Primary SARS-CoV-2 infection in patients with immune-mediated inflammatory diseases: long-term humoral immune responses and effects on disease activity.

BACKGROUND: Patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressants (ISPs) may have impaired long-term humoral immune responses and increased disease activity after SARS-CoV-2 infection. We aimed to investigate long-term humoral immune responses against SARS-CoV-2 and increased disease activity after a primary SARS-CoV-2 infection in unvaccinated IMID patients on ISPs. METHODS: IMID patients on active treatment with ISPs and controls (i.e. IMID patients not on ISP and healthy controls) with a confirmed SARS-CoV-2 infection before first vaccination were included from an ongoing prospective cohort study (T2B! study). Clinical data on infections and increased disease activity were registered using electronic surveys and health records. A serum sample was collected before first vaccination to measure SARS-CoV-2 anti-receptor-binding domain (RBD) antibodies. RESULTS: In total, 193 IMID patients on ISP and 113 controls were included. Serum samples from 185 participants were available, with a median time of 173 days between infection and sample collection. The rate of seropositive IMID patients on ISPs was 78% compared to 100% in controls (p < 0.001). Seropositivity rates were lowest in patients on anti-CD20 (40.0%) and anti-tumor necrosis factor (TNF) agents (60.5%), as compared to other ISPs (p < 0.001 and p < 0.001, respectively). Increased disease activity after infection was reported by 68 of 260 patients (26.2%; 95% CI 21.2-31.8%), leading to ISP intensification in 6 out of these 68 patients (8.8%). CONCLUSION: IMID patients using ISPs showed reduced long-term humoral immune responses after primary SARS-CoV-2 infection, which was mainly attributed to treatment with anti-CD20 and anti-TNF agents. Increased disease activity after SARS-CoV-2 infection was reported commonly, but was mostly mild. TRIAL REGISTRATION: NL74974.018.20, Trial ID: NL8900. Registered on 9 September 2020.

Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies.

BACKGROUND: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. METHODS: In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. FINDINGS: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported. INTERPRETATION: Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis. FUNDING: Arena Pharmaceuticals.

Disease activity in patients with immune-mediated inflammatory diseases after SARS-CoV-2 vaccinations.

For patients with immune-mediated inflammatory diseases (IMIDs), concerns exist about increased disease activity after vaccination. We aimed to assess changes in disease activity after SARS-CoV-2 vaccination in patients with IMIDs, and determine risk factors for increased disease activity. In this substudy of a prospective observational cohort study (Target-to-B!), we included patients with IMIDs who received a SARS-CoV-2 vaccine. Patients reported changes in disease activity on a five-point Likert scale every 60 days for up to twelve months after first vaccination. In case of self-reported increased activity, hospital records were screened whether the treating physician reported increased activity, and for potential intensification of immunosuppressive (ISP) treatment. Mixed models were used to study determinants for self-reported increased disease activity. In total, 2111 patients were included for analysis after primary immunization (mean age 49.7 years [SD 13.7], 1329/2111 (63.0%) female), from which 1266 patients for analysis after first additional vaccination. Increased disease activity at 60 days after start of primary immunization was reported by 223/2111 (10.6%). In 96/223 (43.0%) the increase was confirmed by the treating physician and in 36/223 (16.1%) ISP treatment was intensified. Increased disease activity at seven to 60 days after additional vaccination, was reported by 139/1266 (11.0%). Vaccinations were not temporally associated with self-reported increased disease activity. Conversely, increased disease activity before first vaccination, neuromuscular disease, and multiple sclerosis were associated. Altogether, self-reported increased disease activity after vaccination against SARS-CoV-2 was recorded in a minority of patients and was generally mild. Moreover, multivariate analyses suggest that disease related factors, but not vaccinations are the major determinants for self-reported increased disease activity.

Efficacy of Upadacitinib Dose Escalation in a Phase 3 Long-Term Extension Ulcerative Colitis Study

Introduction: Upadacitinib (UPA), an oral selective and reversible JAK inhibitor, recently demonstrated significantly greater therapeutic efficacy compared to placebo (PBO) in patients with moderate to severe ulcerative colitis (UC) during a Phase 3 program.1,2,3 We evaluated the efficacy of dose escalation to UPA 30 mg QD (UPA30) among patients who demonstrated an inadequate response to UPA 15 mg QD (UPA15) during the long-term extension (LTE) study U-ACTIVATE. Results were based on non-responder imputation (NRI-NC) with 95% confidence intervals (CI) calculated by normal approximation to binomial distribution. F020For patients enrolled from U-ACHIEVE Maintenance due to loss of response, inadequate response was defined as: SFS + RBS value that remains unchanged or has increased from wk 0 on two consecutive visits at least 7 days apart. a Non-responder imputation with no special data handling for missing due to COVID-19 was applied. 95% CI calculated by normal approximation to binomial distribution. b Clinical remission per Adapted Mayo score: SFS≤1 and not greater than baseline (of induction), RBS=0, and endoscopic subscore (ES) ≤ 1. c Clinical remission per Adapted Mayo score and CS-free clinical remission (clinical remission at wk 48 and CS-free for ≥90 days prior to wk 48 among patients with clinical remission at the end of the induction therapy). d Endoscopic improvement: ES ≤ 1 e Endoscopic remission: ES= 0.

