Introduction

Secondary loss of response to Infliximab(IFX) occurs in approximately half of patients with Inflammatory Bowel Disease(IBD), due to drug levels falling below the therapeutic range. This study evaluated IFX levels and related clinical and laboratory parameters and their impact on clinical outcomes.

Aims & Methods

Pre-infusion drug levels, associated laboratory data, and clinical parameters were evaluated in IBD patients receiving maintenance doses of IFX(5–15 mg/kg every 4–8 weeks) between Nov2021-Apr2025. Drug levels were measured using a bedside kit capable of quantitatively detecting values between 0.4–20µg/mL.

Results

A total of 1,059 single pre-infusion measurements from 455 patients and consecutive dual measurements at weeks 4 and 8 from 64 patients were evaluated. In the single and double measurement groups, 75.4% and 84.4% of patients had Crohn’s disease(CD), respectively. The most commonly used doses were 5 mg/8 weeks and 10 mg/4 weeks(Table 1) Drug levels were below 5 µg/mL in 33% of the measurements. Antibody positivity was present in 47.5% of 120 available measurements ranging from 0.4-20 µg/mL, showing no significant correlation with drug levels or immunomodulatory(IM) use (p=0.62 and p=0.61) However, for all positive antibody measurements drug levels were ≤ 3.5 µg/mL. CRP differed significantly across drug level groups, whereas albumin did not(Table 1). A weak negative correlation was found between IFX levels and CRP(r = -0.13, p = 0.001), with no correlation for albumin(p=0.54). In UC patients, the correlation between CRP and IFX levels was slightly stronger(r= -0.280, p=0.004).No significant associations were found between IM use and IFX levels >5 µg/mL(p=0.55), >10 µg/mL(p= 0.93), or >20µg/mL(p = 0.87). Abdominal pain was more common in patients with IFX levels <5 µg/mL (p=0.032) and <10 µg/mL (p=0.044). Smoking status was not associated with achieving IFX levels >5 µg/mL( p=0.57), >10 µg/mL (p=0.89), and >20 µg/mL (p=0.633). Among CD patients, those with IFX levels >5 µg/mL had significantly lower CDAI scores (p = 0.039), and lower daily stool frequency (p=0.002).Regression analysis showed that higher BMI (p=0.045), lower CRP(p < 0.001), higher IFX dose(p < 0.001), and CD diagnosis(p =0.014) to be independently associated with achieving IFX levels >5 µg/mL. These factors also predicted levels >10 µg/mL and >20 µg/mL, except for BMI at the >20 µg/mL threshold. In the dual measurement group, the median CRP levels at weeks 4 and 8 were 2.1(5.1) and 2.5(6.3), respectively (p = 0.108). Among patients with IFX >20 µg/mL at week 4, 75% maintained levels >5 µg/mL at week 8, whereas this rate was 64% for those with levels >10 µg/mL. Only 59.6% of those with >5 µg/mL at week 4 retained >5 µg/mL at week 8(all p <0.001). Week 4 IFX levels was 7.3 times higher than at week 8 for cases within measurable range.

Conclusion

One-third of patients demonstrated sub-therapeutic drug levels, which were associated with elevated CRP levels and worse clinical outcomes. Notably, the 5mg/4 weeks group exhibited higher drug concentrations compared to the 10mg/8 weeks group, suggesting that increased infusion frequency may contribute to achieving higher levels. Moreover, maintaining sufficient drug levels at week 8 requires substantially higher levels at week 4. Measurement of anti-TNF antibodies may not be fruitful if drug level is > 3.5µg/mL. These findings support the drug monitoring and personalized dosing to reduce the risk of loss of response and improve outcomes.

Clinical Case Summary

27-year-old male with penetrating Crohn's disease (CD; A1, L2, pB3), diagnosed at the age of 9, with multiple hospitalizations. The patient was treated with infliximab + azathioprine for three years. Colonoscopy at 16 years showed pancolitis and was complicated with perforation, being submitted to total colectomy with rectal preservation and ileostomy. Therapy was switched to adalimumab+methotrexate, with partial clinical response. After seven years, due to severe complex fistulizing perianal disease, adalimumab was switched to ustekinumab. After 2 years of Ustekinumab monotherapy, he presented disabling symptoms and developed an enterocutaneous fistula peri-ileostomy. Combination therapy with ustekinumab+vedolizumab was started. The patient still maintained discharge from the enterocutaneous and perianal fistulas. After 1 year, a painful circumferential penile ulcer with swelling and seropurulent discharge was noted. Other causes, namely infections were excluded. Biopsies were performed and revealed non-caseous granulomatous inflammation with lymphocytic and eosinophilic infiltrates, compatible with CD. Topical therapy with tacrolimus ointment was applied, with no response. Ustekinumab+vedolizumab was switched to upadacitinib. There was a substantial improvement of the penile lesion, the enterocutaneous fistula discharge reduced, and perianal symptoms resolved on maintenance therapy with Upadacitinib.
Genital metastatic CD is uncommon and mainly occurs in the setting of colonic involvement and perianal disease. Treatment options for MCD remain underwhelming due to the limited available evidence and varying responses of reported therapeutic methods. Optimization of biologic therapy is mandatory.

References

For this case we'll include:
- Pictures ​of the penile ulcers before and during maintenance therapy with upadacitinib
- Endoscopic evaluation during follow-up
- Histological specimen of colectomy and from multiple endoscopic evaluations performed
- Radiological evidence of perianal and peri-ileostomy enterocutaneous fistula