The authors tested whether the anti-interleukin (IL)-17A monoclonal antibody secukinumab was safe and effective for the treatment of active Crohn9s disease.
Design
In a double-blind, randomised, placebo-controlled proof-of-concept study, 59 patients with moderate to severe Crohn9s disease (Crohn9s Disease Activity Index (CDAI) ≥220 to ≤450) were assigned in a 2:1 ratio to 2×10 mg/kg intravenous secukinumab or placebo. The primary end point, addressed by Bayesian statistics augmented with historical placebo information, was the probability that secukinumab reduces the CDAI by ≥50 points more than placebo at week 6. Ancillary analyses explored associations of 35 candidate genetic polymorphisms and faecal calprotectin response.
Results
59 patients (39 secukinumab, 20 placebo, mean baseline CDAI 307 and 301, respectively) were recruited. 18/59 (31%) patients discontinued prematurely (12/39 (31%) secukinumab, 6/20 (30%) placebo), 10/59 (17%) due to insufficient therapeutic effect (8/39 (21%) secukinumab, 2/20 (10%) placebo). Fourteen serious adverse events occurred in 10 patients (seven secukinumab, three placebo); 20 infections, including four local fungal infections, were seen on secukinumab versus none on placebo. Primary end point analysis estimated <0.1% probability (∆CDAI (SD) =33.9 (19.7), 95% credible interval −4.9 to 72.9) that secukinumab reduces CDAI by ≥50 points more than placebo. Secondary area under the curve analysis (weeks 4–10) showed a significant difference (mean ΔCDAI=49; 95% CI (2 to 96), p=0.043) in favour of placebo. Post hoc subgroup analysis showed that unfavourable responses on secukinumab were driven by patients with elevated inflammatory markers (CRP≥10 mg/l and/or faecal calprotectin≥200 ng/ml; mean ΔCDAI=62; 95% CI (−1 to 125), p=0.054 in favour of placebo). Absence of the minor allele of tumour necrosis factor-like ligand 1A was strongly associated with lack of response measured by baseline-adjusted changes in calprotectin at week 6 (p=0.00035 Bonferroni-corrected).
Conclusions
Blockade of IL-17A was ineffective and higher rates of adverse events were noted compared with placebo.
Clinical trial registration
This trial was registered at ClinicalTrial.gov with the number NCT01009281.
The aim of this study was to assess the efficacy and safety of adalimumab (ADA), a recombinant human monoclonal antibody against tumour necrosis factor α (TNF), for the induction of clinical remission in anti-TNF naïve patients with moderately to severely active ulcerative colitis.
Methods
This 8-week, multicentre, randomised, double-blind, placebo-controlled study (NCT00385736), conducted at 94 centres in North America and Europe, enrolled ambulatory adult patients with Mayo score of ≥6 points and endoscopic subscore of ≥2 points despite treatment with corticosteroids and/or immunosuppressants. Under the original study protocol, 186 patients were randomised (1:1) to subcutaneous treatment with ADA160/80 (160 mg at week 0, 80 mg at week 2, 40 mg at weeks 4 and 6) or placebo. Subsequently, at the request of European regulatory authorities, the protocol was amended to include a second induction group (ADA80/40: 80 mg at week 0, 40 mg at weeks 2, 4 and 6). The primary efficacy endpoint was clinical remission (Mayo score ≤2 with no individual subscore >1) at week 8, assessed in 390 patients randomised (1:1:1) to ADA160/80, ADA80/40, or placebo. Safety was assessed in all enrolled patients. Patients, study site personnel, investigators, and the sponsor were blinded to treatment assignment.
Results
At week 8, 18.5% of patients in the ADA160/80 group (p=0.031 vs placebo) and 10.0% in the ADA80/40 group (p=0.833 vs placebo) were in remission, compared with 9.2% in the placebo group. Serious adverse events occurred in 7.6%, 3.8% and 4.0% of patients in the placebo, ADA80/40, and ADA160/80 groups, respectively. There were two malignancies in the placebo group, none in the ADA groups. There were no cases of tuberculosis and no deaths.
Conclusions
ADA160/80 was safe and effective for induction of clinical remission in patients with moderately to severely active ulcerative colitis failing treatment with corticosteroids and/or immunosuppressants.
