Systematic Review With Meta-analysis

Loss of Response and Requirement of Ustekinumab Dose Escalation in Inflammatory Bowel Diseases

Hongsheng Yang; Bingyang Li; Qin Guo; Jian Tang; Bo Peng; Ni Ding; Miao Li; Qingfang Yang; Zicheng Huang; Na Diao; Xia Zhu; Jun Deng; Huili Guo; Pinjin Hu; Kang Chao; Xiang Gao

Disclosures

Aliment Pharmacol Ther. 2022;55(7):764-777. 

In This Article

Results

Study Characteristics

The literature search findings and study selection process are shown in Figure 1. The search yielded 6430 records: 1176 from PubMed, 1997 from Web of Science, 2615 from EMBASE, 440 from the Cochrane Library and 202 from major conference proceedings. After removing duplicates and preliminary screening, 94 studies were assessed for eligibility. Eighty studies were excluded (see Figure 1 and Table S3 for details), and 14 studies were included in the meta-analysis.[5,21–33]

Figure 1.

Flow diagram of the study selection process. CD, Crohn's disease; UC, ulcerative colitis

The characteristics of the included studies are shown in Table 1 and Table S4. Eight studies were full-text articles,[5,22,25,26,29,30,32,33] and six were conference abstracts.[21,23,24,27,28,31] Three studies were multicentre randomised controlled trials,[5,24,31] and the remaining 11 were retrospective cohort studies (six multicentres and five single centres).[21–23,25–30,32,33] Thirteen studies included CD patients,[5,21–30,32,33] and one included UC patients.[31] The majority of patients (40–100%) were previously treated with biologics. Three early cohorts had off-label subcutaneous induction loading prior to drug launch,[21,29,33] whereas nine later cohorts used intravenous induction,[5,23–27,31,32] and two studies used both.[22,30] The common maintenance dose was ustekinumab 90 mg administered subcutaneously q8w or q12w.

Ustekinumab LOR and Dose Escalation in Patients With CD

Percentage and Annual Risk for LOR Among Primary Responders With CD. Nine studies provided data on the percentage and annual risk for ustekinumab LOR among primary responders with CD (Table 2).[21–24,26,29,30,32,33] A total of 1133 primary responders were included in these studies, providing a 1530 person-year follow-up. The LOR rates ranged from 0% to 40%. The overall annual risk of LOR among primary responders was 21% (95% confidence interval [CI] 12–31%; I 2 = 89%, P < .01) per person-year (Figure 2A). The random effects pooled rate of LOR was 23% (95% CI 13–33%; I 2 = 92%, P < .01) with a mean/median follow-up time of 32 weeks to 26.6 months (Figure S1).

Figure 2.

Forest plot: The annual risk of ustekinumab loss of response among primary responders with Crohn's disease. (A) The overall annual risk of loss of response. (B) The subgroup analyses of the annual risk of loss of response based on publication type, study design, induction regimen, maintenance regimen, mean/median follow-up time and definition of loss of response. Studies without adequate information were excluded from subgroup analyses. IV, intravenous; SC, subcutaneous; CDAI, Crohn's disease activity index; HBI, Harvey-Bradshaw index; LOR, loss of response; CI, confidence interval; N/A, not applicable

The subgroup analyses did not show significantly different estimates of the annual risk of LOR by publication type, study design, induction regimen, maintenance regimen, mean/median follow-up time or the definition of LOR (Figure 2B).

Percentage and Annual Risk for Dose Escalation Among Primary Responders With CD. Five studies provided data on the percentage and annual risk of ustekinumab dose escalation among primary responders with CD (Table 2).[5,23,29,30,33] A total of 677 primary responders were included in these studies, providing 657 person-years in the follow-up. The rate of dose escalation ranged from 11% to 36%. The overall annual risk of dose escalation among primary responders was 25% (95% CI 16–37%, I 2 = 86%, P < .01) per person-year (Figure 3A). The random effects pooled rate of LOR was 23% (95% CI 16–30%, I 2 = 84%, P < .01) with a mean/median follow-up time of 32 weeks to 26.6 months (Figure S2).

Figure 3.

Forest plot: The annual risk of ustekinumab dose escalation among primary responders with Crohn's disease. (A) The overall annual risk of dose escalation. (B) the subgroup analyses of the annual risk of dose escalation based on publication type, study design, induction regimen, maintenance regimen, mean/median follow-up time and dose escalation modality. Studies without adequate information were excluded from subgroup analyses. IV, intravenous; SC, subcutaneous; LOR, loss of response; CI, confidence interval; N/A, not applicable

The subgroup analyses showed similar estimates of the annual risk of LOR according to study design, maintenance regimen, mean/median follow-up time and dose escalation modality but significantly different estimates by publication type and induction regimen (Figure 3B).

