treatment of PsA.

Keywords: psoriatic arthritis, guselkumab, treatment, efficacy, psoriasis, arthritis

Introduction

Psoriatic arthritis (PsA) is a chronic inflammatory disease that will develop in about 30% of individuals with psoriasis. The condition is characterized by a wide range of clinical features, making it complex and diverse in its presentation. The pathogenesis of PsA involves a multifaceted interaction between genetic, immunologic, and environmental factors, which leads to immune system activation and subsequent inflammation.¹

Currently, there are no specific diagnostic criteria or tests for PsA. Diagnosis is typically based on the presence of inflammatory musculoskeletal symptoms in joints, entheses, or the spine, alongside skin and/or nail psoriasis, and the usual absence of rheumatoid factor and anti-cyclic citrullinated peptide. The progression from psoriasis to PsA may occur in stages, although the underlying mechanisms remain unclear. Interestingly, the severity of musculoskeletal inflammation does not always correlate with the severity of skin or nail psoriasis, a phenomenon likely influenced by genetic variability, particularly in the human leukocyte antigen (HLA) region.¹

Over the past decade, the understanding of the immune mechanisms underlying PsA has advanced significantly, particularly regarding the role of the interleukin-23 (IL-23)/T helper 17 (Th17) pathway in the disease process. Guselkumab is a human monoclonal antibody that selectively binds to the p19 subunit of IL-23, thereby inhibiting its interaction with the IL-23 receptor. By blocking IL-23 signaling, guselkumab prevents the activation and proliferation of Th17 cells, which are pivotal in the pathogenesis of PsA. Th17 cells produce several pro-inflammatory cytokines, including IL-17A, IL-17F, and IL-22, which contribute to the inflammation and joint damage observed in PsA. By targeting IL-23, guselkumab effectively reduces the levels of these downstream cytokines, thereby attenuating the inflammatory response and improving clinical outcomes in patients with PsA.²

Guselkumab has been approved by the United States Food and Drug Administration (FDA), Health Canada, and the European Medicines Agency (EMA) for the treatment of adult patients with active psoriatic arthritis and moderate-to-severe psoriasis (PSO) who are candidates for systemic therapy. Additionally, the EMA has approved guselkumab for the treatment of active psoriatic arthritis in adults who have had an inadequate response to, or are intolerant of, previous disease-modifying antirheumatic drug (DMARD) therapy.²

This review aims to summarize the current evidence on the efficacy, safety, and clinical utility of guselkumab in the treatment of PsA.

Methods

Our search focused on English-language literature concerning clinical trials of guselkumab in adults with psoriatic arthritis. We conducted a search in the Medline database via PubMed up until September 1, 2024, using the MeSH terms “guselkumab” AND “psoriatic arthritis.” This search yielded 177 results. We excluded books, meta-analyses, reviews, and systematic reviews, narrowing our focus to clinical trials and randomized controlled trials, resulting in 30 trials. Out of these, we included 9 trials and excluded 10 due to integrated analysis of multiple trials, 7 due to duplication, and 4 due to a focus on topics other than PsA.

Results

The included studies primarily consisted of double-blind, randomized, placebo-controlled Phase 3 trials that evaluated the efficacy of guselkumab in patients with PsA (Table 1). Across these trials, guselkumab demonstrated significant efficacy in achieving American College of Rheumatology (ACR) response criteria at various time points:

Table 1

ACR20 Response

Guselkumab consistently showed superior results compared to placebo. For instance, Deodhar et al. reported that 59% of patients treated with guselkumab every 4 weeks and 52% treated every 8 weeks achieved ACR20, compared to 22% in the placebo group.³ Similar trends were observed in other studies, with response rates ranging from 44% to 76% for guselkumab, significantly higher than the placebo groups, which ranged from 20% to 33%.^4-7

ACR50 and ACR70 Responses

Some trials also assessed higher response thresholds. McInnes et al. observed ACR50 and ACR70 responses in 48-56% and 30-36% of patients, respectively, in the guselkumab-treated groups.⁸ Ritchlin et al. noted that 33% and 31% of patients achieved ACR50 at week 24 in the every-4-weeks and every-8-weeks groups, respectively, compared to 14% in the placebo group. ACR70 responses were achieved by 13-19% of guselkumab-treated patients, compared to 4% in the placebo group.⁹

Additional Outcomes

Beyond ACR responses, trials such as Curtis et al. and Orbai et al. assessed work productivity and patient-reported outcomes, showing significant improvements in these domains among patients treated with guselkumab. Improvements in presenteeism, work productivity, non-work activity, and Patient-Reported Outcomes Measurement Information System® (PROMIS)-29 scores were all more substantial in guselkumab groups compared to placebo, with improvements continuing through week 52 after placebo patients were switched to guselkumab.^10,11

These results highlight the efficacy of guselkumab in improving clinical outcomes in PsA patients, particularly in achieving ACR response criteria and enhancing patient-reported outcomes.

Discussion

In the management of PsA, the primary objective of pharmacological treatment is to enhance patients’ health-related quality of life. This is achieved by alleviating symptoms, preventing structural joint damage, and restoring normal function and daily activities. A significant reduction in inflammation is crucial to reaching these goals. Within this therapeutic landscape, guselkumab offers several distinct advantages over other biologics, particularly tumor necrosis factor (TNF) inhibitors and IL-17 inhibitors.

TNF inhibitors are commonly used in PsA treatment, but their efficacy in managing skin symptoms can be variable, and they are associated with a higher risk of certain adverse events (AEs), such as infections and demyelinating diseases. IL-17 inhibitors, including secukinumab and ixekizumab, are effective for both skin and joint manifestations but may increase the risk of inflammatory bowel disease. In contrast, guselkumab specifically targets the IL-23 pathway, offering a more focused modulation of the immune response in PsA. This targeted inhibition may lead to fewer offtarget effects and a more favorable safety profile, particularly concerning infections and autoimmune-related AEs. Additionally, guselkumab has shown efficacy in patients who have not responded adequately to TNF inhibitors, making it an invaluable option for this challenging subset of patients.¹²

The safety profile of guselkumab has been thoroughly evaluated in both clinical trials and post-marketing surveillance. Across these studies, the incidence of AEs was comparable between guselkumab and placebo groups, with the most common being nasopharyngitis, upper respiratory tract infections, and headaches. Serious adverse events were infrequent and occurred at similar rates across treatment groups. Importantly, guselkumab did not increase the risk of serious infections, malignancies, or major cardiovascular events, which supports its suitability for long-term use.

Overall, guselkumab emerges as a promising therapeutic option for PsA, particularly for patients who require an alternative to TNF inhibitors or those concerned with the safety profiles of currently available biologics. Its focused mechanism of action, combined with a robust safety profile, positions guselkumab as an effective and well-tolerated treatment in the ongoing effort to improve patient outcomes in PsA.

Conclusion

Guselkumab represents a significant advancement in the treatment of PsA, providing a novel mechanism of action with robust clinical efficacy and a favorable safety profile. The evidence from RCTs and real-world studies supports its use in a broad range of patients, including those who are biologic-naïve and those with previous biologic exposure. As the understanding of the IL-23/Th17 pathway continues to evolve, guselkumab and other IL-23 inhibitors are likely to play an increasingly important role in the management of PsA, offering patients new hope for improved disease control and quality of life. Future research should focus on long-term outcomes, comparative effectiveness with other biologics, and the identification of biomarkers to personalize treatment strategies for patients with PsA.

References

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