Efficacy and Safety of Upadacitinib Induction Therapy in Patients With Moderately to Severely Active Crohn’s Disease: Results From a Randomized Phase 3 U-EXCEL Study

Introduction: Eligible patients(N=526) with moderate to severe active Crohn’s Disease(CD), defined as average daily stool frequency(SF)≥4 and/or abdominal pain score(APS)≥2, and a Simple Endoscopic Score for CD(SES-CD) (excluding the narrowing component subscore) ≥6(≥4 for subjects with isolated ileal disease). PBO % [95% CI] h Co-Primary Endpoints Clinical remission, wk 12  Per CDAI a  Per SF/APS b 29.1 [22.4, 35.8] 22.2 [16.0, 28.3] 49.5 [44.2, 54.8] 50.7 [45.5, 56.0] 20.8 [12.7, 28.8]** 28.7 [20.9, 36.4]** Endoscopic response c , wk 12 13.1 [8.1, 18.0] 45.5 [40.3, 50.8] 33.0 [26.2, 39.9]** Key Secondary Endpoints Clinical Remission, wk 4  Per CDAI a  Per SF/APS b 26.7 [20.2, 33.3] 14.8 [9.5, 20.0] 37.1 [32.1, 42.2] 35.7 [30.7, 40.7] 10.8 [2.9, 18.6]* 21.2 [14.3, 28.2]** Corticosteroid-free clinical remission, wk 12  per CDAI d  per SF/APS d (N=64) 15.7 [6.8, 24.7] 12.5 [4.4, 20.6] (N=126) 42.9 [34.2, 51.5] 44.4 [35.8, 53.1] 27.7 [15.7, 39.8]** 32.6 [21.5, 43.7]** Clinical Response CR-100 e  Week 2  Week 12 20.4 [14.4, 26.5] 37.3 [30.1, 44.5] 32.2 [27.3, 37.1] 56.6 [51.4, 61.8] 11.7 [4.2, 19.2]* 19.8 [11.3, 28.4]** Endoscopic remission f , wk 12 7.4 [3.5, 11.3] 28.9 [24.2, 33.7] 21.8 [15.8, 27.8]** Patient randomization was stratified by baseline corticosteroid use, endoscopic disease severity, and the number of previously failed biologics. All patients within this dataset were included here within the ITT population. a Clinical remission per CDAI = per US, CDAI < 150. b Clinical remission per SF/APS = per EU, average daily SF ≤ 2.8 and average daily APS ≤ 1.0 and both not greater than baseline c Endoscopic response = decrease in SES-CD > 50% from baseline (or for subjects with a baseline SES-CD of 4, at least a 2-point reduction from baseline), as scored by a central reviewer. d Corticosteroid-free clinical remission = discontinuation of corticosteroid use and achievement of clinical remission per CDAI or SF/APS at wk 12 among patients on corticosteroids at baseline. e Clinical response-100 = decrease of ≥ 100 points in CDAI from baseline. f Endoscopic remission = SES-CD ≤ 4, at least a 2-point reduction versus baseline and no subscore >1 in any individual variable, as scored by a central reviewer. g Results are based on non-responder imputation incorporating multiple imputation to handle missing data due to COVID-19 (NRI-C). h 95% CI for adjusted difference and p-value are calculated according to the Cochran-Mantel-Haenszel (CMH) test adjusted for randomization strata. **P ≤ .0001 or *P ≤ .01 vs PBO;Average daily abdominal pain score, APS;Coronavirus disease 2019, COVID-19;Confidence Interval, CI;Crohn’s Disease Activity Index, CDAI;Simple Endoscopic Score for CD, SES-CD, Placebo, PBO;Once daily, QD;average daily very soft/liquid stool frequency, SF;Upadacitinib, UPA.

52-Week Risankizumab Subcutaneous Maintenance Dosing Is Efficacious and Well Tolerated in Patients With Moderate to Severe Crohn’s Disease Who Had Delayed Response to 12-Weeks IV Risankizumab Induction

