Anti–IL-23 management of severe psoriatic arthritis in a heavily pretreated young obese patient

Presentation and history
The patient is a 29-year-old male who was first diagnosed with psoriatic arthritis (PsA) in November 2010. He had comorbid well-controlled epilepsy and obesity, with body weight fluctuating between 100 kg and 107 kg in recent years.

At the time of diagnosis and until receiving his latest treatment, the patient’s overall skin condition was often very poor, with >90 percent body surface area (BSA) involvement, itchy rashes and bleeding on the upper and lower extremities and his face. (Figure 1A) His severe PsA also affected the lower limbs, including swollen knee and ankle joints. The patient could not stand on his own, and required a crutch to walk in his apartment and a wheelchair to go out.
 

The disease markedly affected the patient’s self-esteem and caused psychological distress. He locked himself up at home and only went out for hospital appointments. Due to his skin condition, even on hot summer days, he covered up fully to avoid exposing his skin in public. In addition, 5 years ago, he lost his customer-facing job at a toy store because the customers found his appearance off-putting, and remained unemployed since. He also developed depression and was on an antidepressant (sertraline) for 2 years before starting his latest treatment.

Upon diagnosis in November 2010, the patient was started on methotrexate and cyclosporin, but did not respond well to treatment. He was switched to adalimumab, a tumour necrosis factor alpha inhibitor (anti–TNF-alpha), in early 2011, with only a moderate degree of success. By the end of 2016, his symptoms were no longer controlled, and he was put on another anti–TNF agent, certolizumab pegol, in October 2016–March 2017, but the response was inadequate.

After switching to anti–interleukin (IL)-17A treatment with secukinumab in March 2017, the patient initially responded well, but the improvement was not sustained, and he had to be switched to the anti–IL-12/23 ustekinumab in August 2018. Similar to his prior experiences with biologic treatments, the patient’s condition improved at first, but he stopped responding to ustekinumab in December 2018.

The patient’s next treatment was with abatacept, a T-cell co-stimulation modulator, which he received between February and October 2019. Again, initial improvement was followed by waning efficacy. The next treatment was with a small-molecule JAK inhibitor, tofacitinib, in October–December 2019, to which the patient failed to respond. In December 2019, he decided to restart ustekinumab under the support of Samaritan Fund. However, treatment was ineffective, with 90 percent of his BSA still affected by psoriasis. The patient was on the immunosuppressant mycophenolate mofetil between January and December 2021. He was put on ixekizumab on 6 December 2021, which resulted in increased fatigue and poor appetite. Furthermore, the patient experienced a flare-up <3 weeks after starting ixekizumab.

Latest treatment
In January 2022, the patient was switched to the latest PsA treatment to become available in Hong Kong – an IL-23 pathway blocker, guselkumab (100 mg by subcutaneous injection at weeks 0 and 4, followed by a maintenance dose every 8 weeks).

Two months after starting guselkumab, the patient began to experience symptom improvement. After 4 months, the improvements were substantial: the BSA affected by PsA decreased to just 1 percent, and lower-limb joint pain had reduced to the extent where the patient became able to walk unaided. (Figure 1B) Of note, the patient was initially frustrated with treatment as he did not see improvements in the first 2 months, but he was strongly recommended to persevere, as the minimal period for declaring biologic treatment ineffective is 3–4 months.

With his skin condition and joint pain vastly improved, the patient has regained self-confidence and goes out a lot more. He feels comfortable wearing more weather-appropriate clothing and gets regular haircuts at a salon. While his lifestyle became more active, his body weight remains at approximately 100 kg as he also dines out more than before.

Following improvements in his overall condition and mental state, the patient started to receive reduced doses of sertraline from April 2022, and the dose was tapered until September 2022, when antidepressant treatment was completely discontinued.

As of October 2022, the patient had been on guselkumab for 10 months, with no reported decrease in efficacy or any side effects.

Discussion
Although PsA is associated with a high incidence of metabolic syndrome, including obesity, most biologics, such as ustekinumab, are designed for patients weighing <100 kg.^1,2 For better therapeutic effect, heavier patients often require higher doses.² A meta-analysis also showed that obese patients generally have poorer response to treatment, particularly to TNF inhibitors, vs patients with normal BMI (odds ratio [OR], 1.60; 95 percent confidence interval [CI], 1.39–1.83).^3,4

Guselkumab is approved in Hong Kong for both moderate-to-severe psoriasis and active PsA.⁵ Its efficacy is independent of body weight, which may in part account for its transformative effect on our obese patient’s condition.⁵ In contrast to prior biologic treatments, which were either ineffective or only led to partial response not lasting >6 months, guselkumab delivered sustained efficacy in our patient.

Notably, a pooled analysis of ACR20 (≥20 percent improvement in American College of Rheumatology response criteria) data from the phase III DISCOVER-1 (biologic-naïve and TNF-inhibitor–experienced patients) and -2 (biologic-naïve patients) trials, guselkumab 100 mg Q4W/Q8W resulted in robust and sustained improvements in PsA signs and symptoms at 52 weeks across various predefined subgroups, including pretreated patients (who had received any disease-modifying antirheumatic drugs before guselkumab; 68 percent), those with long-term (≥3 years) disease (64–69 percent), and BMI ≥30 kg/m² (67–68 percent), like our patient.⁶

The effects of guselkumab took approximately 2 months to be noticed in our patient with very severe PsA and complicated treatment history, during which time he nearly gave up on treatment. This case highlights the importance of staying on a biologic agent for at least 4 months to reliably assess treatment efficacy.

Unlike in the present case study, guselkumab demonstrated a rapid onset of action in the phase IIIb COSMOS trial, where patients with prior inadequate response to TNF inhibitors treated with guselkumab 100 mg Q8W had higher ACR20 response rates vs placebo recipients as early as week 4 (19.0 percent vs 4.2 percent; p<0.001) and higher ACR50 response rates as early as week 8 (8.5 percent vs 2.1 percent; p=0.039). The trial met its primary endpoint of ACR20 at week 24 (guselkumab vs placebo, 44 percent vs 20 percent; p<0.001).⁷

In the same trial, guselkumab was superior to placebo for each key secondary endpoint, including Psoriasis Area and Severity Index (PASI) 100 response in patients with ≥3 percent BSA with psoriasis involvement and Investigator’s Global Assessment of psoriasis (IGA) ≥2 at baseline, which was achieved by 31 percent of patients on guselkumab vs 4 percent of patients on placebo (p<0.001).⁷

In COSMOS, 144.9 adverse events (AEs) per 100 patient-years (PY) were reported among guselkumab-treated patients vs 369.8 AEs per 100 PY for placebo through week 56. Through week 24, the most common AEs with guselkumab were nasopharyngitis (5 percent) and upper respiratory tract infection (4 percent), which occurred in a similar proportion of patients on placebo (5 percent and 3 percent, respectively). Infections were the most common AEs in guselkumab-treated patients through week 56 (37.2 infections per 100 PY vs 99.6 infections per 100 PY for placebo). Through week 56, the rate of serious AEs with guselkumab was 6.3 events per 100 PY, while the rate of AEs leading to treatment discontinuation was 2.7 events per 100 PY.⁷