Efficacy of Dose Escalation Among CD Patients who Lost Response to Ustekinumab. Eight studies reported a regained response after dose escalation among CD patients who lost response to ustekinumab (Table 2).[5,23,25,27–30,33] The random effects pooled clinical response rate was 58% (95% CI 49–67%, I2 = 47%, P = .07, 279 patients; Figure 4A). The subgroup analyses demonstrated similar estimates of clinical response rates after dose escalation by publication type, study design, induction regimen, maintenance regimen, and dose escalation modality (Figure 4B). Only one study has reported the clinical remission rate after dose escalation.[5] Feagan et al. reported that 41% (12/29) of CD patients with LOR regained clinical remission 16 weeks after dose adjustment from ustekinumab 90 mg q12w to q8w.[5]

Figure 4.

Forest plot: Regained response rates of ustekinumab dose escalation in secondary non-responders with Crohn's disease. (A) tThe overall regained response rate of dose escalation. (B) The subgroup analyses of regained response rates of dose escalation based on publication type, study design, induction regimen, maintenance regimen and dose escalation modality. Studies without adequate information were excluded from subgroup analyses. IV, intravenous; LOR, loss of response; CI, confidence interval; N/A, not applicable

Predictors for LOR to Ustekinumab in Primary Responders With CD. Three studies reported 11 significant predictors of LOR to ustekinumab in primary responders with CD.[23,24,30] Eight factors were associated with a higher risk of LOR, including higher Harvey-Bradshaw index (HBI) scores at induction (HBI ≥7 vs HBI <7,[30] higher HBI scores [continuous variable][23] and higher HBI scores [moderate vs mild][23]), a stricturing disease (Montreal classification B2 vs B1),[30] the number of previous biologics,[23] previous anti-TNF exposure/failure,[24] and higher maintenance baseline Crohn's Disease Activity Index scores.[24] On the other hand, three factors were associated with a lower risk of LOR, including colonic disease (Montreal classification L2 vs L1),[30] ileocolonic diseases (Montreal classification L3 vs L1)[30] and concurrent immunomodulation therapy (yes vs no).[30] Of note, neither Chaparro et al.[23] nor Hanauer et al. (data not shown)[24] identified concurrent immunomodulation therapy as a significant predictor of LOR. Details are shown in Figure 5.

Figure 5.

Forest plot: Predictors of ustekinumab loss of response among primary responders with Crohn's disease. HRs and ORs were calculated by using the multivariate Cox proportional hazards model and multivariate logistic regression model respectively. Disease location and phenotype were based on Montreal classification. HBI, Harvey-Bradshaw index; TNF, tumour necrosis factor; IMM, immunomodulator; CDAI, Crohn's disease activity index; HR, hazard ratio; OR, odds ratio; CI, confidence interval

Ustekinumab Loss of Response and Dose Escalation in Patients With UC

No studies have provided data on LOR to ustekinumab in primary responders with UC. Only one randomised controlled study, that is, the UNIFI trial's year 3 extension, provided data on ustekinumab dose escalation among induction responders with UC.[31]

In the UNIFI trial's year 3 extension, 43% (60/141) of UC patients underwent dose adjustment from q12w to q8w, and 28% (40/143) underwent sham dose adjustment from q8w to q8w from Week 44 to 156.[31] The overall rate of dose escalation prior to week 156 was 35%. The annual risk of dose escalation was 18% per person-year for the overall population, 21% per person-year for the q12w group and 14% per person-year for the q8w group. At the visit ≥16 weeks after dose adjustment from q12w to q8w, 58% (14/24) of patients regained symptomatic remission.

Assessment of Risk of Bias and Publication Bias

The risk of bias was assessed in the included studies using the IHE checklist. The quality assessment values are listed in Table S5. The included real-world cohort studies were retrospective in nature. The studies were at high risk of bias due to the following outcomes assessment: (1) no cohort studies reported blind assessment of outcomes and (2) outcomes (the definition of LOR or dose escalation) were not adequately described in five studies.[21,22,26,28,29] Since the number of included studies investigating LOR, dose escalation or efficacy of regained response was <10, neither Begg's nor Egger's tests were performed to evaluate potential publication bias.

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