Introduction: In patients with moderate to severe Crohn's disease (CD), the ADVANCE and MOTIVATE phase 3 induction studies showed intravenous (IV) risankizumab (RZB), an anti-p19 interleukin-23 inhibitor, to be superior to placebo (PBO) for achieving clinical and endoscopic endpoints at Week (Wk) 12.1 Here, we evaluated the long-term efficacy and safety of RZB during the FORTIFY maintenance study in patients with delayed clinical response to IV RZB induction. [...]patients receiving RZB SC (180 mg or 360 mg) also achieved endoscopic response (36.7%, 45.5%), endoscopic remission (40.0%, 42.4%), deep remission (40.0%, 39.4%), ulcer free endoscopy (27.6%, 24.2%), and the combined endpoint of SF/APS clinical remission + endoscopic response (23.3%, 36.4%). [...]a dose-response trend was observed, with numerically higher response rates observed with RZB 360 mg SC relative to 180 mg SC for most outcomes, including clinical remission (CDAI and SF/APS), CDAI clinical response, enhanced clinical response, endoscopic response, endoscopic remission, and the composite endpoint of SF/APS clinical remission + endoscopic response. Efficacy and Safety after 52-Weeks Maintenance SC RZB Dosing in Delayed Responders (NRI-NCa) Responder Group Treatment Group, n (%) [95% CI] CDAI Clinical Response Enhanced Clinical Response CDAI Clinical Remission SF/APS Clinical Remission Endoscopic Response Ulcer Free Endoscopy Endoscopic Remission SF/APS Clinical Remission and Endoscopic Response Deep Remission RZB 180 mg SC delayed responders, Wk 24 53.3 (6/30) [35.5, 71.2] 56.7 (17/30) [38.9, 74.4] 53.3 (16/30) [35.5, 71.2] 43.3 (13/30) [25.6, 61.1] 36.7 (11/30) [19.4, 53.9] 27.6 (8/29) [11.3, 43.9] 40.0 (12/30) [22.5, 57.5] 23.3 (7/30) [8.2, 38.5] 40.0 (12/30) [22.5, 57.5] RZB 360 mg SC delayed responders, Wk 24 75.8 (25/33) [61.1, 90.4] 66.7 (22/33) [50.6, 82.8] 66.7 (22/33) [50.6, 82.8] 54.5 (18/33) [37.6, 71.5] 45.5 (15/33) [28.5, 62.4] 24.2 (8/33) [9.6, 38.9] 42.4 (14/33) [25.6, 59.3] 36.4 (12/33) [20.0, 52.8] 39.4 (13/33) [22.7, 56.1] Responder Group Treatment Group, (E/100PYs) Deaths Serious infections All treatment emergent adverse events AE related to COVID-19 Serious AE Hepatic events Injection site reactions AE leading to discontinuation of study drug Crohn's Disease RZB 180 mg SC (N=31) (PYs=27.5) delayed responders, Wk 24 0 0 132 (479.8) 0 6 (21.8) 0 6 (21.8) 2 (7.3) 7 (25.4) RZB 360 mg SC (N=33) (PYs=32.1) delayed responders, Wk 24 0 1 (3.1) 83 (258.9) 0 4 (12.5) 1 (3.1) 2 (6.2) 0 7 (21.8)

Induction and Maintenance Treatment with Risankizumab Leads to Symptomatic Relief in Patients With Moderate to Severe Crohn’s Disease

Here, the patient reported outcomes (PROs) of AP score (APS) and SF, and their correlation with endoscopic outcomes, were examined during induction and maintenance treatment. Methods: Pooled data from the ADVANCE/MOTIVATE induction studies (PBO, RZB 600 mg intravenous (IV) groups), and data from the FORTIFY maintenance study (180 mg, 360 mg and RZB withdrawal/PBO subcutaneous [SC] groups), were examined for AP and SF clinical outcomes. Patient Reported Outcomes of Abdominal Pain Score (APS) and Stool Frequency (SF) during Induction and Maintenance Dosing with RZB (ITT#) (NRI-NC&) Endpoint ADVANCE + MOTIVATE RZB 600 mg IV PBO RZB 600 mg IV PBO RZB 600 mg IV PBO Wk 4 Wk 8 Wk 12 Decrease in APS from BL 59.4 [54.3, 64.5] 71.7 [67.9, 75.6] P < 0.001 63.8 [58.9, 68.8] 75.9 [72.2, 79.6] P< 0.001 58.8 [53.8, 63.9] 76.9 [73.2, 80.5] P< 0.001 Decrease in SF from BL 65.7 [60.9, 70.6] 81.6 [78.3, 84.9] P< 0.001 63.5 [58.6, 68.5] 84.1 [80.9, 87.2] P< 0.001 58 [52.9, 63.1] 85.4 [82.4, 88.4] P< 0.001 AP =0 in patients with APS ≥1 at Baseline 2.6 [0.9, 4.3] 5.6 [3.6, 7.6] P= 0.052 3.2 [1.3, 5.0] 11.5 [8.7, 14.3] P< 0.001 6.4 [3.8, 8.9] 17.9 [14.5, 21.2] P<0.001 SF ≤1 in patients with SF >2.8 at Baseline 4.8 [2.5, 7.1] 9.8 [7.1, 12.5] P=0.004 6 [3.4, 8.5] 18.2 [14.7, 21.6] P<0.001 11.6 [8.2, 15.1] 26.1 [22.2, 30.0] P<0.001 Endpoint FORTIFY Withdrawal (PBO SC) RZB 180 mg SC RZB 360 mg SC Withdrawal (PBO SC) RZB 180 mg SC RZB 360 mg SC Withdrawal (PBO SC) RZB 180 mg SC RZB 360 mg SC Withdrawal (PBO SC) RZB 180 mg SC RZB 360 mg SC Withdrawal (PBO SC) RZB 180 mg SC RZB 360 mg SC Wk 8 Wk 16 Wk 24 Wk 32 Wk 52 APS Remission (APS ≤1) 67.7 [60.5, 74.8] 72.6 [65.6, 79.6] P=0.413 75.9 [68.8, 82.9] P= 0.033 70.1 [63.1, 77.1] 65.6 [58.2, 73.0] P= 0.311 70.2 [62.7, 77.8] P= 0.743 61 [53.5, 68.4] 66.2 [58.8, 73.6] P= 0.306 68.1 [60.4, 75.8] P= 0.052 54.3 [46.6, 61.9] 66.2 [58.8, 73.6] P = 0.027 63.1 [55.2, 71.1] P= 0.035 46.3 [38.7, 54.0] 57.3 [49.6, 65.1] P= 0.027 55.3 [47.1, 63.5] P= 0.028 SF Remission (SF ≤2.8) 66.5 [59.2, 73.7] 68.2 [60.9, 75.4] P= 0.807 67.4 [59.6, 75.1] P= 0.420 64.6 [57.3, 72.0] 66.2 [58.8, 73.6] P = 0.783 67.4 [59.6, 75.1] P = 0.266 59.8 [52.3, 67.3] 59.9 [52.2, 67.5] P = 0.990 63.8 [55.9, 71.8] P = 0.154 57.3 [49.7, 64.9] 58.6 [50.9, 66.3] P= 0.881 58.2 [50.0, 66.3] P= 0.437 44.5 [36.9, 52.1] 51.6 [43.8, 59.4] P= 0.113 56 [3.6, 24.3] P= 0.008 AP =0 18.3 [12.4, 24.2] 30.6 [23.4, 37.8] P= 0.009 30.6 [23.4, 37.8] P= 0.009 SF ≤1 28.7 [21.7, 35.6] 35.7 [28.2, 43.2] P=0.081 39.0 [31.0, 47.1] P=0.006 AP =0 and SF ≤1 14.6 [9.2, 20.0] 21.7 [15.2, 28.1] P=0.092 23.4 [16.4, 30.4] P=0.021 BL = baseline;Wk = Week;Endoscopic remission = SES-CD ≤4 and at least 2-point reduction from baseline;Ulcer-free endoscopy = SES-CD ulcerated surface subscore =0 in patients with subscore ≥1 at baseline;#Intent-to-treat (ITT) population Includes randomized patients who (ADVANCE/MOTIVATE) received at least one dose of study drug during the 12-Week Induction Period, and had an SES-CD of ≥6 (≥4 for isolated ileal disease) or who (FORTIFY) received IV risankizumab for 12 weeks in the induction study and at least one dose of study drug in FORTIFY sub-study 1 and had an SES-CD of ≥6 (≥ 4 for isolated ileal disease) at baseline of induction. &Calculations were based on non-responder imputation with no special data handling for missing data due to COVID-19 pandemic. 95% CI and p-value for adjusted response rate difference compared to PBO calculated according to the Cochran-Mantel-Haenszel test adjusted for strata.

