IL-12/23 blocker in a TNF-naïve Crohn’s disease patient with steroid dependency
A 38-year-old female solicitor presented with chronic abdominal pain, diarrhoea, and weight loss (from 40 kg to 36 kg within 2 months) in June 2019. She was a nonsmoker without remarkable medical or family history. Physical examination revealed perianal ulcer but no fistula.
Laboratory investigations in June 2019 showed haemoglobin of 11.6 g/dL, C-reactive protein (CRP) of 21 mg/dL, white blood cell count of 12.1 x 109/L and platelet count of 555 x 109/L. The patient’s faecal calprotectin (FC) level was >1,000 μg/mg, indicating intestinal inflammation. Colonoscopy was performed in August 2019 and revealed deep and skipped ulcers in the ileum and the entire colon, which supported the diagnosis of moderate-to-severe Crohn’s disease (Crohn's Disease Activity Index [CDAI], 320).
The patient was put on mesalazine 3,000 mg/day in August 2019 but failed to achieve clinical remission. A short course (6 weeks) of prednisolone 30 mg/day was started and azathioprine 100 mg/day was added during steroid tapering. This combined therapy helped to improve her overall symptoms, and clinical remission was achieved and maintained for 9 months.
In June 2020, the patient experienced relapse requiring hospitalization and another course of prednisolone. Colonoscopy yielded similar findings to index colonoscopy, with no sign of mucosal healing. (Figure) This time, the patient experienced abdominal pain and diarrhoea immediately after dose reduction of prednisolone. In view of her steroid dependency, use of a biologic was deemed necessary and mesalazine was discontinued.
After a lengthy discussion, the patient preferred ustekinumab to tumour necrosis factor-alpha (TNF-α) inhibitors for its ease of administration and fewer systemic adverse events (AEs). Intravenous (IV) ustekinumab at a loading dose of 260 mg was started in July 2020, followed by subcutaneous (SC) ustekinumab maintenance therapy at 90 mg Q8W.1 Azathioprine was discontinued.
Two weeks after starting ustekinumab, the patient reported a significant improvement in symptoms, with a CDAI score of <150. The laboratory markers (CRP, <0.6 mg/dL; FC, <50
μg/g) normalized since October 2020. Steroid use was successfully discontinued 2 months after the use of ustekinumab, and remission was maintained with ustekinumab maintenance therapy. Colonoscopy in April 2021 showed residual scar from previous ulceration. Alongside are normal mucosa with normal vascular pattern. (Figure)
Over 1 year of ustekinumab monotherapy, the patient did not experience any AEs. She remained in steroid-free remission at the time of writing. She has regained weight (from 36 kg to 42 kg) and resumed normal activities, including full-time work.
The rapid advent of biologics for Crohn’s disease has allowed achievement of treatment goals beyond the conventional targets set out in STRIDE-I. To improve long-term treatment outcomes, STRIDE-II has recently updated treat-to-target strategies, including short-term targets of symptom resolution and biomarker remission, and long-term goals of endoscopic remission, restoration of quality of life, and absence of disability.2 Early use of biologics enables patients with moderate-to-severe Crohn’s disease to achieve STRIDE-II targets, which is successfully illustrated in this case.
Our biologic-naïve patient achieved clinical response to ustekinumab at week 2 of treatment and remained in steroid-free remission for over 1 year. Her response is consistent with results of the phase III UNITI-2 trial (ie, TNF-naïve population; n=628) of ustekinumab, which demonstrated early response rates at week 3 (32.5 percent and 38.8 percent for ustekinumab 130 mg and 6 mg/kg body weight, respectively, vs 21.5 percent for placebo; p=0.01 and p<0.001, respectively) and lasting remission at week 44 (62.5 percent and 56.9 percent for ustekinumab Q8W and Q12W, respectively, vs 44.3 percent for placebo; p=0.02 and p=0.15, respectively).3
Importantly, results of IMUNITI 5-year long-term extension (LTE) showed sustained clinical remission rates in TNF-naïve patients at week 252 (Q8W, 59.0 percent; Q12W, 39.5 percent) and high steroid-free remission rates (Q8W, 93.3 percent; Q12W, 89.5 percent) attained by patients in clinical remission at week 252, which we hope to reproduce for our patient in the long term.4
Repeated or prolonged steroid courses are not advisable because of increased risk for corticosteroid-related AEs. Therefore, a biologic was chosen for our steroid-dependent patient.5 Both ustekinumab and TNF inhibitors are viable first-line biologic agents for Crohn’s disease.6 Our patient, a solicitor with a busy schedule, preferred ustekinumab due to its better safety profile and infrequent dosing regimen.
The efficacy and safety of ustekinumab and adalimumab in biologic-naïve patients with moderate-to-severe Crohn’s disease were directly compared in the phase III SEAVUE trial (n=386). Ustekinumab Q8W was comparable to adalimumab Q2W in terms of 52-week clinical remission rate (64.9 percent vs 61.0 percent; 95 percent confidence interval [CI], -5.5–13.5; p=0.42), but with a better safety profile. Ustekinumab was associated with a lower rate of injection-site reactions (1.0 percent vs 10.3 percent), lower infection rate (34.0 percent vs 40.5 percent), lower rate of serious AEs of worsening Crohn’s disease (2.6 percent vs 7.2 percent), and lower discontinuation rate due to AEs (6.3 percent vs 11.3 percent).7
Similarly, real-world data from a national commercial health insurance plan in the US dedicated to inflammatory bowel diseases (n=21,819; Crohn’s disease, 63.36 percent) demonstrated that ustekinumab was associated with a significantly lower risk of infection vs TNF inhibitors (32 percent vs 44 percent; hazard ratio, 0.93; 95 percent CI, 0.86–0.99; p=0.04).8 In IM-UNITI LTE, the risk of tuberculosis (TB) was low, with one case of active pulmonary TB occurring over 5 years of ustekinumab treatment.4 In contrast, the TBNET consensus statement stated that the relative risk of TB is increased up to 25 times following TNF antagonist therapy.8 As TNF is a key component of the antibacterial and inflammatory responses against infections, it is not surprising that TNF inhibitors are associated with increased infection risk.9
To conclude, early initiation of a biologic in patients with moderate-to-severe Crohn’s disease is desirable to improve treatment outcomes as these patients tend to deteriorate over the long term.10 Ustekinumab is as effective as TNF inhibitors, but has a better safety profile and can be chosen as the first-line biologic agent for Crohn’s disease, especially for patients with a strong preference for convenient dosing (Q8W and Q12W) and those vulnerable to infection, including elderly patients and those with primary (ie, autoimmune disease) and secondary immunodeficiencies (ie, chemotherapy, corticosteroids or diabetes).6,11