Nonvalidated definitions of disease-related parameters in inflammatory bowel disease cause variations in diagnosis and disease classification. We determined interobserver agreement on applications of definitions of the Vienna Classification variables and computed the potential influence of misclassification on genotype/phenotype associations. Ten records of patients with Crohn's disease (CD) were independently evaluated by 19 observers using a standardized inflammatory bowel disease documentation system, which included the Vienna Classification. Interobserver agreement (IOA) was calculated as a percentage of the observers' agreement with a predetermined reference observer and by Cohen's kappa. Randomized reclassifications were then computed with 10,000 simulation runs using the IOA results and published NOD2/CARD15 gene status. A chi-square independence test was calculated for each simulation run. IOA for location and behavior was 70% (κ = 0.57) and 95% (κ = 0.91), respectively. IOA for location subgroups ranged from 48% to 88% and for behavior from 91% to 97%. By including the results of histopathology into the evaluation of location, the overall IOA increased significantly, to 80% (P = 0.019). Assuming a true genotype/phenotype association, the proportion of studies with nonsignificant findings (P > 0.05) because of the observed misclassification of location ranged from 13.3% to 63.8% and of behavior from 0.2% to 22.2%, depending on a study sample size of 500 or 150 patients respectively. We concluded that there is appreciable interobserver disagreement on the location of CD according to the original Vienna Classification that may obscure true genotype/phenotype associations. Definitions of disease parameters have to be validated before being used as the bases for classifications.
The objective of our study was to assess the diagnostic value of CT enteroclysis compared with conventional enteroclysis in patients with Crohn's disease.Fifty consecutive patients (26 women, 24 men; mean age, 36.3 years; age range, 18-52 years) with histologically proven Crohn's disease underwent CT enteroclysis and conventional enteroclysis (median time interval, 21.7 days) during a symptomatic stage of their disease. Both techniques were compared with regard to diagnostic yield in assessing the presence and extent of disease. Imaging findings were compared with surgery, follow-up examinations, or both.CT enteroclysis and conventional enteroclysis were successfully performed in all 50 patients. Crohn's disease-associated radiographic changes were found in 44 patients (88%) using CT enteroclysis and in 42 patients (84%) using conventional enteroclysis. Significantly more Crohn's disease-associated abnormalities were diagnosed with CT enteroclysis than with enteroclysis (p < 0.01). Minimal inflammatory changes of the mucosa were diagnosed in 44 patients (88%) using CT enteroclysis and in 42 patients (84%) using enteroclysis. Both imaging methods depicted stenotic bowel segments in 34 patients (68%), and prestenotic dilatation was diagnosed in 20 patients (40%) with CT enteroclysis and in 15 (30%) with enteroclysis. Fistulas were found in 18 patients (36%) with CT enteroclysis and in eight (16%) with enteroclysis (p < 0.01). Skip lesions could be seen in 17 (34%) and three patients (6%), respectively (p < 0.01). Conglomeration of bowel loops tumors was diagnosed with CT enteroclysis in 13 patients (26%) and in three patients (6%) using conventional enteroclysis (p < 0.01). Only CT enteroclysis depicted abscesses in eight patients (16%) (p < 0.01).CT enteroclysis proved to be significantly superior to conventional enteroclysis in depicting Crohn's disease-associated intra- and extramural abnormalities. CT enteroclysis is the imaging method of choice and should replace enteroclysis in patients with Crohn's disease.
Abstract Background The efficacy of a single administration of darvadstrocel (expanded allogeneic adipose-derived mesenchymal stem cells) for treating complex perianal fistulas in patients with Crohn’s disease was demonstrated in a randomized, double-blind trial (ADMIRE-CD [Adipose Derived Mesenchymal Stem Cells for Induction of Remission in Perianal Fistulizing Crohn\'s Disease] trial). The current chart review study (INSPECT [A retrospectIve chart review study evaluatINg the longer-term effectiveneSs of darvadstrocel in PatiEnts who CompleTed ADMIRE-CD]) evaluated the longer-term effectiveness and safety of darvadstrocel. Methods Eligible patients had completed at least 52 weeks in the ADMIRE-CD trial. Data on clinical remission and fistula relapse outcomes were collected retrospectively at 104 and 156 weeks after treatment. Adverse events of special interest (tumorigenicity and ectopic tissue formation) were collected up to 208 weeks after treatment. Results Eighty-nine patients were included (43 darvadstrocel patients, 46 control subjects). At 52, 104, and 156 weeks posttreatment, clinical remission was observed in 29 (67.4%) of 43, 23 (53.5%) of 43, and 23 (53.5%) of 43 darvadstrocel-treated patients, compared with 24 (52.2%) of 46, 20 (43.5%) of 46, and 21 (45.7%) of 46 control subjects, respectively. In patients with clinical remission at week 52, this remission was sustained at 104 and 156 weeks after treatment in 19 (65.5%) of 29 and 16 (55.2%) of 29 darvadstrocel-treated patients and in 17 (70.8%) of 24 and 13 (54.2%) of 24 control subjects, respectively. Time to fistula relapse and incidence of fistula relapse or new fistula occurrence were not significantly different between groups. Tumorigenicity was reported for 1 (2.2%) patient in the control group (malignant epidermoid carcinoma). No ectopic tissue formation was reported. Conclusions Real-world follow-up of patients from the ADMIRE-CD trial indicates that clinical remission of complex perianal fistulas can be sustained in the long term irrespective of whether it is achieved through darvadstrocel administration or maintenance treatment regimens and confirms a favorable long-term safety profile of darvadstrocel.
