IL-23 inhibitor use in a PsA patient with inadequate response to prior bDMARDs

History and presentation
A 29-year-old lady with heavily pre­treated psoriatic arthritis (PsA) was re­ferred to our clinic in 2021.

The patient had good past health be­fore her diagnosis of psoriasis in 2010, and was managed with topical steroids. She de­veloped psoriatic arthritis 5 years later with dactylitis, wrist and knee pain and swelling. She was initially given NSAIDS to manage the pain followed by etanercept, a tumour necosis factor inhibitor (TNFi), to which she responded well for 2 years. Blood tests in 2015 found elevated erythrocyte sedimen­tation rate (ESR), but human leukocyte antigen-B27 (HLA-B27) was not detected.

In 2018, she developed secondary failure with joint and rash flare, and was switched to an interleukin (IL)-12/23 in­hibitor, which provided improvement in skin rash only. Methotrexate was added to manage persistent joint symptoms, but was stopped after deterioration of liver function. In October 2019, she was start­ed on an IL-17 inhibitor plus leflunomide, but leflunomide was discontinued due to tolerability issues.

Despite good psoriasis control with IL-17 inhibitor monotherapy, the patient still reported musculoskeletal pain. Treat­ment was switched to golimumab, an­other TNFi in April 2019. However, due to increasing joint pain, treatment was switched back to IL-17 inhibitor mono­therapy, which led to stable disease control until 2023.

In November 2023, she experienced a skin and arthritic flare, likely triggered by medication noncompliance, and could not regain good disease control despite therapy resumption. She developed dac­tylitis in her left ring finger and left fourth toe, and reported increased nonspecific lower back pain (visual analogue scale [VAS] pain score, 60 out of 100) with morning stiffness, joint stiffness, and ar­thritis in her right knee and left thumb. Physical examination revealed a swollen right knee, three tender joints and three swollen joints, but no nail changes, en­thesitis or uveitis. She also had increased psoriatic rash. She rated her pain 50 out of 100 on the VAS. Her C-reactive protein (CRP) level was elevated at 2.2 mg/dL (reference range, ≤0.5 mg/dL) and ESR was also elevated at 82 mm/h (reference range, ≤20 mm/h in women). MRI of the whole spine and sacroiliac joint did not re­veal active sacroiliitis or spondylitis.

Treatment with guselkumab and response
As the patient preferred injectable medication over daily oral medications, she was switched to the IL-23 inhibitor, guselkumab (100 mg subcutaneously at weeks 0 and 4, followed by Q8W for maintenance) in February 2024.

The patient responded well to gusel­kumab, with no treatment-related side ef­fects. In May 2024, 3 months after gusel­kumab initiation, both her CRP level and ESR had normalized, and her skin condi­tion improved dramatically. The psoriatic rash over her trunk and limbs had mostly resolved, with very mild hairline psoriasis remaining. The number of tender and swollen joints had reduced from three to one. The patient reported improvements in knee pain and toe dactylitis, but still had some persistent pain and vestigial swelling in her left fourth proximal inter­phalangeal (PIP) joint. Musculoskeletal ultrasound revealed synovial hypertrophy with 2+ power doppler signal in the left fourth PIP joint, which was treated with intra-articular steroid.

Last reviewed in November 2024 (9 months after guselkumab initiation), the patient had achieved remission and pain in her joints had largely resolved. CRP level was <0.1 mg/dL.

Discussion
Patients with PsA can have multi­domain involvement, including skin pso­riasis, peripheral arthritis, spondylitis, dactylitis, enthesitis and nail disease. The treatment goal is to achieve lowest level of disease activity across all domains, com­monly referred to as remission or minimal disease activity (MDA), through regu­lar monitoring and appropriate therapy adjustment.^1,2

Our patient, who was not well con­trolled with NSAIDs, was intolerant to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and had inadequate response to multiple bi­ological DMARDs (bDMARDs), includ­ing TNFi’s, IL-17 and IL-12/23 inhibitors, achieved effective disease control across multiple domains with guselkumab, a fully human monoclonal antibody that binds specifically to the p19 subunit of IL-23.³

IL-23 plays a pivotal role in PsA patho­physiology and triggers effector cytokines causing tissue inflammation and injury. Targeting IL-23, particularly with p19 in­hibitors such as guselkumab, is found to be effective and safe for managing mul­tiple clinical PsA domains, most notably the skin, and hence is an appropriate treatment choice for our patient with ac­tive skin involvement, pain, peripheral ar­thritis and dactylitis.³

In the phase III, randomized, placebo-controlled DISCOVER-1 tri­al, use of guselkumab was associated with higher rates of achieving ACR20 and ACR50 responses (ie, ≥20 and ≥50 percent improvement in American Col­lege of Rheumatology [ACR] criteria) and MDA at week 24 vs placebo, and response rates were maintained or in­creased through 52 weeks, regardless of prior TNFi use. Psoriasis Area and Se­verity Index (PASI) score of ≤1 at week 24 was also achieved by a greater pro­portion of patients treated with gusel­kumab vs placebo.^4-7 (Tables 1 and 2)

The phase IIIB, randomized, double-blind COSMOS trial showed that in patients with inadequate response to TNFi, guselkumab provided substantial benefits across multiple domains (swol­len/tender joints, psoriasis, spinal pain, enthesitis/dactylitis) vs placebo, with in­creasing proportions of patients achiev­ing LDA/remission over 1 year.^8,9

Guselkumab was associated with a higher rate of ≥20 percent improvement in pain VAS at week 24 vs placebo in both the DISCOVER-1 and COSMOS trials.^5,9 However, there are no head-to-head trials comparing the efficacy of IL-23 inhibitors vs other therapeutic class­es of bDMARDs.³

Despite active axial symptoms, our patient’s MRI did not reveal any active sacroiliitis. IL-23 inhibition is not routinely recommended in axial PsA since previ­ous trials of IL-23 inhibitors in ankylos­ing spondylitis demonstrated a lack of efficacy,^1,10 However, in biologic-naïve PsA patients with imaging-confirmed sacroiliitis, guselkumab demonstrat­ed durable and meaningful improve­ments in axial symptoms and disease activity in a post-hoc analysis of the DISCOVER-2 trial.¹¹

In this patient with prior inadequate response to multiple bDMARDs of dif­ferent classes, guselkumab provided reductions in disease activity in terms of peripheral arthritis, dactylitis and axial pain.

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