Psoriatic arthritis – Treatment advances in biologic therapies

Psoriatic arthritis (PsA) is a spondyloarthritis associated with psoriasis. It is characterised by the presence of inflammatory articular involvement of the peripheral joints, spine or enthesis and is typically seronegative for rheumatoid factor.¹ PsA is classified using the classification criteria for psoriatic arthritis (CASPAR).² PsA is heterogeneous and hence difficult to diagnose and assess. There are differences in disease mechanisms in different domains. To improve assessment and treatment choices, the group for research and assessment of psoriasis and PsA (GRAPPA) recommends evaluating the patient based on the following domains: peripheral arthritis, axial arthritis, psoriasis, nail psoriasis, skin psoriasis, enthesitis and dactylitis.³ Treatment choice may also be impacted by the presence of associated conditions such as uveitis and inflammatory bowel disease. Moreover, patients with PsA have many comorbidities including obesity, metabolic dysfunction-associated steatohepatitis (MASH), and depression that may impact treatment choice. Choosing the most appropriate biologic therapy may thus be challenging.

Available biologic therapies target different immune interactions.⁴ Drugs such as infliximab, etanercept, adalimumab, golimumab and certolizumab pegol target tumour necrosis factor (TNF). Ustekinumab targets the p40 molecule common to interleukin (IL)-12 and 23 and thus inhibits both these cytokines, whereas drugs such as guselkumab, risankizumab and tildrakizumab target the p19 component unique to IL-23 and are thus specific inhibitors of IL-23. Secukinumab and ixekizumab target IL-17A, whereas brodalumab targets the IL-17 receptor. The most recent IL-17 inhibitor, bimekizumab targets IL-17A and F. Abatacept selectively blocks the interaction between CD80/CD86 receptors and CD28 thus inhibiting T cell proliferation and B cell immunological response.⁴

Efficacy of biologic therapy in PsA

Biologic therapies have proven efficacy vs. placebo. TNF inhibitors (TNFi) are efficacious in the treatment of active PsA with about 60%, 40 and 20% of patients achieving American College of Rheumatology (ACR) 20, 50 and 70 responses at 12-14 weeks in the pivotal clinical trials.⁵ The ACR responses were about 10 percentage points lower in the pivotal clinical trials with the 12/23 inhibitor, ustekinumab. Pivotal trials with the IL-17 inhibitors (IL-17i) secukinumab, ixekizumab and bimekizumab also showed response rates similar to that of TNFi, although those with brodalumab were lower.^5-7 The ACR responses to treatment with abatacept were also lower than that to TNFi and IL17i.⁸ IL-23 inhibitors (IL23i) such as guselkumab and risankizumab also achieve similar ACR 20 responses at 24 weeks.⁵

Comparative efficacy

Unfortunately, few head-to-head studies are comparing biologic therapies in PsA. In a study that compared adalimumab (a TNFi) with ixekizumab, an IL-17Ai, the composite outcome measure of achieving ACR50 response and psoriasis area and severity index (PASI) 100 response was significantly higher with ixekizumab (35%) compared to adalimumab (28%).⁹ The ACR 50 responses were similar but the PASI100 responses were significantly higher with ixekizumab, as expected. A similar study with secukinumab, another IL17Ai, vs. adalimumab showed similar results, although the primary outcome of ACR20 was similar between the two groups.¹⁰ Thus, there does not seem to be a difference in efficacy between TNFi and IL17Ai with respect to overall musculoskeletal outcomes.

In a recent network meta-analysis that compared the relative efficacy and safety of bimekizumab, an IL-17A and F inhibitor to other biologics in biologic treatment-naïve PsA patients, most biologics had similar efficacy to bimekizumab. Intravenous golimumab was favoured over bimekizumab; bimekizumab was favoured over ustekinumab, abatacept, guselkumab and risankizumab.¹¹ Head-to-head studies directly comparing different drugs are required.

Newer therapies

Newer therapies that are in development show promise. These include izokibep, a small protein that targets IL-17A, and sonelokimab, a nanobody that targets IL17A and F.^12,13 The initial results from phase 2 trials are promising.

Choosing therapy for a patient with PsA

When choosing the right drug for a patient it is important to evaluate all domains including musculoskeletal (peripheral and axial) and skin domains as well as associated conditions such as uveitis and inflammatory bowel disease (IBD). The drug that targets the most active domain is chosen such that other involved domains are also treated. The presence of severe uveitis or IBD would require collaboration with an ophthalmologist or gastroenterologist, respectively to ensure appropriate disease assessment and choice of therapy.³ It is recommended that in the case that peripheral arthritis, enthesitis or dactylitis is dominant, the first line of therapy be non-steroidal anti-inflammatory drugs (NSAIDs), intra-articular steroids and conventional disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate, leflunomide or sulfasalazine.¹⁴ Failure of such therapy would require treatment with a biologic agent such as TNFi, IL17i or IL23i. In case of dominant axial disease, if NSAIDs are not effective, treatment with TNF or IL17i is recommended. For skin or nail-dominant disease, if methotrexate of apremilast is ineffective, IL17A, IL23i or TNFi are recommended. If there is associated severe uveitis, methotrexate and TNFi antibodies are recommended. In the presence of active IBD, TNFi and IL12/23i or IL23i would be recommended.¹² Thus, the choice of therapy is most often based on the presence of severe skin psoriasis, axial disease, IBD or uveitis as well as comorbidities such as MASH, risk of infection or depression.^3,12

However, many patients continue to struggle with active PsA despite treatment with agents proven to be efficacious.¹⁵ Even patients who respond uncommonly achieve remission.¹⁶ Thus, novel approaches to treatment including combination treatments need to be considered.¹⁷ Combination therapies are now being evaluated in clinical trials.¹⁸ Given the heterogeneous nature of PsA and the many therapies available with variable responses, a precision medicine approach to treatment would be ideal.

To summarise, PsA is a spondyloarthritis associated with psoriasis. The domains involved include peripheral arthritis, axial arthritis, enthesitis, dactylitis, psoriasis, and nail psoriasis. Biological therapies used in the treatment include TNFi, IL-12/23i, IL-17A/Fi, IL-23i and CTLA4 Ig. The efficacy of these drugs in the different domains varies. The goal of treatment is to achieve the lowest possible level of disease activity in all domains of disease using a treat-to-target approach. However, few patients achieve remission despite modern therapy. Newer drugs and newer strategies are being investigated.

Acknowledgments

Dr. Chandran is supported by a salary award from the Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Funding

None

Conflicts of Interest

VC has received research grants from AbbVie, Amgen, and Eli Lilly and has received honoraria for advisory board member roles from AbbVie, Amgen, BMS, Eli Lilly, Fresenius Kabi, Janssen, Novartis, Pfizer, and UCB. His spouse is an employee of AstraZeneca.

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Posted on 11 November 202422 November 2024