Breakthrough infections with the SARS-CoV-2 omicron (B.1.1.529) variant in patients with immune-mediated inflammatory diseases.

OBJECTIVES: To compare the cumulative incidence and disease severity of reported SARS-CoV-2 omicron breakthrough infections between patients with immune-mediated inflammatory diseases (IMID) on immunosuppressants and controls, and to investigate determinants for breakthrough infections. METHODS: Data were used from an ongoing national prospective multicentre cohort study on SARS-CoV-2 vaccination responses in patients with IMID in the Netherlands (Target-to-B! (T2B!) study). Patients wih IMID on immunosuppressants and controls (patients with IMID not on immunosuppressants and healthy controls) who completed primary immunisation were included. The observation period was between 1 January 2022 and 1 April 2022, during which the SARS-CoV-2 omicron (BA.1 and BA.2 subvariant) was dominant. A SARS-CoV-2 breakthrough infection was defined as a reported positive PCR and/or antigen test at least 14 days after primary immunisation. A multivariate logistic regression model was used to investigate determinants. RESULTS: 1593 patients with IMID on immunosuppressants and 579 controls were included. The cumulative incidence of breakthrough infections was 472/1593 (29.6%; 95% CI 27% to 32%) in patients with IMID on immunosuppressants and 181/579 (31.3%; 95% CI 28% to 35%) in controls (p=0.42). Three (0.5%) participants had severe disease. Seroconversion after primary immunisation (relative risk, RR 0.71; 95% CI 0.52 to 0.96), additional vaccinations (RR 0.61; 95% CI 0.49 to 0.76) and a prior SARS-CoV-2 infection (RR 0.60; 95% CI 0.48 to 0.75) were associated with decreased risk of breakthrough infection. CONCLUSIONS: The cumulative incidence of reported SARS-CoV-2 omicron breakthrough infections was high, but similar between patients with IMID on immunosuppressants and controls, and disease severity was mostly mild. Additional vaccinations and prior SARS-CoV-2 infections may reduce the incidence of breakthrough infections.

Real-world experience of switching from intravenous to subcutaneous vedolizumab maintenance treatment for inflammatory bowel diseases.