Summary Background The Lennard‐Jones criteria are considered the gold standard for diagnosing Crohn's disease ( CD ) and include the items granuloma, macroscopic discontinuity, transmural inflammation, fibrosis, lymphoid aggregates and discontinuous inflammation on histology. The criteria have never been subjected to a formal validation process. Aim To develop a validated and improved diagnostic index based on the items of Lennard‐Jones criteria. Methods Included were 328 adult patients with long‐standing CD (median disease duration 10 years) from three centres and classified as ‘established’, ‘probable’ or ‘non‐ CD ’ by Lennard‐Jones criteria at time of diagnosis. Controls were patients with ulcerative colitis (n = 170). The performance of each of the six diagnostic items of Lennard‐Jones criteria was modelled by logistic regression and a new index based on stepwise backward selection and cut‐offs was developed. The diagnostic value of the new index was analysed by comparing sensitivity, specificity and accuracy vs. Lennard‐Jones criteria. Results By Lennard‐Jones criteria 49% ( n = 162) of CD patients would have been diagnosed as ‘non‐ CD ’ at time of diagnosis (sensitivity/specificity/accuracy, ‘established’ CD : 0.34/0.99/0.67; ‘probable’ CD : 0.51/0.95/0.73). A new index was derived from granuloma, fibrosis, transmural inflammation and macroscopic discontinuity, but excluded lymphoid aggregates and discontinuous inflammation on histology. Our index provided improved diagnostic accuracy for ‘established’ and ‘probable’ CD (sensitivity/specificity/accuracy, ‘established’ CD : 0.45/1/0.72; ‘probable’ CD : 0.8/0.85/0.82), including the subgroup isolated colonic CD (‘probable’ CD , new index: 0.73/0.85/0.79; Lennard‐Jones criteria: 0.43/0.95/0.69). Conclusion We developed an index based on items of Lennard‐Jones criteria providing improved diagnostic accuracy for the differential diagnosis between CD and UC .
Introduction: The global post-marketing observational registry PYRAMID assessed the long-term safety and effectiveness of adalimumab (ADA) as used in routine clinical practice in patients (pts) with moderate to severe Crohn's disease (CD). Methods: Enrolled Pts were newly prescribed or currently receiving ADA according to local product label; pts were followed up to 6 yrs. This analysis assessed the long-term safety of ADA by age subgroups (< 40, 40-59, and ≥60 yrs) at registry enrolment (baseline [BL]). Registry treatment-emergent (TE) adverse events (AEs), (any event with onset on/after first dose of ADA in the registry up to 70 days after last ADA injection) are reported as events per 100 patient-yrs (PY). Results: 5025 pts in the registry received at least one dose of ADA and included in the analysis; at BL, 2981 pts (59.3%) were < 40 yrs (female, 57.1%; median age, 29.0 yrs; median CD duration, 7.0 yrs), 1717 pts (34.2%) were 40-59 yrs (female, 57.8%; median age, 47.0 yrs; median CD duration, 13.0 yrs) and 327 pts (6.5%) were ≥60 yrs (female, 52.9%; median age, 64.0 yrs; median CD duration, 13.5 yrs). Of those ≥60 yrs at BL, 23/327 (7.0%) were ≥75 yrs. Cumulative registry ADA exposure by BL age groups was 9681.1 PY (< 40 yrs), 6009.3 PY (40-59 yrs) and 990.0 PY (≥60 yrs). Approximately 46-52% of pts were receiving ADA monotherapy (without immunomodulators or corticosteroids) at BL across age groups. Rates of any registry TEAEs, including serious AEs and AEs of special interest, by age groups at BL are shown in Table 1. Similar rates of registry TE serious infections and opportunistic infections were observed across younger age groups, but numerically higher in the ≥60 yrs group. Rates of any registry TE malignancies and non-melanoma skin cancer were significantly higher in older pts (≥60 yrs at BL). There was no event of lymphoma reported in aged ≥60 yrs at BL group; however, during the follow-up in the registry, 3 pts classified in the 40-59 yrs at BL age group were diagnosed with lymphoma when they were ≥60 yrs. No pts in the ≥60 yrs group reported active/latent tuberculosis.Table: Table. Cumulative incidence of registry treatment-emergent adverse events (TEAEs)Conclusion: Long-term treatment with ADA was well tolerated in pts with moderate to severe CD, irrespective of patient age. Rate of exposure-adjusted registry TEAEs (per 100 PY) was generally higher in older (≥60 yrs) compared to younger pts (< 60 yrs); however, no new safety signals were identified in this age group.