BACKGROUND: Subcutaneous (SC) vedolizumab is effective in inflammatory bowel diseases (IBD) when administered after induction with two infusions. AIM: To assess the effectiveness, safety and pharmacokinetics of a switch from intravenous (IV) to SC maintenance vedolizumab in patients with IBD METHODS: In this prospective cohort study, patients with IBD who had ≥4 months IV vedolizumab were switched to SC vedolizumab. We studied the time to discontinuation of SC vedolizumab, adverse events (AEs), changes in clinical and biochemical outcomes and vedolizumab concentrations at baseline, and weeks 12 and 24. RESULTS: We included 82 patients with Crohn's disease (CD) and 53 with ulcerative colitis (UC). Eleven (13.4%) patients with CD and five (9.4%) with UC discontinued SC vedolizumab after a median of 18 (IQR 8-22) and 6 weeks (IQR 5-10), respectively. Four patients with CD switched to a different drug due to loss of response, nine switched back to IV vedolizumab due to adverse events, and three due to needle fear. Common AEs were injection site reactions (n = 15) and headache (n = 6). Median clinical and biochemical disease activity remained stable after the switch. Median serum vedolizumab concentrations increased from 19 µg/ml at the time of the switch to 31 µg/ml 12 weeks after the switch (p < 0.005). CONCLUSIONS: Switching from IV to SC vedolizumab maintenance treatment is effective in patients with CD or UC. However, 9% of patients were switched back to IV vedolizumab due to adverse events or fear of needles.

Risankizumab as induction therapy for Crohn's disease: results from the phase 3 ADVANCE and MOTIVATE induction trials.

BACKGROUND: Risankizumab, an interleukin (IL)-23 p19 inhibitor, was evaluated for safety and efficacy as induction therapy in patients with moderately to severely active Crohn's disease. METHODS: ADVANCE and MOTIVATE were randomised, double-masked, placebo-controlled, phase 3 induction studies. Eligible patients aged 16-80 years with moderately to severely active Crohn's disease, previously showing intolerance or inadequate response to one or more approved biologics or conventional therapy (ADVANCE) or to biologics (MOTIVATE), were randomly assigned to receive a single dose of intravenous risankizumab (600 mg or 1200 mg) or placebo (2:2:1 in ADVANCE, 1:1:1 in MOTIVATE) at weeks 0, 4, and 8. We used interactive response technology for random assignment, with stratification by number of previous failed biologics, corticosteroid use at baseline, and Simple Endoscopic Score for Crohn's disease (SES-CD). All patients and study personnel (excluding pharmacists who prepared intravenous solutions) were masked to treatment allocation throughout the study. Coprimary endpoints were clinical remission (defined by Crohn's disease activity index [CDAI] or patient-reported outcome criteria [average daily stool frequency and abdominal pain score]) and endoscopic response at week 12. The intention-to-treat population (all eligible patients who received at least one dose of study drug in the 12-week induction period) was analysed for efficacy outcomes. Safety was assessed in all patients who received at least one dose of study drug. Both trials were registered on ClinicalTrials.gov, NCT03105128 (ADVANCE) and NCT03104413 (MOTIVATE), and are now complete. FINDINGS: Participants were enrolled between May 10, 2017, and Aug 24, 2020 (ADVANCE trial), and Dec 18, 2017 and Sept 9, 2020 (MOTIVATE trial). In ADVANCE, 931 patients were assigned to either risankizumab 600 mg (n=373), risankizumab 1200 mg (n=372), or placebo (n=186). In MOTIVATE, 618 patients were assigned to risankizumab 600 mg (n=206), risankizumab 1200 mg (n=205), or placebo (n=207). The primary analysis population comprised 850 participants in ADVANCE and 569 participants in MOTIVATE. All coprimary endpoints at week 12 were met in both trials with both doses of risankizumab (p values ≤0·0001). In ADVANCE, CDAI clinical remission rate was 45% (adjusted difference 21%, 95% CI 12-29; 152/336) with risankizumab 600 mg and 42% (17%, 8-25; 141/339) with risankizumab 1200 mg versus 25% (43/175) with placebo; stool frequency and abdominal pain score clinical remission rate was 43% (22%, 14-30; 146/336) with risankizumab 600 mg and 41% (19%, 11-27; 139/339) with risankizumab 1200 mg versus 22% (38/175) with placebo; and endoscopic response rate was 40% (28%, 21-35; 135/336) with risankizumab 600 mg and 32% (20%, 14-27; 109/339) with risankizumab 1200 mg versus 12% (21/175) with placebo. In MOTIVATE, CDAI clinical remission rate was 42% (22%, 13-31; 80/191) with risankizumab 600 mg and 40% (21%, 12-29; 77/191) with risankizumab 1200 mg versus 20% (37/187) with placebo; stool frequency and abdominal pain score clinical remission rate was 35% (15%, 6-24; 66/191) with risankizumab 600 mg and 40% (20%, 12-29; 76/191) with risankizumab 1200 mg versus 19% (36/187) with placebo; and endoscopic response rate was 29% (18%, 10-25; 55/191) with risankizumab 600 mg and 34% (23%, 15-31; 65/191) with risankizumab 1200 mg versus 11% (21/187) with placebo. The overall incidence of treatment-emergent adverse events was similar among the treatment groups in both trials. Three deaths occurred during induction (two in the placebo group [ADVANCE] and one in the risankizumab 1200 mg group [MOTIVATE]). The death in the risankizumab-treated patient was deemed unrelated to the study drug. INTERPRETATION: Risankizumab was effective and well tolerated as induction therapy in patients with moderately to severely active Crohn's disease. FUNDING: AbbVie.

Upadacitinib as induction and maintenance therapy for moderately to severely active ulcerative colitis: results from three phase 3, multicentre, double-blind, randomised trials.

BACKGROUND: There is a great unmet need for advanced therapies that provide rapid, robust, and sustained disease control for patients with ulcerative colitis. We assessed the efficacy and safety of upadacitinib, an oral selective Janus kinase 1 inhibitor, as induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. METHODS: This phase 3, multicentre, randomised, double-blind, placebo-controlled clinical programme consisted of two replicate induction studies (U-ACHIEVE induction [UC1] and U-ACCOMPLISH [UC2]) and a single maintenance study (U-ACHIEVE maintenance [UC3]). The studies were conducted across Europe, North and South America, Australasia, Africa, and the Asia-Pacific region at 199 clinical centres in 39 countries (UC1), 204 clinical centres in 40 countries (UC2), and 195 clinical centres in 35 countries (UC3). Patients aged 16-75 years with moderately to severely active ulcerative colitis (Adapted Mayo score 5-9; endoscopic subscore 2 or 3) for at least 90 days were randomly assigned (2:1) to oral upadacitinib 45 mg once daily or placebo for 8 weeks (induction studies). Patients who achieved clinical response following 8-week upadacitinib induction were re-randomly assigned (1:1:1) to upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 52 weeks (maintenance study). All patients were randomly assigned using web-based interactive response technology. The primary endpoints were clinical remission per Adapted Mayo score at week 8 (induction) and week 52 (maintenance). The efficacy analyses in the two induction studies were based on the intent-to-treat population, which included all randomised patients who received at least one dose of treatment. In the maintenance study, the primary efficacy analyses reported in this manuscript were based on the first 450 (planned) clinical responders to 8-week induction therapy with upadacitinib 45 mg once daily. The safety analysis population in the induction studies consisted of all randomised patients who received at least one dose of treatment; in the maintenance study, this population included all patients who received at least one dose of treatment as part of the primary analysis population. These studies are registered at ClinicalTrials.gov, NCT02819635 (U-ACHIEVE) and NCT03653026 (U-ACCOMPLISH). FINDINGS: Between Oct 23, 2018, and Sept 7, 2020, 474 patients were randomly assigned to upadacitinib 45 mg once daily (n=319) or placebo (n=155) in UC1. Between Dec 6, 2018, and Jan 14, 2021, 522 patients were randomly assigned to upadacitinib 45 mg once daily (n=345) or placebo (n=177) in UC2. In UC3, a total of 451 patients (21 from the phase 2b study, 278 from UC1, and 152 from UC2) who achieved a clinical response after 8 weeks of upadacitinib induction treatment were randomly assigned again to upadacitinib 15 mg (n=148), upadacitinib 30 mg (n=154), and placebo (n=149) in the primary analysis population. Statistically significantly more patients achieved clinical remission with upadacitinib 45 mg (83 [26%] of 319 patients in UC1 and 114 [34%] of 341 patients in UC2) than in the placebo group (seven [5%] of 154 patients in UC1 and seven [4%] of 174 patients; p<0·0001; adjusted treatment difference 21·6% [95% CI 15·8-27·4] for UC1 and 29·0% [23·2-34·7] for UC2). In the maintenance study, clinical remission was achieved by statistically significantly more patients receiving upadacitinib (15 mg 63 [42%] of 148; 30 mg 80 [52%] of 154) than those receiving placebo (18 [12%] of 149; p<0·0001; adjusted treatment difference 30·7% [21·7-39·8] for upadacitinib 15 mg vs placebo and 39·0% [29·7-48·2] for upadacitinib 30 mg vs placebo). The most commonly reported adverse events in UC1 were nasopharyngitis (15 [5%] of 319 in the upadacitinib 45 mg group vs six [4%] of 155 in the placebo group), creatine phosphokinase elevation (15 [4%] vs three [2%]), and acne (15 [5%] vs one [1%]). In UC2, the most frequently reported adverse event was acne (24 [7%] of 344 in the upadacitinib 45 mg group vs three [2%] of 177 in the placebo group). In both induction studies, serious adverse events and adverse events leading to discontinuation of treatment were less frequent in the upadacitinib 45 mg group than in the placebo group (serious adverse events eight [3%] vs nine (6%) in UC1 and 11 [3%] vs eight [5%] in UC2; adverse events leading to discontinuation six [2%] vs 14 [9%] in UC1 and six [2%] vs nine [5%] in UC2). In UC3, the most frequently reported adverse events (≥5%) were worsening of ulcerative colitis (19 [13%] of 148 in the upadacitinib 15 mg group vs 11 [7%] of 154 in the upadacitinib 30 mg group vs 45 [30%] of 149 in the placebo group), nasopharyngitis (18 [12%] vs 22 [14%] vs 15 [10%]), creatine phosphokinase elevation (nine [6%] vs 13 [8%] vs three [2%]), arthralgia (nine [6%] vs five [3%] vs 15 [10%]), and upper respiratory tract infection (seven [5%] vs nine [6%] vs six [4%]). The proportion of serious adverse events (ten [7%] vs nine [6%] vs 19 [13%]) and adverse events leading to discontinuation (six [4%] vs ten [6%] vs 17 [11%]) was lower in both upadacitinib groups than in the placebo group. Events of cancer, adjudicated major adverse cardiac events, or venous thromboembolism were reported infrequently. There were no treatment-related deaths. INTERPRETATION: Upadacitinib demonstrated a positive efficacy and safety profile and could be an effective treatment option for patients with moderately to severely active ulcerative colitis. FUNDING: AbbVie.

Humoral responses after second and third SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders on immunosuppressants: a cohort study.

Background: Disease-specific studies have reported impaired humoral responses after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory disorders treated with specific immunosuppressants. Disease-overarching studies, and data on recall responses and third vaccinations are scarce. Our primary objective was to investigate the effects of immunosuppressive monotherapies on the humoral immune response after SARS-CoV-2 vaccination in patients with prevalent immune-mediated inflammatory disorders. Methods: We did a cohort study in participants treated in outpatient clinics in seven university hospitals and one rheumatology treatment centre in the Netherlands as well as participants included in two national cohort studies on COVID-19-related disease severity. We included patients aged older than 18 years, diagnosed with any of the prespecified immune-mediated inflammatory disorders, who were able to understand and complete questionnaires in Dutch. Participants with immune-mediated inflammatory disorders who were not on systemic immunosuppressants and healthy participants were included as controls. Anti-receptor binding domain IgG responses and neutralisation capacity were monitored following standard vaccination regimens and a three-vaccination regimen in subgroups. Hybrid immune responses-ie, vaccination after previous SARS-CoV-2 infection-were studied as a proxy for recall responses. Findings: Between Feb 2 and Aug 1, 2021, we included 3222 participants in our cohort. Sera from 2339 participants, 1869 without and 470 participants with previous SARS-CoV-2 infection were analysed (mean age 49·9 years [SD 13·7]; 1470 [62·8%] females and 869 [37·2%] males). Humoral responses did not differ between disorders. Anti-CD20 therapy, sphingosine 1-phosphate receptor (S1P) modulators, and mycophenolate mofetil combined with corticosteroids were associated with lower relative risks for reaching seroconversion following standard vaccination (0·32 [95% CI 0·19-0·49] for anti-CD20 therapy, 0·35 [0·21-0·55] for S1P modulators, and 0·61 [0·40-0·90] for mycophenolate mofetil combined with corticosteroids). A third vaccination increased seroconversion for mycophenolate mofetil combination treatments (from 52·6% after the second vaccination to 89·5% after the third) but not significantly for anti-CD20 therapies (from 36·8% to 45·6%) and S1P modulators (from 35·5% to 48·4%). Most other immunosuppressant groups showed moderately reduced antibody titres after standard vaccination that did not increase after a third vaccination, although seroconversion rates and neutralisation capacity were unaffected. In participants with previous SARS-CoV-2 infection, SARS-CoV-2 antibodies were boosted after vaccination, regardless of immunosuppressive treatment. Interpretation: Humoral responses following vaccination are impaired by specific immunosuppressants. After standard vaccination regimens, patients with immune-mediated inflammatory disorders taking most immunosuppressants show similar seroconversion to controls, although antibody titres might be moderately reduced. As neutralisation capacity and recall responses are also preserved in these patients, this is not likely to translate to loss of (short-term) protection. In patients on immunosuppressants showing poor humoral responses after standard vaccination regimens, a third vaccination resulted in additional seroconversion in patients taking mycophenolate mofetil combination treatments, whereas the effect of a third vaccination in patients on anti-CD20 therapy and S1P modulators was limited. Funding: ZonMw (The Netherlands Organization for Health Research and Development).

Breakthrough SARS-CoV-2 infections with the delta (B.1.617.2) variant in vaccinated patients with immune-mediated inflammatory diseases using immunosuppressants: a substudy of two prospective cohort studies.

Background: Concerns have been raised regarding the risks of SARS-CoV-2 breakthrough infections in vaccinated patients with immune-mediated inflammatory diseases treated with immunosuppressants, but clinical data on breakthrough infections are still scarce. The primary objective of this study was to compare the incidence and severity of SARS-CoV-2 breakthrough infections between patients with immune-mediated inflammatory diseases using immunosuppressants, and controls (patients with immune-mediated inflammatory diseases not taking immunosuppressants and healthy controls) who had received full COVID-19 vaccinations. The secondary objective was to explore determinants of breakthrough infections of the delta (B.1.617.2) variant of SARS-CoV-2, including humoral immune responses after vaccination. Methods: In this substudy, we pooled data collected in two large ongoing prospective multicentre cohort studies conducted in the Netherlands (Target to-B! [T2B!] study and Amsterdam Rheumatology Center COVID [ARC-COVID] study). Both studies recruited adult patients (age ≥18 years) with immune-mediated inflammatory diseases and healthy controls. We sourced clinical data from standardised electronic case record forms, digital questionnaires, and medical files. We only included individuals who were vaccinated against SARS-CoV-2. For T2B!, participants were recruited between Feb 2 and Aug 1, 2021, and for ARC-COVID, participants were recruited between April 26, 2020, and March 1, 2021. In this study we assessed data on breakthrough infections collected between July 1 and Dec 15, 2021, a period in which the delta SARS-CoV-2 variant was the dominant variant in the Netherlands. We defined a SARS-CoV-2 breakthrough infection as a PCR-confirmed or antigen test-confirmed SARS-CoV-2 infection that occurred at least 14 days after vaccination. All breakthrough infections during this period were assumed to be due to the delta variant due to its dominance during the study period. We analysed post-vaccination serum samples for anti-receptor binding domain (RBD) antibodies to assess the humoral vaccination response (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC-COVID study only). We used multivariable logistic regression analyses to explore potential clinical and humoral determinants associated with the odds of breakthrough infections. The T2B! study is registered with the Dutch Trial Register, Trial ID NL8900, and the ARC-COVID study is registered with Dutch Trial Register, trial ID NL8513. Findings: We included 3207 patients with immune-mediated inflammatory diseases who receive immunosuppressants, and 1807 controls (985 patients with immune-mediated inflammatory disease not on immunosuppressants and 822 healthy controls). Among patients receiving immunosuppressants, mean age was 53 years (SD 14), 2042 (64%) of 3207 were female and 1165 (36%) were male; among patients not receiving immunosuppressants, mean age was 54 years (SD 14), 598 (61%) of 985 were female and 387 (39%) were male; and among healthy controls, mean age was 57 years (SD 13), 549 (67%) of 822 were female and 273 (33%) were male. The cumulative incidence of PCR-test or antigen-test confirmed SARS-CoV-2 breakthrough infections was similar in patients on immunosuppressants (148 of 3207; 4·6% [95% CI 3·9-5·4]), patients not on immunosuppressants (52 of 985; 5·3% [95% CI 4·0-6·9]), and healthy controls (33 of 822; 4·0% [95% CI 2·8-5·6]). There was no difference in the odds of breakthrough infection for patients with immune-mediate inflammatory disease on immunosuppressants versus combined controls (ie, patients not on immunosuppressants and healthy controls; adjusted odds ratio 0·88 [95% CI 0·66-1·18]). Seroconversion after vaccination (odds ratio 0·58 [95% CI 0·34-0·98]; T2B! cohort only) and SARS-CoV-2 infection before vaccination (0·34 [0·18-0·56]) were associated with a lower odds of breakthrough infections. Interpretation: The incidence and severity of SARS-CoV-2 breakthrough infections in patients with immune-mediated inflammatory diseases on immunosuppressants was similar to that in controls. However, caution might still be warranted for those on anti-CD20 therapy and those with traditional risk factors. Funding: ZonMw (the Netherlands Organization for Health Research and Development) and Reade foundation.

Risk factors associated with short-term adverse events after SARS-CoV-2 vaccination in patients with immune-mediated inflammatory diseases.

BACKGROUND: Studies have suggested incremental short-term adverse events (AE) after repeated vaccination. In this report, we assessed occurrence and risk factors for short-term AEs following repeated SARS-CoV-2 vaccination in patients with various immune-mediated inflammatory diseases (IMIDs). METHODS: Self-reported daily questionnaires on AEs during the first 7 days after vaccination were obtained of 2259 individuals (2081 patients and 178 controls) participating in an ongoing prospective multicenter cohort study on SARS-CoV-2 vaccination in patients with various IMIDs in the Netherlands (T2B-COVID). Relative risks were calculated for potential risk factors associated with clinically relevant AE (rAE), defined as AE lasting longer than 2 days or impacting daily life. RESULTS: In total, 5454 vaccinations were recorded (1737 first, 1992 second and 1478 third vaccinations). Multiple sclerosis, Crohn's disease and rheumatoid arthritis were the largest disease groups. rAEs were reported by 57.3% (95% CI 54.8-59.8) of patients after the first vaccination, 61.5% (95% CI 59.2-63.7) after the second vaccination and 58% (95% CI 55.3-60.6) after the third vaccination. At day 7 after the first, second and third vaccination, respectively, 7.6% (95% CI 6.3-9.1), 7.4% (95% CI 6.2-8.7) and 6.8% (95% CI 5.4-8.3) of patients still reported AEs impacting daily life. Hospital admissions and allergic reactions were uncommon (<0.7%). Female sex (aRR 1.43, 95% CI 1.32-1.56), age below 50 (aRR 1.14, 95% CI 1.06-1.23), a preceding SARS-CoV-2 infection (aRR 1.14, 95% CI 1.01-1.29) and having an IMID (aRR 1.16, 95% CI 1.01-1.34) were associated with increased risk of rAEs following a vaccination. Compared to the second vaccination, the first vaccination was associated with a lower risk of rAEs (aRR 0.92, 95% CI 0.84-0.99) while a third vaccination was not associated with increased risk on rAEs (aRR 0.93, 95% CI 0.84-1.02). BNT162b2 vaccines were associated with lower risk on rAEs compared to CX-024414 (aRR 0.86, 95% CI 0.80-0.93). CONCLUSIONS: A third SARS-CoV-2 vaccination was not associated with increased risk of rAEs in IMID patients compared to the second vaccination. Patients with an IMID have a modestly increased risk of rAEs after vaccination when compared to controls. Most AEs are resolved within 7 days; hospital admissions and allergic reactions were uncommon. TRIAL REGISTRATION: NL74974.018.20 , Trial ID: NL8900. Registered on 9 September 2020.